CN115463117A

CN115463117A - Budesonide salbutamol compound aerosol inhalation suspension with high delivery efficiency and preparation method thereof

Info

Publication number: CN115463117A
Application number: CN202211116675.3A
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: 2022-12-13
Anticipated expiration: 2042-09-14

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 the prior art, salbutamol is prepared into aerosol in order to improve the delivery efficiency of the salbutamol, but the cost of a propellant used in the aerosol is high, and the propellant used in the aerosol needs to be inhaled by a patient and inhaled synchronously, so that the problems of inaccurate delivered dose and low 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; a history of respiratory symptoms with wheezing, shortness of breath, chest tightness and coughing, with variable expiratory airflow limitation, which may vary in respiratory symptoms and intensity over time. Asthma can develop at any age, mostly starting before the age of 4-5 years. The vast majority of asthma is due to respiratory tract infections, with symptoms manifested as paroxysmal episodes of cough and wheezing, with severity at night and in the early morning. It has watery nasal discharge/sneezing and chest distress before onset, dyspnea during onset, and prolonged expiratory phase accompanied by wheezing. In severe cases, the patient is seated and breathed, feared, profuse sweat, cyanosis in the face, flapping of nasal wings, lips and nails, even cold sweat, and panic and restlessness in the face, which often indicates a critical state.

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 lung diseases associated with airflow obstruction. Airflow limitation is usually progressive and is associated with abnormal inflammatory responses of the lungs to harmful particles or gases mainly caused by smoking.

β ₂ Receptor agonists are currently the most widely used bronchodilators in clinical applications. Salbutamol (salbutamol), a short-acting beta ₂ An adrenergic receptor agonist is used as an antiasthmatic agent, and is effective in inhibiting the release of an allergic substance such as histamine and preventing bronchospasm. The levosalbutamol is a single optical isomer of salbutamol, the drug effect is 80 times of that of the dextrosalbutamol, the side effect is reduced, the curative effect is further improved, the levosalbutamol can generate the same curative effect only by 1/4 dose of racemate, and the effect is superior to that of the racemate at 1/2 dose. In COPD, the pro-inflammatory effects of levosalbutamol are weaker than salbutamol.

Budesonide is a glucocorticoid with high-efficiency local anti-inflammatory action, which can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune reaction and reduce antibody synthesis, thereby promoting the release reduction and activity reduction of allergic active mediators such as histamine and the like, relieving the enzymatic process stimulated by antigen-antibody combination, inhibiting the synthesis and release of bronchoconstrictor substances and relieving the contraction reaction of bronchial smooth muscles. The composition is clinically used for patients with glucocorticoid-dependent or non-dependent bronchial asthma and asthmatic chronic bronchitis and for treating COPD.

Budesonide and albuterol are clinically used for treating bronchial asthma and asthmatic chronic bronchitis (Von Billin, tonglinong, chua Kunlong, xu Yahong. Budesonide is combined with albuterol aerosol inhalation for treating clinical effects of patients suffering from acute attack of bronchial asthma. China and foreign medical research, 2020,18 (02): 149-151.); after the two single materials are mixed, the total amount of the liquid medicine is increased except the dispersibility and the chemical stability, the atomization time is long, and the compliance of patients is poor; the atomization is separated, and the atomization time is longer.

Meanwhile, the inventor of the invention finds that the single-component aerosol inhalation of salbutamol has the problems of large residual quantity of an atomizing cup, low delivery efficiency and poor chemical stability (the impurity D of salbutamol is easy to generate).

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

It should be noted, however, that this solution produces an aerosol, rather than a nebulant, which does not itself present the problem of residue from the nebulising cup due to the aerosol's requirement for packaging pressure resistance. In addition, the aerosol has the characteristic of poor compliance, needs good patient synergy and has higher requirements on the 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 finds that after budesonide and salbutamol are prepared into the atomization inhalation suspension, compared with the single formula of the salbutamol, the delivery efficiency of the prepared compound salbutamol is obviously improved, the residual quantity of an atomization cup is obviously reduced, the chemical stability of the atomization cup is also increased, the delivery efficiency of the budesonide is ensured, and the atomization time is shortened under the same experimental conditions.

