Dry powder inhalation composition for inhalation, dry powder inhalation for inhalation and preparation method thereof, and dry powder inhalation for inhalation

Abstract

The invention provides a dry powder inhalation composition for inhalation, a dry powder inhalation for inhalation, a preparation method of the dry powder inhalation and an inhalation dry powder inhalation, and belongs to the technical field of pharmaceutical preparations. The dry powder inhalation composition comprises a first component and a second component, the first component is corticoid or pharmaceutically acceptable salt or isomer thereof; the second component is a beta2 adrenergic receptor agonist or a pharmaceutically acceptable salt or an isomer of the beta2 adrenergic receptor agonist; the molar ratio of the first component to the second component is (0.1-25): 1. According to the dry powder inhalation composition provided by the invention, the delivery efficiency of the first component and the second component in the dry powder inhalation composition can be higher than the delivery efficiency of a single component of the first component and the delivery efficiency of a single component of the second component, so that the drug effects of corticoid and a beta2 adrenergic receptor stimulant in the dry powder inhalation composition can be fully exerted; the traditional Chinese medicine composition can help patients with lung diseases such as mild and moderate asthma, chronic obstructive pneumonia and the like to relieve respiratory obstruction and has the effect of treating inflammation at the same time.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations. Specifically, it relates to a powder aerosol composition for inhalation, a powder aerosol for inhalation, its preparation method, and an inhaled powder aerosol. Background Art

[0002] Asthma is a chronic respiratory inflammatory disease, which is a chronic airway inflammation involving multiple cells and cellular components, including mast cells, eosinophils, and T lymphocytes, etc.; this inflammation will cause asthma patients to have repeated episodes of wheezing, dyspnea, chest tightness, and coughing. Chronic Obstructive Pulmonary Disease (COPD) is an internal disease of the respiratory tract caused by chronic inflammation or bronchial swelling. The airways of COPD patients are smaller than normal, and the narrowing of the airways will cause dyspnea. The treatment regimens for pulmonary diseases such as asthma and COPD mainly include the use of corticosteroids or β2-adrenergic receptor agonists, etc.; among them, corticosteroids can play an anti-inflammatory treatment role; β2-adrenergic receptor agonists can play a role in relaxing airway smooth muscle, thereby dilating the respiratory tract.

[0003] Currently, the commonly used drugs for treating pulmonary diseases such as asthma and COPD on the market are mainly divided into dosage forms such as oral tablets, inhaled solution agents, inhaled aerosol agents, and inhaled powder aerosol agents; among them, oral tablets have a larger dose and are a systemic administration type, with a lower utilization efficiency for bronchodilation, and will be accompanied by certain side effects such as nausea, headache, and palpitations; inhaled solution agents have higher requirements for the device, and the device for inhaling the solution is larger, not convenient to carry, and difficult to use emergently; inhaled aerosol agents are active administrations, there are problems with the incoordination between activation and inhalation, with higher requirements for patient use, and inhaled aerosol agents need to use environmentally unfriendly propellants, which may cause damage to the ozone layer; although inhaled powder aerosol agents are also drug-device combination products like inhaled aerosol agents, inhaled powder aerosol agents are used by patients through self-inhalation, which is more convenient, there is no problem of incoordination between activation and inhalation, and there is no need to use environmentally unfriendly propellants. The inhalation device of inhaled powder aerosol agents is simple, easy to carry, and the powder preparation makes the drug components not affected by solubility, and the stability of the drug components is relatively high. Therefore, it is a better choice to select the inhaled powder aerosol agent dosage form for drugs for treating pulmonary diseases such as asthma and COPD.

[0004] However, for compound (i.e., having two or more drug components) inhaled powder aerosol agents, the various drug components often affect each other, resulting in a lower delivery efficiency of the powdered drug components in the compound inhaled powder aerosol agent, and further leading to the inability to effectively exert the efficacy of each drug component. Summary of the Invention

[0005] The purpose of the present application is to provide an aerosol composition for inhalation, an aerosol for inhalation and its preparation method, and an inhaled aerosol, which can enable both the corticosteroid and the β2-adrenergic receptor agonist in the inhaled aerosol to have a high delivery efficiency, thereby being beneficial to the effective treatment of lung diseases such as asthma and COPD.

[0006] In a first aspect, the present application provides an aerosol composition for inhalation, which includes a first component and a second component; wherein, the first component is a corticosteroid or a pharmaceutically acceptable salt thereof or an isomer thereof; the second component is a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof or an isomer thereof; the molar ratio of the first component to the second component is (0.1 - 25):1.

[0007] In the aerosol composition for inhalation provided by the present application, the corticosteroid drug (i.e., the first component) and the β2-adrenergic receptor agonist drug (i.e., the second component) are used in combination, which can treat bronchial inflammation while effectively dilating the respiratory tract; and by adjusting the molar ratio of the first component and the second component in the aerosol composition to the range of (0.1 - 25):1, the delivery efficiency of the first component and the second component in the aerosol composition can be higher than that of the corresponding single agent, which is beneficial to improving the utilization rate of the corticosteroid drug and the β2-adrenergic receptor agonist drug, and further beneficial to giving full play to the efficacy of the corticosteroid drug and the β2-adrenergic receptor agonist drug in the aerosol composition. It can help patients with mild and moderate asthma and lung diseases such as COPD relieve respiratory obstruction while treating inflammation, which is beneficial to the effective treatment of lung diseases such as asthma and COPD.

[0008] In combination with the first aspect, in an alternative embodiment of the present application, the β2-adrenergic receptor agonist is salbutamol; and / or, the corticosteroid includes at least one of beclomethasone, budesonide, fluticasone, beclomethasone dipropionate, fluticasone propionate, ciclesonide, flunisolide, deflazacort, alclometasone, betamethasone, prednisone acetate, prednisolone, chloroprednisone, clobetasol, clobetasone butyrate, clocortolone, cloprednol, cortisone, hydrocortisone, cortisone acetate, hydrocortisone acetate, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, diflorprednate, fluazacort, flurocortide, flumethasone, flunisolide, fluocinolone acetonide, flucortebutate, fluocortolone, fluorometholone, fluperolone acetate, fluprednisolone acetate, fluocinolone acetonide, halometasone, hydrocortamate, etiprednol dicloacetate, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, sodium prednisolone phosphate, prednisone, prednisolone valerate, lymecycline, triamcinolone, triamcinolone acetonide, cortivazol, amcinonide, and hexacetonide.

[0009] In the above technical solution, the β2-adrenergic receptor agonist is salbutamol, which is a short-acting β2-adrenergic receptor agonist. It can dilate bronchial smooth muscle and expand the airway. At the same time, it can also stabilize mast cells and basophils, inhibit the release of allergic mediators such as histamine, thereby reducing bronchospasm and respiratory mucosa edema, and can be clinically used for the emergency treatment of diseases such as asthma and chronic obstructive pulmonary disease. Selecting the above substances as corticosteroids can play an effective anti-inflammatory treatment role.

[0010] Combined with the first aspect, in an alternative embodiment of the present application, salbutamol is levalbuterol; and / or, the corticosteroid is budesonide.

[0011] In the above technical solution, salbutamol is levalbuterol. Compared with dextralbuterol and racemic salbutamol, levalbuterol has a more efficient airway smoothing effect, higher metabolic rate and fewer side effects. And compared with the compound inhaled powder aerosol compositions formed by dextralbuterol and racemic salbutamol respectively combined with corticosteroid drugs (i.e., the first component), the delivery efficiency and delivery uniformity of the compound inhaled powder aerosol formed by levalbuterol and corticosteroid drugs (i.e., the first component) are higher. The corticosteroid is budesonide, which has a good anti-inflammatory effect, is not prone to moisture absorption, has high stability, and is beneficial to better achieve delivery.

[0012] Optionally, levalbuterol includes at least one of levalbuterol hydrochloride, levalbuterol tartrate, and levalbuterol sulfate.

[0013] Combined with the first aspect, in an alternative embodiment of the present application, the molar ratio of the first component to the second component is (0.25 - 4):1.

[0014] In the above technical solution, in the powder aerosol composition for inhalation, when "salbutamol is levalbuterol; and / or, the corticosteroid is budesonide", the molar ratio of the first component to the second component is in the range of (0.25 - 4):1, which is beneficial to further improve the delivery efficiency of the first component and the second component in the powder aerosol composition at the same time, and further beneficial to improving the utilization rate of corticosteroid drugs and β2-adrenergic receptor agonists.

[0015] Optionally, the molar ratio of the first component to the second component is (0.8 - 1.2):1.

[0016] Combined with the first aspect, in an alternative embodiment of the present application, the D50 of the first component is 1.0 μm - 5.0 μm; and / or, the D50 of the second component is 1.0 μm - 5.0 μm.

[0017] In the above technical solution, in the powder aerosol composition for inhalation, when the particle size (D50) of the first component or / and the second component is within the above range, the first component or / and the second component in the powder aerosol composition can have relatively high stability, and the delivery efficiency of the first component and the second component in the powder aerosol composition can be relatively high.

[0018] In a second aspect, the present application provides a powder aerosol for inhalation, which includes a carrier and the powder aerosol composition for inhalation provided in any one of the above first aspects.

[0019] Since the powder aerosol for inhalation provided by the present application contains the powder aerosol composition for inhalation provided in the above first aspect, the delivery efficiency of the first component and the second component in the powder aerosol can be higher than that of the corresponding single agent, which is beneficial to improving the utilization rate of corticosteroid drugs and β2-adrenergic receptor agonist drugs. Furthermore, it is beneficial to fully exert the efficacy of the corticosteroid drugs and β2-adrenergic receptor agonist drugs in the powder aerosol composition, and can have a therapeutic effect on inflammation while relieving respiratory obstruction in patients with mild and moderate asthma and COPD and other lung diseases, which is beneficial to effectively treating asthma and COPD and other lung diseases.

[0020] In combination with the second aspect, in an alternative embodiment of the present application, the carrier is lactose; the total mass of the first component and the second component accounts for 0.1% to 12% of the mass of the powder aerosol for inhalation.

[0021] In the above technical solution, the powder aerosol for inhalation can have certain fluidity, which is beneficial to improving the delivery efficiency of the first component and the second component in the powder aerosol.

[0022] In a third aspect, the present application provides a preparation method of a powder aerosol for inhalation provided in any one of the above second aspects, and the preparation method includes: mixing the first component, the second component and the carrier.

[0023] In combination with the third aspect, in an alternative embodiment of the present application, the carrier is divided into a first part, a second part and a third part; the preparation method of the powder aerosol for inhalation includes: sequentially adding the first part, the first component, the second part, the second component and the third part into a mixing device, and then mixing.

