Pharmaceutical composition for preventing and treating pulmonary fibrosis

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from benidipine, folic acid substances and acceptable auxiliary materials. The ratio range of the benidipine to the folic acid is (2-10): (0.2-2.0) according to the content of the benidipine and the folic acid. The pharmaceutical composition has the advantages that the pharmaceutical composition can inhibit pulmonary fibrosis, can be provided for pulmonary fibrosis high-risk groups such as pulmonary tuberculosis, chronic bronchitis, interstitial pneumonia and silicosis, and is used for preventing or treating pulmonary fibrosis. In addition, the compound form of the pharmaceutical composition is beneficial to improving the curative effect, reducing the side effect and increasing the medication compliance.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition containing benidipine and a folic acid substance for preventing and treating pulmonary fibrosis. BACKGROUND

[0002] Pulmonary fibrosis (PF) is a late-stage manifestation of interstitial lung disease, characterized by fibroblast proliferation and massive extracellular matrix deposition, leading to destruction of lung tissue structure, and eventually the lung parenchyma is replaced by fibrous scar tissue and loses function. There are many factors that can cause pulmonary fibrosis, such as drugs, chemicals, organic or inorganic dust, radiation, disease factors and genetic factors, etc., which can all cause pulmonary fibrosis. Among them, disease factors involve tuberculosis, chronic bronchitis, interstitial pneumonia, silicosis, etc. Since pulmonary fibrosis has an insidious onset, no specific clinical manifestations, early diagnosis is difficult, and there is no effective treatment method, the mortality rate is very high.

[0003] At present, the main treatment measures for pulmonary fibrosis are the application of hormones and immunosuppressants for treatment, which only has a role in alleviating the condition of part of the patients, and large doses of hormone treatment can easily cause serious side effects, such as metabolic disorders, immune suppression and secondary infection, etc. Therefore, it is necessary to open up new ideas and find effective prevention and treatment drugs for pulmonary fibrosis to meet the clinical needs.

[0004] Benidipine is a dihydropyridine calcium channel inhibitor that binds to the DHP binding site of the cell membrane potential-dependent calcium channel to inhibit the influx of calcium ions, thereby dilating the coronary artery and peripheral blood vessels. The affinity of the DHP binding site of the product is strong and the dissociation rate is very slow, so it shows a sustained pharmacological effect, and has no correlation with blood drug concentration. It is clinically used for hypertension and angina pectoris, can dilate blood vessels, can lower blood pressure and increase coronary flow, and has a stronger effect than nifedipine, but the bioavailability is lower.

[0005] Folic acid is a B vitamin necessary for human growth and development, and has important functions of promoting nervous system development and nutrition. Folic acid deficiency in pregnant women can cause adverse consequences such as neural tube defects in fetuses, placental abruption, and megaloblastic anemia. 5-methyltetrahydrofolic acid is the active form of folic acid, which converts homocysteine (Hcy) into methionine through its methylation, reducing the production of harmful substances Hcy. SUMMARY

[0006] In view of the deficiencies of the existing pulmonary fibrosis prevention and treatment products, the present application provides a pharmaceutical composition which has a significant effect of preventing and treating pulmonary fibrosis, and is an improvement over the prior art.

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0008] A composition comprising:

[0009] a) benidipine or its derivative; b) a folic acid substance; c) a pharmaceutically acceptable excipient.

[0010] In the present invention, the derivative includes, but is not limited to, various salts, esters, hydrates, prodrugs, in vivo active metabolites of the compound.

[0011] In the present invention, the folic acid substance is selected from one or more of 5-methyltetrahydrofolic acid, formyltetrahydrofolic acid, calcium folinate, active metabolites of folic acid or folic acid salts, and substances that can release / generate folic acid in vivo.

[0012] In the present invention, the ratio of benidipine and its derivative to the folic acid substance ranges from 2 to 10:0.2 to 2.0, preferably from 4 to 8:0.4 to 1.6, in terms of the mass of folic acid.

