A nintedanib solution for inhalation and a method for preparing the same

Abstract

The present application provides a kind of nintedanib solution for inhalation and preparation method and application, the inhalation solution includes active substance, solvent and auxiliary material, the single dose specification of the inhalation solution is 1-5ml, and the active substance in single dose specification is 2.41-12.04mg / ml nintedanib ethanesulfonic acid;The solvent is sterile injection solution water;The auxiliary material includes isotonicity regulator and pH regulator and can also include antioxidant;The addition amount of the isotonicity regulator is to make the inhalation solution have the weight molal osmotic concentration of 240-400mOsmol / kg;The addition of the pH regulator is to make the pH value of the inhalation solution preparation 3.0-4.0.The inhalation nintedanib solution of the present application can provide a kind of nintedanib for inhalation with convenient, safe and effective, and good stability of drug dosage form and drug delivery system in combination with liquid atomization device.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical science, specifically relating to an inhaled nintedanib solution, its preparation method, and its application. Background Technology

[0002] Idiopathic pulmonary fibrosis (IPF) is a rare disease with an unknown etiology and poor prognosis, characterized by progressive fibrosis of the interstitial lung tissue leading to decreased lung volume and progressive pulmonary insufficiency. Studies have shown that smoking, dust exposure, certain viral infections (such as cytomegalovirus and Epstein-Barr virus), and gastroesophageal reflux are risk factors for IPF, and certain mutations in the telomerase gene may be associated with familial IPF. Statistics show that the global prevalence is approximately (2–29) per 100,000 people annually, and is showing a gradual increasing trend. On May 11, 2018, five departments, including the National Health Commission of my country, jointly formulated the "First Batch of Rare Disease Catalogues," which included idiopathic pulmonary fibrosis.

[0003] As a country with a severely aging population, my country is seeing a year-on-year increase in the number of people suffering from interstitial lung disease (IPF), conservatively estimated at at least 500,000. As a chronic interstitial lung disease, IPF has an insidious onset and gradually worsens, but can also manifest as acute exacerbations. The average survival time after IPF diagnosis is only 2.8 years, and the mortality rate is higher than that of most cancers; IPF is often referred to as a "tumor-like disease."

[0004] Nintedanib is a small-molecule tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim, Germany, for idiopathic pulmonary fibrosis (IPF). This drug has been shown to act on potentially influential growth factor receptors in the pathological mechanism of pulmonary fibrosis, most notably platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR). By blocking these signal transduction pathways involved in the fibrotic process, nintedanib is believed to slow the progression of IPF by reducing the rate of decline in lung function. Two existing global phase III clinical trials (the INPULSIS™-1 and INPULSIS™-2 studies) evaluated the efficacy and safety of nintedanib in treating IPF. The results of these studies were presented at the American Thoracic Society (ATS) Annual Meeting in May 2014 and published in the NEJM journal. Nintedanib is the first IPF-targeted therapy with consistent clinical evidence that it can slow the progression of IPF by significantly reducing the annual decline in lung function (by up to 50%).

[0005] Currently, the FDA-approved nintedanib dosage form is a capsule, with the original product available in 100mg and 150mg strengths. Its product information states that the absolute bioavailability is only 4.7%, with significant first-pass and transporter effects in the liver, and a high probability of gastrointestinal and hepatic side effects. Considering that IPF patients require long-term medication, the numerous adverse reactions of the oral capsule formulation limit the drug's applicability.

[0006] In summary, the nintedanib formulations disclosed in the prior art have certain defects. Therefore, developing a nintedanib formulation that can act directly on the lesion site, avoid the first-pass effect of the liver and the damage and degradation of the gastrointestinal tract, has low irritation, and has a simple preparation process is an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides an inhaled nintedanib solution formulation, its preparation method, and its application.

