Drug formulations containing a combination of a long-acting inhaled glucocorticoid and a long-acting beta-2 receptor agonist

Abstract

A drug formulation comprising a combination of a long-acting inhaled steroid and a long-acting β2-receptor agonist, wherein the long-acting inhaled steroid drug is selected from fluticasone or a pharmaceutically acceptable salt thereof, the β2-receptor agonist is selected from vilanterol, olodaterol, indacaterol or a pharmaceutically acceptable salt, isomer or hydrate thereof, the dosage form of the drug formulation is a suspension or co-suspension, and the drug formulation can prevent or treat respiratory diseases such as asthma and chronic obstructive pulmonary disease.

Description

[Technical Field]

[0001] The present invention relates to an application filed with the China Patent Office on August 30, 2022, with application number 202211044167.9, and the invention title is "Long-acting inhalable Glucocortiroids and a long-acting β2 receptor agonist," the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of drug formulations, in particular long-acting inhalable Glucocortiroids and a long-acting beta2 receptor agonist. [Background technology]

[0003] Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease with a high prevalence and mortality rate, affecting public health and resulting in a heavy economic burden on society. COPD primarily presents with airflow limitation that is not fully reversible, and the condition usually worsens gradually. It is associated with an abnormal inflammatory response of lung tissue to harmful particles and gases. Due to the frequent inhalation and complex device requirements, treatment adherence is a common medical challenge for COPD and asthma patients. Therefore, novel long-acting beta-agonists (LABAs), which offer rapid onset and sustained 24-hour bronchodilatory activity, are expected to improve treatment adherence.

[0004] Current treatment and prevention strategies for COPD and asthma include long-acting bronchodilators or one or more inhaled corticosteroids. Glucocortiroids This includes the use of (ICS).

[0005] Inhaled bronchodilators are the cornerstone of COPD and asthma therapy because they can relieve symptoms, reduce disease attacks, and improve quality of life. By improving airflow limitation and hyperinflation, these medications can also reduce respiratory effort and improve exercise tolerance. Furthermore, bronchodilators can reduce respiratory muscle fatigue and improve mucociliary clearance function.

[0006] Bronchodilators include beta2 agonists, which can be short acting for immediate relief of asthma symptoms or long acting for long term prevention of asthma symptoms.

[0007] Long-acting β2 agonists (LABAs) or ultra-long-acting β2 agonists (ULABAs) are effective in improving lung function, reducing symptoms, and preventing exercise-induced dyspnea in patients with asthma and COPD. LABAs induce bronchodilation by prolonged relaxation of airway smooth muscle. LABAs also exert effects on non-smooth muscle, such as inhibiting airway smooth muscle cell proliferation and the release of inflammatory mediators, stimulating mucociliary transport, protecting airway mucosal cells, and attenuating neutrophil migration and activation.

[0008] LABAs can reduce the frequency of medication intake; commercially available twice-daily LABAs include salmeterol, formoterol, and arformoterol, while commercially available once-daily ultra-long-acting beta-2 agonist ULABAs include indacaterol, vilanterol, carmoterol, and olodaterol.

[0009] Although β2 agonists and anticholinergics provide symptomatic relief of bronchoconstriction, another component of inflammatory COPD, e.g. Glucocortiroids Monotherapy with inhaled corticosteroids is necessary, and most Glucocortiroids should be administered in a multiple dose scheme.

[0010] Cortico Glucocortiroidsexhibits inhibitory effects on inflammatory cells and inflammatory mediators involved in the pathology of respiratory disorders such as COPD. Glucocortiroids Glucocorticoid therapy is considered one of the most potentially effective treatments currently available for COPD.

[0011] Currently, LABAs and inhaled corticosteroids Glucocortiroids There are several commercially available inhaled drug compositions containing combinations with an ICS (Interventional Coronary Syndrome). Examples of drug combinations used to treat asthma and chronic obstructive pulmonary disease (COPD) include dry powder inhalers (DPIs) and aerosol inhalers (MDIs) such as salmeterol / fluticasone propionate (Advair® diskus and Advair® HFA) and formoterol fumarate dihydrate / budesonide (Symbicort), formoterol and mometasone (Dulera), salmeterol / fluticasone furoate (AirDuo® Respiclick®), and vilanterol, fluticasone furoate (Breo® Ellipta®).

[0012] Here, fluticasone furoate has the following chemical structure: [ka] Fluticasone furoate is a new synthetic fluorinated glucocorticoid approved by the US FDA in April 2007 for the treatment of seasonal and perennial allergic rhinitis. It is a potent glucocorticoid with rapid onset of action, making it a classic treatment for allergic rhinitis. Compared with fluticasone propionate, fluticasone furoate has higher receptor affinity, faster transport from the glucocorticoid receptor to the cell nucleus, longer nuclear retention time, greater selectivity than other glucocorticoids, reduced extracellular efflux, increased intracellular binding, and a longer duration of drug action. Compared with other glucocorticoids, fluticasone furoate has the strongest effect on maintaining epithelial integrity and reducing epithelial permeability in response to proteases or mechanical cell injury.

[0013] Vilanterol trifenatate has the following chemical structure: [ka] Vilanterol trifenatate is a new, orally inhaled, long-acting, selective beta-2 receptor agonist with a faster onset of action and a longer duration of action compared to salmeterol. Furthermore, vilanterol trifenatate has a high degree of selectivity, with an affinity for beta-2 receptors 1,000 times higher than for J31 and beta-2 receptors. Clinical trials have shown that vilanterol trifenatate's bronchodilatory effect can last 24 hours. Once-daily administration for four weeks of continuous therapy significantly improved pulmonary function in COPD patients, while also demonstrating good tolerability and safety, with a low incidence of adverse reactions to LABAs (elevated blood glucose, hypertension, decreased blood potassium levels, tremors, and palpitations).

