CN111297837B

CN111297837B - Preparation method of dry powder inhalant

Info

Publication number: CN111297837B
Application number: CN202010222607.XA
Authority: CN
Inventors: 金方; 薄浩洋; 闻聪
Original assignee: Shenzhen Haibin Pharmaceutical Co ltd; Shanghai Front Health Pharmaceutical Technology Co ltd
Current assignee: Shenzhen Haibin Pharmaceutical Co ltd; Shanghai Front Health Pharmaceutical Technology Co ltd
Priority date: 2020-03-26
Filing date: 2020-03-26
Publication date: 2022-02-22
Anticipated expiration: 2040-03-26
Also published as: CN111297837A

Abstract

The invention provides a preparation method of a dry powder inhalant, which comprises the step of dispersing an effective component in a carrier by a specific mixing mode, wherein the specific mixing mode is extrusion type shear mixing. The dry powder inhalant prepared by the method provided by the invention has the advantages that the particles of the effective components are not easy to be excessively crushed in the mixing process, and the prepared dry powder inhalant has the characteristics of proper aerodynamic Fine Particle Fraction (FPF), good content uniformity, excellent inhalation property and the like when the prepared dry powder inhalant is administrated to the lung through a dry powder inhalation device.

Description

Preparation method of dry powder inhalant

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of a dry powder inhalant.

Background

The dry powder inhalant is a new drug formulation, the drug of the formulation can be atomized by a drug delivery device and deposited in the lung for absorption, the drug targeting is further enhanced, the toxic and side effects are obviously reduced, the onset speed is also obviously increased, and the clinical test verifies that the dry powder inhalant has good safety and tolerance.

The preparation of dry powder inhalation products often has higher technical difficulty, because the aerodynamic diameter of the active ingredients is usually required to be between 1 and 5 μm in order to deposit and exert local action of the active ingredients in the lung, however, the binding force among particles, such as electrostatic force, van der waals force, capillary force and the like, has complex action, and the influence on the performance of the final preparation is difficult to estimate.

Generally, in the preparation of dry powder inhalation preparations, the active ingredients in the dry powder inhalation preparations need to be subjected to a certain micronization treatment, and then the active ingredients are uniformly dispersed by mixing with a carrier. However, because the cohesion of the micronized active ingredients is strong, agglomerates are easy to form, and the proportion of the micronized active ingredients in the composition is very low, the active ingredient particles after micronization are formed into loose agglomerates by adopting a common mixing mode such as three-dimensional mixing, and the introduced mechanical energy is low and can not break the cohesion among the active ingredient particles, so that the difficulty of mixing is increased, and the prepared dry powder inhalant can not be effectively dispersed and atomized when the inspiratory airflow of a patient is weak, so that the active ingredient has a large aerodynamic particle size and can not be easily intercepted in the oropharynx, and can not enter the lung to play a role. In order to solve the problem, the prior art adopts impact high-shear mixing, and utilizes a stirring paddle or a cutter to impact active ingredient particles or agglomerates, introduce higher mechanical energy to break the cohesive force among the active ingredient particles, and force the active ingredient particles to disperse so as to realize better dispersion, thereby obtaining a dry powder inhalation preparation with good uniformity and inhalation performance. However, the impact type high shear mixing as described above easily causes the effective components to be crushed again during the preparation process, so that the actual particle size of the effective components in the finished preparation is too fine and difficult to control, and the too fine effective components are exhaled with the airflow and cannot stay in the lung, which greatly reduces the actual efficacy of the drug.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a preparation method of a dry powder inhalant, and the active ingredients in the dry powder inhalant prepared by the method have the characteristics of good dispersibility, proper aerodynamic Fine Particle Fraction (FPF), excellent inhalation property and the like.

The invention is realized by adopting the following technical scheme.

In one aspect, the present invention provides a method of preparing a dry powder inhaler, the method comprising dispersing an active ingredient in a carrier by specific mixing means, wherein the specific mixing means is extrusion shear mixing;

preferably, the extrusion shear mixing is achieved by an apparatus selected from the group consisting of: high speed mixers and high speed mixers, more preferably high speed mixers;

preferably, the linear speed of a cutting knife or a stirring paddle of the equipment is 1-20m/s, more preferably 5-8m/s, and most preferably 5 m/s;

preferably, the clearance between the blade of the stirring paddle and the wall of the equipment container is 0.1-3.0 mm, more preferably 0.5-1.0 mm, and most preferably 0.5 mm;

preferably, the method of the present invention may further comprise the step of premixing the effective ingredient and the carrier by a mixing device such as a V-type mixer, a three-dimensional mixer, a wet mixing granulator, and a universal mixer, before dispersing the effective ingredient in the carrier by a specific mixing means.

