Inhalable pharmaceutical powder formulation and preparation method therefor

Abstract

Provided in the present invention is an inhalable dry powder formulation using enoximone as an active ingredient. The formulation features small particle size, high lung delivery efficiency, and low dosage in use, and can significantly improve patient compliance in drug administration. The inhalable dry powder formulation can significantly reduce the leukocyte level in the alveolar lavage fluid of the bronchial asthma rat model and improve the lung function and ameliorate the disease state of the trachea, bronchus, and lung, demonstrating significant therapeutic effect on bronchial asthma.

Description

Inhalable drug powder preparation and preparation method thereof

[0001] This application requires the following:

[0002] Priority to the prior application, patent application number 202410322547.7, filed with the State Intellectual Property Office of China on March 20, 2024, entitled “An inhalable pharmaceutical powder preparation and its preparation method”;

[0003] The entire content of this prior application is incorporated into this application by reference. Technical Field

[0004] The present disclosure relates to the field of pharmaceutical preparations, and in particular to an inhalable pharmaceutical powder preparation and a preparation method thereof. Background Art

[0005] Dry powder inhalers (also known as inhalation powder aerosols) are a new type of formulation that consists of a powder mixture of one or more micronized drugs and a carrier, which is filled and stored in capsules or blisters. After being processed by a special drug delivery device, the aerosol generated during inhalation achieves drug deposition in the lungs, thereby exerting its therapeutic effect. Initially designed, dry powder inhalers were mainly used for the targeted treatment of lung diseases such as asthma, chronic obstructive pulmonary disease, and lung infections. With the continuous confirmation of its clinical value, this technology has developed into a drug delivery system that uses the lungs as a drug delivery environment to achieve systemic therapeutic effects. Powder aerosols for inhalation refer to preparations that use micronized drugs or carriers in the form of capsules, blisters, or multiple doses. They are stored using a special dry powder inhalation device and the patient actively inhales the aerosolized drug into the lungs. They are also called dry powder inhalations.

[0006] Enoximone, a novel phosphodiesterase III inhibitor, has both positive inotropic and vasodilatory effects and is used in the study of congestive heart failure. It also has bronchodilatory, anti-asthmatic, and anti-inflammatory effects, with few adverse reactions and good tolerability. Due to its relatively short plasma half-life of approximately 60 minutes, the drug is typically administered by continuous parenteral infusion.

[0007] Inhalation is the most effective or preferred route of administration for asthma treatment. This route offers a stronger local anti-inflammatory effect, effectively controlling airway inflammation, reducing the frequency and severity of asthma attacks, and lowering mortality. However, the current dosage form of enoximone is not suitable for inhalation administration. Therefore, the development of an inhalable formulation of enoximone is urgently needed. Summary of the Invention

[0008] In order to solve the above problems, the present invention provides a dry powder inhalation preparation, which comprises: enoximone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0009] According to an embodiment of the present invention, the preparation can effectively deliver the active ingredient enoximone or a pharmaceutically acceptable salt thereof to the lungs. According to an embodiment of the present invention, the preparation is suitable for use by a medicated powder inhaler or a capsule-type oral inhaler. According to an embodiment of the present invention, the preparation is suitable for administration by a dry powder inhaler; for example, a capsule dry powder inhaler, a blister dry powder inhaler, or a reservoir type dry powder inhaler.

[0010] According to an embodiment of the present invention, the mass median aerodynamic particle diameter MMAD of the preparation after inhaler administration is 0.5 μm-10.0 μm, preferably 1.0 μm-8.0 μm, for example 2.0 μm, 2.5 μm, 2.6 μm, 2.7 μm, 3.0 μm, 3.2 μm, 3.3 μm, 3.6 μm, 4.0 μm, 4.5 μm, 4.8 μm, 5.0 μm, 5.5 μm, 5.7 μm.

[0011] According to an embodiment of the present invention, the lung deposition percentage FPF after administration of the preparation inhaler is 30%-80%, preferably 35%-80%, and further preferably 35%-70%, for example 30%, 36%, 38%, 40%, 43%, 45%, 50%, 54%, 56%, 59%, 60%, 65%, 69%.

[0012] According to an embodiment of the present invention, calculated as the active ingredient enoximone, the content of enoximone is 0.1%-99.9%, preferably 1%-99%, further preferably 5%-95%, more preferably 10%-90%, for example 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%.

[0013] According to an embodiment of the present invention, pharmaceutically acceptable salts of enoximone include, but are not limited to, hydrochloride, bromate, and ethanesulfonate.

[0014] According to an embodiment of the present invention, enoximone or a pharmaceutically acceptable salt thereof is a micronized API. Preferably, the API is further sieved after micronization, for example, through a 60-mesh sieve. According to an embodiment of the present invention, the micronization process is selected from a process commonly used in the art, such as airflow milling, ball milling, etc. According to an embodiment of the present invention, the micronized API should be stored in a sealed manner. According to an embodiment of the present invention, the parameter conditions of airflow milling are: Venturi pressure: 0.5 bar-6.0 bar, ring pressure: 0.5 bar-6.0 bar, feed rate 0.1 g / min-5 g / min; for example, Venturi pressure: 4.0 bar-4.5 bar, ring pressure: 3.5 bar-4.0 bar, feed rate 0.3 g / min.

[0015] According to an embodiment of the present invention, the particle size D10 of the micronized API is 0.1 μm to 2.0 μm, preferably 0.3 μm to 1.0 μm, for example 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm.

[0016] According to an embodiment of the present invention, the particle size D50 of the micronized raw material is less than 5.0 μm, for example, 0.1 μm to 5.0 μm, preferably 0.5 μm to 4.0 μm, for example, 1.0 μm, 1.5 μm, 1.8 μm, 1.9 μm, 2.0 μm, 2.5 μm, 2.9 μm, 3.0 μm, 3.1 μm, 3.5 μm, 4.0 μm.

[0017] According to an embodiment of the present invention, the particle size D90 of the micronized raw material is 0.1 μm to 15.0 μm, preferably 1.0 μm to 10.0 μm, for example 2.0 μm, 3.0 μm, 4.0 μm, 5.0 μm, 6.0 μm, 7.0 μm, 7.4 μm, 7.7 μm, 8.0 μm.

[0018] According to an embodiment of the present invention, the pharmaceutically acceptable excipients include a filler. Preferably, the content of the filler is 10%-90%, preferably 20%-80%, more preferably 30%-70%, for example 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%.

