Compound inhalation powder inhalation and preparation method thereof

Abstract

The invention discloses a compound inhalation powder inhalation and a preparation method thereof. The compound inhalation dry powder comprises apremilast or a pharmaceutically acceptable salt thereof, and an efficacy enhancing substance, wherein the efficacy enhancing substance is nintedanib or a pharmaceutically acceptable salt thereof; the dosage of the efficacy enhancing substance is 0.1-10 times of the mass of the dosage of the apremilast or the pharmaceutically acceptable salt of the apremilast. In the compound inhalation powder inhalation provided by the invention, the drug exposure of apremilast is greatly improved under the action of nintedanib, and a remarkable enhancement effect is shown; meanwhile, the effect of the nintedanib is further improved; the apremilast or the pharmaceutically acceptable salt thereof and the nintedanib or the pharmaceutically acceptable salt thereof are used for treating lung diseases, so that the medicines can be directly delivered to effective parts, the administration dosage is further effectively reduced or the utilization rate of the medicines is increased, the deposition rate is increased, and the curative effect is improved. The treatment effect is greatly improved.

Description

Technical Field

[0001] The invention relates to a compound inhalation powder aerosol and a preparation method thereof. Background Art

[0002] Interstitial lung disease (ILD) is a large group of diseases characterized by inflammation and fibrosis of the lung interstitium, affecting the alveolar epithelium, capillary endothelium and surrounding tissues. When lung damage triggers an abnormal healing response, it may lead to progressive fibrosing interstitial lung disease (PF-ILD), which is characterized by the self-maintenance and development of fibrosis, independent of the initial triggering factors, and is usually accompanied by a progressive decline in lung function and a poor prognosis. Among them, idiopathic pulmonary fibrosis (IPF) is the most common diffuse pulmonary fibrosis disease, with unknown etiology, unclear pathogenesis, lack of effective treatment, and a median survival of only 3-5 years.

[0003] Apremilast (Apremilast, molecular formula C 22 H 24 N 2 O 7 S, CAS number 608141-41-9) is a phosphodiesterase 4 (PDE4) inhibitor that reduces inflammatory responses by regulating the release of inflammatory mediators. Studies have shown that Apremilast can interfere with fibroblast proliferation and transformation to myofibroblasts, inhibit the fibrosis process, and has the potential to improve the therapeutic effect of fibrotic diseases, and can provide a new treatment option for the treatment of IPF. However, after intrapulmonary administration of Apremilast, the concentration in the lungs and plasma is average. If it can be improved, its effect in clinical applications can be further expanded, and its effectiveness and recognition can be further expanded.

[0004] Therefore, developing a drug that can quickly and effectively improve the treatment effect of pulmonary fibrosis and is relatively safe and reasonably priced has important market value and medical value. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of Apremilast as a drug for treating IPF, that the concentration in the lungs and plasma after administration is low, and the therapeutic effect still has room for improvement, and provide a compound inhalation powder and a preparation method thereof. In the compound inhalation powder provided by the present invention, the drug exposure of Apremilast is greatly improved under the action of Nintedanib, showing a significant enhancement effect; at the same time, Nintedanib itself is also a drug active ingredient for treating pulmonary fibrosis, which can further improve the efficacy; the present invention is administered by pulmonary inhalation in the form of a powder, and Apremilast or its pharmaceutically acceptable salt and Nintedanib or its pharmaceutically acceptable salt are also used together to treat lung diseases, which can achieve direct delivery of drugs to effective sites, further effectively reduce the dosage or improve the utilization rate of drugs, improve the deposition rate, and greatly improve the therapeutic effect.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The present invention provides a compound inhalation powder, which comprises apremilast or a pharmaceutically acceptable salt thereof, and an efficacy enhancing substance, wherein the efficacy enhancing substance is nintedanib or a pharmaceutically acceptable salt thereof; and the dosage of the efficacy enhancing substance is 0.1-10 times the dosage of the apremilast or the pharmaceutically acceptable salt thereof by mass.

[0008] In the present invention, the use form of nintedanib is generally nintedanib free base.

[0009] In the present invention, the pharmaceutically acceptable salt of nintedanib may be nintedanib ethanesulfonate. The English name of nintedanib is Nintedanib, and the molecular formula is C 31 H 33 N 5 O 4 , CAS number is 656247-17-5; the English name of nintedanib esylate is Nintedanib esylate, and the molecular formula is C 31 H 33 N 5 O 4 ·C 2 H 6 O 3 S, CAS number is 656247-18-6.

