Use of (-)-epigallocatechin gallate compound

Abstract

The present invention relates to the field of chemical medicine and discloses the use of the (-)-epigallocatechin gallate (EGCG) compound. Specifically, the present invention relates to the use of the EGCG compound in the manufacture of an inhalable drug for the prevention and / or treatment of pulmonary fibrosis, an inhalable pharmaceutical composition for the prevention and / or treatment of pulmonary fibrosis, and a method for the prevention and / or treatment of pulmonary fibrosis. In the above uses, the EGCG compound is EGCG or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. The use of a drug / pharmaceutical composition containing the EGCG compound as an active ingredient provided by the present invention as an inhalable drug for the prevention and treatment of pulmonary fibrosis allows for a significant reduction in dosage, a wider therapeutic window, fewer adverse reactions, and less frequent administration, providing a new treatment option for patients with pulmonary fibrosis.

Description

[Technical Field]

[0001] (Priority) This PCT patent application claims priority to a Chinese patent with application number 202211485124.4, filed on November 24, 2022, and the technical means of the above patent are incorporated into this patent.

[0002] (Technical field) The present invention relates to the chemical medicine field, and in particular to the use of (-)-epigallocatechin gallate compound. [Background technology]

[0003] Pulmonary fibrosis (PF) is a terminal clinical manifestation of pulmonary interstitial diseases with multiple etiologies. It is characterized by persistent alveolar damage, fibroblast proliferation, and the deposition of large amounts of extracellular matrix (ECM). This leads to varying degrees of inflammation and fibrosis in the alveoli and interstitium, resulting in structural destruction and respiratory failure. Therefore, it is also known as interstitial lung disease (ILD) or diffuse parenchymal lung disease (DPLD). ILDs are primarily classified into four types: idiopathic interstitial pneumonias (IIPs), autoimmune or connective tissue disease-induced pulmonary interstitial fibrosis, contact- or treatment-induced pulmonary interstitial fibrosis, and sarcoidosis. Idiopathic pulmonary fibrosis (IPF) is the most important and common type of idiopathic interstitial pneumonia (IIPs), and clinical research into pulmonary fibrosis currently focuses primarily on IPF. Clinically, IPF manifests as progressive dyspnea accompanied by an irritating, dry cough, and patients experience symptoms such as weight loss, fatigue, general discomfort, and muscle and joint pain. The average survival time is approximately 2.8 years, with a 5-year survival rate of less than 50%, and most patients die from respiratory failure and secondary lung infections.

[0004] Pulmonary fibrosis develops through a variety of mechanisms, including dysregulation of the intracellular environment leading to epithelial-mesenchymal transition (EMT) due to persistent damage to the alveolar epithelium, activation of signaling pathways such as transforming growth factor-β (TGF-β), Wnt, and Notch, epithelial cell dysfunction and apoptosis, and disruption of the pulmonary environment due to scar tissue formation. Currently, only two drugs, nintedanib and pirfenidone, are approved worldwide for the treatment of pulmonary fibrosis. Both are oral formulations, and while they can slow the rate of decline in lung function, they cannot reverse disease progression. Both require large oral dosages and have severe adverse reactions. Specifically, the dose of nintedanib is 150 mg BID (i.e., 150 mg twice daily). The most common adverse reaction is gastrointestinal reactions, with a high incidence of diarrhea in clinical studies (61.5%). The dose of pirfenidone is 801 mg TID (i.e., 801 mg three times daily), and the most common adverse reaction is photosensitivity, with an incidence as high as 51% in clinical studies. These serious adverse reactions are also the most common reason patients are forced to reduce their medication dose or discontinue the medication prematurely.

[0005] Among the many cytokines that promote the formation of pulmonary fibrosis, TGF-β1 signaling is a key promoter of collagen accumulation and fibrotic disease and a key regulator of inflammation and epithelial cell proliferation. However, the multifunctional nature of this cytokine has limited the development of therapeutic TGF-β1 inhibitors. Studies have shown that lysyl oxidase-like 2 protein (LOXL2), an extracellular matrix protein, is negligibly expressed in healthy adult tissues but is induced in various fibrotic diseases and tumors and secreted by activated fibroblasts, disease-associated smooth muscle cells, endothelial cells, and epithelial cells. Combined inhibition of LOXL2 and TGF-β1 activity by triphenolic hydroxy compounds effectively blocks pathological collagen accumulation in vivo without the toxicity associated with global inhibitors.

[0006] (-)-Epigallocatechin gallate (EGCG) is the most abundant active ingredient in catechins found in green tea extract (GTE), and is a polyphenol flavonoid compound that accounts for 50-80% of the total catechin content. Its chemical structure is shown below.

[0007] [ka]

[0008] EGCG has various biological functions, including preventing free radical-induced cell damage, antibacterial properties, reducing inflammation, and preventing certain chronic diseases, including heart disease, diabetes, and some cancers. Studies have shown that EGCG can effectively inhibit lysyl oxidase-like 2 protein (LOXL2) and TGFβ receptor 1 and 2 (TGFβR1 / 2) kinases (Ying Wei et al., 2017; Harold A. Chapman et al., 2020). In currently published pulmonary fibrosis-related EGCG studies, EGCG has been administered orally. Oral administration of EGCG has shown some efficacy in pulmonary fibrosis animal models and human patients, but intestinal absorption after oral administration is poor and drug absorption is affected by food. After oral administration, EGCG undergoes hydrolysis by salivary esterases and undergoes extensive enzymatic metabolic reactions, such as glucuronidation and sulfation, after entering the blood and liver. This results in extremely low bioavailability of oral EGCG, requiring very high doses to exert its anti-pulmonary fibrosis effects. For example, the dose reported in the Harold A. Chapman et al. publication is 600 mg, and long-term administration of high doses may pose a safety risk.

[0009] Previously published human and animal studies have demonstrated a link between oral green tea extract (GTE) and liver damage (Jianghu et al., 2018; Garcia-Cortes et al., 2016; Harrison-Dunn, 2016; Teschke et al., 2014). A safety assessment of green tea extract EGCG published in 2018 by the European Food Safety Authority (EFSA) Scientific Cooperation Project (ESCO) noted that evidence from interventional clinical trials indicated that oral EGCG intake of 800 mg or more per day significantly increased serum transaminases in subjects, indicating liver damage and therefore cannot be considered safe. Hepatotoxicity has also been reported in products containing 80% green tea extract, equivalent to 375 mg of EGCG per day (EFSA, 2018). Other clinical studies have shown that oral EGCG can significantly reduce body weight in patients (I-Ju Chen et al., 2016). Compared with overweight patients, underweight patients with IPF have a higher mortality rate and shorter survival times. The median survival times for patients with a BMI of <25 and >30 are approximately 3.6 and 5.8 years, respectively (Mazen Alakhras et al., 2007; Nobuyasu Awano et al., 2021). Therefore, oral EGCG has a narrow safety margin for IPF treatment, being ineffective at low doses and posing a risk of toxicity at high doses. Furthermore, due to the complexity of the disease, IPF patients require dosage adjustments as the condition progresses, and oral EGCG cannot meet the needs of individualized dosing. After oral administration, EGCG undergoes extensive enzymatic metabolism in the body. While EGCG is not a substrate for the drug-metabolizing CYP450 enzyme system, it can inhibit the activity of various CYP enzymes to different degrees. EGCG can also inhibit drug transporters, such as OATPs. Therefore, EGCG may significantly affect the bioavailability of various drugs. Some researchers suggest that patients taking OATP substrate drugs, especially those with narrow therapeutic indices, should avoid or at least take them with caution when taking large doses of GTE or EGCG (Ahmed A. Albassam, 2017).In a study of 26 IPF patients, coadministration of oral EGCG reduced the plasma exposure of nintedanib by approximately 21%, a statistically significant effect that may compromise efficacy (GD Marijn Veerman et al., 2022). The clinical use of oral EGCG in the treatment of pulmonary fibrosis is limited by deficiencies such as a narrow safe and effective therapeutic window and serious drug interactions.

[0010] Currently, no effective inhaled medications are approved worldwide for the treatment of IPF, and development of related inhaled medications is very limited. Pirfenidone requires very large oral doses to achieve effective drug concentrations in the lungs; the approved dose is 801 mg TID, resulting in high plasma drug concentrations and poor patient tolerance. A nebulized formulation is under development, but Phase II studies have discontinued low doses (50 mg once daily) due to their ineffectiveness. Higher doses, still under study, require higher inhaled doses and more frequent administration (100 mg twice daily). Furthermore, current clinical efficacy is not significantly superior to oral administration, as expected. Animal studies have shown that after switching to inhaled administration of pirfenidone, the drug's half-life in the lungs (t 1 / 2 The time to release of pirfenidone was shown to be only about 10 minutes. In a Phase I study, human pharmacokinetics (PK) was substantially consistent with animal studies. For a 100 mg nebulized dose of pirfenidone, the maximum drug concentration in the alveolar epithelial lining fluid (ELF) was C max is the C in alveolar epithelial lining fluid at an oral dose of 801 mg. maxThe pulmonary drug concentration reached only 35 times that of oral administration, and the pulmonary drug concentration decreased to a lower level in a short period of time than oral administration. Systemic exposure was approximately 15 times lower than that reported for oral administration. Even after inhalation administration, pirfenidone still had high plasma drug concentrations (807-1370 ng / mL). Therefore, even after switching to inhalation administration, pirfenidone still carries a high risk of adverse reactions. This demonstrates that after inhalation administration, the drug rapidly enters the bloodstream from the lungs, making it difficult to maintain effective drug concentrations in the lungs for extended periods, preventing the ideal effects initially anticipated.

[0011] Not all drugs are suitable for pulmonary delivery. Most drugs fail to maintain effective lung retention after inhalation and enter the bloodstream rapidly, failing to maintain high concentrations in the lungs and resulting in poor sustained efficacy. Furthermore, the complex pathological mechanisms of pulmonary fibrosis and its rapid progression make drug development extremely challenging and result in a high failure rate. Growth factors, such as TGF-β and platelet-derived growth factor (PDGF), involved in the progression of fibrosis, have diverse physiological functions in the body, maintaining homeostasis, and systemic inhibition of the toxic side effects of these growth factors is common. Therefore, therapeutic agents for pulmonary fibrosis must have a wide therapeutic window and develop individualized dosing regimens for patients with mild to severe disease. In particular, therapeutic agents that can be delivered via inhalation and exert sustained effects locally in the lungs remain an urgent need to meet clinical needs.

[0012] Therefore, the prior art still needs improvement and growth. Summary of the Invention [Problem to be solved by the invention]

[0013] In view of the above-mentioned deficiencies of the prior art, an object of the present invention is to provide a (-)-epigallocatechin gallate compound that can solve the problems of conventional EGCG, which, when administered orally, has very low bioavailability, requires high dosages, has a narrow safe and effective therapeutic window, and has serious drug interactions between various drugs when used clinically to treat pulmonary fibrosis. [Means for solving the problem]

[0014] The technical means of the present invention are as follows. In a first aspect, the present invention provides use of a (-)-epigallocatechin gallate compound that is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof, in the manufacture of an inhalation medicament for the prevention and / or treatment of pulmonary fibrosis.

[0015] In a second aspect, there is provided an inhalable pharmaceutical composition for the prevention and / or treatment of pulmonary fibrosis, comprising an active ingredient, a (-)-epigallocatechin gallate compound, and a pharmaceutically acceptable excipient, wherein the (-)-epigallocatechin gallate compound is EGCG or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof.

