A nintedanib suspension formulation, its preparation method and use in the treatment of pulmonary fibrosis

Abstract

The application belongs to the technical field of nintedanib preparation development, and particularly relates to a nintedanib suspension preparation, a preparation method thereof and application of the nintedanib suspension preparation in treatment of pulmonary fibrosis. A phospholipid material is dissolved in an organic solvent under the condition of 50-70 DEG C to obtain solution A; an inorganic salt is dissolved in water for injection to obtain solution B; nintedanib ethanesulfonic acid is dissolved in water for injection to obtain solution C; an osmotic pressure regulator is dissolved in water for injection to obtain solution D; solution A and solution B are mixed by microfluidic to obtain suspension E; the organic solvent in the suspension E is removed by tangential flow membrane filtration, then solution C is added and kept for a period of time, and solution D is added as needed and mixed; the suspension can be filtered by a sterilization filter to obtain the nintedanib suspension preparation. The nintedanib prepared in the application is in a stable physical state, has excellent slow-release effect, is suitable for low-dose inhalation administration in the lung, and is helpful to improve the treatment effect and reduce side effects.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of nintedanib preparation development, and particularly relates to a nintedanib suspension preparation, a preparation method thereof and application of the nintedanib suspension preparation in treatment of pulmonary fibrosis. BACKGROUND

[0002] Pulmonary fibrosis is a severe lung disease with unknown causes and irreversible course. In clinical practice, dyspnea, dry cough, fatigue and easy fatigue are the main manifestations of patients with pulmonary fibrosis. Medical imaging tests show that a large amount of collagen fibers are deposited in the lungs of patients with pulmonary fibrosis, a large number of alveoli are lost, the normal lung tissue structure is changed, and other phenomena, the gas exchange function is lost, and finally the patients die of respiratory failure. Pulmonary fibrosis can be divided into idiopathic pulmonary fibrosis, secondary pulmonary fibrosis, hereditary pulmonary fibrosis and other pulmonary fibrosis.

[0003] At present, the drugs for treating pulmonary fibrosis include pirfenidone, nintedanib, antacids and N-acetylcysteine. Among them, only pirfenidone and nintedanib have been approved as effective drugs for treating idiopathic pulmonary fibrosis. Nintedanib is an intracellular tyrosine kinase inhibitor, and its target mechanism is clear. It is mainly used for the treatment of idiopathic pulmonary interstitial fibrosis. Nintedanib competitively inhibits two non-receptor tyrosine kinases and receptor tyrosine kinases. The NRTK targets of nintedanib include Lck, Lyn and Src. The RTK targets of nintedanib include platelet-derived growth factor receptors alpha and beta; fibroblast growth factor receptors 1, 2 and 3; vascular endothelial growth factor receptors 1, 2 and 3; and FLT3. Its use in idiopathic pulmonary fibrosis depends on the inhibition of PDGFR, FGFR and VEGFR, which increases the proliferation, migration and transformation of fibroblasts.

[0004] The marketed product nintedanib is an oral soft capsule, and its product specifications are large, with two specifications of 100 mg and 150 mg. However, the product has low bioavailability, only less than 5% bioavailability, significant liver first-pass effect and transporter effect, and high probability of gastrointestinal and liver side effects. The most common adverse reactions (≥5%) are diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, loss of appetite, headache, weight loss, and hypertension, and there is a risk of bleeding: 10% of patients treated with nintedanib reported bleeding events in clinical trials. In order to consider the long-term medication needs of patients with pulmonary fibrosis, the many adverse reactions of the oral capsule preparation limit the application range of the drug.

[0005] Patent CN112867707A shows that ethanesulfonic acid nintedanib is more sensitive to pH and ions, and the prepared solution has poor stability and is not easy to store for a long time. The patent tests various solution systems, and finally adopts a compromise method by mixing the first solution and the second solution before use to solve the above problem of not easy to store for a long time. But this method needs to mix two solutions before use, the operation is more complicated, and the mixing effect has uncertainty.

