CN118436601A

CN118436601A - Budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and preparation method thereof

Info

Publication number: CN118436601A
Application number: CN202410562879.2A
Authority: CN
Inventors: 侯曙光; 贺钢民; 舒宏; 叶春浩; 秦莉娜; 洪道鑫; 邓婷; 王震宇
Original assignee: Sichuan Pu Et Pharmaceutical Co ltd
Current assignee: Sichuan Pu Et Pharmaceutical Co ltd
Priority date: 2022-09-14
Filing date: 2022-09-14
Publication date: 2024-08-06
Also published as: CN115463117B; CN115463117A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and a preparation method thereof. In order to improve the delivery efficiency of salbutamol, the salbutamol is prepared into aerosol, but the propellant used in the aerosol has high cost, and when the salbutamol is used, the medicine sucking and the air sucking of a patient are required to be synchronously carried out, so that the problems of inaccurate delivery dosage and lower compliance exist. In order to solve the problems, the invention provides a budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and a preparation method thereof. The aerosol inhalation suspension has the characteristics of convenient use, high delivery efficiency and good stability, and the preparation method is stable and reliable.

Description

Budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and a preparation method thereof.

Background

Bronchial asthma, a heterogeneous disease characterized by chronic airway inflammation; respiratory symptoms history with wheezing, shortness of breath, chest distress and cough, with variable expiratory airflow limitation, respiratory symptoms and intensity can vary over time. Asthma can develop at any age, most originating before 4 to 5 years of age. Most of the asthma is caused by respiratory tract infections and symptoms are manifested as paroxysmal attacks of cough and wheezing, with the night and early morning being heavy. There may be runny nose/sneeze and chest distress before onset, dyspnea during onset, prolonged exhalation accompanied by wheezing. Severe cases are sitting and breathing, fear, sweaty, pale complexion, nasal flapping, cyanosis of lips and nails, even cold sweats, frightening, and often show critical conditions.

Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. COPD (chronic obstructive pulmonary disease) is a term used to describe a lung disease associated with airflow obstruction. Airflow restriction is often progressive and is associated with an abnormal inflammatory response of the lungs to harmful particles or gases primarily caused by smoking.

Beta ₂ receptor agonists are currently the most clinically used bronchodilators. Salbutamol (salbutamol), a short-acting beta ₂ adrenergic receptor agonist, is used as an antiasthmatic agent, and can effectively inhibit the release of allergic substances such as histamine and prevent bronchospasm. The levosalbutamol is a single optical isomer of the salbutamol, the drug effect is 80 times of that of the dextrsalbutamol, the side effect is reduced, the curative effect is further improved, the same curative effect can be produced by only 1/4 dose of the raceme of the levosalbutamol, and the effect is better than that of the raceme at 1/2 dose. In COPD, the pro-inflammatory response of levalbuterol is weaker than albuterol.

Budesonide is a glucocorticoid with high-efficiency local anti-inflammatory effect, which can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune response and reduce antibody synthesis, thereby promoting the reduction of release and activity of anaphylactic active mediums such as histamine and the like, and can alleviate enzymatic processes excited during antigen-antibody combination, inhibit synthesis and release of bronchoconstrictor substances and alleviate contraction response of bronchial smooth muscles. Clinically used for the treatment of glucocorticoid dependent or independent bronchial asthma and asthmatic chronic bronchitis patients, and COPD.

Clinical combination of budesonide and salbutamol for treatment of bronchial asthma and asthmatic chronic bronchitis (Feng Bilin, tong Linrong, cai Kunsong, xu Yagong. Clinical effect of budesonide in combination with salbutamol nebulized inhalation for treatment of patients with acute episodes of bronchial asthma. In external and chinese medical research, 2020,18 (02): 149-151.); after the two single components are mixed, the total amount of the liquid medicine is increased, the atomization time is long, and the patient compliance is poor besides the dispersibility and the chemical stability; separate atomization, the atomization time is longer.

Meanwhile, the inventor of the invention discovers that the single aerosol inhalant of salbutamol has the problems of large residue of an aerosol cup, low delivery efficiency and poor chemical stability (salbutamol impurity D is easy to generate).

Chinese patent 201210346685.6 discloses an inhalation type compound aerosol containing salbutamol, which is characterized in that composition particles such as salbutamol salts and the like which are wrapped by inactive components (namely additives) of one or more drug particles are obtained by a supercritical fluid crystallization technology, and the aerosol has good dispersion performance and stability in a suspension solution, and the drug transfer efficiency is effectively improved.

