Nintedanib suspension preparation, preparation method thereof and application of nintedanib suspension preparation in treatment of pulmonary fibrosis

Abstract

The invention belongs to the technical field of development of nintedanib preparations, and particularly relates to a nintedanib suspension preparation, a preparation method thereof and application of the nintedanib suspension preparation in treatment of pulmonary fibrosis. The preparation method comprises the following steps: dissolving a phospholipid material in an organic solvent at 50-70 DEG C, and preserving heat to obtain a solution A; dissolving inorganic salt in water for injection, and preserving heat to obtain a solution B; dissolving the ethanesulfonic acid nintedanib in the water for injection to obtain a solution C; dissolving an osmotic pressure regulator in the water for injection to obtain a solution D; mixing the solution A and the solution B by using microfluidics to obtain a suspension E; filtering through a tangential flow membrane to remove the organic solvent in the suspension E, adding the solution C, keeping the temperature for a period of time, adding the solution D as required, and uniformly mixing; and filtering the suspension with a sterilization filter to obtain the nintedanib suspension preparation. The liposome suspension prepared from the nintedanib prepared by the invention is stable in physical state and excellent in slow release effect, is suitable for low-dose inhalation administration in the lung, and is beneficial to improving the treatment effect and reducing side effects.

Description

Technical Field

[0001] The present invention belongs to the technical field of nintedanib preparation development, and in particular relates to a nintedanib suspension preparation and a preparation method thereof, and an application thereof in treating pulmonary fibrosis. Background Art

[0002] Pulmonary fibrosis is a serious lung disease with unknown etiology and irreversible course. Clinically, dyspnea, dry cough, fatigue, and easy fatigue are the main manifestations of patients with pulmonary fibrosis. Medical imaging tests show that patients with pulmonary fibrosis have a large amount of collagen fiber deposition, a large amount of alveolar loss, changes in normal lung tissue structure, loss of gas exchange function, and eventually death from respiratory failure. Pulmonary fibrosis can be divided into idiopathic pulmonary fibrosis, secondary pulmonary fibrosis, hereditary pulmonary fibrosis, and other pulmonary fibrosis.

[0003] Currently, the drugs for the treatment of pulmonary fibrosis include pirfenidone, nintedanib, antacids, and N-acetylcysteine. Among them, only pirfenidone and nintedanib are approved for the effective treatment of idiopathic pulmonary fibrosis. Nintedanib is an intracellular tyrosinase and tyrosine kinase inhibitor with a clear targeted mechanism of action. It is mainly used for the treatment of idiopathic pulmonary fibrosis. Nintedanib competitively inhibits these two non-receptor tyrosine kinases and receptor tyrosine kinases. Nintedanib's NRTK targets include Lck, Lyn, and Src. Nintedanib's RTK targets include platelet-derived growth factor receptors α and β; 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 increase the proliferation, migration, and transformation of fibroblasts.

[0004] The marketed product Nintedanib is an oral soft capsule with large specifications, 100mg and 150mg. However, the product has low bioavailability, less than 5%, significant liver first-pass effect and transporter effect, and a high probability of gastrointestinal and liver side effects. The most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, elevated liver enzymes, loss of appetite, headache, weight loss, and hypertension, and there is a risk of bleeding: in clinical trials, 10% of patients treated with Nintedanib reported bleeding events. Considering that patients with pulmonary fibrosis need to take medication for a long time, the many adverse reactions of oral capsule preparations limit the scope of application of this drug.

[0005] Patent CN112867707A shows that nintedanib ethanesulfonate is sensitive to pH and ions, and the prepared solution has poor stability and is not easy to store for a long time. The patent tested various solution systems and finally adopted a compromise method to solve the above-mentioned problem of difficult long-term stable storage by mixing the first solution and the second solution before use. However, this method requires mixing the two solutions before use, which is cumbersome and the mixing effect is uncertain.

[0006] Patent CN109758437A provides a nintedanib freeze-dried liposome preparation and a preparation method thereof, but also fails to achieve a long-term stable nintedanib solution preparation. Although the nintedanib freeze-dried liposome preparation can be stored stably for a long time, it needs to be reconstituted before use, which is cumbersome, and the state after reconstitution also affects the efficacy of the drug to a certain extent. Summary of the invention

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

[0008] The purpose of the present invention is to develop a nintedanib suspension solution with high utilization rate that can be stored stably for a long time and can be directly administered to the lungs, so that it can 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 invention provides a method for preparing a nintedanib suspension preparation, comprising the following steps:

[0010] Step S1: dissolving phospholipids and cholesterol in an organic solvent at 50-70° C. and keeping the temperature to obtain solution A;

[0011] Step S2: dissolving the inorganic salt in water for injection at 50-70° C. and keeping the temperature to obtain solution B;

[0012] Step S3: dissolving nintedanib ethanesulfonate in water for injection to obtain solution C;

[0013] Step S4: mixing solution A and solution B at 50-70° C. using microfluidics to obtain suspension E;

[0014] Step S5: removing the organic solvent in the suspension E by tangential flow membrane filtration, then adding solution C, and keeping warm at 50-70° C. for a period of time; adding an osmotic pressure regulator as needed during the preparation process to make the final suspension physiologically isotonic, thereby obtaining the nintedanib suspension preparation.

