A pressurized metered dose inhaler of nintedanib solution and a preparation method thereof

Abstract

The application discloses a nintedanib solution type pressurized metered dose inhalation aerosol and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, which comprises an active ingredient, the active ingredient being nintedanib; a pharmaceutically acceptable cosolvent; a pharmaceutically acceptable propellant; a pressure-resistant container and a valve system; and the preparation method is as follows: controlling the relative humidity of an environment to be less than or equal to 65%, dissolving the nintedanib in the cosolvent to form a drug-containing solution A; adding the drug-containing solution A into the pressure-resistant container, installing a metering valve, sealing, filling the propellant, and preparing the inhalation aerosol; the application accurately controls the dose delivered each time through the metering valve, and the active ingredient is completely dissolved in the preparation as a uniform solution, so that the uniformity and accuracy of the delivered dose are ensured, and the dose uncertainty caused by artificial factors or improper operation of a patient is avoided; and the problems of dose fluctuation of an existing inhalation solution and dependence of an inhalation powder aerosol on an inhalation technique of a patient are solved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a nintedanib solution-type pressurized metered-dose inhaler and its preparation method. Background Technology

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by repeated minor damage to alveolar epithelial cells, leading to abnormal fibrosis in the lung tissue, resulting in pulmonary insufficiency and ultimately manifesting as progressively worsening dyspnea. The disease has an insidious onset, and most patients are diagnosed at an advanced stage. Even with treatment, the condition continues to deteriorate, resulting in a poor prognosis.

[0003] Currently, nintedanib ethsylate is one of the effective drugs for treating idiopathic pulmonary fibrosis, and its commercially available dosage form is an oral soft capsule. However, the bioavailability of nintedanib administered orally is extremely low, only about 4.7%, and it is often accompanied by serious gastrointestinal adverse reactions, including diarrhea, nausea, vomiting, abdominal pain, loss of appetite, and weight loss. These adverse reactions severely limit patient adherence and clinical efficacy.

[0004] To overcome the limitations of oral administration, inhalation has become an important direction in the development of nintedanib formulations. Inhalation delivers the drug directly to the lungs, reducing systemic drug exposure even at lower doses. Furthermore, airway narrowing is common in patients with idiopathic pulmonary fibrosis, leading to reduced inspiratory flow rate, which may decrease drug deposition in the lungs. Therefore, pressurized metered-dose inhalers can partially compensate for insufficient inspiratory flow rate by increasing the initial inhalation velocity, thereby improving drug deposition in the lungs. Based on this, pressurized metered-dose inhalers containing nintedanib have become an ideal treatment option for patients with idiopathic pulmonary fibrosis.

[0005] Pressurized metered-dose inhalers rely on propellant pressure to deliver medication without any external power, making them particularly suitable for patients with idiopathic pulmonary fibrosis who have impaired lung function. At the same time, their metering valve allows for precise control of the dose delivered each time, resulting in better dosage accuracy than other inhaled formulations.

[0006] Several nintedanib inhalation formulations have been disclosed in the prior art, but no technical solution for formulating nintedanib into a solution-type pressurized metered-dose inhaler (DPI) has been found. Although some literature mentions the concept of "aerosol delivery" in general, these all refer to the aerosol delivery of dry powder compositions, not pressurized metered-dose inhalers. This formulation relies on the patient's inhalation drive, and for IPF patients with impaired lung function, insufficient inspiratory flow rate may lead to low drug delivery efficiency. In addition, the dry powder preparation process of DPIs is difficult, requiring high control over the particle size distribution of the active ingredient. Furthermore, inhaled solutions require squeezing the solution into the nebulizer cup, and the amount squeezed each time varies from person to person, which may lead to fluctuations in dosage. Moreover, nebulizers are required for administration, but nebulizers are not portable and the single administration time is relatively long. Therefore, developing a convenient, accurate, stable, and highly efficient nintedanib solution-type pressurized metered-dose inhaler has significant clinical significance and market value. Summary of the Invention

[0007] The purpose of this invention is to provide a nintedanib solution-type pressurized metered-dose inhaler and its preparation method, in order to solve the problems of inaccurate dosage and inconvenient use of inhaled solution in the prior art, as well as low drug delivery efficiency and high difficulty in preparation process of inhaled powder inhaler.

