An inhalable composition containing nintedanib and uses thereof

Abstract

The present application relates to the technical field of medicine, in particular to a kind of inhalable composition containing nintedanib drug and its use, which can be used for treating interstitial lung disease (ILD) and significantly reducing the adverse reactions such as liver damage and gastrointestinal discomfort commonly seen in oral drug treatment. The drug composition preparation form is pressure metered dose inhalation aerosol (pMDI) containing nintedanib esylate drug. The present application solves the problems of instability of nintedanib esylate drug under oxidation and hydrolysis conditions, and the feasibility problem of not easy to disperse preparation of inhalation preparation finished product caused by its own high viscosity through creative prescription screening. Through the parameter screening of preparation prescription and inhalation device, the fine particle dose proportion (FPF) of the inhalation aerosol product prepared by the present application can meet the requirement of more than 60%, and the effective lung deposition of ideal dose drug can be realized.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to an inhalable composition containing nintedanib and its use. Background Technology

[0002] Interstitial lung disease (ILD) is a broad category of lung diseases characterized by inflammation or fibrosis of the lung parenchyma. This leads to the formation of "scarring" and "inflammation" in the blood vessels and surrounding tissues of the lungs, affecting gas exchange. The scarring can stiffen the lung tissue, causing shortness of breath. Most patients with ILD experience symptoms such as shortness of breath, cough, decreased exercise capacity, fatigue, and weight loss. ILD is a collective term for approximately 200 different sub-indications, and IPF is one of them. Currently, the latest international guidelines for IPF treatment conditionally recommend nintedanib ethoxylate soft capsules (OFEV) and pirfenidone (Esbriet) (although the mechanism of action of pirfenidone is not yet fully understood), depending on patient tolerance and key considerations in clinical practice. Nintedanib ethoxylate and pirfenidone are also currently the only two drugs approved for the treatment of IPF on the market.

[0003] In patients receiving nintedanib, the proportion of liver tissue enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than or equal to 3 times the upper limit of normal was significantly higher in the nintedanib group (5.0% vs 0.7%). Additionally, the proportion of patients with bilirubin levels greater than or equal to 1.5 times the upper limit of normal was significantly higher in the nintedanib group (2.4% vs 0.7%). In a retrospective single-center study in Japan, approximately 34% of patients experienced elevated AST / ALT levels after treatment.

[0004] Based on the clinical cases of liver damage, gastrointestinal adverse reactions, and low oral bioavailability of OFEV, existing literature CN112867707A developed a nebulized inhalation solution containing nintedanib hydrochloride and hydrobromide. Administering the medication via nebulization helps reduce the dosage and overcomes the aforementioned problems of adverse clinical reactions and low bioavailability of OFEV. However, the inhalation solution requires a relatively long nebulization time, leading to issues such as poor drug compliance.

[0005] As described in existing patents CN112867707A, US20230093124A1, WO2009147212A1 and US10105323B2, nintedanib ethanesulfonate has a high viscosity when dissolved in water, and under conditions of light, oxidation and high humidity, it is extremely easy to generate related substances and crystal transformation phenomena. A research paper published in the *Journal of Pharmaceutical and Biomedical Analysis* (Characterization of stress degradation products of nintedanib by UPLC, TOF / MS / MS and NMR: Evidence of a degradation product with a structure alert for mutagenicity; Doi: 10.1016 / j.jpba.2021.114037) indicates that the degradation products of nintedanib under oxidative conditions—(Z)-methyl 3-((4-(N-methyl-2-(4-methyl-1,4-dioxopiperazin-1-yl)acetamyl)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylic acid ester and (Z)-methyl 3-((4-(N-methyl-2-(4-methyl-1,4-dioxopiperazin-1-yl)acetamyl)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylic acid ester—have a potential risk of mutagenicity. The OFEV dosage form patent document US10105323B2 describes that nintedanib ethanesulfonate raw material is easily hydrolyzed and is relatively sensitive to moisture conditions. Based on the unstable factor of nintedanib ethanesulfonate raw material being easily hydrolyzed, hydrophobic lipid-based pharmaceutical excipients are selected for preparation in the formulation screening.

[0006] Compared to inhaled powder medications, which require strong inhalation to provide the necessary power, aerosols significantly reduce vital capacity (FVC) in patients with moderate to severe interstitial lung disease (IPF). For example, as described in the literature (Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis, DOI: 10.1056 / NEJMoa1402584), the placebo group experienced a 239.9 ml decrease in FVC over 52 weeks. The patient's lung function significantly impacts the deposition of powder medications in the lungs, while aerosols, with their own propellant system, do not entirely depend on the patient's inhalation strength. Furthermore, aerosols have a lower manufacturing cost per unit dose, reducing the economic burden on healthcare systems when switching to them. Therefore, the cost and applicability advantages of aerosols make them a better choice for treating chronic diseases such as interstitial lung disease. However, there are currently no inhaled aerosols based on nintedanib ethoxylate. Summary of the Invention

[0007] Therefore, the technical problem to be solved by the present invention is to provide an inhalable nintedanib-containing drug composition and its use. The inhalable nintedanib-containing drug composition delivers the drug to the lungs via inhalation. Delivery of nintedanib ethanesulfonate to the lungs has been shown to achieve therapeutic effects with less medication compared to oral OFEV, reducing drug exposure in plasma and thus reducing side effects such as abnormally elevated liver enzyme levels caused by liver injury.

[0008] Therefore, the present invention provides the following technical solution: This invention discloses an inhalable composition containing nintedanib, comprising: Nintedanib or a pharmaceutically acceptable salt thereof; and at least one inhalation excipient that can be aerosolized.

[0009] Based on the current situation regarding liver damage and gastrointestinal adverse reactions observed in the clinical application of existing marketed drugs (OFEV), this invention provides an inhalable composition containing nintedanib. This composition delivers the drug to the lungs via inhalation, achieving the same therapeutic effect with less drug compared to oral administration. Therefore, it can reduce the amount of drug exposed in plasma and the liver damage and gastrointestinal discomfort side effects caused by systemic exposure to oral drugs, such as reducing abnormal elevations in liver enzyme indicators like AST and ALT caused by liver damage. As shown in the comparative inhalation / nasal drop pharmacokinetic experiments detailed in the following invention description: G1 (nasal inhalation; 0.3 mg / kg), G2 (nasal inhalation; 1 mg / kg), G3 (nasal inhalation; 3 mg / kg), and G4 (intratracheal administration; 1 mg / kg), inhalation administration of nintedanib ethoxylate significantly reduces the amount of drug exposed in plasma compared to oral administration. Furthermore, as detailed in the invention below, a comparison of the changes in liver enzyme indicators glutamate dehydrogenase (GLDH) and ALT under the intervention conditions of oral OFEV dose of 100 mg / kg and intratracheal administration of nintedanib ethoxylate doses of 0.5 mg / kg and 1.5 mg / kg demonstrates that inhaled administration can significantly improve the side effect of elevated liver enzyme indicators.