[0013] In the present invention, the ratio of the benidipine or its derivative to the folic acid substance is 4:0.4, or the ratio of the benidipine or its derivative to the folic acid substance is 4:0.6, or the ratio of the benidipine or its derivative to the folic acid substance is 4:0.8, or the ratio of the benidipine or its derivative to the folic acid substance is 4:1.2, or the ratio of the benidipine or its derivative to the folic acid substance is 4:1.6, or the ratio of the benidipine or its derivative to the folic acid substance is 8:0.4, in terms of the content.

[0014] In the present invention, as a preferred embodiment, the folic acid substance is folic acid and 5-methyltetrahydrofolic acid. Among them, the ratio of the benidipine or its derivative to folic acid to 5-methyltetrahydrofolic acid ranges from 4 to 8:0.4 to 0.8:0.4 to 0.8, in terms of the content. As a more preferred embodiment, the ratio of the benidipine or its derivative to folic acid to 5-methyltetrahydrofolic acid is 4:0.4:0.4, or the ratio of the benidipine or its derivative to folic acid to 5-methyltetrahydrofolic acid is 4:0.8:0.4, or the ratio of the benidipine or its derivative to folic acid to 5-methyltetrahydrofolic acid is 4:0.8:0.8, or the ratio of the benidipine or its derivative to folic acid to 5-methyltetrahydrofolic acid is 8:0.4:0.4, or the ratio of the benidipine or its derivative to folic acid to 5-methyltetrahydrofolic acid is 8:0.8:0.4, in terms of the content.

[0015] In the present invention, the amount of benidipine is 2 to 10 mg, preferably 4 to 8 mg.

[0016] In the present application, the amount of folic acid substance is 0.2-2.0 mg, preferably 0.4-1.6 mg. Among them, the content of folic acid is 0.2-1.2 mg, preferably 0.4-0.8 mg; the content of 5-methyltetrahydrofolic acid is 0.2-2.0 mg, preferably 0.4-0.8 mg.

[0017] In the present application, the composition consists of benidipine, folic acid or 5-methyltetrahydrofolic acid. Among them, the content of benidipine is 4 mg, the content of 5-methyltetrahydrofolic acid is 0.4 mg; or the content of benidipine is 8 mg, the content of 5-methyltetrahydrofolic acid is 0.8 mg; or the content of benidipine is 4 mg, the content of folic acid is 0.4 mg; or the content of benidipine is 8 mg, the content of folic acid is 0.8 mg.

[0018] In the present application, the composition consists of benidipine, folic acid and 5-methyltetrahydrofolic acid, wherein the content of benidipine is 2-10 mg, the content of folic acid is 0.2-1.2 mg, and the content of 5-methyltetrahydrofolic acid is 0.2-2.0 mg. As a preferred, the content of benidipine is 4-8 mg, the content of folic acid is 0.4-0.8 mg, and the content of 5-methyltetrahydrofolic acid is 0.4-0.8 mg.

[0019] In the present application, the composition consists of benidipine, folic acid and 5-methyltetrahydrofolic acid, wherein the content of benidipine is 2-10 mg, the content of folic acid is 0.2-1.2 mg, and the content of 5-methyltetrahydrofolic acid is 0.2-2.0 mg. As a preferred, the content of benidipine is 4-8 mg, the content of folic acid is 0.4-0.8 mg, and the content of 5-methyltetrahydrofolic acid is 0.4-0.8 mg.

[0020] In the present application, the acceptable excipients or carriers or mixtures thereof include one or more of sugars or functional sweeteners, fillers, wetting agents, binders and lubricants.