[0008] To achieve the above objectives, the present invention provides the following technical solution: a nintedanib solution-type pressurized metered-dose inhaler, comprising:

[0009] Active ingredients;

[0010] Pharmaceutically acceptable solubilizer;

[0011] Pharmaceutically acceptable propellants;

[0012] Pressure vessels and valve systems;

[0013] The inhaled aerosol is a solution-type pressurized metered-dose inhaler, the active ingredient is nintedanib, and the active ingredient is dissolved in a mixture containing a cosolvent and a propellant. The sum of the contents of the active ingredient, cosolvent, and propellant is 100% by weight.

[0014] Furthermore, the active ingredient is nintedanib ethanesulfonate; the content of nintedanib ethanesulfonate is 0.1% to 2% (w / w) of the total weight of the inhaled aerosol solution.

[0015] Furthermore, the co-solvent is at least one of propylene glycol, ethanol, and glycerol.

[0016] Furthermore, the content of the cosolvent is 20% to 50% (w / w) of the total weight of the inhaled aerosol solution.

[0017] Furthermore, the cosolvent is a mixture of anhydrous ethanol and propylene glycol in a 1:1 weight ratio or glycerol.

[0018] Furthermore, the propellant is 1,1,1,2-tetrafluoroethane, and its content is 48.0% to 79.9% (w / w) of the total weight of the inhaled aerosol solution.

[0019] Furthermore, the pressure-resistant container has a capacity of 10ml to 20ml, and the valve system is a metering valve, wherein each press of the metering valve delivers a volume of liquid medicine of 40 to 150μl.

[0020] This invention also discloses a method for preparing a nintedanib solution-type pressurized metered-dose inhaler, which is used to prepare the aforementioned nintedanib solution-type pressurized metered-dose inhaler. The preparation method specifically includes the following steps:

[0021] S1. Control the relative humidity of the environment to ≤65%, dissolve nintedanib in a co-solvent to form a drug-containing solution A;

[0022] S2. Add the drug-containing solution A into a pressure-resistant container, install a metering valve, seal the container, and fill it with propellant to obtain an inhalation aerosol.

[0023] Compared with the prior art, the nintedanib solution-type pressurized metered-dose inhaler and its preparation method provided by the present invention have the following beneficial effects:

[0024] (1) The present invention uses pressurized metered inhalation aerosol, which relies on propellant pressure to drive the administration of the drug. No external power or equipment is required. The patient can complete the administration by pressing the button, realizing "ready to use". It is convenient to use and solves the problem that existing inhalation solutions require the use of a nebulizer and have poor portability.

[0025] (2) The present invention precisely controls the delivery dose each time through a metering valve, and the active ingredient is completely dissolved in the formulation into a homogeneous solution, which ensures the uniformity and accuracy of the delivery dose and avoids the dose uncertainty caused by human factors or improper operation by the patient; it solves the problems of dose fluctuation of existing inhaled solutions and dependence of inhaled powder on the patient's inhalation technique.

[0026] (3) By selecting a suitable propellant and cosolvent system, the present invention achieves a fine particle fraction of more than 50%, ensuring a high delivery efficiency and enabling efficient lung-targeted delivery, thus solving the problem of low delivery efficiency of inhaled powder aerosols in patients with impaired lung function.

[0027] (4) By selecting a suitable propellant and cosolvent system, the active ingredient can be completely dissolved without the need for special control of the particle size of nintedanib raw material, which significantly reduces the difficulty of the process and is conducive to industrial scale-up production.

[0028] (5) The present invention provides a nintedanib solution-type pressurized metered inhalation aerosol, which overcomes the technical obstacles of existing solution-type pMDI and fills the current technical gap of no such dosage form. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this invention. For those skilled in the art, other drawings can be obtained based on these drawings.