[0024] In the above technical solution, by preparing the powder aerosol for inhalation in the above manner, it is beneficial to further improve the delivery efficiency of the first component and the second component in the powder aerosol for inhalation.

[0025] Optionally, the mass ratio of the first part, the second part and the third part is 1:(0.8 - 1.2):(0.8 - 1.2).

[0026] Optionally, a three-dimensional mixing method is adopted, the rotation speed of the three-dimensional mixing is 20 rpm to 200 rpm, and the time of the three-dimensional mixing is 10 min to 60 min.

[0027] Fourthly, the present application provides an inhalable powder aerosol, which includes an inhalation device and the powder aerosol for inhalation provided in any one of the above second aspects; the powder aerosol for inhalation is placed in the inhalation device.

[0028] Since the inhalable powder aerosol provided in the present application has the powder aerosol for inhalation provided in the above second aspect, the delivery efficiency of the first component and the second component in the powder aerosol can be higher than that of the corresponding single agent, which is beneficial to improving the utilization rate of corticosteroid drugs and β2-adrenergic receptor agonist drugs. Furthermore, it is beneficial to give full play to the efficacy of corticosteroid drugs and β2-adrenergic receptor agonist drugs in the powder aerosol composition, and can have a therapeutic effect on inflammation while relieving respiratory obstruction for patients with mild and moderate asthma and COPD and other lung diseases, which is beneficial to effectively treating asthma and COPD and other lung diseases.

[0029] Optionally, the inhalation device includes a reservoir-type inhalation device, a capsule-type inhalation device, a disposable inhalation device or a blister-type inhalation device.

[0030] Optionally, the inhalation device is a reservoir-type inhalation device. Description of the Drawings

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings required to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings.

[0032] Figure 1 It is the aerodynamic distribution diagram of the first component and the second component in the inhalable powder aerosol prepared in Example 1 of the present application.

[0033] Figure 2 It is the aerodynamic distribution diagram of the first component and the second component in the inhalable powder aerosol prepared in Example 2 of the present application.

[0034] Figure 3 It is the aerodynamic distribution diagram of the first component and the second component in the inhalable powder aerosol prepared in Example 3 of the present application.

[0035] Figure 4 It is the result diagram of the delivery uniformity of the first component and the second component in the inhalable powder aerosol prepared in Example 1 of the present application.

[0036] Figure 5 This is a result diagram of the delivery uniformity of the first component and the second component in the inhaled powder aerosol prepared in Example 2 of this application.

[0037] Figure 6 This is a result diagram of the delivery uniformity of the first component and the second component in the inhaled powder aerosol prepared in Example 3 of this application.

[0038] Figure 7 This is a result diagram of the delivery stability of the first component in the inhaled powder aerosol prepared in Example 2 of this application.

[0039] Figure 8 This is a result diagram of the delivery stability of the second component in the inhaled powder aerosol prepared in Example 2 of this application. Detailed implementation mode

[0040] The inventor found that for inhaled powder aerosols of compound formulations (i.e., having two or more drug components), the various powdered drug components often affect each other, resulting in a low delivery efficiency of the powdered drug components in the compound inhaled powder aerosol. The delivery efficiency of each powdered drug component in the compound inhaled powder aerosol is often lower than that of the corresponding single-component inhaled powder aerosol, thereby making it difficult for the compound inhaled powder aerosol to fully exert the efficacy of each drug component.

[0041] The inventor's research found that when the drug components in the inhaled powder aerosol simultaneously have corticosteroid drugs and β2-adrenergic receptor agonist drugs, by regulating the ratio of corticosteroid drugs to β2-adrenergic receptor agonist drugs to a specific ratio, the delivery efficiency of the two drug components, namely corticosteroid drugs and β2-adrenergic receptor agonist drugs, in the inhaled powder aerosol will not be affected by each other, and the delivery efficiency of the two drug components, namely corticosteroid drugs and β2-adrenergic receptor agonist drugs, in the inhaled powder aerosol is respectively higher than that of the corresponding single-component inhaled powder aerosol.

[0042] Therefore, this application provides an inhaled powder aerosol composition, which includes a first component and a second component; wherein, the first component is a corticosteroid or a pharmaceutically acceptable salt thereof or an isomer thereof; the second component is a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof or an isomer thereof; the molar ratio of the first component to the second component is (0.1 - 25):1.

[0043] In the above aerosol composition for inhalation, the present application uses a corticosteroid drug (i.e., the first component) and a β2-adrenergic receptor agonist drug (i.e., the second component) in combination, which can treat bronchial inflammation while effectively dilating the respiratory tract. And by adjusting the molar ratio of the first component and the second component in the aerosol composition to the range of (0.1-25):1, the delivery efficiency of the first component and the second component in the aerosol composition can be higher than that of the corresponding single agent, which is beneficial to improving the utilization rate of the corticosteroid drug and the β2-adrenergic receptor agonist drug, and further beneficial to giving full play to the efficacy of the corticosteroid drug and the β2-adrenergic receptor agonist drug in the aerosol composition, and can have a therapeutic effect on patients with mild and moderate asthma and COPD and other lung diseases while relieving respiratory obstruction, which is beneficial to effectively treating asthma and COPD and other lung diseases.

[0044] Exemplarily, the molar ratio of the first component to the second component can be any value among 0.1:1, 0.2:1, 0.25:1, 0.5:1, 0.75:1, 1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 9:1, 10:1, 12:1, 15:1, 20:1 and 25:1 or the range value between any two of them.

[0045] In some alternative embodiments of the present application, the β2-adrenergic receptor agonist is salbutamol. Salbutamol is a short-acting β2-adrenergic receptor agonist, which can play a role in relaxing bronchial smooth muscle and dilating the airway; at the same time, it can also stabilize mast cells and basophils and inhibit the release of allergy mediators such as histamine, thereby reducing bronchospasm and respiratory mucosa edema, and can be clinically used for the emergency treatment of diseases such as asthma and chronic obstructive pulmonary disease.

[0046] It should be noted that in other alternative embodiments of the present application, the β2-adrenergic receptor agonist may not be limited to salbutamol. For example, the β2-adrenergic receptor agonist can be clenbuterol, etc.

[0047] Furthermore, in some alternative embodiments of the present application, the β2-adrenergic receptor agonist is levalbuterol; compared with racemic salbutamol and dextral salbutamol, levalbuterol has a more efficient airway smoothing effect, and its metabolic rate is higher and the side effects are smaller; and compared with the compound inhalation aerosol compositions formed by racemic salbutamol and dextral salbutamol respectively combined with the corticosteroid drug (i.e., the first component), the delivery efficiency and delivery uniformity of the compound inhalation aerosol formed by levalbuterol combined with the corticosteroid drug (i.e., the first component) are higher.

[0048] In some alternative embodiments of the present application, the levalbuterol includes at least one of levalbuterol hydrochloride, levalbuterol tartrate, and levalbuterol sulfate. When the levalbuterol selects the above substances, the above substances are not prone to moisture absorption and have high stability, which is beneficial to better achieve delivery; and the above substances can all make the delivery efficiency, delivery stability, and delivery uniformity of the compound inhalation powder aerosol composition formed by the combination of levalbuterol and corticosteroid drugs (i.e., the first component) relatively high.

[0049] Furthermore, compared with the compound inhalation powder aerosol compositions formed by the combination of levalbuterol tartrate and levalbuterol sulfate with corticosteroid drugs (i.e., the first component) respectively, the compound inhalation powder aerosol composition formed by the combination of levalbuterol hydrochloride (i.e., the second component) with corticosteroid drugs (i.e., the first component) is beneficial to further improve the delivery efficiency and delivery uniformity of salbutamol and corticosteroid drugs in the inhalation powder aerosol.

[0050] Still further, compared with the compound inhalation powder aerosol compositions formed by the combination of levalbuterol hydrochloride and levalbuterol sulfate with corticosteroid drugs (i.e., the first component) respectively, the compound inhalation powder aerosol composition formed by the combination of levalbuterol tartrate (i.e., the second component) with corticosteroid drugs (i.e., the first component) is beneficial to further improve the delivery stability of salbutamol and corticosteroid drugs in the inhalation powder aerosol.

[0051] It should be noted that in other alternative embodiments of the present application, the β2 adrenergic receptor agonist can also be dextralbuterol or racemic salbutamol; in the present application, for salbutamol, if not specified as levo or dextro, it all represents the racemic form. For example, salbutamol sulfate is racemic salbutamol and its salt form is sulfate.

[0052] In some alternative embodiments of the present application, the corticosteroid includes at least one of beclomethasone, budesonide, fluticasone, beclomethasone dipropionate, fluticasone propionate, ciclesonide, flunisolide, deflazacort, alclometasone, betamethasone, prednisone acetate, prednisolone acetate, chloroprednisone, clobetasol propionate, clobetasone butyrate, clocortolone, cloprednol, cortisone, hydrocortisone, cortisone acetate, hydrocortisone acetate, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluazacort, flurocortide, flumethasone, flunisolide, fluocinolone acetonide, flucortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednisolone acetate, fluocinolone acetonide, halometasone, hydrocortamate, etiprednol dicloacetate, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone sodium phosphate, prednisone, prednisolone valerate, rimcortolone, triamcinolone, triamcinolone acetonide, cortivazol, amcinafal, and triamcinolone hexacetonide.

[0053] It should be noted that in other alternative embodiments of the present application, the corticosteroid is not limited to the above-listed corticosteroids, as long as it is a corticosteroid with anti-inflammatory therapeutic effects.

[0054] In some alternative embodiments of the present application, the corticosteroid is a glucocorticoid, which can play an effective role in anti-inflammatory treatment.

[0055] Furthermore, the corticosteroid is budesonide. Budesonide has a good effect on treating inflammation, is not prone to moisture absorption, has high stability, and is conducive to better achieving delivery.

[0056] In some alternative embodiments of the present application, salbutamol is levalbuterol, and the corticosteroid is budesonide; levalbuterol and budesonide can cooperate with each other, can give full play to the efficacy of the drug components, and can treat inflammation while relieving respiratory obstruction in patients with mild and moderate asthma and COPD and other lung diseases.

[0057] Furthermore, when "salbutamol is levalbuterol and the corticosteroid is budesonide", that is, when "the first component is budesonide or a pharmaceutically acceptable salt or an isomer thereof, and the second component is levalbuterol or a pharmaceutically acceptable salt or an isomer thereof", the molar ratio of the first component to the second component is (0.25 - 4):1, which is conducive to further improving the delivery efficiency of the first component and the second component in the powder aerosol composition, and further conducive to improving the utilization rate of the drug components in the powder aerosol composition.