[0010] In some embodiments, the dosage form of the inhalable nintedanib-containing drug composition includes an inhalation aerosol; preferably, the inhalation aerosol includes a suspension inhalation aerosol.

[0011] As described in the background section, existing research indicates that genotoxic degradation products are easily generated under oxidative conditions, and hydrolysis is also prone to produce degradation products under humid conditions. During the production, preparation, and storage of inhaled powder inhalers, the risk of drug degradation due to oxidation and hydrolysis is even greater. In this embodiment of the invention, the dosage form of the inhalable nintedanib-containing drug composition is selected as an inhaled aerosol. The canister of the finished aerosol is sealed, filled with inert excipients such as propellants, and the moisture content must be strictly controlled. The ethanol pharmaceutical excipient added during the aerosol preparation process, in addition to regulating the aerosol propellant pressure, also possesses certain reducing pharmaceutical excipient properties, ensuring that the nintedanib isosulfate aerosol sample provided by this invention does not have an external environment conducive to oxidation and hydrolysis. The nintedanib isosulfate inhaled aerosol sample provided by this invention exhibits high stability, low content of related substances, and is less prone to generating genotoxic degradation products, resulting in technical effects unexpected by those skilled in the art.

[0012] Furthermore, as described in the background section, patients with moderate to severe pulmonary fibrosis often experience a decline in respiratory function. In contrast, inhaled powder inhalers require strong inhalation, while aerosol inhalers are not dependent on the intensity of the patient's inhalation. Compared to inhaled powder inhalers, inhaled aerosol inhalers have a lower manufacturing cost per unit dose, and switching to aerosol inhalers can reduce the economic burden on healthcare systems. Inhaled solution formulations require prolonged nebulization, resulting in poor medication adherence. Therefore, the cost and applicability advantages of choosing inhaled aerosol in this embodiment of the invention make it a better choice for treating chronic diseases such as interstitial lung disease.

[0013] In some embodiments, the inhalable nintedanib-containing drug composition, wherein the aerosolizable inhalational pharmaceutical excipients include: surfactants, propellants, saturated vapor pressure regulators, and / or suspending agents.

[0014] In some embodiments, the inhalable nintedanib-containing composition comprises: nintedanib or a pharmaceutically acceptable salt thereof in a content ranging from 0.01 to 20 parts by weight; a surfactant in a content of 0 to 5 parts by weight; a propellant in a content of 50 to 99.99 parts by volume; a saturated vapor pressure regulator in a content of 0 to 30 parts by volume; and a suspending agent in a content of 0 to 5 parts by weight; wherein the ratio of parts by weight to parts by volume is g:ml.

[0015] In some implementations, the pharmaceutically acceptable salt of nintedanib is nintedanib ethanesulfonate.

[0016] In some embodiments, the particle size distribution (D50) of nintedanib issylate raw material ranges from 0.1 to 10 μm; more preferably, its particle size distribution (D50) ranges from 0.1 to 5 μm. By selecting the above-mentioned specific particle size range for the nintedanib issylate raw material, the problem of the interaction between the drug particle content in each aerosol droplet and droplet evaporation affecting the FPF is solved. Simultaneously, the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of the aerosol product is addressed. Ultimately, the prepared inhalable nintedanib issylate-containing drug composition has the advantages of high FPF, good uniformity of total delivery, and good product stability.

[0017] In some embodiments, the surfactant is selected from at least one of Tween 80, Tween 20, Span 20, Span 85, oleic acid, and phospholipid pharmaceutical excipients; preferably, the phospholipid pharmaceutical excipients include lecithin and / or distearate phosphatidylcholine; preferably, the surfactant is oleic acid. By selecting the specific types and amounts of the above-mentioned surfactants, the problem of the interaction between the drug particle content in each aerosol droplet and the droplet evaporation is solved, as is the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of aerosol products. Ultimately, the prepared inhalable drug composition containing nintedanib ethoxylate has the advantages of high FPF and better product stability.

[0018] In some embodiments, the propellant is selected from at least one of HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane, and HFO-1234ze; preferably, the propellant is HFA-134a; preferably, the propellant is HFA-152a; preferably, the propellant is HFO-1234ze. By selecting the specific type and amount of the propellant mentioned above, the problem of the interaction between the drug particle content in each aerosol droplet and the droplet evaporation is solved, as well as the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of aerosol products. Ultimately, the prepared inhalable nintedanib issylate-containing drug composition has the advantages of high FPF and better product stability. This invention uses an anhydrous liquid propellant to fully disperse and suspend nintedanib issylate drug particles, solving the problem of high viscosity and difficulty in dispersion of nintedanib issylate in aqueous systems.

[0019] In some embodiments, the saturated vapor pressure regulator is selected from at least one of ethanol, propylene glycol, and polyethylene glycol; preferably, the saturated vapor pressure regulator is anhydrous ethanol; preferably, the content of the saturated vapor pressure regulator in the pharmaceutical composition ranges from 0-30% v / v. By selecting the specific type and amount of the saturated vapor pressure regulator mentioned above, the problem of the interaction between the drug particle content in each aerosol droplet and the droplet evaporation affecting the FPF is solved. Simultaneously, the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of aerosol products is solved, ultimately resulting in an inhalable pharmaceutical composition containing nintedanib issylate that has the advantages of high FPF and better product stability. More preferably, the present invention uses an anhydrous dispersion medium such as ethanol to fully disperse the suspended nintedanib issylate drug particles, solving the problem of high viscosity and difficulty in dispersion of nintedanib issylate in aqueous solution systems.

[0020] In some embodiments, a particulate suspending agent may be added to the aerosol formulation. The suspending agent is selected from polyvinylpyrrolidone (PVP); preferably, the suspending agent is at least one of PVP (K25), PVP / 17PF, and PVP (K30). By selecting the specific type and amount of the above-mentioned suspending agent, the problem of the interaction between the drug particle content in each aerosol droplet and droplet evaporation is solved. At the same time, the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of aerosol products is solved. Ultimately, the prepared inhalable drug composition containing nintedanib ethoxylate has the advantages of high FPF and better product stability.