However, it should be noted that this solution produces an aerosol rather than an aerosol, which itself does not present the problem of aerosol cup residue due to the pressure resistance of the aerosol to the package. In addition, the aerosol has the characteristic of poor compliance, and needs good cooperativity of patients, and has higher requirements on medication compliance of pediatric patients. Meanwhile, the aerosol also uses a supercritical fluid crystallization technology, so that the cost is extremely high, the medical burden of a patient is increased, and the method is complex to operate and is not beneficial to industrialization.

Disclosure of Invention

The inventor surprisingly found that after budesonide and salbutamol are prepared into an aerosol inhalation suspension, compared with single prescription of salbutamol, under the same experimental conditions, the delivery efficiency of salbutamol after being prepared into a compound prescription is obviously improved, the residual quantity of an aerosol cup is obviously reduced, the chemical stability is also improved, the delivery efficiency of budesonide is also ensured, and the atomization time is reduced.

Therefore, the invention aims to provide budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency.

The technical scheme of the invention is as follows:

Mixing salbutamol and budesonide, wherein the salbutamol and budesonide comprise the following raw and auxiliary materials in concentration: 0.1 to 0.6mg/ml of budesonide, 0.08 to 3.0mg/ml of salbutamol, 0.01 to 0.2mg/ml of metal ion complexing agent and 0.01 to 0.3mg/ml of wetting agent; regulating osmotic pressure to 250-330 mOsmol/kg with osmotic pressure regulator and regulating pH of the system to 3.0-5.0 with pH buffering agent and/or pH regulator; the balance being water.

A number of clinical combinations of salbutamol and the glucocorticoid budesonide have been reported for the treatment of chronic obstructive pulmonary disease such as bronchitis, bronchial asthma and the like. Therefore, the invention mixes salbutamol and the glucocorticoid budesonide for use and has the drug safety.

In the invention, the salbutamol comprises salbutamol and salbutamol pharmaceutically acceptable salts or isomers. For example, including but not limited to salbutamol, salbutamol sulphate, levosalbutamol hydrochloride, salbutamol fumarate, salbutamol lithonate, levosalbutamol and the like.

The metal ion complexing agent is one or more of sodium ethylenediamine tetraacetate, calcium ethylenediamine tetraacetate, potassium ethylenediamine tetraacetate and ethylenediamine tetraacetic acid;

the osmotic pressure regulator is one or more of sodium chloride, mannitol, glucose, glycerol and lactose.

In the invention, the wetting agent is fatty acid sorbitan and/or polysorbate; the fatty acid sorbitan is an ester compound formed by the reaction of sorbitan and various higher fatty acids, and comprises, but is not limited to span 20, span 40, span 60, span 80 and the like; the polysorbate is an ether compound prepared by combining polyoxyethylene groups on the residual hydroxyl groups in the molecular structure of span surfactant, and the ether compound comprises, but is not limited to, tween 20, tween 40, tween 60, tween 80 and the like.

Further, the wetting agent is one or more selected from tween 20, tween 40, tween 60, tween 80, span 20 span 40, span 60 or span 80.

Further, the wetting agent is selected from tween 80.

In the present invention, the pH buffering agent includes, but is not limited to, citric acid and sodium citrate systems, acetic acid-sodium acetate systems, sodium dihydrogen phosphate-disodium hydrogen phosphate systems, and the like.

In the invention, the pH regulator is one or more of inorganic acid, organic acid or inorganic alkali;

Further, the pH regulator is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, hydrobromic acid, nitric acid, ascorbic acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, formic acid, propionic acid, hydrochloric acid, acetic acid and sulfuric acid;

Further, the pH regulator is one or more of sodium hydroxide, hydrochloric acid, acetic acid and sulfuric acid.

The water in the invention is water for injection.

The inventors have unexpectedly found that the use of levalbuterol hydrochloride or salbutamol sulphate in combination with budesonide, the compound aerosol inhalation suspension used in the invention is capable of effectively improving the delivery efficiency of Gao Sha butylamine compared with the single formulation of levalbuterol hydrochloride or salbutamol sulphate.