[0030] Figure 1 A flowchart illustrating a method for preparing a nintedanib solution-type pressurized metered-dose inhaler, provided in an embodiment of the present invention. Detailed Implementation

[0031] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0032] Example 1:

[0033] Please see Figure 1 A nintedanib solution-type pressurized metered-dose inhaler, composed of the following components:

[0034] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.6% (w / w) of the total weight of the inhaled aerosol solution;

[0035] Pharmaceutically acceptable cosolvent: The cosolvent is a mixture of anhydrous ethanol and propylene glycol in a 1:1 weight ratio, and its content is 40% (w / w) of the total weight of the inhaled aerosol solution;

[0036] Pharmaceutically acceptable propellant: The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 59.4% (w / w) of the total weight of the inhaled aerosol solution;

[0037] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0038] The inhaled aerosol is a solution-type pressurized metered-dose inhaler. The active ingredient passes through a 0.22μm filter membrane without residue and is completely dissolved in a mixture containing a cosolvent and a propellant, resulting in a bright yellow, clear solution. By weight percentage, the sum of the contents of the active ingredient, cosolvent, and propellant is 100%.

[0039] Its preparation method specifically includes the following steps:

[0040] S1. Control the relative humidity of the environment to ≤65%, dissolve nintedanib in a co-solvent to form a drug-containing solution A;

[0041] The specific implementation method is as follows: control the relative humidity of the environment to ≤65% (in order to effectively avoid the adverse effects of moisture on drug solubility and formulation stability), combine ethanol and propylene glycol in a 1:1 ratio, mix them evenly to obtain a mixed solution; then add nintedanib ethanesulfonate to the mixed solution, stir to dissolve, and obtain drug-containing solution A.

[0042] S2. Add the drug-containing solution A into a pressure-resistant container, install a metering valve, seal the container, and fill it with propellant to obtain an inhalation aerosol.

[0043] The specific implementation method is as follows: Drug-containing solution A is added to a 14ml pressure-resistant container, a 100μl metering valve is installed and sealed, and 1,1,1,2-tetrafluoroethane (HFA-134a) is filled to 12g to obtain an inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.6%, the ethanol / propylene glycol content is 40%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 59.4%. Each actuation measure: 600μg of nintedanib isosulfate.

[0044] Example 2:

[0045] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1: a nintedanib solution-type pressurized metered-dose inhaler, composed of the following components:

[0046] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 2% (w / w) of the total weight of the inhaled aerosol solution;

[0047] Pharmaceutically acceptable cosolvent: The cosolvent is a mixture of anhydrous ethanol and propylene glycol in a 1:1 weight ratio, and its content is 50% (w / w) of the total weight of the inhaled aerosol solution;

[0048] Pharmaceutically acceptable propellant: The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 48% (w / w) of the total weight of the inhaled aerosol solution;

[0049] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0050] The inhaled aerosol is a solution-type pressurized metered-dose inhaler. The active ingredient passes through a 0.22μm filter membrane without residue and is completely dissolved in a mixture containing a cosolvent and a propellant, resulting in a bright yellow, clear solution. By weight percentage, the sum of the contents of the active ingredient, cosolvent, and propellant is 100%.

[0051] Its preparation method specifically includes the following steps:

[0052] S1. Control the relative humidity of the environment to ≤65%, combine ethanol and propylene glycol in a 1:1 ratio, mix them evenly to obtain a mixed solution; then add nintedanib ethanesulfonate to the mixed solution, stir to dissolve, and obtain drug-containing solution A.

[0053] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal the container, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12g to obtain an inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 2%, the ethanol / propylene glycol content is 50%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 48%. Each actuation: nintedanib is 2.4mg.

[0054] Example 3:

[0055] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1: a nintedanib solution-type pressurized metered-dose inhaler, composed of the following components:

[0056] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.1% (w / w) of the total weight of the inhaled aerosol solution;

[0057] Pharmaceutically acceptable cosolvent: The cosolvent is a mixture of anhydrous ethanol and propylene glycol in a 1:1 weight ratio, and its content is 20% (w / w) of the total weight of the inhaled aerosol solution;

[0058] Pharmaceutically acceptable propellant: The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 79.9% (w / w) of the total weight of the inhaled aerosol solution;

[0059] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0060] The inhaled aerosol is a solution-type pressurized metered-dose inhaler. The active ingredient passes through a 0.22μm filter membrane without residue and is completely dissolved in a mixture containing a cosolvent and a propellant, resulting in a bright yellow, clear solution. By weight percentage, the sum of the contents of the active ingredient, cosolvent, and propellant is 100%.