[0015] As an optimized solution for the preparation method of the nintedanib suspension preparation, it also includes step S6: after completing step S5, filtering the suspension with a sterilizing filter to obtain the nintedanib suspension preparation.

[0016] As an optimized solution for the preparation method of the nintedanib suspension preparation, the osmotic pressure regulator is dissolved in water for injection to obtain solution D. During the preparation process, solution D is added as needed to finally obtain the nintedanib suspension preparation with physiological isotonicity.

[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 optimized solution for the preparation method of the nintedanib suspension preparation, the phospholipid material used in step S1 includes dipalmitoylphosphatidylcholine.

[0019] As an optimized solution for the preparation method of the nintedanib suspension preparation, the phospholipid material used in step S1 further includes cultured phosphatidylethanolamine.

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

[0021] As an optimized solution for the preparation method of the nintedanib suspension preparation, the osmotic pressure regulator is selected from: sucrose, lactose, trehalose, and mannitol.

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

[0023] As an optimized solution for the preparation method of the nintedanib suspension preparation, 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 in a volume ratio of 2:1 to 5:1.

[0024] The second aspect of the present invention is to provide a nintedanib suspension preparation, which is used to treat pulmonary fibrosis; the nintedanib suspension preparation is a suspension of liposomes containing nintedanib ethanesulfonate, and the phospholipid material in the liposomes at least contains dipalmitoylphosphatidylcholine and cholesterol.

[0025] Preferably, the nintedanib suspension preparation is prepared by the above-mentioned 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 80-150 nm.

[0027] The third aspect of the present invention is to provide the use of the above-mentioned nintedanib suspension preparation in the treatment of pulmonary fibrosis, and the nintedanib suspension preparation is directly applied to the patient's lungs by inhalation after being atomized. Liposomes have good biocompatibility without immunogenicity, and liposomes of about 100nm can easily penetrate biological barriers such as blood vessel walls and cell membranes. Therefore, after the above-mentioned nintedanib suspension preparation is inhaled by the patient, it can be targeted and continuously released in the lungs, reducing the irritation to the lung tissue, while reducing the drug dosage and improving the bioavailability.

[0028] Beneficial Effects

[0029] The present invention 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 a good therapeutic effect with a lower dose and reduce side effects.

[0030] The suspension formula provided by the present invention combined with the preparation method solves the problem that nintedanib ethanesulfonate is sensitive to pH and ions. There are a large number of ions on the surface of the respiratory tract, which can cause the inhaled nintedanib ethanesulfonate to precipitate. The liposome suspension prepared by the present invention using specific phospholipids and process encapsulation overcomes the precipitation problem of nintedanib ethanesulfonate, and remains stable in physiological saline to ensure the long-term stability of the drug suspension, without relying on the first two steps of mixing or freeze-drying and re-dissolution process. The improvement of stability is not only convenient for transportation, storage and administration, but also has important significance for ensuring the effectiveness and safety of the drug.

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

[0032] Figure 1 This is a diagram showing the state of the liposome sample in Example 1 after overnight storage.

[0033] Figure 2 This is a state diagram of the liposome sample in Example 2 after cooling.

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

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

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

[0037] Figure 6 This is a graph showing the in vitro release test results of nintedanib ethanesulfonate suspension. DETAILED DESCRIPTION

[0038] The present invention is further illustrated by specific examples below. These examples are exemplary and are intended to illustrate the problem and explain the present invention, but are not intended to be limiting.

[0039] Example 1

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

[0041] Example 2

[0042] Take dipalmitoylphosphatidylglycerol and cholesterol, add anhydrous ethanol, stir at 60°C, keep warm, dipalmitoylphosphatidylglycerol concentration is 85 mg / g, cholesterol concentration is 28 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, keep warm, ammonium sulfate concentration is 33 mg / g; take nintedanib ethanesulfonate, add water for injection to dissolve it at 60°C, and prepare a 5 mg / ml solution; take sucrose, add water for injection to dissolve it, sucrose concentration is 100 mg / g; use a microreactor to mix the phospholipid solution and the ammonium sulfate solution at 60°C, the flow rate of the phospholipid solution is 15 ml / min, the flow rate of the ammonium sulfate solution is 60 ml / min, keep warm at 60°C for 60 minutes, use tangential membrane ultrafiltration of the sucrose solution to remove ethanol, then add the nintedanib ethanesulfonate solution to the mixed sample at a volume ratio of 4:1, keep at 60°C for 60 minutes, and become a gel after cooling.