[0014] Olodaterol hydrochloride (Olodaterol HCl) has the following chemical structure: [ka] Olodaterol hydrochloride is an ultra-long-acting β2-adrenergic receptor agonist with a longer half-life, allowing for once-daily dosing, which is expected to improve patient adherence. Olodaterol hydrochloride was developed by Boehringer Ingelheim and launched in the United States in 2014. The single-component formulation is marketed as Striverdi®, and the combined formulation is marketed as Spiolto®. It is a new, selective, fast-acting LABA with high selectivity for β2-adrenergic receptors (abbreviated as β2-receptors), rapid onset of action, and a long half-life of more than 12 hours, allowing it to maintain 24-hour bronchodilatory activity, allowing it to be administered once daily.

[0015] Indacaterol maleate has the following chemical structure: [ka] Indacaterol is a long-acting inhaled beta-2 receptor agonist (LABA) bronchodilator suitable for the maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD). Its onset of action is within five minutes and its effectiveness lasts for 24 hours, allowing for once-daily administration. Indacaterol maleate is manufactured by Novartis Pharmaceuticals of Switzerland and has been available in over 70 countries and regions worldwide since 2009. In June 2012, it was approved by the China National Medical Products Administration and listed on the Chinese stock exchange under the trade name Onbrez®, making it the first LABA-based monotherapy formulation approved in China for the treatment of COPD.

[0016] US Patent US11116721 B2 includes a long-acting beta-2 agonist, vilanterol trifenatate, and a long-acting Glucocortiroids A combination dry powder inhaler containing fluticasone furoate is disclosed. Chinese Patent CN104470503 A discloses a combination dry powder inhaler containing vilanterol trifenatate, a long-acting beta-2 agonist, and a long-acting GlucocortiroidsA combination dry powder inhaler containing fluticasone furoate and umeclidinium bromide is disclosed.China Patent CN103501776 A discloses a combination dry powder inhaler containing glycopyrronium bromide, vilanterol and fluticasone furoate.

[0017] Considering the above prior art, most current pharmaceutical compositions are dry powder inhalants and aerosols. These require patients to be able to hold their breath or have sufficient inspiratory flow, and also require hand-breathing coordination, which means they cannot meet the clinical needs of children with severe and very severe asthma and COPD. Commercially available pharmaceutical compositions are often administered multiple times a day, limiting patient compliance. Currently, there are no once-daily ICS / LABA ultra-long-acting atomized inhalation suspension formulations. Therefore, it is necessary to provide a treatment method for patients who cannot use portable devices such as dry powder inhalers (DPIs), metered-dose inhalers (MDIs), and soft mist inhalers (SMIs), and to develop a once-daily long-acting inhalable suspension for the treatment of asthma and COPD for patients at all stages of the disease. Glucocortiroids and a long-acting beta-2 receptor agonist. Summary of the Invention [Problem to be solved by the invention]

[0018] In response to the problems in the prior art, one of the objects of the present invention is to provide a long-acting inhalable Glucocortiroids and a long-acting β2 receptor agonist in combination, wherein the pharmaceutical formulation can be administered once a day for treating asthma and COPD. [Means for solving the problem]

[0019] Long-acting inhalable Glucocortiroids the drug is selected from fluticasone or a pharmaceutically acceptable salt of fluticasone; Preferably, the long-acting inhalable Glucocortiroids The drug is fluticasone furoate, the beta-2 receptor agonist is selected from vilanterol, olodaterol, indacaterol, or a pharmaceutically acceptable salt, isomer, or hydrate thereof; Preferably, the vilanterol is in the form of vilanterol triphenylacetate, the olodaterol is in the form of olodaterol hydrochloride, and the indacaterol is in the form of indacaterol maleate; Preferably, the long-acting β2 agonist is one or more selected from vilanterol trifenatate, olodaterol hydrochloride, and indacaterol maleate.

[0020] The dosage form of the drug formulation is a suspension or co-suspension, and the pH of the drug formulation is 2.5 to 6.0.

[0021] At least 90% by volume of the active agent particles of the suspension or co-suspension have an optical diameter of 7 μm or less, and at least 50% by volume of the active agent particles have an optical diameter of 5 μm or less.

[0022] In a preferred embodiment, the pharmaceutical formulation is a compound co-suspension formulation comprising fluticasone furoate or a physiologically acceptable salt of fluticasone furoate and vilanterol; Preferably, the drug formulation is an nebulized inhalation co-suspension formulation comprising vilanterol and fluticasone furoate; The vilanterol is in the form of vilanterol containing triphenylacetate dissolved in an aqueous phase; The drug formulation is an atomized inhalation co-suspension formulation containing vilanterol trifenatate and fluticasone furoate.

[0023] The daily inhalation dose of vilanterol trifenatate in the drug formulation is 10-100 μg, and the daily inhalation dose of fluticasone furoate is 25-1000 μg.

[0024] In some preferred embodiments, the vilanterol trifenatate and fluticasone furoate nebulized inhalation suspension formulation further comprises sulfobutyl-β-cyclodextrin, and contains between 5 mg and 500 mg of sulfobutyl-β-cyclodextrin per ml of liquid formulation.

[0025] In another preferred embodiment, the pharmaceutical formulation is a compound suspension formulation comprising fluticasone furoate or a physiologically acceptable salt of fluticasone furoate and olodaterol; Preferably, the drug formulation is an nebulized inhalation suspension formulation comprising olodaterol and fluticasone furoate; The olodaterol is in the form of olodaterol containing the hydrochloride salt dissolved in an aqueous phase, The drug formulation is an atomized inhalation suspension formulation containing olodaterol hydrochloride and fluticasone furoate.