[0058] Exemplarily, when "the first component is budesonide or a pharmaceutically acceptable salt or isomer thereof, and the second component is levalbuterol or a pharmaceutically acceptable salt or isomer thereof", the molar ratio of the first component to the second component can be any value among 0.25:1, 0.5:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, 0.95:1, 1:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, 1.25:1, 1.5:1, 2.0:1, 2.5:1, 3.0:1, 3.5:1 and 4.0:1 or a range value between any two of them.

[0059] Furthermore, when "the first component is budesonide or a pharmaceutically acceptable salt or isomer thereof, and the second component is levalbuterol or a pharmaceutically acceptable salt or isomer thereof", the molar ratio of the first component to the second component of (0.8 - 1.2):1 is beneficial to further improve the delivery efficiency of both the first component and the second component in the powder aerosol composition, and thus is beneficial to further improve the utilization rate of the drug components in the powder aerosol composition.

[0060] In some alternative embodiments of the present application, the D50 of the first component is 1.0 μm to 5.0 μm, which can make the first component in the powder aerosol composition have high stability and can also make the delivery efficiency of the first component in the powder aerosol composition relatively high.

[0061] Exemplarily, the D50 of the first component can be any value among 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm and 5.0 μm or a range value between any two of them.

[0062] In some alternative embodiments of the present application, the D50 of the second component is 1.0 μm to 5.0 μm, which can make the second component in the powder aerosol composition have high stability and can also make the delivery efficiency of the second component in the powder aerosol composition relatively high.

[0063] Exemplarily, the D50 of the second component can be any value among 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm and 5.0 μm or a range value between any two of them.

[0064] In some alternative embodiments of the present application, when "the first component is budesonide or a pharmaceutically acceptable salt thereof or an isomer thereof, and the second component is levalbuterol or a pharmaceutically acceptable salt thereof or an isomer thereof", in each puff of the powder aerosol composition for inhalation, the content of the first component (calculated as budesonide) is 9 μg to 360 μg, and the content of the second component (calculated as salbutamol) is 2.5 μg to 200 μg.

[0065] It should be noted that in the present application, "calculated as salbutamol" means that the mass of this substance is presented as "the mass of salbutamol corresponding to the same molar amount of this substance"; for example, "levosalbutamol hydrochloride (calculated as salbutamol) is Mg" means that levalbuterol hydrochloride is presented as "the mass of salbutamol corresponding to the same molar amount of levalbuterol hydrochloride (i.e., M)", where M = n × C, n is the molar amount of levalbuterol hydrochloride, and C is the relative molecular mass of salbutamol.

[0066] The present application also provides a powder aerosol for inhalation, which includes a carrier and the powder aerosol composition for inhalation provided above.

[0067] The powder aerosol for inhalation provided by the present application can make the delivery efficiency of the first component and the second component in the powder aerosol higher than that of the corresponding single agent, which is beneficial to improving the utilization rate of corticosteroid drugs and β2-adrenergic receptor agonist drugs, and further beneficial to giving full play to the efficacy of corticosteroid drugs and β2-adrenergic receptor agonist drugs in the powder aerosol composition. It can have a therapeutic effect on inflammation while relieving respiratory obstruction for patients with mild and moderate asthma, COPD and other lung diseases, and is beneficial to effectively treating asthma, COPD and other lung diseases.

[0068] It can be understood that in the powder aerosol for inhalation, the powder aerosol composition includes a first component and a second component. The selection and ratio of the first component and the second component are the same as those described above. Please refer to the above content and will not be elaborated here.

[0069] Exemplarily, the carrier can be lactose, trehalose, mannitol, sucrose, liposome, etc.

[0070] It should be noted that the present application does not limit the specific selection of the carrier in the powder aerosol for inhalation, and a carrier commonly used in inhalation powder aerosols can be used.

[0071] In some alternative embodiments of the present application, the carrier is lactose; for example, lactose can be specifically selected as 100, SV010, 70 or 120, etc. It should be noted that the present application does not limit the specific type of lactose either.

[0072] Further, in some alternative embodiments of the present application, when the carrier is lactose, the total mass of the first component and the second component accounts for 0.1% to 12% of the mass of the powder inhaler for inhalation; this can make the powder inhaler for inhalation have a certain fluidity, which is beneficial to improving the delivery efficiency of the first component and the second component in the powder inhaler.

[0073] Exemplarily, when the carrier is lactose, the total mass of the first component and the second component may account for any value among 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, and 12% or the range value between any two of them in the mass of the powder inhaler for inhalation.

[0074] In some alternative embodiments of the present application, the D50 of lactose is 5 μm to 200 μm.

[0075] Rationally, the D50 of lactose may be any value among 5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, and 200 μm or the range value between any two of them.

[0076] In other alternative embodiments of the present application, for the case where the carrier selected is not lactose, the D50 of the carrier may also be 5 μm to 200 μm.

[0077] In some alternative embodiments of the present application, when "the first component is budesonide or its pharmaceutically acceptable salt or its isomer, and the second component is levalbuterol or its pharmaceutically acceptable salt or its isomer, and the carrier is lactose", in each inhalation dose of 5000 μg of the powder inhaler for inhalation, the content of the first component (calculated as budesonide) is 9 μg to 360 μg, the content of the second component (calculated as salbutamol) is 2.5 μg to 200 μg, and the balance is lactose.

[0078] The present application also provides a preparation method of the above-mentioned powder inhaler for inhalation, and the preparation method includes: mixing the first component, the second component, and the carrier.

[0079] It is understandable that the specific selection of the first component, the second component and the carrier in the preparation method of the powder inhaler provided by the present application is consistent with the foregoing content, and the ratios of the first component, the second component and the carrier in the prepared powder inhaler for inhalation are also consistent with the foregoing content. Please refer to the above content and will not be elaborated here.

[0080] It should be noted that during the preparation of the powder inhaler for inhalation, there may be losses of some raw materials (i.e., the first component, the second component or / and the carrier) due to adhesion and other situations in the mixing equipment. Therefore, when the first component, the second component and the carrier are fed for mixing, the feeding conditions of each component need to be adjusted adaptively according to the performance of each component, as long as the ratios of the first component, the second component and the carrier in the prepared powder inhaler for inhalation meet the limitations of the present application. As an example, when the first component is budesonide, there will be adhesion loss of budesonide in the mixing equipment, so budesonide can be fed at 105% of the target delivery amount during feeding.

[0081] The inventors have found through research that the mixing method of the first component, the second component and the carrier will further affect the delivery efficiency of each component in the powder inhaler for inhalation.

[0082] The present application provides three exemplary preparation methods for the powder inhaler for inhalation. Example 1 (one-step method) is as follows: The carrier is divided into three parts, which are respectively denoted as the first part, the second part and the third part; the preparation method of the powder inhaler for inhalation includes: sequentially adding the first part, the first component, the second part, the second component and the third part into the mixing equipment, and then mixing. Using the above method to prepare the powder inhaler for inhalation is beneficial to further improve the delivery efficiency of the first component and the second component in the powder inhaler for inhalation.

[0083] Furthermore, in the preparation method shown in Example 1, the mass ratio of the first part, the second part and the third part is 1:(0.8 - 1.2):(0.8 - 1.2); this is beneficial to further improve the delivery efficiency of the first component and the second component in the powder inhaler for inhalation.

[0084] As an example, in the preparation method described in Example 1, the mixing adopts a three-dimensional mixing method, the rotation speed of the three-dimensional mixing is 20 rpm - 200 rpm, and the time of the three-dimensional mixing is 10 min - 60 min.

[0085] In the preparation method shown in Example 1, the carrier can be first added to the mixing equipment for pre-mixing for 3 min - 8 min, then the second part and the third part of the carrier are taken out from the mixing equipment, and then the first component, the second part, the second component and the third part are sequentially added to the mixing equipment where the first part of the carrier is placed, and then mixed.

[0086] Example 2 (two-step method) is as follows: The carrier is divided into two parts, denoted as the first part and the second part respectively; The preparation method of the powder aerosol for inhalation includes: sequentially adding the first part, the second component, and the second part into a mixing device for first mixing to obtain a mixed system; Then, a part of the mixed system is taken out (the mixed system remaining in the mixing device is denoted as the first mixed part, and the taken-out mixed system is denoted as the second mixed part), and then the first component and the second mixed part are sequentially added into the mixing device, and then second mixing is carried out.

[0087] Furthermore, in the preparation method shown in Example 2, the mass ratio of the first part to the second part is 1:(0.8 - 1.2); The mass ratio of the first mixed part to the second mixed part is 1:(0.8 - 1.2).

[0088] Exemplarily, in the preparation method described in Example 2, both the first mixing and the second mixing adopt three-dimensional mixing methods. The rotation speed of the first mixing is 20 rpm to 200 rpm, the rotation speeds of the second mixing are each independently 20 rpm to 200 rpm, the time of the first mixing is 3 min to 8 min, and the time of the second mixing is 10 min to 60 min.

[0089] In the preparation method shown in Example 2, the carrier can be first added into the mixing device for pre-mixing for 3 min to 8 min, then the second part of the carrier is taken out from the mixing device, and then the second component and the second part are sequentially added into the mixing device where the first part of the carrier is placed for first mixing to obtain a mixed system; Then, the second mixed part of the mixed system is taken out, and then the first component and the second mixed part are sequentially added into the mixing device, and then second mixing is carried out.

[0090] Example 3 (three-step method) is as follows: The carrier is divided into two parts, denoted as the first part and the second part respectively; The second component is divided into two parts, denoted as the third part and the fourth part respectively; The preparation method of the powder aerosol for inhalation includes: sequentially adding the first part, the third part, and the second part into a mixing device for first mixing to obtain a first mixed system; Then, a part of the first mixed system is taken out (the first mixed system remaining in the mixing device is denoted as the first mixed part, and the taken-out first mixed system is denoted as the second mixed part), and then the first component and the second mixed part are sequentially added into the mixing device, and then second mixing is carried out to obtain a second mixed system; Then, a part of the second mixed system is taken out (the second mixed system remaining in the mixing device is denoted as the third mixed part, and the taken-out second mixed system is denoted as the fourth mixed part), and then the fourth part and the fourth mixed part are sequentially added into the mixing device, and then third mixing is carried out.

[0091] Further, in the preparation method shown in Example 3, the mass ratio of the first part to the second part is 1:(0.8 - 1.2), the mass ratio of the third part to the fourth part is 1:(0.1 - 10), the mass ratio of the first mixing part to the second mixing part is 1:(0.8 - 1.2), and the mass ratio of the third mixing part to the fourth mixing part is 1:(0.8 - 1.2).

[0092] Exemplarily, in the preparation method described in Example 3, the first mixing, the second mixing, and the third mixing are all carried out in a three-dimensional mixing manner. The rotation speed of the first mixing is 20 rpm - 200 rpm, the rotation speed of the second mixing is 20 rpm - 200 rpm, the rotation speeds of the third mixing are each independently 20 rpm - 200 rpm, the times of the first mixing and the second mixing are each independently 2 min - 8 min, and the time of the third mixing is 10 min - 60 min.