[0021] The dosage form of the pharmaceutical composition provided by the present application is oral preparation, including but not limited to common tablets, double-layer tablets, multi-layer tablets, sustained-release tablets, single-chamber controlled-release tablets, double-chamber controlled-release tablets, microporous controlled-release tablets, sublingual tablets, oral quick-disintegration tablets, dispersible tablets, enteric-coated tablets, granules, pills, enteric-coated capsules, delayed-release tablets, time / position release tablets, common capsules, sustained-release capsules, controlled-release capsules, capsules containing pellets or small tablets, pH-dependent capsules containing pellets or small tablets, granules, oral liquids, films or patches, etc., among which tablets, capsules or granules are preferred.

[0022] The mass of the folate substance in the present application is calculated based on the mass of an equivalent molar folate, such as 0.416 mg of 5-methyltetrahydrofolic acid, 0.451 mg of calcium 5-methyltetrahydrofolic acid and 0.4 mg of folic acid, which are equivalent molar masses. In this case, the mass of 5-methyltetrahydrofolic acid or calcium 5-methyltetrahydrofolic acid (calculated based on the mass of an equivalent molar folate) is 0.4 mg.

[0023] The compounds in the pharmaceutical composition provided by the present application can be administered simultaneously to the patient in the same preparation, or administered separately and sequentially to the patient. If administered sequentially to the patient, the delay in administration of the second (or additional) active ingredient should not result in the loss of the beneficial effects of the combination of active ingredients. If administered simultaneously to the patient, the compounds in the composition can be mixed in the same pharmaceutical preparation, or can exist independently in the same preparation. If they exist independently in the same preparation, the pharmaceutical composition can exist in the form of a "combination kit". The "combination kit" is a box-like container containing one or more dosage forms of the pharmaceutical composition and its instructions for use. In the present application, the preferred combination is benidipine, folic acid and 5-methyltetrahydrofolic acid; in the present application, the preferred combination is benidipine and folic acid; in the present application, the preferred combination is benidipine and 5-methyltetrahydrofolic acid.

[0024] In the present application, the use of the composition in the preparation of a product for preventing or treating pulmonary fibrosis.

[0025] The present application has the following beneficial effects: the pharmaceutical composition provided by the present application has obvious synergistic effect, can effectively reduce the expression of plasminogen activator inhibitor in the fibrinolysis system, reduce the expression of TGF-β1 protein in non-inflammatory cells in the fibrosis stage of the lung, inhibit the proliferation and activation of fibroblasts in the lung interstitium, and thus improve pulmonary fibrosis, and is especially suitable for high-risk groups of pulmonary fibrosis such as pulmonary tuberculosis, chronic bronchitis, interstitial pneumonia and silicosis. DETAILED DESCRIPTION

[0026] The present application is further described below in conjunction with the specific embodiments, which are not intended to limit the present application. Any equivalent replacement in the art in accordance with the content of the present application is within the scope of the present application.

[0027] To prove the scientificity of the pharmaceutical composition provided by the present application, the combination of two / three components of the pharmaceutical composition is reasonable, and the combination can exert a synergistic effect instead of a simple superposition of pharmacological effects. Gold Q value method is introduced for analysis. Gold Q value method is also called probability addition method. According to the pharmacological effects of two drugs in combination and the pharmacological effects of two drugs used alone in the dose-effect curve area, the following calculation formula is used: Q = E A+B / (E A +E B -E A *E B ), wherein the numerator represents the “measured combined effect”, and the denominator represents the “expected combined effect” (in order to meet the analysis of the pharmacological relationship of the components and the composition, the pharmacological effects are converted into effects that can directly reflect the strength of the pharmacological effects, the calculation formula is: E i = 1-P i / P 模型组 , P i is the pharmacological index of each component, and P 模型组 is the pharmacological index of the model group), and Q is the ratio of the two: when Q is less than 0.85, it is considered that the two drugs are in antagonistic effect; when Q is less than 1.15 and greater than 0.85, it is considered that the two drugs are in additive effect; and when Q is greater than or equal to 1.15, it is considered that the two drugs are in synergistic effect.