[0016] In a third aspect, the present invention provides a method for preventing and / or treating pulmonary fibrosis, comprising administering to a subject by inhalation a (-)-epigallocatechin gallate compound, which is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. [Effects of the Invention]

[0017] Beneficial effects: Compared to the conventional use of EGCG in the form of oral administration for the treatment of pulmonary fibrosis, the present invention uses an EGCG compound such as EGCG or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof in the manufacture of a drug for treating pulmonary fibrosis that is administered in the form of inhalation administration, thereby making it possible to achieve: (1) a reduction in dosage and administration frequency; (2) a reduction in adverse reactions and side effects; (3) an increase in the concentration and retention time of the drug in the lungs; (4) an expansion of the safe and effective therapeutic range; and (5) a reduction in the effect on the bioavailability of other drugs used in combination, and avoidance of drug-drug interactions between other drugs. [Brief explanation of the drawings]

[0018] [Figure 1] This is a comparison of the time course curves (time, unit: hour) of drug concentration (concentration, unit: ng / mL) in the plasma and lungs of rats after different doses of EGCG were administered via nebulizer (inh, doses of 1.6 mg / kg, 3.2 mg / kg, and 6.4 mg / kg, respectively). [Figure 2] This is a comparison of the time course curves (time, unit: hour) of drug concentration (concentration, unit: ng / mL) in the plasma and lungs of rats after intravenous administration of EGCG (iv, dose 3.2 mg / kg) and oral administration of EGCG (po, dose 60 mg / kg). [Figure 3] This is a comparison of the time course curves (time, unit: hour) of drug concentration in the plasma and lungs of rats after nebulizing EGCG solution (0.8 mg / kg) and then orally administering EGCG solution (60 mg / kg). [Figure 4] This is a comparison of the time course curves (time, unit: hour) of drug concentration in the lungs (lung concentration, unit: ng / mL) of rats after low doses of EGCG were administered by nebulizer (doses of 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, and 0.4 mg / kg, respectively) and then orally administered EGCG solution (dosage 60 mg / kg). [Figure 5]The effect on lung weight index (unit: %) of mice given EGCG solution via nebulizer and then oral administration of EGCG solution is shown compared to pulmonary fibrosis model mice (Kruskal-Wallis test, *: p<0.05, statistically significant difference; **: p<0.01, highly statistically significant difference; ***: p<0.001, highly statistically significant difference). [Figure 6] The effect of EGCG on mouse body weight (unit: g) after nebulized administration and oral administration is shown compared to pulmonary fibrosis model mice (statistical analysis was performed using two-way ANOVA and Tukey's multiple comparison test). [Figure 7a] The effect of EGCG administered by nebulizer and then orally on the degree of bleomycin-induced pulmonary fibrosis in mice is shown (Masson staining, 100x). [Figure 7b] The effect of nebulized and oral administration of EGCG on bleomycin-induced histopathological structural changes in mouse lungs is shown (H&E staining, 100x). [Figure 8] This figure shows the effects of nebulized administration of EGCG solution on alveolar inflammatory cell infiltration, hemorrhage, alveolar expansion, and alveolar fibrinous exudate in mice with pulmonary fibrosis, compared with oral administration. [Figure 9] This shows the effect of EGCG on the fibrosis score of mice after nebulized administration and oral administration, compared with mice in a pulmonary fibrosis model group. [Figure 10] The effect of oral and nebulized administration of EGCG on the hydroxyproline content (unit: μg / μL) in mouse lung tissue is shown, compared to pulmonary fibrosis model mice (one-way ANOVA analysis was used to analyze homogeneity of variance, and intergroup comparisons were performed in combination with Dunnett's test analysis). [Figure 11]The figures show the effects of oral and nebulized administration of EGCG, and nebulized administration of the control drug pirfenidone (AP01), on hydroxyproline content (unit: μg / μL) in rat lung tissue, compared to pulmonary fibrosis model rats (using the Kruskal-Wallis test; *: p<0.05, statistically significant difference; **: p<0.01, highly statistically significant difference; ***: p<0.001, highly statistically significant difference; ****: p<0.0001, highly statistically significant difference). [Figure 12] Healthy subjects were orally administered EGCG capsules (150 mg / capsule, total of 4 capsules), and then EGCG solution (3 mg dose group, 10 mg dose group, 30 mg dose group) was administered via nebulizer. The graph shows the time course of the average plasma concentration of EGCG in the blood. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention provides the use of (-)-epigallocatechin gallate compound, and in order to clarify its purpose, technical means and effects, the present invention will be described in more detail below. It should be understood that the specific examples described herein are only used to illustrate the present invention, and are not used to limit the present invention.

[0020] In a first aspect, an embodiment of the present invention provides the use of a (-)-epigallocatechin gallate compound that is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, in the manufacture of an inhalation medicament for treating pulmonary fibrosis.

[0021] In some embodiments, the (-)-epigallocatechin gallate compound is (-)-epigallocatechin gallate or a pharmaceutically acceptable ester thereof. In certain embodiments, the pharmaceutically acceptable ester refers to a fatty acid ester of EGCG, i.e., obtained by esterifying at least one hydroxyl group in the EGCG structure with a C1-C30 carboxylic acid.

[0022] In some embodiments, the inhalant is prepared in an inhalable dosage form selected from a solution, a suspension, an aerosol, or a powder inhalant.

[0023] In some embodiments, the inhalant is formed by processing the (-)-epigallocatechin gallate compound by a drying process to form a powder, which is then redissolved in a diluent.

[0024] In some embodiments, when the dosage form is a solution, the inhalation drug comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, and at least one of a pH adjuster, an osmotic pressure adjuster, and an antioxidant, and the (-)-epigallocatechin gallate compound is completely dissolved in the diluent.

[0025] In some embodiments, when the dosage form is a suspension, the inhalation drug comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, and at least one of a surfactant, a pH adjuster, and a tonicity adjuster, and the (-)-epigallocatechin gallate compound or the (-)-epigallocatechin gallate compound forms particles with a carrier suitable for inhalation administration and is suspended in the diluent.

[0026] In some embodiments, when the dosage form is an aerosol, the inhalation drug comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, a propellant, and at least one of a surfactant, a co-solvent, and a pH adjuster.

[0027] When the dosage form is a powder inhalant, the inhalant contains the (-)-epigallocatechin gallate compound as an active ingredient, a carrier suitable for inhalation administration, and at least one of an excipient and a surfactant.

[0028] In some embodiments, the diluent is one or more of water, ethanol, and glycerin, and preferably, the diluent is water.

[0029] In some embodiments, the inhalant has a pH value of 3.0 to 5.0.

[0030] In some embodiments, the concentration of the (-)-epigallocatechin gallate compound in the inhalant is 0.1 to 25 mg / mL.

[0031] In some embodiments, the inhaled medication comprises the (-)-epigallocatechin gallate compound, or the inhaled medication comprises the (-)-epigallocatechin gallate compound and another anti-pulmonary fibrosis agent, in some embodiments, the other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, glucocorticoids, immunosuppressants, prostacyclin and analogs thereof, CTGF antibodies, Galectin-3 inhibitors, integrin antagonists, recombinant serum amyloid P and analogs thereof, PDE inhibitors, LPA antagonists, JAK kinase inhibitors, and various cytokine receptor TKIs.

[0032] Preferably, in some embodiments, the other anti-pulmonary fibrosis agent is pirfenidone, nintedanib, BI 1015550 ([1-({(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}amino)cyclobutyl]methanol, CAS number: 1423719-30-5, [ka] ), treprostinil and its analogs, recombinant serum amyloid P, and LPA antagonists.

[0033] In some embodiments, the inhaled drug can be used in combination with other anti-pulmonary fibrosis drugs. In this invention, "combination" refers to an administration method in which at least one dose of a (-)-epigallocatechin gallate compound and at least one dose of another compound are administered within a certain time period, allowing both compounds to exert their pharmacological effects. The time period is one administration cycle, preferably within 24 hours, more preferably within 12 hours. The (-)-epigallocatechin gallate compound and other anti-pulmonary fibrosis drugs can be administered simultaneously or sequentially. This period includes treatment in which the (-)-epigallocatechin gallate compound and other anti-pulmonary fibrosis drugs are administered by the same or different administration routes. In this invention, the combination administration method can be selected from simultaneous administration, independently prepared and co-administered, or independently prepared and sequentially administered.

[0034] In some embodiments, the (-)-epigallocatechin gallate compound is administered in an amount of 0.1 to 100 mg per administration.

[0035] Preferably, in some embodiments, the dose of the (-)-epigallocatechin gallate compound is 0.1 to 50 mg / dose.

[0036] More preferably, in some embodiments, the dose of the (-)-epigallocatechin gallate compound is 0.1 to 30 mg / dose.

[0037] Most preferably, in some embodiments, the dose of the (-)-epigallocatechin gallate compound is 0.1 to 15 mg / dose.

[0038] For example, the dosage of the (-)-epigallocatechin gallate compound may be 0.1 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 3.5 mg / dose, 4 mg / dose, 4.5 mg / dose, 5 mg / dose, 5.5 mg / dose, 6 mg / dose, 6.5 mg / dose, 7 mg / dose, 7.5 mg / dose, 8 mg / dose, 8.5 mg / dose, 9 mg / dose, 9.5 mg / dose, 10 mg / dose, 10.5 mg / dose, 11 mg / dose, 11.5 mg / dose, 12 mg / dose, 12.5 mg / dose, 13 mg / dose, 13. The dose can be selected from 5 mg / dose, 14 mg / dose, 14.5 mg / dose, 15 mg / dose, 15.5 mg / dose, 16 mg / dose, 16.5 mg / dose, 17 mg / dose, 17.5 mg / dose, 18 mg / dose, 18.5 mg / dose, 19 mg / dose, 19.5 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 90 mg / dose, 100 mg / dose, etc.

[0039] The oral dosage of EGCG reported in prior literature is 400 mg to 600 mg per dose. In some embodiments, the dosage of the (-)-epigallocatechin gallate compound is 1 / 1000 to 1 / 10 of the oral dosage.

[0040] Preferably, in some embodiments, the dosage of the (-)-epigallocatechin gallate compound is 1 / 600 to 1 / 10 of the oral dosage, and more preferably, in some embodiments, the dosage of the (-)-epigallocatechin gallate compound is 1 / 200 to 1 / 10 of the oral dosage.

[0041] In some embodiments, the pulmonary fibrosis is an interstitial lung disease, including one or more of idiopathic interstitial pneumonia, pulmonary interstitial fibrosis caused by an autoimmune disease or a connective tissue disease, pulmonary interstitial fibrosis associated with contact or occupational exposure, treatment-induced pulmonary interstitial fibrosis, and sarcoidosis.

[0042] In some embodiments, the idiopathic interstitial pneumonia includes idiopathic pulmonary fibrosis, the pulmonary interstitial fibrosis caused by an autoimmune disease or connective tissue disease includes interstitial lung disease associated with lupus, scleroderma, polymyositis or dermatomyositis, and rheumatoid arthritis, the pulmonary interstitial fibrosis associated with contact or occupational exposure includes asbestosis, silicosis, and hypersensitivity pneumonitis, and the treatment-induced pulmonary interstitial fibrosis includes interstitial lung disease induced by chemotherapy, radiation therapy, and some drug treatments.

[0043] In a second aspect, an embodiment of the present invention provides an inhalable pharmaceutical composition for the prevention and / or treatment of pulmonary fibrosis, comprising an active ingredient, a (-)-epigallocatechin gallate compound, and a pharmaceutically acceptable excipient, wherein the (-)-epigallocatechin gallate compound is EGCG or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

[0044] In some embodiments, the amount of the (-)-epigallocatechin gallate compound in the inhalable pharmaceutical composition may be 0.1 to 100 mg, 0.1 to 80 mg, 0.1 to 70 mg, 0.1 to 60 mg, 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 15 mg, etc.

[0045] In some embodiments, the content of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is 0.1 to 50 mg.

[0046] In some embodiments, the amount of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is 0.5 to 30 mg.

[0047] In some embodiments, the content of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is, for example, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, or 30 mg.

[0048] In one embodiment, the inhalable pharmaceutical composition is prepared by preparing the (-)-epigallocatechin gallate compound and the pharmaceutically acceptable excipients into an inhalation formulation using a conventional or special formulation process, and the inhalation formulation is an inhalation solution, an inhalation suspension, an aerosol, a powder inhalant, or other inhalation formulation.