[0026] The daily inhalation dose of olodaterol hydrochloride in the drug formulation is 1-100 μg, and the daily inhalation dose of fluticasone furoate is 25-1000 μg.

[0027] In a further preferred embodiment, the drug formulation is a compound co-suspension formulation comprising fluticasone furoate or a physiologically acceptable salt of fluticasone furoate and indacaterol maleate; Preferably, the drug formulation is an nebulized inhalation co-suspension formulation comprising indacaterol and fluticasone furoate; the indacaterol is in a form containing the maleate salt dissolved in an aqueous phase; The drug formulation is an nebulized inhalation co-suspension formulation containing indacaterol maleate and fluticasone furoate.

[0028] The daily inhalation dose of indacaterol maleate in the drug formulation is 20-200 μg, and the daily inhalation dose of fluticasone furoate is 25-500 μg.

[0029] the drug formulation is an inhalable drug formulation; The administration method of the drug formulation is spray administration, the drug formulation further comprises one or more of an isotonicity agent, a buffering agent, an excipient, a stabilizer, and a chelating agent; the isotonic agent is sodium chloride; the buffer is a citrate or phosphate buffer; The excipient is one or more selected from the group consisting of polysorbate 20, polysorbate 80, sorbitan monolaurate, poloxamer, polyoxyethylene castor oil, polyethylene glycol, solutol HS 15, and polyvinylpyrrolidone, and is preferably polysorbate 80.

[0030] The stabilizer is one or more selected from the group consisting of ethylenediaminetetraacetic acid, dehydrated disodium ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, and citric acid, and is preferably ethylenediaminetetraacetic acid.

[0031] The present invention also provides a method for producing the above-mentioned drug formulation, (1) adding the prescribed amount of auxiliary ingredients to water for injection, stirring and dissolving, adjusting the pH with a buffer solution, and filtering through a 0.22 μm filter membrane to prepare a sterile buffer solution; (2) Using a disperser, long-acting inhalable drug after dry heat sterilization Glucocortiroids The raw material was dispersed in the above 10% volume of buffer solution, and the inhalable Glucocortiroidsobtaining a raw material dispersion, and then adding the β2 receptor agonist raw material to a certain amount of buffer solution, and after undergoing a specific process treatment, filtering through a 0.22 μm filtration membrane to obtain a β2 receptor agonist raw material dispersion; (3) Mixing the dispersion liquid of the two raw materials with the remaining buffer solution, and dispersing it in a disperser to obtain a sterile suspension or co-suspension; (4) Filling and sealing the suspension into LDPE bottles to obtain a sterile suspension or co-suspension for inhalation.

[0032] The present invention also provides the application of the above drug formulation in the manufacture of a drug for treating respiratory diseases, including but not limited to chronic obstructive pulmonary disease (COPD) and all types of asthma. [Effects of the Invention]

[0033] The beneficial effects of the present invention compared to the prior art include: (1) Long-acting inhalable drugs manufactured using conventional technology Glucocortiroids Most drug formulations containing a combination of a long-acting β2 receptor agonist and a long-acting β2 receptor agonist are dry powder inhaled drugs and aerosols, but the use of such drugs requires patients to be able to hold their breath or have sufficient inspiratory flow, and also requires patients to be able to coordinate their hands and breaths, which does not meet the clinical needs of children with severe and very severe asthma and COPD. Glucocortiroids and a long-acting beta-2 receptor agonist, which are administered by nebulized inhalation, resulting in rapid onset of action, reduced systemic drug exposure, and decreased detargeting effects, providing a reliable treatment method for patients of any age who are unable to use portable inhalers such as dry powder inhalers (DPIs), metered-dose inhalers (MDIs), and soft mist inhalers (SMIs).

[0034] (2) In the process of implementing the present invention, by rationally controlling the drugs, such as controlling the type and amount of auxiliary drug ingredients, controlling the particle size of the drug ingredients, and controlling the pH of the drug preparation to 2.5 to 6.0, the stability of the suspension or co-suspension prepared is significantly improved, and the contents of individual impurities and total impurities in the drug preparation do not significantly increase after being left for a long time or at high temperatures, and the dispersibility of the drug preparation is good.

[0035] (3) In the prior art, long-acting β2 receptor agonists, such as vilanterol and indacaterol, are insoluble in water and cannot be filtered for sterilization. They are also susceptible to decomposition under high temperature conditions, making high-temperature sterilization impossible. In the present invention, a specific process is used to achieve filtration sterilization of vilanterol and indacaterol, and ultimately to produce a once-daily long-acting inhalable fluticasone furoate. Glucocortiroids and a long-acting β2 receptor agonist. [Brief explanation of the drawings]

[0036] [Figure 1] FIG. 1 is a particle size distribution diagram of Sample 1 in Test Example 1. [Figure 2] FIG. 1 is a particle size distribution diagram of Sample 2 in Test Example 1. [Figure 3] FIG. 1 is a particle size distribution diagram of Sample 3 in Test Example 1. [Figure 4] FIG. 1 shows the total impurities evolution profile of fluticasone furoate-vilanterol trifenatate co-suspension at different pH ranges at 60° C. over 10 days. [Figure 5] Figure 1 shows the total impurities evolution chart of fluticasone furoate-vilanterol trifenatate-cyclodextrin suspension at different pH ranges at 60°C over 10 days. [Figure 6] FIG. 1 shows the total impurities evolution chart of fluticasone furoate-olodaterol hydrochloride suspension at different pH ranges at 60° C. over 10 days. [Figure 7]FIG. 1 shows the total impurities evolution profile of fluticasone furoate-indacaterol maleate co-suspension at different pH ranges at 60° C. over 10 days. DETAILED DESCRIPTION OF THE INVENTION