[0010] In the present invention, the dosage of the efficacy enhancing substance may be 0.1-2 times, preferably 0.2-1 times, such as 0.1 times, 0.2 times, 0.8 times, 1 times or 2 times, of the dosage of Apremilast or its pharmaceutically acceptable salt.

[0011] In the present invention, the amount of Apremilast or its pharmaceutically acceptable salt can be 2wt%-80wt%, preferably 4.2wt%-30wt%, for example, 2.5wt%, 4.2wt%, 5wt%, 5.5wt%, 15wt%, 25wt%, 30wt%, 40wt%, 50wt%, 54.5wt% or 79.2wt%, and the above percentages are the mass percentages of Apremilast or its pharmaceutically acceptable salt in the compound inhalation powder.

[0012] In the present invention, the dosage of the efficacy enhancing substance can be 0.5wt%-55wt%, preferably 0.8wt%, 2.5wt%, 5wt%, 5.5wt%, 10wt%, 12.5wt%, 15wt%, 15.8wt%, 30wt%, 40wt% or 54.5wt%, and the above percentages are the mass percentages of the efficacy enhancing substance in the compound inhalation powder.

[0013] In the present invention, the sum of the amounts of Apremilast or its pharmaceutically acceptable salt, and the efficacy enhancing substance may be 5wt%-95wt%, preferably 5wt%-80wt%, more preferably 5wt%-60wt%, for example 5wt%, 15wt%, 20wt%, 27wt%, 27.5wt%, 28wt%, 30wt%, 60wt%, 80wt%, 90wt% or 95wt%, where the percentage is the mass percentage of the sum of the amounts of Apremilast or its pharmaceutically acceptable salt, and the efficacy enhancing substance in the compound inhalation powder.

[0014] In the present invention, the compound inhalation powder may further comprise an excipient.

[0015] Among them, the excipient can be selected from one or more of amino acid surface modifiers, phospholipid excipients, sugar excipients, sugar alcohol excipients, volatile salt excipients and antistatic agents; preferably a mixture of amino acid surface modifiers and antistatic agents, a mixture of amino acid surface modifiers, phospholipid excipients and antistatic agents, a mixture of amino acid surface modifiers, sugar excipients and antistatic agents, a mixture of amino acid surface modifiers, sugar alcohol excipients and antistatic agents, a mixture of amino acid surface modifiers, volatile salt excipients and antistatic agents, or a mixture of amino acid surface modifiers, sugar alcohol excipients, volatile salt excipients and antistatic agents.

[0016] The amino acid surface modifier can be selected from one or more of leucine, isoleucine, dileucine, trileucine and glycine; the leucine is preferably L-leucine.

[0017] The amino acid surface modifier may be used in an amount of 1 wt%-50 wt%, preferably 29 wt%-50 wt%, for example 1.9 wt%, 3.5 wt%, 4.5 wt%, 15 wt%, 19.5 wt%, 29.5 wt%, 30 wt%, 34.5 wt%, 39.5 wt% or 47.5 wt%.

[0018] The phospholipid excipient may be selected from one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and lecithin.

[0019] The phospholipid excipient may be used in an amount of 0wt%-60wt%, preferably 0wt%-55wt%, for example 10wt%, 19.5wt%, 36wt%, 37.6wt%, 47wt%, 54.5wt% or 57wt%.

[0020] The carbohydrate excipient may be selected from trehalose.

[0021] The sugar alcohol excipient can be selected from mannitol.

[0022] The carbohydrate excipient or the sugar alcohol excipient may be used in an amount of 30 wt % to 40 wt %, for example, 30 wt %, 35 wt % or 39.5 wt %.

[0023] The volatile salt excipient may be selected from ammonium carbonate and / or ammonium bicarbonate.

[0024] The volatile salt excipient may be used in an amount of 10 wt % to 50 wt %, for example 10 wt % or 47 wt %.

[0025] The static dissipator may be selected from alkaline earth metal salts and / or alkali metal salts, preferably one or more of calcium chloride, sodium chloride, sodium citrate and sodium metaphosphate.

[0026] The static dissipator may be used in an amount of 0.5 wt % to 4 wt %, preferably 0.5 wt % to 1 wt %, such as 0.5 wt % or 1 wt %.

[0027] The above percentages are the mass percentages of each component in the compound inhalation powder.

[0028] In some preferred embodiments, the excipient is a mixture of an amino acid surface modifier, a phospholipid excipient and an antistatic agent, and the mass ratio of the amino acid surface modifier to the phospholipid excipient is 1:(0-20), preferably 1:(0.3-10.3), for example 1:0.3, 1:1, 1:1.8, 1:3.6, 1:3.8, 1:10.3 or 1:19.8.