[0019] According to an embodiment of the present invention, the filler is selected from one, two or more of saccharides, sugar alcohols, celluloses, tragacanth powder, gelatin, talc, amino acids, phospholipids, magnesium stearate, silicon dioxide, sodium chloride, potassium chloride, calcium chloride, etc. According to an embodiment of the present invention, saccharides and sugar alcohols include starch (such as corn starch and potato starch), lactose (including monohydrate lactose, anhydrate lactose), mannitol, glucose, trehalose, maltose and sucrose. According to an embodiment of the present invention, celluloses are such as microcrystalline cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate. According to an embodiment of the present invention, amino acids are such as leucine, lysine, glutamic acid. According to an embodiment of the present invention, phospholipids include synthetic phospholipids and natural phospholipids, such as egg yolk lecithin, soy lecithin, DPPC, HSPC.

[0020] According to an embodiment of the present invention, the filler is selected from one or both of lactose and magnesium stearate.

[0021] According to an embodiment of the present invention, the filler comprises lactose and magnesium stearate. According to an embodiment of the present invention, the content of lactose is 10%-90%, preferably 30%-80%, for example, 30%, 34%, 40%, 45%, 49.5%, 50%, 55%, 60%, 65%, 70%, 74%, 75%, 80%. According to an embodiment of the present invention, the content of magnesium stearate is 0%-2%, preferably, 0-1%, for example, 0%, 0.3%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%. According to an embodiment of the present invention, the mass ratio of lactose to magnesium stearate is 1-100:0-2, 1-100:0-1, preferably 50-100:0-2, 50-100:0-1, further preferably 70-100:0-2, 70-100:0-1, 60-90:0-2, 60-90:0-1, 70-80:0-2, 70-80:0-1, 65:0-2, 65:0-1, 75:0-2, 75:0-1, 80:0-2, 80:0-1, for example, 99:1-2, 99:1, 95:1-2, 90:1-2, 85:1-2, 80:1-2, 75:1-2, 74:1-2, 75:0.

[0022] According to an embodiment of the present invention, the pharmaceutically acceptable excipient is a micronized excipient.

[0023] According to an embodiment of the present invention, the particle size D10 of the micronized lactose is 3 μm to 20 μm, for example, 5 μm, 10 μm, or 15 μm.

[0024] According to an embodiment of the present invention, the particle size D50 of the micronized lactose is 40 μm to 80 μm, such as 50 μm, 60 μm, or 70 μm.

[0025] According to an embodiment of the present invention, the particle size D90 of the micronized lactose is 110 μm to 160 μm, for example, 120 μm, 130 μm, 140 μm, or 150 μm.

[0026] According to an embodiment of the present invention, the particle size D90 of the micronized magnesium stearate is less than 40 μm, such as less than 30 μm, or less than 20 μm.

[0027] According to an embodiment of the present invention, the mass ratio of enoximone to the filler is 1:50-50:1, preferably 1:20-20:1, and further preferably 1:10-10:1, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 7:3, and 3:7.

[0028] According to an embodiment of the present invention, the preparation comprises the following components:

[0029] Enoximone or a pharmaceutically acceptable salt thereof

[0030] Fillers;

[0031] Preferably, calculated as the active ingredient enoximone, the content of enoximone is 0.1%-99.9%, preferably 1%-99%, further preferably 5%-95%, more preferably 10%-90%, for example 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%:

[0032] Preferably, the content of the filler is 10%-90%, preferably 20%-80%, more preferably 30%-70%, for example 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%.

[0033] According to an embodiment of the present invention, the preparation comprises the following components:

[0034] 10%-100% (preferably 25%-70%, 25%-50%) of enoximone or a pharmaceutically acceptable salt thereof;

[0035] Filler 90%-0% (preferably 30%-75%, 50%-75%).

[0036] According to an embodiment of the present invention, the preparation comprises the following components:

[0037] Enoximone 10%-100% (preferably 25%-70%, 25%-50%)

[0038] Lactose 90%-0% (preferably 30%-75%, 50%-75%).

[0039] According to an embodiment of the present invention, the preparation comprises the following components:

[0040] Enoximone 10%-100% (preferably 25%-70%, 25%-50%, for example 25%, 50%, 70%)

[0041] Lactose 90%-0% (preferably 30%-75%, such as 30%, 49.5%, 50%, 74%, 75%)

[0042] Magnesium stearate 0%-1% (e.g., 0%, 0.3%, 0.5%, 0.8%, 1%);

[0043] Preferably, the mass ratio of lactose to magnesium stearate is 70-100:0-2.

[0044] According to an embodiment of the present invention, the preparation comprises the following components:

[0045] Enoximone 25%, 50%, or 70%

[0046] Lactose 75% or 50% or 30%;

[0047] Preferably, the formulation comprises the following components: enoximone 25%, lactose 75%;

[0048] Preferably, the formulation comprises the following components: 50% enoximone, 50% lactose;

[0049] Preferably, the preparation comprises the following components: enoximone 70%, lactose 30%;

[0050] Preferably, the enoximone is micronized enoximone;

[0051] Preferably, the particle size D50 of the enoximone after micronization is less than 5.0 μm, preferably 0.1 μm to 5.0 μm.

[0052] According to an embodiment of the present invention, the preparation comprises the following components:

[0053] Enoximone 25%, 50%, or 70%

[0054] Lactose 74% or 75% or 49.5% or 50% or 30%

[0055] Magnesium stearate 0% or 0.5% or 1%;

[0056] Preferably, the formulation comprises the following components: enoximone 25%, lactose 74%, magnesium stearate 1%;

[0057] Preferably, the formulation comprises the following components: enoximone 50%, lactose 49.5%, magnesium stearate 0.5%;

[0058] Preferably, the enoximone is micronized enoximone;

[0059] Preferably, the particle size D50 of the enoximone after micronization is less than 5.0 μm, preferably 0.1 μm to 5.0 μm.

[0060] According to an embodiment of the present invention, the preparation is obtained by mixing raw materials and auxiliary materials, and sieving and granulating.

[0061] According to an embodiment of the present invention, each capsule or single dose form of the preparation comprises: 5.0 mg of enoximone, 1.0 mg-20.0 mg of lactose (e.g., 1.5 mg, 2.0 mg, 2.1 mg, 2.5 mg, 3.0 mg, 4.95 mg, 5.0 mg, 8.0 mg, 10.0 mg, 12.0 mg, 14.8 mg, 15.0 mg, 18.0 mg).

[0062] According to an embodiment of the present invention, each capsule or single dose form of the preparation includes: 5.0 mg of enoximone, 1.0 mg-20.0 mg of lactose (for example, 1.5 mg, 2.0 mg, 2.1 mg, 2.5 mg, 3.0 mg, 4.95 mg, 5.0 mg, 8.0 mg, 10.0 mg, 12.0 mg, 14.8 mg, 15.0 mg, 18.0 mg), and 0 mg-0.5 mg of magnesium stearate (for example, 0 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg).