[0061] Its preparation method specifically includes the following steps:

[0062] S1. Control the relative humidity of the environment to ≤65%, combine ethanol and propylene glycol in a 1:1 ratio, mix them evenly to obtain a mixed solution; then add nintedanib ethanesulfonate to the mixed solution, stir to dissolve, and obtain drug-containing solution A.

[0063] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal the container, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12g to obtain an inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.1%, the ethanol / propylene glycol content is 20%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 79.9%. Each actuation measure: 120μg nintedanib isosulfate.

[0064] The inhalation aerosols prepared in Examples 1 to 3 were analyzed for their properties, moisture content, and related substances. The results are shown in Table 1. As can be seen from Table 1, the formulations with different nintedanib concentrations all produced bright yellow, clear solutions with a moisture content not exceeding 0.2%, and no significant differences in related substances.

[0065] Table 1. Prescriptions with different concentrations of active ingredients

[0066]

[0067] Example 4:

[0068] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1: a nintedanib solution-type pressurized metered-dose inhaler, composed of the following components:

[0069] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.3% (w / w) of the total weight of the inhaled aerosol solution;

[0070] Pharmaceutically acceptable solubilizer: The solubilizer is glycerin, and its content is 30% (w / w) of the total weight of the inhaled aerosol solution;

[0071] Pharmaceutically acceptable propellant: The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 69.7% (w / w) of the total weight of the inhaled aerosol solution;

[0072] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0073] The inhaled aerosol is a solution-type pressurized metered-dose inhaler. The active ingredient passes through a 0.22μm filter membrane without residue and is completely dissolved in a mixture containing a cosolvent and a propellant, resulting in a bright yellow, clear solution. By weight percentage, the sum of the contents of the active ingredient, cosolvent, and propellant is 100%.

[0074] Its preparation method specifically includes the following steps:

[0075] S1. Control the relative humidity of the environment to ≤65%, mix nintedanib ethanesulfonate with glycerin, stir to dissolve, and obtain drug-containing solution A.

[0076] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal it, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12.0g to obtain the inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.3%, the glycerin content is 30%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 69.7%. Each actuation measure: 600μg of nintedanib isosulfate.

[0077] Example 5:

[0078] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1: a nintedanib solution-type pressurized metered-dose inhaler, composed of the following components:

[0079] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.3% (w / w) of the total weight of the inhaled aerosol solution;

[0080] Pharmaceutically acceptable cosolvent: The cosolvent is ethanol, and its content is 50% (w / w) of the total weight of the inhaled aerosol solution;

[0081] Pharmaceutically acceptable propellant: The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 49.7% (w / w) of the total weight of the inhaled aerosol solution;

[0082] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0083] The inhaled aerosol is a solution-type pressurized metered-dose inhaler. The active ingredient passes through a 0.22μm filter membrane without residue and is completely dissolved in a mixture containing a cosolvent and a propellant, resulting in a bright yellow, clear solution. By weight percentage, the sum of the contents of the active ingredient, cosolvent, and propellant is 100%.

[0084] Its preparation method specifically includes the following steps:

[0085] S1. Control the relative humidity of the environment to ≤65%, mix nintedanib ethanesulfonate with ethanol, stir to dissolve, and obtain drug-containing solution A.

[0086] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal it, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12.0g to obtain the inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.3%, the ethanol content is 50%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 49.7%. Each actuation measure: 600μg of nintedanib isosulfate.

[0087] Example 6:

[0088] Please see Figure 1 This embodiment provides a technical solution based on Embodiment 1: a nintedanib solution-type pressurized metered-dose inhaler, composed of the following components:

[0089] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.3% (w / w) of the total weight of the inhaled aerosol solution;

[0090] Pharmaceutically acceptable cosolvent: The cosolvent is propylene glycol, and its content is 35% (w / w) of the total weight of the inhaled aerosol solution;

[0091] Pharmaceutically acceptable propellant: The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 64.7% (w / w) of the total weight of the inhaled aerosol solution;

[0092] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0093] The inhaled aerosol is a solution-type pressurized metered-dose inhaler. The active ingredient passes through a 0.22μm filter membrane without residue and is completely dissolved in a mixture containing a cosolvent and a propellant, resulting in a bright yellow, clear solution. By weight percentage, the sum of the contents of the active ingredient, cosolvent, and propellant is 100%.

