Budesonide inhalable solution composition and preparation method thereof

Abstract

The invention provides a budesonide inhalable solution composition and a preparation method thereof. Compared with an existing budesonide suspension preparation, the budesonide inhalable solution composition provided by the invention is stable in property; the budesonide and the terbutaline sulfate contained in the solution composition have excellent delivery performance and pharmacokinetic properties, can be better distributed on the surface of bronchus or lung, and can be quickly dissolved and absorbed, quickly exert efficacy and relieve asthma symptoms. The budesonide inhalable solution composition provided by the invention is simple in preparation method and easy for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a budesonide inhalable solution composition and its preparation method. Background Technology

[0002] The incidence of respiratory diseases, primarily asthma and chronic obstructive pulmonary disease (COPD), has increased significantly. Inhaled administration delivers drugs directly to the bronchi and lungs, improving therapeutic efficacy while significantly reducing oral dosage and systemic side effects, making it the preferred route of administration for the treatment of asthma and COPD.

[0003] Budesonide is a glucocorticoid with highly effective local anti-inflammatory properties. Compared to other glucocorticoids, its systemic side effects, such as weight loss and atrophy of lymphoid tissue and adrenal cortex, are relatively weaker, and it has been widely used in the treatment of asthma and COPD. Currently, all commercially available products containing budesonide are in powder or suspension form. The use of budesonide is limited because highly efficient delivery devices such as soft atomizers cannot carry budesonide powder or suspension. Summary of the Invention

[0004] To address the aforementioned problems in the prior art, this invention proposes a budesonide inhalable solution composition and its preparation method.

[0005] This invention provides a budesonide inhalable solution composition, the budesonide inhalable solution composition comprising the following components:

[0006] Active ingredients, solubilizers, solvents;

[0007] The active ingredients include (1) budesonide or a pharmaceutically acceptable salt thereof; and (2) terbutaline or a pharmaceutically acceptable salt thereof, budesonide.

[0008] According to embodiments of the present invention, the content (mass percentage) of budesonide or its pharmaceutically acceptable salt is 0.005%-0.5%, preferably 0.01%-0.3%, and exemplary contents are 0.0125%, 0.025%, 0.05%, 0.08%, 0.1%, and 0.2%.

[0009] According to embodiments of the present invention, the content (mass percentage) of terbutaline or its pharmaceutically acceptable salt is 0.05%-1.0%, preferably 0.1%-0.5%, and exemplary contents are 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, and 0.4%.

[0010] According to an embodiment of the present invention, the pharmaceutically acceptable salt of terbutaline is terbutaline sulfate.

[0011] According to embodiments of the present invention, the mass ratio of budesonide to terbutaline or a pharmaceutically acceptable salt thereof is 1:1-50, preferably 1:2-30, and exemplary ratios are 1:2.5, 1:5, 1:6, 1:8, 1:10, 1:12, 1:15, 1:18, and 1:20.

[0012] According to an embodiment of the present invention, the solubilizer is selected from one, two or more of tylosap, Span 85, vitamin E polyethylene glycol succinate (TPGS), Tween 80, and polyethylene glycol (15)-hydroxystearate (HS15); preferably one, two or more of tylosap, Span 85, Tween 80, and polyethylene glycol (15)-hydroxystearate (HS15).

[0013] According to an embodiment of the invention, the solubilizer is thioxaparin. According to an embodiment of the invention, the solubilizer is polyethylene glycol (15)-hydroxystearate (HS15). According to an embodiment of the invention, the solubilizer comprises Span 85 and Tween 80; preferably, the mass ratio of Span 85 to Tween 80 is 0.1-2.0:1.0-4.0, more preferably 0.5-1.0:2.0-3.0, for example 0.7:2.4. According to an embodiment of the invention, the solubilizer comprises Span 85 and polyethylene glycol (15)-hydroxystearate (HS15); preferably, the mass ratio of Span 85 to Tween 80 is 0.1-2.0:1.0-4.0, more preferably 0.5-1.0:1.5-3.0, for example 0.7:2.1.

[0014] According to embodiments of the present invention, the content (mass percentage) of the solubilizer is 0.1%-10.0%, preferably 0.2%-8.0%, more preferably 0.5%-7.0%, and exemplary values ​​are 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 4.0%, 5.0%, 6.0%, and 7.0%.