[0063] According to an embodiment of the present invention, the preparation is a filled dry powder inhalation preparation, such as a capsule-type dry powder inhalation preparation.

[0064] According to an embodiment of the present invention, the administration frequency of the preparation can be once a day, twice a day, three times a day, once every other day, once a week, twice a week, three times a week, once every other week, once every two weeks, once every three weeks, once every four weeks, etc.

[0065] According to an embodiment of the present invention, the dosage of the preparation (calculated as active ingredient) is 0.1 mg / day-20 mg / day, preferably 1 mg / day-15 mg / day, for example 5 mg / day-10 mg / day (adults), 1.25 mg / day-6.5 mg / day (children).

[0066] According to an embodiment of the present invention, the dosage of the preparation (calculated as active ingredient) is 0.001 mg / kg to 10 mg / kg, preferably 0.01 mg / kg to 5 mg / kg, and more preferably 0.0625-0.125 mg / kg.

[0067] The present invention also provides a method for preparing the above-mentioned preparation, which comprises:

[0068] The preparation is obtained by mixing enoximone or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients and sieving the mixture to obtain granules.

[0069] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0070] (1) micronizing enoximone or a pharmaceutically acceptable salt thereof;

[0071] (2) The micronized enoximone or a pharmaceutically acceptable salt thereof is mixed with pharmaceutically acceptable excipients and sieved to obtain the preparation.

[0072] According to an embodiment of the present invention, the preparation is a mixed dry powder preparation.

[0073] According to an embodiment of the present invention, step (1) further comprises the step of micronizing the pharmaceutically acceptable excipients.

[0074] According to an embodiment of the present invention, in step (2), the micronized enoximone or a pharmaceutically acceptable salt thereof is mixed with micronized pharmaceutically acceptable excipients and sieved to obtain the preparation.

[0075] According to an embodiment of the present invention, the micronized enoximone or a pharmaceutically acceptable salt thereof is sealed and stored.

[0076] According to an embodiment of the present invention, the micronization treatment is selected from treatment methods commonly used in the art, such as air flow pulverization and ball milling.

[0077] According to an embodiment of the present invention, the mixing is selected from a mixing method commonly used in the art, such as high shear mixing and three-dimensional mixing.

[0078] According to an embodiment of the present invention, the preparation method further comprises the following steps:

[0079] (3) Filling the preparation obtained in step (2) into a filling container.

[0080] According to an embodiment of the invention, the filling container is selected from a capsule, a blister or a reservoir.

[0081] According to an embodiment of the present invention, the capsule is selected from capsule No. 3; preferably, the capsule No. 3 comprises HPMC and gelatin capsule.

[0082] According to an embodiment of the present invention, the preparation method further comprises a packaging step.

[0083] According to an embodiment of the present invention, the packaging is selected from packaging methods commonly used in the art, such as aluminum foil bags, aluminum boxes, aluminum-plastic panels and the like.

[0084] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0085] (1) micronizing enoximone or its pharmaceutically acceptable salt and excipients separately or together;

[0086] (2) mixing the micronized enoximone or its pharmaceutically acceptable salt raw material with the micronized pharmaceutically acceptable excipients, and sieving and granulating the mixture to obtain a mixed dry powder preparation;

[0087] (3) Filling the mixed dry powder preparation into a filling container to obtain the preparation.

[0088] The present invention also provides an inhaler comprising the above formulation; preferably a dry powder inhaler (DPI), such as a blister DPI, a capsule DPI or a reservoir DPI.

[0089] According to an embodiment of the present invention, dry powder inhalation devices include Aerolizer™ (Novartis), Diskhaler™ (GlaxoSmithKline), Diskus or Accuhaler™ (GlaxoSmithKline), Handihaler™ (Boehringer Ingelheim), Easyhaler™ (Orion Pharma), Turbuhaler™ (AstraZeneca).

[0090] The present invention also provides use of the above-mentioned preparation or inhaler in the preparation of a medicament for preventing and / or treating a disease or disease state, wherein the disease or disease state is selected from any one or more of the following:

[0091] Asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin diseases, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases.

[0092] The present invention also provides a method for preventing and / or treating a disease or disease state, comprising administering to a patient an effective amount of the above-mentioned preparation or inhaler, wherein the disease or disease state is selected from any one or more of the following:

[0093] Asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin diseases, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases. Beneficial effects

[0094] The present invention provides a dry powder inhalation formulation containing enoximone as the active ingredient. The formulation has a small particle size, high pulmonary delivery efficiency, and a small dosage, significantly improving patient compliance. The dry powder inhalation formulation can significantly reduce white blood cell levels in bronchoalveolar lavage fluid of a bronchial asthma rat model, improve lung function, and the severity of tracheal, bronchi, and lung lesions, demonstrating a significant therapeutic effect on bronchial asthma. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] FIG1 shows the DVS measurement results of the micronized API of Example 1.

[0096] Figure 2 shows lung tissue pathological sections (HE, ×200). A. Normal control group; B. Model control group; C. Salbutamol sulfate solution inhalation group; D. Enoximone inhalation powder mixture low-dose group; E. Enoximone inhalation powder mixture medium-dose group; F. Enoximone inhalation powder mixture high-dose group.

[0097] Figure 3 shows pathological sections of tracheal tissue (HE, ×200). A. Normal control group; B. Model control group; C. Salbutamol sulfate solution inhalation group; D. Enoximone inhalation powder mixture low-dose group; E. Enoximone inhalation powder mixture medium-dose group; F. Enoximone inhalation powder mixture high-dose group.

[0098] Figure 4 shows pathological sections of bronchial tissue (HE, ×200). A. Normal control group; B. Model control group; C. Salbutamol sulfate solution inhalation group; D. Enoximone inhalation powder mixture low-dose group; E. Enoximone inhalation powder mixture medium-dose group; F. Enoximone inhalation powder mixture high-dose group. DETAILED DESCRIPTION

[0099] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0100] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0101] Unless otherwise indicated, all numbers used in this specification and claims to represent content, concentration, ratio, weight, particle size, percentage, technical effect, etc. should be understood as being modified by the term "about" or "approximately" under any circumstances. Therefore, unless otherwise indicated, the numerical parameters listed in the following specification and the appended claims are approximate values. Unless otherwise indicated, the terms used herein have the usual meanings understood by those skilled in the art. For those skilled in the art, it can vary according to the desired properties and effects sought to be obtained through this disclosure, and each numerical parameter should be interpreted according to the number of significant digits and conventional rounding methods or in a manner understood by those skilled in the art.