Preferably, the particle size D50 of the effective component is 1-5 μm, most preferably 2-3 μm;

preferably, the active ingredient is any active pharmaceutical ingredient that can be prepared into a dry powder inhaler; further preferably, the active ingredient is selected from tiotropium, glycopyrronium, aclidinium, umeclidinium and pharmaceutically acceptable salts thereof, indacaterol, formoterol, vilanterol, salmeterol, olopaterol and pharmaceutically acceptable salts thereof, and mometasone, budesonide, beclomethasone, fluticasone and pharmaceutically acceptable salts thereof, more preferably, the active ingredient is aclidinium and pharmaceutically acceptable salts thereof.

Preferably, the carrier is any pharmaceutically acceptable carrier that does not react with the active ingredient, further preferably, the carrier is selected from one or more of sugars and sugar alcohols, more preferably lactose monohydrate and/or lactose anhydrous.

Further preferably, the carrier can also be added with a proper amount of lubricant or force control agent;

preferably, the lubricant or force control agent is selected from one or more of stearate, amino acid and its derivatives and polyethylene glycol;

in the dry powder inhalant, the weight ratio of the effective component to the carrier is 1: 20-1: 2500.

In some preferred embodiments of the present invention, there is provided a method of preparing a dry powder inhaler, the method comprising the steps of:

1) micronizing the effective components by jet mill to obtain micronized effective components with D50 of 2.8 μm;

2) mixing the micronized active ingredients obtained in the step 1) with lactose monohydrate in a three-dimensional mixer for 10min to obtain a premix;

3) transferring the premix obtained in the step 2) into a high-speed mixer, and fully dispersing the micronized active ingredients in the premix into lactose monohydrate in an extrusion type shear mixing mode.

Wherein, in the step 1), the effective component is aclidinium bromide;

in the step 2), the weight ratio of the effective components to the lactose monohydrate is 1:99

In the step 3), the linear speed of a stirring paddle in the high-speed mixer is 5m/s, and the clearance between a blade of the stirring paddle and the wall of the equipment container is 0.5 mm.

In another aspect, the present invention also provides a dry powder inhaler prepared by the method of the present invention, preferably, the prepared dry powder inhaler can be administered to the lung by being loaded in a single-dose or multi-dose dry powder inhaler device in a metered dose.

Detailed Description

In the preparation method of the dry powder inhalant provided by the invention, micronization is carried out to control the particle size D50 of the active ingredient to be 1-5 μm, and then extrusion type shearing mixing is carried out to disperse the active ingredient.

In the context of the present invention, the extrusion type shear mixing refers to that particles in a material group are subjected to extrusion action from the wall of the mixing container and the stirring paddle, extrusion force is provided perpendicular to the moving direction of the stirring paddle, so that a sliding action of a shear plane is formed inside an effective component mass, a small mass formed by the effective component is broken up, powder is driven to move, and local mixing is caused, and a schematic diagram of the extrusion type shear mixing is shown in fig. 1. The equipment to effect the extrusion shear mixing may be any agitation mixing equipment conventional in the art including, but not limited to, high speed mixers, and the like, preferably high speed mixers. The paddle of the stirring paddle rotating at high speed in the equipment can force the material to pass through the gap between the stirring paddle and the wall of the mixing container, so that loose active ingredient lumps are broken into basic particles under the extrusion action of the paddle of the stirring paddle and the wall of the container, and the basic particles are uniformly dispersed and combined on the carrier, but the effective ingredients cannot be crushed.

In the research process of the method, the inventor of the application discovers through a large number of experiments that too high linear velocity of the stirring paddle in the extrusion type mixing process may cause too high impact force to crush the materials, and too low linear velocity of the stirring paddle may cause low mixing efficiency and insufficient uniform mixing. In the process of the present invention, the linear velocity of the stirring blade is preferably 1 to 20m/s, more preferably 5 to 8m/s, most preferably 5 m/s. In addition, the inventor of the application also finds through experiments that the too narrow gap between the paddle and the container wall causes the larger carrier particles to be crushed due to too large stress, which reduces the flowability of the material, affects the precision of quantitative filling, and reduces the content uniformity of the product. When the gap between the blade and the wall of the container is too wide, the extrusion force applied to the material block is too weak, and the effective components cannot be fully dispersed. In the method of the invention, the clearance between the blade of the stirring paddle and the wall of the container is 0.1-3.0 mm, preferably 0.5-1.0 mm, and more preferably 0.5 mm.