[0008] This invention aims to address the shortcomings of existing technologies to a certain extent, and provides the following technical solutions:

[0009] On one hand, the present invention provides an inhaled nintedanib solution comprising an active substance, a solvent, and excipients;

[0010] The inhalation solution has a single-dose strength of 1-5 ml, preferably 4-5 ml;

[0011] The single-dose inhalation solution contains 2.41–12.04 mg / ml nintedanib ethoxylate as the active ingredient, preferably 6.02–12.04 mg / ml nintedanib ethoxylate.

[0012] The solvent is sterile water for injection;

[0013] The excipients include isotonicity regulators and pH regulators;

[0014] The amount of the isotonic adjuster added is such that the inhalation solution has a weight molar osmotic concentration of 240–400 mOsmol / kg.

[0015] The amount of pH adjuster added is such that the pH value of the inhalation solution is 3.0 to 4.0;

[0016] The isotonicity regulator can be selected from propylene glycol or glycerin;

[0017] The pH adjuster may be selected from pharmaceutically acceptable inorganic bases;

[0018] The pharmaceutically acceptable inorganic base may be selected from sodium carbonate or sodium hydroxide;

[0019] The excipients may also include antioxidants;

[0020] The antioxidant is selected from one or more of vitamin C, cysteine ​​hydrochloride, and sodium bisulfite.

[0021] On the other hand, the present invention provides a method for preparing an inhaled nintedanib solution, comprising the following steps:

[0022] (1) Measure out 60% to 80% of the total volume of the solvent required to prepare the solution to obtain the first solution;

[0023] (2) Under the condition of controlling the temperature of the first solution to be 40℃~70℃, nidanib ethanesulfonic acid is brought into contact with the first solution and stirred evenly to obtain the second solution;

[0024] Preferably, under the condition that the temperature of the first solution is controlled at 50℃~70℃, nitrogen gas is introduced throughout the subsequent process to remove oxygen and to avoid light, and nintedanib ethanesulfonic acid is brought into contact with the first solution and stirred evenly to obtain the second solution;

[0025] (3) The osmotic pressure regulator is brought into contact with the second solution and stirred to dissolve it, thus obtaining the third solution;

[0026] Preferably, the osmotic pressure regulator and the antioxidant are contacted with the second solution and stirred to dissolve, thus obtaining a third solution;

[0027] (4) Contact the pH adjuster with the third solution, stir evenly, and adjust the pH of the solution to 3-4 to obtain the fourth solution;

[0028] (5) The remaining solvent is brought into contact with the fourth solution and stirred until homogeneous to obtain the fifth solution, which is then filtered using a 0.22 μm filter membrane or filter cartridge;

[0029] (6) Fill into 1-5 ml ampoules and seal; preferably fill into 4-5 ml ampoules and seal.

[0030] On another aspect: The present invention provides an inhalation system for nebulizing nintedanib solution into the human respiratory tract, comprising 1 ml to 5 ml of nintedanib solution for inhalation and a liquid nebulizer;

[0031] The airflow pressure of the liquid atomizing device is 5 bar;

[0032] The flow rate of the liquid atomizing device is (15±0.75) L / min;

[0033] The inhaled nintedanib solution is atomized into an aerosol using a liquid atomizing device.

[0034] The delivery rate of the active ingredient in the atomized aerosol is >2 mg / min;

[0035] The atomized aerosol delivery rate is >70%;

[0036] The fine particle fraction (FPF) in the atomized aerosol NGI is >60%;

[0037] The atomized aerosol droplets have a particle size distribution of 1–6 μm.

[0038] The beneficial effects of this invention are:

[0039] 1. This invention provides a nintedanib inhalation solution, which improves the stability of the solution by adding an antioxidant and using a nitrogen-filling process; the addition of an isotonic regulator reduces the irritation to the respiratory mucosa, increases compliance, and makes the formulation safer; the nintedanib inhalation solution has good solubility and stability within the pH range of this application.

[0040] 2. This invention provides a stable nintedanib inhalation solution, administered via the lungs. Lung administration allows the drug to reach the target organ directly through the respiratory tract, enabling rapid onset of action, avoiding the first-pass effect, and significantly improving bioavailability. Therefore, it can reduce the dosage and thus alleviate the economic burden on patients.