[0006] Patent CN109758437A provides a nintedanib lyophilized liposome preparation and a preparation method thereof, which also fails to realize a long-term stable nintedanib solution preparation. Although the nintedanib lyophilized liposome preparation can be stored for a long time, it needs to be reconstituted before use, which is complicated to operate, and the state after reconstitution also affects the exertion of drug efficacy to a certain extent. SUMMARY

[0007] In view of the deficiencies of the prior art, the present application provides a nintedanib suspension solution preparation, a preparation method thereof and an application thereof in treating pulmonary fibrosis.

[0008] The purpose of the present application is to develop a nintedanib suspension solution which can be stored for a long time and can be directly administered to the lung with high utilization rate, so as to be used for the treatment of pulmonary fibrosis at a lower dose, thereby being more beneficial to the treatment of patients.

[0009] The first aspect of the present application provides a preparation method of a nintedanib suspension solution, comprising the following steps:

[0010] Step S1: dissolve phospholipid and cholesterol in an organic solvent under the condition of 50-70℃, and obtain solution A by incubation;

[0011] Step S2: dissolve inorganic salt in water for injection under the condition of 50-70℃, and obtain solution B by incubation;

[0012] Step S3: dissolve ethanesulfonic acid nintedanib in water for injection to obtain solution C;

[0013] Step S4: mix solution A and solution B under the condition of 50-70℃ by microfluidic mixing to obtain suspension E;

[0014] Step S5: remove the organic solvent in suspension E by tangential flow membrane filtration, then add solution C, and incubate under the condition of 50-70℃ for a period of time; add an osmotic pressure regulator as needed during the preparation process to make the finally formed suspension isotonic, and obtain the nintedanib suspension solution preparation.

[0015] As an optimization scheme of the preparation method of the nintedanib suspension solution preparation, it further comprises step S6: after step S5 is completed, filter the suspension with a sterilization filter to obtain the nintedanib suspension solution preparation.

[0016] As an optimization of the preparation method of the nintedanib suspension preparation, the osmotic pressure regulator is dissolved in water for injection to obtain solution D, and solution D is added as needed during preparation to make the final nintedanib suspension preparation physiologically isotonic.

[0017] Preferably, the concentration of the osmotic pressure regulator in solution D is in the range of 50 mg / g to 300 mg / g, and solution D is added before or after the tangential flow membrane filtration operation.

[0018] As an optimization of the preparation method of the nintedanib suspension preparation, the phospholipid material used in step S1 includes dipalmitoyl phosphatidylcholine.

[0019] As an optimization of the preparation method of the nintedanib suspension preparation, the phospholipid material used in step S1 also includes phosphatidyl ethanolamine.

[0020] As an optimization of the preparation method of the nintedanib suspension preparation, the inorganic salt used in step S2 is ammonium sulfate.

[0021] As an optimization of the preparation method of the nintedanib suspension preparation, the osmotic pressure regulator is selected from the group consisting of sucrose, lactose, trehalose, and mannitol.

[0022] As an optimization of the preparation method of the nintedanib suspension preparation, in step S4, solution A is used as the oil phase at a flow rate of 10 ml / min to 20 ml / min; and solution B is used as the aqueous phase at a flow rate of 40 ml / min to 90 ml / min.

[0023] As an optimization of the preparation method of the nintedanib suspension preparation, the total concentration of phospholipid and cholesterol in solution A is in the range of 113 mg / g to 182 mg / g; the concentration of inorganic salt in solution B is in the range of 33 mg / g to 66 mg / g; the concentration of nintedanib esilate in solution C is in the range of 2.5 mg / ml to 15 mg / ml; and in step S5, the suspension E after removal of the organic solvent is mixed with solution C at a volume ratio of 2:1 to 5:1.

[0024] The second aspect of the present application provides a nintedanib suspension preparation for treating pulmonary fibrosis, wherein the nintedanib suspension preparation is a suspension of liposomes containing nintedanib esilate, and the phospholipid material in the liposomes at least includes dipalmitoyl phosphatidylcholine and cholesterol.

[0025] Preferably, the nintedanib suspension preparation is prepared by the above preparation method.

[0026] Preferably, the pH value of the nintedanib suspension preparation is in the range of 5 to 7, and the average particle size of the liposomes in the suspension is in the range of 80 nm to 150 nm.