[0029] In some preferred embodiments, the excipient is a mixture of an amino acid surface modifier, a carbohydrate excipient and an antistatic agent, and the mass ratio of the amino acid surface modifier to the carbohydrate excipient is 1:(0-5), preferably 1:(0-3), for example 1:1.

[0030] In some preferred embodiments, the excipient is a mixture of an amino acid surface modifier, a sugar alcohol excipient and an antistatic agent, and the mass ratio of the amino acid surface modifier to the sugar alcohol excipient is 1:(0-5), preferably 1:(0-3), for example 1:1.

[0031] In some preferred embodiments, the excipient is a mixture of an amino acid surface modifier, a volatile salt excipient and a destaticizer, and the mass ratio of the amino acid surface modifier to the volatile salt excipient is 1:(0-5), preferably 1:(0-3), for example 1:1.

[0032] In some preferred embodiments, the excipient is a mixture of an amino acid surface modifier, a sugar alcohol excipient, a volatile salt excipient and a destaticizer, wherein the mass ratio of the amino acid surface modifier to the sugar alcohol excipient is 1:(0-5), preferably 1:(0-3), for example 1:1; the mass ratio of the amino acid surface modifier to the volatile salt excipient is 1:(0-5), preferably 1:(0-3), for example 1:0.3.

[0033] In some preferred embodiments, the excipient can be selected from any one of the following combinations: "leucine and calcium chloride", "isoleucine and calcium chloride", "leucine, dipalmitoylphosphatidylcholine (DPPC) and calcium chloride", "leucine, dipalmitoylphosphatidylcholine (DPPC) and sodium chloride", "leucine, trehalose and calcium chloride", "leucine, mannitol and calcium chloride", "leucine, ammonium carbonate and calcium chloride" or "leucine, mannitol, ammonium carbonate and calcium chloride".

[0034] Among them, the amount of the excipient can be 4wt%-95wt%, preferably 20wt%-95wt%, more preferably 39wt%-70wt%, for example 4.5wt%, 19.5wt%, 39wt%, 39.5wt%, 69.5wt%, 72wt%, 84.5wt%, 89.5wt% or 94.5wt%, and the above percentages are the mass percentages of the excipient in the compound inhalation powder.

[0035] In the present invention, the preparation process of the compound inhalation powder can be a spray drying process.

[0036] In the present invention, the compound inhalation powder can be used to prepare a drug for treating pulmonary fibrosis. The pulmonary fibrosis can be idiopathic pulmonary fibrosis.

[0037] In some preferred embodiments, the compound inhalation powder comprises an active ingredient and an excipient;

[0038] Wherein, the active ingredient comprises apremilast or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, and the dosage of nintedanib or a pharmaceutically acceptable salt thereof is 0.1-10 times the dosage of apremilast or a pharmaceutically acceptable salt thereof;

[0039] The excipient comprises any of the following:

[0040] a mixture of the amino acid surface modifier and the antistatic agent; the amount of the amino acid surface modifier is 3.5wt% -50wt%;

[0041] b. a mixture of the amino acid surface modifier, the phospholipid excipient and a mixture of an antistatic agent, wherein the mass ratio of the amino acid surface modifier and the phospholipid excipient is 1: (0.3-10.3);

[0042] c. a mixture of the amino acid surface modifier, the carbohydrate excipient and a mixture of an antistatic agent, wherein the amino acid surface modifier and the carbohydrate excipient have a mass ratio of 1: (0-3);

[0043] d. A mixture of the amino acid surface modifier, the sugar alcohol excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier to the sugar alcohol excipient is 1:(0-3).

[0044] In some preferred embodiments, the compound inhalation powder comprises an active ingredient, an excipient and an antistatic agent;

[0045] Wherein, the active ingredient comprises apremilast or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof, and the dosage of nintedanib or a pharmaceutically acceptable salt thereof is 0.2-1 times the dosage of apremilast or a pharmaceutically acceptable salt thereof;

[0046] The excipient comprises any of the following:

[0047] a. The amino acid surface modifier and the antistatic agent; the amount of the amino acid surface modifier is 3.5wt%-50wt%;

[0048] b. a mixture of the amino acid surface modifier, the phospholipid excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier and the phospholipid excipient is 1: (0.3-1);

[0049] c. a mixture of the amino acid surface modifier, the carbohydrate excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier and the carbohydrate excipient is 1:1;

[0050] d. A mixture of the amino acid surface modifier, the sugar alcohol excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier to the sugar alcohol excipient is 1:1.

