阅读说明：本技术 一种筛选适用于β2受体激动剂的雾化装置的方法 (Method for screening atomization device suitable for beta 2 receptor agonist ) 是由 金方 徐博淳 闻聪 于 2020-05-11 设计创作，主要内容包括：本发明涉及一种筛选适用于β2受体激动剂药物的雾化装置的方法,该方法包括：(1)检测待筛选的雾化装置中1～5μm的雾化颗粒的粒径的比例、体积平均粒径和表面积平均粒径；(2)检测电解质溶液的浓度；(3)选取同时满足以下a)和b)条件的雾化装置：a)所述1～5μm的雾化颗粒的粒径的比例为50％～70％,所述体积平均粒径和所述表面积平均粒径的比值小于和/或等于3；b)所述电解质溶液的浓度为0.2～1％w/v。(The invention relates to a method for screening an atomization device suitable for beta 2 receptor agonist drugs, which comprises the following steps: (1) detecting the proportion of the particle size, the volume average particle size and the surface area average particle size of 1-5 mu m atomized particles in an atomization device to be screened; (2) detecting the concentration of the electrolyte solution; (3) selecting an atomization device which simultaneously meets the following conditions a) and b): a) the proportion of the particle size of the atomized particles with the particle size of 1-5 mu m is 50% -70%, and the ratio of the volume average particle size to the surface area average particle size is less than and/or equal to 3; b) the concentration of the electrolyte solution is 0.2-1% w/v.)

1. A method of screening a nebulizing device for a β 2 receptor agonist comprising:

(1) detecting the following parameters of the atomization device to be screened: i) the proportion of the particle size of atomized particles of 1-5 μm; ii) the volume average particle size of the atomized particles; iii) the surface area average particle size of the atomized particles; and iv) concentration of the electrolyte solution;

(2) screening an atomization device satisfying the following conditions a), b) and c) at the same time: a) the proportion of the particle size of the atomized particles of 1-5 mu m is 50-70%; b) the ratio of the volume average particle diameter of the atomized particles to the surface area average particle diameter of the atomized particles is less than and/or equal to 3; c) the concentration of the electrolyte solution is 0.2-1% w/v.

2. The method according to claim 1, wherein the condition a) is that the proportion of the particle diameter of the atomized particles of 1 to 5 μm is 60 to 70%.

3. The method according to claim 1 or 2, wherein the condition c) is that the concentration of the electrolyte solution is 0.5-1% w/v.

4. The method according to any one of claims 1 to 3, wherein the particle size of the atomized particles of 1 to 5 μm, the volume average particle size of the atomized particles, and the surface area average particle size of the atomized particles are measured by a light scattering method.

5. The method according to any one of claims 1 to 4, wherein when the ratio of the particle diameters of the atomized particles of 1 to 5 μm detected does not satisfy the condition a), no other parameters are detected.

6. The method according to any one of claims 1 to 5, characterized in that when the volume average particle diameter of the resulting atomized particles and the surface area average particle diameter of the atomized particles are detected not to satisfy condition b), no further parameters are detected.

7. The method according to any one of claims 1 to 6, characterized in that when the concentration of the detected electrolyte solution does not satisfy condition c), no further parameters are detected.

8. The method according to any one of claims 1 to 7, wherein the atomizing device comprises: the atomizing cup, the atomizing driving device and the driving energy source are preferably a compressed air atomizing device or a vibrating screen atomizing device.

9. The method according to any one of claims 1 to 8, wherein the β 2 receptor agonist drug is formoterol, salmeterol, indacaterol, abediterol, or a pharmaceutically acceptable salt thereof, preferably formoterol.

Technical Field

The invention relates to the technical field of medicines, in particular to a method for screening an atomization device suitable for a beta 2 receptor agonist.

Background

According to the latest epidemiological survey of chronic obstructive pulmonary disease, the prevalence rate of chronic obstructive pulmonary disease of 20-39 years old people in China is 2.1%, the prevalence rate of people over 40 years old is 13.7%, and the prevalence rate of people over 70 years old is as high as 35.5%. According to the calculation of the prevalence rate, the chronic obstructive pulmonary disease in China exceeds 1 hundred million patients.

The existing treatment modes of chronic obstructive pulmonary disease mainly comprise oral administration, injection, inhalation and the like, but the oral administration and the injection firstly send the medicine to blood and then to the lung, so that the medicine treatment efficiency is lower. With the development of medicine and formulation science, and the deep understanding of lung function and pulmonary diseases such as asthma and chronic obstructive pulmonary disease, it has been recognized that pulmonary administration is the best mode of administration for pulmonary diseases. The inhalation therapy can directly act on the lung, has high local drug concentration, quicker response and better curative effect, and can avoid or reduce the side effect possibly generated by systemic medication.