[0027] The third aspect of the present application provides the use of the above-mentioned nintedanib suspension preparation in the treatment of pulmonary fibrosis, which is inhaled after atomization to directly act on the lungs of the patient. Liposomes have good biocompatibility without immunogenicity, and liposomes of about 100 nm can easily penetrate biological barriers such as blood vessel walls and cell membranes. Therefore, after the patient inhales the above-mentioned nintedanib suspension preparation, it can be targeted in the lungs for sustained release, reduce the irritation to the lung tissue, and at the same time reduce the drug dosage and improve the bioavailability.

[0028] Advantages

[0029] The present application prepares nintedanib into a liposome suspension, which can achieve targeted release of the drug in the lungs, greatly improve the bioavailability of nintedanib, and help to achieve good therapeutic effect with lower dosage and reduce side effects.

[0030] The suspension formula provided by the present application solves the problem of sensitivity of nintedanib esylate to pH and ions. There are a large number of ions on the surface of the respiratory tract, which can cause nintedanib esylate to be precipitated. The liposome suspension prepared by using specific phospholipids and processes can overcome the precipitation problem of nintedanib esylate, and remains stable in physiological saline to ensure the long-term stability of the drug suspension. It does not need to rely on the two-step mixing or freeze-drying reconstitution process before use. The improvement of stability not only facilitates transportation, storage and administration process, but also has important significance for ensuring the effectiveness and safety of the drug.

[0031] The nintedanib esylate suspension provided by the present application has good sustained release performance, can maintain stable drug release for a long time, helps to maintain effective blood drug concentration, and further enhances the therapeutic effect. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 The state diagram of the liposome sample of Example 1 after overnight storage.

[0033] Figure 2 The state diagram of the liposome sample of Example 2 after cooling.

[0034] Figure 3 a is the initial state diagram of the nintedanib esylate solution; Figure 3 b is the initial state diagram of the nintedanib esylate liposome suspension.

[0035] Figure 4 a is the state diagram of the nintedanib esylate solution after adding an equal volume of 0.9% sodium chloride solution; Figure 4 b is the state diagram of the nintedanib esylate liposome suspension after adding an equal volume of 0.9% sodium chloride solution.

[0036] Figure 5 a is the state diagram of the nintedanib esylate solution after adding an equal volume of 0.9% sodium chloride solution and standing for a period of time; Figure 5 b is the state diagram of the nintedanib esylate suspension after adding an equal volume of 0.9% sodium chloride solution and standing for a period of time.

[0037] Figure 6 Figure is the in vitro release test result diagram of the nintedanib esylate suspension. DETAILED DESCRIPTION

[0038] The present application is further illustrated by the following specific examples, which are exemplary and intended to illustrate the problem and explain the present application, and are not a limitation.

[0039] Example 1

[0040] Take hydrogenated soybean phospholipid and cholesterol, add anhydrous ethanol, stir at 60°C, incubate, hydrogenated soybean phospholipid concentration 85mg / g, cholesterol concentration 28mg / g; take ammonium sulfate, add water for injection, stir at 60°C, incubate, ammonium sulfate concentration 33mg / g; take nintedanib esylate, add water for injection to dissolve at 60°C, prepare a 5mg / ml solution; take sucrose, add water for injection to dissolve, sucrose concentration 100mg / g; use a microreactor to mix the phospholipid solution with the ammonium sulfate solution at 60°C, phospholipid solution flow rate 15ml / min, ammonium sulfate solution flow rate 60ml / min, incubate at 60°C for 60min, use sucrose solution tangential membrane ultrafiltration to remove ethanol, then add nintedanib esylate solution at a volume ratio of 4:1, mix the sample, incubate at 60°C for 60min, obtain a 1mg / ml nintedanib esylate suspension, store at 2-8°C. The sample precipitates at the bottom overnight.

[0041] Example 2

[0042] Take dipalmitoyl phosphatidylglycerol and cholesterol, add anhydrous ethanol, stir at 60°C, incubate, dipalmitoyl phosphatidylglycerol concentration 85mg / g, cholesterol concentration 28mg / g; take ammonium sulfate, add water for injection, stir at 60°C, incubate, ammonium sulfate concentration 33mg / g; take nintedanib esylate, add water for injection to dissolve at 60°C, prepare a 5mg / ml solution; take sucrose, add water for injection to dissolve, sucrose concentration 100mg / g; use a microreactor to mix the phospholipid solution with the ammonium sulfate solution at 60°C, phospholipid solution flow rate 15ml / min, ammonium sulfate solution flow rate 60ml / min, incubate at 60°C for 60min, use sucrose solution tangential membrane ultrafiltration to remove ethanol, then add nintedanib esylate solution at a volume ratio of 4:1, mix the sample, incubate at 60°C for 60min, cool to form a gel.