In the method of the present invention, a step of premixing the active ingredient and the carrier using a mixing device such as a V-type mixer, a three-dimensional mixer, a wet mixing granulator, a universal mixer, etc. may be further included before the extrusion shear mixing.

In the method of the present invention, in order to obtain a better targeting effect, a step of micronizing the active ingredients by a jet mill may be further included before the premixing. Preferably, the particle size D50 of the micronized active ingredient is 1-5 μm, more preferably 2-3 μm.

In the context of the present invention, the active ingredient is any active pharmaceutical ingredient that can be prepared as a dry powder inhaler. For example, the active ingredient may be selected from tiotropium, glycopyrronium, aclidinium, umeclidinium and pharmaceutically acceptable salts thereof, indacaterol, formoterol, vilanterol, salmeterol, olopaterol and pharmaceutically acceptable salts thereof, and mometasone, budesonide, beclomethasone, fluticasone and pharmaceutically acceptable salts thereof.

The carrier of the invention is any pharmaceutically acceptable carrier which does not react with the effective components. For example, lactose whose safety has been sufficiently verified can be selected as the carrier. In recent years, it has been reported that mannitol and amino acid are used as carriers, and the carrier to be used finally is usually a mixture of a carrier component having a relatively large particle size and a carrier component having a relatively small particle size. In the present invention, the carrier is selected from sugars, sugar alcohols or a mixture thereof, preferably lactose monohydrate, lactose anhydrous or a mixture thereof.

In the process of the present invention, a suitable amount of a lubricant or force control agent may also be added to the carrier. The lubricant or force control agent is selected from one or more of stearate, amino acid and derivatives thereof, and polyethylene glycol.

In the invention, the weight ratio of the effective components to the medicinal carrier is 1: 20-1: 2500. The dry powder inhalants prepared by the method provided by the invention can be pre-dosed in single-dose or multi-dose containers, which can be capsules or blisters, preferably capsules, and can be administered by active or passive inhalation devices by means of appropriate packaging to provide chemical and physical protection.

The beneficial effects of the invention at least comprise the following aspects:

the invention further researches a proper mixing device mode and mixing parameters on the basis of the previous research, and provides a preparation method of the dry powder inhalant. The dry powder inhalant prepared by the method provided by the invention has the advantages that the particles of the effective components are not easy to be excessively crushed in the mixing process, and the prepared dry powder inhalant has the characteristics of proper aerodynamic Fine Particle Fraction (FPF), good content uniformity, excellent inhalation property and the like when the prepared dry powder inhalant is administrated to the lung through a dry powder inhalation device.

Drawings

Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:

FIG. 1 is a schematic view of the extruder shear mixing of the present invention.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

The experimental procedures in the following examples are conventional unless otherwise specified. The equipment, raw materials, reagents and the like used in the following examples are all commercially available products unless otherwise specified.

EXAMPLE 1 preparation of micronized active principles

Micronizing aclidinium bromide in jet mill under 0.6MPa to obtain product with particle diameter D50 of 2.8 μm and D10 > 1 μm.

Micronizing ammonium bromide in a jet mill respectively under the crushing pressure of 0.4Mpa, wherein the particle size D50 of the obtained product is 2-3 mu m, and D10 is more than 1 mu m.

The glycopyrronium bromide is respectively micronized in a jet mill under the crushing pressure of 0.4Mpa, the particle size D50 of the obtained product reaches 2-3 mu m, and D10 is more than 1 mu m.

The formoterol fumarate dihydrate and the formoterol fumarate are respectively micronized in an airflow pulverizer, the pulverizing pressure is 0.6Mpa, the particle size D50 of the obtained product reaches 2-3 mu m, and D10 is larger than 1 mu m.

The indacaterol fumarate is respectively micronized in a jet mill under the crushing pressure of 0.8MPa, and the particle size D50 of the obtained product is 2-3 mu m, and D10 is more than 1 mu m.