[0021] This invention provides a method for preparing an inhalable nintedanib-containing drug composition, comprising: sieving a raw material of nintedanib or a pharmaceutically acceptable salt thereof, followed by pulverizing to obtain micronized nintedanib or a pharmaceutically acceptable salt thereof; and then mixing the micronized nintedanib or a pharmaceutically acceptable salt thereof with at least one aerosolizable inhalation pharmaceutical excipient.

[0022] In some embodiments, the active pharmaceutical ingredient nintedanib or a pharmaceutically acceptable salt thereof is passed through a 60-mesh and / or 120-mesh sieve.

[0023] In some embodiments, the pulverization process includes at least one of air jet milling, ball milling, high-pressure homogenization, and ultrasonic milling to obtain micro-particles with low surface energy, no significant surface depressions or cracks, and regular shape. Preferably, the particle size distribution D50 of the micro-particles of nintedanib or its pharmaceutically acceptable salts ranges from 0.1 to 10 μm; more preferably, the particle size distribution D50 ranges from 0.1 to 5 μm.

[0024] In some embodiments, micronized particles of nintedanib or its pharmaceutically acceptable salts, surfactants, and vapor pressure regulators are dispersed in a propellant, and the resulting suspension mixture is filled into an aerosol can. This invention provides a method for preparing a pMDI formulation containing nintedanib issylate, creatively combining the characteristics of pMDI product preparation processes to solve problems such as oxidation and hydrolysis of nintedanib issylate, resulting in degradation products. The preparation process of the suspension-type inhalation aerosol containing nintedanib issylate according to this invention includes: mixing the nintedanib issylate active pharmaceutical ingredient (API) with pharmaceutically acceptable excipients in a precise ratio, the main component of which is the propellant, to obtain a material of a specific concentration. The mixed material is injected into a pre-sealed can through a metering valve under conditions above atmospheric pressure, where the liquefied propellant mixture exists. Alternatively, in a low-temperature environment, the mixture is injected into the pre-sealed can using a filling device, where the propellant exists in liquid form to ensure no evaporation during filling. After filling, the can is sealed by applying vertical and radial pressure to tighten the gasket and simultaneously form a crimp, securing the valve and can together. Air is typically purged from the can before crimping.

[0025] This invention provides an aerosol inhalation device for an inhalable composition containing nintedanib ethoxylate, comprising a metering valve, a driver, an adapter, a nozzle, a canister, and a metering counter. The driver has a spray orifice diameter ranging from 0.15 to 0.7 mm and a length ranging from 0.3 to 2 mm; preferably, the driver has a spray orifice diameter ranging from 0.2 to 0.5 mm and a length ranging from 0.5 to 1.5 mm. More preferably, the driver has a spray orifice diameter ranging from 0.3 to 0.4 mm and a length ranging from 0.6 to 1.0 mm. By selecting the specific spray orifice diameter and length described above, the problem of the interplay between the drug particle content in each aerosol droplet and droplet evaporation affecting the plasma flow rate (FPF) is solved. Simultaneously, the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of the aerosol product is addressed, ultimately resulting in an inhalable drug composition containing nintedanib ethoxylate with advantages of high FPF and better product stability.

[0026] In some embodiments, the volume range of the metering valve is 25-250 μL; preferably, the volume range of the metering valve is 50-100 μL. By selecting the specific volume of the metering valve described above, the problem of the interaction between the drug particle content in each aerosol droplet and droplet evaporation affecting the FPF is solved. Simultaneously, the problem of drug particle agglomeration caused by the interaction between drug particles during long-term storage of the aerosol product is addressed. Ultimately, the prepared inhalable drug composition containing nintedanib ethoxylate has the advantages of high FPF and better product stability.

[0027] In some embodiments, when the pharmaceutical composition is applied, its spray parameters satisfy at least one of the following: (1) The plume angle is 15-60°; preferably, the plume angle is 20-40°; (2) The fine particle dose distribution FPF value is greater than 15%; preferably, the fine particle dose distribution FPF value is greater than 40%; (3) The aerodynamic mass median particle size (MMAD) of the aerosol particles is in the range of 1-10 μm; preferably, it is 1-5 μm.

[0028] Furthermore, the suspension-type inhalation aerosol containing nintedanib ethsulfate provided by the present invention is used for the prevention and treatment of ILD; Optionally, the suspension-type inhalation aerosol containing nintedanib ethsulfate provided by the present invention is used for the prevention and treatment of idiopathic pulmonary fibrosis (IPF). Optionally, the suspension-type inhaled aerosol containing nintedanib ethsulfate provided by the present invention is used for the prevention and treatment of progressive fibrotic interstitial lung disease (PF-ILD). Optionally, the suspension-type inhaled aerosol containing nintedanib ethsulfate provided by the present invention is used for the prevention and treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).

[0029] The technical solution of this invention has the following advantages: 1. This invention provides an inhalable composition containing nintedanib, comprising: nintedanib or a pharmaceutically acceptable salt thereof; and at least one inhalation excipient suitable for aerosolization. The inhalable composition containing nintedanib provided by this invention delivers the drug to the lungs via inhalation, delivering an effective therapeutic dose of nintedanib acesylate to the lungs. It has been demonstrated that this invention requires less drug to achieve a therapeutic effect compared to oral OFEV, reducing drug exposure in plasma and minimizing liver damage and gastrointestinal side effects caused by systemic exposure to oral drugs, such as reducing abnormal elevations in liver enzymes like ALT and GLDH caused by liver damage.

[0030] 2. The dosage form of the inhalable nintedanib-containing drug composition provided by the present invention is selected from inhaled aerosols, which have high stability, simple production and storage conditions, and are not prone to producing genotoxic degradation products. Attached Figure Description

[0031] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0032] Figure 1 shows the pharmacokinetic curves of each group in Example 1 of the present invention; Figure 2 shows the detection results of ALT, a liver enzyme index, in SD rats in each group of oral and inhaled administration in Example 2 of the present invention. Figure 3 shows the detection results of the liver enzyme index GLDH in SD rats in each group of oral and inhaled administration in Example 2 of the present invention. Figure 4 is a microscope image of the nintedanib drug particles in Example 4 of the present invention. Detailed Implementation

[0033] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0034] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0035] One embodiment of this invention is that, at the animal research level, it has been demonstrated that, under different dosage conditions, nintedanib administered via the lungs achieves the same pharmacokinetic parameter C as orally administered nintedanib ethoxylate. maxWhen the results are essentially consistent, the changes in liver enzyme indicators, such as GLDH, compared to normal healthy levels are shown in ΔGLDH. The ΔGLDH index in the nintedanib pulmonary administration group is smaller than that in the oral original drug group. Furthermore, based on the research results of this invention, it is evident that patients administering the inhaled aerosol containing nintedanib prepared according to the embodiments of this invention can reduce the incidence of abnormal liver enzyme indicators compared to oral nintedanib. The inhalable drug composition containing nintedanib provided by the embodiments of this invention can improve the safety and tolerability of patient medication.