[0037] The technical solutions of the present invention will be further defined below in connection with specific embodiments, but the scope of protection claimed is not limited to those described. The raw material components used in this invention were purchased from the following manufacturers and model numbers: Fluticasone furoate: Manufacturer: Aurisco Lot number: A28-180801F13 Vilanterol trifenatate: Manufacturer: Inke Lot number: PP-6M Olodaterol Hydrochloride: Manufacturer: Inke Lot Number: PP-1 Indacaterol Maleate: Manufacturer: Inke Lot Number: P-4 The equipment manufacturers and model numbers used in this invention are as follows: Disperser: Manufacturer: IKA Model: T18 Micro Jet Homogenizer: Manufacturer: PSI Model: PSI 20

[0038] Example 1 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Its Method of Preparation The ingredients and total dosage for one bottle of inhaled fluticasone furoate vilanterol co-suspension are shown in the table below.

[0039] [Table 1]

[0040] Manufacturing Process: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution.

[0041] (2) Using a disperser, the fluticasone furoate raw material was dispersed in the above 100 ml buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Subsequently, the vilanterol trifenatate raw material was added, and the mixture was subsequently dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0042] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0043] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol co-suspension for inhalation.

[0044] Example 2 Preparation of a Single-Component Suspension of Fluticasone Furoate for Inhalation The ingredients and dosages for one vial of single-component suspension of inhaled fluticasone furoate are shown in the table below.

[0045] [Table 2]

[0046] Manufacturing Process: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution.

[0047] (2) The fluticasone furoate raw material was dispersed in the above 100 ml buffer solution using a disperser, the rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes.

[0048] (3) The raw drug dispersion and the remaining buffer solution are mixed and processed in a disperser at 9000 rpm for 30 minutes to obtain a suspension.

[0049] (4) The suspension obtained above is filled into a 2 ml LDPE bottle and sealed to obtain a single-component suspension of fluticasone furoate for inhalation.

[0050] Example 3 Preparation of a Single-Component Suspension of Vilanterol Trifenatate for Inhalation The ingredients and dosages for one bottle of vilanterol single-component suspension for inhalation are shown in the table below.

[0051] [Table 3]

[0052] Manufacturing Process: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution.

[0053] (2) The vilanterol trifenatate raw material was dispersed in the above 100 ml buffer solution using a disperser, the rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes.

[0054] (3) The raw drug dispersion and the remaining buffer solution are mixed and processed in a disperser at 9000 rpm for 30 minutes to obtain a suspension.

[0055] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a vilanterol trifenatate single-ingredient suspension for inhalation.

[0056] Test Example 1 The particle sizes of the co-suspensions and single-component suspensions prepared in Examples 1 to 3 were measured using a laser particle size distribution analyzer manufactured by Sympatec. Sample 1, Sample 2, and Sample 3 were fluticasone furoate vilanterol co-suspension (Example 1), fluticasone furoate single-component suspension (Example 2), and vilanterol single-component suspension (Example 3), respectively. The particle size distributions thereof are shown in Table 1 below.

[0057] [Table 4]

[0058] Test Example 2 Preparation and stability considerations of fluticasone furoate vilanterol trifenatate co-suspensions at different pH ranges Seven groups of co-suspensions were prepared according to the formulation and manufacturing method in Example 1. A 0.1 M citric acid-sodium citrate buffer solution at pH 3.0, a 0.1 M citric acid-sodium citrate buffer solution at pH 6.6, and a 1 M sodium citrate solution were prepared, and the co-suspensions were adjusted to pH 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, and 7.0 using the above solutions, respectively. The formulation stability in different pH ranges was examined by subjecting them to a high temperature impact factor test (60°C, 10 days). The results are shown in Table 2 below.

[0059] [Table 5]

[0060] According to the data in Table 2 above, the fluticasone furoate ester vilanterol trifenatate co-suspension has good stability at pH 3.5 to 6.0, and especially at pH 3.5 to 5.0, the fluticasone furoate ester vilanterol trifenatate co-suspension has the best stability, low contents of total impurities and maximum single impurities, and good dispersibility.

[0061] Example 4 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Method for Making the Same The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0062] [Table 6]

[0063] In this example, an inhalable fluticasone furoate-vilanterol trifenatate co-suspension in 0.005% (w / w) EDTA / 0.01% (w / w) polysorbate 80 (pH 3.5) was prepared.

[0064] The manufacturing method is as follows: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 3.5 with 0.1 M citric acid-sodium citrate buffer solution at pH 3.0.

[0065] (2) Using a disperser, the fluticasone furoate raw material was dispersed in the above 100 ml buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Subsequently, the vilanterol trifenatate raw material was added, and the mixture was subsequently dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0066] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0067] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0068] Example 5 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Method for Making the Same The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0069] [Table 7]

[0070] In this example, an inhalable fluticasone furoate-vilanterol trifenatate co-suspension in 0.015% (w / w) EDTA / 0.01% (w / w) polysorbate 80 (pH 3.5) was prepared.

[0071] The manufacturing method is as follows: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 3.5 with 0.1 M citric acid-sodium citrate buffer solution at pH 3.0.