[0049] Furthermore, in some embodiments, the inhalation solution is a nebulized inhalation solution, and the inhalation suspension is a nebulized inhalation suspension. Nebulized inhalation refers to the use of a nebulizer to disperse the pharmaceutical composition into fine droplets, which are suspended in the gas and inhaled into the airways and lungs. Nebulized inhalation of the pharmaceutical composition can achieve both local and systemic therapeutic purposes, for example, it has strong anti-fibrotic and anti-inflammatory effects.

[0050] In some embodiments, the (-)-epigallocatechin gallate compound is first processed into a powder by a drying process, and before administration to a subject, the powder is reconstituted with the pharmaceutically acceptable excipients using a diluent, and then delivered to the subject's lungs in the form of an aerosol. The drying process can be freeze-drying, spray-drying, spray-freeze drying, or supercritical fluid technology.

[0051] In some embodiments, the inhalable pharmaceutical composition is in the form of an inhalable solution, and the pharmaceutically acceptable additive is selected from one or more of a surfactant, a pH adjuster, an antioxidant, a preservative, a osmolality adjuster, a metal ion complexing agent, water, and an additive. In other embodiments, the inhalable pharmaceutical composition is in the form of an inhalable suspension, and the pharmaceutically acceptable additive is selected from one or more of a surfactant, a pH adjuster, an antioxidant, a preservative, a osmolality adjuster, a metal ion complexing agent, water, and an additive. Furthermore, in some embodiments, the inhalable solution or inhalable suspension is substantially free of preservatives.

[0052] In some embodiments, the concentration of the (-)-epigallocatechin gallate compound in the inhalation solution and inhalation suspension is 0.1 to 35 mg / mL, 0.1 to 30 mg / mL, 0.1 to 25 mg / mL, 0.5 to 25 mg / mL, 0.5 to 15 mg / mL, 0.5 to 10 mg / mL, 0.5 to 5 mg / mL, etc.

[0053] In some embodiments, the concentration of the (-)-epigallocatechin gallate compound in the inhalation solution and the inhalation suspension is, for example, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, or 25 mg / mL.

[0054] In some embodiments, the dosage form of the inhalable pharmaceutical composition is an aerosol, and the pharmaceutically acceptable excipient is selected from one or more of a cosolvent, a surfactant, a propellant, and an additive.

[0055] Furthermore, in some embodiments, the propellant is a hydrofluoroalkane compound. Preferably, the propellant is one or two of 1,1,1,2-tetrafluoroethane (abbreviated as HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (abbreviated as HFA227). Furthermore, in some embodiments, the additive includes a solvent, and the solvent is selected from one or more of glycerol, propylene glycol, polyethylene glycol, ethanol, and oleic acid, and preferably, the solvent is one or two of ethanol and propylene glycol.

[0056] In some embodiments, the dosage form of the inhalable pharmaceutical composition is a powder inhalant, and the pharmaceutically acceptable additives include excipients, carriers, and additives. Furthermore, in some embodiments, the excipients include one or more of sugars, sugar alcohols, starches, high molecular weight polymers, fatty acids or salts thereof, waxes, calcium sulfate, calcium carbonate, talc, iron oxide, and light anhydrous silicic acid. The sugars include one or more of lactose, glucose, white sugar, trehalose, sucrose, etc.; the sugar alcohols include one or more of erythritol, mannitol, sorbitol, etc.; the high molecular weight polymers include one or more of crystalline cellulose, methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose calcium, hydroxypropylmethylcellulose, carboxymethyl ether cellulose sodium, pullulan, dextrin, gum arabic, agar, gelatin, tragacanth gum, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, etc.; and the fatty acids may be one or more of palmitic acid, stearic acid, oleic acid, etc.

[0057] Preferably, in some embodiments, the excipient is selected from one or more of a sugar, a sugar alcohol, a high molecular weight polymer, and calcium carbonate. The sugar is lactose or sucrose, the sugar alcohol is erythritol, sorbitol, or mannitol, and the high molecular weight polymer is calcium carboxymethylcellulose, pullulan, polyvinylpyrrolidone, or methylcellulose. Most preferably, the excipient is lactose or erythritol.

[0058] In some embodiments, the carrier includes lactose, glucose, fructose, sucrose, maltose, dextran, erythritol, sorbitol, mannitol, calcium sulfate, calcium carbonate, talc, or iron oxide.

[0059] In some embodiments, the epigallocatechin gallate compound may be in a crystalline or amorphous form.

[0060] In some embodiments, during the prevention and / or treatment of pulmonary fibrosis, the inhalable pharmaceutical composition is delivered to the subject's respiratory tract and lungs as aerosol droplets or micronized particles ejected by an inhalation administration device. Furthermore, in some embodiments, the aerosol droplets have an average particle size of 0.5-10 μm, such as 1-8 μm, 1-5 μm, 1-3 μm, or 2-3 μm. Furthermore, in some embodiments, the micronized particles have an average particle size of 20 μm or less, preferably 10 μm or less, more preferably 1-9 μm, and most preferably 3-8 μm, and micronized particles within this particle size range can reach the subject's respiratory tract (e.g., bronchi) and lungs.

[0061] In a third aspect, embodiments of the present invention provide a method for preventing and / or treating pulmonary fibrosis, comprising administering to a subject by inhalation a (-)-epigallocatechin gallate compound, which is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

[0062] Specifically, in some embodiments, the method may include delivering a therapeutically effective amount of the (-)-epigallocatechin gallate compound to the lungs of a mammal via inhalation. Pulmonary fibrosis diseases include idiopathic interstitial pneumonia, pulmonary interstitial fibrosis caused by autoimmune or connective tissue diseases, pulmonary interstitial fibrosis caused by contact or treatment, and interstitial lung diseases such as sarcoidosis. Idiopathic interstitial pneumonia includes idiopathic pulmonary fibrosis. Pulmonary interstitial fibrosis caused by autoimmune or connective tissue diseases includes interstitial lung diseases associated with lupus, scleroderma, polymyositis or dermatomyositis, and rheumatoid arthritis. Pulmonary interstitial fibrosis associated with contact or occupational exposure includes asbestosis, silicosis, and hypersensitivity pneumonitis. Treatment-related pulmonary interstitial fibrosis includes interstitial lung diseases caused by chemotherapy, radiation therapy, and some drug treatments.

[0063] In some embodiments, the (-)-epigallocatechin gallate compound is administered at a dose of 0.01 to 2.0 mg / kg. Specifically, the dose of EGCG, the active ingredient in the treatment method, administered to test animals is 0.01 to 2.0 mg / kg, which corresponds to a pseudo-clinical dose of 0.1 to 100 mg for human patients. The corresponding dose is calculated based on clinical or literature-reported methods (E. Boger et al., 2016; Ramon Hendrickx et al., 2018; Therese Ericsson et al., 2017). Taking into account the patient's weight and other physiological and pathological aspects, in some embodiments, the human dose may be 0.1 to 80 mg, 0.1 to 70 mg, 0.1 to 60 mg, 0.1 to 50 mg, 0.1 to 30 mg, or 0.1 to 15 mg. In some embodiments, the dosage for a human can be, for example, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, etc.

[0064] The oral dosage of EGCG reported in prior literature is 400 mg to 600 mg per dose. In some embodiments, the treatment method includes delivering to the patient's lungs a dose of (-)-epigallocatechin gallate compound that is 1 / 1000 to 1 / 10 of the oral dosage. Preferably, the dose may be 1 / 600 to 1 / 10 of the oral dosage. For example, the dose may be 1 / 200 to 1 / 10 of the oral dosage, or 1 / 50 to 1 / 10 of the oral dosage.

[0065] In some embodiments, the dosage of the (-)-epigallocatechin gallate compound may be 0.1 to 80 mg / dose, 0.1 to 70 mg / dose, 0.1 to 50 mg / dose, 0.5 to 30 mg / dose, 0.5 to 15 mg / dose, etc.

[0066] Most preferably, the dose of the (-)-epigallocatechin gallate compound is 0.5 to 15 mg / dose.

[0067] For example, the dosage of the (-)-epigallocatechin gallate compound may be 0.1 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 3.5 mg / dose, 4 mg / dose, 4.5 mg / dose, 5 mg / dose, 5.5 mg / dose, 6 mg / dose, 6.5 mg / dose, 7 mg / dose, 7.5 mg / dose, 8 mg / dose, 8.5 mg / dose, 9 mg / dose, 9.5 mg / dose, 10 mg / dose, 10.5 mg / dose, 11 mg / dose, 11.5 mg / dose, 12 mg / dose, 12.5 mg / dose, 13 mg / dose, 14 mg / dose, 15 mg / dose, 16 mg / dose, 17 mg / dose, 18 mg / dose, 19 mg / dose, 20 mg / dose, 21 mg / dose, 22 mg / dose, 23 mg / dose, 24 mg / dose, 25 mg / dose, 26 mg / dose, 27 mg / dose, 28 mg / dose, 29 mg / dose, 30 mg / dose, 31 mg / dose, 32 mg / dose, 33 mg / dose, 34 mg / dose, 35 mg / dose, 36 mg / dose, 37 mg / dose, 38 mg / dose, 39 mg / dose, 40 mg / dose, 41 mg / dose, 42 mg / dose, 43 mg / dose, 44 mg / dose, 45 mg / dose, 46 mg / dose, 47 mg / dose, 1 dose, 13.5mg / dose, 14mg / dose, 14.5mg / dose, 15mg / dose, 15.5mg / dose, 16mg / dose, 16.5mg / dose, 17mg / dose, 17.5mg / dose, 18mg / dose, 18.5mg / dose, 19mg / dose, 19.5mg / dose, 20mg / dose, 25mg / dose, 30mg / dose, 35mg / dose, 40mg / dose, 45mg / dose, 50mg / dose, 55mg / dose, 60mg / dose, 65mg / dose, 70mg / dose, 75mg / dose, 80mg / dose, 90mg / dose, 100mg / dose, etc.

[0068] Furthermore, in some embodiments, the method of treatment includes delivering 0.1 to 100 mg of a (-)-epigallocatechin gallate compound to the patient's lungs, e.g., 0.1 to 80 mg of a (-)-epigallocatechin gallate compound, 0.1 to 70 mg of a (-)-epigallocatechin gallate compound, 0.1 to 60 mg of a (-)-epigallocatechin gallate compound, or 0.1 to 50 mg of a (-)-epigallocatechin gallate compound, or 0.1 to 50 mg of a (-)-epigallocatechin gallate compound, e.g., 0.1 to 30 mg of a (-)-epigallocatechin gallate compound. For example, the pulmonary delivery dose may be 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, etc.

[0069] In some embodiments, administering the (-)-epigallocatechin gallate compound to the subject by inhalation includes initially delivering a lower dose of the (-)-epigallocatechin gallate compound to the subject's lungs as an initial dose, and then delivering increasing doses of the (-)-epigallocatechin gallate compound to the subject's lungs depending on the patient's condition.

[0070] In some embodiments, the method further comprises administering to the subject by inhalation an active agent administered simultaneously, independently, or sequentially with the (-)-epigallocatechin gallate compound.

[0071] In some embodiments, the active agent is selected from one or more of pirfenidone, nintedanib, glucocorticoids, immunosuppressants, prostacyclin and its analogs, CTGF antibodies, Galectin-3 inhibitors, integrin antagonists, recombinant serum amyloid P (abbreviated as recombinant pentraxin-2, e.g., PRM-151) and its analogs, PDE inhibitors, LPA antagonists, JAK kinase inhibitors, and various cytokine receptor TKIs. Furthermore, in some embodiments, the prostacyclin and analogs thereof are optionally selected from treprostinil and iloprost, the CTGF antibody is optionally selected from pamrevlumab, the Galectin-3 inhibitor may be optionally selected from GB0139, the integrin antagonist is an integrin (αβ1, αβ6) antagonist, the integrin antagonist is optionally selected from PLN-74809, the recombinant Pentraxin-2 is optionally selected from PRM-151, the PDE inhibitor is optionally selected from BI 1015550, and the LPA antagonist may be optionally selected from BMS-986278.