The salmeterol xinafoate is micronized in a jet mill respectively, the milling pressure is 1.0Mpa, the particle size D50 of the obtained product reaches 2-3 mu m, and D10 is more than 1 mu m.

Micronizing mometasone furoate in a jet mill respectively, wherein the grinding pressure is 1.0Mpa, the particle size D50 of the obtained product reaches 2-3 mu m, and D10 is more than 1 mu m.

Micronizing fluticasone propionate in an airflow pulverizer respectively, wherein the pulverizing pressure is 1.0Mpa, the particle size D50 of the obtained product reaches 2-3 mu m, and D10 is more than 1 mu m.

EXAMPLE 2 preparation of Dry Addendrium Bromide inhalant

Lactose monohydrate and micronized aclidinium bromide in example 1 are weighed according to the following table, mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, the proper paddle is selected to ensure that the gap between the paddle and the wall of the container is 0.5mm, the paddle is reversed, mixed for 10min at the linear speed of the paddle of 5m/s, and properly kept stand to prepare the dry powder inhalant of aclidinium bromide.

EXAMPLE 3 preparation of Dry Additrium Bromide inhalant

Lactose monohydrate and micronized aclidinium bromide in example 1 are weighed according to the following table and mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, the proper paddle is selected to ensure that the gap between the paddle and the wall of the container is 1.0mm, the paddle is reversed, mixed for 10min at the linear speed of the paddle of 8m/s, and properly kept stand to prepare the dry powder inhalant of aclidinium bromide.

EXAMPLE 4 preparation of Dry Additrium Bromide inhalant

Lactose monohydrate and micronized aclidinium bromide in example 1 are weighed according to the following table and mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, the proper paddle is selected to ensure that the gap between the paddle and the wall of the container is 1.0mm, the paddle is reversed, mixed for 10min at the linear speed of the paddle of 3m/s, and properly kept stand to prepare the dry powder inhalant of aclidinium bromide.

EXAMPLE 5 preparation of Dry powder Addisomium Bromide inhalants

Lactose monohydrate and micronized aclidinium bromide in example 1 are weighed according to the following table and mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, a proper paddle is selected to ensure that the gap between the paddle and the wall of the container is 0.2mm, the paddle is reversed, mixed for 10min at the linear speed of the paddle of 20m/s, and appropriately kept stand to prepare the dry powder inhalant of aclidinium bromide.

EXAMPLE 6 preparation of mometasone furoate Dry powder inhaler

Lactose monohydrate and micronized mometasone furoate from example 1 were weighed according to the following table, mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, the appropriate paddle was selected to give a gap of 0.7mm between the paddle and the container wall, the paddle was reversed, mixed at a paddle linear velocity of 7m/s for 10min, and appropriately left to stand to prepare a carrier complex.

EXAMPLE 7 preparation of indacaterol fumarate dihydrate Dry powder inhaler

Mannitol and micronized indacaterol fumarate dihydrate in example 1 are weighed according to the following table, mixed in a three-dimensional mixer for 10min, transferred to a high-speed stirrer, a proper paddle is selected to ensure that the gap between the paddle and the wall of a container is 0.7mm, the paddle is reversed, extrusion mixing is carried out at the linear speed of the paddle of 7m/s for 10min, and the indacaterol fumarate dry powder inhalant is prepared after proper standing.

EXAMPLE 8 preparation of glycopyrronium Bromide Dry powder inhalants

The lactose monohydrate was weighed according to the table below and mixed with the micronized glycopyrrolate of example 1 in a three-dimensional mixer for 10min, transferred to a high speed mixer, with appropriate blade selection to give a blade clearance of 0.7mm from the vessel wall, the paddles were reversed, mixed at 7m/s paddle line speed for 10min, and allowed to stand appropriately to prepare the glycopyrrolate dry powder inhaler.

Comparative example 1

The micronized aclidinium bromide prepared in example 1 and lactose monohydrate were weighed according to the following table, mixed in a three-dimensional mixer for 10min, then transferred to a knife mill for milling at a cutter linear velocity of 25m/s for 10min, and left to stand appropriately to prepare dry powder inhalant of aclidinium bromide.

Comparative example 2

The micronized aclidinium bromide prepared in example 1 and lactose monohydrate were weighed according to the following table, mixed in a three-dimensional mixer at a rotational speed of 49rpm for 20min, and left to stand appropriately to prepare dry powder inhalants of aclidinium bromide.