[0072] (2) Using a disperser, the fluticasone furoate raw material was dispersed in the above 100 ml buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Subsequently, the vilanterol trifenatate raw material was added, and the mixture was subsequently dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0073] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0074] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0075] Example 6 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Method for Making the Same The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0076] [Table 8]

[0077] In this example, an inhaled fluticasone furoate-vilanterol trifenatate co-suspension in 0.015% (w / w) EDTA / 0.03% (w / w) polysorbate 80 (pH 3.5) was prepared.

[0078] The manufacturing method is as follows: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 3.5 with 0.1 M citric acid-sodium citrate buffer solution at pH 3.0.

[0079] (2) Using a disperser, the fluticasone furoate raw material was dispersed in the above 100 ml buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Subsequently, the vilanterol trifenatate raw material was added, and the mixture was subsequently dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0080] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0081] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0082] Example 7 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Method for Making the Same The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0083] [Table 9]

[0084] In this example, an inhalable fluticasone furoate-vilanterol trifenatate co-suspension in 0.005% (w / w) EDTA / 0.01% (w / w) polysorbate 80 (pH 6.5) was prepared.

[0085] Manufacturing method: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 6.5 with 0.1 M citric acid-sodium citrate buffer solution at pH 6.6.

[0086] (2) Using a disperser, the fluticasone furoate raw material was dispersed in 100 ml of buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Then, the vilanterol trifenatate raw material was added, and the mixture was dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0087] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0088] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0089] Example 8 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Method for Making the Same The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0090] [Table 10]

[0091] In this example, an inhalable fluticasone furoate-vilanterol trifenatate co-suspension in 0.015% (w / w) EDTA / 0.01% (w / w) polysorbate 80 (pH 6.5) was prepared.

[0092] Manufacturing method: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 6.5 with 0.1 M citric acid-sodium citrate buffer solution at pH 6.6.

[0093] (2) Using a disperser, the fluticasone furoate raw material was dispersed in 100 ml of buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Then, the vilanterol trifenatate raw material was added, and the mixture was dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0094] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0095] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0096] Example 9 Inhaled Fluticasone Furoate-Vilanterol Trifenatate Co-Suspension and Method for Making the Same The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0097] [Table 11]

[0098] In this example, an inhalable fluticasone furoate-vilanterol trifenatate co-suspension in 0.015% (w / w) EDTA / 0.03% (w / w) polysorbate 80 (pH 6.5) was prepared.

[0099] Manufacturing method: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 6.5 with 0.1 M citric acid-sodium citrate buffer solution at pH 6.6.

[0100] (2) Using a disperser, the fluticasone furoate raw material was dispersed in the above 100 ml buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Subsequently, the vilanterol trifenatate raw material was added, and the mixture was subsequently dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0101] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0102] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0103] Example 10: Fluticasone furoate-vilanterol trifenatate co-suspension for inhalation and method for its preparation The ingredients and dosages for one bottle of inhaled fluticasone furoate vilanterol trifenatate co-suspension are as follows:

[0104] [Table 12]

[0105] In this example, an inhalable fluticasone furoate-vilanterol trifenatate co-suspension (pH 5.0) in 0.01% (w / w) EDTA / 0.02% (w / w) polysorbate 80 was prepared.

[0106] Manufacturing method: (1) Add the prescribed amount of auxiliary ingredients to 800 ml of water for injection, stir and dissolve, and then adjust the volume to 1000 ml to prepare a buffer solution. Adjust the pH to 5.0 with 0.1 M citric acid-sodium citrate buffer solution at pH 6.6.

[0107] (2) Using a disperser, the fluticasone furoate raw material was dispersed in 100 ml of buffer solution. The rotation speed of the disperser was 9000 rpm, and the dispersion time was 30 minutes. Then, the vilanterol trifenatate raw material was added, and the mixture was dispersed in the disperser at 9000 rpm for 30 minutes to obtain a dispersion of two raw materials.

[0108] (3) The raw drug dispersion and the remaining buffer solution are mixed and dispersed in a disperser at 9000 rpm for 30 minutes to prepare a co-suspension.

[0109] (4) The above suspension is filled into a 2 ml LDPE bottle and sealed to obtain a fluticasone furoate vilanterol trifenatate co-suspension for inhalation.

[0110] Test Example 3 Comparison of co-suspension stability sampling related materials prepared at different pH and EDTA dosages. The samples prepared in Examples 4 to 10 were subjected to a high temperature influence factor test by leaving them at 60°C for 10 days, and the stability of the samples was compared based on the results of the related substances in the influence factor test, as shown in Table 3 below.

[0111] [Table 13]

[0112] According to the measurement data in Table 3 above, the pH value has a significant effect on the stability of the fluticasone furoate ester / vilanterol trifenatate co-suspension. At a pH of 6.5, the high-temperature stability of the vilanterol trifenatate component in the fluticasone furoate ester / vilanterol trifenatate co-suspension is significantly weakened and the impurity content is significantly increased. Therefore, the optimal pH range for the fluticasone furoate ester / vilanterol trifenatate co-suspension is 3.5 to 5.0, which is consistent with the conclusions of Test Example 2. In addition, the co-suspension with EDTA (0.015% w / w) and Polysorbate 80 (0.01% w / w) has the best stability.

[0113] Test Example 4 Comparison of related substances before and after sterilization of raw drug substance In this test example, a series of experiments were conducted to clarify the effects of sterilization temperature and time on related substances in fluticasone furoate and vilanterol drug substances.

[0114] Fluticasone furoate and vilanterol trifenatate were treated for a certain period of time using two methods: moist heat sterilization and dry heat sterilization. Sample 1 was treated for 8 minutes at 120°C, Sample 2 for 15 minutes at 121°C, Sample 3 for 2 hours at 110°C, and Sample 4 for 2 hours at 120°C. After sterilization, the related substances in each group of samples were analyzed as shown in Table 4 below.