[0102] Although the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are provided as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in its respective testing measurements. Every numerical range given herein will include every narrower numerical range that falls within that broader numerical range, as if each narrower numerical range were expressly written herein.

[0103] When used in this article, the term "aerodynamic diameter (Da)", also known as the aerodynamic equivalent diameter, is a fictitious particle size (particle diameter) that describes particle motion. W. Stober defined it as: the diameter of a sphere of unit density (ρ0 = 1 g / cm3) that reaches the same terminal settling velocity (Vs) as the actual particle when moving at a low Reynolds number in still air. That is, the actual particle size is converted into an equivalent diameter (or equivalent diameter) with the same aerodynamic properties. Since the actual particle size and density cannot usually be measured, the aerodynamic particle size can be directly measured by dynamic methods, which provides a unified measurement for the particle size of particles with different shapes, densities, optical and electrical properties. The aerodynamic particle size can be calculated according to the following method: The particle size (volume particle size) Dv of the powder sample is measured using a laser particle size analyzer, according to Da = (ρ / ρ1) 1 / 2 The aerodynamic particle size Da is calculated by XDv. Where ρ is the density of the particle, ρ1 = 1 g / cm 3 'Dv is the average particle size. The ρ value can be estimated from the tap density, which is approximately 1.26 times the tap density.

[0104] As used herein, the term "mass median aerodynamic diameter" or "MMAD (mass median aerodynamic diameter)" means that when the total mass of particles of various sizes smaller than a certain aerodynamic diameter in particulate matter accounts for 50% of the mass of all particulate matter (i.e., the sum of the masses of all particles of different sizes), then this particle size is called the mass median aerodynamic diameter.

[0105] As used herein, the term "pulmonary deposition percentage" or "FPF" (fine particle fraction) refers to the percentage of the total delivered dose that is composed of particles ≤5 μm, calculated as follows:

[0106] in:

[0107] FPD is the fine particle dose, that is, the particle dose with a mass median aerodynamic particle size of 5 μm or less. It is calculated based on the drug mass of each level of ACI or NGI and the corresponding cutoff particle size of each level at the test flow rate. The higher the FPD and FPF, the higher the drug delivery efficiency and the higher the lung deposition.

[0108] Emitted Dose is the total delivered dose, which refers to the sum of the drug mass entering each layer of ACI or NGI excluding capsule residue and device residue.

[0109] GSD: Geometric standard deviation.

[0110] NGI stages: NGI cascade sampler with 7 stages (s1 to s7) and 1 microporous collector.

[0111] The various embodiments and preferences described above for the formulations or preparation methods thereof of the present disclosure can be combined with each other (as long as they are not inherently inconsistent with each other), and the various embodiments formed by such combinations are all considered to be part of the present disclosure.

[0112] The following examples will be used to more clearly and specifically illustrate the technical solutions of the present disclosure. It should be understood that these examples are for illustrative purposes only and are in no way intended to limit the scope of protection of the present disclosure. The scope of protection of the present disclosure is defined solely by the claims.

[0113] Materials and methods

[0114] Enoximone used in the examples was purchased from Xianju (Jiaxing) Pharmaceutical Technology Co., Ltd., lactose monohydrate was purchased from DFE Pharma GmbH & Co. KG, mannitol was purchased from Merck KGaA, sucrose was purchased from Guangxi Chencan Pharmaceutical Co., Ltd., trehalose was purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd., and magnesium stearate was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.

[0115] The mass median aerodynamic particle size was measured using a new generation eight-stage impactor (NGI cascade sampler). The specific operating procedures were as follows: the drug powder was filled into a No. 3 capsule, and the inhaler device and device adapter were connected to the air inlet end of the impactor's artificial throat; the pump's suction flow rate and suction time were adjusted to the specified range, the capsule was punctured, and inhalation began, allowing the drug powder to enter different levels of the impactor with the air flow; the drug powder at different levels of the impactor was cleaned into a volumetric flask with an appropriate cleaning fluid and fixed to volume, and the drug powder content at each level of the impactor was detected by high-performance liquid chromatography.

[0116] Example 1: Study on the stability of enoximone bulk drug powder and micronized bulk drug

[0117] a prescription

[0118] Enoximone API.

[0119] b process

[0120] 1) Weigh 2g of enoximone, sieve it through a 60-mesh sieve, and use MC Enoximone was micronized using a jet mill with different parameters set. The micronized API from all parts was collected, passed through a 60-mesh sieve, and mixed to give micronized batches ST-230601-2307-M01 (Venturi pressure: 4.5 bar, ring pressure: 4 bar, feed rate 0.3 g / min) and ST-230601-2307-M02 (Venturi pressure: 4.0 bar, ring pressure: 3.5 bar, feed rate 0.3 g / min).

[0121] 2) The micronized API was placed in an open container under long-term conditions (25±2°C / 60±5% RH) and accelerated conditions (40±2°C / 75%±5% RH) in a stability test chamber to observe the physical (properties, particle size distribution, etc.) and chemical (content and related substances, etc.) stability of the micronized API.

[0122] cResults

[0123] 1) Dynamic moisture sorption (DVS) results of micronized API ST-230601-2307-M01

[0124] The DVS results are shown in Figure 1. As can be seen from Figure 1, the maximum wet weight gain is about 2.5%, indicating that the micronized enoximone API is hygroscopic (i.e., the wet weight gain is less than 15% but not less than 2%).

[0125] 2) Properties, content, particle size distribution and related substances of micronized API under long-term conditions

[0126] In the table, / indicates not determined.

[0127] 3) Properties, content, particle size distribution and related substances of micronized API under accelerated conditions

[0128] In the table, / indicates not determined.

[0129] The long-term and accelerated stability results of the micronized API indicate that the properties, content, and related substances of the micronized enoximone API remained unchanged after 30 days of exposure under both long-term and accelerated conditions, and its particle size distribution remained unchanged over 6 days. However, after 10 days of exposure under both long-term and accelerated conditions, the particle size distribution of the micronized enoximone API increased, indicating agglomeration. Particle size agglomeration typically reaches equilibrium within 10 to 30 days, suggesting that micronized APIs should be stored in a sealed container to prevent moisture absorption and agglomeration.

[0130] Example 2: Enoximone dry powder inhaler I

[0131] a prescription

[0132] b process

[0133] The temperature and humidity of all the following experiments must be controlled within the range of 20℃~30℃ / 35%RH~55%RH.