Comparative example 3

Lactose monohydrate and micronized aclidinium bromide in example 1 are weighed according to the following table, mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, the proper paddle is selected to ensure that the gap between the paddle and the wall of the container is 0.05mm, the paddle is reversed, mixed for 20min at the linear speed of the paddle of 8m/s, and properly kept stand to prepare the dry powder inhalant of aclidinium bromide.

Comparative example 4

Lactose monohydrate and micronized aclidinium bromide in example 1 are weighed according to the following table and mixed in a three-dimensional mixer for 10min, transferred to a high-speed mixer, the proper paddle is selected to ensure that the gap between the paddle and the wall of the container is 5mm, the paddle is reversed, mixed for 10min at the linear speed of the paddle of 8m/s, and properly kept stand to prepare the dry powder inhalant of aclidinium bromide.

Example 9 particle size study of active ingredients in Addisium Bromide Dry powder inhalants

The purpose of this study was to test the particle size change of the active ingredient before and after mixing.

Taking a proper amount of the micronized aclidinium bromide in example 1, establishing a Raman spectrum database and setting proper morphological filter parameters in a Raman spectrum of a Morphogi G3SE-ID particle size shape analyzer in combination, taking a proper amount of samples of examples 2-5 and comparative examples 1-4, measuring the particle size of each particle in each sample, removing auxiliary material particles, screening the aclidinium bromide particles in the powder for statistics according to the Raman spectrum database and the morphological filter,

dispersing conditions are as follows: sample amount: 11mm³And dispersing by the SUD method, setting the pressure to be 4bar, setting the pressure to be 20ms, and standing for 60 s.

The scanning range is 10mm x 10mm,

the results are as follows:

EXAMPLE 10 content uniformity of active ingredients in Addisium Bromide Dry powder inhalant

The purpose of this study was to compare the effect of mixing and filling in different mixing regimes.

The dry powder inhalants prepared in examples 2 to 5 and comparative examples 1 to 4 were filled at a dose of 25 mg/capsule using a capsule filling machine. Sample preparation: 10 capsules were taken for each example, and the content of aclidinium bromide in each sample was checked by high performance liquid chromatography per capsule, and the RSD of the aclidinium bromide content in the samples of the different examples was calculated as follows:

it can be seen from examples 9 and 10 that the extrusion shear mixing and impact high shear mixing used in example 2 and comparative example 1 respectively are both effective in improving the mixing effect of dry powder inhalers, rather than three-dimensional mixing alone, but the particle size of the active ingredient in the formulation is significantly reduced when impact high shear mixing is used, due to the pulverization effect of the mixing on the active ingredient. The dry powder inhalant prepared by the extrusion type shearing mixing process and the dry powder inhalant prepared by the three-dimensional mixing mode have no obvious change on the particle size of the active ingredients, namely the two mixing modes have weak crushing effect on the active ingredients. However, when the gap between the blade and the container wall used in the extrusion type shear mixing process is too narrow, the carrier particles are crushed by the blade, which greatly reduces the fluidity of the mixture and slightly increases the friction crushing effect on the effective components, increases the mixing difficulty of the low-content components including the effective components and greatly reduces the precision of micro quantitative filling.

EXAMPLE 11 Studies of Properties of Dry powder inhalers

The purpose of this study was to mimic the behavior of the dry powder inhaler prepared during administration.

Generally, the deposition process of the inhaled aerosol powder in the respiratory tract can be simulated by using a multi-stage impactor (CI), the measured deposition conditions of different aerodynamic fine particles are simulation results of the drug deposited in bronchioles and alveoli, and it is considered that the drug particles with the aerodynamic particle size of more than 5 μm are not easy to enter the lung, the drug particles with the aerodynamic particle size of less than 1 μm are easy to exhale after entering the lung so as not to be easily deposited in the lung, and the drug particles with the aerodynamic particle size of 1-5 μm are easy to deposit in the lung so as to exert the treatment effect.

The powders of examples 2 to 8 and comparative examples 1 to 4 were filled into capsules at a dose of 25 mg/capsule to prepare dry powder inhalation preparations which can be administered to the lung by a dry powder inhalation device, the aerodynamic deposition of fine particles of the dry powder in each capsule was measured at a flow rate of 30L/min by a next generation cascade impactor (NGI), and the ratio of the deposition amount of fine particles having an aerodynamic particle diameter range of 5 μm or more, 1 to 5 μm and 1 μm or less to the total dose collected by each impact plate was calculated and recorded as the effective component deposition factor of each stage.