[0041] 3. The preparation process of the nintedanib inhalation solution provided by the present invention controls the appropriate solution temperature to ensure that the active ingredient has a suitable dissolution rate in the solvent; the use of filtration sterilization process ensures the sterility level of the product while further improving the stability of the formulation, resulting in reliable quality, simple operation, easy control, and suitability for large-scale production.

[0042] 4. This invention provides a nebulized drug delivery system for inhaled nintedanib solution. By controlling the airflow pressure, flow rate, and delivery rate, total amount, and particle size distribution of the active ingredient in the aerosol from the nebulizing aerosol device, the drug solution can be precisely controlled to form aerosol droplets with a uniform particle size distribution within the optimal range of 1-6 μm for lung inhalation. This ensures that sufficient drug solution is absorbed by the lungs, thereby exerting the corresponding pharmacological effect. This allows for precise adjustment of the dosage of nintedanib inhalation solution. Detailed Implementation

[0043] To better illustrate the present invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. The following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Any equivalent substitutions made in accordance with the content of this invention are within the scope of protection of this invention.

[0044] The following describes the components constituting the nintedanib inhalation solution of the present invention.

[0045] Experiment 1: Investigation at different pH values

[0046] With the same formulation, the effect of different solution pH values ​​on sample quality was investigated. The formulation composition is as follows:

[0047] name composition Nintanib ethanesulfonate 6.02g 1M sodium hydroxide solution Add appropriate amounts to adjust the pH to 3.0, 4.0, 5.0, and 6.0. Propylene glycol 23g Add water for injection to 1000ml

[0048] Measure 800 ml of water for injection at room temperature (80% of the prescription amount), then add nintedanib ethanesulfonate and propylene glycol, continue stirring to dissolve, add 1M sodium hydroxide solution to adjust the pH value to the target value, stir evenly, add solvent to make up the total volume, filter with a 0.22μm filter membrane or filter cartridge, fill into 5 ml ampoules, seal, and the product is ready.

[0049] Table 1. Stability of solutions at different pH values

[0050]

[0051] Table 1 shows that the amount of impurities in the samples is not significantly different when the pH value is within the range of 3.0 to 6.0, as determined by the total amount of related substances. However, when the pH value is greater than 5.0, the solution becomes turbid, indicating that nintedanib ethanesulfonate precipitates under this pH condition, meaning its solubility decreases. Therefore, the pH value range of 3.0 to 4.0 was selected.

[0052] Experimental Example 2: Investigation of Nitrogen Protection Process and Different Antioxidants

[0053] Based on the formulation in Experimental Example 1, the stability of the samples was investigated under conditions with and without antioxidants and / or nitrogen flushing protection, and the types of antioxidants were screened.

[0054] Table 2. Investigation of Nitrogen Protection Process and Antioxidants

[0055]

[0056]

[0057] Table 2 shows that during solution preparation, the total impurities were relatively high without nitrogen protection and antioxidants, indicating that the active ingredient is sensitive to oxygen and easily oxidized and deteriorates. Using nitrogen purging alone or adding antioxidants effectively suppressed the growth of impurities; using antioxidants while simultaneously purging with nitrogen protection suppressed impurity growth and prevented the antioxidants from being rapidly consumed by oxygen. Regarding the screening of different antioxidants, as shown in Table 2, the growth of impurities was still relatively rapid even with the addition of sodium metabisulfite solution, indicating that sodium metabisulfite is not suitable as an antioxidant for nintedanib ethanesulfonate solution.

[0058] Experimental Example 3: Investigation of Isotonic Conditioners

[0059] Based on the prescription in Experimental Example 1, different types of isotonic modifiers were selected, and the prescription composition is as follows:

[0060]

[0061] The effects of different isotonic conditioners on sample stability were investigated, and related substances in the samples were detected. The results are shown in Table 3.

[0062] Table 3. Stability assessment of samples by different isotonic conditioners.