[0134] 1) Weigh the prescribed amount of lactose monohydrate (inhalable lactose, purchased from DFE Pharma; D10: 12-26 μm, D50: 62-85 μm, D90: 121-140 μm) and micronized enoximone and add them sequentially to a glass vial. Manually mix for 150 seconds and pass through a 60-mesh sieve to obtain powder mix 1. Manually mix powder mix 1 for another 150 seconds and pass through a 60-mesh sieve to obtain powder mix 2. Manually mix powder mix 2 for 150 seconds and pass through a 60-mesh sieve to obtain powder mix 2. Powder mix batch number 23EXN07-B01.

[0135] 2) Manually fill capsules with 20 mg ± 1 mg (19 mg to 21 mg) of mixed powder per capsule to obtain filled capsules. The batch number of filled capsules is 23EXN07-F01.

[0136] 3) Seal the filled capsules into aluminum foil bags according to the test items, then seal them in another aluminum foil bag. After packaging, place them in a long-term test at 25±2°C / 60±5% RH and an accelerated test at 40±2°C / 75±5% RH to initially assess their stability.

[0137] cResults

[0138] 1) Test results of properties, content, related substances, moisture content and NGI of filled capsules under long-term storage conditions

[0139] 2) Test results of properties, content, related substances, moisture content and NGI of filled capsules under accelerated conditions

[0140] After sealed in aluminum foil bags and placed under long-term and accelerated conditions, the filled capsules showed no significant changes in filler properties, content, related substances, and moisture content over 60 days, demonstrating that the physical and chemical properties of the filled capsules were stable and controllable. The NGI results showed no significant changes in fine particle size distribution over 60 days, either under long-term or accelerated conditions. Most drugs penetrated into the S3 and S4 grades, with mass median aerodynamic diameters (MMAD) around 2.5 μm. The in vitro aerodynamic particle size distribution characteristics of the filled capsules were stable and controllable.

[0141] Example 3: Screening of API Particle Size

[0142] a prescription

[0143] b process

[0144] The temperature and humidity of all the following experiments must be controlled within the range of 20℃~30℃ / 35%RH~55%RH.

[0145] 1) Weigh the prescribed amount of lactose monohydrate and micronized enoximone (lot number ST-230601-2307-M01) (or unmicronized enoximone) and add them sequentially to a glass vial. Manually mix for 150 seconds and pass through a 60-mesh sieve to obtain powder mix 1. Manually mix powder mix 1 for another 150 seconds and pass through a 60-mesh sieve to obtain powder mix 2. Manually mix powder mix 2 for 150 seconds and pass through a 60-mesh sieve to obtain powder mix. Powder mix batch numbers 23EXN07-B01 and 23EXN07-B11.

[0146] 2) Manually fill capsules with 20 mg ± 1 mg (19 mg to 21 mg) of mixed powder per capsule to obtain filled capsules. The filled capsule batch numbers are 23EXN07-F01 and 23EXN07-F11.

[0147] 3) Seal the filled capsules into aluminum foil bags according to the test items, then seal them in another aluminum foil bag. After packaging, place them at 25±2°C / 60±5% RH for 7 days to eliminate static electricity before testing.

[0148] cResults

[0149] 1) Test results of properties, content, related substances and moisture content of filled capsules

[0150] 2) Test results of fine particle dosage of filled capsules

[0151] There were no significant differences in properties, content, or related substances between formulations filled with different API particle sizes. The FPF of the micronized API formulation reached 68.59%, while the FPF of the non-micronized API formulation was only 35.86%. Therefore, when the API is micronized to a D50 particle size below 5μm, the inhalation effect of the formulation is better.

[0152] Example 4: Selection of lactose dosage

[0153] a. Screening formula with lactose addition (5 mg / pill)

[0154] Lactose addition levels of 0%, 30%, 50% and 75% were selected for investigation.

[0155] b process

[0156] The temperature and humidity of all the following experiments must be controlled within the range of 20℃~30℃ / 35%RH~55%RH.

[0157] 1) Weigh the prescribed amount of lactose monohydrate and micronized enoximone, add them sequentially to a glass vial, manually mix for 150 strokes, and pass through a 60-mesh sieve to obtain powder mix 1; continue to manually mix powder mix 1 for 150 strokes and pass through a 60-mesh sieve to obtain powder mix 2; manually mix powder mix 2 for 150 strokes and pass through a 60-mesh sieve to obtain powder mixes 23EXN07-B01 to 23EXN07-B04.

[0158] 2) Manually fill capsules to give 5 mg of enoximone per capsule, obtaining filled capsule batch numbers 23EXN07-F01 to 23EXN07-F04.

[0159] 3) Seal the filled capsules into aluminum foil bags according to the test items, then seal them in another aluminum foil bag. After packaging, place them at 25±2°C / 60±5% RH for 7 days to eliminate static electricity before testing.

[0160] cResults

[0161] 1) Test results of properties, content, related substances and moisture content of filled capsules

[0162] 2) Test results of fine particle dosage of filled capsules

[0163] There were no significant differences in properties, content, or related substances between capsules filled with formulations containing different lactose ratios. However, the NGI results showed that the FPF% of the dry powder increased with increasing lactose ratios.

[0164] Example 5: Selection of excipient types

[0165] a prescription (5mg / pill)

[0166] b process

[0167] The temperature and humidity of all the following experiments must be controlled within the range of 20℃~30℃ / 35%RH~55%RH.

[0168] 1) Weigh the prescribed amount of excipients and micronized enoximone, add them sequentially to a glass vial, manually mix for 150 strokes, and pass through a 60-mesh sieve to obtain mixed powder 1; continue to manually mix mixed powder 1 for 150 strokes and pass through a 60-mesh sieve to obtain mixed powder 2; manually mix mixed powder 2 for 150 strokes and pass through a 60-mesh sieve to obtain mixed powders 23EXN07-B01 and 23EXN07-B05 to 23EXN07-B08.

[0169] 2) Manually fill capsules to give 5 mg of enoximone per capsule, obtaining filled capsule batches 23EXN07-F01 and 23EXN07-F05 to 23EXN07-F08.

[0170] 3) Seal the filled capsules into aluminum foil bags according to the test items, then seal them in another aluminum foil bag. After packaging, place them at 25±2°C / 60±5% RH for 7 days to eliminate static electricity before testing.

[0171] cResults

[0172] 1) Test results of properties, content, related substances and moisture content of filled capsules

[0173] 2) Test results of fine particle dosage of filled capsules

[0174] There were no significant differences in properties, content, related substances, or moisture content between capsules filled with different carriers. The NGI results showed no significant difference between the lactose and lactose + magnesium stearate formulations, while the mannitol, trehalose, and sucrose formulations exhibited lower recoveries and median aerodynamic particle sizes above 3 μm.