Beta 2 receptor agonist drugs are the first choice drugs for treating airway spasm as bronchodilators, and atomization devices sold on the market are various in shape, but the atomization devices are not really suitable for the drugs and are not known, the delivery dosage of different drugs by the same atomization device is different, and the therapeutic effect on patients cannot be effectively maintained if the required delivery dosage of the drugs with short-acting or long-acting functions cannot be achieved. Although the effective inhalation amount of the atomization device is detected directly, the device is high in cost because the effective inhalation amount needs to be detected by using a breathing simulation device, and after the device is adopted for collection, the high performance liquid chromatography is still needed for detection, so that the operation is complex, and mistakes are easy to make.

Therefore, there is a need for a simple and effective method for screening a suitable aerosolization device for β 2 receptor agonists.

Disclosure of Invention

In order to make up for the defects of the prior art, the invention aims to provide a method for screening an atomization device suitable for a beta 2 receptor agonist, which can quickly and accurately select the atomization device matched with a specific drug of the beta 2 receptor agonist, so that the atomization effect of the drug is optimal, and the curative effect of the drug is exerted to the maximum extent.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a method for screening an atomization device suitable for a beta 2 receptor agonist, which comprises the following steps:

(1) detecting the following parameters of the atomization device to be screened: i) the proportion of the particle size of atomized particles of 1-5 μm; ii) the volume average particle size of the atomized particles; iii) the surface area average particle size of the atomized particles; and iv) concentration of the electrolyte solution;

(2) screening an atomization device satisfying the following conditions a), b) and c) at the same time: a) the proportion of the particle size of the atomized particles of 1-5 mu m is 50-70%; b) the ratio of the volume average particle diameter of the atomized particles to the surface area average particle diameter of the atomized particles is less than and/or equal to 3; c) the concentration of the electrolyte solution is 0.2-1% w/v.

Preferably, the condition a) is that the proportion of the particle diameter of the atomized particles of 1 to 5 μm is 60 to 70%.

Preferably, the condition c) is that the concentration of the electrolyte solution is 0.5-1% w/v.

Preferably, the particle size of the atomized particles of 1 to 5 μm, the volume average particle size of the atomized particles, and the surface area average particle size of the atomized particles are measured by a light scattering method.

Preferably, when the detected proportion of the particle diameters of the atomized particles with the particle diameters of 1-5 μm does not meet the condition a), other parameters are not detected.

Preferably, when the volume average particle diameter of the resulting atomized particles and the surface area average particle diameter of the atomized particles are detected not to satisfy the condition b), no other parameters are detected.

Preferably, when the detected concentration of the electrolyte solution does not satisfy the condition c), no other parameter is detected.

Preferably, the atomizing device comprises: the atomizing cup, the atomizing driving device and the driving energy source are preferably a compressed air atomizing device or a vibrating screen atomizing device.

Preferably, the beta 2 receptor agonist drug is formoterol, salmeterol, indacaterol, abediterol, or a pharmaceutically acceptable salt thereof, preferably formoterol.

The invention aims to use different atomization devices to carry out in-vitro determination on the beta 2 receptor agonist, and the obtained result provides a basis for judging whether the atomization devices are suitable for the medicines or not and has high accuracy.

Compared with the prior art, the invention selects the atomization device most suitable for the beta 2 receptor stimulant medicine by controlling key parameters in the screening process of the atomization device, thereby achieving the purpose of optimal administration treatment.

Drawings

FIG. 1 is an electron micrograph of an atomized particle;

FIG. 2 is a graph showing atomization curves of different atomization devices of the same brand;

FIG. 3 is a graph of atomization curves for different brands of atomization devices;

FIG. 4 is a graph showing atomization curves of atomization devices of the same brand and different models;

FIG. 5 is a graph of atomization curves for different brands of vibrating screen atomizing devices;

fig. 6 shows atomization curves of different types of atomization devices.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, belong to the protection scope of the present invention.

In the following examples, unless otherwise specified, the electrolyte solution used was a sodium chloride solution; the beta 2 receptor agonist was formulated using an electrolyte solution at the time of detection such that the concentration of electrolyte material in the drug solution was 0.7% w/v.