[0115] [Table 14]

[0116] As can be seen from the measurement results in Table 4 above, neither fluticasone furoate branate nor vilanterol trifenatate raw drug substance could withstand moist heat sterilization, but fluticasone furoate branate could withstand dry heat sterilization at 120°C for 2 hours, and although the total impurities and maximum single impurity of vilanterol trifenatate increased after 2 hours at 110°C, they were within the acceptable range.

[0117] Test Example 5: Preparation and Stability of Drug Substance Co-suspension after Dry Heat Sterilization Test Example 4 showed that fluticasone furoate could withstand dry heat sterilization, while vilanterol trifenatate showed a partial increase in related substances after dry heat sterilization. After preparing a co-suspension using the sterilized drug substance, the related substances of fluticasone furoate and vilanterol trifenatate were analyzed, and the stability at a one-month accelerated temperature and 10 days at high temperature was re-examined at different pH ranges (3.5, 4.0, 4.5, 5.0) using the previously determined amounts of EDTA (0.015%) and polysorbate 80 (0.01%). The results are shown in Table 5 below.

[0118] [Table 15]

[0119] According to the measurement data in Table 5 and Figure 4 above, fluticasone furoate has good stability within the pH range of 3.5 to 5.0, while vilanterol trifenatate already has a high total impurity content at 0 days. When the pH is within the range of 4.5 to 5.0 and the solution is left at 60°C for 10 days, the total impurity content increases significantly, indicating that the optimal pH value for vilanterol trifenatate is 3.5 to 4.0.

[0120] Example 11 Preparation of Vilanterol Trifenatate-Cyclodextrin Sterile Inhalation Solution (0.5% Cyclodextrin) 0.075g EDTA, 4.25g NaCl, and 0.05g polysorbate 80 were weighed and added to water for injection to make a 500ml solution to prepare a buffer solution. 50ml of buffer solution was weighed out and 2.5g sulfobutyl-β-cyclodextrin was added to disperse and dissolve the solution. 17mg of vilanterol trifenatate raw material was weighed and added to the solution. The solution was dispersed in a disperser at 9000 rpm for 30 minutes to obtain a clear vilanterol trifenatate solution. This solution and the remaining 450ml of buffer solution were dispersed in a disperser at 9000 rpm for 30 minutes to thoroughly mix. The solution remained clear and no precipitation occurred. The solution was filtered through a 0.45+0.22μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a sterile vilanterol trifenatate inhalation solution.

[0121] Example 12 Preparation of Vilanterol Trifenatate-Cyclodextrin Sterile Inhalation Solution (1.5% Cyclodextrin) 0.075 g of EDTA, 4.25 g of NaCl, and 0.05 g of polysorbate 80 were weighed and added to water for injection to make a 500 ml solution. 150 ml of buffer solution was weighed out, and 7.5 g of sulfobutyl-β-cyclodextrin was added to disperse and dissolve the solution. 17 mg of vilanterol trifenatate raw material was weighed and added to the solution. The solution was dispersed in a disperser at 9000 rpm for 30 minutes to obtain a clear vilanterol trifenatate solution. This solution and the remaining 350 ml of buffer solution were dispersed in a disperser at 9000 rpm for 30 minutes to thoroughly mix. The solution remained clear and no precipitation occurred. The solution was filtered through a 0.45 + 0.22 μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a sterile vilanterol trifenatate inhalation solution.

[0122] Example 13 Preparation of Inhaled Fluticasone Furoate-Vilanterol Trifenatate-Cyclodextrin Sterile Suspension 0.075 g of EDTA, 4.25 g of NaCl, and 0.05 g of polysorbate 80 were weighed and added to water for injection to make a final volume of 500 ml. The solution was filtered through a 0.45 + 0.22 μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a sterile buffer solution. 150 ml of buffer solution was weighed out, and 7.5 g of sulfobutyl-β-cyclodextrin was added and dispersed. 17 mg of vilanterol trifenatate drug substance was weighed and dispersed in a disperser at 9000 rpm for 30 minutes. The solution was then filtered through a 0.45 + 0.22 μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a clear vilanterol trifenatate solution.

[0123] 50 ml of buffer solution was then weighed out, 42.5 mg of dry-heat sterilized fluticasone furoate raw material was weighed out, and the mixture was dispersed using a disperser at 9,000 rpm for 30 minutes to obtain a fluticasone furoate suspension. The fluticasone furoate suspension, vilanterol trifenatate solution, and the remaining buffer solution were dispersed using a disperser at 9,000 rpm for 30 minutes to thoroughly mix, yielding a sterile fluticasone furoate-vilanterol-cyclodextrin suspension for inhalation.

[0124] Test Example 6 Comparison of the stability of vilanterol trifenatate single-component suspension and vilanterol trifenatate-cyclodextrin inhalation solution 0.075g of EDTA, 4.25g of NaCl, and 0.05g of polysorbate 80 were weighed and added to water for injection to make a 500ml solution to prepare a buffer solution. 50ml of buffer solution was weighed, and 17mg of vilanterol trifenatate raw material was weighed and added to the solution. The solution was dispersed in a disperser at 9000rpm for 30 minutes to obtain a vilanterol trifenatate dispersion. This dispersion and the remaining 450ml of buffer solution were thoroughly mixed in a disperser at 9000rpm for 30 minutes to obtain a vilanterol trifenatate single-component suspension.

[0125] Vilanterol trifenatate-cyclodextrin inhalation solution was prepared according to the formulation and process of Example 11, and the stability of both was compared based on the content and related substances at high temperature influence factors, and the results are shown in Table 6.