[0051] In a specific embodiment, the compound inhalation powder consists of 15wt% apremilast, 15wt% nintedanib ethanesulfonate, 15wt% leucine, 54.5wt% DPPC and 0.5wt% calcium chloride.

[0052] In a specific embodiment, the compound inhalation powder consists of 15wt% apremilast, 12.5wt% nintedanib free base, 15wt% leucine, 57wt% DPPC and 0.5wt% calcium chloride.

[0053] In a specific embodiment, the compound inhalation powder consists of 5wt% apremilast, 10wt% nintedanib ethanesulfonate, 30wt% leucine, 54.5wt% DPPC and 0.5wt% calcium chloride.

[0054] In a specific embodiment, the compound inhalation powder consists of 54.5wt% apremilast, 5.5wt% nintedanib ethanesulfonate, 3.5wt% leucine, 36wt% DPPC and 0.5wt% calcium chloride.

[0055] In a specific embodiment, the compound inhalation powder consists of 54.5wt% apremilast, 5.5wt% nintedanib ethanesulfonate, 19.5wt% leucine, 19.5wt% DPPC and 1wt% sodium chloride.

[0056] In a specific embodiment, the compound inhalation powder consists of 25wt% apremilast, 5wt% nintedanib ethanesulfonate, 29.5wt% leucine, 30wt% mannitol, 10wt% ammonium carbonate and 0.5wt% calcium chloride.

[0057] In a specific embodiment, the compound inhalation powder consists of 50wt% apremilast, 10wt% nintedanib ethanesulfonate, 29.5wt% leucine, 10wt% DPPC and 0.5wt% calcium chloride.

[0058] In a specific embodiment, the compound inhalation powder consists of 30wt% apremilast, 30wt% nintedanib ethanesulfonate, 39.5wt% leucine and 0.5wt% calcium chloride.

[0059] In a specific embodiment, the compound inhalation powder consists of 4.2wt% apremilast, 0.8wt% nintedanib ethanesulfonate, 47.5wt% leucine, 47wt% ammonium carbonate and 0.5wt% calcium chloride.

[0060] In a specific embodiment, the compound inhalation powder consists of 25wt% apremilast, 5wt% nintedanib ethanesulfonate, 34.5wt% leucine, 35wt% trehalose and 0.5wt% calcium chloride.

[0061] In a specific embodiment, the compound inhalation powder consists of 40wt% apremilast, 40wt% nintedanib ethanesulfonate, 19.5wt% isoleucine and 0.5wt% calcium chloride.

[0062] In a specific embodiment, the compound inhalation powder consists of 2.5wt% apremilast, 2.5wt% nintedanib ethanesulfonate, 47.5wt% leucine, 47wt% DPPC and 0.5wt% calcium chloride.

[0063] In a specific embodiment, the compound inhalation powder consists of 79.2wt% apremilast, 15.8wt% nintedanib ethanesulfonate, 4.5wt% isoleucine and 0.5wt% calcium chloride.

[0064] In a specific embodiment, the compound inhalation powder consists of 5.5wt% apremilast, 54.5wt% nintedanib ethanesulfonate, 39.5wt% DPPC and 0.5wt% calcium chloride.

[0065] In a specific embodiment, the compound inhalation powder consists of 5.5wt% apremilast, 54.5wt% nintedanib ethanesulfonate, 39.5wt% mannitol and 0.5wt% calcium chloride.

[0066] In a specific embodiment, the compound inhalation powder consists of 54.5wt% apremilast, 5.5wt% nintedanib ethanesulfonate, 1.9wt% leucine, 37.6wt% DPPC and 0.5wt% calcium chloride.

[0067] In the present invention, the compound inhalation powder can be in the form of capsules.

[0068] Wherein, the material of the capsule can be gelatin or hydroxypropyl methylcellulose HPMC.

[0069] Wherein, the capsule can be selected from No. 0, No. 1, No. 2, No. 3 or No. 4 capsule.

[0070] In the present invention, the geometric particle size D of the compound inhalation powder is 50It may be 1 μm-5 μm, preferably 1 μm-2.5 μm, for example 1.08 μm, 1.26 μm, 1.34 μm, 1.36 μm, 1.37 μm, 1.40 μm, 1.42 μm, 1.6 μm, 1.61 μm, 1.85 μm, 2.01 μm, 2.17 μm or 2.32 μm.