In the invention, the aerosol inhalation suspension comprises the following raw and auxiliary materials in concentration:

Budesonide: 0.1-0.6 mg/ml, levosalbutamol hydrochloride: 0.08-0.75 mg/ml, metal ion complexing agent: 0.01-0.2 mg/ml, wetting agent: 0.01-0.3 mg/ml; the osmotic pressure is regulated by an osmotic pressure regulator within the range of: 250-330 mOsmol/kg; regulating the pH value of the system to 3.0-5.0 by using a pH regulator; the balance being water; further, the pH regulator is one of sulfuric acid and hydrochloric acid.

In some embodiments of the invention, the aerosol inhalation suspension comprises the following concentrations of raw and auxiliary materials:

Budesonide: 0.1-0.6 mg/ml, levosalbutamol hydrochloride: 0.08-0.75 mg/ml, edetate disodium: 0.01-0.2 mg/ml, polysorbate 80: 0.01-0.3 mg/ml; the osmotic pressure is regulated by sodium chloride in the following range: 250-330 mOsmol/kg; regulating the pH value of the system to 3.0-5.0 by using a pH regulator; the balance being water; further, the pH regulator is one of sulfuric acid and hydrochloric acid.

Specifically, the method comprises the following raw and auxiliary materials in concentration: budesonide: 0.5mg/ml, levosalbutamol hydrochloride: 0.42mg/ml, edetate disodium: 0.1mg/ml, polysorbate 80:0.1mg/ml; sodium chloride:

8.5mg/ml, and regulating the pH value of the system to 3.0-5.0 by sulfuric acid or hydrochloric acid; the balance being water.

0.1 to 0.6mg/ml of budesonide, 0.8 to 3.0mg/ml of salbutamol sulfate, 0.01 to 0.2mg/ml of metal ion complexing agent and 0.01 to 0.3mg/ml of wetting agent; regulating osmotic pressure to 250-330 mOsmol/kg with osmotic pressure regulator and regulating pH of the system to 3.0-5.0 with pH buffering agent and/or pH regulator; the balance being water.

0.1 to 0.6mg/ml of budesonide, 0.8 to 3.0mg/ml of salbutamol sulfate, disodium edentate: 0.01-0.2 mg/ml, polysorbate 80: 0.01-0.3 mg/ml; regulating osmotic pressure to 250-330 mOsmol/kg with sodium chloride, and regulating pH of the system to 3.0-4.0 with pH buffering agent and/or pH regulator; the balance being water.

Further, the pH regulator is one of sulfuric acid and hydrochloric acid.

In addition, in the invention, the inventor also unexpectedly discovers that the salbutamol sulfate in the compound aerosol inhalation suspension is placed under the ampoule bottle packaging condition, and the impurity content of the salbutamol sulfate can be obviously improved. Through screening of the types, the dosage, the process conditions and the like of raw materials and auxiliary materials, the invention finally discovers that under the compatibility condition of the raw materials and auxiliary materials, when the pH value is 3.0-4.0, the impurity D and the maximum unknown single impurity of the compound (budesonide and salbutamol sulfate) can be obviously reduced, the impurity content is obviously lower than that of the salbutamol sulfate single atomized inhalation suspension, and the stability of the salbutamol sulfate is effectively improved.

As a preferable scheme, the aerosol inhalation suspension comprises the following raw and auxiliary materials with the concentration: budesonide: 0.5mg/ml salbutamol sulphate: 2.4mg/ml, edetate disodium: 0.1mg/ml, polysorbate 80:0.1mg/ml, sodium chloride: 8.5mg/ml, and adjusting the pH to 3.0-4.0 by using citric acid and sodium citrate; the balance being water.

When the suspension of the present invention is commercialized, the raw materials and auxiliary materials are formulated into an aerosol inhalation suspension according to the above concentration ratio, and the volume of the suspension may be 2.0ml,2.1ml, 2.5ml, 3ml, 4ml, 5ml, etc.

The invention also provides a preparation method of the aerosol inhalation suspension, which comprises the following steps:

Step A: dissolving an osmotic pressure regulator, a metal ion complexing agent, a part of wetting agent and a beta ₂ receptor agonist in water, sterilizing and filtering to form a solution b;

And (B) step (B): dissolving part of wetting agent in water to form a solution c, adding micronized budesonide into the solution c, performing ultrasonic dispersion or shearing by a high-speed shearing machine to form a suspension d, performing high-pressure steam sterilization on the suspension d, and performing high-pressure homogenization treatment on the suspension d after sterilization to obtain a suspension e;

Step C: mixing solution b and suspension e under aseptic condition, adding water, and adjusting pH to prescribed range with pH buffer and/or pH regulator.