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

The technical scheme of the invention is as follows:

mixing salbutamol and budesonide, and comprising the following raw and auxiliary materials in concentration: 0.1-0.6 mg/ml of budesonide, 0.08-3.0 mg/ml of salbutamol, 0.01-0.2 mg/ml of metal ion complexing agent and 0.01-0.3 mg/ml of wetting agent; regulating the osmotic pressure range to 250-330 mOsmol/kg by using an osmotic pressure regulator, and regulating the pH of the system to 3.0-5.0 by using a pH buffering agent and/or a pH regulator; the balance of water.

Budesonide is a glucocorticoid with highly effective local anti-inflammatory action, which can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune reaction and reduce antibody synthesis, thereby promoting the release reduction and activity reduction of allergic active mediators such as histamine, etc., relieving the enzymatic process triggered by antigen-antibody binding, inhibiting the synthesis and release of bronchoconstrictor substances and relieving the constriction reaction of bronchial smooth muscle. The composition is clinically used for patients with glucocorticoid-dependent or non-dependent bronchial asthma and asthmatic chronic bronchitis and for treating COPD.

A great deal of clinical combined medicines for treating chronic obstructive pulmonary diseases such as bronchitis, bronchial asthma and the like are reported for salbutamol and glucocorticoid budesonide. Therefore, the invention has the advantages of drug safety when the salbutamol and the glucocorticoid budesonide are mixed for use.

In the invention, the salbutamol comprises salbutamol, and pharmaceutically acceptable salt or isomer of salbutamol. For example, including but not limited to albuterol, albuterol sulfate, levalbuterol hydrochloride, albuterol fumarate, albuterol tartrate, levalbuterol, and the like.

The metal ion complexing agent is one or more of sodium ethylene diamine tetracetate, calcium ethylene diamine tetracetate, potassium ethylene diamine tetracetate and ethylene diamine tetracetic 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 includes 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 on the residual hydroxyl in the molecular structure of the span surfactant, and includes, but is not limited to, tween 20, tween 40, tween 60, tween 80 and the like.

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

Further, the wetting agent is selected from tween 80.

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

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

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 inventor unexpectedly finds that the compound atomization inhalation suspension used by the invention can effectively improve the delivery efficiency of the salbutamol compared with the single component of the levosalbutamol hydrochloride or the salbutamol sulfate by combining the levosalbutamol hydrochloride or the salbutamol sulfate with the budesonide.

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 range is adjusted by an osmotic pressure regulator: 250-330 mOsmol/kg; adjusting the pH of the system to 3.0-5.0 by using a pH regulator; the balance of water; further, the pH regulator is one of sulfuric acid and hydrochloric acid.

In some embodiments of the invention, the aerosolized inhalation suspension comprises the following concentrations of the raw materials: budesonide: 0.1-0.6 mg/ml, levosalbutamol hydrochloride: 0.08-0.75 mg/ml, disodium edetate: 0.01-0.2 mg/ml, polysorbate 80: 0.01-0.3 mg/ml; the osmotic pressure range was adjusted with sodium chloride: 250-330 mOsmol/kg; adjusting the pH of the system to 3.0-5.0 by using a pH regulator; the balance of 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 adjusting the pH value of the system to 3.0-5.0 by using sulfuric acid or hydrochloric acid; the balance of water.