[0028] Example 1: Effect of the composition of the present application on rats with pulmonary fibrosis

[0029] Bleomycin is an antitumor drug, and one of its adverse reactions is to cause pulmonary fibrosis. Replicating a pulmonary fibrosis animal model with bleomycin has become a recognized method for modeling pulmonary fibrosis at home and abroad. In this embodiment, a bleomycin-induced pulmonary fibrosis model in rats is used to evaluate the effect of the composition of the present application on rats with pulmonary fibrosis.

[0030] I. Methods

[0031] Experimental animals and grouping: SD rats, half male and half female, weighing 200±20 g, purchased from Guangdong Medical Laboratory Animal Center. They were raised in an environment with a room temperature of 18-28°C and a relative humidity of 40%-70%, and were allowed to drink water freely. They were adaptively fed with ordinary feed for 1 week, and were then randomly divided into the groups in Table 1 below, with 10 rats in each group.

[0032] Model construction and drug administration: Except for the blank control group that was given normal saline, the other groups were given intratracheal injection of bleomycin (5 mg / kg) to establish a pulmonary fibrosis model. On the same day, the drugs in Table 1 below were administered by gavage (the model control group was given normal saline by gavage), once a day, for 28 consecutive days.

[0033] 28 days after the rats were killed, the following indicators were detected: (1) the content of plasma plasminogen activator inhibitor-1 (PAI-1): 2 ml of blood was taken from the left ventricle of the rat, placed in a test tube containing 1 / 10 volume of 0.109 mol / L sodium citrate anticoagulant, centrifuged at 3000 rpm for 10 min, the supernatant was collected, and the PAI-1 content was determined according to the kit instructions. (2) The content of lung tissue hydroxyproline (HYP): the wet weight of rat lung tissue was taken, and the HYP content was measured by sample alkaline hydrolysis method.

[0034] (1) Plasma PAI-1: Changes in plasminogen activation system are a very key link in the development of pulmonary fibrosis. PAI-1 is an inhibitor of plasminogen activator in the fibrinolytic system, and the plasminogen activity in the bronchial lavage fluid (BAL) of patients with pulmonary fibrosis is often impaired due to the lack of urokinase-type plasminogen activator (uPA) and the increase of PAI-1 expression. (2) Lung tissue HYP: Hydroxyproline is a component of collagen, accounting for about 13% of the total amount of amino acids. By measuring the content of hydroxyproline in lung tissue, the collagen protein catabolism can be understood.

[0035] II. Results

[0036] The general condition of the rats in the blank control group was good, the animal fur was close to the body, white and shiny, the eyes were bright and active, the body weight increased significantly, and the lips and claws were light red. Compared with the blank control group, the rats in the model control group had difficulty breathing, with mild cyanosis of the claws and lips, different degrees of piloerection, and mental debilitation, and the reaction was slow, and as shown in Table 1, the content of plasma PAI-1 and lung tissue HYP was significantly increased, indicating that the dynamic balance of coagulation and anticoagulation system in the rat body was broken, and the pulmonary fibrosis model was successfully constructed.

[0037] Compared with the model control group, there was no significant change in the low-dose and high-dose 5-methyltetrahydrofolate groups; the plasma PAI-1 content of the high-dose benidipine group was significantly reduced; the plasma PAI-1 content and lung tissue HYP content of the low-dose benidipine + 5-methyltetrahydrofolate group and the high-dose benidipine + 5-methyltetrahydrofolate group were significantly reduced (P<0.05 or P<0.01), indicating that the above compositions had a significant effect on reducing the expression of thrombin in the lung of bleomycin-induced pulmonary fibrosis rats, reducing fibrin deposition and accelerating collagen degradation.