[0093] In the preparation method shown in Example 3, the carrier can be first added to the mixing device for pre-mixing for 2 min - 8 min, then the second part of the carrier is taken out from the mixing device, and then the third part and the second part are sequentially added to the mixing device containing the first part of the carrier for the first mixing to obtain a first mixing system; then the second mixing part of the first mixing system is taken out, and the first component and the second mixing part are sequentially added to the mixing device, and then the second mixing is carried out to obtain a second mixing system; then the fourth mixing part in the second mixing system is taken out, and the fourth part and the fourth mixing part are sequentially added to the mixing device, and then the third mixing is carried out.

[0094] Exemplarily, in the preparation methods shown in Example 1, Example 2, and Example 3, the mixing device can be a three-dimensional mixer, a high-shear mixer, a V-type mixer, a double-cone mixer, a horizontal ribbon mixer, a single-cone double-screw mixer, a square-cone mixer, or a planetary mixer, etc.; it should be noted that the specific type of the mixing device is not limited in this application. When different mixing devices are used, the mixing rotation speed can be adjusted according to the actual situation, and this application does not make a limitation.

[0095] In the preparation methods provided in the foregoing Example 1 to Example 3, compared with the preparation method of Example 2, the preparation methods shown in Example 1 and Example 3 are more conducive to improving the delivery efficiency of the first component and the second component in the inhalable powder aerosol; compared with the preparation methods shown in Example 2 and Example 3, the preparation method shown in Example 1 is simpler and easier to implement, and is easy to mass-produce. It can not only improve the production efficiency, but also improve the delivery efficiency of the first component and the second component in the inhalable powder aerosol.

[0096] The present application also provides an inhalable powder aerosol, which comprises an inhalation device and the powder aerosol for inhalation provided as above; wherein, the powder aerosol for inhalation is placed in the inhalation device.

[0097] The inhalable powder aerosol provided by the present application can make the delivery efficiency of the first component and the second component in the powder aerosol higher than that of the corresponding single agent, which is beneficial to improving the utilization rate of corticosteroid drugs and β2-adrenergic receptor agonist drugs, and further beneficial to giving full play to the efficacy of corticosteroid drugs and β2-adrenergic receptor agonist drugs in the powder aerosol composition. It can have a therapeutic effect on inflammation while relieving respiratory obstruction in patients with mild and moderate asthma and COPD and other lung diseases, and is beneficial to effectively treating asthma and COPD and other lung diseases.

[0098] It can be understood that in the inhalable powder aerosol, the powder aerosol for inhalation comprises a first component, a second component and a carrier. The selection and ratio of the first component, the second component and the carrier are the same as those described above. Please refer to the above content and will not be elaborated here.

[0099] In some alternative embodiments of the present application, the inhalation device includes a reservoir-type inhalation device, a capsule-type inhalation device, a disposable inhalation device or a blister-type inhalation device.

[0100] Exemplarily, the reservoir-type inhalation device can be The disposable inhalation device can be

[0101] Furthermore, in some alternative embodiments of the present application, the inhalation device is a reservoir-type inhalation device, which can improve the delivery efficiency of the first component and the second component in the inhalable powder aerosol.

[0102] It should be noted that in other alternative embodiments of the present application, the inhalation device is not limited to the above devices, as long as it can accommodate and deliver the powder aerosol for inhalation.

[0103] To make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Those not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0104] Example 1

[0105] This embodiment provides an inhalable powder aerosol, which is prepared by the following steps:

[0106] (1) Prepare raw materials:

[0107] Weigh 0.36 g of budesonide, 0.23 g of levosalbutamol hydrochloride, and 19.41 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, the D50 of levosalbutamol hydrochloride is 2.00 μm, and the D50 of lactose is 119.4 μm.

[0108] (2) Mixing of raw materials (one-step method):

[0109] Add 19.41 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 12.94 g of lactose, and then successively add 0.36 g of budesonide, 6.47 g of the aforementioned taken-out lactose, 0.23 g of levosalbutamol hydrochloride, and 6.47 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0110] (3) Filling:

[0111] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain the inhaled powder aerosol.

[0112] Example 2

[0113] This example provides an inhaled powder aerosol, which is prepared by the following steps:

[0114] (1) Prepare raw materials:

[0115] Weigh 0.36 g of budesonide, 0.2628 g of levosalbutamol tartrate, and 19.3772 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, the D50 of levosalbutamol tartrate is 1.82 μm, and the D50 of lactose is 119.4 μm.

[0116] (2) Mixing of raw materials (one-step method):

[0117] Add 19.3772 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 12.92 g of lactose, and then successively add 0.36 g of budesonide, 6.46 g of the aforementioned taken-out lactose, 0.2628 g of levosalbutamol tartrate, and 6.46 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0118] (3) Filling:

[0119] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and leave it standing for 24 h under the conditions of 20 °C and 45% RH humidity to obtain an inhalable powder aerosol.

[0120] Example 3

[0121] This example provides an inhalable powder aerosol, which is prepared by the following steps:

[0122] (1) Prepare raw materials:

[0123] Weigh 0.36 g of budesonide, 0.24 g of levosalbutamol sulfate, and 19.40 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, the D50 of levosalbutamol sulfate is 2.01 μm, and the D50 of lactose is 119.4 μm.

[0124] (2) Mix raw materials (one-step method):

[0125] Add 19.4 g of lactose to a three-dimensional mixer, premix for 5 min at 72 rpm, take out 12.94 g of lactose, and then sequentially add 0.36 g of budesonide, 6.47 g of the aforementioned taken-out lactose, 0.24 g of levosalbutamol sulfate, and 6.47 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix for 20 min at 72 rpm, then leave it standing for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0126] (3) Filling:

[0127] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and leave it standing for 24 h under the conditions of 20 °C and 45% RH humidity to obtain an inhalable powder aerosol.

[0128] Example 4

[0129] This example provides an inhalable powder aerosol, which is prepared by the following steps:

[0130] (1) Prepare raw materials:

[0131] Weigh 0.36 g of budesonide, 0.24 g of salbutamol, and 19.40 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, the D50 of salbutamol is 1.90 μm, and the D50 of lactose is 119.4 μm.

[0132] (2) Mix raw materials (one-step method):

[0133] Add 19.40 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 12.94 g of lactose, and then successively add 0.36 g of budesonide, 6.47 g of the previously taken out lactose, 0.24 g of salbutamol sulfate, and 6.47 g of the previously taken out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0134] (3) Filling:

[0135] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhaled powder aerosol.

[0136] Example 5

[0137] This example provides an inhaled powder aerosol. The difference between this example and Example 4 lies in step (2). The step (2) (three-step method) of this example is as follows:

[0138] Add 19.40 g of lactose ( 100) to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.70 g of lactose, and then successively add 0.12 g of salbutamol sulfate and the previously taken out 9.70 g of lactose to the three-dimensional mixer, mix at 72 rpm for 3 min, let stand for 3 min to obtain the first mixed system; then take out 50 wt% of the first mixed system from the three-dimensional mixer, successively add 0.36 g of budesonide and the previously taken out 50 wt% of the first mixed system to the three-dimensional mixer, mix at 72 rpm for 3 min, let stand for 3 min to obtain the second mixed system; then take out 50 wt% of the second mixed system from the three-dimensional mixer, successively add 0.12 g of salbutamol sulfate and the previously taken out 50 wt% of the second mixed system to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0139] Example 6

[0140] This example provides an inhaled powder aerosol. The difference between this example and Example 4 lies in step (2). The step (2) (two-step method) of this example is as follows:

[0141] Add 19.40 g of lactose ( 100) Lactose was added to a three-dimensional mixer and premixed at 72 rpm for 5 min. 9.70 g of lactose was taken out, and then 0.24 g of salbutamol sulfate and the previously taken out 9.70 g of lactose were successively added to the three-dimensional mixer. It was mixed at 72 rpm for 5 min and left to stand for 3 min to obtain a mixed system. Then, 50 wt% of the mixed system was taken out from the three-dimensional mixer, 0.36 g of budesonide and the previously taken out 50 wt% of the mixed system were successively added to the three-dimensional mixer. It was mixed at 72 rpm for 20 min and then left to stand for 3 min. The mixed powder was taken out from the three-dimensional mixer to obtain the mixed powder.

[0142] Example 7

[0143] This example provides an inhalable powder aerosol, which is prepared by the following steps:

[0144] (1) Prepare raw materials:

[0145] Weigh 0.18 g of budesonide, 0.48 g of salbutamol sulfate and 19.34 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, the D50 of salbutamol sulfate is 1.90 μm, and the D50 of lactose is 119.4 μm.

[0146] (2) Mix raw materials (two-step method):

[0147] Add 19.34 g of lactose to a three-dimensional mixer and premix at 72 rpm for 5 min. Take out 9.67 g of lactose, and then successively add 0.48 g of salbutamol sulfate and the previously taken out 9.67 g of lactose to the three-dimensional mixer. Mix at 72 rpm for 5 min and leave to stand for 3 min to obtain a mixed system. Then, take out 50 wt% of the mixed system from the three-dimensional mixer, successively add 0.18 g of budesonide and the previously taken out 50 wt% of the mixed system to the three-dimensional mixer. Mix at 72 rpm for 20 min and then leave to stand for 3 min. Take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0148] (3) Filling:

[0149] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler and leave it to stand at 20 °C and 45% RH humidity for 24 h to obtain the inhalable powder aerosol.

[0150] Example 8

[0151] This example provides an inhalable powder aerosol, which is prepared by the following steps:

[0152] (1) Prepare raw materials:

[0153] Weigh 0.36 g of budesonide, 0.48 g of salbutamol sulfate, and 19.16 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, the D50 of salbutamol sulfate is 1.90 μm, and the D50 of lactose is 119.4 μm.

[0154] (2) Mixing of raw materials (two-step method):

[0155] Add 19.16 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.58 g of lactose, then sequentially add 0.48 g of salbutamol sulfate and the previously taken out 9.58 g of lactose to the three-dimensional mixer, mix at 72 rpm for 5 min, let stand for 3 min to obtain a mixed system; then take out 50 wt% of the mixed system from the three-dimensional mixer, sequentially add 0.36 g of budesonide and the previously taken out 50 wt% of the mixed system to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0156] (3) Filling:

[0157] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhaled powder aerosol.

[0158] Example 9

[0159] This example provides an inhaled powder aerosol. The difference between this example and Example 1 is that the inhaler is replaced with a disposable inhaler.

[0160] Example 10

[0161] This example provides an inhaled powder aerosol. The difference between this example and Example 1 is that the inhaler is replaced with a capsule-type inhaler (purchased from Shanghai Huarui Aerosol Co., Ltd., model BDD11).