[0015] According to embodiments of the present invention, the budesonide inhalable solution composition optionally includes a buffer; preferably, the buffer includes a pharmaceutical acid and a pharmaceutical base.

[0016] According to an embodiment of the present invention, the pharmaceutical acid is selected from one, two, or more of citric acid, phosphoric acid, acetic acid, tartaric acid, succinic acid, boric acid, and sodium phosphate. According to an embodiment of the present invention, the pharmaceutical alkali is selected from one, two, or more of sodium citrate, sodium dihydrogen phosphate, sodium acetate, disodium hydrogen phosphate, and sodium acetate.

[0017] According to an embodiment of the present invention, the buffer is selected from one, two or more of citric acid, sodium citrate, and sodium dihydrogen phosphate; for example, it is selected from citric acid and sodium citrate, or citric acid and sodium dihydrogen phosphate.

[0018] According to an embodiment of the invention, the pH of the budesonide inhalable solution composition is 4.0-6.0, preferably 4.5-5.5, for example 5.0.

[0019] According to an embodiment of the present invention, the content (mass percentage) of the buffer is 0.01%-0.5%, preferably 0.05%-0.1%, and exemplary values ​​are 0.07%, 0.078%, 0.08%, and 0.09%.

[0020] According to an embodiment of the present invention, the content (mass percentage) of pharmaceutical acid in the buffer is 0.01%-0.5%, preferably 0.02%-0.05%, and exemplary is 0.028%.

[0021] According to an embodiment of the present invention, the content (mass percentage) of pharmaceutical alkali in the buffer is 0.01%-0.5%, preferably 0.02%-0.1%, and exemplary is 0.050%.

[0022] According to an embodiment of the present invention, the budesonide inhalable solution composition optionally includes a chelating agent; preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate (EDTA disodium).

[0023] According to an embodiment of the present invention, the content (mass percentage) of the chelating agent is 0.005%-0.5%, preferably 0.01%-0.3%, and exemplary values ​​are 0.01%, 0.05%, 0.1%, and 0.2%.

[0024] According to an embodiment of the present invention, the solvent is selected from anhydrous ethanol and water.

[0025] According to an embodiment of the present invention, the budesonide inhalable solution composition optionally includes an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from one, two or more of glycerol, sodium chloride, propylene glycol, glucose, and mannitol.

[0026] According to an embodiment of the present invention, the content (mass percentage) of the osmotic pressure regulator is 0.5%-8.0%, preferably 0.6%-6.0%, and exemplary contents are 0.6%, 0.8%, 0.85%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 7.0%, and 7.5%.

[0027] According to an embodiment of the present invention, the budesonide inhalable solution composition optionally includes an antioxidant; preferably, the antioxidant is selected from one, two or more of solid or liquid antioxidants and gaseous antioxidants; preferably, the solid or liquid antioxidant is selected from one, two or more of vitamin C, glutathione, and sodium metabisulfite; the gaseous antioxidant is selected from one, two or more of nitrogen and carbon dioxide.

[0028] According to an embodiment of the present invention, the content (mass percentage) of the antioxidant is 0.01%-1.0%, preferably 0.05%-0.5%, and exemplary is 0.1%, 0.2%, 0.3%, or 0.4% (when the antioxidant is selected from solid or liquid antioxidants).

[0029] According to an embodiment of the present invention, the antioxidant has an oxygen content of less than 0.3 mg / L (when the antioxidant is selected from gaseous antioxidants).

[0030] According to an embodiment of the present invention, the budesonide inhalable solution composition comprises the following components:

[0031] Budesonide, terbutaline sulfate, tylosap, osmotic pressure regulator, buffer, chelating agent, water;

[0032] Preferably, the content of budesonide is 0.0125%-0.05%;

[0033] Preferably, the content of terbutaline sulfate is 0.15%-0.25%;

[0034] Preferably, the content of teroxaprol is 0.5%-7.0%;

[0035] Preferably, the osmotic pressure regulator is selected from glycerol and sodium chloride;

[0036] Preferably, the content of the osmotic pressure regulator is 0.85%-5.0% (e.g., 5.0% glycerol, 0.85% sodium chloride);

[0037] Preferably, the buffer is selected from citric acid and sodium citrate, or citric acid and sodium dihydrogen phosphate;

[0038] Preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate; preferably, the content of the chelating agent is 0.01%;

[0039] Preferably, the budesonide inhalable solution composition includes an antioxidant; preferably, the antioxidant is selected from gaseous antioxidants (e.g., nitrogen, carbon dioxide).