[0071] In the present invention, the mass median aerodynamic diameter (MMAD) of the apremilast or a pharmaceutically acceptable salt thereof may be 1 μm-5 μm, for example, 1.42 μm, 1.58 μm, 1.63 μm, 1.75 μm, 1.8 μm, 1.89 μm, 2.02 μm, 2.17 μm, 2.31 μm, 2.35 μm, 2.56 μm, 2.6 μm, 2.61 μm, 3.0 μm or 4.1 μm; the nintedanib or its The pharmaceutically acceptable salt has a mass median aerodynamic diameter (MMAD) of 1-5 μm, for example 1.42 μm, 1.58 μm, 1.63 μm, 1.75 μm, 1.8 μm, 1.89 μm, 2.01 μm, 2.17 μm, 2.31 μm, 2.35 μm, 2.56 μm, 2.6 μm, 2.61 μm, 3.0 μm or 4.1 μm.

[0072] The present invention provides a method for preparing the above-mentioned compound inhalation powder, which comprises the following steps: dissolving the apremilast or a pharmaceutically acceptable salt thereof and the efficacy enhancing substance in an organic phase or an aqueous phase respectively, mixing the aqueous phase with the organic phase to obtain a spray drying precursor solution; and obtaining powder by spray drying.

[0073] In the present invention, the Apremilast or its pharmaceutically acceptable salt, and the efficacy enhancing substance are dissolved in the organic phase or the aqueous phase, respectively. Those skilled in the art will appreciate that they can be selectively dissolved in the organic phase or the aqueous phase, respectively, according to the solubility of the substance to be dissolved.

[0074] In the present invention, preferably, the apremilast is dissolved in the organic phase, and the pharmaceutically acceptable salt of apremilast, the nintedanib or a pharmaceutically acceptable salt thereof is dissolved in the aqueous phase; the aqueous phase and the organic phase are mixed to obtain a spray drying precursor solution; and the powder is obtained by spray drying.

[0075] In the present invention, the organic phase may be ethanol, or a mixture of ethanol and acetone.

[0076] In the present invention, the organic phase may further contain the phospholipid excipient.

[0077] In the present invention, the aqueous phase may further contain one or more of the sugar excipient, the sugar alcohol excipient, the volatile salt excipient and the antistatic agent.

[0078] In the present invention, the spray drying is a drying technology that converts liquid materials into powder or granular solids by atomizing the liquid material into fine droplets and drying them quickly in a hot air flow. The process generally includes the following steps: Atomization: The liquid material is atomized into fine droplets by an atomizer (such as a pressure, centrifugal or air flow atomizer). Drying: The atomized droplets quickly evaporate water in a hot air flow to form dry powder or particles. Collection: The dried powder or particles are collected by a cyclone separator or a bag filter. In the present invention, the spray drying can adopt the parameters of conventional spray drying, or those skilled in the art can know that the raw material is dissolved or formed into a suspended material for spray drying to obtain the final product. The inlet air temperature of the spray drying can be 90-150°C, preferably 110-125°C, for example 110°C, 120°C or 125°C. The outlet air temperature of the spray drying may be 40-80°C, preferably 50-60°C, such as 51°C, 55°C, 56°C, 57°C, 58°C, 59°C or 60°C.

[0079] The present invention also provides a compound inhalation powder inhalation preparation, which is prepared by the preparation method of the compound inhalation powder inhalation preparation.

[0080] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0081] The reagents and raw materials used in the present invention are commercially available.

[0082] The positive and progressive effects of the present invention are:

[0083] 1. In the compound inhalation powder provided by the present invention, the drug exposure of Apremilast is greatly improved under the action of Nintedanib, showing a significant enhancement effect; at the same time, Nintedanib itself is also an active ingredient of a drug for treating pulmonary fibrosis, which can further improve the efficacy.

[0084] At the same time, in the cell experiment, compared with the positive control group, the control group using apremilast alone, and the control group using nintedanib alone, the combined administration had a more significant inhibitory effect on fibrosis-related RNA in human pulmonary fibrosis cells.

[0085] 2. The compound inhalation powder provided by the present invention can maintain the fine particle fraction (FPF) within a good range. The FPF value of the preferred solution can reach 70%-95%. The powder is administered by pulmonary inhalation in the form of a powder. Apremilast or a pharmaceutically acceptable salt thereof and nintedanib or a pharmaceutically acceptable salt thereof are used together to treat lung diseases, which can achieve direct drug delivery to the effective site, further effectively reduce the dosage or increase the utilization rate of the drug, increase the deposition rate, and greatly improve the treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 1 is a graph of the mRNA expression levels of proteins in Example 2. The types of proteins from left to right are smooth muscle actin (α-SMA), fibronectin and collagen I.