[0072] In some preferred embodiments, the active agent is selected from one or more of pirfenidone, nintedanib, BI 1015550, treprostinil and its analogs, recombinant serum amyloid P, and an LPA antagonist.

[0073] In some embodiments, the administration frequency is once every two days, once a day, or twice a day. That is, the (-)-epigallocatechin gallate compound is administered to the subject once every two days, once a day, or twice a day. Furthermore, in some embodiments, the daily dose administered to the subject is 150 mg or less, and preferably, the daily dose administered to the subject is 100 mg or less. For example, the daily dose administered to the subject may be 150 mg, 140 mg, 120 mg, 100 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 19.5 mg, 19 mg, 18.5 mg, 18 mg, 17.5 mg, 17 mg, 16.5 mg, 16 mg, 15.5 mg, 15 mg, 14.5 mg, 14 mg, 15 mg, 16 ... mg, 13.5 mg, 13 mg, 12.5 mg, 12 mg, 11.5 mg, 11 mg, 10.5 mg, 10 mg, 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.5 mg, 4 mg, 3.5 mg, 3 mg, 2.5 mg, 1 mg, 0.5 mg, 0.2 mg, 0.1 mg, etc.

[0074] In some embodiments, the inhalation administration refers to delivering the drug to the subject using an inhalation administration device filled with the drug.

[0075] In some embodiments, the inhalation administration device is a nebulizer, a pressurized metered dose inhaler, a dry powder inhaler, or a soft mist inhaler.

[0076] It should be understood that the dosages described herein may be the dose emitted from an inhalation device (i.e., device-delivered dose) or may be the dose delivered to a patient's lungs (i.e., pulmonary dose), calculated to be approximately 25% to 75% of the delivery efficiency of inhalation administration devices well known in the art.

[0077] When the subject is a human, the most preferred dose of the (-)-epigallocatechin gallate compound is 1 to 15 mg / dose, and when administered by inhalation, the dose of the (-)-epigallocatechin gallate compound administered to the subject is 3 to 50 mg / dose.

[0078] The drug / pharmaceutical composition containing (-)-epigallocatechin gallate as an active ingredient provided by the present invention is administered (e.g., delivered) to a subject by inhalation. After delivery, the (-)-epigallocatechin gallate is effectively deposited in the subject's lungs, increasing the drug concentration in the subject's lungs and reducing the drug concentration in the systemic blood, thereby avoiding potential side effects such as liver toxicity. By improving the therapeutic effect and reducing toxicity, the drug has a very wide therapeutic window when administered by inhalation.

[0079] Furthermore, the high lung concentrations of (-)-epigallocatechin gallate provided by the drug / pharmaceutical composition of this example can be administered by inhalation to rapidly and effectively regulate the activity of key proteins associated with pulmonary fibrosis and inflammation, such as α-smooth muscle actin (α-SMA), SNAI1, type I collagen (collagen I), fibronectin, phosphorylated SMAD3 (pSMAD3), and phosphorylated SMAD2 (pSMAD2), resulting in superior efficacy. Some proteins in lung tissue cannot be effectively inhibited by oral administration of EGCG. After inhalation administration of the drug / pharmaceutical composition of this example, (-)-epigallocatechin gallate can be maintained at higher drug concentrations in the subject's lungs for a longer period of time, allowing for reduced dosing frequency and improved subject compliance. Furthermore, inhalation administration of the drug / pharmaceutical composition of this example also avoids the potential for drug-drug interactions between orally administered EGCG and other IPF treatments.

[0080] In summary, the use of the drug / pharmaceutical composition containing the (-)-epigallocatechin gallate compound as an active ingredient provided by the examples of the present invention as an inhalable drug for the prevention and treatment of pulmonary fibrosis can significantly reduce the dosage, broaden the therapeutic range, reduce adverse reactions, and reduce the frequency of administration, thereby providing a new treatment option for patients with pulmonary fibrosis and bringing great social and economic benefits.

[0081] The technical solutions of the present invention will be described in detail below through specific examples.

[0082] Example 1: Pharmacokinetic study of EGCG in rat plasma after nebulizer administration, intravenous injection, and oral administration 1.1 Preparation Material: EGCG, content>98wt% Preparation of nebulizer administration solution: Accurately weigh the EGCG compound and add solvent 1 to prepare a transparent, clear liquid drug solution. The components of solvent 1 are purified water, citric acid, and sodium citrate. Preparation of solutions for intravenous administration and oral administration: Accurately weigh the EGCG compound and add saline to prepare a solution. Equipment: Liquid pulmonary administration nebulizer. Animals: clean-grade male SD rats, provided by Qinglongshan Animal Breeding Farm, Jiangning District, Nanjing, weight range 160–200 g.

[0083] 1.2 Administration method and dosage Nebulizer administration: After isoflurane inhalation anesthesia, mice in each nebulizer group were placed in a mouse restrainer. An anesthesia laryngoscope was used to compress the base of the tongue and expose the glottis. A blunt needle containing a fixed amount of EGCG solution was gently inserted into the trachea, and the test sample was sprayed into the lungs. The needle was then quickly removed, the mouse removed from the restrainer, and turned left and right with its head facing up to distribute the drug solution as evenly as possible throughout each lung lobe. The nebulizer doses were 1.6 mg / kg, 3.2 mg / kg, and 6.4 mg / kg, with five mice in each dose group. Oral administration: Determine the dosage for each animal based on the animal's weight, and use the appropriate syringe and oral administration hose to extract the dosage for each animal. The dose is 60 mg / kg, for a total of 5 animals. Intravenous administration: administered via tail vein injection to rats at a dose of 3.2 mg / kg, for a total of 5 rats.

[0084] 1.3 Sample collection and processing methods For each experimental group, blood was collected from the fundus venous plexus before drug administration (0 min), and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 6 h after drug administration (a total of eight blood collection sites). Approximately 50-100 μL of whole blood was collected from each blood collection site. After blood was collected at the designated times, the blood was placed in a sodium heparin anticoagulant tube and centrifuged, and plasma was collected from the centrifuge tube and frozen at -70°C for storage before use.

[0085] 1.4 Analytical conditions and calculation methods for pharmacokinetic parameters Mass spectrometry conditions: measured using UPLC-MS / MS. Chromatography conditions: measured using HPLC. WinNonlin pharmacokinetic software was used to calculate the corresponding pharmacokinetic parameters of each animal using the statistical moment method.

[0086] 1.5 Experimental results and data analysis The pharmacokinetic parameters in rat plasma after nebulized (intravenous, doses of 1.6 mg / kg, 3.2 mg / kg, and 6.4 mg / kg), intravenous (iv, dose of 3.2 mg / kg), and oral (po, dose of 60 mg / kg) administration of EGCG are shown in Table 1. Figure 1 shows the time course curves of drug concentration in the plasma and lungs of rats after nebulized (intravenous, doses of 1.6 mg / kg, 3.2 mg / kg, and 6.4 mg / kg) administration of EGCG at different doses. Figure 2 shows the time course curves of drug concentration in the plasma and lungs of rats after intravenous (iv, dose of 3.2 mg / kg) and oral (po, dose of 60 mg / kg) administration of EGCG. The experimental results shown in Table 1, Figures 1 and 2 indicate that the bioavailability of EGCG was significantly improved after administration by inhalation (e.g., nebulizer). When the same plasma exposure level was achieved, the dose ratio between oral and inhaled administration was 37.5-fold (po 60 mg / kg: inh 1.6 mg / kg), indicating that the EGCG dose was significantly reduced by inhalation administration.

[0087] [Table 1]

[0088] (Example 2) Study of changes in drug concentrations in rat plasma and lungs after nebulized and oral administration of EGCG As can be seen from Example 1, after 1.6 mg / kg of EGCG was administered by inhalation (nebulizer) and after 60 mg / kg of EGCG was administered orally, the AUC 0-t Based on this, in this example, we investigated the time course of drug concentrations in the plasma and lungs of rats after a single nebulized dose of EGCG (0.8 mg / kg) compared with oral administration of EGCG (60 mg / kg). Five rats were used in each of the inhalation and oral administration groups.

[0089] 2.1 Blood sampling method: Blood samples were taken from the femoral artery at 30 minutes, 2 hours, 4 hours, and 6 hours after administration (a total of four sampling sites). After blood sampling, 0.9 wt% saline was injected into the trachea to wash the lungs twice, after which the entire lungs were removed, absorbed with filter paper, and placed in a refrigerator at -20°C in preparation for measurement.

[0090] 2.2 Plasma sample processing method: 1 mL of plasma sample was collected, mixed with 3 mL of ethyl acetate solution, swirled, centrifuged, the supernatant was evaporated, reconstituted with reconstitution solution, swirled, and 100 μL of sample was collected to measure the blood drug concentration.

[0091] 2.3 Lung tissue sample processing method: Lung tissue samples were collected, weighed, and suspended in 3x saline (w:v). 1 mL of the suspended sample was mixed with 3 mL of ethyl acetate solution, swirled, centrifuged, the supernatant evaporated, reconstituted with reconstitution solution, swirled, and 100 μL of the sample was collected to measure the drug concentration in the lungs.

[0092] 2.4 Experimental results and data analysis C in plasma and lungs of rats after inhalation (e.g., nebulizer inhalation) of EGCG solution (dose 0.8 mg / kg) and oral administration of EGCG solution (dose 60 mg / kg) max and AUC 0-t Table 2 shows the time course curves of drug concentrations in the plasma and lungs of rats after nebulized administration of EGCG solution (0.8 mg / kg) and oral administration of EGCG solution (60 mg / kg). The experimental results shown in Table 2 and Figure 3 show that the plasma drug concentration levels and time course curves were similar after inhalation administration of 0.8 mg / kg EGCG solution and oral administration of 60 mg / kg EGCG solution. However, after inhalation administration, the drug concentration in the lungs reached 100-fold higher than that in plasma. This indicates that the drug concentration in the lungs after inhalation administration is significantly higher than that in the systemic circulation, and that inhalation administration can further expand the safe and effective range of EGCG for the anti-pulmonary fibrosis effect.

[0093] [Table 2]

[0094] Example 3: Pharmacokinetic study of EGCG in rat plasma and lungs after low-dose nebulized and oral administration As in Example 1, rats were administered different doses of EGCG solution orally or via nebulizer to examine the pharmacokinetic parameters of the drug in the rat lungs. The nebulizer doses were 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, and 0.4 mg / kg, with 6-8 rats in each dose group. The oral dose was 60 mg / kg, with a total of 6 rats.

[0095] The blood collection method and sample processing method were as described in Example 2. The blood collection times in this experiment were 5 minutes, 2 hours, 6 hours, 8 hours, 10 hours, and 16 hours after administration, and approximately 3.5 mL of whole blood was collected from each blood collection site.

[0096] 3.1 Experimental results and data analysis The time course of drug concentration in the lungs of rats was compared after low doses of EGCG were administered by nebulizer (doses of 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, and 0.4 mg / kg, respectively) and after oral administration of EGCG solution (dosage of 60 mg / kg). The results are shown in Figure 4. As shown in Figure 4, (1) when the inhaled dose was 0.2 mg / kg or more, the maximum drug concentration C in the lungs of rats was 0.2 mg / kg. maxAlthough the concentrations measured after oral administration were above 1 μg / mL (e.g., 1–20 μg / mL), the mean lung and plasma drug concentrations measured after oral administration were both below 100 ng / mL, indicating that the lung drug concentrations after inhalation administration of EGCG solution were very high. (2) Even at a very low inhaled dose (0.05 mg / kg), the lung drug concentration reached a level equivalent to that after oral administration (60 mg / kg), and the inhaled dose was only 1 / 1200 of the oral dose, indicating that inhalation delivery of EGCG significantly expands the effective therapeutic dose range of the drug. (3) After nebulized administration of EGCG solution at 0.1, 0.2, and 0.4 mg / kg, the lung drug concentration was maintained above the corresponding peak concentration (32 ng / mL) after oral administration for 16 hours (greater than 50 ng / mL), indicating that higher drug concentration levels can be maintained in the lung for a longer period after inhalation administration of EGCG solution.