[0094] Its preparation method specifically includes the following steps:

[0095] S1. Control the relative humidity of the environment to ≤65%, mix nintedanib ethanesulfonate with propylene glycol, stir to dissolve, and obtain drug-containing solution A.

[0096] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal it, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12.0g to obtain the inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.3%, the content of propylene glycol is 35%, and the content of 1,1,1,2-tetrafluoroethane (HFA-134a) is 64.7%. Each actuation measure: 600μg of nintedanib isosulfate.

[0097] The properties and related substances of the inhaled aerosols prepared in Examples 4 to 6 were analyzed, and the results are shown in Table 2.

[0098] Table 2 Formulas with different solvent compositions

[0099]

[0100] As shown in Table 2, all formulations with different concentrations of nintedanib are clear, bright yellow solutions with no significant differences in related substances.

[0101] Comparative Example 1:

[0102] A nintedanib solution-type pressurized metered-dose inhaler is composed of the following components:

[0103] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.6% (w / w) of the total weight of the inhaled aerosol solution;

[0104] The cosolvent is ethanol, and its content is 10% (w / w) of the total weight of the inhaled aerosol solution;

[0105] The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 89.4% (w / w) of the total weight of the inhaled aerosol solution.

[0106] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0107] Its preparation method specifically includes the following steps:

[0108] S1. Mix ethanol and nintedanib ethanesulfonate, stir to dissolve, and obtain drug-containing solution A.

[0109] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal it, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12g to obtain an inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.6%, the ethanol content is 10%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 89.4%. Each actuation measure: 600μg of nintedanib isosulfate.

[0110] Comparative Example 2:

[0111] A nintedanib solution-type pressurized metered-dose inhaler is composed of the following components:

[0112] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.6% (w / w) of the total weight of the inhaled aerosol solution;

[0113] The cosolvent is propylene glycol, and its content is 10% (w / w) of the total weight of the inhaled aerosol solution;

[0114] The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 89.4% (w / w) of the total weight of the inhaled aerosol solution.

[0115] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0116] Its preparation method specifically includes the following steps:

[0117] S1. Mix propylene glycol and nintedanib ethanesulfonate, stir to dissolve, and obtain drug-containing solution A.

[0118] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal it, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12g to obtain an inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.6%, the content of propylene glycol is 10%, and the content of 1,1,1,2-tetrafluoroethane (HFA-134a) is 89.4%. Each actuation measure: 600μg of nintedanib isosulfate.

[0119] Comparative Example 3:

[0120] A nintedanib solution-type pressurized metered-dose inhaler is composed of the following components:

[0121] Active ingredient: The active ingredient is nintedanib ethoxylate, with a content of 0.6% (w / w) of the total weight of the inhaled aerosol solution;

[0122] The cosolvent is a mixture of anhydrous ethanol and propylene glycol in a 1:1 weight ratio, and its content is 5% (w / w) of the total weight of the inhaled aerosol solution.

[0123] The propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), which accounts for 94.6% (w / w) of the total weight of the inhaled aerosol solution.

[0124] Pressure vessel and valve system: The pressure vessel has a capacity of 14 ml; the valve system is a metering valve that delivers 100 μl of liquid per press.

[0125] Its preparation method specifically includes the following steps:

[0126] S1. Combine ethanol and propylene glycol in a 1:1 ratio and mix thoroughly to obtain a mixed solution; then add nintedanib ethanesulfonate to the mixed solution and stir to dissolve to obtain drug-containing solution A.

[0127] S2. Add drug-containing solution A to a 14ml pressure-resistant container, install a 100μl metering valve and seal the container, then fill with 1,1,1,2-tetrafluoroethane (HFA-134a) to a final volume of 12g to obtain an inhalation aerosol. Based on the total weight of the inhalation aerosol, the content of nintedanib is 0.6%, the ethanol / propylene glycol content is 5%, and the 1,1,1,2-tetrafluoroethane (HFA-134a) content is 94.6%. Each actuation measure: 600μg of nintedanib isosulfate.

[0128] The results of comparing the properties of Example 1 and Comparative Examples 1 to 3 are shown in Table 3.