[0175] Example 6: Screening of drug delivery devices

[0176] Based on the market availability of inhalers, the powder inhaler of Zhejiang Baian Medical Technology Co., Ltd. and the capsule-type oral inhaler of Jiangsu Xinmaide Medical Equipment Technology Co., Ltd. were selected for research.

[0177] a drug delivery device

[0178] b process

[0179] The 23EXN07-B01 powder mix was filled into capsules and inhalers, respectively, at a dose of 5 mg of enoximone per dose, yielding 23EXN07-F01 and 23EXN07-F10. The filled capsules were sealed in aluminum foil bags, which were then sealed in another aluminum foil bag. After packaging, the capsules were stored at 25±2°C / 60±5% RH for 7 days to eliminate static electricity. Fine particle measurements were then performed using two different inhalers.

[0180] cResults

[0181] In terms of drug delivery device properties, the capsule-type oral inhaler has less air resistance and greater airflow at the same pressure. In terms of drug delivery results, there was no significant difference between the two devices. In terms of fine particle dose results, the capsule-type oral inhaler achieved a higher fine particle dose and a smaller mass median aerodynamic particle size.

[0182] Example 7: Pharmacodynamics Study

[0183] 1. Experimental Methods

[0184] Sixty-four SPF-grade SD rats that passed quarantine were selected and randomly divided into a normal control group (8 rats) and a model group (56 rats). The model group rats were sensitized by intraperitoneal injection of 4% ovalbumin (OVA) 0.5 mL / rat and intraperitoneal injection of 2% Al(OH) 3 0.5 mL / rat, once a week for a total of two times. On the 15th day of sensitization, the model rats were placed in a small animal oral and nasal exposure system, and 2% ovalbumin solution was atomized and injected at 20 g / cm 3 Aerosol inhalation challenge was performed for 30 minutes, once a week for a total of three times. The sensitization and challenge times of the normal control group animals were the same as those of the model group animals. Sensitization was performed by intraperitoneal injection of 2% Al(OH)3 at a dose of 0.5 mL / animal. The challenge was inhalation of 0.9% sodium chloride injection for 30 minutes. Asthma attacks were induced in the model group animals. After challenge, the animals showed symptoms such as shortness of breath, abdominal muscle spasms, and mania, which confirmed the success of the model (rat bronchial asthma model). The day after the last modeling, 48 successfully modeled animals were selected and randomly divided into five groups according to body weight: a model control group (8 animals), an inhalation salbutamol sulfate solution group (0.90 mg / kg, 10 animals), and a low-, medium-, and high-dose enoximone inhalation powder mixture (EXN-2401) group (the doses of the active ingredient enoximone were 0.225 mg / kg, 0.45 mg / kg, and 0.90 mg / kg, 10 animals, 10 animals, and 10 animals, respectively). The next day after the last modeling, the animals in each group were given corresponding doses of drugs through oral and nasal inhalation. The normal control group and the model control group were given 0.9% sodium chloride injection mixed with the enoximone inhalation powder spray group through oral and nasal inhalation for the same duration, once a day for 7 consecutive days.

[0185] EXN-2401 prescription

[0186] The aerosol content and particle size of the enoximone inhalation powder mixture and salbutamol sulfate solution for inhalation were analyzed at the first dose. After the last dose, 8 animals were randomly selected from each group to test the changes in lung function indicators Penh, PIF, and PEF before and after ACh stimulation. After the lung function test, the bronchoalveolar lavage fluid (BALF) was collected to detect the white blood cell (WBC) and eosinophil (Eos) content. After the last dose, the trachea, bronchi, and lungs of the rats were obtained for pathological examination.

[0187] 2. Experimental Results

[0188] 2.1 Effect on leukocyte classification of bronchoalveolar lavage fluid

[0189] As shown in Table 2, compared with the normal control group, the levels of white blood cells (WBC) and eosinophils (Eos) in the model control group were significantly increased (P ≤ 0.01); compared with the model control group, the WBC and Eos in the medium- and high-dose groups of enoximone inhalation powder mixture and the salbutamol sulfate solution inhalation group were significantly decreased (P ≤ 0.05 or P ≤ 0.01).

[0190] Table 2 Effects of Enoximone Inhalation Powder Mixture on Rat Bronchoalveolar Lavage Fluid

[0191] Note: Compared with the normal control group ++ P≤0.01; compared with the model control group ** P≤0.05 or * P≤0.01.

[0192] 2.2 Effects on lung function

[0193] As shown in Table 3, compared with the normal control group, the maximum inspiratory flow rate (PIF) of the rats in the model control group was significantly decreased, and the airway resistance (Penh) was significantly increased (P≤0.01); compared with the model control group, the PIF of the rats in the low-, medium-, and high-dose groups of enoximone inhalation powder mixture and the inhalation salbutamol sulfate solution group were significantly increased (P≤0.01 or P≤0.05), the peak flow rate (PEF) of the rats in the low-, medium-, and high-dose groups of enoximone inhalation powder mixture were significantly increased (P≤0.05), and the Penh of the rats in the medium-, high-dose groups of enoximone inhalation powder mixture and the inhalation salbutamol sulfate solution group were significantly decreased (P≤0.01).

[0194] Table 3 Effects of Enoximone Inhalation Powder Mixture on Lung Function in Model Rats (Before Ach Challenge)

[0195] Note: Compared with the normal control group ++ P≤0.01; compared with the model control group * P≤0.05 or ** P≤0.01.

[0196] As shown in Table 4, airway hyperresponsiveness was induced in rats of each group by sublingual intravenous injection of 0.1 mL of 20 mg / mL acetylcholine (Ach). Compared with the normal control group, the PIF of the rats in the model control group was significantly decreased, and the Penh was significantly increased (P ≤ 0.01). Compared with the model control group, the PIF and PEF of the rats in the low-, medium-, and high-dose enoximone inhalation powder mixture groups and the salbutamol sulfate solution inhalation group were significantly increased, and the Penh was significantly decreased (P ≤ 0.01 or P ≤ 0.05).

[0197] Table 4 Effect of Enoximone Inhalation Powder Mixture on Pulmonary Function of Model Rats (After Ach Challenge)

[0198] Note: Compared with the normal control group ++ P≤0.01; compared with the model control group ** P≤0.01 or * P≤0.05.

[0199] As shown in Table 5, compared with the normal control group, the PIF change rate of the rats in the model control group was significantly decreased (P≤0.05); compared with the model control group, the PIF change rates of the rats in the low-, medium-, and high-dose groups of enoximone inhalation powder mixture and the salbutamol sulfate solution group were significantly increased (P≤0.01 or P≤0.05), and the Penh change rates of the rats in the salbutamol sulfate solution group and the high-dose group of enoximone inhalation powder mixture were significantly decreased (P≤0.05).