[0063]

[0064] Table 3 shows that sodium chloride cannot dissolve in nitedanib ethanesulfonic acid solution and will cause a significant increase in solution viscosity. Therefore, sodium chloride is not suitable as an osmotic pressure regulator in nitedanib solution. Propylene glycol and glycerin do not affect the product properties and the solution still has good stability after 5 days of storage, so they can be selected as osmotic pressure regulators.

[0065] Experimental Example 4: Investigation of pH Adjusters

[0066] Based on the formulation in Experimental Example 1, different types of pH adjusters were selected to examine the stability of the samples. Related substances were tested on the samples, and the results are shown in Table 4.

[0067] Table 4. Investigation of different types of pH adjusters

[0068]

[0069] Table 4 shows that when citrate and phosphate are used as pH adjusters, the related substances in the solution increase rapidly, indicating that the two substances have poor compatibility with nintedanib and should not be used. Therefore, sodium hydroxide or sodium carbonate should be chosen as the pH adjuster.

[0070] Experiment 5: Investigation of different solution preparation temperatures

[0071] Based on the formulation in Experimental Example 1, the solubility at different solution preparation temperatures was investigated. After incubation for 6 hours, the total amount of related substances in the sample was measured to assess stability. The results are shown in Table 5.

[0072] Table 5. Effects of different solution temperatures on dissolution time and stability.

[0073] Solution preparation temperature Properties Dissolution time Total amount of relevant substances (%) 30℃ Yellow clear liquid 70min 0.938 40℃ Yellow clear liquid 40min 0.952 50℃ Yellow clear liquid 20min 0.955 70℃ Yellow clear liquid 10min 1.153 90℃ Yellow clear liquid 9min 1.505

[0074] Table 5 shows that when the solution preparation temperature is 40℃, the dissolution time is significantly shorter than that at 30℃, and the content of related substances does not increase significantly. When the solution preparation temperature is increased to 90℃, the dissolution time is not significantly shorter than that at 70℃, and the content of related substances increases more rapidly. Therefore, the solution preparation temperature is selected to be 40℃~70℃.

[0075] The present invention will now be described in detail with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0076] Example 1

[0077] name composition Nintanib ethanesulfonate 6.02g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 3.0. Propylene glycol 23g Add water for injection to 1000ml

[0078] Preparation method:

[0079] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 40°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and propylene glycol, continue stirring to dissolve, add 1M sodium hydroxide solution to adjust the pH to 3.0, stir evenly, then add solvent to make up the total volume, filter with a 0.22 μm filter membrane or filter cartridge, fill into 5 ml ampoules, seal, and the product is ready.

[0080] Example 2

[0081] name composition Nintanib ethanesulfonate 6.02g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 3.2. Propylene glycol 23g Add water for injection to 1000ml

[0082] Preparation method:

[0083] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 50°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and continue stirring to dissolve it. Then add propylene glycol and continue stirring to mix evenly. Add 1M sodium hydroxide solution to adjust the pH to 3.2, stir evenly, and then add solvent to make up the total volume. Filter with a 0.22 μm filter membrane or filter cartridge, fill into 5 ml ampoules, and seal.

[0084] Example 3

[0085] name composition Nintanib ethanesulfonate 6.02g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 3.5. Propylene glycol 23g Add water for injection to 1000ml

[0086] Preparation method:

[0087] Take 600 ml of water for injection at room temperature (60% of the prescription amount), heat it to 60°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and continue stirring to dissolve it. Then add propylene glycol and continue stirring to mix evenly. Add 1M sodium hydroxide solution to adjust the pH to 3.5, stir evenly, and then add solvent to make up the total volume. Filter with a 0.22 μm filter membrane or filter cartridge, fill into 2 ml ampoules, and seal.