[0043] Example 3

[0044] Take dipalmitoyl phosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 60°C, keep warm, dipalmitoyl phosphatidylcholine concentration 85 mg / g, cholesterol concentration 28 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, keep warm, ammonium sulfate concentration 33 mg / g; take nintedanib esylate, add water for injection to dissolve at 60°C, prepare a 2.5 mg / ml solution; take sucrose, add water for injection to dissolve, sucrose concentration 100 mg / g; use a microreactor to mix the phospholipid solution with the ammonium sulfate solution at 60°C, phospholipid solution flow rate 15 ml / min, ammonium sulfate solution flow rate 60 ml / min, 60°C for 60 min, use sucrose solution tangential membrane ultrafiltration to remove ethanol, then add nintedanib esylate solution 4:1 by volume, mix at 60°C for 60 min, obtain 0.5 mg / ml nintedanib esylate suspension, store at 2-8°C.

[0045] Example 4

[0046] Take dipalmitoyl phosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 60°C, keep warm, dipalmitoyl phosphatidylcholine concentration 136 mg / g, cholesterol concentration 46 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, keep warm, ammonium sulfate concentration 66 mg / g; take nintedanib esylate, add water for injection to dissolve at 60°C, prepare a 15 mg / ml solution, cool for standby; take trehalose, add water for injection to dissolve, concentration 50 mg / g; use a microreactor to mix the phospholipid solution with the ammonium sulfate solution at 60°C, phospholipid solution flow rate 15 ml / min, ammonium sulfate solution flow rate 60 ml / min, 60°C for 60 min, use trehalose solution tangential membrane to remove ethanol, then add nintedanib esylate solution 4:1 by volume, mix at 60°C for 60 min, obtain 3 mg / ml nintedanib esylate suspension, store at 2-8°C.

[0047] Example 5

[0048] Take dipalmitoyl phosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 60°C, incubate, dipalmitoyl phosphatidylcholine concentration 136 mg / g, cholesterol concentration 46 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, incubate, ammonium sulfate concentration 33 mg / g; take nintedanib esylate, add water for injection 60°C to dissolve, prepare a 6 mg / ml solution, cool for standby; take lactose, add water for injection to dissolve, concentration 100 mg / g; use microreactor to mix phospholipid solution with ammonium sulfate solution at 60°C, phospholipid solution flow rate 15 ml / min, ammonium sulfate solution flow rate 60 ml / min, 60°C incubation for 60 min, use water for injection to remove ethanol, then add nintedanib esylate solution 2:1 by volume, mix at 60°C for 60 min, to get 2 mg / ml nintedanib esylate suspension, store at 2-8°C.

[0049] Example 6

[0050] Take dipalmitoyl phosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 70°C, incubate, dipalmitoyl phosphatidylcholine concentration 85 mg / g, cholesterol concentration 28 mg / g; take ammonium sulfate, add water for injection, stir at 70°C, incubate, ammonium sulfate concentration 61.9 mg / g; take nintedanib esylate, add water for injection 60°C to dissolve, prepare a 6 mg / ml solution, cool for standby; take mannitol, add water for injection to dissolve, concentration 200 mg / g; use microreactor to mix phospholipid solution with ammonium sulfate solution at 70°C, phospholipid solution flow rate 11 ml / min, ammonium sulfate solution flow rate 89 ml / min, 70°C incubation for 60 min, use tangential membrane and water for injection ultrafiltration to remove ethanol, then add nintedanib esylate solution 4:1 by volume, mix at 60°C for 60 min, add mannitol solution 5:1, to 1 mg / ml nintedanib esylate suspension, store at 2-8°C.