[0126] [Table 16]

[0127] As can be seen from the measurement data in Table 6 above, compared to the vilanterol trifenatate single-component suspension, Example 11 used an inhalation solution prepared by mixing sulfobutyl-β-cyclodextrin and vilanterol trifenatate, which had better stability for 10 days at 60°C and higher stability of the content and related substances.

[0128] Test Example 7: Stability of Fluticasone Furoate-Vilanterol Trifenatate-Cyclodextrin Suspensions at Different pHs: Comparison of Sampling Related Substances A 0.1 M citric acid-sodium citrate buffer solution with a pH of 3.0 and a 0.1 M citric acid-sodium citrate buffer solution with a pH of 6.6 were prepared. The fluticasone furoate-vilanterol trifenatate-cyclodextrin suspension prepared in Example 13 was adjusted to pH 3.5, 4.0, 4.5, 5.0, and 5.5 using these buffer solutions, respectively. The formulation stability in different pH ranges was examined by subjecting the suspension to a high temperature impact factor test (60°C for 10 days). The results are shown in Table 7.

[0129] [Table 17]

[0130] According to the measurement data in Table 7 and Figure 5, when the pH was 3.5, the total impurity content of vilanterol at 60°C for 10 days increased significantly, and when the pH was 5.5, the total impurity content of vilanterol trifenatate at 60°C for 10 days increased significantly. Therefore, it was found that the appropriate pH value for the fluticasone furoate-vilanterol trifenatate-cyclodextrin co-suspension was 4.0 to 5.0.

[0131] Example 14 Preparation of Inhaled Fluticasone Furoate-Olodaterol Hydrochloride Sterile Suspension 0.075 g of EDTA, 4.25 g of NaCl, and 0.05 g of polysorbate 80 were weighed and added to water for injection to make a final volume of 500 ml. The solution was filtered through a 0.45 + 0.22 μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a sterile buffer solution. 50 ml of the buffer solution was weighed and added to 42.5 mg of dry-heat-sterilized fluticasone furoate raw material. The mixture was dispersed in a disperser at 9000 rpm for 30 minutes to obtain a fluticasone furoate suspension.

[0132] 34.2 mg of olodaterol hydrochloride raw drug was weighed and added to the remaining buffer solution, stirred magnetically at 300 rpm for 30 minutes, and filtered through a 0.45 + 0.22 μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a sterile, clear olodaterol hydrochloride solution. The fluticasone furoate suspension and olodaterol hydrochloride solution were dispersed thoroughly in a disperser at 9000 rpm for 30 minutes to obtain a sterile fluticasone furoate-olodaterol hydrochloride suspension for inhalation.

[0133] Test Example 8 Comparison of Fluticasone Furoate-Olodaterol Hydrochloride Suspension Stability Sampling Related Materials at Different pHs A 0.1 M citric acid-sodium citrate buffer solution of pH 3.0, a 0.1 M citric acid-sodium citrate buffer solution of pH 6.6, and a 1 M citric acid solution were prepared. Fluticasone furoate-olodaterol hydrochloride suspensions were adjusted to pH 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, and 5.5 using the above three solutions, respectively. The formulation stability at different pH ranges was examined by subjecting them to a high temperature impact factor test (60°C for 10 days). The results are shown in Table 8.

[0134] [Table 18]

[0135] As can be seen from the measurement data in Table 8 and Figure 6 above, in the suspension formed from olodaterol hydrochloride and fluticasone furoate, the raw material fluticasone furoate was stable within the pH range of 2.5 to 5.5, while the raw material olodaterol hydrochloride was stable within the pH range of 2.5 to 4.0, with the pH being particularly stable at 3.0. When the pH value was greater than 4.0, the total impurity content increased significantly after 10 days at 60°C.

[0136] Example 15 Preparation of Indacaterol Maleate Single-Component Nanosterile Suspension 0.075 g of EDTA, 4.25 g of NaCl, and 0.05 g of polysorbate 80 were weighed and added to water for injection, and the resulting solution was adjusted to 500 ml to prepare a buffer solution. 39 mg of indacaterol maleate raw material was weighed and added to 50 ml of the buffer solution. The solution was dispersed in a disperser at 9000 rpm for 30 minutes. The solution was then homogenized in a high-pressure homogenizer at 1000 bar for three cycles and then at 2000 bar for six cycles to obtain a homogenized solution. The homogenized solution and the remaining buffer solution were thoroughly mixed in a disperser at 9000 rpm for 30 minutes. The resulting solution was then filtered through a 0.22 μm PVDF filter membrane (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a single-component sterile nanosuspension of indacaterol maleate.

[0137] Example 16 Preparation of a Sterile Fluticasone Furoate-Indacaterol Maleate Co-Suspension for Inhalation 0.075 g of EDTA, 4.25 g of NaCl, and 0.05 g of polysorbate 80 were weighed out and added to water for injection to make a final volume of 500 ml. The solution was filtered through a 0.45+0.22 μm PVDF needle filter (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain a sterile buffer solution. 50 ml of the buffer solution was weighed out and 42.5 mg of dry-heat sterilized fluticasone furoate raw material was added, and the mixture was dispersed using a disperser at 9000 rpm for 30 minutes to obtain a fluticasone furoate suspension.

[0138] 50 ml of the buffer solution was then taken, and 39 mg of indacaterol maleate raw material was added to the buffer solution. The mixture was dispersed at 9000 rpm for 30 minutes using a disperser. The solution was then homogenized using a high-pressure homogenizer at 1000 bar for three cycles, and then at 2000 bar for six cycles to obtain a homogenized solution. The homogenized solution was then filtered through a 0.22 μm PVDF filter membrane (manufacturer: Cobetter, model number: SFM25DLHPVND4522P) to obtain an indacaterol maleate nanosuspension.