[0097] Mean C in lung tissue after nebulized and oral administration of EGCG solution max and AUC 0-t The average C in Table 3 is shown. max and AUC 0-t The data further demonstrate that after inhalation administration of EGCG solution, the EGCG solution has a good retention effect in the lungs, preventing rapid absorption of the drug into the blood circulation after administration and significantly improving local drug concentration in lung tissue. It is speculated that the anti-IPF activity of EGCG is likely promoted by its high exposure in lung tissue. Therefore, compared with oral administration, inhalation administration significantly expands the safe and effective range of EGCG, and delivery of EGCG via inhalation allows for longer administration intervals and more flexible treatment plans.

[0098] [Table 3]

[0099] Example 4: Effect of inhaled EGCG on bleomycin-induced pulmonary fibrosis in mice 4.1 Experimental animals A total of 56 C57BL / 6J mice, SPF grade, male, 7-10 weeks old, weighing 20-35 g, purchased from Siberian (Beijing) Biotechnology Co., Ltd.

[0100] 4.2 Main Reagents Bleomycin hydrochloride for injection (Bleomycin, BLM, 15 mg / vial, batch number 20067411, Hanhui Pharmaceutical Co., Ltd.). Solvent 1: The ingredients are purified water, citric acid, and sodium citrate, and it is a clear, transparent liquid. Solvent 2: Sodium chloride injection (batch number K21080307), purchased from Hunan Kelun Pharmaceutical Co., Ltd. Hydroxyproline (HYP) kit: purchased from Sigma Aldrich Merck.

[0101] 4.3 Building a faunal model Mice were randomly divided into a sham-operated group (normal control group), a pulmonary fibrosis model group, an oral administration group, and nebulizer-administered groups 1 to 4, each consisting of eight mice. On day 1, to construct the model, mice in the normal control group were administered vehicle 2 (sodium chloride injection, 1 mL / kg) via nebulizer, and mice in the remaining groups were administered bleomycin (2 mg / kg, 1 mL / kg) via nebulizer once in the morning and once in the afternoon.

[0102] 4.4 Dosage and frequency The oral dose for mice was 100 mg / kg (the equivalent oral dose for mice calculated by body surface area calculations according to FDA guidelines based on the oral dose of 60 mg / kg for rats), and the nebulized dose was divided into four doses: 0.2 mg / kg, 0.4 mg / kg, 0.8 mg / kg, and 1.6 mg / kg. The normal control group and pulmonary fibrosis model group were administered nebulized inhalation solvent 1 once daily from day 10 after modeling.

[0103] 4.5 Specimen Collection On day 22, mice in each group were anesthetized by intraperitoneal injection of chloral hydrate (50 mg / mL, 0.1 mL / 10 g) and killed by exsanguination via the abdominal aorta. All animals were dissected, lung tissue preserved, and the entire lung was weighed (including animals found dead, moribund, and euthanized). The left lung was excised and stored in a refrigerator below -60°C for hydroxyproline content measurement. The remaining right lung tissue and bronchioles were fixed in 10% neutral buffered formalin solution and subjected to standard histological processing, including paraffin embedding, sectioning, slide preparation, HE staining, and Masson staining.

[0104] 4.6 Metrics (1) Lung Coefficient Lung index = lung weight (mg) / body weight (g). Massive exudation of inflammatory cells in the early stages of the model, massive proliferation of fibroblasts in the later stages, and excessive collagen deposition can all lead to elevated lung index. Therefore, the lung index can indirectly reflect the degree of inflammation and fibrosis in pulmonary fibrosis mice.

[0105] (2) Mouse weight Animals were weighed after receiving them, before group allocation, on the day of modeling, at the first administration, and every three days thereafter. Animals were also weighed before scheduled euthanasia, when they were found dead, or when they were in a moribund state. Changes in mouse weight could indirectly reflect the effects of drug administration on the mice. Statistical analysis was performed using two-way ANOVA and Tukey's multiple comparison test.

[0106] (3) Pathological examination Lesions such as inflammatory cell infiltration and the degree of fibrosis in lung tissue on HE-stained sections are graded using an optical microscope, and the degree of lung tissue fibrosis is evaluated by Masson staining. Fibrosis, inflammatory cell infiltration, alveolar hemorrhage, dilation, epithelial proliferation, and fibrinous exudates are diagnosed and classified according to a four-stage classification system (almost normal, mild, moderate, and severe) using standardized terminology.

[0107] (4) Measurement of collagen content in lung tissue That is, the hydroxyproline content is measured by measuring hydroxyproline in lung tissue according to the operating procedure of the kit.

[0108] (5) Statistical analysis Any statistical test known in the art, such as the Students' t test, chi-square test, Mann and Whitney U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, or Wilcoxon test, can be used for the analysis. The SPSS (13.0) statistical software package was used for the analysis and analysis. Results were expressed as mean ± standard error, and overall differences were evaluated. One-way ANOVA analysis was used to analyze homogeneity of variance for group means, and intergroup comparisons were performed using a combination of Dunnett's test. If the normality test for parameters failed, Kruskal-Wallis was used for intergroup comparisons. Two-way ANOVA and Tukey's test were used for multiple intergroup comparisons. Statistically significant differences were indicated with an asterisk (*P<0.05, **P<0.01, ***P<0.001).

[0109] 4.7 Experimental results and data analysis 4.7.1 Effect of inhaled EGCG on pulmonary indices in mice with bleomycin-induced pulmonary fibrosis The effects of nebulized and oral administration of EGCG solution on lung weight index in mice compared to pulmonary fibrosis model mice are shown in Figure 5 (using the Kruskal-Wallis test; *: p<0.05, statistically significant difference; **: p<0.01, highly statistically significant difference; ***: p<0.001, highly statistically significant difference). After modeling, the lung index of the model mice was significantly higher than that of the normal control mice (**: p<0.01). As shown in Figure 5, the lung index of each nebulized and oral administration group was significantly reduced compared to the lung index of the diseased mice in the nebulized and oral administration groups. In particular, the lung index of the diseased mice in the 0.2 mg / kg and 0.4 mg / kg nebulized administration groups (**: p<0.01, ***: p<0.001) was significantly reduced, but there was no significant difference in the oral administration group compared to the model group.

[0110] 4.7.2 Effect of inhaled EGCG on body weight in mice with bleomycin-induced pulmonary fibrosis The effects of nebulized and oral administration of EGCG on mouse body weight compared with the pulmonary fibrosis model mice (statistical analysis was performed using two-way ANOVA and Tukey's multiple comparison test) are shown in Figure 6. As shown in Figure 6, (1) after bleomycin induction, the body weight of each group of mice significantly decreased. (2) After oral or inhaled administration of the test drug from day 10, the body weight of the mice tended to increase. However, the weight gain in the oral administration group was slower. However, the body weight of the mice in the nebulized administration groups of 0.2 mg / kg and 0.4 mg / kg returned to almost baseline levels by day 22, showing significant differences from the model group (*p<0.05, **p<0.01, ***p<0.001). This indicates that inhaled administration of an appropriate amount of EGCG has less effect on the body weight of pulmonary fibrosis mice compared with oral administration, thereby reducing the side effects in pulmonary fibrosis mice.

[0111] 4.7.3 Effect of inhalation administration of EGCG solution on pathological structural changes in lung tissue of mice with bleomycin-induced pulmonary fibrosis On day 22, lung tissue sections from healthy control mice, pulmonary fibrosis model mice, 100 mg / kg oral (i.e., po 100) EGCG group, and each inhalation dose group (inhalation dose 0.2, inhalation dose 0.4, inhalation dose 0.8, inhalation dose 1.6) were stained with Masson's stain and H&E stain, and the results are shown in Figure 7a and Figure 7b, respectively.

[0112] As shown in Figures 7a and 7b, the lung tissue structure of healthy control / blank mice was clear, with uniform alveolar septa, no fluid edema, no obvious myofibroblasts, no signs of inflammation or pulmonary fibrosis, and no obvious exudation within the alveolar space. The alveolar structure of the pulmonary fibrosis model mice was severely damaged, with severe atrophy and collapse, thickened alveolar septa, hyaline membrane formation, and obvious alveolar congestion. Large numbers of inflammatory cells infiltrated around small airways, damaged vascular endothelium, abnormal proliferation of fibroblasts, significant deposition of collagen fibers in the pulmonary interstitium, and stiff lung tissue.

[0113] Furthermore, Masson's staining results (Figure 7a) showed a significant reduction in collagen deposition after nebulized EGCG compared with the model group. Each inhaled dose showed a clear dose-effect relationship. In particular, doses of 0.4 mg / kg and above significantly reduced the extent of pulmonary fibrosis in mice, with doses of 0.8 mg / kg and 1.6 mg / kg showing results approaching those of healthy control mice. However, oral administration of EGCG slightly reduced collagen deposition in the lungs of mice, but this was not significantly different from the model group, and the effect was significantly weaker than that of nebulized administration. H&E staining results (Figure 7b) showed that after nebulized EGCG administration in mice, alveolar interstitial hypertrophy was significantly reduced and alveolar morphology tended to improve, with the 0.4 mg / kg and 0.8 mg / kg doses showing the most significant effect. After oral administration of EGCG, lung tissue morphology in mice improved slightly, but the effect was significantly weaker than that of nebulized administration and not significantly different from the model group.

[0114] 4.7.4 Effects of inhaled EGCG solution on alveolar inflammation and pulmonary fibrosis in mice with bleomycin-induced pulmonary fibrosis The effects of nebulized EGCG administration on alveolar inflammatory cell infiltration, hemorrhage, alveolar dilation, and alveolar fibrinous exudates in pulmonary fibrosis mice compared with oral administration are shown in Figure 8. As can be seen from the comparison of alveolar inflammation scores (scores) for each group in Figure 8, (1) compared with the model group, inhaled EGCG solution significantly inhibited the further progression of alveolar inflammation in lung tissue. However, there was no significant difference between the oral administration group and the pulmonary fibrosis model group. Alveolar hemorrhage and alveolar epithelial proliferation tended to worsen, indicating that oral administration of EGCG solution was not effective in inhibiting alveolar inflammation. (2) In the inhibition of alveolar dilation, each inhaled administration group showed significant differences compared with the pulmonary fibrosis model group (score *: p<0.05 for 1.6 mg / kg inhalant; scores **: p<0.01 for both 0.2 mg / kg and 0.8 mg / kg inhalant; score ****: p<0.0001 for 0.4 mg / kg inhalant). Among these, the 0.4 mg / kg inhaled group showed the most remarkable effect (score ****: p<0.0001). (3) In terms of the inhibition of alveolar hemorrhage, the 0.2 mg / kg and 0.4 mg / kg EGCG solution inhaled groups were significantly superior to the oral administration group. (4) In terms of the inhibition of alveolar fibrinous exudation, the 1.6 mg / kg EGCG solution inhaled group showed a significant difference from the pulmonary fibrosis model group. (5) In terms of the inhibition of inflammatory cell infiltration, oral administration of EGCG solution showed no anti-inflammatory effect, but all inflammatory cell infiltrations were reduced in each inhaled dose group, with the 0.4 mg / kg EGCG solution inhaled group showing the greatest anti-inflammatory effect (score *: p<0.05).

[0115] Figure 9 shows the effects of nebulized and oral administration of EGCG on the fibrosis scores of mice compared to those of pulmonary fibrosis model mice. The comparison of scores indicating the degree of pulmonary fibrosis in Figure 9 shows that oral administration and each inhaled dose significantly reduced the pulmonary fibrosis scores of mice. Inhalation of 0.4 mg / kg or higher significantly reduced pulmonary fibrosis (score *p<0.05). The inhaled doses of 0.2 mg / kg, 0.4 mg / kg, and 0.8 mg / kg showed a good dose-effect relationship. However, no significant difference was observed between the oral administration group and the pulmonary fibrosis model group.