In step A of the present invention, the osmotic pressure regulator, the metal ion complexing agent and a portion of the wetting agent may be dissolved in water to form solution a, and then the beta ₂ receptor agonist may be added.

The sterilization filtration in the invention is to remove bacteria in liquid or air by a physical blocking method so as to achieve the aim of sterility. The device used was a bacterial filter with a small pore size. The high-pressure steam sterilization and the high Wen Jiagao pressure sterilization can kill common bacteria, fungi and other microorganisms, have the effect of killing spores and spores, and are the most reliable and most commonly applied physical sterilization method. The high-pressure homogenization can lead the material in the suspension state to flow through the containing cavity with a special internal structure at a high speed under the action of ultrahigh pressure, so that the material is subjected to a series of changes of physical, chemical, structural properties and the like, and finally the homogenization effect is achieved. The ultrasonic dispersion or the shearing by a high-speed shearing machine is to disperse the budesonide in the solution.

In some embodiments of the invention, the filter size used in the aseptic filtration is 0.22 μm.

In some embodiments of the invention, the high pressure steam sterilization is performed at 115℃or 121℃for 12-30 minutes.

In some embodiments of the invention, the high pressure homogenizing pressure of the invention is 300-1500 bar, and the cycle is 3-8 times.

In some embodiments of the present invention, the high speed shears may be shearing at 10000-30000 rpm for 5-15 min.

In some embodiments of the invention, the preparation of the aerosol further comprises a sterile filling process step.

The invention has the beneficial effects that:

1. The budesonide and the levo-salbutamol hydrochloride or the salbutamol sulfate are combined, and compared with the single prescription of the levo-salbutamol hydrochloride or the salbutamol sulfate, the compound atomized inhalation suspension can effectively improve the delivery efficiency of Gao Sha salbutamol, thereby reducing the administration dosage, reducing the occurrence probability of adverse reactions, reducing the administration cost to a certain extent and lowering the medical cost of patients.

2. When budesonide and salbutamol sulfate are combined and the pH of the aerosol inhalation suspension is adjusted to 3.0-4.0, compared with unilateral (salbutamol sulfate), the compound (budesonide and salbutamol sulfate) has better stability, which indicates that the stability of salbutamol is improved after combination.

3. Clinically, salbutamol and budesonide are simply combined, such as the dispersibility, delivery efficiency, chemical stability and other ambiguities of budesonide; after the two single components are mixed, the total amount of the liquid medicine is increased, the atomization time is long, and the patient compliance is poor besides the dispersibility and the chemical stability; separate atomization, the atomization time is longer. The invention prepares the budesonide and the salbutamol into suspension, so that the budesonide has better dispersibility and physical and chemical stability; the salbutamol delivery efficiency is high, the residual quantity of an atomizing cup is small, and the chemical stability is good; the compound atomization time is short, and the compliance is good.

Drawings

FIG. 1 is an APSD diagram of budesonide single side (BD) and compound (BD+AS);

FIG. 2 is an APSD of salbutamol sulfate unilateral (AS) and compound (BD+AS);

FIG. 3 is an APSD of levosalbutamol hydrochloride unilateral (LH) and compound (BD+LH);

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Example 1

1. Prescription composition:

Step A: dissolving sodium chloride, edetate disodium and polysorbate 80 in water to form a solution a, adding salbutamol sulfate into the solution a, and filtering by a 0.22 mu m PES needle type sterilization filter after the salbutamol sulfate is completely dissolved to form a solution b;

And (B) step (B): dissolving polysorbate 80 in water to form a solution c with the concentration of 5mg/ml, adding micronized budesonide into the solution c according to the concentration of 50mg/ml, performing ultrasonic dispersion to form a suspension d, performing high-pressure steam sterilization at 121 ℃/20min on the suspension d, and performing high-pressure homogenization treatment for 5-6 times according to the pressure cycle of 1000bar after sterilization to obtain a suspension e;

Step C: mixing solution b and 5.0ml suspension e under aseptic condition, adding injectable water to 500ml, adjusting pH to about 3.0, 4.0 and 5.0 with 20mg/ml citric acid or sodium citrate solution, respectively, and filling into low density polyethylene plastic ampoule at a filling amount of 2.1 ml/branch.

2. Stability test

Example 1 was examined at 60℃for 31 days under the influence of a factor test, and compared with the related substances of AS (salbutamol sulfate) alone, the following results were obtained:

TABLE 1 example 1 Compound (BD+AS) and unilateral (AS) stability experiments

Note that: salbutamol sulfate single raw and auxiliary materials comprise the following components in percentage by weight: salbutamol sulphate: 6.02mg of sodium chloride, 23.06mg; adjusting the pH to 4.0 with 0.1mol/L sulfuric acid; water for injection was added to 2.5ml.