[0040] According to an embodiment of the present invention, the budesonide inhalable solution composition comprises the following components:

[0041]

[0042]

[0043] According to an embodiment of the present invention, the budesonide inhalable solution composition comprises the following components:

[0044]

[0045] Unless otherwise stated, all percentages used to define the content of components in this invention refer to mass percentages.

[0046] According to an embodiment of the present invention, the budesonide inhalable solution composition can be administered to the lungs using nebulized inhalation or other inhalation devices.

[0047] This invention also provides a method for preparing the above-mentioned budesonide inhalable solution composition, the method comprising the following steps:

[0048] S1) Dissolve a solubilizer (e.g., tylosap) and budesonide in an organic solvent (e.g., ethanol) to obtain a mixed solution, and then remove the organic solvent to obtain a solubilized solution containing budesonide.

[0049] S2) Dissolve terbutaline or a pharmaceutically acceptable salt thereof, along with optional buffers, chelating agents, osmotic regulators, and antioxidants in a solvent;

[0050] S3) Add the solution obtained in step S2 to the solubilizing solution containing budesonide in step S1, mix well, and the budesonide inhalable solution composition can be obtained.

[0051] According to an embodiment of the present invention, in step S1, the organic solvent is removed by a rotary evaporator; preferably, the conditions of the rotary evaporator are: temperature 40 degrees Celsius, rotary evaporation for 1-2 hours.

[0052] According to an embodiment of the present invention, in step S3, a clear solution is obtained by mixing evenly, and optionally further sterilization and filtration are performed to obtain the budesonide inhalable solution composition.

[0053] The present invention also provides the use of the above-described budesonide inhalable solution composition in the preparation of medicaments for the treatment and / or prevention of lung diseases, including bronchitis, asthma, and chronic obstructive pulmonary disease.

[0054] According to an embodiment of the present invention, the bronchitis includes acute bronchitis and chronic bronchitis.

[0055] According to an embodiment of the present invention, the asthma includes acute asthma, chronic asthma, severe asthma, allergic asthma, bronchial asthma, and endogenous asthma.

[0056] Beneficial effects

[0057] This invention provides a budesonide inhalable solution composition. Compared with existing budesonide suspensions, the budesonide inhalable solution composition provided by this invention is stable; and the budesonide and terbutaline sulfate contained in the solution composition have excellent delivery performance and pharmacokinetic properties, can be better distributed on the surface of the bronchi or lungs, and can be rapidly dissolved and absorbed, exerting a rapid therapeutic effect and relieving asthma symptoms.

[0058] The present invention provides a budesonide inhalable solution composition, which is simple to prepare and easy to industrialize. Attached Figure Description

[0059] Figure 1 The aerodynamic distribution of budesonide in prescription 26.

[0060] Figure 2 The aerodynamic particle size distribution of terbutaline sulfate in prescription 26 is shown. Detailed Implementation

[0061] The present invention will now be described in detail with reference to specific embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention are still within the scope of protection of the present invention.

[0062] ISM, impactor-sized mass: the total mass of the drug in all stages of the impactor plus the terminal filter, excluding the top of the impactor.

[0063] FPD: fine particle dose; refers to the total mass of active agent emitted from the device by a drive, existing with an aerodynamic particle size smaller than a specified limit. This limit is usually set at 5 μm.

[0064] MMAD: Mass Median Aerodynamic Diameter; it refers to the particle size in which the mass of particles larger than and smaller than the aerodynamic diameter each account for half of the total mass, and is an effective tool for measuring the "average" particle size.

[0065] GSD: geometric standard deviation; a dimensionless parameter representing the ratio of the aerodynamic diameter (μm) of particles with a cumulative distribution below 84.1% and 15.9%.

[0066] Example 1: Investigation of Solubilization

[0067] Formulas 1-7 containing budesonide were prepared, and their formulations are shown in Table 1. After standing for 1 hour, the appearance of formulas 1-7 was observed. Furthermore, the maximum single impurity and total impurity content in formulas 1-7 were determined.