[0036] One embodiment of this invention involves designing a formulation composition and process capable of delivering an effective dose of nintedanib, based on the characteristics of pMDI formulations. Specifically, suitable propellants (such as HFA-134a, HFA-227, HFA-152A, and HFO-1234ze) are selected, and surfactants, saturated vapor pressure regulators, and / or suspending agents are added to improve the physical stability of the suspension system and prevent aggregation, agglomeration, precipitation, and stratification. Furthermore, long-term and accelerated stability tests are conducted to monitor the size and distribution of drug particles in the propellant system, ensuring that the aerosol's spray characteristics meet the requirements for effective pulmonary deposition. Through these measures, a highly efficient and safe nintedanib ethoxylate aerosol product can be developed to meet patients' treatment needs and improve medication adherence and quality of life.

[0037] One embodiment of this invention involves assessing how different ethanol concentrations in the aerosol formulation affect the evaporation rate of each spray of the aerosol, based on the characteristics of pMDI formulations. This droplet evaporation rate directly impacts the aerodynamic parameters of each spray of the pMDI product and drug deposition in the lungs. This embodiment evaluates different ethanol concentrations in the formulation, such as 0.1%, 0.25%, 0.5%, 1%, 2.5%, 5%, 10%, 15%, and 30%, or any concentration within the range of 0.1% to 30%. Furthermore, this embodiment also examines the combined effects of propellant type, saturated vapor pressure regulator, active ingredient characteristics, other excipients, and device parameter design on the aerodynamic parameters of each spray of the pMDI product: plume angle, velocity, and duration. This further examines the impact on key quality attributes such as cumulative drug dose (ADD), delivery rate (DE), total delivery efficiency (TDE), fine particle fraction (FPF), and fine particle dose (FPD).

[0038] One embodiment of the present invention further includes, but is not limited to, the selection factors for the actuator device parameters of the present invention, such as: nozzle orifice diameter and orifice length parameters; further still, the device parameters of the present invention also include the valve cavity volume and geometry, etc. This includes, but is not limited to, cavity volumes designed to be 10μL, 50μL, 100μL, 200μL, 300μL, and 500μL, or any number of volumes within the range of 10μL-500μL.

[0039] One embodiment of the present invention provides an inhaled aerosol for treating interstitial lung disease and / or pulmonary hypertension comprising nintedanib ethoxylate at a lower and equivalent dose to OFEV, and comprising one or more pharmaceutically acceptable drug carriers, excipients, suspending agents, and / or surfactants. The drug carriers, excipients, suspending agents, and / or surfactants are formulated for inhalation administration and may contain surfactants to improve the physical stability of the suspension system and prevent drug particle precipitation and stratification.

[0040] One embodiment of this invention addresses the issues of abnormally elevated liver enzymes and potential liver damage caused by hepatotoxicity during nintedanib treatment. This embodiment optimizes the dosing regimen, adjusting it based on patient tolerability. The dosing regimen will evaluate the efficacy and safety of this inhaled aerosol in patients with idiopathic pulmonary fibrosis, focusing on liver function indicators and comparing it with conventional oral administration. This inhaled aerosol aims to reduce systemic exposure through local lung administration, thereby lowering the risk of liver damage while improving patient adherence and quality of life.

[0041] One embodiment of this invention provides a lower dosage compared to the original drug's starting dose of 100 or 150 mg twice daily. For inhaled aerosols containing nintedanib ethsulfate for the treatment of interstitial lung disease, this lower dosage is achieved by referring to the currently disclosed effective dosage range in clinical trials, or a dosage range optimized based on this more advanced approach. Publicly available research data includes, for example, Avalyn's publicly available information on inhaled AP02 (nintedanib hydrobromide and hydrochloride inhalable solution formulation): The pharmacokinetic behavior of inhaled AP02 used in sheep at a dose of 0.06 mg / kg compared to an oral nintedanib dose of 2.14 mg / kg, and the maximum concentration of the drug reached in the lungs (C0). maxThe area under the curve (AUC) determines the duration of the residual effect of the drug. Nintedanib concentration / elimination curves in sheep alveolar epithelial lining fluid (ELF) were used to estimate the drug concentration and AUC in ELF after human inhalation. This data supports single-dose ranges of 0.5 mg, 1 mg, or 2 mg for inhaled nintedanib (AP02), administered using an optimized eFlow Technology Nebulizer, which demonstrated good tolerability in the Phase 1 clinical study. In one exemplary embodiment, an inhaled aerosol for the treatment of interstitial lung disease and / or pulmonary hypertension comprises nintedanib ethoxylate, with per-spray doses of up to 5 mg, 4 mg, 2 mg, 1 mg, 0.5 mg, 0.25 mg, 0.2 mg, 0.1 mg, or 0.05 mg, and other doses ranging from 0.05 to 5 mg.

[0042] One embodiment of this invention provides that the selected nintedanib active pharmaceutical ingredient, or its form of existence, exhibits good solubility in pulmonary tissue fluid or alveolar epithelial lining fluid (ELF), allowing it to fully dissolve within a certain time after inhalation into the lungs to achieve a local therapeutic effect. Compared to clinically investigated nintedanib hydrochloride or hydrobromide forms, the embodiment provided by this invention ensures that the pharmacokinetic parameters of the selected nintedanib active pharmaceutical ingredient after inhalation into the lungs are consistent with or better than those of nintedanib hydrochloride or hydrobromide forms. The nintedanib active pharmaceutical ingredient in the embodiments of this invention can exist in the following forms: ethanesulfonate, mesylate, hydrochloride, hydrobromide, acetate, mesylate, sulfate, phosphate, fumarate, succinate, lactate, citrate, or their free bases. For the preparation of the suspension formulation required for pMDI formulations, the active pharmaceutical ingredient is preferably presented in a micronized crystalline solid form. It will be apparent to those skilled in the art that other forms of active pharmaceutical ingredients may also be suitable for the preparation of suspension formulations consistent with those disclosed in this embodiment. Examples include active pharmaceutical ingredients prepared by methods such as air jet milling, micronization (e.g., ball milling or jet milling), spray drying, freeze drying, spray freeze drying, high-pressure homogenization, supercritical fluid technology, controlled crystallization, sonic crystallization, and wet milling. The active pharmaceutical ingredient can be in a solvated, hydrated, or anhydrous form, all of which are pharmaceutically acceptable. Further embodiments include dissolving the active pharmaceutical ingredient in an organic solvent, or adding a certain amount of amino acid pharmaceutical excipients (such as leucine, glycine, and aspartic acid), sugar pharmaceutical excipients (such as trehalose and mannitol), and PVP to an organic solvent, and further processing the prepared solution containing the active pharmaceutical ingredient through a spray drying device to obtain particles containing the active pharmaceutical ingredient.