From the data, both impurity D and the maximum unknown single impurity of the compound (BD+AS) are better than salbutamol sulfate (AS) at pH 3.0-4.0, which can indicate that the stability of salbutamol is improved after combination. 3. Unilateral and compound Aerodynamic Particle Size Distribution (APSD)

The APSD of budesonide and salbutamol sulphate of example 1 was tested, as well as the APSD of budesonide and salbutamol sulphate of the single party. With reference to four parts of Chinese pharmacopoeia 2020 edition, the inhalation preparation fine particle aerodynamic feature measurement method (general rule 0951) is carried out according to the method of the device 3 (NGI) by matching with a PARI Turbo BOY compressor and a Pari-LC Plus atomizer. The sum of the drug particle contents of the primary NGI from grade 4 to MOC grade was examined (powder particles in this interval are inhalable effective particles), and the results are shown in tables 2 and 3.

1. Budesonide single and compound (BD+AS)

TABLE 2 delivery Rate and APSD of budesonide unilateral and Compound (BD+AS)

Budesonide unilateral: BD. Sodium chloride, disodium edentate, citric acid/sodium citrate, polysorbate 80, water for injection; the pH is 4-5.

AS can be seen from the experimental results of fig. 1 and table 2, the compound (bd+as) and the single component (BD) were identical, regardless of the P4-MOC (%) value or the total percentage, and it was revealed that the particle size distribution of budesonide and the delivery efficiency thereof were not affected by the addition of salbutamol sulfate to Xiang Bu budesonide.

2. Salbutamol sulfate single and compound

Salbutamol sulphate unilateral (2.5 ml:5 mg) and dose-reduced compound (2 ml:4 mg) were used for salbutamol sulphate delivery rate and APSD (NGI):

TABLE 3 delivery Rate and APSD of salbutamol sulfate unilateral and Compound (BD+AS)

AS can be seen from the experimental results in fig. 2 and table 3, in the case where the dose of salbutamol sulfate used in the compound (bd+as) was lower than that in the single formulation (AS) (in the case where the dose of compound was 4mg, single formulation was 5mg, and the delivered dose was 20% lower), the compound delivery amount was high because the compound atomizing cup remaining amount was lower than that in the single formulation. Meanwhile, P4-MOC (%) is a fine particle dose percentage, representing an effective dose percentage delivered to the lung, table 1 shows that the P4-MOC (%) value of the compound (bd+as) is 26.04%, the P4-MOC (%) value of the single prescription (AS) is 19.07%, and the fine particle dose percentage of the compound is higher than that of the single prescription, so that the effective delivery amount of the compound is increased, the drug waste is reduced, and the delivery efficiency is improved.

Example 2

Prescription composition

Table 4 prescription composition

Prescription (LH single prescription)	220401
		Levosalbutamol hydrochloride (calculated as salbutamol)	1.25mg
Sodium chloride	27mg
		Edetic acid disodium salt	0.15mg
Sulfuric acid	To pH4.0
		Water for injection	To 3ml
Prescription (BD+LH compound)	220101
		Budesonide	1.5mg
Levosalbutamol hydrochloride (calculated as salbutamol)	1.25mg
		Polysorbate 80	0.3mg
Sodium chloride	25.5mg
		Edetic acid disodium salt	0.3mg
Sulfuric acid	To pH4.0
		Water for injection	To 3ml

The preparation method is the same as in example 1.

2. Unilateral and compound Aerodynamic Particle Size Distribution (APSD)

The delivery rates and APSD of levosalbutamol hydrochloride unilateral and compound (bd+lh) of table 4 were tested as in example 1.

TABLE 5 delivery Rate and APSD of Levalmol hydrochloride unilateral and Compound (BD+LH)

The results are shown in conjunction with table 5 and fig. 3: the residual quantity of the atomizing cup of the compound (BD+LH) is less than that of the single compound (LH), which indicates that the compound can atomize more medicines with less medicine waste under the same condition; the P4-MOC (%) value compound (BD+HL) is higher than that of single prescription (LH), which indicates that the content of the drug effectively delivered to the lung by the compound is higher than that of the single prescription, and the delivery efficiency of the compound is high.