In the following examples, the compressed air nebulizer assay was as follows:

and (3) selecting a compressed air atomization device to measure the atomization effect of the beta 2 receptor agonist.

And testing the proportion of the particle size, the volume average particle size and the surface area average particle size of 1-5 mu m atomized particles of the compressed air atomization device, and inspecting the drug atomization effect.

By volume average particle diameter is meant the volume of 1 particle having this diameter, which is exactly equal to the volume average of all particles.

Surface area average particle diameter the specific surface area (surface area per unit volume of particle) of 1 particle having this diameter is exactly equal to the average of the specific surfaces of all particles.

The data were measured using a laser particle sizer (Sympatec GmbH) whose principle is light scattering.

The particles of drug droplets nebulized by the compressed air nebulizing device were collected by a breathing simulator (respiratory Scientific Limited) and the total amount of drug delivered by the nebulizing device was determined by high performance liquid chromatography (Agilent Technologies, Inc.).

The atomizing device is connected on the breathing analogue device, sets the tidal volume of the breathing analogue device to be 500ml, 15cyc/min, collects the fogdrop particles of the medicine ejected by the atomizing device, the atomizing time is 9min, and 10 groups of parallel tests are carried out.

The effective inhalation amount of the drug was collected by a cascade impactor having 7 stages and 1 micropore collector, and the effective inhalation amount of the collected drug was measured by high performance liquid chromatography.

The cascade impactor is connected with the L-shaped throat pipe and placed in an environment at 5 ℃ for 90 minutes, the effective inhalation amount of the medicine is tested within 5 minutes after the medicine is taken out, atomized particles with the cut-off particle size of less than 5 mu m are collected and then are measured by high performance liquid chromatography.

Drawing an atomization curve of the atomization device, collecting the drug delivery amount at different time points by using a breathing simulation device, and then measuring by using high performance liquid chromatography.

The atomization device is connected to the respiration simulation device, the tidal volume of the respiration simulation device is set to be 500ml and 15cyc/min, the jig collects the fogdrop particles of the medicine sprayed by the atomization device, the atomization time is selected from 1min, 2min, 3min, 4min, 5min, 7min and 9min, and a change relation graph of the atomization time and the delivery amount is drawn according to the measured result, namely an atomization curve.

In the following examples, the vibrating screen atomizer assay method was as follows:

and (3) selecting a vibrating screen atomization device to measure the atomization effect of the beta 2 receptor agonist drug.

And testing the proportion of the particle size of atomized particles of 1-5 mu m of the atomized particles of the vibrating screen atomization device, the volume average particle size and the surface area average particle size to investigate the drug atomization effect.

By volume average particle diameter is meant the volume of 1 particle having this diameter, which is exactly equal to the volume average of all particles.

Surface area average particle diameter the specific surface area (surface area per unit volume of particle) of 1 particle having this diameter is exactly equal to the average of the specific surfaces of all particles.

The data were measured using a laser particle sizer (Sympatec GmbH) whose principle is light scattering.

Particles of drug droplets nebulized by a vibrating screen nebulizing device were collected by a breath simulator (respiratory Scientific Limited) and the total amount of drug delivered by the nebulizing device was determined by high performance liquid chromatography (Agilent Technologies, Inc.).

The aerosolization device was connected to a breath simulator, the tidal volume of the breath simulator (Copley scientific Limited) was set to 500ml, 15cyc/min, the droplet particles of the drug emitted by the aerosolization device were collected for 9min, and 10 groups were tested in parallel.

The effective inhalation amount of the drug was collected by a cascade impactor having 7 stages and 1 micropore collector, and the effective inhalation amount of the collected drug was measured by high performance liquid chromatography.

The cascade impactor is connected with the L-shaped throat pipe and placed in an environment at 5 ℃ for 90 minutes, the effective inhalation amount of the medicine is tested within 5 minutes after the medicine is taken out, atomized particles with the cut-off particle size of less than 5 mu m are collected and then are measured by high performance liquid chromatography.

Drawing an atomization curve of the atomization device, collecting the drug delivery amount at different time points by using a breathing simulation device, and then measuring by using high performance liquid chromatography.

The atomization device is connected to the respiration simulation device, the tidal volume of the respiration simulation device is set to be 500ml and 15cyc/min, the atomization device is used for collecting the fogdrop particles of the medicine sprayed by the atomization device, the atomization time is selected from 1min, 2min, 3min, 4min, 5min, 7min and 9min, and a change relation graph of the atomization time and the delivery amount is drawn according to a measured result, namely an atomization curve.