[0129] Table 3 Formulations with different cosolvent concentrations

[0130]

[0131] As shown in Table 3, reducing the amount of cosolvent results in the raw drug not being completely dissolved in the solution, resulting in a suspension.

[0132] Performance testing:

[0133] (a) Stability evaluation:

[0134] The stability test was carried out on the inhalation aerosol prepared in Example 4. The specific operation was as follows: the pressure-resistant container containing the drug solution was placed at 40°C for 1 month and at 25°C for 3 months. The properties and related substances before and after the placement were compared. The results are shown in Table 4.

[0135] Table 4. Stability of the drug solution at different temperatures

[0136]

[0137] As shown in Table 4, the properties and related substances of the samples did not change during the storage period.

[0138] (ii) Delivery dose uniformity test:

[0139] The delivery dose uniformity and aerodynamic particle size distribution of the inhalation aerosol prepared in Example 5 were tested. The specific operation was as follows: a pressure-resistant container containing the drug solution was placed in the aerosol driver, wherein the spray orifice diameter of the aerosol driver was 0.3 mm, and the delivery dose uniformity test was performed. The results are shown in Tables 4 and 5.

[0140] Table 4. Delivery Dosage Uniformity in Example 5*

[0141]

[0142] *Delivery dose is calculated based on nintedanib.

[0143] Table 5 Aerodynamic particle size distribution of Example 5*

[0144]

[0145] *Content is calculated based on Nydanib.

[0146] As shown in Tables 4 and 5, the delivery dose of the inhaled aerosol samples is uniform, with the delivered dose accounting for 98.4% to 102.0% of the labeled amount, indicating high delivery efficiency and an FPF value > 50%.

[0147] The foregoing has only described certain exemplary embodiments of the present invention by way of illustration. Undoubtedly, those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the foregoing drawings and descriptions are illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.

Claims

1. A nintedanib solution-type pressurized metered-dose inhaler, characterized in that, include: Active ingredients; Pharmaceutically acceptable solubilizer; Pharmaceutically acceptable propellants; Pressure vessels and valve systems; The inhaled aerosol is a solution-type pressurized metered-dose inhaler, the active ingredient is nintedanib, and the active ingredient is dissolved in a mixture containing a cosolvent and a propellant. The sum of the contents of the active ingredient, cosolvent, and propellant is 100% by weight.

2. The nintedanib solution-type pressurized metered-dose inhaler according to claim 1, characterized in that, The active ingredient is nintedanib ethanesulfonate; the content of nintedanib ethanesulfonate is 0.1% to 2% of the total weight of the inhaled aerosol solution.

3. The nintedanib solution-type pressurized metered-dose inhaler according to claim 1, characterized in that, The cosolvent is at least one of propylene glycol, ethanol, and glycerol.

4. The nintedanib solution-type pressurized metered-dose inhaler according to claim 3, characterized in that, The content of the cosolvent is 20% to 50% of the total weight of the inhaled aerosol solution.

5. The nintedanib solution-type pressurized metered-dose inhaler according to claim 3, characterized in that, The cosolvent is a mixture of anhydrous ethanol and propylene glycol in a 1:1 weight ratio or glycerol.

6. The nintedanib solution-type pressurized metered-dose inhaler according to claim 1, characterized in that, The propellant is 1,1,1,2-tetrafluoroethane, and its content is 48.0% to 79.9% of the total weight of the inhaled aerosol solution.

7. The nintedanib solution-type pressurized metered-dose inhaler according to claim 1, characterized in that, The pressure-resistant container has a capacity of 10ml to 20ml, and the valve system is a metering valve, wherein each press of the metering valve delivers a volume of liquid medicine of 40 to 150μl.

8. A method for preparing a nintedanib solution-type pressurized metered-dose inhaler, characterized in that, It is used to prepare a nintedanib solution-type pressurized metered-dose inhaler according to any one of claims 1-7, and the preparation method specifically includes the following steps: S1. Control the relative humidity of the environment to ≤65%, dissolve nintedanib in a co-solvent to form a drug-containing solution A; S2. Add the drug-containing solution A into a pressure-resistant container, install a metering valve, seal the container, and fill it with propellant to obtain an inhalation aerosol.

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