[0068] The method for detecting budesonide impurities was as follows: phosphate buffer (pH 3.2)-acetonitrile-ethanol (65:35:2) was used as the mobile phase, L1 was used as the stationary phase, the flow rate was 1.5 mL / min, the column temperature was 40 ℃, the detection wavelength was 240 nm, and the injection volume was 200 μL.

[0069] The method for determining the maximum single heterozygote is as follows:

[0070] Table 1 Formulas for Prescriptions 1-7

[0071]

[0072] The preparation methods of prescriptions 1-7 are as follows: Weigh the prescribed amount of budesonide and the corresponding solubilizer, add anhydrous ethanol and mix to dissolve; remove the ethanol by rotary evaporation at 40 degrees Celsius for 1 hour, and then vacuum dry in a vacuum drying oven (40 degrees Celsius, 180 min) to obtain a solubilizer solution containing budesonide; dissolve the remaining excipients in purified water, add the obtained aqueous solution to the solubilizer solution containing budesonide, and hydrate at 40 degrees Celsius until completely dissolved; filter the obtained aqueous solution through a 0.22 μm aqueous needle filter membrane to obtain an aqueous solution containing budesonide.

[0073] Table 2 Appearance and maximum single impurity content of prescriptions 1-7

[0074] Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Appearance Colorless and transparent White sediment White sediment Colorless and transparent Colorless and transparent Colorless and transparent Colorless and transparent Maximum single hybrid 0.74％ - - 0.21％ 0.16％ 0.22％ 0.26％ General Miscellaneous 3.15％ - - 0.88％ 0.64％ 0.98％ 2.09％

[0075] As shown in Table 2, prescriptions 4, 5 and 6 are colorless and transparent solutions, and contain relatively low levels of maximum single impurities and total impurities.

[0076] Formulas 4, 5, and 6 were placed at 40°C to investigate the changes in impurities under high-temperature conditions. The results are shown in Table 3.

[0077] Table 3. Changes in impurities in prescriptions 4-6 under high-temperature conditions.

[0078] As can be seen from the high-temperature stability results in Table 3, the growth of impurities in Formula 5 is relatively small. Therefore, Tyloxapine was selected for formula process screening and control.

[0079] Example 2: Investigation of solubilizer concentration

[0080] Formula 8-14, containing budesonide, was prepared as shown in Table 4. The appearance of Formula 8-14 was observed after standing for 1 hour.

[0081] Table 4 Formulas for Prescriptions 8-14

[0082]

[0083] The preparation methods for prescriptions 8-14 are as follows: Weigh the prescribed amounts of budesonide and tylosap, add anhydrous ethanol and mix to dissolve; remove the ethanol by rotary evaporation at 40 degrees Celsius for 1 hour, and then vacuum dry in a vacuum drying oven (40 degrees Celsius, 180 min) to obtain a tylosap solution containing budesonide; dissolve the remaining raw materials and excipients in purified water, add the obtained aqueous solution to the tylosap solution containing budesonide, and hydrate at 40 degrees Celsius until completely dissolved to obtain an aqueous solution containing budesonide.

[0084] Table 5 Appearance of Prescription 8-14

[0085]

[0086] As shown in Table 5, budesonide solutions with a tylosporin content of 0.5% or higher are aqueous solutions, but at a concentration of 10%, the solution becomes a viscous solution.

[0087] Example 3: Investigation of Budesonide Dosage

[0088] Formula 15-19, containing budesonide, was prepared as shown in Table 6. After standing for 1 hour, the appearance of Formula 15-19 was observed.

[0089] Table 6. Investigation of different amounts of budesonide

[0090]

[0091] The preparation methods for prescriptions 15-19 are as follows: Weigh the prescribed amounts of budesonide and tylosap, add anhydrous ethanol and mix to dissolve; remove the ethanol by rotary evaporation at 40 degrees Celsius for 1 hour, and then vacuum dry in a vacuum drying oven (40 degrees Celsius, 180 min) to obtain a tylosap solution containing budesonide; dissolve the remaining raw materials and excipients in purified water, add the obtained aqueous solution to the tylosap solution containing budesonide, and hydrate at 40 degrees Celsius until completely dissolved to obtain an aqueous solution containing budesonide.