In some embodiments of the invention, the aerosolized inhalation suspension comprises the following concentrations of the raw materials:

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

In some embodiments of the invention, the aerosolized inhalation suspension comprises the following concentrations of the raw excipients:

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

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

In addition, in the invention, the inventor also unexpectedly finds that the impurity content of the salbutamol sulfate in the compound aerosol inhalation suspension can be obviously improved when the salbutamol sulfate is placed under the condition of ampoule bottle packaging. By screening the types, the use amounts, the process conditions and the like of the raw materials and the auxiliary materials, the final finding shows that under the compatibility conditions of the raw materials and the 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 a suspension in which salbutamol sulfate is singly atomized and absorbed, and the stability of the salbutamol sulfate is effectively improved.

Preferably, the aerosol inhalation suspension comprises the following raw materials and auxiliary materials in 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, adjusting the pH value to 3.0-4.0 by using citric acid and sodium citrate; the balance of water.

When the suspension of the present invention is commercialized, the adjuvants 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.

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

step A: mixing osmotic pressure regulator, metal ion complexing agent, partial wetting agent and beta ₂ Dissolving the receptor agonist in water, sterilizing and filtering to form a solution b;

and B: dissolving part of wetting agent in water to form a solution c, adding micro-powdered 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 the sterilization is finished to obtain a suspension e;

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

In step A, the osmotic pressure regulator, the metal ion complexing agent and part of the wetting agent are dissolved in water to form a solution a, and then beta is added ₂ A receptor agonist.

The sterilization filtration is to remove bacteria in liquid or air by a physical retention method so as to achieve the purpose of sterility. The apparatus used is a bacteria filter with a tiny pore size. High-pressure steam sterilization, high-temperature and high-pressure sterilization, can kill common microbes such as bacteria and fungi, has a killing effect on spores and spores, and is the most reliable and most popular physical sterilization method. The high-pressure homogenization can enable the material in a 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 and structural properties, and the like, and finally the homogenization effect is achieved. The ultrasonic dispersion or 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 for sterile 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 min.

In some embodiments of the invention, the high-pressure homogenization pressure is 300-1500 bar, and the circulation is performed for 3-8 times.

In some embodiments of the present invention, the shearing speed of the high speed shearing machine is 10000-30000 rpm, and the shearing time is 5-15 min.

In some embodiments of the invention, the preparation of the nebulant further comprises an aseptic filling step.

The invention has the beneficial effects that:

1. the budesonide and the levosalbutamol hydrochloride or the salbutamol sulfate are used together, and compared with the single formula of the levosalbutamol hydrochloride or the salbutamol sulfate, the compound atomization inhalation suspension can effectively improve the delivery efficiency of the salbutamol, thereby reducing the administration dosage, reducing the occurrence probability of adverse reactions, reducing the medication cost to a certain extent and reducing the medical expense of patients.

2. When the pH value of the atomized inhalation suspension is adjusted to 3.0-4.0, the stability of the compound (budesonide and salbutamol sulfate) is better than that of the single component (salbutamol sulfate), which shows that the stability of the salbutamol is improved after the combination.

3. The clinical application is to simply combine the salbutamol and the budesonide, such as the uncertainty of the dispersibility, the delivery efficiency, the chemical stability and the like of the budesonide; after the two single components are mixed, the total amount of the liquid medicine is increased except the dispersibility and the chemical stability, the atomization time is long, and the compliance of patients is poor; the atomization is carried out separately, and the atomization time is longer. The invention prepares budesonide and salbutamol into suspension, so that the budesonide has better dispersibility and physical and chemical stability; the delivery efficiency of the salbutamol is high, the residual amount of the 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 a diagram of APSD of budesonide single (BD) and compound (BD + AS);

FIG. 2 shows APSD of salbutamol sulfate single component (AS) and compound (BD + AS);

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

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as the scope of the present invention. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

Example 1

1. The prescription composition is as follows:

step A: dissolving sodium chloride, disodium edetate and polysorbate 80 in water to form a solution a, adding salbutamol sulfate into the solution a for complete dissolution, and filtering by adopting a 0.22 mu m PES needle sterilization filter to form a solution b;

and B: dissolving polysorbate 80 in water to form a solution c 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 pressure circulation of 1000bar after sterilization to obtain a suspension e;

and C: and uniformly mixing the solution b and 5.0ml of the suspension e under the aseptic condition, adding water for injection to 500ml, respectively adjusting the pH to about 3.0, 4.0 and 5.0 by using 20mg/ml citric acid or sodium citrate solution, and respectively filling the mixture into low-density polyethylene plastic ampoules according to the filling amount of 2.1 ml/ampoule.