[0087] Figure 2 The X-ray powder diffraction (XRD) characterization diagrams of API, blank preparation, and the compound inhalation powder prepared in Example 4 at 0 day and after acceleration of 1M.

[0088] Figure 3 XRD characterization diagrams of API, blank preparation, and the compound inhalation powder prepared in Example 5 at 0 day and after acceleration of 1M.

[0089] Figure 4 This is a scanning electron microscope (SEM) characterization image of the compound inhalation powder prepared in Example 7.

[0090] Figure 5 This is a SEM characterization image of the compound inhalation powder prepared in Example 14.

[0091] Figure 6 This is the APSD distribution diagram of nintedanib ethanesulfonate of the compound inhalation powder prepared in Example 1 at 0 day and after 3M acceleration.

[0092] Figure 7 The APSD distribution diagram of Apremilast of the compound inhalation powder prepared in Example 1 at 0 day and after 3M acceleration. DETAILED DESCRIPTION

[0093] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0094] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by technicians in the technical field to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not used to limit the present invention.

[0095] The terms "include", "comprises", and "have" and any variations thereof in the present invention are intended to cover non-exclusive inclusions. The "plurality" mentioned in the present invention refers to two or more. "And / or" describes the association relationship of associated objects, indicating that three relationships may exist.

[0096] Examples 1-16, Comparative Examples 1-2

[0097] The percentages in the following examples are the mass percentages of the various components in the total amount of the compound inhalation powder.

[0098] Example 1: 15wt% of Apremilast and 54.5wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 15wt% of Nintedanib ethanesulfonate, 15wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0099] Example 2: 15wt% of Apremilast and 57wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 12.5wt% of nintedanib free base (those skilled in the art know that this is the drug presentation form in which nintedanib is conventionally used as an active ingredient), 15wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was slowly added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0100] Example 3: 5wt% of Apremilast and 54.5wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 10wt% of Nintedanib ethanesulfonate, 30wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0101] Example 4: 54.5wt% of Apremilast and 36wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 5.5wt% of Nintedanib ethanesulfonate, 3.5wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0102] Example 5: 54.5wt% of Apremilast and 19.5wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 5.5wt% of Nintedanib ethanesulfonate, 19.5wt% of leucine and 1wt% of sodium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0103] Example 6: 25 wt% of Apremilast was dissolved in an ethanol solution to obtain an organic phase; 5 wt% of Nintedanib ethanesulfonate, 29.5 wt% of leucine, 30 wt% of mannitol, 10 wt% of ammonium carbonate and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0104] Example 7: 50wt% of Apremilast and 10wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 10wt% of Nintedanib ethanesulfonate, 29.5wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0105] Example 8: 30 wt% of Apremilast was dissolved in an ethanol solution to obtain an organic phase; 30 wt% of Nintedanib ethanesulfonate, 39.5 wt% of leucine and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0106] Example 9: 4.2 wt% of Apremilast was dissolved in an ethanol solution to obtain an organic phase; 0.8 wt% of Nintedanib ethanesulfonate, 47.5 wt% of leucine, 47 wt% of ammonium carbonate and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0107] Example 10: 25 wt% of Apremilast was dissolved in an ethanol solution to obtain an organic phase; 5 wt% of Nintedanib ethanesulfonate, 34.5 wt% of leucine, 35 wt% of trehalose and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0108] Example 11: 40 wt% of Apremilast was dissolved in an ethanol solution to obtain an organic phase; 40 wt% of Nintedanib ethanesulfonate, 19.5 wt% of isoleucine and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0109] Example 12: 2.5wt% of Apremilast and 47wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 2.5wt% of Nintedanib ethanesulfonate, 47.5wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder to obtain a compound inhalation powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0110] Example 13: 79.2 wt% of Apremilast was dissolved in an ethanol solution to obtain an organic phase; 15.8 wt% of Nintedanib ethanesulfonate, 4.5 wt% of isoleucine and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0111] Example 14: 5.5wt% of Apremilast and 39.5wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 54.5wt% of Nintedanib ethanesulfonate and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0112] Example 15: 5.5 wt% of Apremilast and 39.5 wt% of mannitol were dissolved in an ethanol solution to obtain an organic phase; 54.5 wt% of Nintedanib ethanesulfonate and 0.5 wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0113] Example 16: 54.5wt% of Apremilast and 37.6wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 5.5wt% of Nintedanib ethanesulfonate, 1.9wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0114] Comparative Example 1: 5wt% of Apremilast and 60.75wt% of DPPC were dissolved in an ethanol solution to obtain an organic phase; 33.75wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0115] Comparative Example 2: 57.4wt% of DPPC was dissolved in an ethanol solution to obtain an organic phase; 10wt% of nintedanib ethanesulfonate, 32.1wt% of leucine and 0.5wt% of calcium chloride were dissolved in water to obtain an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-dried precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder. The spray drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

[0116] 10 mg of the powders prepared in the above Examples 1-16 and Comparative Examples 1-2 were filled into No. 3 hydroxypropyl methylcellulose (HPMC) hollow capsules to prepare inhalation powders.