It will be apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed with preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

Claims

1. The budesonide and salbutamol compound aerosol inhalation suspension with high delivery efficiency is characterized in that salbutamol and budesonide are mixed, and the budesonide and salbutamol compound aerosol inhalation suspension comprises the following raw and auxiliary materials with the concentration:

0.1 to 0.6mg/ml of budesonide, 0.08 to 3.0mg/ml of salbutamol, 0.01 to 0.2mg/ml of edetate disodium and 0.01 to 0.3mg/ml of wetting agent, wherein the wetting agent is fatty acid sorbitan and/or polysorbate; regulating osmotic pressure to 250-330 mOsmol/kg with osmotic pressure regulator, and regulating pH of the system to 3.0-5.0 with citric acid and sodium citrate or pH regulator; the balance being water;

The salbutamol is selected from salbutamol sulphate and levosalbutamol hydrochloride.

2. The aerosol inhalation suspension of claim 1, wherein the osmolality adjusting agent is one or more of sodium chloride, mannitol, glucose, glycerol, lactose.

3. The aerosol inhalation suspension of claim 2, wherein the wetting agent is selected from one or more of tween 20, tween 40, tween 60, tween 80, span 20, span 40, span 60 or span 80.

4. The aerosol inhalation suspension of claim 1, wherein the pH modifier is one or more of an inorganic acid, an organic acid, an inorganic base.

5. The aerosol inhalation suspension of claim 1, wherein the pH modifier is one or more of sodium hydroxide, hydrochloric acid, acetic acid, sulfuric acid.

6. An aerosol inhalation suspension according to any one of claims 1to 5 comprising the following concentrations of raw and auxiliary materials: budesonide: 0.1-0.6 mg/ml, levosalbutamol hydrochloride: 0.08-0.75 mg/ml, edetate disodium: 0.01-0.2 mg/ml, polysorbate 80: 0.01-0.3 mg/ml; the osmotic pressure is regulated by sodium chloride in the following range: 250 to 330mOsmol/kg, and regulating the pH of the system to 3.0 to 5.0 by using a pH regulator; the balance being water;

the pH regulator is one of sulfuric acid and hydrochloric acid.

7. An aerosol inhalation suspension according to claim 5 comprising the following concentrations of raw and auxiliary materials: budesonide: 0.5mg/ml, levosalbutamol hydrochloride: 0.42mg/ml, edetate disodium: 0.1mg/ml, sodium chloride: 8.5g/ml, polysorbate 80:0.1mg/ml; adjusting the pH value of the system to 3.0-5.0 by sulfuric acid; the balance being water.

8. An aerosol inhalation suspension according to any one of claims 1 to 4 comprising the following concentrations of raw and auxiliary materials: budesonide: 0.1-0.6 mg/ml salbutamol sulfate: 0.8-3.0 mg/ml, edetate disodium: 0.01-0.2 mg/ml, polysorbate 80: 0.01-0.1 mg/ml; the osmotic pressure is regulated by sodium chloride in the following range: 250-330 mOsmol/kg, and adjusting pH to 3.0-4.0 with citric acid and sodium citrate or pH regulator; the balance being water;

the pH regulator is one of sulfuric acid and hydrochloric acid.

9. An aerosol inhalation suspension according to claim 7 comprising the following concentrations of raw and auxiliary materials: budesonide: 0.5mg/ml salbutamol sulphate: 2.4mg/ml, edetate disodium: 0.1mg/ml, polysorbate 80:0.1mg/ml, sodium chloride: 8.5mg/ml, and adjusting the pH to 3.0-4.0 by using citric acid and sodium citrate; the balance being water.

10. A method of preparing an aerosol inhalation suspension according to any one of claims 1 to 9 comprising the steps of:

step A: dissolving osmotic pressure regulator, metal ion complexing agent, partial wetting agent and salbutamol in water, sterilizing and filtering to form solution b;

11. The method of claim 10, wherein in step a, the osmotic pressure regulator, the metal ion complexing agent, and a portion of the wetting agent are dissolved in water to form solution a, and salbutamol is added.

12. The method according to claim 10, wherein the filter size used in the aseptic filtration is 0.22 μm; sterilizing by high-pressure steam at 115 ℃ or 121 ℃ for 12-30 min; the high-pressure homogenizing pressure is 500-1500 bar, and the cycle is 3-8 times; when the high-speed shearing machine is used for shearing and dispersing, the shearing speed is 10000-30000 rpm, and the shearing time is 5-15 min.