[0043] Example 3

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

[0045] Example 4

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

[0047] Example 5

[0048] Take dipalmitoylphosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 60°C, keep warm, dipalmitoylphosphatidylcholine concentration is 136 mg / g, cholesterol concentration is 46 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, keep warm, ammonium sulfate concentration is 33 mg / g; take nintedanib ethanesulfonate, add water for injection and dissolve it at 60°C to prepare a 6 mg / ml solution, cool for standby use; take lactose, add water for injection and dissolve it, the concentration is 100 mg / g; use a microreactor to mix the phospholipid solution and the ammonium sulfate solution at 60°C, the flow rate of the phospholipid solution is 15 ml / min, the flow rate of the ammonium sulfate solution is 60 ml / min, keep warm at 60°C for 60 min, use water for injection to remove ethanol through a tangential membrane, then add the nintedanib ethanesulfonate solution in a volume ratio of 2:1 to mix, keep at 60°C for 60 min, obtain a 2 mg / ml nintedanib ethanesulfonate suspension, and store at 2-8°C.

[0049] Example 6

[0050] Take dipalmitoylphosphatidylcholine and cholesterol, add anhydrous ethanol, stir at 70°C, keep warm, dipalmitoylphosphatidylcholine concentration 85mg / g, cholesterol concentration 28mg / g; take ammonium sulfate, add water for injection, stir at 70°C, keep warm, ammonium sulfate concentration 61.9mg / g; take nintedanib ethanesulfonate, add water for injection at 60°C to dissolve it, prepare a 6mg / ml solution, cool it for use; take mannitol, add water for injection to dissolve it, concentration 20 0mg / g; a phospholipid solution and an ammonium sulfate solution were mixed at 70°C using a microreactor, the flow rate of the phospholipid solution was 11ml / min, the flow rate of the ammonium sulfate solution was 89ml / min, and the mixture was kept at 70°C for 60min. Ethanol was removed by ultrafiltration using a tangential membrane and water for injection, and then the nintedanib ethanesulfonate solution was added in a volume ratio of 4:1 and mixed, and the mixture was kept at 60°C for 60min. A mannitol solution was added in a volume ratio of 5:1 to obtain a nintedanib ethanesulfonate suspension of 1mg / ml, which was stored at 2-8°C.

[0051] Example 7

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

[0053] Example 8

[0054] Take dipalmitoylphosphatidylcholine, phosphatidylethanolamine and cholesterol, add anhydrous ethanol, stir at 60°C, keep warm, dipalmitoylphosphatidylcholine concentration is 84 mg / g, phosphatidylethanolamine concentration is 1 mg / g, and cholesterol concentration is 28 mg / g; take ammonium sulfate, add water for injection, stir at 60°C, keep warm, and the concentration is 66 mg / g; take nintedanib ethanesulfonate, add water for injection and dissolve it at 60°C to prepare a 6 mg / ml solution, cool it for use; take mannitol, add Dissolve it with water for injection to a concentration of 300 mg / g; use a microreactor to mix the phospholipid material with an aqueous ammonium sulfate solution at 60°C, keep warm for 60 minutes, use a tangential membrane and water for injection to ultrafilter to remove ethanol, then add the nintedanib ethanesulfonate solution in a volume ratio of 4:1 and mix, keep at 60°C for 90 minutes, then add mannitol solution in a volume ratio of 5:1 to obtain a 1 mg / ml nintedanib ethanesulfonate suspension, filter through a 0.2um filter membrane, fill into a vial, seal, and store at 2-8°C.

[0055] Observe the physical state

[0056] The liposome sample prepared in Example 1 was stored overnight, and a precipitate was observed to form at the bottom. Figure 1 The liposome sample prepared in Example 2 is in a gel state after cooling, as shown in FIG. Figure 2 After being cooled and stored overnight, the liposome samples prepared in Examples 3 to 8 still maintained a uniform suspension state with fluidity.

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

[0058] The samples of Examples 3 to 8 were tested for particle size, pH value, and encapsulation efficiency, and the results are shown in Table 1. From the aspects of particle size, PI, pH value, content, and encapsulation efficiency, the nintedanib ethanesulfonate suspension prepared in Examples 3 to 8 had good quality, the product particle size was between 80 and 150 nm, the particle size distribution was narrow, and the liposomes of about 100 nm could easily penetrate biological barriers such as blood vessel walls and cell membranes. The pH value of the product was basically weakly acidic, and the irritation to the respiratory tract was small, which met the use requirements of atomization inhalation for the treatment of pulmonary fibrosis.