[0117] Effect Example 1 Cell Experiment Drug Efficacy Detection

[0118] Comparison of lung and plasma exposure of apremilast, nintedanib and the combination after intratracheal administration - rats

[0119] 1. Experimental animals: 27 SD rats. The animals were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., with the experimental animal use license number: 20241119Aa220619000995.

[0120] 2. Animal dosing grouping: 27 SD rats were randomly divided into 3 groups, 9 rats in each group, and apremilast alone (the inhalation powder prepared in Comparative Example 1), nintedanib alone (the inhalation powder prepared in Comparative Example 2), and apremilast and nintedanib compound (the inhalation powder prepared in Example 3) were administered intratracheally, and blood and lung samples were collected 5 minutes, 1 hour, and 4 hours after administration for analysis, and HPLC-MS was used for detection.

[0121] 3. The results of HPLC-MS blood sample testing are shown in Tables 1 and 2 below:

[0122] Table 1 Concentrations of Apremilast in rat lungs and plasma after administration of single or combined drugs

[0123]

[0124] Table 2 Concentrations of nintedanib in rat lungs and plasma after administration of single or combined drugs

[0125]

[0126] As can be seen from Table 1, after single-agent apremilast was administered into the airways, it was rapidly absorbed, with the highest concentration detected 5 minutes after administration; after administration of apremilast and nintedanib combination, the lung concentration was higher than that of single-agent apremilast, with the exposure increased by 30%-236%. The plasma exposure of single-agent apremilast and combination apremilast was similar.

[0127] As can be seen from Table 2, after intratracheal administration of nintedanib alone, it is rapidly absorbed, with a higher lung exposure and a longer exposure time than apremilast; after administration of nintedanib alone and apremilast and nintedanib in combination, the lung exposure and plasma exposure are similar.

[0128] This confirms that the drug exposure of Apremilast was greatly improved under the action of Nintedanib, showing a significant enhancement effect.

[0129] Effect Example 2 Cell Experimental Drug Efficacy Detection

[0130] Inhibitory effects of apremilast and nintedanib alone and in combination on fibrotic RNA in human pulmonary fibrosis cells

[0131] Detection method: Human lung fibrosis cells were seeded in 6-well plates, with 5×10 5 cells. When 50 ng / mL of transforming growth factor β1 (TGFβ1) recombinant protein was added, 1 μM apremilast solution (A), 0.1 μM nintedanib ethanesulfonate solution (B), 1 μM apremilast solution and 0.1 μM nintedanib solution were added respectively. After 24 h of culture, the cells were washed three times with pre-cooled phosphate buffered saline (PBS) and 1 mL of Trizol was added to the cells. The ribonucleic acid (RNA) in the cells was extracted, 50 μL of diethyl pyrocarbonate (DEPC) was added to dissolve in water, the concentration was detected by nanodrop, and the quantitative polymerase chain reaction (qPCR) instrument was used for detection, using the above reaction system. The data were analyzed according to the values ​​collected by the instrument.

[0132] Test results such as Figure 1 As shown, A represents 1 μM apremilast solution and B represents 0.1 μM nintedanib solution. As can be seen from the figure, after TGFβ1 induces human fibrotic cells, it will promote the occurrence of cell fibrosis and increase the RNA expression of pulmonary fibrosis-related proteins such as smooth muscle actin (α-SMA), fibronectin and collagen I. After adding apremilast solution, nintedanib solution, and apremilast and nintedanib mixed solution, the results showed that the addition of apremilast or nintedanib alone had no significant inhibitory effect on the RNA expression of smooth muscle actin and collagen I, but after the two were co-incubated, the RNA expression of the above two proteins was significantly inhibited, proving that the combined administration of the two will produce a good synergistic effect; apremilast solution, nintedanib solution, and apremilast and nintedanib mixed solution all had a significant inhibitory effect on the RNA expression of fibronectin, and the inhibitory effect of apremilast and nintedanib mixed solution was the best.