[0038] Meanwhile, the Q values ​​for plasma PAI-1 content and lung tissue HYP content in the low-dose benidipine + 5-methyltetrahydrofolate group, compared to the corresponding low-dose benidipine alone and low-dose 5-methyltetrahydrofolate alone groups, were 3.03 and 2.00, respectively, both Q values ​​> 1.15. Similarly, the Q values ​​for the high-dose benidipine + 5-methyltetrahydrofolate group, compared to the corresponding high-dose benidipine alone and high-dose 5-methyltetrahydrofolate alone groups, were all > 1.15, indicating that the combined group had a surprisingly synergistic effect in reducing collagen fiber accumulation compared to the single-drug groups, and therefore could be used to inhibit pulmonary fibrosis.

[0039] Table 1. Effects of the compositions of the present invention on plasma PAI-1 content and lung tissue HYP content in rats (x±s, n=8~10)

[0040]

[0041] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

[0042] Example 2: Effects of the composition of the present invention on bleomycin-induced pulmonary fibrosis in rats

[0043] I. Methods

[0044] Experimental animals and grouping: Wistar rats, half male and half female, weighing 200±20g, were purchased from Guangdong Provincial Medical Laboratory Animal Center. They were housed in an environment with room temperature of 18–28℃ and relative humidity of 40%–70%, with free access to food and water. After one week of acclimatization feeding with standard diet, they were randomly divided into groups as shown in Table 2 below, with 10 rats in each group.

[0045] Model establishment and drug administration: Except for the blank control group which was given normal saline, the other groups were given bleomycin (5 mg / kg) via intratracheal injection to establish a pulmonary fibrosis model. On the same day, the drugs listed in Table 2 below were administered by gavage (the model control group was given normal saline by gavage), once a day for 30 consecutive days.

[0046] Rats were sacrificed after 30 days, and lung tissue, bronchoalveolar lavage fluid, and carotid artery blood were collected to detect the following indicators:

[0047] (1) Hydroxyproline (HYP) content in lung tissue: Wet weight of rat lung tissue was taken and HYP content was determined by alkaline hydrolysis of the sample.

[0048] (2) Grading of alveolitis and pulmonary fibrosis: HE staining was used to observe the degree of alveolitis, and Masson staining was used to observe the degree of pulmonary fibrosis. The results of Masson staining and HE staining of lung tissue were observed to grade the degree of alveolitis and fibrosis in rats. Two to three different sites in the right lobe of each rat were selected for sectioning. Ten fields of view were randomly selected from each section for observation and grading, and the average value was calculated.

[0049] Alveolitis severity grading: Grade 0, no alveolitis; Grade I, mild alveolitis, affected area <20%; Grade II, moderate alveolitis, affected area 20%–50% of the entire lung; Grade III, severe alveolitis, affected area >50%. Scores of 1, 2, 3, and 4 represent grades 0, I, II, and III, respectively.

[0050] Pulmonary fibrosis severity grading: Grade 0, no fibrosis; Grade I, mild fibrosis, lesion area <10%; Grade II, moderate fibrosis, lesion area covering 10%–25% of the entire lung; Grade III, severe fibrosis, lesion area covering 26%–40% of the entire lung; Grade IV, very severe fibrosis, lesion area >40%. Scores of 1, 2, 3, 4, and 5 represent grades 0, I, II, III, and IV, respectively, for pulmonary fibrosis assessment.

[0051] (3) Immunohistochemical observation of TGF-β1 protein expression in lung tissue: Paraffin sections (4 μm) were stained with TGF-β1 using the SP method, with strict control over the staining process and development time. Two to three different sites in the right lung lobe of each rat were selected for sectioning. Ten fields of view were randomly selected from each section for observation. The total number of cells and the number of positive cells in each field were counted, and the positive cell rate was calculated. TGF-β1 is an important cytokine in the formation and development of pulmonary fibrosis. During pulmonary fibrosis, TGF-β1 is widely and significantly upregulated in various lung tissues and cells.