[0139] The fluticasone furoate suspension, indacaterol maleate nanosuspension and the remaining buffer solution were dispersed in a disperser at 9000 rpm for 30 minutes to thoroughly mix, thereby obtaining a sterile fluticasone furoate-indacaterol maleate co-suspension for inhalation.

[0140] Test Example 9: Stability of Fluticasone Furoate-Indacaterol Maleate Co-Suspensions at Different pH Levels 0.1 M citric acid-sodium citrate buffer solution of pH 3.0 and 0.1 M citric acid-sodium citrate buffer solution of pH 6.6 were prepared, and fluticasone furoate-indacaterol maleate co-suspensions were adjusted to pH 3.5, 4.0, 4.5, 5.0, and 5.5, respectively, using the buffer solutions. The formulation stability at different pH ranges was examined by subjecting them to a high temperature impact factor test (60°C for 10 days). The results are shown in Table 8.

[0141] [Table 19]

[0142] As can be seen from the measurement data in Table 8 above and Figure 7, the raw material fluticasone furoate in the fluticasone furoate-indacaterol maleate co-suspension has good stability within a pH range of 3.5 to 5.5, with no significant difference in the amount of single impurities and total impurities under each pH condition. The raw material indacaterol maleate has good stability within a pH range of 3.5 to 4.5, with the pH at 3.5 being the most stable. At pH values ​​greater than 4.5, the total impurity content increased significantly after 10 days at 60°C.

[0143] Based on the above, the present application is a once-daily, ultra-long-acting inhalable Glucocortiroids The company provides a sterile suspension or co-suspension containing a combination of an ultra-long-acting beta-2 receptor agonist and a benzodiazepine, providing a treatment option for patients who cannot use portable inhalers such as dry powder inhalers (DPIs), metered-dose inhalers (MDIs), and soft mist inhalers (SMIs), as well as children and critically ill patients.

[0144] Finally, it should be noted that the above examples are only used to explain the technical solutions of the present invention, rather than limiting the protection scope of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. 1. A pharmaceutical formulation comprising a combination of a long-acting inhaled steroid and a long-acting beta-2 receptor agonist, the long-acting inhaled steroid drug is selected from fluticasone or a pharmaceutically acceptable salt of fluticasone, and the long-acting beta-2 receptor agonist is selected from vilanterol, olodaterol, indacaterol, or any pharmaceutically acceptable salt, isomer, or hydrate thereof; The drug formulation is in the form of a suspension or co-suspension, and has a pH of 2.5 to 6.

0.

2. 2. The drug formulation of claim 1, wherein at least 90% by volume of the active agent particles have an optical diameter of 7 μm or less and at least 50% by volume of the active agent particles have an optical diameter of 5 μm or less.

3. the long-acting inhaled steroid drug is selected from fluticasone and is fluticasone furoate; The pharmaceutical formulation of claim 1, wherein the long-acting beta-2 agonist is one or more selected from vilanterol, olodaterol, and indacaterol, wherein the vilanterol is in the form of vilanterol triphenylacetate, the olodaterol is in the form of olodaterol hydrochloride, and the indacaterol is in the form of indacaterol maleate.

4. 4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is an atomized inhalation suspension or co-suspension containing fluticasone furoate and vilanterol trifenatate, wherein the daily inhalation dose of fluticasone furoate is 25-1000 μg and the daily inhalation dose of vilanterol trifenatate is 10-100 μg.

5. The pharmaceutical formulation according to claim 4, further comprising sulfobutyl-β-cyclodextrin, wherein the concentration of sulfobutyl-β-cyclodextrin in the pharmaceutical formulation is 5 to 500 mg / mL.

6. 4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is an nebulized inhalation suspension containing fluticasone furoate and olodaterol hydrochloride, wherein the daily inhalation dose of fluticasone furoate is 25-1000 μg and the daily inhalation dose of olodaterol hydrochloride is 1-100 μg.

7. 4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is an nebulized inhalation co-suspension containing fluticasone furoate and indacaterol maleate, wherein the daily inhalation dose of fluticasone furoate is 25-500 μg and the daily inhalation dose of indacaterol maleate is 20-200 μg.

8. The drug formulation according to any one of claims 1 to 7, further comprising one or more of an isotonic agent, a buffering agent, an excipient, a stabilizer, and a chelating agent.

9. A method for producing the drug formulation according to any one of claims 1 to 7, comprising: (1) adding the prescribed amount of auxiliary ingredients to water for injection, stirring and dissolving, adjusting the pH with a buffer solution, and filtering through a 0.22 μm filter membrane to prepare a sterile buffer solution; (2) dispersing the dry-heat sterilized long-acting inhalable steroid raw material in the 10% volume of the buffer solution using a disperser to obtain an inhalable steroid raw material dispersion; subsequently, adding a certain amount of the β2 receptor agonist raw material to the buffer solution, and after undergoing a specific process, filtering through a 0.22 μm filter membrane to obtain a β2 receptor agonist raw material dispersion; (3) Mixing the dispersions of the two raw materials with the remaining buffer solution, and dispersing the mixture in a disperser to obtain a sterile suspension or co-suspension; (4) filling and sealing LDPE bottles with the suspension to obtain a sterile suspension or co-suspension for inhalation.

10. 10. The application of the drug formulation according to any one of claims 1 to 7 in the manufacture of a drug for treating respiratory diseases, including but not limited to chronic obstructive pulmonary disease (COPD) and all types of asthma.

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