[0116] These results indicate that inhalation of low doses (0.2 mg / kg) of EGCG solution can exert an anti-inflammatory effect on the lungs, and the anti-fibrotic effect gradually increases with increasing inhaled dose, with the anti-fibrotic effect of inhaled EGCG solution at a dose of 1.6 mg / kg being particularly pronounced. This indicates that the effective dose range of EGCG administered by inhalation is very wide.

[0117] 4.7.5 Effect of inhalation administration of EGCG solution on hydroxyproline content in lung tissue of pulmonary fibrosis mice The effects of nebulized and oral EGCG on the inhibition of bleomycin-induced hydroxyproline content are shown in Table 4. Figure 10 shows the effects of oral and nebulized EGCG on hydroxyproline content in lung tissue of mice compared with those in the pulmonary fibrosis model group (one-way ANOVA analysis for homogeneity of variance combined with Dunnett's test for between-group comparisons). As shown in Table 4, on day 22, hydroxyproline content in lung tissue of pulmonary fibrosis mice was significantly increased (***: p<0.001). After nebulized administration of 0.2 mg / kg, 0.4 mg / kg, and 0.8 mg / kg EGCG solutions, hydroxyproline content in lung tissue was reduced in a dose-dependent manner. Table 4 and Figure 10 show that inhaled administration of EGCG solution is significantly more effective than oral administration in reducing hydroxyproline content in lung tissue, especially at an inhaled dose of 0.8 mg / kg (score: ***: p<0.001). However, the plasma drug exposure after 0.8 mg / kg inhaled administration (e.g., via nebulizer) as described in Example 2 is equivalent to an oral dose of 60 mg / kg in rats (equivalent to an oral dose of 100 mg / kg in mice). One-way ANOVA analysis was used to analyze homogeneity of variance, and intergroup comparisons were performed using Dunnett's test. Unless otherwise specified, statistical analysis was performed using the Student's T-test. *: p<0.05, statistically significant difference; **: p<0.01, highly statistically significant difference; ***: p<0.001, highly statistically significant difference).

[0118] [Table 4]

[0119] Example 5: Effect of inhalation administration of EGCG on bleomycin-induced pulmonary fibrosis in rats 5.1 Research purpose The effects of different doses of EGCG solution administered by nebulizer inhalation on collagen content in lung tissue of rats with bleomycin-induced pulmonary fibrosis were measured, compared with oral administration of EGCG and nebulized administration of pirfenidone solution, and histopathological sections were also observed to evaluate the therapeutic effect of inhaled EGCG on pulmonary fibrosis in rats.

[0120] 5.2 Main Reagents The solvent 1 for the EGCG nebulizer solution, the modeling reagent, and the solvent 2 for the modeling reagent were as described in Example 4. The positive control was pirfenidone (99% purity, pharmaceutical grade). The components of the positive control, solvent 3, included NaCl, citric acid, etc., and were a transparent liquid.

[0121] 5.3 Model construction, grouping, and administration A total of 88 SPF SD rats, 6-9 weeks old and weighing approximately 200-300 g, were used. The mice were randomly divided into the following groups: a sham-operated (normal control) group (8 mice), a pulmonary fibrosis model control group (10 mice), oral EGCG administration group 1 (10 mice), oral EGCG administration group 2 (10 mice), nebulized EGCG solution administration groups 1-4 (10 mice per group, total of 40 mice), and a nebulized pirfenidone solution administration group (10 mice).

[0122] On day 1, to construct the model, the normal control group mice were administered vehicle 2 (sodium chloride injection, 1 mL / kg) via nebulizer, while the remaining groups of mice were administered bleomycin (2.5 mg / kg, 1 mL / kg) via nebulizer once in the morning and once in the afternoon. On day 8, the animals in each group were weighed. From day 10 to day 28, the normal control group and the pulmonary fibrosis model group were administered vehicle 1 via nebulizer, while the remaining groups of rats were administered the test product EGCG or the control product pirfenidone once daily. The dosage and administration method for each group were as follows:

[0123] The EGCG doses for oral EGCG administration groups 1 and 2 were 30 mg / kg and 60 mg / kg, respectively. The doses for nebulized EGCG administration groups 1 to 4 were 0.05 mg / kg, 0.4 mg / kg, 0.8 mg / kg, and 1.6 mg / kg, respectively. The dose for the nebulized control drug pirfenidone solution group was 0.9 mg / kg. The dose design for these groups was based on the previous publication by MW Surber et al. (ATS POSTER, 2014).

[0124] 5.4 Specimen Collection On day 29, all animals were euthanized and autopsied, and their tissues were preserved. During autopsy, the lungs, trachea, and bronchi of the animals were examined for abnormalities. Left lung tissue was collected and stored at -60°C or below to measure the hydroxyproline content in the lung tissue. Right lung tissue was collected and histopathological sections were prepared. HE staining and Masson staining were used to observe the pathological morphology of the lung tissue and evaluate the degree of pulmonary fibrosis.

[0125] 5.5 Effect of inhalation of EGCG solution on hydroxyproline content in lung tissue of rats with pulmonary fibrosis The data on the effects of oral administration of EGCG, nebulized administration of EGCG solution, and nebulized administration of pirfenidone solution on the suppression of bleomycin-induced hydroxyproline content in rat lungs are shown in Table 5 and FIG.

[0126] Each group was compared with the model group, and statistical analysis was performed using the Kruskal-Wallis test. *: p<0.05, statistically significant difference; **: p<0.01, highly statistically significant difference; ***: p<0.001, highly statistically significant difference; ****: p<0.0001, highly statistically significant difference.

[0127] On day 28, the hydroxyproline content in the lung tissue of the pulmonary fibrosis model rats was significantly increased (****: p<0.0001) compared with the normal control group. After oral administration of EGCG and nebulized administration of the control drug pirfenidone solution, the hydroxyproline content in the lungs of rats decreased, but the difference was not statistically significant compared with the model control group. However, after inhalation administration of EGCG, the hydroxyproline content in the lungs of rats was significantly reduced (statistically significant compared with the model control group; EGCG 0.4 mg / kg inhalation group ****: p<0.0001, EGCG 0.8 mg / kg and 1.6 mg / kg inhalation groups ***: p<0.001). Furthermore, even a very low dose of 0.05 mg / kg significantly reduced the hydroxyproline content in the lung tissue of pulmonary fibrosis rats (*: p<0.05). These results indicate that inhalation administration of EGCG can significantly reduce the degree of pulmonary fibrosis in model animals and provides a wide effective dose range.

[0128] [Table 5]

[0129] Example 6 Preparation of EGCG nebulizer solution 6.1 Prescription EGCG 10g Citric acid (appropriate amount) Sodium citrate (appropriate amount) Water for injection 1000ml

[0130] 6.2 Preparation method: The EGCG raw material and additives are mixed in a liquid preparation container, 1000 ml of water for injection is added, stirred and dissolved, then cooled, and the pH of the solution is adjusted to 3-4 with citric acid and sodium citrate. The EGCG solution is pre-filtered and then sterile-filtered, and then placed in a sterile container to obtain the EGCG nebulizer solution.

[0131] Another example of an EGCG nebulizer solution preparation differs from the formulation described in 6.1 by further including an appropriate amount of EDTA, and the preparation method is the same as that described in 6.2.

[0132] Example 7: Single Ascending Dose Study of EGCG Nebulized Inhalation Solution in Healthy Subjects A randomized, double-blind, placebo-controlled clinical trial was conducted in 22 healthy subjects to evaluate the safety, tolerability, and pharmacokinetic properties of a single inhaled dose of EGCG nebulized solution in healthy subjects, and to compare it with a nebulized solution placebo and oral EGCG capsules.

[0133] Test drug: Test group: EGCG nebulizer inhalation solution (ie, EGCG nebulizer solution containing EDTA as described in Example 6), initial concentration 10 mg / mL, diluted according to dose before administration. Placebo group: blank formulation Oral control group: EGCG capsules, each weighing 150 mg, with an EGCG content of approximately 94% of the total weight.

[0134] Grouping and Dosing: Referring to Table 6, four subjects are randomly assigned to the oral control group and administered 600 mg of EGCG capsules (four capsules in total, containing approximately 564 mg of EGCG) in an open-label manner.

[0135] Three groups were included in the EGCG nebulizer administration: (1) 3 mg group: Before administration, 1 mL of the original solution was diluted with 1 mg / mL diluent, and 3 mL was taken and administered via a nebulizer. (2) 10 mg group: Before administration, 1 mL of the original solution was diluted with 3.33 mg / mL diluent, and 3 mL was taken and administered via a nebulizer. (3) 30 mg group: 3 mL was taken undiluted and administered directly via a nebulizer. Six subjects were randomly assigned to each nebulizer dose group, with two subjects from each group acting as sentinels (1:1 randomization, one for the EGCG nebulizer group and one for the placebo group) in ascending order of dose, and observed for at least 24 hours. Researchers conducted safety assessments of the subjects and, with investigator permission, administered the drug to the remaining four subjects (3:1 randomization, three for the EGCG nebulizer group and one for the placebo group).

[0136] [Table 6]

[0137] Blood sample collection: Blood samples will be collected from the subjects using a venous catheter from a total of 13 blood collection sites at 0 hours (within 1 hour before administration), 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after administration (timed from the start of nebulizer administration or completion of oral administration of EGCG capsules). 4 mL of blood will be collected each time, and the collected plasma will be used for PK testing, backup, and metabolite identification.

[0138] Safety rating: Adverse event (AE) monitoring, physical examination, vital signs (temperature, blood pressure, pulse, respiration) and blood oxygen saturation, cardiac function, and pulmonary function.

[0139] Subject screening: criteria for group entry Subjects must meet the following criteria: Healthy adult male or female between 18 and 59 years of age (inclusive). Understand the study procedures and methods, voluntarily participate in this study, and sign written informed consent. Body mass index (BMI = weight / height squared (kg / m 2 )):18≦BMI<28, male weight 50.0kg or more and less than 90.0kg, female weight 45.0kg or more and less than 90.0kg. -No clinically significant abnormalities are identified through medical history, physical examination, laboratory tests, vital signs, or electrocardiogram, and the investigator determines the subject to be medically healthy. Agree to use effective contraception during the study. Female subjects of childbearing potential will use contraception for at least one month prior to the screening test, throughout the study, and continue to use contraception for three months after the end of the study. Male subjects will use contraception during the study and for three months after the end of the study, and will not donate sperm. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) ≥ 80% of predicted values, FEV1 / FVC ≥ 0.7, and a normal chest x-ray. Agree to refrain from consuming coffee, tea, or any beverages or foods containing coffee or tea for 48 hours prior to and 48 hours after administration. -Ability to use nebulizer correctly and effectively during screening and testing. Do not take any other medications within 7 days of receiving this medicine and do not take any other medications within 24 hours of receiving this medicine.

[0140] Subject Screening: Exclusion Criteria Subjects who meet any of the following criteria will be excluded from this study: -Any significant medical history that may adversely affect study participation. Pregnant or lactating female subjects. Female subjects of childbearing potential who have not used contraception for at least 30 days prior to dosing, male subjects who are unwilling to use contraception (or who cannot guarantee not to donate sperm) during the study and within 90 days after dosing, and female subjects of childbearing potential. -People who are allergic to the test drug or its ingredients. - Have tested positive for COVID-19, HIV, Hepatitis B, or Hepatitis C. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma-glutamyltransferase (GGT) above the upper limit of normal (ULN) or total bilirubin above the upper limit of normal (ULN) at the screening / baseline visit. -Having smoked cigarettes or e-cigarettes within 6 months prior to the first dose. - A history of drug abuse or alcoholism within the 3 months prior to the screening period, where alcoholism is defined as consuming more than 21 units of alcohol per week (1 unit is equivalent to 284 mL of beer, 25 mL of 40% alcohol, or 125 mL of wine). -Donated 400mL or more of blood / plasma within 3 months prior to treatment.