[0052] (4) Plasma MDA assay: Blood was collected from the common carotid artery and the MDA assay was performed according to the instructions of the MDA kit.

[0053] II. Results

[0054] HE staining of the blank control group showed clear lung tissue structure, normal capillaries, intact alveolar cavities, and no inflammatory cell infiltration. Masson staining also showed clear lung tissue structure without significant fibrosis. Therefore, the lung tissue inflammation and fibrosis grade were both 1 point. Compared with the blank control group, HE staining of the model control group showed a large number of inflammatory cells infiltrating the alveolar cavities and lung interstitium, significant thickening of alveolar septa, significant capillary proliferation, and extensive lesions. Masson staining showed lung tissue structure destruction, severe inflammatory cell infiltration, and extensive collagen fiber deposition in bundles, resulting in significant alveolar wall thickening and alveolar morphology changes. Extensive collagen deposition was also observed around the bronchi and blood vessels, with obvious interstitial fibrosis. As shown in Tables 2 and 3, the lung tissue HYP, lung tissue inflammation and fibrosis grade, lung tissue TGF-β1 positivity rate, and plasma MDA were significantly increased in the model control group (P < 0.01), indicating that the pulmonary fibrosis model was successfully established.

[0055] Compared with the model control group, there were no significant changes in the low / high dose 5-MTHF groups. The low dose benidipine + folic acid group showed significantly reduced HYP in lung tissue, grade of lung inflammation and fibrosis, positive rate of TGF-β1 in lung tissue, and plasma MDA (P < 0.05). The relevant indicators in the high dose benidipine + folic acid group, the low dose benidipine + folic acid + 5-MTHF group, and the high dose benidipine + folic acid + 5-MTHF group were all further reduced (P < 0.01). HE staining showed significantly widened alveolar septa, and in a few lung tissues, mononuclear macrophage infiltration and hemorrhage were observed in the alveolar cavities, which were mild. Masson staining showed a significant reduction in inflammatory cell infiltration and fibrous tissue. This indicates that the above-mentioned combination has a significant effect on reducing lung tissue damage, pulmonary fibrosis, lung collagen content, plasma MDA content, and TGF-β1 protein expression in lung tissue in rats.

[0056] Meanwhile, the Q values ​​of five indicators—hypophyllosis (HYP) in lung tissue, grading of lung tissue inflammation and fibrosis, positive rate of TGF-β1 in lung tissue, and plasma MDA—were all >1.15 in the low (high) benidipine + folic acid + 5-MTHF group, the corresponding low (high) dose benidipine + folic acid group, and the low (high) dose 5-MTHF group alone. This indicates that the triple combination has a synergistic effect compared with the dual combination and the single drug group in reducing collagen synthesis and deposition in lung tissue, anti-oxidative stress, and alleviating alveolitis and pulmonary fibrosis in bleomycin-induced pulmonary fibrosis rats. Therefore, it can be used to inhibit pulmonary fibrosis.

[0057] Table 2. Effects of the composition of the present invention on the HYP, lung inflammation, and fibrosis grading of rat lung tissue ( ) n = 8 to 10)

[0058]

[0059]

[0060] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01. Table 3 Effects of the composition of the present invention on the positive rate of TGF-β1 in rat lung tissue and plasma MDA ( n = 8 to 10)

[0061]

[0062] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

Claims

1. A composition comprising: a) benidipine or a derivative thereof; b) a folic acid substance; c) a pharmaceutically acceptable excipient.

2. The composition of claim 1, wherein, The folic acid substance is selected from one or more of 5-methyltetrahydrofolic acid, formyltetrahydrofolic acid, calcium folinate, active metabolites of folic acid or folate salts, and substances that release / generate folic acid in vivo.

3. The composition of claim 2, wherein, The ratio of the benidipine or a derivative thereof:folic acid substance is in the range of 2-10:0.2-2.0 by content.