[0043] In one exemplary embodiment, due to the excellent solubility of nintedanib isosulfonate, the pharmacokinetic parameters of nintedanib isosulfonate drugs after intratracheal administration, as described in the background art, can be considered equivalent to those of its hydrobromide and hydrochloride solutions. In the embodiments provided by this invention, the inhalable aerosol formulation technology can solve the drug-likeness problems caused by the nintedanib isosulfonate active pharmaceutical ingredient's susceptibility to oxidation and hydrolysis, resulting in degradation impurities, genotoxic impurities, and high viscosity in solution. In these embodiments, the active pharmaceutical ingredient can exist in one form as nintedanib isosulfonate.

[0044] In one exemplary embodiment, through inventive screening by those skilled in the art, at least one of excipients, surfactants, suspending agents, and cosolvents may be added to the inhalable aerosol formulation provided by this invention, in addition to the active pharmaceutical ingredient and propellant. These components may have various uses and functions, including but not limited to promoting suspension formation, stabilizing suspensions, and helping to solve technical problems such as improving the FPF of each spray, drug particle agglomeration within the container during long-term storage of formulation samples, and the physical stability requirements of the suspension formulation for pMDI formulations.

[0045] In one exemplary embodiment, the present invention preferably uses hydrophobic amino acids (such as leucine, isoleucine, and alanine) and phospholipids (such as dipalmitoylphosphatidylcholine, distearylphosphatidylcholine, arachidonic acid phosphatidylcholine, dibenzylphosphatidylcholine, and diphosphatidylglycerol) as excipients in the preparation of nintedanib isothrix isothrix inhalation aerosol to improve particle performance and stability. The preparation process includes solution preparation (adding the hydrophobic amino acids and phospholipids to purified water, fully dissolving and uniformly dispersing them), spray drying (using spray drying equipment and setting appropriate process parameters to obtain the desired particle characteristics), and filling (filling the particles into aerosol cans, adding propellant, and sealing). Throughout the process, the pharmaceutical acceptability of the materials must be ensured, and quality control must be performed to ensure that the aerosol performance meets expectations.

[0046] In one exemplary embodiment, the formulation in the aerosol can provided by the present invention is expected to provide a drug dose of about 30 to 200 puffs, or 60 to 200 puffs, or 60 to 120 puffs. In one exemplary embodiment, the formulation in the aerosol can provided by the present invention comprises at least 1 mg / mL, at least 5 mg / mL, at least 10 mg / mL, at least 20 mg / mL, at least 50 mg / mL, at least 100 mg / mL, and at least 200 mg / mL of nintedanib ethanesulfonate active pharmaceutical ingredient. In one exemplary embodiment, the formulation in the can comprises at least 0.1% wt, 1% wt, 2% wt, 3% wt, 5% wt, 10% wt, or 20% wt of nintedanib active ingredient.

[0047] the term: As used in this article, particle size distribution D50 represents the median particle size in a particle group, meaning that 50% of the particles have a particle size less than or equal to D50.

[0048] The reagents used in the following examples, such as oleic acid, are injection grade. The propellants, such as HFA-134a, are commercially available products of conventional inhalation propellants.

[0049] The inhalation aerosol devices involved in the following examples are conventional commercially available inhalation aerosol devices.

[0050] Example 1: Pharmacokinetic Study of Pulmonary Administration vs. Oral Administration This pharmacokinetic study primarily investigated the differences in absorption and distribution characteristics of nintedanib ethanesulfonate in mice (model: C57, weight: 25g±2g, sex: male, age: 6-8 weeks) via different routes of administration (nasal inhalation, intratracheal inhalation, and oral administration). The aim was to compare the pharmacokinetic characteristics of nintedanib ethanesulfonate under different administration routes.

[0051] Experimental samples: Groups G1-G3: Nintedanib issylate solution. Preparation method: Weigh the nintedanib issylate raw material according to the prescribed dosage, add the corresponding volume of water for injection, and dissolve thoroughly until a clear solution is obtained. Group G4: Drugs administered via endotracheal spray: Weigh nintedanib ethoxylate raw material according to the dosage, add the corresponding volume of water for injection, and dissolve thoroughly until a clear solution is obtained.

[0052] Group G5: OFEV capsule contents were diluted and dispersed using medium-chain glycerides as a matrix, with a concentration of 50 mg / ml. Experimental Methods: The experiment was divided into five groups (G1-G5, 3 animals per group): G1-G3 were administered via nasal inhalation. The dosages were set as follows: 0.3 mg / kg body weight of nintedanib ethoxylate (the animal preparation used was nintedanib ethoxylate solution with a concentration of 0.75 mg / ml), 1 mg / kg body weight of nintedanib ethoxylate (the animal preparation used was nintedanib ethoxylate solution with a concentration of 2.5 mg / ml), and 3 mg / kg body weight of nintedanib ethoxylate (the animal preparation used was nintedanib ethoxylate solution with a concentration of 7.5 mg / ml). The animal preparation used for administration was nintedanib ethoxylate solution. The administration frequency was once daily. After administration, blood samples were collected at 0h, 5min, 15min, 30min, 1h, 2h, 4h, 8h, and 24h, a total of 9 time points, and the concentration of nintedanib ethoxylate was measured. Group G4 received intratracheal spray inhalation once daily at a dose of nintedanib ethanesulfonate 1 mg / kg body weight, with an animal formulation concentration of 2.5 mg / ml. Blood samples were collected within one day after administration, as described above. Group G5 received oral administration of the original nintedanib ethanesulfonate soft capsule contents to an animal formulation of 100 mg / kg (medium-chain triglycerides were used as a matrix for dilution and dispersion, with a concentration of 50 mg / ml). Blood samples were collected within 24 hours after administration, as described above.

[0053] The method for detecting the concentration of nintedanib ethoxylate in blood samples was the conventional LC-MS method. The concentration of nintedanib ethoxylate in the blood samples was recorded at each time point, and the data were statistically analyzed and a time-concentration curve was plotted.