[0092] Table 7 Appearance of Prescriptions 15-19

[0093]

[0094]

[0095] As shown in Table 7, the solubility of budesonide can be increased to 0.503 mg / mL.

[0096] Example 4: Investigation of Antioxidants

[0097] Formula 20-25 containing budesonide was prepared, and the formulation is shown in Table 8. The formula was stored at 40℃ and 75% for 0 days, 0.5 months, and 1 month, and the impurity content of budesonide and terbutaline sulfate in the formula was determined.

[0098] The method for detecting budesonide impurities was as follows: using phosphate buffer (pH 3.2)-acetonitrile-ethanol (65:35:2) as the mobile phase, L1 as the stationary phase, a flow rate of 1.5 mL / min, a column temperature of 40 ℃, a detection wavelength of 240 nm, and an injection volume of 200 μL.

[0099] Method for detecting impurities in terbutaline sulfate: Ammonium formate solution (pH 3.0)-methanol (72:28) was used as the mobile phase, L1 was used as the stationary phase, the flow rate was 1.0 mL / min, the column temperature was 40℃, the detection wavelength was 276 nm, and the injection volume was 20 μL.

[0100] Table 8 Formulas for Prescriptions 20-25

[0101]

[0102] The preparation methods of prescriptions 20-23 are as follows: Weigh the prescribed amounts of budesonide and tylosap, add anhydrous ethanol and mix to dissolve; remove the ethanol by rotary evaporation at 40 degrees Celsius for 1 hour, and then vacuum dry in a vacuum drying oven (40 degrees Celsius, 180 min) to obtain a tylosap solution containing budesonide; dissolve the remaining raw materials and excipients in purified water, add the obtained aqueous solution to the tylosap solution containing budesonide, hydrate at 40 degrees Celsius until completely dissolved, and then filter the obtained aqueous solution through a 0.22 μm aqueous needle filter membrane to obtain an aqueous solution containing budesonide.

[0103] The preparation methods of prescriptions 24 and 25 are as follows: Weigh the prescribed amounts of budesonide and tylosap, add anhydrous ethanol and mix to dissolve; remove the ethanol by rotary evaporation at 40 degrees Celsius for 1 hour, and then vacuum dry in a vacuum drying oven (40 degrees Celsius, 180 min) to obtain a tylosap solution containing budesonide; dissolve the remaining raw materials and excipients in purified water (purged with nitrogen or carbon dioxide until the oxygen content is less than 0.3 mg / L), add the obtained aqueous solution to the tylosap solution containing budesonide, hydrate at 40 degrees Celsius until completely dissolved, and then filter the obtained aqueous solution through a 0.22 μm aqueous needle filter membrane to obtain an aqueous solution containing budesonide.

[0104] Prescription stability: The results are shown in Tables 9-10.

[0105] Table 9. Impurities of Budesonide in Prescriptions 20-25

[0106]

[0107] Table 10. Impurities in Terbutaline Sulfate in Prescriptions 20-25

[0108]

[0109] As shown in Table 9-10, the formulations using nitrogen or carbon dioxide for deoxygenation have high stability.

[0110] Example 5: Study on prescription delivery

[0111] Table 11 Formula 26

[0112]

[0113]

[0114] The preparation method of Formula 26 is as follows: weigh budesonide and tylosap, add anhydrous ethanol and mix to dissolve; remove ethanol by rotary evaporation at 40 degrees Celsius for 1 hour, and then vacuum dry in a vacuum drying oven (40 degrees Celsius, 180 min) to obtain a tylosap solution containing budesonide; dissolve the remaining raw materials and excipients in purified water (purged with nitrogen until the oxygen content is less than 0.3 mg / L), add the obtained aqueous solution to the tylosap solution containing budesonide, hydrate at 40 degrees Celsius until completely dissolved, and then filter the obtained aqueous solution through a 0.22 μm aqueous needle filter membrane to obtain an aqueous solution containing budesonide.

[0115] 26 doses of the above formulation (0.5 mg / 4 mg / 2 mL) were taken, and budesonide inhalation suspension (1 mg / 2 mL, trade name: Pulmicort, manufacturer: AstraZeneca Pty Ltd) was used as a comparison. The delivery rate, total delivery volume, and aerodynamic particle size distribution of the two formulations were measured. The results are shown in Tables 12-14. Figure 1-2 As shown.