[0200] Table 5 Effect of Enoximone Inhalation Powder Mixture on the Change Rate of Lung Function in Model Rats

[0201] Note: ① Change rate of pulmonary function index = (pulmonary function index measured after Ach stimulation - pulmonary function index measured before Ach stimulation) / pulmonary function index measured after Ach stimulation * 100%. ② Comparison with the normal control group ++ P≤0.01; compared with the model control group

[0202] ** P≤0.01 or * P≤0.05.

[0203] 2.3 Histopathological examination

[0204] As shown in Figures 2 to 4, after the last administration, microscopic observation showed no obvious changes in the trachea, bronchi and lung tissues of the animals in the normal control group, and no inflammatory cell infiltration was observed. In the model control group, the rats had tracheal mucosal epithelial hyperplasia and submucosal inflammatory cell infiltration, bronchi had mucosal epithelial hyperplasia and submucosal inflammatory cell infiltration, and lung bronchial epithelial goblet cell hyperplasia, peripheral inflammatory cell infiltration, and perivascular inflammatory cell infiltration in the lungs. The tracheal and bronchial tissue lesions of the animals in the low-, medium-, and high-dose groups of enoximone inhalation powder mixture and the inhalation salbutamol sulfate solution group were alleviated to varying degrees compared with the model control group, and the lung tissue lesions of the animals in the high-dose group of enoximone inhalation powder mixture were alleviated to varying degrees compared with the model control group.

[0205] As shown in Table 6, compared with the normal control group, the histopathological scores of the trachea, bronchi, and lungs of the animals in the model control group were significantly increased (P≤0.01); compared with the model control group, the histopathological scores of the trachea and bronchi of the rats in the low-, medium-, and high-dose groups of enoximone inhalation powder mixture and the inhalation salbutamol sulfate solution group were significantly decreased (P≤0.05 or P≤0.01), and the histopathological score of the lungs of the high-dose group of enoximone inhalation powder mixture was significantly decreased (P≤0.05).

[0206] Table 6 Effects of Enoximone Inhalation Powder Mixture on the Histopathological Scores of the Respiratory Tract of Rats

[0207] Note: Compared with the normal control group ++ P≤0.01; compared with the model control group * P≤0.05 or ** P≤0.01.

[0208] 3. Conclusion and Evaluation

[0209] Bronchial asthma is a common and frequently occurring disease, and also a chronic inflammatory disease of the airways. This chronic inflammation is associated with airway hyperresponsiveness, often with widespread and variable reversible airflow limitation, leading to recurrent symptoms such as wheezing, shortness of breath, chest tightness, and / or cough, which often occur and worsen at night and / or in the early morning. Clinically, asthma is often diagnosed using indicators such as lung function and sputum eosinophil counts. Egg white albumin is a heterologous protein with strong immunogenicity and is often used to construct asthma models. Therefore, in this study, egg white albumin was combined with aluminum hydroxide adjuvant to construct a rat bronchial asthma model. After oral and nasal inhalation of the corresponding dose of enoximone inhalation powder mixture, the rats were observed for changes in lung function, lung pathology, and white blood cell and eosinophil counts in the alveolar lavage fluid.

[0210] During recurrent asthma attacks, airway ventilation function can be impaired to varying degrees. Pulmonary function tests can directly assess airway ventilation status, reversibility, and airway hyperresponsiveness. Pulmonary function indices such as Penh and PEF can reflect airway ventilation function. The results of this study showed that the lung function in model rats was significantly different from that in the normal control group, with Penh and PEF showing significant differences. Pathological findings revealed epithelial cell necrosis and desquamation, mucosal fold hyperplasia, luminal stenosis, and inflammatory cell infiltration in the bronchi of the animals, indicating varying degrees of airway restriction in the asthma model rats. A bronchial asthma model was successfully established. After orally and nasally inhaled enoximone powder inhaler, lung function tests before and after ACh provocation in the model rats showed significant improvement in ventilation restriction and alleviated airway hyperresponsiveness.

[0211] Asthma is a chronic inflammatory disease of the airways, and inflammatory responses play a crucial role in the development and progression of the disease. The number of white blood cells (WBCs) and endoscopy (Eos) in the BALF of rats directly reflects the level of inflammation in rat lung tissue. The results of this study showed that WBC and Eos levels in the BALF of model rats were significantly elevated, and inflammatory cell infiltration was present in the lungs and bronchi, suggesting that asthmatic rats are in a state of hyperinflammatory response. Oral and nasal inhalation of enoximone powder inhalation mixture significantly reduced WBC levels in the BALF of model rats, and the severity of bronchial and lung lesions was significantly alleviated. This suggests that enoximone powder inhalation mixture has a significant regulatory effect on the inflammatory level in the BALF of model rats and can significantly improve the severity of tracheal, bronchial, and lung lesions.

[0212] In summary, enoximone powder inhaler mixture can significantly reduce the WBC level in BALF of model rats, improve lung function and the degree of tracheal, bronchi and lung lesions, indicating that enoximone powder inhaler mixture has a significant therapeutic effect on bronchial asthma model rats.

[0213] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A dry powder inhalation preparation, comprising: Enoximone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; Pharmaceutically acceptable excipients include fillers; the fillers are selected from one or two of lactose and magnesium stearate; Preferably, the content of the filler is 10%-90%, preferably 20%-80%, and more preferably 30%-70%.

2. The preparation according to claim 1, characterized in that The mass ratio of enoximone to filler is 1:50-50:0, preferably 1:20-20:0; Preferably, the filler is selected from lactose; preferably, the content of lactose is 10%-90%, preferably 30%-80%; Preferably, the filler comprises lactose and magnesium stearate; preferably, the mass ratio of lactose to magnesium stearate is 1-100:0-2, preferably 50-100:0-2; preferably, the content of lactose is 10%-90%, preferably 30%-80%; preferably, the content of magnesium stearate is 0%-2%, preferably 0-1%; Preferably, the pharmaceutically acceptable excipient is a micronized excipient; preferably, the particle size D10 of the micronized lactose is 3 μm to 20 μm; preferably, the particle size D50 of the micronized lactose is 40 μm to 80 μm; preferably, the particle size D90 of the micronized lactose is 110 μm to 160 μm; preferably, the particle size D90 of the micronized magnesium stearate is <40 μm.