[0054] The results are as follows Figure 1 As shown, in groups G1-G3, nasal inhalation and in group G4, intratracheal spray inhalation resulted in higher efficiency of drug absorption into the bloodstream via lung tissue. The relationship between nasal inhalation dosage and blood drug concentration C... max The linear relationship was good. In this example, the nasal inhalation dose for group G3 was 3 mg / kg, and the blood drug concentration C was... max The detected value was 263.89 ng / mL. The oral dose for group G5 was 100 mg / kg, and the blood drug concentration C was... max The detected value was 428 ng / mL.

[0055] Furthermore, according to the existing literature CN112867707A (specifically formulated compositions of nintedanib and nintedanib salts for inhalation), nasal inhalation doses of 0.021 mg / kg, 0.21 mg / kg, and 2.1 mg / kg are equally effective intervention and treatment doses for animals with pulmonary fibrosis compared to an oral dose of 30 mg / kg. Theoretically, the dosage range of 0.021 to 2.1 mg / kg can achieve the same therapeutic effect as oral intervention with 30 mg / kg.

[0056] Example 2: Liver enzyme detection experiment comparing intratracheal administration with oral administration This embodiment further investigated the different effects of intratracheal and oral administration on liver enzyme levels, with the oral administration dose being 100 mg / kg. Intratracheal administration was performed at doses of 0.5 mg / kg and 1.5 mg / kg. Blood samples were collected after both intratracheal and oral administration at 0h, 4h, 8h, 24h, 32h, and 48h. Liver enzyme levels GLDH and ALT in the blood samples were measured, and the changes in GLDH and ALT values ​​at 0h, 4h, 8h, 24h, 32h, and 48h compared to baseline levels were statistically analyzed: ΔGLDH and ΔALT. The specific steps are as follows: Laboratory animals: Rats (model: SD rat, weight: 250g±10g, sex: male) Oral formulation: Nintedanib ethoxylate active pharmaceutical ingredient, suspended and dispersed using medium-chain glycerides as a matrix, at a concentration of 10 mg / ml; Intratracheal administration preparation: Nintedanib ethsulfate solution, prepared by weighing the Nintedanib ethsulfate raw material according to the dosage and adding the corresponding volume of water for injection, and dissolving it thoroughly until a clear solution is obtained.

[0057] Experimental methods: Oral administration group (3 rats / group): The oral dose for rats was 100 mg / kg (animal formulation concentration of 10 mg / mL). Blood samples were collected after administration at the following time points: 0h, 4h, 8h, 24h, 32h, and 48h. Intratracheal administration group (3 animals / group): Nintedanib ethoxylate was administered via intratracheal route at doses of 0.5 mg / kg and 1.5 mg / kg (animal formulation concentrations of 2.5 mg / ml and 3.75 mg / ml, respectively; intratracheal administration dose of 400 μL / kg; according to existing technical data, intratracheal administration doses correspond to 1 and 3 times the equivalent dose of oral 100 mg / kg, respectively). Blood collection time points were the same as those in the oral administration group: 0h, 4h, 8h, 24h, 32h, and 48h.

[0058] After drug administration, blood and serum were collected from each group, and GLDH and ALT levels were subsequently measured using a biochemical analyzer. Statistical analysis was performed by comparing changes in liver enzymes under different administration methods. GLDH and ALT levels at each time point were recorded, and the changes in GLDH and ALT compared to the healthy baseline were calculated as ΔGLDH and ΔALT. Corresponding time-ΔGLDH and time-ΔALT curves were then plotted.

[0059] The results are as follows Figure 2 (Time - ΔALT) and Figure 3 As shown in the (time-ΔGLDH) curves, comparing the time-ΔGLDH and time-ΔALT curves under oral administration (100 mg / kg) and intratracheal administration (0.5 mg / kg and 1.5 mg / kg), it can be found that: the ΔALT index of the oral group (100 mg / kg) is greater than that of the intratracheal administration of 1.5 mg / kg (this dose is 3 times the equivalent dose of the oral 100 mg / kg intratracheal administration); the ΔGLDH index of the oral group (100 mg / kg) is greater than that of the intratracheal administration of 1.5 mg / kg (this dose is 3 times the equivalent dose of the oral 100 mg / kg intratracheal administration).

[0060] Example 3 Screening of active pharmaceutical ingredients in different forms of nintedanib This embodiment compares the dissolution of nintedanib ethanesulfonate and nintedanib free base in simulated lung tissue fluid (SLF) in vitro (SLF reagent model: MGS2937; manufacturer: Shanghai Maiji Biotechnology Co., Ltd.) to screen and determine the active pharmaceutical ingredient form that meets the criteria for local dissolution and therapeutic use after inhalation into the lungs. The screening experimental protocol is as follows: Dissolution assay of nintedanib active ingredient: 500 mL of SLF was added to each dissolution vessel, and the temperature was maintained at 37℃. One of the two commercially available forms of nintedanib active ingredient—nintedanib isosulfonate and nintedanib free base—was used. The average particle size of the active pharmaceutical ingredient was controlled to be 2-5 μm. 50 mg of the sample was accurately weighed, and the stirring speed was 125 rpm. At 0.5, 1, 2, 4, 6, 8, 10, 15, 30, and 60 minutes, 2 mL of sample was taken using a 13 mm water-wetted PTFE syringe filter. 0.5 mL was discarded, and the remaining sample was retained. The sample was diluted 1:4 (by volume) with SLF reagent and analyzed repeatedly using HPLC. Finally, the dissolution percentage at different time points was recorded, and the dissolution curves and dissolution rates of nintedanib isosulfonate and nintedanib free base in SLF were compared to determine the time required for complete dissolution of the nintedanib active ingredient. The results are shown in the table below. Table 1: Dissolution of nintedanib ethanesulfonate and nintedanib free base in SLF

[0061] As can be seen from the table above, among the two forms of nintedanib drug raw materials currently available on the market: nintedanib isosulfonate and nintedanib free base (both with an average particle size range of 2-5 μm), nintedanib isosulfonate has a better solubility in simulated human lung fluid, and nintedanib isosulfonate particles can better exert their dissolution and absorption therapeutic effects after being inhaled into the lungs.