[0088] Example 4

[0089] name composition Nintanib ethanesulfonate 6.02g 1M sodium carbonate solution Add an appropriate amount and adjust the pH to 3.8. Propylene glycol 23g Add water for injection to 1000ml

[0090] Preparation method:

[0091] Take 700 ml of water for injection at room temperature (70% of the prescription amount), heat it to 70°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and continue stirring to dissolve it. Then add propylene glycol and continue stirring to mix evenly. Add 1M sodium carbonate solution to adjust the pH to 3.8, stir evenly, and then add solvent to make up the total volume. Filter with a 0.22 μm filter membrane or filter cartridge, fill into 5 ml ampoules, and seal.

[0092] Example 5

[0093] name composition Nintanib ethanesulfonate 6.02g glycerin 15g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 4.0. Add water for injection to 1000ml

[0094] Preparation method:

[0095] Take 750 ml of water for injection at room temperature (75% of the prescription amount), heat it to 65°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and continue stirring to dissolve it. Then add glycerin and continue stirring to mix evenly. Add 1M sodium hydroxide solution to adjust the pH to 4.0, stir evenly, and then add solvent to make up the total volume. Filter with a 0.22 μm filter membrane or filter cartridge, fill into 4 ml ampoules, and seal.

[0096] Example 6

[0097] name composition Nintanib ethanesulfonate 6.02g Propylene glycol 23g Sodium bisulfite 2g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 4.0. Add water for injection to 1000ml

[0098] Preparation method:

[0099] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 55°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and continue stirring to dissolve. Next, add propylene glycol and sodium bisulfite and continue stirring to dissolve. Add 1M sodium hydroxide solution to adjust the pH to 4.0, stir evenly, and then add solvent to make up the total volume. Filter through a 0.22 μm filter membrane or filter cartridge, fill into 5 ml ampoules, and seal.

[0100] Example 7

[0101] name composition Nintanib ethanesulfonate 6.02g Propylene glycol 23g Cysteine ​​hydrochloride 2g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 4.0. Add water for injection to 1000ml

[0102] Preparation method:

[0103] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 50°C, purge with nitrogen for 1 hour, then add nintedanib ethanesulfonate and continue stirring to dissolve. Next, add propylene glycol and cysteine ​​hydrochloride and continue stirring to dissolve. Add 1M sodium hydroxide solution to adjust the pH to 4.0, stir evenly, and then add solvent to make up the total volume. Filter with a 0.22 μm filter membrane or filter cartridge, fill into 5 ml ampoules, and seal.

[0104] Example 8

[0105] name composition Nintanib ethanesulfonate 6.02g Propylene glycol 23g Vitamin C 2g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 4.0. Add water for injection to 1000ml

[0106] Preparation method:

[0107] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 60°C, purge with nitrogen for 1 hour, then add nintedanib ethoxylate and continue stirring until dissolved. Next, add vitamin C and continue stirring until dissolved. Add 1 M sodium hydroxide solution to adjust the pH to 4.0, stir well, and then add solvent to make up the total volume. Filter with a 0.22 μm filter membrane or filter cartridge, fill into 5 ml ampoules, and seal.

[0108] Example 9

[0109] name composition Nintanib ethanesulfonate 12.04g 1M sodium hydroxide solution Add an appropriate amount and adjust the pH to 4.0. Propylene glycol 23g Vitamin C 2g Add water for injection to 1000ml

[0110] Preparation method:

[0111] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 50°C, then add nintedanib ethanesulfonate and continue stirring to dissolve it. Then add propylene glycol and vitamin C and continue stirring to dissolve it. Add 1M sodium hydroxide solution to adjust the pH to 4.0, stir well, and then add solvent to make up the total volume. Filter it through a 0.22 μm filter membrane or filter cartridge, fill it into 5 ml ampoules, and seal it.

[0112] Example 10

[0113]

[0114]

[0115] Preparation method:

[0116] Take 800 ml of water for injection at room temperature (80% of the prescription amount), heat it to 70°C, then add nintedanib ethanesulfonate and continue stirring to dissolve it. Then add propylene glycol and cysteine ​​hydrochloride and continue stirring to dissolve it. Add 1M sodium hydroxide solution to adjust the pH to 4.0, stir well, and then add solvent to make up the total volume. Filter it through a 0.22 μm filter membrane or filter cartridge, fill it into 5 ml ampoules, and seal it.