[0059] Table 1

[0060]

[0061] Stability testing

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

[0063] The salt environment of the human respiratory tract was simulated by adding physiological saline to further investigate the stability of the sample. The nintedanib ethanesulfonate solution and the nintedanib ethanesulfonate liposome suspension prepared in Example 7 were taken, and the concentration of nintedanib ethanesulfonate was controlled to be 1 mg / ml. An equal volume of 0.9% sodium chloride solution was added to each of them, and the solution stability was observed at room temperature.

[0064] The initial state of the nintedanib ethanesulfonate solution is a yellow clear solution. Figure 3 a; The initial state of the nintedanib ethylsulfonate liposome suspension of Example 7 is a stable yellow suspension, as shown in Figure 3 As shown in b. After adding an equal volume of 0.9% sodium chloride solution, the nintedanib ethanesulfonate solution is still a yellow clear solution, but a small amount of solid suspended matter appears, such as Figure 4 As shown in a; the nintedanib ethylsulfonate liposome suspension remained in a stable yellow suspension state just after adding an equal volume of 0.9% sodium chloride solution, and the color only slightly faded 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 suspended matter appeared in the nintedanib ethanesulfonate solution, such as Figure 5 As shown in a; after adding an equal volume of 0.9% sodium chloride solution and standing for a period of time, the state of the liposome suspension of nintedanib ethanesulfonate did not change significantly, and remained a stable yellow suspension, as shown in Figure 5 As shown in b.

[0065] The above results show that compared with the nintedanib ethanesulfonate solution directly dissolved in water, the nintedanib ethanesulfonate suspension prepared in the embodiment has significantly improved stability. This stability includes both the stability of the overall physical state of the preparation and the ability of the active ingredients of the drug to remain evenly distributed for a long time without precipitation or aggregation. The nintedanib ethanesulfonate suspension with excellent stability is essential for the effectiveness and safety of the drug during transportation, storage and final administration. In particular, for nintedanib ethanesulfonate that requires atomized inhalation to treat pulmonary fibrosis, it helps to effectively maintain the active ingredient in the lesion site, thereby improving the therapeutic effect.

[0066] In vitro release testing

[0067] 8 ml of the nintedanib ethanesulfonate suspension prepared in Example 7 was placed in a 200 ml volumetric flask, and the dissolution medium was added to the volume. The release rate was measured at 37°C at 0.5 h, 3 h, 6 h, 12 h, 18 h, and 24 h. The results are shown in FIG. Figure 6 As shown, the nintedanib esylate suspension showed a good sustained-release effect.

[0068] The above embodiments are exemplary, and their purpose is to illustrate the technical concept and features of the present invention so that people familiar with the technology in this field can understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a nintedanib suspension preparation, characterized in that: The following steps are involved: Step S1: dissolving phospholipids and cholesterol in an organic solvent at 50-70° C. and keeping the temperature to obtain solution A; Step S2: dissolving the inorganic salt in water for injection at 50-70° C. and keeping the temperature to obtain solution B; Step S3: dissolving nintedanib ethanesulfonate in water for injection to obtain solution C; Step S4: mixing solution A and solution B by microfluidics at 50-70° C. to obtain suspension E; Step S5: removing the organic solvent in the suspension E by tangential flow membrane filtration, then adding solution C, and keeping warm at 50-70° C. for a period of time; adding an osmotic pressure regulator as needed during the preparation process to make the final suspension physiologically isotonic, thereby obtaining the nintedanib suspension preparation.

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

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

4. The method for preparing the nintedanib suspension preparation according to claim 1, characterized in that: The inorganic salt used in step S2 is ammonium sulfate; and / or The osmotic pressure regulator is selected from: sucrose, lactose, trehalose, and mannitol.

5. The method for preparing the nintedanib suspension preparation 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 water phase with a flow rate of 40 ml / min to 90 ml / min.

6. The method for preparing the nintedanib suspension preparation according to any one of claims 1 to 5, 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 in a volume ratio of 2:1 to 5:

1.

7. A nintedanib suspension preparation, characterized in that: Used for treating pulmonary fibrosis; the nintedanib suspension preparation is a suspension of liposomes containing nintedanib ethanesulfonate, and the phospholipid material in the liposomes at least contains dipalmitoylphosphatidylcholine and cholesterol.

8. The nintedanib suspension preparation according to claim 7, characterized in that: The method is prepared according to any one of claims 1 to 6.

9. The nintedanib suspension preparation according to claim 8, characterized in that: The pH value of the suspension is in the range of 5-7, and the average particle size of the liposomes in the suspension is in the range of 80-150 nm.

10. Use of the nintedanib suspension preparation according to claim 8 or 9 in the treatment of pulmonary fibrosis, characterized in that: The nintedanib suspension preparation is atomized and directly acts on the patient's lungs through inhalation.

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