[0116] Table 12 Delivery rate and total amount of budesonide in prescription formulations

[0117]

[0118] As shown in Table 12, the delivery rate of the solution-type budesonide formulation (0.5 mg / 2 mL) is significantly higher than that of the existing suspension formulation (1 mg / 2 mL).

[0119] Table 13 Comparison of aerodynamic particle size distribution of budesonide in prescription formulations

[0120] Prescription 26 Marketed product: Budesonide inhalation suspension ISM 295.07μg 327.88μg FPD 196.42μg 153.097μg MMAD 3.747 5.515 GSD 2.407 1.855

[0121] Table 14. Delivery rate, total delivery amount, and aerodynamic particle size distribution of terbutaline sulfate in Formula 26

[0122]

[0123]

[0124] Example 6: Pharmacokinetic Study of the Formulation

[0125] Twelve SD rats, weighing 200g–250g, half male and half female, were randomly divided into three groups of four rats each. One group received prescription 26, containing budesonide 0.045mg / kg and terbutaline sulfate 0.36mg / kg; another group received budesonide inhalation suspension (batch number: 2209088, manufacturer: Changfeng Pharmaceutical Co., Ltd.), 0.045mg / kg; and the third group received terbutaline sulfate inhalation solution (batch number: 23013127, manufacturer: Sichuan Meida Huakang Pharmaceutical Co., Ltd.), 0.45mg / kg. Blood samples were collected via tracheal injection at 0h before administration and at 2min, 15min, 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h after administration to determine the plasma concentrations of budesonide and terbutaline sulfate, as well as pharmacokinetic parameters. The results are shown in Tables 15-16.

[0126] Table 15. Main pharmacokinetic parameters of budesonide in plasma of SD rats after a single intratracheal injection of budesonide suspension and formulation 26 days later.

[0127]

[0128] Note: "Tmax(hr)" indicates that the median (range) is used.

[0129] Table 16. Main pharmacokinetic parameters of terbutaline sulfate in plasma of SD rats after a single intratracheal injection of terbutaline sulfate inhalation solution and prescription 26 months later.

[0130]

[0131]

[0132] Note: "Tmax(hr)" indicates the median (range), AUC0-tD is the area under the plasma drug concentration-time curve after dose normalization, and Cmax-D is the peak concentration after dose normalization.

[0133] In SD rats administered Prescription 26 (0.045 mg / kg / 0.36 mg / kg; budesonide / terbutaline sulfate) via tracheal injection, compared with the group administered the same dose of inhaled budesonide suspension alone, the plasma budesonide C content in Prescription 26 was significantly lower. max It was significantly higher than that of the inhaled budesonide suspension group.

[0134] In SD rats, after intratracheal administration of prescription 26 (0.045 mg / kg / 0.36 mg / kg; budesonide / terbutaline sulfate), compared with the group receiving terbutaline sulfate inhalation solution alone (0.45 mg / kg), the plasma half-life of prescription 26 was 0.7675 h, which was shorter than the 0.9234 h of the terbutaline sulfate inhalation solution group. At the same unit dose (dose normalized), the ratio of exposure AUC0-t to Cmax was 0.9 and 1.0, respectively.

[0135] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A budesonide inhalable solution composition, said budesonide inhalable solution composition comprising the following components: Active ingredients, solubilizers, solvents; The active ingredients include (1) budesonide or a pharmaceutically acceptable salt thereof; and (2) terbutaline or a pharmaceutically acceptable salt thereof, budesonide; The solubilizer is thioxaparin.

2. The budesonide inhalable solution composition according to claim 1, characterized in that, The content of budesonide or its pharmaceutically acceptable salt is 0.005%-0.5%, preferably 0.01%-0.3%; Preferably, the content of terbutaline or its pharmaceutically acceptable salt is 0.05%-1.0%, more preferably 0.1%-0.5%; Preferably, the pharmaceutically acceptable salt of terbutaline is terbutaline sulfate; Preferably, the mass ratio of budesonide to terbutaline or a pharmaceutically acceptable salt thereof is 1:1-50, more preferably 1:2-30.

3. The budesonide inhalable solution composition according to claim 1 or 2, characterized in that, The content of the solubilizer is 0.1%-10.0%, preferably 0.2%-8.0%.