[0141] Test results: Physical examination, vital signs, cardiac function, and pulmonary function of all subjects showed no obvious abnormalities. In the placebo and inhaled groups, a small number of subjects experienced localized symptoms of the oropharynx and respiratory tract, such as itchy throat, dry mouth, bitter taste in the mouth, and cough. These symptoms were mild and disappeared after discontinuation of treatment. One of four subjects in the 10 mg group, one of two subjects in the placebo group, and two of four subjects in the 30 mg group experienced these symptoms, but none in the 3 mg group. The researchers concluded that EGCG was generally well tolerated after administration by nebulizer inhalation, with a high safety margin.

[0142] The time course curves of the mean plasma EGCG concentrations of subjects in each group after administration are shown in Figure 12. The test results shown in Figure 12 demonstrate a good correlation between the plasma drug exposure and the administered dose after inhalation administration. The difference in plasma drug exposure after inhalation administration and oral administration is much higher than the difference between the oral and inhaled doses.

[0143] In general, pulmonary administration has a faster absorption rate than oral administration, and drugs rapidly enter the systemic circulation through the highly permeable pulmonary capillaries and alveolar surfaces, quickly reaching a very high peak level. However, surprisingly, the time to peak drug concentration in the blood after inhalation administration of EGCG is 100 msec. max is slow, C max The level is low. If the lung exposure is equivalent to or greater than that of oral administration, i.e., the dose exerts the same or greater therapeutic effect, the drug concentration entering the blood circulation after inhalation administration is much lower than the drug concentration in plasma after oral administration. For example, in the 10 mg group, the inhaled dose was 1 / 56 of the oral dose, but the plasma C max is C after oral administration max This is approximately 1 / 227 of the previous study. This also indicates that after nebulized administration of EGCG, the retention amount and retention time of the drug in the lungs are significantly increased, and the drug concentration in plasma is significantly reduced. These results suggest that nebulized administration of EGCG can significantly reduce the risk of systemic adverse reactions while enhancing the therapeutic effect of pulmonary drugs.

[0144] In summary, the use of the (-)-epigallocatechin gallate compound provided by the present invention directly delivers EGCG to lung tissue via inhalation, thereby increasing the drug's exposure in lung tissue and significantly increasing the ratio of drug concentration in lung tissue to plasma concentration, improving drug efficacy while reducing potential hepatotoxicity. Furthermore, even at very low inhaled doses, it exerts significant anti-inflammatory and anti-pulmonary fibrosis effects, significantly expanding the safe therapeutic range of EGCG for IPF. Inhaled administration of EGCG maintains high effective concentrations in the lungs for extended periods, which are higher than the drug concentration levels achieved in lung tissue following oral administration, allowing for reduced dosing frequency, improved patient compliance, and individualized dosing schedules. Furthermore, inhaled administration avoids potential drug-drug interactions between oral EGCG and other IPF therapeutics.

[0145] The use of the present invention is not limited to the above examples, and those skilled in the art can make improvements and modifications based on the above description, and all of these improvements and modifications should fall within the scope of protection of the claims of the present invention.

[0146] (Addendum) (Appendix 1) Use of a (-)-epigallocatechin gallate compound in the manufacture of an inhalation drug for the prevention and / or treatment of pulmonary fibrosis, comprising: The (-)-epigallocatechin gallate compound is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof. Use of (-)-epigallocatechin gallate compound.

[0147] (Appendix 2) The inhalant is prepared in an inhalable dosage form selected from a solution, a suspension, an aerosol, or a powder inhalant; Use as described in Appendix 1.

[0148] (Appendix 3) The inhalant is formed by further dissolving the powder obtained by drying the (-)-epigallocatechin gallate compound in a diluent. Use as described in Appendix 1.

[0149] (Appendix 4) When the dosage form is a solution, the inhalation medicine comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, and at least one of a pH adjuster, an osmotic pressure adjuster, and an antioxidant, and the (-)-epigallocatechin gallate compound is completely dissolved in the diluent; When the dosage form is a suspension, the inhalation medicine comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, and at least one of a surfactant, a pH adjuster, and a tonicity adjuster, and the (-)-epigallocatechin gallate compound or the (-)-epigallocatechin gallate compound forms particles with a carrier suitable for inhalation administration and is suspended in the diluent; When the dosage form is an aerosol, the inhalation medicine contains the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, a propellant, and at least one of a surfactant, a co-solvent, and a pH adjuster; When the dosage form is a powder inhalant, the inhalant contains an active ingredient, a (-)-epigallocatechin gallate compound, a carrier suitable for inhalation administration, and at least one of an excipient and a surfactant. Use as described in Appendix 2.

[0150] (Appendix 5) (1) The diluent is one or more of water, ethanol, and glycerin; (2) The pH value of the inhalant is 3.0 to 5.0. (3) The concentration of the (-)-epigallocatechin gallate compound in the inhalation drug satisfies at least one of the following three conditions: 0.1 to 25 mg / mL. 1. Use as described in Appendix 3 or 4.

[0151] (Appendix 6) The inhaled medicine contains the (-)-epigallocatechin gallate compound, or the inhaled medicine contains the (-)-epigallocatechin gallate compound and another anti-pulmonary fibrosis drug. Use as described in Appendix 1.

[0152] (Appendix 7) The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, glucocorticoids, immunosuppressants, prostacyclin and its analogs, CTGF antibodies, Galectin-3 inhibitors, integrin antagonists, recombinant serum amyloid P and its analogs, PDE inhibitors, LPA antagonists, JAK kinase inhibitors, and various cytokine receptor TKIs; Use as described in Appendix 6.

[0153] (Appendix 8) The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, BI 1015550, treprostinil and its analogs, recombinant serum amyloid P, and LPA antagonists. Use as described in Appendix 7.

[0154] (Appendix 9) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 100 mg / dose. Use as described in Appendix 1.

[0155] (Appendix 10) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 50 mg / dose. Use as described in Appendix 9.

[0156] (Appendix 11) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 30 mg / dose. Use as described in Appendix 10.

[0157] (Appendix 12) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 15 mg / dose. Use as described in Appendix 11.

[0158] (Appendix 13) The dosage of the (-)-epigallocatechin gallate compound is 0.1 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 3.5 mg / dose, 4 mg / dose, 4.5 mg / dose, 5 mg / dose, 5.5 mg / dose, 6 mg / dose, 6.5 mg / dose, 7 mg / dose, 7.5 mg / dose, 8 mg / dose, 8.5 mg / dose, 9 mg / dose, 9.5 mg / dose, 10 mg / dose, 10.5 mg / dose, 11 mg / dose, 11.5 mg / dose, 12 mg / dose, 12.5 mg / dose, 13 ... Selected from 0.5mg / dose, 14mg / dose, 14.5mg / dose, 15mg / dose, 15.5mg / dose, 16mg / dose, 16.5mg / dose, 17mg / dose, 17.5mg / dose, 18mg / dose, 18.5mg / dose, 19mg / dose, 19.5mg / dose, 20mg / dose, 25mg / dose, 30mg / dose, 35mg / dose, 40mg / dose, 45mg / dose, 50mg / dose, 55mg / dose, 60mg / dose, 65mg / dose, 70mg / dose, 75mg / dose, 80mg / dose, 90mg / dose or 100mg / dose Use as described in Appendix 9.

[0159] (Appendix 14) The dosage of the (-)-epigallocatechin gallate compound is 1 / 1000 to 1 / 10 of the oral dosage. Use as described in Appendix 1.

[0160] (Appendix 15) The dosage of the (-)-epigallocatechin gallate compound is 1 / 600 to 1 / 10 of the oral dosage. Use as described in Appendix 14.

[0161] (Appendix 16) The pulmonary fibrosis is an interstitial lung disease, including one or more of idiopathic interstitial pneumonia, pulmonary interstitial fibrosis caused by autoimmune or connective tissue disease, pulmonary interstitial fibrosis associated with contact or occupational exposure, treatment-induced pulmonary interstitial fibrosis, and sarcoidosis. 16. The use according to any one of appendices 1 to 15.

[0162] (Appendix 17) The idiopathic interstitial pneumonia includes idiopathic pulmonary fibrosis; The pulmonary interstitial fibrosis caused by an autoimmune disease or connective tissue disease includes interstitial lung disease associated with lupus, scleroderma, polymyositis or dermatomyositis, and rheumatoid arthritis; The pulmonary interstitial fibrosis associated with said contact or occupational exposure includes asbestosis, silicosis, and hypersensitivity pneumonitis; The treatment-induced pulmonary interstitial fibrosis includes interstitial lung diseases caused by chemotherapy, radiation therapy, and some drug treatments. Use as described in Appendix 16.

[0163] (Appendix 18) 1. An inhalable pharmaceutical composition for the prevention and / or treatment of pulmonary fibrosis, comprising: The present invention comprises an active ingredient, a (-)-epigallocatechin gallate compound, and a pharmaceutically acceptable additive, The (-)-epigallocatechin gallate compound is EGCG or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. Pharmaceutical compositions.

[0164] (Appendix 19) The content of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is 0.1 to 50 mg. 19. The pharmaceutical composition of claim 18.

[0165] (Appendix 20) The content of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is 0.5 to 30 mg. 19. The pharmaceutical composition of claim 19.

[0166] (Appendix 21) The dosage form of the inhalable pharmaceutical composition is an inhalable solution, an inhalable suspension, an aerosol or a powder inhalant; 21. A pharmaceutical composition according to any one of claims 18 to 20.

[0167] (Appendix 22) When the dosage form of the inhalable pharmaceutical composition is an inhalation solution, the pharmaceutically acceptable additive is selected from one or more of a surfactant, a pH adjuster, an antioxidant, a preservative, an osmolality adjuster, a metal ion complexing agent, water, and an additive; When the dosage form of the inhalable pharmaceutical composition is an inhalation suspension, the pharmaceutically acceptable additive is selected from one or more of a surfactant, a pH adjuster, an antioxidant, a preservative, an osmotic pressure adjuster, a metal ion complexing agent, water, and an additive; When the dosage form of the inhalable pharmaceutical composition is an aerosol, the pharmaceutically acceptable additive is selected from one or more of a cosolvent, a surfactant, a propellant, and an additive; When the dosage form of the inhalable pharmaceutical composition is a powder inhalant, the pharmaceutically acceptable additives include excipients, carriers and mixtures. 22. The pharmaceutical composition of claim 21.

[0168] (Appendix 23) A method for preventing and / or treating pulmonary fibrosis, comprising administering to a subject by inhalation a (-)-epigallocatechin gallate compound, which is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof; A method for preventing and / or treating pulmonary fibrosis.

[0169] (Appendix 24) The dose of the (-)-epigallocatechin gallate compound is 0.01 to 2.0 mg / kg. 24. The method described in Appendix 23.

[0170] (Appendix 25) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 80 mg / dose. 24. The method described in Appendix 23.

[0171] (Appendix 26) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 50 mg / dose. The method described in Appendix 25.

[0172] (Appendix 27) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 30 mg / dose. 26. The method described in Appendix 26.

[0173] (Appendix 28) The dosage of the (-)-epigallocatechin gallate compound is 0.1 to 15 mg / dose. 27. The method described in Appendix 27.

[0174] (Appendix 29) The dosage of the (-)-epigallocatechin gallate compound is 0.1 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 3.5 mg / dose, 4 mg / dose, 4.5 mg / dose, 5 mg / dose, 5.5 mg / dose, 6 mg / dose, 6.5 mg / dose, 7 mg / dose, 7.5 mg / dose, 8 mg / dose, 8.5 mg / dose, 9 mg / dose, 9.5 mg / dose, 10 mg / dose, 10.5 mg / dose, 11 mg / dose, 11.5 mg / dose, 12 mg / dose, 12.5 mg / dose, 13 ... Selected from 0.5mg / dose, 14mg / dose, 14.5mg / dose, 15mg / dose, 15.5mg / dose, 16mg / dose, 16.5mg / dose, 17mg / dose, 17.5mg / dose, 18mg / dose, 18.5mg / dose, 19mg / dose, 19.5mg / dose, 20mg / dose, 25mg / dose, 30mg / dose, 35mg / dose, 40mg / dose, 45mg / dose, 50mg / dose, 55mg / dose, 60mg / dose, 65mg / dose, 70mg / dose, 75mg / dose, 80mg / dose, 90mg / dose or 100mg / dose The method described in Appendix 25.