[0062] Example 4: Nintedanib ethanesulfonate API Granule Engineering This embodiment uses airflow milling technology to control the particle size of nintedanib ethanesulfonate in order to optimize its treatment effect. Specific steps: Nintedanib isosulfate raw materials numbered 1-3 were passed through a 120-mesh sieve, and nintedanib isosulfate raw materials numbered 4-6 were passed through a 60-mesh sieve to separate larger drug particles from the nintedanib isosulfate raw material. Nintedanib isosulfate was further pulverized using an air jet mill. The process specifically included: using a Novize JetMill air jet mill, the raw material (feed rate shown in Table 2 below) was fed into the pulverizing chamber of the air jet mill through a feeding device, and pulverized under the action of high-speed airflow. The inlet pressure, pulverizing pressure, and feed rate parameters were controlled (see Table 2 below) to obtain nintedanib isosulfate of the desired particle size. The specific particle size of the nintedanib isosulfate raw material was measured using a Neopatek laser particle size analyzer (dry method). The specific air jet milling experimental conditions and particle size measurement results are shown in the table below. Microscopic observation results are as follows. Figure 4 As shown: Before pulverization and sieving, the particle size range of the raw drug was relatively wide, and the particle surface was rough and irregular. After sieving and air jet milling, the particle size distribution range became narrower and the surface became relatively smooth and regular.

[0063] Table 2: Experimental conditions and particle size determination results of airflow pulverization

[0064] Example 5: Preparation of Nintedanib Ethyl Acetate Suspension-Type Inhalation Aerosol 1. Preparation process: The raw material for nintedanib ethanesulfonate was selected from item (2) in Example 4; The prescribed amount of surfactant and saturated vapor pressure regulator are thoroughly mixed. The prescribed amount of nintedanib is added, and the mixing speed is controlled at 4000 rpm for 5 minutes to ensure thorough mixing. The prescribed amount of propellant HFA-134a is injected into the mixture through the pores on the canister to prepare 100 bottles of nintedanib isosulfate suspension inhalation aerosol with a theoretical dosage of 500 μg / spray. Approximately 200 sprays are filled with a 50 μL metering valve volume, and approximately 100 sprays are filled with a 100 μL metering valve volume. To ensure the accuracy of the dosage per actuation (each actuation refers to the amount of medication sprayed per press of the aerosol valve, and the amount of medication sprayed per actuation is fixed), over-dosing may occur during actual preparation. The following formulation is calculated based on the theoretical dosage. The formulation composition is as follows: Table 3: Formulation and Device Parameters of Nintedanib Ethylenediate

[0065] 2. Detection of the dose ratio (FPF) of micro-samples: After ensuring the Anderson ACI (Advanced Multistage Impactor) equipment was clean, the prepared nintedanib isosulfate aerosol was connected to the throat of the ACI equipment via an interface. After setting the detection flow rate (28.3 L / min), the aerosol was sprayed five times to ensure sufficient sample was collected for analysis. The collection port, throat, each stage of the deposition plate, and filter test components were thoroughly cleaned with 50 mL of methanol. High-performance liquid chromatography (HPLC) was used to analyze the collected samples at each location to determine the amount of drug deposited on each test component. The drug deposition amount (in μg / bunch) of each test component was imported into the analysis software program, which output the aerodynamic particle size distribution parameters, such as MMAD and FPF, of the aerosol.

[0066] Table 4 below shows the MMAD and FPF values ​​output by the analysis software after the drug content detection values ​​of each component in the ACI experiment of prescription 1-12 are imported. According to the Chinese Pharmacopoeia Method for Determination of Aerodynamic Characteristics of Fine Particles in Inhalation Preparations (General Rule 0951), the FPF should not be less than 15% of the labeled dose, and the median aerodynamic diameter (MMAD) should be less than 5 μm.

[0067] Table 4: Aerodynamic particle size distribution parameters of various nitedanib ethanesulfonate aerosols

[0068] The table above shows that by screening parameters such as the pore size and pore length of the inhalation device, the concentration of ethanol and the concentration of surfactant in the formulation, a suspension-type inhalation aerosol sample that meets the pharmacopoeia requirements (FPF and MMAD parameters) and uses nintedanib ethanesulfonate as the active pharmaceutical ingredient can be prepared.

[0069] Example 6: Stability Study of Nintedanib Isylate Suspension-Type Inhalation Aerosol This embodiment uses formulations with different proportions (the raw material for nintedanib ethanesulfonate is selected from item (2) in Example 4), combined with aerosol devices with a metering valve volume of 50 μL or 100 μL; a nozzle diameter of 0.35 mm; and nozzle lengths of 0.5 mm, 0.7 mm, or 1.0 mm, respectively, as the research object. A spray pattern analyzer (manufactured by Proveris, USA) was used to measure the spray pattern, analyze the spray duration and plume geometry data, and obtain qualitative and quantitative information on the spray pattern. The specific spray pattern parameters that can be qualitatively and quantitatively defined include: Area (spray area): refers to the area of ​​the spray shape. Studies have shown that the spray area is negatively correlated with the average spray velocity, that is, as the spray area decreases, the spray velocity increases; Dmax (maximum diameter): refers to the maximum diameter of the spray pattern; Dmin (minimum diameter): refers to the minimum diameter of the spray pattern; Ovality (ellipticity): refers to the degree of ellipticity of the spray shape; Plume Angle (plume angle): refers to the unfolding angle of the spray plume. Studies have shown that the plume angle is negatively correlated with the average spray velocity; that is, as the plume angle decreases, the spray velocity increases. Plume Width refers to the width of the spray plume. Studies have also shown that plume width is negatively correlated with the average spray velocity; that is, as the plume width decreases, the spray velocity increases. The specific formulation composition and aerosol device parameter combinations, as well as the detection results of spray morphology parameters such as Area, Dmax, Dmin, Ovality, Plume Angle, and Plume Width, are shown in Tables 5-16 below. Table 5: Spray pattern at 30mm (30mm distance from the cross section)

[0070] Table 6: Spray pattern at 60mm (cross-section distance)

[0071] Table 7: Spray pattern at 30mm (30mm distance from the cross section)

[0072] Table 8: Spray pattern at 60mm (cross-section distance of 60mm)

[0073] Table 9: SP 30mm (Spray pattern at a distance of 30mm from the cross section)

[0074] Table 10: Spray pattern at 60mm (cross-section distance of 60mm)

[0075] Table 11: SP 30mm (Spray pattern at a distance of 30mm from the cross section)

[0076]

[0077] Table 12: Spray pattern at 60mm (cross-section distance of 60mm) Table 13: Detected values ​​of plume angle and plume width

[0078] Table 14: Detected values ​​of plume angle and plume width

[0079] Table 15: Detected values ​​of plume angle and plume width

[0080] Table 16: Detected values ​​of plume angle and plume width

[0081] Example 7 Preparation and Screening of Nintedanib Isylate Suspension Inhalation Aerosol Preparation process and formulation composition: The prescribed amount of surfactant and suspending agent PVP (K25) was fully dissolved or dispersed in anhydrous ethanol, and then the prescribed amount of nintedanib isosulfate micro powder (the raw material of nintedanib isosulfate selected from the material in item (2) of Example 4) was added. The stirring speed was controlled at 4000 rpm and stirred for 5 minutes to ensure thorough and uniform mixing. The thoroughly mixed dispersion was dispensed into aluminum cans, and then the corresponding propellant was filled into the cans equipped with metering valves (50 μL or 100 μL) to the theoretical total amount through a press-filling device. The fine particle dose ratio (FPF) of each formulation combination was detected and analyzed according to the Anderson multistage impactor (ACI) equipment detection method. The formulation composition and FPF detection results are shown in Table 17 below.