[0051] Example 7

[0052] Take dipalmitoyl phosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 60°C, incubate, dipalmitoyl phosphatidylcholine concentration 85 mg / g, cholesterol concentration 28 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, incubate, ammonium sulfate concentration 61.9 mg / g; take nintedanib esylate, add water for injection to dissolve at 60°C, prepare a 2.5 mg / ml solution, cool for standby; take mannitol, add water for injection to dissolve, concentration 50 mg / g; use microreactor to mix phospholipid material with inorganic salt aqueous solution at 60°C, phospholipid solution flow rate 12 ml / min, ammonium sulfate solution flow rate 72 ml / min, incubate for 60 min, use tangential membrane and mannitol solution ultrafiltration to remove ethanol, then add nintedanib esylate solution at a volume ratio of 4:1 to mix, keep at 60°C for 90 min, to obtain 0.5 mg / ml nintedanib esylate suspension, store at 2-8°C.

[0053] Example 8

[0054] Take dipalmitoyl phosphatidylcholine, phosphatidyl ethanolamine and cholesterol, add anhydrous ethanol, stir at 60°C, incubate, dipalmitoyl phosphatidylcholine concentration 84 mg / g, phosphatidyl ethanolamine concentration 1 mg / g, cholesterol concentration 28 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, incubate, concentration 66 mg / g; take nintedanib esylate, add water for injection to dissolve at 60°C, prepare a 6 mg / ml solution, cool for standby; take mannitol, add water for injection to dissolve, concentration 300 mg / g; use microreactor to mix phospholipid material with ammonium sulfate aqueous solution at 60°C, incubate for 60 min, use tangential membrane and water for injection ultrafiltration to remove ethanol, then add nintedanib esylate solution at a volume ratio of 4:1 to mix, keep at 60°C for 90 min, then add mannitol solution at a volume ratio of 5:1, to 1 mg / ml nintedanib esylate suspension, filter through 0.2 um filter membrane, fill into vials, seal, store at 2-8°C.

[0055] Observation of physical state

[0056] The liposome sample prepared in Example 1 was stored overnight, and the formation of precipitate at the bottom was observed, as shown in Figure 1 The liposome sample prepared in Example 2 was gelled after cooling, as shown in Figure 2 The liposome samples prepared in Examples 3-8 remained uniform and flowable suspension after cooling and overnight storage.

[0057] Particle size, pH value, and encapsulation efficiency detection

[0058] The samples of Examples 3-8 were taken to detect the particle size, pH value, and encapsulation rate, and the results are shown in Table 1. From the particle size, PI, pH value, content, and encapsulation rate, the quality of the nintedanib esylate suspensions prepared in Examples 3-8 is good, the product particle size is between 80-150 nm, the particle size distribution is narrow, the liposomes of about 100 nm can easily pass through the biological barriers such as blood vessel wall and cell membrane, the product pH value is basically weakly acidic, the irritability to respiratory tract is small, and the use requirements for treating pulmonary fibrosis inhalation are met.

[0059] Table 1

[0060]

[0061] Stability detection

[0062] Mucus is an important secretion of the human respiratory tract, and plays a crucial role in airway integrity and lung defense. A healthy person secretes about 10-100 ml of mucus per day, forming a mucus layer with a thickness of about 2-5 μm, extending from the bronchioles to the upper respiratory tract, and the mucus is produced by goblet cells on the surface of the mucosa and is composed of mucins suspended in water and inorganic salts.

[0063] The method of adding physiological saline was used to simulate the salt environment of the human respiratory tract to further investigate the stability of the samples. The nintedanib esylate solution and the nintedanib esylate liposome suspension prepared in Example 7 were taken, the concentration of nintedanib esylate was controlled to be 1 mg / ml, and an equal volume of 0.9% sodium chloride solution was added, and the solution stability was observed at room temperature.

[0064] The nintedanib esylate solution was initially a yellow clear solution, as shown in Figure 3 a; the nintedanib esylate liposome suspension of Example 7 was initially a stable yellow suspension, as shown in Figure 3 b. After adding an equal volume of 0.9% sodium chloride solution, the nintedanib esylate solution as a whole was still a yellow clear solution, but a small amount of solid suspension appeared, as shown in Figure 4 a; after adding an equal volume of 0.9% sodium chloride solution, the nintedanib esylate liposome suspension remained a stable yellow suspension state, and only the color was slightly lighter due to dilution, as shown in Figure 4 b. After adding an equal volume of 0.9% sodium chloride solution and standing for a period of time, a large amount of flocculent solid suspension appeared in the nintedanib esylate solution, as shown in Figure 5 a; after adding an equal volume of 0.9% sodium chloride solution and standing for a period of time, the nintedanib esylate liposome suspension had no obvious change in state, and still remained a stable yellow suspension, as shown in Figure 5 b.