2. Stability test

The test of example 1 was conducted at 60 ℃ for 31 days, and compared with AS (salbutamol sulfate) in the single component, the results are AS follows:

table 1 example 1 stability test for compound (BD + AS) and Single (AS)

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

From data, when the pH is 3.0-4.0, the impurity D and the maximum unknown single impurity of the compound (BD + AS) are superior to salbutamol sulfate (AS), which can show that the stability of salbutamol is improved after combination.

3. Single and compound Aerodynamic Particle Size Distribution (APSD)

The APSD of budesonide and salbutamol sulfate of example 1 were tested, as well as the APSD of budesonide monol and salbutamol sulfate monol. Referring to the four parts of the 2020 edition of Chinese pharmacopoeia, the measurement is carried out according to the method of the aerodynamic characteristic measurement method (general rule 0951) of fine particles of inhalation preparations and the method of the device 3 (NGI) and matched with a PARI Turbo BOY compressor and a Pari-LC Plus atomizer. The results of examining the total content of the drug particles mainly aiming at the NGI from the 4 th grade to the MOC grade (the powder particles in the interval are inhalable effective particles) are shown in tables 2 and 3.

1. Budesonide single and compound recipe (BD + AS)

TABLE 2 delivery rates and APSD of budesonide single and compound (BD + AS)

Budesonide single formula: BD. Sodium chloride, disodium edetate, citric acid/sodium citrate, polysorbate 80, and water for injection; the pH value is 4-5.

From the experimental results of fig. 1 and table 2, it can be seen that the compound formula (BD + AS) is consistent with the simple formula (BD) regardless of the P4-MOC (%) or the percentage of the total amount delivered, indicating that the particle size distribution of budesonide and the delivery efficiency thereof are not affected by the addition of albuterol sulfate to budesonide.

2. Salbutamol sulfate single and compound

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

TABLE 3 delivery rates and APSD of salbutamol sulfate mono and co-formulated (BD + AS)

AS shown in fig. 2 and table 3, when the dose of salbutamol sulfate used in the combination (BD + AS) is lower than that of the single formulation (AS) (4 mg for the combination, 5mg for the single formulation, and 20% lower dose), the amount of residue in the compound atomizing cup is lower than that of the single formulation, so the delivery amount of the combination is high. Meanwhile, P4-MOC (%) is the percentage of fine particle dose, which represents the percentage of effective dose delivered to the lung, and table 1 shows that the P4-MOC (%) of the combination (BD + AS) is 26.04%, the P4-MOC (%) of the single formula (AS) is 19.07%, and the percentage of fine particle dose of the combination is higher than that of the single formula, which increases the effective delivered amount of the combination, reduces drug waste, and improves the delivery efficiency.

Example 2

A prescription composition

TABLE 4 prescription composition

The preparation method is the same as that of example 1.

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

The delivery rate and APSD of levosalbutamol hydrochloride single and compound (BD + LH) in table 4 were tested in the same manner as in example 1.