[0162] Example 11

[0163] This example provides an inhaled powder aerosol, which is prepared by the following steps:

[0164] (1) Prepare raw materials:

[0165] Weigh 0.036 g of budesonide, 0.23 g of levosalbutamol hydrochloride, and 19.734 g of lactose ( (100); wherein, the D50 of budesonide is 2.34 μm, the D50 of levosalbutamol hydrochloride is 2.00 μm, and the D50 of lactose is 119.4 μm.

[0166] (2) Raw material mixing (one-step method):

[0167] Add 19.734 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 13.156 g of lactose, and then sequentially add 0.036 g of budesonide, 6.578 g of the aforementioned taken-out lactose, 0.23 g of levosalbutamol hydrochloride, and 6.578 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0168] (3) Filling:

[0169] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhalable powder aerosol.

[0170] Example 12

[0171] This example provides an inhalable powder aerosol, which is prepared by the following steps:

[0172] (1) Prepare raw materials:

[0173] Weigh 0.36 g of budesonide, 0.0115 g of levosalbutamol hydrochloride, and 19.6285 g of lactose ( (100); wherein, the D50 of budesonide is 2.34 μm, the D50 of levosalbutamol hydrochloride is 2.00 μm, and the D50 of lactose is 119.4 μm.

[0174] (2) Raw material mixing (one-step method):

[0175] Add 19.6285 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 13.086 g of lactose, and then sequentially add 0.36 g of budesonide, 6.543 g of the aforementioned taken-out lactose, 0.0115 g of levosalbutamol hydrochloride, and 6.543 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0176] (3) Filling:

[0177] Take 0.5 g of the mixed powder obtained in step (2) and fill it into A reservoir-type inhaler was left standing for 24 h under the conditions of 20 °C and 45% RH humidity to obtain an inhalable powder aerosol.

[0178] Comparative Example 1

[0179] This comparative example provides an inhalable powder aerosol, which is prepared by the following steps:

[0180] (1) Prepare raw materials:

[0181] Weigh 0.36 g of budesonide and 19.64 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, and the D50 of lactose is 119.4 μm.

[0182] (2) Mix raw materials (one-step method):

[0183] Add 19.64 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.82 g of lactose, then sequentially add 0.36 g of budesonide and 9.82 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0184] (3) Filling:

[0185] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and leave it standing for 24 h under the conditions of 20 °C and 45% RH humidity to obtain an inhalable powder aerosol.

[0186] Comparative Example 2

[0187] This comparative example provides an inhalable powder aerosol, which is prepared by the following steps:

[0188] (1) Prepare raw materials:

[0189] Weigh 0.036 g of budesonide and 19.964 g of lactose ( 100); among them, the D50 of budesonide is 2.34 μm, and the D50 of lactose is 119.4 μm.

[0190] (2) Mix raw materials (one-step method):

[0191] Add 19.964 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.982 g of lactose, then sequentially add 0.036 g of budesonide and 9.982 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0192] (3) Filling:

[0193] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and leave it standing for 24 h under the conditions of 20 °C and 45% RH humidity to obtain an inhalable powder aerosol.

[0194] Comparative Example 3

[0195] This comparative example provides an inhalable powder aerosol, which is prepared by the following steps:

[0196] (1) Prepare raw materials:

[0197] Weigh 0.23 g of levosalbutamol hydrochloride and 19.77 g of lactose ( 100); among them, the D50 of levosalbutamol hydrochloride is 2.00 μm, and the D50 of lactose is 119.4 μm.

[0198] (2) Raw material mixing (one-step method):

[0199] Add 19.77 g of lactose to a three-dimensional mixer, premix it at 72 rpm for 5 min, take out 9.885 g of lactose, then sequentially add 0.23 g of levosalbutamol hydrochloride and 9.885 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix it at 72 rpm for 20 min, then leave it standing for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0200] (3) Filling:

[0201] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and leave it standing for 24 h under the conditions of 20 °C and 45% RH humidity to obtain an inhalable powder aerosol.

[0202] Comparative Example 4

[0203] This comparative example provides an inhalable powder aerosol, which is prepared by the following steps:

[0204] (1) Prepare raw materials:

[0205] Weigh 0.0115 g of levosalbutamol hydrochloride and 19.9885 g of lactose ( 100); among them, the D50 of levosalbutamol hydrochloride is 2.00 μm, and the D50 of lactose is 119.4 μm.

[0206] (2) Raw material mixing (one-step method):

[0207] Add 19.9885 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.9942 g of lactose, and then successively add 0.0115 g of levalbuterol hydrochloride and 9.9942 g of the previously taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0208] (3) Filling:

[0209] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhaled powder aerosol.

[0210] Comparative Example 5

[0211] This comparative example provides an inhaled powder aerosol, which is prepared by the following steps:

[0212] (1) Prepare raw materials:

[0213] Weigh 0.2628 g of levalbuterol tartrate and 19.7372 g of lactose ( 100); among them, the D50 of levalbuterol tartrate is 1.82 μm, and the D50 of lactose is 119.4 μm.

[0214] (2) Raw material mixing (one-step method):

[0215] Add 19.7372 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.8686 g of lactose, and then successively add 0.2628 g of levalbuterol tartrate and 9.8686 g of the previously taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let stand for 3 min, and take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0216] (3) Filling:

[0217] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhaled powder aerosol.

[0218] Comparative Example 6

[0219] This comparative example provides an inhaled powder aerosol, which is prepared by the following steps:

[0220] (1) Prepare raw materials:

[0221] Weigh 0.24 g of levalbuterol sulfate and 19.76 g of lactose ( 100); among them, the D50 of levalbuterol sulfate is 2.01 μm, and the D50 of lactose is 119.4 μm.

[0222] (2) Raw material mixing (one-step method):

[0223] Add 19.76 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.88 g of lactose, then sequentially add 0.24 g of levalbuterol sulfate and 9.88 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let it stand for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0224] (3) Filling:

[0225] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhalable powder aerosol.

[0226] Comparative Example 7

[0227] This comparative example provides an inhalable powder aerosol, which is prepared by the following steps:

[0228] (1) Prepare raw materials:

[0229] Weigh 0.24 g of salbutamol sulfate and 19.76 g of lactose ( 100); among them, the D50 of salbutamol sulfate is 1.90 μm, and the D50 of lactose is 119.4 μm.

[0230] (2) Raw material mixing (one-step method):

[0231] Add 19.76 g of lactose to a three-dimensional mixer, premix at 72 rpm for 5 min, take out 9.88 g of lactose, then sequentially add 0.24 g of salbutamol sulfate and 9.88 g of the aforementioned taken-out lactose to the three-dimensional mixer, mix at 72 rpm for 20 min, then let it stand for 3 min, take out the mixed powder from the three-dimensional mixer to obtain the mixed powder.

[0232] (3) Filling:

[0233] Take 0.5 g of the mixed powder obtained in step (2) and fill it into a reservoir-type inhaler, and let it stand at 20 °C and 45% RH humidity for 24 h to obtain an inhalable powder aerosol.

[0234] Experimental Example 1

[0235] The hygroscopicity of the raw materials used in Examples 1 to 12 and Comparative Examples 1 to 7 was tested, and the test results of hygroscopicity are shown in Table 1.

[0236] The test steps for hygroscopicity are as follows: Take a weighing bottle, let it stand for 24 h under the conditions of 25°C and 80% RH humidity, weigh the mass of the weighing bottle, and record it as m1; Add 0.3 g of different raw materials (i.e., budesonide, levosalbutamol hydrochloride, levosalbutamol tartrate, levosalbutamol sulfate or salbutamol sulfate) to the weighing bottle respectively, weigh the total mass of the weighing bottle and the different raw materials in the weighing bottle, and record it as m2; Place the weighing bottle containing the raw materials under the conditions of 25°C and 80% RH humidity and let it stand for 24 h, weigh the total mass of the weighing bottle and the different raw materials in the weighing bottle, and record it as m3; Conduct five parallel experiments, and the percentage of hygroscopic weight gain = (m3 - m2) / (m2 - m1)×100%.

[0237] The basis for evaluating hygroscopic properties is as follows: When the percentage of hygroscopic weight gain is 0.00%, it indicates no hygroscopicity; when the percentage of hygroscopic weight gain ≤ 0.2%, it indicates almost no hygroscopicity; when the percentage of hygroscopic weight gain > 0.2% and ≤ 2%, it indicates slightly hygroscopic.

[0238] Table 1

[0239] Percentage of weight gain due to hygroscopicity (%) Hygroscopicity performance evaluation Budesonide 0.11 Almost no hygroscopicity Levosalbutamol hydrochloride 0.00 No hygroscopicity Levosalbutamol tartrate 0.14 Almost no hygroscopicity Levosalbutamol sulfate 0.42 Slightly hygroscopic Salbutamol sulfate 0.10 Almost no hygroscopicity

[0240] As can be seen from Table 1, the raw materials used in Examples 1 to 12 and Comparative Examples 1 to 7 are relatively stable, not easily hygroscopic, have high stability, and are beneficial to better realizing the drug delivery of the inhaled powder aerosol; compared with salbutamol sulfate, levosalbutamol sulfate and levosalbutamol tartrate, levosalbutamol hydrochloride is the least hygroscopic.

[0241] Experimental Example 2

[0242] The delivery efficiency of the inhaled powder aerosols prepared in Examples 1 to 12 and Comparative Examples 1 to 7 was tested. The differences in the preparation of the inhaled powder aerosols in Examples 1 to 12 and Comparative Examples 1 to 7 are shown in Table 2, and the feeding concentrations and actual concentrations of the first component and the second component in the inhaled powder aerosols prepared in Examples 1 to 12 are shown in Table 3. The test results of the delivery efficiency of the inhaled powder aerosols prepared in Examples 1 to 12 and Comparative Examples 1 to 7 are shown in Table 4.