[0117] Example 11 Aerodynamic Atomized Particle Size Measurement

[0118] The atomized particle size of the samples in each embodiment was measured using a new Partek particle size analyzer. The results are as follows:

[0119] Table 6. Measurement of Aerodynamic Atomized Particle Size

[0120]

[0121] As shown in Table 6, the atomized particle size X of the nintedanib ethanesulfonic acid solution in each embodiment of this application is... 50 All are between 2 and 4 μm, X 84 <6μm, meeting the aerodynamic parameter requirements of atomized formulations.

[0122] Example 12 Comparison of different atomizing devices

[0123] The sample from Example 1 was atomized using atomizers of different brands, and the atomization results are shown in Table 7.

[0124] Table 7. Evaluation of Atomization Effects of Different Atomizing Devices

[0125] Atomizer Brands 3-minute atomization rate % 5-minute atomization rate % 8-minute atomization rate % Bairui 52.09±0.78 76.31±0.53 86.77±0.36 Omron 52.19±1.10 73.52±1.23 85.69±1.22 Yinghua Rongtai 52.55±0.67 69.59±1.54 77.31±1.90

[0126] Note: Three sets of data were continuously and parallelly examined for each brand of atomizer.

[0127] As shown in Table 7, after a total of 8 minutes of atomization using three different brands of atomizers, the atomization rate reached over 70%.

[0128] Example 13 Atomization Performance Measurement - Delivery Rate and Total Delivery

[0129] Using an Omron NEU22 nebulizer (compressed air nebulization), inhaled nintedanib (nebulization volume as per sample specifications) from Examples 1-10 were taken and placed in a pre-weighed nebulizer. After precise weighing, nebulization was initiated until no more mist was released, and the nebulizer was weighed again. Delivery rate, total delivery volume, aerosol loss, nebulizer cup residue, equilibrium recovery rate, and output drug volume were calculated. The results are as follows:

[0130] Table 8. Atomization Performance Measurement of Each Example - Delivery Rate and Total Delivery Amount

[0131]

[0132] Note: Each set of sample samples was measured in three parallel trials.

[0133] As shown in Table 8: 1) With a fixed atomizing model and using the atomizing pressure and flow rate controlled by this application, the sample of the example has good atomization performance and high durability. There is no significant difference in delivery rate and total delivery volume among the samples of Examples 1 to 10; 2) The sample filling specifications of different examples are different. Except for the time required for complete atomization, there is no difference in atomization performance; 3) Under the atomization parameters protected in this application, the total delivery volume of the inhaled nintedanib solution is high and the residual amount in the atomizing cup is low.

[0134] Example 14 Atomization Performance Measurement - Fine Particle Dosage

[0135] Using an Omron NEU22 nebulizer (compressed air nebulization), inhalation nintedanib solutions (nebulization volume as sample size) from Examples 1 to 10 were placed in the nebulizer. The FPF% and MMAD values ​​of the examples were determined using NGI at the set airflow pressure (5 bar) and flow rate (15 ± 0.75 L / min). The results are shown in Table 9.

[0136] Table 9. Atomization Performance Measurement - Microparticle Dosage Study

[0137]

[0138] Note: Each set of sample samples was measured in three parallel trials.

[0139] As shown in Table 9, the nitedanib ethoxylate solutions prepared according to Examples 1-10 of this application, when atomized according to the set parameters, have a fine particle fraction (FPF%) > 60% and a particle size distribution between 1-6 μm, all of which meet the requirements for atomized inhalation solutions.