[0175] (Appendix 30) The dosage of the (-)-epigallocatechin gallate compound is 1 / 1000 to 1 / 10 of the oral dosage. 24. The method described in Appendix 23.

[0176] (Appendix 31) The dosage of the (-)-epigallocatechin gallate compound is 1 / 600 to 1 / 10 of the oral dosage. 31. The method described in Appendix 30.

[0177] (Appendix 32) and administering to the subject by inhalation another anti-pulmonary fibrosis drug, administered simultaneously, independently, or sequentially with the (-)-epigallocatechin gallate compound. 24. The method described in Appendix 23.

[0178] (Appendix 33) The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, glucocorticoids, immunosuppressants, prostacyclin and its analogs, CTGF antibodies, Galectin-3 inhibitors, integrin antagonists, recombinant serum amyloid P and its analogs, PDE inhibitors, LPA antagonists, JAK kinase inhibitors, and various cytokine receptor TKIs; 32. The method described in Appendix 32.

[0179] (Appendix 34) The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, BI 1015550, treprostinil and its analogs, recombinant serum amyloid P, and LPA antagonists. 34. The method described in Appendix 33.

[0180] (Appendix 35) The administration frequency is once every two days, once a day, or twice a day. 35. The method of any one of appendices 23 to 34.

[0181] (Appendix 36) The inhalation administration is delivery of the drug to the subject using an inhalation administration device filled with the drug. 35. The method of any one of appendices 23 to 34.

[0182] (Appendix 37) The inhalation administration device is a nebulizer, a pressurized metered dose inhaler, a dry powder inhaler or a soft mist inhaler, The method described in Appendix 36.

Claims

1. 1. Use of a (−)-epigallocatechin gallate compound in the manufacture of an inhalation drug for the prevention and / or treatment of pulmonary fibrosis, comprising: The (-)-epigallocatechin gallate compound is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof. Use of (-)-epigallocatechin gallate compound.

2. The inhalant is prepared in an inhalable dosage form selected from a solution, a suspension, an aerosol, or a powder inhalant; 2. The use according to claim 1.

3. The inhalant is formed by further dissolving the powder obtained by drying the (-)-epigallocatechin gallate compound in a diluent.

2. The use according to claim 1.

4. When the dosage form is a solution, the inhalation medicine comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, and at least one of a pH adjuster, an osmotic pressure adjuster, and an antioxidant, the (-)-epigallocatechin gallate compound being completely dissolved in the diluent; When the dosage form is a suspension, the inhalation medicine comprises the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, and at least one of a surfactant, a pH adjuster, and a tonicity adjuster, and the (-)-epigallocatechin gallate compound or the (-)-epigallocatechin gallate compound forms particles together with a carrier suitable for inhalation administration and is suspended in the diluent; When the dosage form is an aerosol, the inhalation medicine contains the (-)-epigallocatechin gallate compound as an active ingredient, a diluent, a propellant, and at least one of a surfactant, a co-solvent, and a pH adjuster; When the dosage form is a powder inhalant, the inhalant contains a (-)-epigallocatechin gallate compound as an active ingredient, a carrier suitable for inhalation administration, and at least one of an excipient and a surfactant.

3. The use according to claim 2.

5. (1) The diluent is one or more of water, ethanol, and glycerin; (2) The pH value of the inhalant is 3.0 to 5.

0. (3) The concentration of the (-)-epigallocatechin gallate compound in the inhalation drug satisfies at least one of the following three conditions: 0.1 to 25 mg / mL.

5. Use according to claim 3 or 4.

6. The inhaled medicine contains the (-)-epigallocatechin gallate compound, or the inhaled medicine contains the (-)-epigallocatechin gallate compound and another anti-pulmonary fibrosis drug.

2. The use according to claim 1.

7. The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, glucocorticoids, immunosuppressants, prostacyclin and its analogs, CTGF antibodies, Galectin-3 inhibitors, integrin antagonists, recombinant serum amyloid P and its analogs, PDE inhibitors, LPA antagonists, JAK kinase inhibitors, and various cytokine receptor TKIs; 7. The use according to claim 6.

8. The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, BI 1015550, treprostinil and its analogs, recombinant serum amyloid P, and LPA antagonists; 8. The use according to claim 7.

9. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 100 mg / dose.

2. The use according to claim 1.

10. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 50 mg / dose.

10. The use according to claim 9.

11. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 30 mg / dose. The use according to claim 10.

12. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 15 mg / dose.

12. The use according to claim 11.

13. The dosage of the (−)-epigallocatechin gallate compound is 0.1 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 3.5 mg / dose, 4 mg / dose, 4.5 mg / dose, 5 mg / dose, 5.5 mg / dose, 6 mg / dose, 6.5 mg / dose, 7 mg / dose, 7.5 mg / dose, 8 mg / dose, 8.5 mg / dose, 9 mg / dose, 9.5 mg / dose, 10 mg / dose, 10.5 mg / dose, 11 mg / dose, 11.5 mg / dose, 12 mg / dose, 12.5 mg / dose, 13 ... 5 mg / dose, 14 mg / dose, 14.5 mg / dose, 15 mg / dose, 15.5 mg / dose, 16 mg / dose, 16.5 mg / dose, 17 mg / dose, 17.5 mg / dose, 18 mg / dose, 18.5 mg / dose, 19 mg / dose, 19.5 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 90 mg / dose, or 100 mg / dose; 10. The use according to claim 9.

14. The dosage of the (-)-epigallocatechin gallate compound is 1 / 1000 to 1 / 10 of the oral dosage.

2. The use according to claim 1.

15. The dosage of the (-)-epigallocatechin gallate compound is 1 / 600 to 1 / 10 of the oral dosage.

15. The use according to claim 14.

16. The pulmonary fibrosis is an interstitial lung disease, including one or more of idiopathic interstitial pneumonia, pulmonary interstitial fibrosis caused by autoimmune or connective tissue diseases, pulmonary interstitial fibrosis associated with contact or occupational exposure, treatment-induced pulmonary interstitial fibrosis, and sarcoidosis. Use according to any one of claims 1 to 15.

17. The idiopathic interstitial pneumonia includes idiopathic pulmonary fibrosis; The pulmonary interstitial fibrosis caused by an autoimmune disease or connective tissue disease includes interstitial lung disease associated with lupus, scleroderma, polymyositis or dermatomyositis, and rheumatoid arthritis; The pulmonary interstitial fibrosis associated with said contact or occupational exposure includes asbestosis, silicosis, and hypersensitivity pneumonitis; The treatment-induced pulmonary interstitial fibrosis includes interstitial lung diseases caused by chemotherapy, radiation therapy, and some drug treatments.

17. The use according to claim 16.

18. 1. An inhalable pharmaceutical composition for the prevention and / or treatment of pulmonary fibrosis, comprising: The present invention comprises an active ingredient, a (-)-epigallocatechin gallate compound, and a pharmaceutically acceptable additive, The (-)-epigallocatechin gallate compound is EGCG or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. Pharmaceutical compositions.

19. The content of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is 0.1 to 50 mg.

19. The pharmaceutical composition of claim 18.

20. The content of the (-)-epigallocatechin gallate compound in each dose of the inhalable pharmaceutical composition is 0.5 to 30 mg.

20. The pharmaceutical composition of claim 19.

21. The dosage form of the inhalable pharmaceutical composition is an inhalable solution, an inhalable suspension, an aerosol or a powder inhalant; 21. The pharmaceutical composition according to any one of claims 18 to 20.

22. When the dosage form of the inhalable pharmaceutical composition is an inhalation solution, the pharmaceutically acceptable additive is selected from one or more of a surfactant, a pH adjuster, an antioxidant, a preservative, an osmolality adjuster, a metal ion complexing agent, water, and an additive; When the dosage form of the inhalable pharmaceutical composition is an inhalation suspension, the pharmaceutically acceptable additive is selected from one or more of a surfactant, a pH adjuster, an antioxidant, a preservative, an osmotic pressure adjuster, a metal ion complexing agent, water, and an additive; When the dosage form of the inhalable pharmaceutical composition is an aerosol, the pharmaceutically acceptable additive is selected from one or more of a cosolvent, a surfactant, a propellant, and an additive; When the dosage form of the inhalable pharmaceutical composition is a powder inhalant, the pharmaceutically acceptable additives include excipients, carriers and mixtures.

22. The pharmaceutical composition of claim 21.

23. A method for preventing and / or treating pulmonary fibrosis, comprising administering to a subject by inhalation a (-)-epigallocatechin gallate compound, which is (-)-epigallocatechin gallate or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof; A method for preventing and / or treating pulmonary fibrosis.

24. The dose of the (-)-epigallocatechin gallate compound is 0.01 to 2.0 mg / kg.

24. The method of claim 23.

25. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 80 mg / dose.

24. The method of claim 23.

26. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 50 mg / dose.

26. The method of claim 25.

27. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 30 mg / dose.

27. The method of claim 26.

28. The dose of the (-)-epigallocatechin gallate compound is 0.1 to 15 mg / dose.

28. The method of claim 27.

29. The dosage of the (−)-epigallocatechin gallate compound is 0.1 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 3.5 mg / dose, 4 mg / dose, 4.5 mg / dose, 5 mg / dose, 5.5 mg / dose, 6 mg / dose, 6.5 mg / dose, 7 mg / dose, 7.5 mg / dose, 8 mg / dose, 8.5 mg / dose, 9 mg / dose, 9.5 mg / dose, 10 mg / dose, 10.5 mg / dose, 11 mg / dose, 11.5 mg / dose, 12 mg / dose, 12.5 mg / dose, 13 ... 5 mg / dose, 14 mg / dose, 14.5 mg / dose, 15 mg / dose, 15.5 mg / dose, 16 mg / dose, 16.5 mg / dose, 17 mg / dose, 17.5 mg / dose, 18 mg / dose, 18.5 mg / dose, 19 mg / dose, 19.5 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 90 mg / dose, or 100 mg / dose; 26. The method of claim 25.

30. The dosage of the (-)-epigallocatechin gallate compound is 1 / 1000 to 1 / 10 of the oral dosage.

24. The method of claim 23.

31. The dosage of the (-)-epigallocatechin gallate compound is 1 / 600 to 1 / 10 of the oral dosage.

31. The method of claim 30.

32. and administering to the subject by inhalation another anti-pulmonary fibrosis drug, administered simultaneously, independently, or sequentially with the (-)-epigallocatechin gallate compound.

24. The method of claim 23.

33. The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, glucocorticoids, immunosuppressants, prostacyclin and its analogs, CTGF antibodies, Galectin-3 inhibitors, integrin antagonists, recombinant serum amyloid P and its analogs, PDE inhibitors, LPA antagonists, JAK kinase inhibitors, and various cytokine receptor TKIs; 33. The method of claim 32.

34. The other anti-pulmonary fibrosis agent is selected from one or more of pirfenidone, nintedanib, BI 1015550, treprostinil and its analogs, recombinant serum amyloid P, and LPA antagonists; 34. The method of claim 33.

35. The administration frequency is once every two days, once a day, or twice a day; 35. The method of any one of claims 23 to 34.

36. The inhalation administration is delivery of the drug to the subject using an inhalation administration device filled with the drug.

35. The method of any one of claims 23 to 34.

37. The inhalation administration device is a nebulizer, a pressurized metered dose inhaler, a dry powder inhaler or a soft mist inhaler, 37. The method of claim 36.

Images