[0243] The test steps for the actual concentrations of the first component and the second component in the inhaled powder aerosol are as follows: Weigh budesonide and salbutamol (i.e., levosalbutamol hydrochloride, levosalbutamol tartrate, levosalbutamol sulfate or salbutamol sulfate) respectively, and prepare a standard solution with a solution concentration of 10 μg / mL to 30 μg / mL using a 40% methanol aqueous solution (i.e., the concentration is C0-1 Budesonide standard solution and salbutamol standard solution with a concentration of C 0-2 (wherein the mass of levalbuterol hydrochloride, levalbuterol tartrate, levalbuterol sulfate or salbutamol sulfate is calculated as salbutamol), and the different standard solutions prepared above are respectively passed through liquid chromatography to detect the chromatogram integration areas of budesonide standard solutions with different concentrations (denoted as S 0-1 ) and the chromatogram integration areas of salbutamol standard solutions with different concentrations (denoted as S 0-2 ). Subsequently, 10 mg - 20 mg of the mixed powders prepared in Examples 1 - 12 are respectively weighed, dissolved with 40% methanol aqueous solution and fixed volume to a 10 mL volumetric flask to obtain the test solutions. The above test solutions are passed through liquid chromatography to detect the corresponding chromatogram integration areas of budesonide and salbutamol in the test solutions, denoted as S1 and S2 respectively. Through the concentration of the standard solution and the area ratio of the chromatogram, the concentration C1 of budesonide in the test solution (unit: μg / mL, C1 = (C 0-1 ×S1) / S 0-1 ) and the concentration C2 of salbutamol (unit: μg / mL, C2 = (C 0-2 ×S2) / S 0-2 ) are obtained. And from the mass M (unit: μg) of the weighed mixed powder, the mass percentage D1 of budesonide in the mixed powder (unit: %, D1 = [(C1×10 mL) / M)]×100%) and the mass percentage D2 of salbutamol in the mixed powder (unit: %, D2 = [(C2×10 mL) / M)]×100%) are calculated.

[0244] The test steps for the delivery efficiency are as follows: Use the Next Generation Impactor (NGI) device of Copley company to detect the delivery dose (DD), fine particle dose (FPD), mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) of the inhaled powder aerosols prepared in Examples 1 - 12 and Comparative Examples 1 - 7.

[0245] Table 2

[0246]

[0247] In Table 2, " / " indicates: no corresponding parameter; the total feeding amount of the first component, the second component and lactose in Examples 1 - 12 and Comparative Examples 1 - 7 is 20 g.

[0248] Table 3

[0249]

[0250]

[0251] In Table 3, "feeding concentration" means the ratio of "the feeding mass of the first component or the second component (calculated as salbutamol)" to "the total mass of the first component and / or the second component (calculated as the feeding amount) and lactose (i.e., 20 g)".

[0252] Table 4

[0253]

[0254] In Table 4, " / " means: no corresponding parameter.

[0255] It can be seen from Table 2 to Table 4 that the delivery efficiencies of the first component and the second component in the inhalable powder aerosols prepared in Examples 1 to 12 are both relatively high.

[0256] From the comparison between Example 1 and Comparative Example 1 and Comparative Example 3, the comparison between Example 2 and Comparative Example 1 and Comparative Example 5, the comparison between Example 3 and Comparative Example 1 and Comparative Example 6, the comparison between Examples 4 to 6 and Comparative Example 1 and Comparative Example 7, the comparison between Example 11 and Comparative Example 2 and Comparative Example 3, and the comparison between Example 12 and Comparative Example 1 and Comparative Example 4, it can be seen that the delivery efficiency of the drug components of the compound inhalable powder aerosol (i.e., containing both the first component and the second component) is higher than that of the corresponding single-component inhalable powder aerosol (i.e., containing only the first component or only the second component).

[0257] From the comparison between Examples 1 to 4, it can be seen that compared with using salbutamol sulfate as the second component (i.e., Example 4), using levosalbutamol hydrochloride (i.e., Example 1), levosalbutamol tartrate (i.e., Example 2), and levosalbutamol sulfate (i.e., Example 3) as the second component can further improve the delivery efficiency of the first component and the second component in the inhalable powder aerosol; among them, when using levosalbutamol hydrochloride (i.e., Example 1) as the second component, the delivery efficiency of the first component and the second component in the inhalable powder aerosol is the highest.

[0258] From the comparison between Examples 4 to 6, it can be seen that the mixing method of the raw materials can further affect the delivery efficiency of the first component and the second component in the inhalable powder aerosol; compared with using the two-step method (i.e., Example 6), using the one-step method (i.e., Example 4) and the three-step method (i.e., Example 5) can further improve the delivery efficiency of the first component and the second component in the inhalable powder aerosol.

[0259] From the comparison between Example 1 and Examples 9 to 10, it can be seen that the selection of the inhalation device in the inhalable powder aerosol can further affect the delivery efficiency of the first component and the second component in the inhalable powder aerosol; compared with the inhalation device using a disposable inhaler (i.e., Example 9) and a capsule inhaler (i.e., Example 10), when the inhalation device uses a reservoir inhaler (i.e., Example 9), the delivery efficiency of the first component and the second component in the inhalable powder aerosol can be further improved.

[0260] Experimental Example 3

[0261] The aerodynamic distribution of the inhalable powder aerosols prepared in Examples 1 to 3 was tested. For the differences in the preparation of the inhalable powder aerosols in Examples 1 to 3, please refer to Table 2, and the test results of the delivery performance of the inhalable powder aerosols prepared in Examples 1 to 3 are shown in Table 5 and Figures 1 to 3 as follows.

[0262] The test steps for the aerodynamic distribution are as follows: Use the Next Generation Impactor (NGI) device of Copley Company to detect the aerodynamic particle size distribution (APSD) of the inhalable powder aerosols prepared in Examples 1 to 3. The detection items include: the distribution of the inhalable powder aerosol at each level of the NGI; among them, ADP is the Adapter (device adapter), IND is the throat part of the NGI, Pre is the pre-separator of the NGI, S1 - S7 represent the 7 impact plates of the NGI, and MOC (Micro orifice collector) represents the micro-orifice collector of the NGI.

[0263] Figure 1 In , levalbuterol is levalbuterol hydrochloride; Figure 2 In , levalbuterol is levalbuterol tartrate; Figure 3 In , levalbuterol is levalbuterol sulfate.

[0264] Table 5

[0265]

[0266]

[0267] From Table 2, Table 3 and Table 5 and Figures 1 to 3It can be seen that the inhalable powder aerosols prepared in Examples 1 to 3 all have high delivery performance, and the proportions of the first component and the second component at the S3 to S5 levels are both high; compared with the case where the second component is levalbuterol tartrate (i.e., Example 2) and levalbuterol sulfate (i.e., Example 3), when the second component is levalbuterol hydrochloride (i.e., Example 1), the proportions of the first component and the second component at the S3 to S5 levels are the highest.

[0268] Experimental Example 4

[0269] The delivery uniformity of the inhalable powder aerosols prepared in Examples 1 to 3 was tested. For the differences in the preparation of the inhalable powder aerosols in Examples 1 to 3, please refer to Table 2. The test results of the delivery performance of the inhalable powder aerosols prepared in Examples 1 to 3 are shown in Table 6 and Figures 4 to 6 as follows.

[0270] The test steps for delivery uniformity are as follows: Use the Next Generation Impactor (NGI) device of Copley to detect the delivery dose uniformity (DDU) of the inhalable powder aerosols prepared in Examples 1 to 3.

[0271] Figure 4 In [specific context], the levalbuterol is levalbuterol hydrochloride; Figure 5 In [specific context], the levalbuterol is levalbuterol tartrate; Figure 6 In [specific context], the levalbuterol is levalbuterol sulfate.

[0272] Table 6

[0273]

[0274] From Table 2, Table 3 and Table 6 and Figures 4 to 6 it can be seen that the inhalable powder aerosols prepared in Examples 1 to 3 all have high delivery uniformity; compared with the case where the second component is levalbuterol tartrate (i.e., Example 2) and levalbuterol sulfate (i.e., Example 3), when the second component is levalbuterol hydrochloride (i.e., Example 1), the delivery uniformity of the inhalable powder aerosol is the highest.

[0275] Experimental Example 5

[0276] The delivery stability of the inhalable powder aerosols prepared in Examples 1 to 3 was tested. For the differences in the preparation of the inhalable powder aerosols in Examples 1 to 3, please refer to Table 2. The test results of the delivery performance of the inhalable powder aerosols prepared in Examples 1 to 3 are shown in Table 7 and Figures 7 to 8 as follows.

[0277] The test procedure for delivery stability is as follows: The inhalable powder aerosols prepared in Examples 1 to 3 were placed under the conditions of 40 °C and 75% RH humidity and allowed to stand for 0 days, 14 days, 30 days, and 60 days respectively; then the Next Generation Impactor (NGI) device of Copley was used to detect the delivery stability of the corresponding inhalable powder aerosols, and the detection items included: delivered dose (DD), fine particle dose (FPD), and fine particle fraction (FPF).

[0278] Table 7

[0279]

[0280] As can be seen from Table 2, Table 3, and Table 7, and Figures 7 to 8 it can be seen that the inhalable powder aerosols prepared in Examples 1 to 3 all have high delivery stability; compared with when the second component is levosalbutamol hydrochloride (i.e., Example 1) and levosalbutamol sulfate (i.e., Example 3), when the second component is levosalbutamol tartrate (i.e., Example 2), the delivery stability of the inhalable powder aerosol is the highest.

[0281] Experimental Example 6

[0282] The inhalable powder aerosol prepared in Example 4 was used for verification of the guinea pig asthma model, and the verification results are shown in Table 8 and Table 9.

[0283] The comparative verification procedure of the inhalable powder aerosol prepared in Example 4 and the salbutamol sulfate powder aerosol (i.e., single agent) is as follows:

[0284] (1) Construction of the guinea pig asthma model:

[0285] ① Use ovalbumin (OVA) to induce airway hyperresponsiveness in guinea pigs to establish an asthma model. Twenty guinea pigs of the British breed, weighing 300 ± 50 g, with an equal number of males and females, were selected.

[0286] ② Prepare a glass airtight container (i.e., the drug administration box). The glass airtight container has an air inlet with a diameter of 2 cm, which can be connected to the flow head of the recording box or the drug delivery nozzle of the drug delivery device. And the glass airtight container has an air outlet with a diameter of 1 cm with a drug filter membrane, which can balance the air pressure in the drug administration box during drug administration and maintain the state of the animal during the drug administration process.

[0287] ③ On the first day of the experiment, 1 mL of 10 wt% ovalbumin (with normal saline as the solvent) was intraperitoneally injected for the first sensitization. Two weeks later, the guinea pigs were placed in the drug administration box prepared in step ②, and a 1 wt% ovalbumin saline solution was sprayed with a Type 402 ultrasonic nebulizer until asthma symptoms appeared, lasting for several seconds to several minutes each time, once a day for 5 consecutive days to establish an asthma model.

[0288] ④ After stopping nebulization, observe the induction latency of the guinea pigs (i.e., the time from the start of spraying to the appearance of asthma symptoms such as dyspnea, convulsions, and falling in the guinea pigs). Those with a latency exceeding 2 min were discarded. The selected ones were returned to the animal breeding cage, allowed to rest, and freely fed and given water, and were used after 24 h.

[0289] ⑤ After screening, 10 guinea pigs (5 males and 5 females) were used for the pharmacodynamic experiment.