TABLE 5 delivery rates and APSD of levosalbutamol hydrochloride mono and co-formulated (BD + LH)

The results, combined with table 5 and figure 3, show that: the residual amount of the atomizing cup of the compound (BD + LH) is less than that of the single formula (LH), which indicates that the compound can atomize more medicines under the same condition and the medicine waste is less; the P4-MOC (%) value of the compound (BD + HL) is higher than that of the single prescription (LH), which indicates that the content of the medicine effectively delivered to the lung of 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 may 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 by 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 the mixture of the budesonide and the salbutamol comprises the following raw and auxiliary materials in concentration:

0.1-0.6 mg/ml of budesonide, 0.08-3.0 mg/ml of salbutamol, 0.01-0.2 mg/ml of metal ion complexing agent and 0.01-0.3 mg/ml of wetting agent; regulating the osmotic pressure range to 250-330 mOsmol/kg by using an osmotic pressure regulator, and regulating the pH of the system to 3.0-5.0 by using a pH buffering agent and/or a pH regulator; the balance of water;

the salbutamol comprises salbutamol and pharmaceutically acceptable salts or isomers of the salbutamol.

2. The aerosolized inhalation suspension of claim 1, wherein said pharmaceutically acceptable salt of salbutamol is selected from the group consisting of salbutamol sulfate, levosalbutamol hydrochloride, salbutamol fumarate, salbutamol tartrate;

the pharmaceutically acceptable isomer of salbutamol is selected from levosalbutamol;

the wetting agent is fatty acid sorbitan and/or polysorbate;

the pH buffering agent is a citric acid and sodium citrate system, an acetic acid-sodium acetate system or a sodium dihydrogen phosphate-disodium hydrogen phosphate system;

3. The aerosolized inhalation suspension of claim 2, wherein said 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 aerosolized inhalation suspension of claim 1, wherein said pH adjusting agent is one or more of an inorganic acid, an organic acid, an inorganic base; further, the pH regulator is one or more of sodium hydroxide, hydrochloric acid, acetic acid and sulfuric acid.

5. The aerosolized inhalation suspension of claims 1-4, comprising the following concentrations of the raw excipients: 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 range was adjusted with sodium chloride: 250-330 mOsmol/kg, and adjusting the pH of the system to 3.0-5.0 by using a pH regulator; the balance of water;

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

6. The aerosolized inhalation suspension of claim 5, comprising the following concentrations of the raw excipients: budesonide: 0.5mg/ml, levosalbutamol hydrochloride: 0.42mg/ml, edetate disodium: 0.1mg/ml, sodium chloride: 8.5g/ml, polysorbate 80:0.1mg/ml; regulating the pH value of the system to 3.0-5.0 by using sulfuric acid or hydrochloric acid; the balance of water.

7. Aerosol inhalation suspension according to any of claims 1 to 4, comprising the following concentrations of the raw 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 range was adjusted with sodium chloride: 250-330 mOsmol/kg, and adjusting the pH value to 3.0-4.0 by using citric acid and sodium citrate or a pH regulator; the balance of water;

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

8. The aerosolized inhalation suspension of claim 7, comprising the following concentrations of the raw excipients: budesonide: 0.5mg/ml, salbutamol sulfate: 2.4mg/ml, edetate disodium: 0.1mg/ml, polysorbate 80:0.1mg/ml, sodium chloride: 8.5mg/ml, and adjusting the pH value to 3.0-4.0 by using citric acid and sodium citrate; the balance of water.

9. A process for the preparation of an aerosolized inhalation suspension according to any of claims 1 to 8, 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;

and B, step B: dissolving part of wetting agent in water to form a solution c, adding micro-powdered 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 the sterilization is finished to obtain a suspension e;

step C: uniformly mixing the solution b and the suspension e under the aseptic condition, adding water, and adjusting the pH to a specified range by using a pH buffering agent and/or a pH adjusting agent;

further, in the step A, the osmotic pressure regulator, the metal ion complexing agent and part of the wetting agent are dissolved in water to form a solution a, and then the salbutamol is added.

10. The method according to claim 9, wherein the sterile filtration is carried out using a filter size of 0.22 μm; sterilizing for 12-30 min at 115 ℃ or 121 ℃ by adopting high-pressure steam; the high-pressure homogenizing pressure is 300-1500 bar, and the circulation is carried out for 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.