[0082] Table 17: Formulation and FPF Test Results of Nintedanib Ethylened Suspension Inhaler Aerosol

[0083] Conclusion: The formulation screening results of this invention show that, regardless of the propellant used or the addition of different concentrations of surfactants (such as oleic acid or Tween) and suspending agents, formulations using inhalation aerosol devices with a nozzle diameter of 0.2-0.5 mm and a nozzle length of 0.5-1.5 mm generally exhibit higher fine particle dose ratio (FPF) results compared to formulations deviating from this range. This indicates that when equipped with an inhalation device with a nozzle diameter of 0.2-0.5 mm and a nozzle length of 0.5-1.5 mm, the nintedanib issylate suspension inhalation aerosol prepared according to this invention can maintain an extremely high level of pulmonary drug delivery efficiency.

[0084] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. An inhalable composition containing nintedanib, characterized in that, Include: Nintedanib or a pharmaceutically acceptable salt thereof; and at least one inhalation excipient that can be aerosolized.

2. The inhalable nintedanib-containing composition according to claim 1, characterized in that, The dosage form of the inhalable nintedanib-containing drug composition includes an inhaled aerosol. Preferably, the inhaled aerosol includes a suspension-type inhaled aerosol.

3. The composition of the inhalable nintedanib-containing drug according to claim 1 or 2, characterized in that, The aerosolizable inhalation pharmaceutical excipients include: Surfactants, propellants, saturated vapor pressure regulators and / or suspending agents.

4. The composition of an inhalable nintedanib-containing drug according to any one of claims 1-3, characterized in that, include: The content of nintedanib or its pharmaceutically acceptable salts ranges from 0.01 to 20 parts by weight, with surfactants comprising 0 to 5 parts by weight; propellants comprising 50 to 99.99 parts by volume; saturated vapor pressure regulators comprising 0 to 30 parts by volume; and suspending agents comprising 0 to 5 parts by weight; the ratio of parts by weight to parts by volume is g:ml. Preferably, the pharmaceutically acceptable salt of nintedanib is nintedanib ethanesulfonate; Preferably, the particle size distribution D50 of nintedanib or its pharmaceutically acceptable salt is in the range of 0.1-10 μm; more preferably, the particle size distribution D50 is in the range of 0.1-5 μm.

5. The composition of an inhalable nintedanib-containing drug according to claim 3 or 4, characterized in that, The surfactant is selected from at least one of Tween 80, Tween 20, Span 20, Span 85, oleic acid, and phospholipid pharmaceutical excipients; Preferably, the phospholipid pharmaceutical excipients include lecithin and / or distearate phosphatidylcholine; Preferably, the surfactant is oleic acid.

6. The composition of an inhalable nintedanib-containing drug according to any one of claims 3-5, characterized in that, The propellant is selected from at least one of HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane and HFO-1234ze; Preferably, the propellant is HFA-134a; Preferably, the propellant is HFA-152a; Preferably, the propellant is HFO-1234ze.

7. The composition of an inhalable nintedanib-containing drug according to any one of claims 3-6, characterized in that, The saturated vapor pressure regulator is selected from at least one of anhydrous ethanol, propylene glycol, and polyethylene glycol. Preferably, the saturated vapor pressure regulator is anhydrous ethanol; Preferably, the content of the saturated vapor pressure regulator in the pharmaceutical composition ranges from 0-30% v / v.

8. The composition of an inhalable nintedanib-containing drug according to any one of claims 3-7, characterized in that, The suspending agent is selected from polyvinylpyrrolidone; Preferably, the suspending agent is at least one of PVP (K25), PVP / 17PF and PVP (K30).

9. A method for preparing an inhalable nintedanib-containing drug composition as described in any one of claims 1-8, characterized in that, include: The active pharmaceutical ingredient of nintedanib or its pharmaceutically acceptable salt is sieved and then pulverized to obtain micronized nintedanib or its pharmaceutically acceptable salt. Then, the fine powder particles of the nintedanib or its pharmaceutically acceptable salt are mixed with at least one inhalation excipient that can be aerosolized.

10. The method for preparing the inhalable nintedanib-containing drug composition according to claim 9, characterized in that, The active pharmaceutical ingredient, nintedanib or its pharmaceutically acceptable salt, is sieved through a 60-120 mesh sieve. And / or, the pulverization process includes at least one of air jet milling, ball milling, high pressure homogenization, and ultrasonic pulverization; And / or, the particle size distribution D50 of nintedanib or its pharmaceutically acceptable salts is in the range of 0.1-10 μm; more preferably, the particle size distribution D50 is in the range of 0.1-5 μm; And / or, dispersing micronized particles of nintedanib or a pharmaceutically acceptable salt thereof, surfactants, and vapor pressure regulators in a propellant, forming a suspension mixture, and filling the mixture into an aerosol can.

11. An inhalation device for aerosolizing an inhalable composition containing nintedanib as claimed in any one of claims 1-8 or an inhalable composition containing nintedanib prepared according to claim 9 or 10, comprising a metering valve, an actuator, an adapter, a nozzle, a canister, and a metering counter, characterized in that, The nozzle diameter of the actuator ranges from 0.15 to 0.7 mm, and the nozzle length ranges from 0.3 to 2 mm; preferably, the nozzle diameter of the actuator ranges from 0.2 to 0.5 mm, and the nozzle length ranges from 0.5 to 1.5 mm.

12. The aerosolized inhalation device for the inhalable nintedanib-containing drug composition according to claim 11, characterized in that, The volume range of the metering valve is 25-250 μL; preferably, the volume range of the metering valve is 50-100 μL.

13. Use of the inhalable nintedanib-containing composition of claims 1-8, the inhalable nintedanib-containing composition of claim 9 or 10, or the aerosolized inhalation device for the inhalable nintedanib-containing composition of claim 11 or 12 in the preparation of a medicament for the prevention and treatment of interstitial lung disease (ILD); preferably, the ILD subtype includes at least one of idiopathic pulmonary fibrosis (IPF), progressive fibrotic interstitial lung disease (PF-ILD), and systemic sclerosis-associated interstitial lung disease (SSc-ILD).

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