[0290] (2) Observation of airway resistance and dynamic compliance:

[0291] ① 24 hours after the last nebulization attack, the guinea pigs were anesthetized by intraperitoneal injection of 2 wt% sodium pentobarbital (with normal saline as the solvent) (2 mL / kg). The guinea pigs were fixed with their abdomens upward, the neck skin was incised, and tracheal intubation and jugular vein intubation were performed.

[0292] ② After the operation, the guinea pigs were placed in a 2 L guinea pig plethysmograph box. The positive electrode, negative electrode, and ground wire of the electrocardiogram measurement probe were inserted into the left upper limb, right upper limb, and right lower limb of the guinea pigs respectively. The tracheal intubation was extended outside the plethysmograph box through the pipeline on the box wall and connected to the flow head for measuring the respiratory flow rate value.

[0293] ③ An intrathoracic pressure cannula was inserted between the fourth and fifth ribs on the right chest of the guinea pig. This cannula was connected to a pressure transducer through a catheter from the opening on the side of the plethysmograph box and connected to a Power lab (ADInstruments, Australia) biological signal acquisition and processing system through a bridge amplifier.

[0294] ④ After all the above pipelines were connected, the lid of the plethysmograph box was covered and made completely airtight. At this time, there was another opening on the side of the plethysmograph box connected to the bridge amplifier to measure the monitoring indicators after the animal inhaled the corresponding drug. The airway resistance (RL) and dynamic compliance (Cdyn) were measured before the test drug administration as the baseline values before drug administration.

[0295] (3) Grouping of drug administration doses:

[0296] ① The test animals were given the inhalable powder aerosol prepared in Example 4 as the test drug, including a blank group (inhaled blank excipient lactose), a positive control group (inhaled salbutamol sulfate powder aerosol 200 μg (calculated as salbutamol)), test group A (inhaled 1-fold dose of the inhalable powder aerosol prepared in Example 4, with a target delivery dose of 80 μg budesonide / 45 μg salbutamol sulfate (wherein the mass of salbutamol sulfate is calculated as salbutamol)), test group B (inhaled 2-fold dose of the inhalable powder aerosol prepared in Example 4, with a target delivery dose of 160 μg budesonide / 90 μg salbutamol sulfate (wherein the mass of salbutamol sulfate is calculated as salbutamol)), test group C (inhaled 4-fold dose of the inhalable powder aerosol prepared in Example 4, with a target delivery dose of 320 μg budesonide / 180 μg salbutamol sulfate (wherein the mass of salbutamol sulfate is calculated as salbutamol)), and test group D (inhaled 6-fold dose of the inhalable powder aerosol prepared in Example 4, with a target delivery dose of 480 μg budesonide / 270 μg salbutamol sulfate (wherein the mass of salbutamol sulfate is calculated as salbutamol)).

[0297] ② The administered drug was placed in a dosing container. One end of the dosing container was connected to a compressed inhaler, and the other end was connected to a tracheal cannula through a dosing nozzle. The air pump of the compressed inhaler was started, and the powder aerosol was carried into the dosing chamber by the air flow. The guinea pigs inhaled the drug through the mouth and nose.

[0298] (4) Efficacy test:

[0299] ① Tracheal challenge: The flow head connected to the wall of the recording chamber was removed, and the dosing nozzle was connected and made to be connected to the tracheal cannula. The dosing device was removed, and the flow head was reconnected to the recording chamber. After the animal was stable for 1 - 2 min, a 1 wt% ovalbumin saline solution was nebulized with a Model 402 ultrasonic nebulizer until asthma symptoms appeared, and the changes in parameters were observed. Wait for the animal's condition to stabilize (about 2 hours).

[0300] ② Administration to the blank group: The flow head connected to the wall of the recording chamber was removed, and the dosing nozzle was connected and made to be connected to the tracheal cannula. The drug of the blank dose group was inhaled by the animal until the blank excipient in the dosing container was completely administered. The dosing device was removed, and the flow head was reconnected to the recording chamber. After the animal was stable for 1 - 2 min, 0.5 mL of 15 μg / mL histamine was injected intravenously, and the changes in parameters were observed. Wait for the animal's condition to stabilize (about 2 hours).

[0301] ③ Administration to other dose groups in sequence: According to the above step ②, 10 asthmatic guinea pigs were given the drug in sequence, from test group A, test group B, test group C, and test group D. The dosing interval was 2 hours each time. After dosing, the recording chamber was connected in sequence according to the experimental step 2, and the airway resistance (RL) and dynamic compliance (Cdyn) were measured.

[0302] ④ After 10 animals successively completed inhalation administration in the blank and each drug dosage group, RL and Cdyn were measured respectively, and the baseline values were subtracted to obtain the airway resistance increase rate and the dynamic compliance decrease rate, and statistical analysis was performed.

[0303] (5) Test results:

[0304] By calculating the data collected by Power lab, the changes in airway resistance (RL) and dynamic compliance (Cdyn) can be obtained. The experimental results are all expressed as mean ± standard error (X±SE), and data analysis is performed using SPSS 24.0 software. One-way ANOVA is used for comparison between groups, and the LSD method is used for multiple analysis. The statistical test standard is α = 0.05; the verification results are shown in Table 7.

[0305] Table 7 Changes in respiratory parameters of guinea pigs after drug administration in each group (n = 10, X±SE)

[0306] Dose administered Percentage increase in airway resistance Percentage decrease in dynamic lung compliance Blank dose 425.37±85.25 -83.85±1.63 Positive control <![CDATA[140.34±21.12 ÷ > <![CDATA[-62.24±3.57 ÷ > Test group A <![CDATA[145.67±14.85 ÷ > <![CDATA[-62.09±5.52 ÷ > Test group B <![CDATA[132.17±13.85 ÷ > <![CDATA[-50.89±4.34 ÷ > Test group C <![CDATA[65.97±14.05 ÷ *]]> <![CDATA[-38.82±4.95 ÷ *]]> Test group D <![CDATA[35.15±11.56 ÷ *]]> <![CDATA[-38.59±4.53 ÷ *]]>

[0307] In Table 7, "÷" indicates: p < 0.05 compared with the blank group; "*" indicates: p < 0.05 compared with the positive control group in the test group.

[0308] It can be seen from Table 1 that compared with the blank excipient group, the airway resistance increase rates of the positive control group and test groups A - D after drug administration were all significantly reduced (p < 0.01); compared with the blank excipient group, the dynamic lung compliance decrease rates of the positive control group and test groups A - D after drug administration were all significantly improved (p < 0.01).

[0309] Compared with the positive control group, the airway resistance increase rates of test groups C and D were both significantly reduced (p < 0.01); compared with the positive control group, the dynamic lung compliance decrease rates of test groups C and D were both significantly improved (p < 0.01). Compared with the positive control group, the airway resistance increase rates of test groups A and B were not significantly reduced (p = 0.059, P = 0.068); compared with the positive control group, the dynamic lung compliance decrease rates of test groups A and B were not significantly improved (p = 0.063, P = 0.060).

[0310] The test results show that test groups A and B have the same effect as the positive control group, while test groups C and D can significantly reduce airway resistance and improve lung compliance after inhalation by asthmatic guinea pigs. This test proves that after compounding salbutamol sulfate and budesonide in a certain proportion and inhaling them into animals, the pulmonary function of guinea pigs can be significantly improved, and its effect can be significantly better than that of using salbutamol sulfate alone at the same dose; at the same time, compared with the positive control drug, low-dose salbutamol sulfate and budesonide can significantly reduce the dosage of salbutamol sulfate, while the effect of improving lung function is not significantly reduced.

[0311] The comparative verification steps of the inhalable powder aerosol prepared in Example 4 and the budesonide powder aerosol (i.e., the single agent) are as follows:

[0312] (1) Construction of a guinea pig asthma model:

[0313] ① Use ovalbumin (OVA) to induce airway hyperresponsiveness in guinea pigs to establish an asthma model. Select 20 guinea pigs of the British breed, with a body weight of 300 ± 50 g, and an equal number of males and females.

[0314] ② Prepare a glass airtight container (i.e., the drug administration box). The glass airtight container has an air inlet with a diameter of 2 cm, which can be connected to the flow head of the recording box or the drug delivery nozzle of the drug delivery device. And the glass airtight container has an air outlet with a diameter of 1 cm with a drug filter membrane, which can balance the air pressure in the drug administration box during drug administration and maintain the state of the animal during the drug administration process.

[0315] ③ On the first day of the experiment, intraperitoneally inject 1 mL of 10 wt% ovalbumin (the solvent is physiological saline) for the first sensitization. Two weeks later, place the guinea pigs in the drug administration box prepared in step ②, and use a Model 402 ultrasonic nebulizer to spray 1 wt% ovalbumin saline solution until asthma symptoms appear, for several seconds to several minutes each time, once a day for 5 consecutive days to establish an asthma model.

[0316] ④ After stopping atomization, observe the induction latency of the guinea pigs (i.e., the time from the start of spraying to the appearance of asthma symptoms such as dyspnea, convulsions, and falling in the guinea pigs). Those with a latency exceeding 2 min are discarded. The selected ones are returned to the animal breeding cage, allowed to rest, and freely eat and drink water, and are reserved for use 24 h later.

[0317] ⑤ After screening, 10 guinea pigs (5 males and 5 females) are used for the pharmacodynamic experiment.

[0318] (2) Observation of forced expiratory volume in 0.3 seconds and forced vital capacity:

[0319] ① 24 hours after the last atomization attack, anesthetize the guinea pigs by intraperitoneal injection of 2 wt% pentobarbital sodium (the solvent is physiological saline) (2 mL / kg). Fix the whole body of the guinea pigs with their abdomens facing up, cut the skin of the neck, and perform tracheal intubation.

[0320] ② After the operation, place the guinea pigs in a guinea pig recording box with a volume of 2 L, and insert the positive electrode, negative electrode, and ground wire of the electrocardiogram measurement probe into the left upper limb, right upper limb, and right lower limb of the guinea pigs respectively. Extend the tracheal intubation outside the recording box through the pipeline on the wall of the recording box and connect it to the flow head for the measurement of respiratory flow rate values.

[0321] ③Insert an intrathoracic pressure cannula between the fourth and fifth ribs on the right chest of the guinea pig. This cannula is connected to a pressure transducer through a catheter from the opening on the side of the plethysmograph box and is connected to a Powerlab (ADInstruments, Australia Ed Instruments Co., Ltd.) biological signal acquisition and processing system through a bridge amplifier.

[0322] ④After all the above pipelines are connected, cover the lid of the plethysmograph box and make it completely airtight. At this time, there is another opening on the side of the plethysmograph box connected to the bridge amplifier to measure the monitoring indicators after the animal inhales the corresponding drug. Measure the forced expiratory volume in 0.3 seconds (FEV0.3) and forced vital capacity (FVC) before drug administration as the baseline value before drug administration.