4. The composition of claim 3, wherein, The ratio of the benidipine or a derivative thereof:folic acid substance is in the range of 4-8:0.4-1.6 by content.

5. The composition of claim 3, wherein, The ratio of the benidipine or a derivative thereof:folic acid substance is 4:0.4 by content; or the ratio of the benidipine or a derivative thereof:folic acid substance is 4:0.6 by content; or the ratio of the benidipine or a derivative thereof:folic acid substance is 4:0.8 by content; or the ratio of the benidipine or a derivative thereof:folic acid substance is 4:1.2 by content; or the ratio of the benidipine or a derivative thereof:folic acid substance is 4:1.6 by content; or the ratio of the benidipine or a derivative thereof:folic acid substance is 8:0.4 by content.

6. The composition of claim 2, wherein, The folic acid substance is folic acid and 5-methyltetrahydrofolic acid, wherein the ratio of the benidipine or a derivative thereof:folic acid:5-methyltetrahydrofolic acid is in the range of 4-8:0.4-0.8:0.4-0.8 by content.

7. The composition of claim 6, wherein, The ratio of the benidipine or a derivative thereof:folic acid:5-methyltetrahydrofolic acid is 4:0.4:0.4 by content; or the ratio of the benidipine or a derivative thereof:folic acid:5-methyltetrahydrofolic acid is 4:0.8:0.4 by content; or the ratio of the benidipine or a derivative thereof:folic acid:5-methyltetrahydrofolic acid is 4:0.8:0.8 by content; or the ratio of the benidipine or a derivative thereof:folic acid:5-methyltetrahydrofolic acid is 8:0.4:0.4 by content; or the ratio of the benidipine or a derivative thereof:folic acid:5-methyltetrahydrofolic acid is 8:0.8:0.4 by content.

8. The composition of claim 2, wherein, The benidipine is used in an amount of 2-10 mg, preferably 4-8 mg; the folic acid substance is used in an amount of 0.2-2.0 mg, preferably 0.4-1.6 mg; wherein the folic acid substance is selected from one or more of 5-methyltetrahydrofolic acid, formyltetrahydrofolic acid, calcium folinate, active metabolites of folic acid or folate salts, and substances that release / generate folic acid in vivo; wherein the content of folic acid is 0.2-1.2 mg, preferably 0.4-0.8 mg; and the content of 5-methyltetrahydrofolic acid is 0.2-2.0 mg, preferably 0.4-0.8 mg.

9. The composition according to claim 8, characterized in that: the content of benidipine is 4 mg and the content of 5-methyltetrahydrofolic acid is 0.4 mg; or the content of benidipine is 8 mg and the content of 5-methyltetrahydrofolic acid is 0.8 mg; or the content of benidipine is 4 mg and the content of folic acid is 0.4 mg; or the content of benidipine is 8 mg and the content of folic acid is 0.8 mg; or the content of the benidipine is 4 mg, the content of the folic acid is 0.4 mg, and the content of the 5-methyltetrahydrofolic acid is 0.4 mg; or the content of the benidipine is 4 mg, the content of the folic acid is 0.8 mg, and the content of the 5-methyltetrahydrofolic acid is 0.4 mg; or the content of the benidipine is 4 mg, the content of the folic acid is 0.8 mg, and the content of the 5-methyltetrahydrofolic acid is 0.8 mg; or the content of the benidipine is 8 mg, the content of the folic acid is 0.8 mg, and the content of the 5-methyltetrahydrofolic acid is 0.8 mg; or the content of the benidipine is 8 mg, the content of the folic acid is 0.4 mg, and the content of the 5-methyltetrahydrofolic acid is 0.8 mg; or the content of the benidipine is 8 mg, the content of the folic acid is 0.4 mg, and the content of the 5-methyltetrahydrofolic acid is 0.4 mg.

10. Use of the composition according to any one of claims 1 to 9 in the preparation of a product for preventing or treating pulmonary fibrosis.

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