The results are as follows:

these data show that at lower inspiratory flow rates, the use of an impact high shear device tends to have a crushing effect on the active ingredient, resulting in an increased proportion of particles having an aerodynamic particle size below 1 μm after being formulated into an inhalable dry powder inhaler product; the multidirectional motion mixing equipment is independently adopted or loose lumps formed by cohesion of the active ingredients cannot be effectively destroyed when the gap between the blades and the container wall is wide, so that more particles with the aerodynamic particle size of more than 5 mu m are generated, the proportion of particles with the aerodynamic particle size of 1-5 mu m, which are easy to deposit in the lung to exert the drug effect, is low, the deposition proportion of the active ingredients with the aerodynamic particle size of 1-5 mu m is high after the dry powder inhalant for inhalation prepared by the method is adopted, and the drug is easy to stay in the lung to exert the drug effect.

Summarizing examples 2-5 and comparative examples 1-4, it can be found that the dry powder inhalant prepared by the present invention has both good content uniformity (RSD below 5%) and excellent deposition distribution of active ingredients (deposition factor with aerodynamic particle size of 1-5 μm is higher than 70%), and has the advantages of uniform content and high delivery efficiency after being made into a dry powder inhalant product for inhalation.

Claims

1. A method for preparing a dry powder inhaler, the method comprising dispersing an active ingredient in a carrier by a specific mixing means, wherein the specific mixing means is extrusion shear mixing;

the extrusion shear mixing is achieved by a device selected from the group consisting of a high speed mixer and a high speed mixer;

the linear speed of a cutter or a stirring paddle of the equipment is 5-8 m/s;

the clearance between the paddle of the stirring paddle and the wall of the equipment container is 0.5-1.0 mm.

2. The method of manufacturing of claim 1, wherein the extrusion shear mixing is achieved by a high speed mixer.

3. The production method according to claim 1, wherein a linear velocity of a cutter or a stirring paddle of the apparatus is 5 m/s.

4. The production method according to claim 1, wherein a clearance between a blade of the stirring paddle and a wall of the apparatus container is 0.5 mm.

5. The preparation method according to claim 1, wherein the method further comprises a step of premixing the effective ingredient and the carrier by a mixing device such as a V-type mixer, a three-dimensional mixer, a wet mixing granulator, a universal mixer, before dispersing the effective ingredient in the carrier by a specific mixing manner.

6. The method according to claim 1, wherein the particle diameter D50 of the active ingredient is 1 to 5 μm.

7. The method according to claim 6, wherein the particle diameter D50 of the active ingredient is 2 to 3 μm.

8. The method of claim 1, wherein the active ingredient is any active pharmaceutical ingredient that can be prepared as a dry powder inhaler.

9. The preparation method according to claim 8, wherein the active ingredient is selected from tiotropium, glycopyrronium, aclidinium, umeclidinium and pharmaceutically acceptable salts thereof, indacaterol, formoterol, vilanterol, salmeterol, odaterol and pharmaceutically acceptable salts thereof, and mometasone, budesonide, beclomethasone, fluticasone and pharmaceutically acceptable salts thereof.

10. The preparation method according to claim 9, wherein the active ingredient is aclidinium and pharmaceutically acceptable salts thereof.

11. The preparation method according to claim 1, wherein the carrier is any pharmaceutically acceptable carrier that does not react with the active ingredient.

12. The method according to claim 11, wherein the carrier is selected from one or more of saccharides and sugar alcohols.

13. The method of claim 12, wherein the carrier is lactose monohydrate and/or lactose anhydrous.

14. The method according to claim 1, wherein a lubricant or force control agent is further added to the carrier in an appropriate amount.

15. The method of claim 14 wherein the lubricant or force control agent is selected from one or more of stearates, amino acids and their derivatives, and polyethylene glycols.

16. The preparation method according to claim 1, wherein the weight ratio of the effective component to the carrier is 1:20 to 1: 2500.

17. The dry powder inhaler prepared according to the method of any one of claims 1-16, wherein the prepared dry powder inhaler can be administered to the lung by metered dose loading in a single-dose or multi-dose dry powder inhaler device; wherein in the prepared dry powder inhalant, the deposition factor with aerodynamic particle size of 1-5 μm is higher than 70%.