4. The budesonide inhalable solution composition according to any one of claims 1-3, characterized in that, The budesonide inhalable solution composition optionally includes a buffer; Preferably, the buffer comprises a pharmaceutical acid and a pharmaceutical alkali; Preferably, the medicinal acid is selected from one, two or more of citric acid, phosphoric acid, acetic acid, tartaric acid, succinic acid, boric acid, and sodium phosphate; Preferably, the medicinal alkali is selected from one, two or more of sodium citrate, sodium dihydrogen phosphate, sodium acetate, disodium hydrogen phosphate, and sodium acetate; Preferably, the pH of the budesonide inhalable solution composition is 4.0-6.0, more preferably 4.5-5.5, for example 5.

0. Preferably, the content of the buffer is 0.01%-0.5%; Preferably, the content of pharmaceutical acid in the buffer is 0.01%-0.5%; Preferably, the buffer contains 0.01%-0.5% pharmaceutical alkali.

5. The budesonide inhalable solution composition according to any one of claims 1-4, characterized in that, The budesonide inhalable solution composition optionally includes a chelating agent; Preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate; Preferably, the content of the chelating agent is 0.005%-0.5%, more preferably 0.01%-0.3%; Preferably, the solvent is selected from anhydrous ethanol and water.

6. The budesonide inhalable solution composition according to any one of claims 1-5, characterized in that, The budesonide inhalable solution composition optionally includes an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from one, two or more of glycerol, sodium chloride, propylene glycol, glucose, and mannitol; preferably, the content of the osmotic pressure regulator is 0.5%-8.0%, more preferably 0.6%-6.0%; Preferably, the budesonide inhalable solution composition optionally includes an antioxidant; preferably, the antioxidant is selected from one, two, or more of solid or liquid antioxidants and gaseous antioxidants; preferably, the solid or liquid antioxidant is selected from one, two, or more of vitamin C, glutathione, and sodium metabisulfite; preferably, the gaseous antioxidant is selected from one, two, or more of nitrogen and carbon dioxide. Preferably, the antioxidant content is 0.01%-1.0%, more preferably 0.05%-0.5%; Preferably, the antioxidant has an oxygen content of less than 0.3 mg / L.

7. The budesonide inhalable solution composition according to any one of claims 1-6, characterized in that, The budesonide inhalable solution composition comprises the following components: Budesonide, terbutaline sulfate, tylosap, osmotic pressure regulator, buffer, chelating agent, water; Preferably, the content of budesonide is 0.0125%-0.05%; Preferably, the content of terbutaline sulfate is 0.15%-0.25%; Preferably, the content of teroxaprol is 0.5%-7.0%; Preferably, the osmotic pressure regulator is selected from glycerol and sodium chloride; preferably, the content of the osmotic pressure regulator is 0.85%-5.0%; Preferably, the buffer is selected from citric acid and sodium citrate, or citric acid and sodium dihydrogen phosphate; Preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate; preferably, the content of the chelating agent is 0.01%; Preferably, the budesonide inhalable solution composition includes an antioxidant; preferably, the antioxidant is selected from gaseous antioxidants.

8. The budesonide inhalable solution composition according to any one of claims 1-7, characterized in that, The budesonide inhalable solution composition comprises the following components: Preferably, the budesonide inhalable solution composition comprises the following components:

9. A method for preparing the budesonide inhalable solution composition according to any one of claims 1-8, the method comprising the following steps: S1) Dissolve the solubilizer and budesonide in an organic solvent to obtain a mixed solution, and then remove the organic solvent to obtain a solubilizer solution containing budesonide; S2) Dissolve terbutaline or a pharmaceutically acceptable salt thereof, along with optional buffers, chelating agents, osmotic regulators, and antioxidants in a solvent; S3) Add the solution obtained in step S2 to the solubilizing solution containing budesonide in step S1, mix well, and the budesonide inhalable solution composition can be obtained.

10. The use of the budesonide inhalable solution composition according to any one of claims 1-8 in the preparation of a medicament for treating and / or preventing lung diseases; said lung diseases include bronchitis, asthma, and chronic obstructive pulmonary disease; Preferably, the bronchitis includes acute bronchitis and chronic bronchitis; preferably, the asthma includes acute asthma, chronic asthma, severe asthma, allergic asthma, bronchial asthma, and endogenous asthma.

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