[0065] The above results show that the nintedanib esilate suspension prepared in the examples has significantly improved stability compared to the nintedanib esilate solution dissolved directly in water. This stability includes both the stability of the overall physical state of the preparation and the ability of the active ingredient to remain uniformly distributed without precipitation or aggregation over a long period of time. The nintedanib esilate suspension with excellent stability is essential for the effectiveness and safety of the drug during transportation, storage, and ultimately administration. In particular, for nintedanib esilate, which is required to be inhaled for the treatment of pulmonary fibrosis, it is helpful for the active ingredient to be effectively maintained at the lesion site, thereby improving the therapeutic effect.

[0066] In vitro release test

[0067] An 8ml sample of the nintedanib esilate suspension prepared in Example 7 was measured into a 200ml volumetric flask, diluted to volume with the dissolution medium, and sampled at 0.5h, 3h, 6h, 12h, 18h, and 24h at 37°C to determine the release rate. As shown in Table 2, the nintedanib esilate suspension exhibited good sustained-release effect. Figure 6

[0068] The above embodiments are exemplary and are intended to illustrate the technical concept and features of the present application so that those skilled in the art can understand the content of the present application and implement it, and do not limit the protection scope of the present application. Any equivalent changes or modifications made in accordance with the spirit and essence of the present application should be covered within the protection scope of the present application.​

Claims

1. A method for preparing a nintedanib suspension formulation, characterized in that: Includes the following steps: Step S1: Dissolve phospholipids and cholesterol in an organic solvent at 50-70°C and keep warm to obtain solution A; Step S2: Dissolve the inorganic salt in water for injection at 50~70℃ and keep warm to obtain solution B; Step S3: Dissolve nintedanib ethanesulfonate in water for injection to obtain solution C; Step S4: Mix solution A and solution B at 50~70℃ using microfluidics to obtain suspension E; Step S5: Remove the organic solvent from suspension E by tangential flow membrane filtration, then add solution C and keep warm at 50~70℃ for a period of time; during the preparation process, add osmotic pressure regulators as needed to make the final suspension physiologically isotonic, and obtain the nintedanib suspension preparation; The phospholipid material used in step S1 includes dipalmitoylphosphatidylcholine; The inorganic salt used in step S2 is ammonium sulfate; the osmotic pressure regulator is selected from: sucrose, lactose, trehalose, and mannitol.

2. The method for preparing the nintedanib suspension formulation according to claim 1, characterized in that: The phospholipid material used in step S1 also includes phosphatidylethanolamine.

3. The method for preparing the nintedanib suspension formulation according to claim 1, characterized in that: In step S4, solution A is used as the oil phase with a flow rate of 10 ml / min to 20 ml / min; solution B is used as the aqueous phase with a flow rate of 40 ml / min to 90 ml / min.

4. The method for preparing the nintedanib suspension formulation according to any one of claims 1 to 3, characterized in that: The total concentration of phospholipids and cholesterol in solution A is in the range of 113 mg / g to 182 mg / g; the concentration of inorganic salts in solution B is in the range of 33 mg / g to 66 mg / g; the concentration of nintedanib ethanesulfonate in solution C is in the range of 2.5 mg / ml to 15 mg / ml; in step S5, the suspension E after removing the organic solvent is mixed with solution C at a volume ratio of 2:1 to 5:

1.

5. A nintedanib suspension formulation, characterized in that: For the treatment of pulmonary fibrosis; the nintedanib suspension formulation is a suspension of liposomes containing nintedanib ethoxylate, wherein the phospholipid material in the liposomes contains at least dipalmitoylphosphatidylcholine and cholesterol; the nintedanib suspension formulation is prepared by the preparation method according to any one of claims 1 to 4.

6. The nintedanib suspension formulation according to claim 5, characterized in that: The pH value of the suspension is in the range of 5 to 7, and the average particle size of the liposomes in the suspension is in the range of 80-150 nm.

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