3. The preparation according to claim 1 or 2, characterized in that The preparation is suitable for administration via a powder inhaler or a capsule-type oral inhaler; Preferably, the formulation is suitable for administration by dry powder inhaler; Preferably, the mass median aerodynamic particle diameter MMAD of the preparation after administration by inhaler is 0.5 μm-10.0 μm, preferably 1.0 μm-8.0 μm; Preferably, the lung deposition percentage FPF of the preparation after administration by inhaler is 30%-80%, preferably 35%-80%; Preferably, the content of enoximone is 0.1%-99.9%, preferably 1%-99%, calculated as the active ingredient enoximone; Preferably, enoximone or a pharmaceutically acceptable salt thereof is a micronized API; preferably, the API is further sieved after micronization; Preferably, the micronization treatment is selected from air flow milling, ball milling, etc.; Preferably, the particle size D10 of the micronized API is 0.1 μm to 2.0 μm, preferably 0.3 μm to 1.0 μm; Preferably, the particle size D50 of the micronized raw material is less than 5.0 μm, for example, 0.1 μm to 5.0 μm, preferably 0.5 μm to 4.0 μm; Preferably, the particle size D90 of the micronized raw material is 0.1 μm to 15.0 μm, and more preferably 1.0 μm to 10.0 μm.

4. The preparation according to any one of claims 1 to 3, characterized in that The preparation includes the following components: Enoximone or a pharmaceutically acceptable salt thereof Fillers; Preferably, the content of enoximone is 0.1%-99.9%, preferably 1%-99%, calculated as the active ingredient enoximone; Preferably, the content of the filler is 10%-90%, preferably 20%-80%; Preferably, the formulation comprises the following components: Enoximone or its pharmaceutically acceptable salt 10%-100% (preferably 25%-70%, 25%-50%) Filler 90%-0% (preferably 30%-75%, 50%-75%); Preferably, the formulation comprises the following components: Enoximone 10%-100% (preferably 25%-70%, 25%-50%) Lactose 90%-0% (preferably 30%-75%, 50%-75%); Preferably, the formulation comprises the following components: Enoximone 10%-100% (preferably 25%-70%, 25%-50%) Lactose 90%-0% (preferably 30%-75%) Magnesium stearate 0%-1%; Preferably, the mass ratio of lactose to magnesium stearate is 70-100:0-2; Preferably, the formulation comprises the following components: Enoximone 25%, 50%, or 70% Lactose 75%, 50%, or 30%; Preferably, the formulation comprises the following components: enoximone 25%, lactose 75%; Preferably, the formulation comprises the following components: 50% enoximone, 50% lactose; Preferably, the preparation comprises the following components: enoximone 70%, lactose 30%; Preferably, the formulation comprises the following components: Enoximone 25%, 50%, or 70% Lactose 74% or 75% or 49.5% or 50% or 30% Magnesium stearate 0%, 0.5%, or 1%; Preferably, the formulation comprises the following components: enoximone 25%, lactose 74%, magnesium stearate 1%; Preferably, the formulation comprises the following components: enoximone 50%, lactose 49.5%, magnesium stearate 0.5%; Preferably, the enoximone is micronized enoximone; Preferably, the particle size D50 of the enoximone after micronization is less than 5.0 μm, preferably 0.1 μm to 5.0 μm; Preferably, each capsule or single dose of the preparation comprises: 5.0 mg of enoximone, 1.0 mg to 20.0 mg of lactose; Preferably, each capsule or single dose form of the preparation comprises: 5.0 mg of enoximone, 1.0 mg to 20.0 mg of lactose, and 0 mg to 0.5 mg of magnesium stearate.

5. The preparation according to any one of claims 1 to 4, characterized in that The preparation is a filled dry powder inhalation preparation, such as a capsule-type dry powder inhalation preparation; Preferably, the administration frequency of the preparation is selected from once a day, twice a day, three times a day, once every other day, once a week, twice a week, three times a week, once every other week, once every two weeks, once every three weeks, once every four weeks, etc.; Preferably, the dosage of the preparation (calculated as active ingredient) is 0.1 mg / day to 20 mg / day, preferably 1 mg / day to 15 mg / day, for example 5 mg / day to 10 mg / day (adults), 1.25 mg / day to 6.5 mg / day (children); Preferably, the dosage of the preparation (calculated as active ingredient) is 0.001 mg / kg to 10 mg / kg, preferably 0.01 mg / kg to 5 mg / kg, and more preferably 0.0625-0.125 mg / kg.

6. A method for preparing the preparation according to any one of claims 1 to 5, comprising: The preparation is obtained by mixing enoximone or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients and sieving the mixture to obtain granules.

7. The preparation method according to claim 6, characterized in that The preparation method comprises the following steps: (1) micronizing enoximone or a pharmaceutically acceptable salt thereof; (2) mixing the micronized enoximone or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient and sieving the mixture to obtain the preparation; Preferably, step (1) further comprises the step of micronizing the pharmaceutically acceptable excipients; Preferably, in step (2), the micronized enoximone or a pharmaceutically acceptable salt thereof is mixed with micronized pharmaceutically acceptable excipients and sieved to obtain the preparation; Preferably, the micronized enoximone or its pharmaceutically acceptable salt is sealed and stored; Preferably, the micronization treatment is selected from air flow milling and ball milling; Preferably, the mixing is selected from high shear mixing, three-dimensional mixing; Preferably, the preparation method further comprises the following steps: (3) filling the preparation prepared in step (2) into a filling container; Preferably, the filling container is selected from a capsule, a blister or a reservoir; Preferably, the capsule is selected from capsule size 3; Preferably, the preparation method further comprises a packaging step; preferably, the packaging is selected from aluminum foil bags, aluminum boxes, aluminum-plastic panels and the like; Preferably, the preparation method comprises the following steps: (1) micronizing enoximone or its pharmaceutically acceptable salt and excipients separately or together; (2) mixing the micronized enoximone or its pharmaceutically acceptable salt raw material with the micronized pharmaceutically acceptable excipients, and sieving and granulating the mixture to obtain a mixed dry powder preparation; (3) Filling the mixed dry powder preparation into a filling container to obtain the preparation.

8. An inhaler comprising the formulation of any one of claims 1 to 5; preferably a dry powder inhaler (DPI).

9. Use of the formulation according to any one of claims 1 to 5 or the inhaler according to claim 8 in the preparation of a medicament for preventing and / or treating a disease or disease state, wherein the disease or disease state is selected from any one or more of the following: Asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin diseases, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases.

10. A method for preventing and / or treating a disease or condition, the method comprising administering to a patient an effective amount of the formulation of any one of claims 1 to 5 or the inhaler of claim 8, wherein the disease or condition is selected from any one or more of the following: Asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin diseases, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases.

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