[0323] (3) Dosage grouping for drug administration:

[0324] ①Use the inhaled powder aerosol prepared in Example 4 as the test drug for the test animals, including a blank group (inhaling blank excipient lactose), a positive control group (inhaling 200 μg of budesonide powder aerosol (calculated as salbutamol)), test group A (inhaling 1-fold dose of the inhaled powder aerosol prepared in Example 4, with a target delivery dose of 80 μg of budesonide / 45 μg of salbutamol sulfate (where the mass of salbutamol sulfate is calculated as salbutamol)), test group B (inhaling 2-fold dose of the inhaled powder aerosol prepared in Example 4, with a target delivery dose of 160 μg of budesonide / 90 μg of salbutamol sulfate (where the mass of salbutamol sulfate is calculated as salbutamol)), test group C (inhaling 4-fold dose of the inhaled powder aerosol prepared in Example 4, with a target delivery dose of 320 μg of budesonide / 180 μg of salbutamol sulfate (where the mass of salbutamol sulfate is calculated as salbutamol)), and test group D (inhaling 6-fold dose of the inhaled powder aerosol prepared in Example 4, with a target delivery dose of 480 μg of budesonide / 270 μg of salbutamol sulfate (where the mass of salbutamol sulfate is calculated as salbutamol)).

[0325] ②Place the drug to be administered in the drug administration container. One end of the drug administration container is connected to a compressed inhaler, and the other end can be connected to the tracheal cannula with a drug administration nozzle. Start the air pump of the compressed inhaler, and the powder aerosol is driven by the air flow into the drug administration box, and the guinea pig inhales the drug through the mouth and nose.

[0326] (4) Efficacy test:

[0327] ①Tracheal challenge: Remove the flow head connected to the wall of the plethysmograph box, connect the drug administration nozzle, and make it connected to the tracheal cannula. Remove the drug administration device and reconnect the flow head to the plethysmograph box. After the animal is stable for 1 - 2 minutes, use a Model 402 ultrasonic nebulizer to spray a 1 wt% ovalbumin saline solution until asthma symptoms appear, observe the changes in parameters, and wait for the animal's condition to stabilize (about 2 hours).

[0328] ② Administration to the blank group: Disconnect the flow head connected to the wall of the recording box, connect the dosing nozzle, and connect it to the tracheal cannula. Start inhaling the drug of the blank dose group for the animal until all the blank excipients in the dosing container are completely administered. Withdraw the dosing device, reconnect the flow head to the recording box. After the animal stabilizes for 1 - 2 minutes, inject 0.5 mL of 15 μg / mL histamine intravenously, observe the changes in parameters, and wait for the animal's condition to stabilize (about 2 hours).

[0329] ③ Administration to other dose groups in sequence: Administer the drug to 10 asthmatic guinea pigs in sequence according to step ② above. From experimental group A, experimental group B, experimental group C, and experimental group D, with an interval of 2 hours between each administration. After administration, connect the recording box in sequence according to experimental step 2, and measure the forced expiratory volume in 0.3 seconds (FEV0.3) and forced vital capacity (FVC).

[0330] ④ After 10 animals have successively completed the inhalation administration of the blank and each dosing group, measure FEV0.3 and FVC respectively, calculate the ratio of the two, and conduct statistical analysis.

[0331] (5) Test results:

[0332] The forced expiratory volume in 0.3 seconds (FEV0.3) and forced vital capacity (FVC) can be obtained from the data collected by Power lab. The experimental results are all expressed as mean ± standard error (X ± SE). Data analysis is performed using SPSS 24.0 software. One-way ANOVA is used for comparison between groups, and the LSD method is used for multiple analysis. The statistical test standard is α = 0.05; the verification results are shown in Table 8.

[0333] Table 8 Changes in respiratory parameters of guinea pigs in each group after administration (n = 10, X ± SE)

[0334] Dose administered FEV0.3 (mL) FVC (mL) FEV0.3 / FVC (%) Blank dose 3.76±1.23 5.37±0.52 39.75±8.56 Positive control <![CDATA[5.31±1.08 ÷ > <![CDATA[7.21±1.31 ÷ > <![CDATA[55.24±6.49 ÷ > Test group A <![CDATA[5.70±1.25 ÷ > <![CDATA[8.03±1.21 ÷ > <![CDATA[57.33±5.24 ÷ > Test group B <![CDATA[7.06±1.42 ÷ > <![CDATA[9.52±1.64 ÷ > <![CDATA[65.3±7.31 ÷ > Test group C <![CDATA[9.11±1.13 ÷ *]]> <![CDATA[14.02±1.15 ÷ *]]> <![CDATA[74.9±8.63 ÷ *]]> Test group D <![CDATA[9.04±1.63 ÷ *]]> <![CDATA[13.75±1.53 ÷ *]]> <![CDATA[75.3±8.37 ÷ *]]>

[0335] In Table 8, "÷" indicates: p < 0.05 compared with the blank group; "*" indicates: p < 0.05 when the experimental group is compared with the positive control group.

[0336] As can be seen from Table 8, compared with the blank excipient group, the FEV0.3, FVC, and FEV0.3 / FVC of the positive control group and experimental groups A - D after administration are all significantly increased (p < 0.01); compared with the blank excipient group, the FEV0.3 and FVC of the positive control group and experimental groups A - D after administration are all significantly improved (p < 0.01).

[0337] Compared with the positive control group, the FEV0.3 and FVC of experimental group C and experimental group D were significantly increased (p < 0.01); compared with the positive control group, the FEV0.3 / FVC of experimental group C and experimental group D were significantly improved (p < 0.01). Compared with the positive control group, there were no significant improvements in FEV0.3, FVC, and FEV0.3 / FVC of experimental group A and experimental group B (p > 0.05).

[0338] The experimental results showed that experimental group A and experimental group B had comparable effects to the positive control group (budesonide powder for inhalation, 200 μg), while experimental group C and experimental group D could significantly increase FEV0.3 and FVC and improve FEV0.3 / FVC after inhalation by asthmatic guinea pigs. This experiment proved that the compound of salbutamol sulfate and budesonide in a certain proportion could significantly improve the pulmonary function of guinea pigs after inhalation administration, and its effect was significantly better than that of single use of budesonide at the same dose; meanwhile, compared with the positive control drug, low-dose salbutamol sulfate and budesonide could significantly reduce the dosage of budesonide, while the effect of improving pulmonary function was not significantly reduced.

[0339] In summary, the powder aerosol composition provided by the present application can make the delivery efficiency of the first component and the second component in the powder aerosol composition higher than the delivery efficiency of the first component alone and the delivery efficiency of the second component alone, which is beneficial to giving full play to the pharmacodynamic effects of the corticosteroid and β2-adrenergic receptor agonist in the powder aerosol composition, and can have the effect of treating inflammation while relieving respiratory obstruction for patients with pulmonary diseases such as mild and moderate asthma and chronic obstructive pneumonia.

[0340] The embodiments described above are some, but not all, of the embodiments of the present application. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application claimed, but merely represents selected embodiments of the present application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without creative efforts shall fall within the scope of protection of the present application.

Claims

1. A powder aerosol composition for inhalation, characterized in that, The aerosol composition for inhalation comprises a first component and a second component; Wherein, the first component is a corticosteroid or a pharmaceutically acceptable salt thereof or an isomer thereof; the second component is a β2-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof or an isomer thereof; The molar ratio of the first component to the second component is (0.1 - 25):

1.

2. The powder aerosol composition for inhalation according to claim 1, characterized in that, The β2-adrenergic receptor agonist is salbutamol; Or / and, the corticosteroid includes at least one of beclomethasone, budesonide, fluticasone, beclomethasone dipropionate, fluticasone propionate, ciclesonide, flunisolide, deflazacort, alclometasone, betamethasone, prednisone acetate, prednisolone acetate, chloroprednisone, clobetasol, clobetasone butyrate, clocortolone, cloprednol, cortisone, hydrocortisone, cortisone acetate, hydrocortisone acetate, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, diflorprednate, fluazacort, flurocortide, flumethasone, flunisolide, fluocinolone acetonide, fluocortin butyl, fluocortolone, flurometholone, fluperolone acetate, fluprednisolone acetate, fluocinolone acetonide, halometasone, hydrocortamate, etiprednol dicloacetate, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone sodium phosphate, prednisone, prednisolone valerate, rimcazole, triamcinolone, triamcinolone acetonide, cortivazol, amcinonide, and hexacetonide triamcinolone.

3. The powder aerosol composition for inhalation according to claim 2, characterized in that, The salbutamol is levalbuterol; Or / and, the corticosteroid is budesonide; Optionally, the levalbuterol includes at least one of levalbuterol hydrochloride, levalbuterol tartrate, and levalbuterol sulfate.

4. The powder aerosol composition for inhalation according to claim 3, characterized in that, The molar ratio of the first component to the second component is (0.25 - 4):1; Optionally, the molar ratio of the first component to the second component is (0.8 - 1.2):

1.

5. The powder aerosol composition for inhalation according to any one of claims 1 to 4, characterized in that, The D50 of the first component is 1.0 μm - 5.0 μm; Or / and, the D50 of the second component is 1.0 μm - 5.0 μm.

6. A powder aerosol for inhalation, characterized in that, The aerosol for inhalation comprises a carrier and the aerosol composition for inhalation according to any one of claims 1 - 5.

7. The powder aerosol for inhalation according to claim 6, characterized in that, The carrier is lactose; the total mass of the first component and the second component accounts for 0.1% - 12% of the mass of the aerosol for inhalation.

8. A method for preparing a powder aerosol for inhalation according to claim 6 or 7, characterized in that, Comprising: Mixing the first component, the second component, and the carrier.

9. The method for preparing a powder aerosol for inhalation according to claim 8, characterized in that, Dividing the carrier into a first part, a second part, and a third part; The preparation method of the aerosol for inhalation includes: sequentially adding the first part, the first component, the second part, the second component, and the third part into a mixing device, and then mixing; Optionally, the mass ratio of the first part, the second part, and the third part is 1:(0.8 - 1.2):(0.8 - 1.2); Optionally, the mixing adopts a three-dimensional mixing method, the rotation speed of the three-dimensional mixing is 20 rpm - 200 rpm, and the time of the three-dimensional mixing is 10 min - 60 min.

10. An inhalation powder aerosol, characterized in that, The inhaled powder aerosol includes an inhalation device and the powder aerosol for inhalation as described in claim 6 or 7; the powder aerosol for inhalation is placed in the inhalation device; Optionally, the inhalation device includes a reservoir-type inhalation device, a capsule-type inhalation device, a disposable inhalation device or a blister-type inhalation device; Optionally, the inhalation device is a reservoir-type inhalation device.

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