[0140] Example 15 Stability Study

[0141] Inhalation solution samples were prepared according to Examples 1-10 of this application, and the samples were simultaneously released for stability factor determination. The results are shown in the table below:

[0142] Table 10 Stability test data for samples from each embodiment

[0143]

[0144]

[0145] Based on the stability and nebulized output drug content (%) determination results of each embodiment in Table 10, it can be seen that the inhaled nintedanib solution prepared under the formulation composition and preparation process conditions protected in this application has stable quality, the total amount of related substances is <2.0%, and the nebulized output drug content of the inhaled nintedanib solution using the nebulization parameters and specific equipment protected in this patent is >70%.

Claims

1. A nintedanib inhalation solution, characterized in that, It contains an active substance, a solvent, and excipients, wherein the active substance is nintedanib ethanesulfonate, and the excipients include an isotonic adjuster and a pH adjuster.

2. The nintedanib inhalation solution according to claim 1, characterized in that, The single-dose specification of the inhalation solution is 1-5 ml, preferably 4-5 ml.

3. The inhaled nintedanib solution according to claim 1, wherein the single-dose specification of the inhaled solution contains 2.41 to 12.04 mg / ml of nintedanib ethanesulfonate as the active ingredient, preferably 6.02 to 12.04 mg / ml of nintedanib ethanesulfonate.

4. The nintedanib inhalation solution according to claim 1, wherein the solvent is sterile water for injection.

5. The nintedanib inhalation solution according to claim 1, characterized in that, The amount of isotonic adjuster added is such that the inhalation solution has a weight molar osmotic concentration of 240–400 mOsmol / kg, and the isotonic adjuster may be selected from propylene glycol or glycerol.

6. The nintedanib inhalation solution according to claim 1, characterized in that, The amount of pH adjuster added is such that the pH value of the inhalation solution is 3.0 to 4.

0. The pH adjuster may be selected from pharmaceutically acceptable inorganic bases, which may be selected from sodium carbonate or sodium hydroxide.

7. The nintedanib inhalation solution according to claim 1, characterized in that, The excipients may also include antioxidants.

8. The nintedanib inhalation solution according to claim 7, characterized in that, The antioxidant is selected from one or more of vitamin C, cysteine ​​hydrochloride, and sodium bisulfite.

9. The method for preparing an inhaled nintedanib solution according to any one of claims 1-8, characterized in that, Includes the following steps: (1) Measure out 60% to 80% of the total volume of the solvent required to prepare the solution to obtain the first solution; (2) Under the condition of controlling the temperature of the first solution to be 40℃~70℃, nydanib is brought into contact with the first solution and stirred evenly to obtain the second solution; Preferably, under the condition that the temperature of the first solution is controlled at 50℃~70℃, nitrogen gas is introduced throughout the subsequent process to remove oxygen and to avoid light, and nintedanib is brought into contact with the first solution and stirred evenly to obtain the second solution; (3) The osmotic pressure regulator is brought into contact with the second solution and stirred to dissolve it, thus obtaining the third solution; Preferably, the osmotic pressure regulator and the antioxidant are contacted with the second solution and stirred to dissolve, thus obtaining a third solution; (4) Contact the pH adjuster with the third solution, stir evenly, and adjust the pH of the solution to 3-4 to obtain the fourth solution; (5) The remaining solvent is brought into contact with the fourth solution and stirred until homogeneous to obtain the fifth solution, which is then filtered using a 0.22 μm filter membrane or filter cartridge; (6) Fill into 1-5 ml ampoules and seal; preferably fill into 4-5 ml ampoules and seal.

10. An inhalation system for nebulizing nintedanib solution for inhalation into the human respiratory tract, characterized in that, Includes 1ml-5ml nintedanib inhalation solution and liquid nebulizer. The airflow pressure of the liquid atomizing device is 5 bar; The flow rate of the liquid atomizing device is (15±0.75) L / min; The inhaled nintedanib solution is atomized into an aerosol using a liquid atomizing device. The delivery rate of the active ingredient in the atomized aerosol is >2 mg / min; The atomized aerosol delivery rate is >70%; The fine particle fraction (FPF) in the atomized aerosol NGI is >60%; The atomized aerosol droplets have a particle size distribution of 1–6 μm.