[0133] Effect Example 3 XRD and SEM Characterization

[0134] The API, the blank preparation and the compound inhalation powder prepared in Example 4, as well as the API, the blank preparation and the compound inhalation powder prepared in Example 5 were characterized by XRD, and the results were as follows: Figure 2 and Figure 3 Wherein, the API is a mixture of 50wt% apremilast and 50wt% nintedanib, the blank preparation is a mixture of 50wt% leucine and 50wt% DPPC, and the accelerated 1M is a compound inhalation powder obtained by storing Example 4 or Example 5 at 40°C / 75% RH for 1 month.

[0135] from Figure 2 and Figure 3 It can be seen that the API exists in an amorphous form; the blank preparation shows characteristic peaks of DPPC and leucine; the main crystallization peaks of the drug-containing preparations (Example 4 and Example 5) are all excipient peaks; under accelerated conditions, the drug-containing preparations did not undergo crystal transformation. It can be seen that under high temperature and high humidity conditions, the API of the drug-containing preparation can still maintain an amorphous state and has good stability.

[0136] The compound inhalation powder prepared in Example 7 and Example 14 was characterized by SEM, and the results were as follows: Figure 4-Figure 5 shown.

[0137] from Figure 4-Figure 5 It can be seen that in Example 7, a mixture of leucine and DPPC is used as an excipient, and the prepared pharmaceutical particles are mainly in a hollow and wrinkled state. In Example 14, only DPPC is used as an excipient without adding leucine, and the surface of the prepared pharmaceutical particles is relatively smooth.

[0138] Effect Example 4 In vitro experimental test

[0139] The inhalation powders prepared in the above Examples 1-16 and Comparative Examples 1-2 were subjected to the following in vitro experimental effect tests.

[0140] 1. Particle size determination

[0141] The geometric particle size distribution measurement method - laser particle size analysis was used: the dispersion pressure was 3.0 bar, the feed rate was 65%, and each sample was measured twice in parallel. The test results are statistically shown in Table 4.

[0142] 2. Aerodynamic Particle Size Distribution (APSD) Determination

[0143] The aerodynamic particle size distribution was determined using an Anderson cascade impactor (ACI):

[0144] (1) ACI installation

[0145] S1. Place a suitable filter paper (81mm diameter, 1μm pore size) in the F layer of ACI and press the sealing ring into it to seal it. Then, according to the flow rate required for the experiment, install the corresponding layers step by step from bottom to top, then connect the pre-separator, fix it with three spring clips, and then connect the L-shaped connecting pipe to ensure the sealing of the system. Among them, drip 1-2 drops of coating liquid onto the surface of each collection plate and spread it evenly with a silicone spatula, and add 10mL of receiving liquid to the pre-separator.

[0146] S2. Connect the outlet of the ACI base to the flow controller, connect the flow controller to the vacuum pump, connect the L-shaped connecting pipe to the flow meter, ensure air tightness, turn on the vacuum pump, adjust the flow rate to reach the required flow rate Q=60L / min for the experiment, and then remove the flow meter.

[0147] S3. Put the L-shaped connecting tube on the clamping device, insert the appropriate nozzle adapter to connect the drug delivery device, and ensure that the inhaler port is flush with the nozzle adapter and the L-shaped connecting tube.

[0148] S4. Set the flow controller to the number of particles to be sucked in the experiment (1 particle) and the time for each suction (4 seconds). Wait for 5 seconds, turn off the vacuum pump, and remove the impactor (remove it step by step from top to bottom).

[0149] (2) Sample cleaning and recovery

[0150] The prepared capsules, dosing device, L-shaped connecting tube, pre-separator, grading plate, collecting plate and filter paper were washed into a volumetric flask of appropriate volume in sequence, diluted to an appropriate multiple and filtered for sampling. The test results are summarized in Table 4.

[0151] 3. Determination of active ingredient content

[0152] Determine the content according to high performance liquid chromatography (General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia):

[0153] (1) Sample processing

[0154] Test solution: Take an appropriate amount of the product, weigh it accurately, add an appropriate amount of acetonitrile-water (40:60) to dissolve and quantitatively dilute to make a solution containing approximately 0.01 mg of apremilast and 0.01 mg of nintedanib per 1 mL.

[0155] Reference solution: Take appropriate amount of apremilast reference substance and nintedanib reference substance, about 20 mg respectively, accurately weigh, place in a 100 mL volumetric flask, add 4 mL of acetonitrile and sonicate to dissolve, add 6 mL of water, dilute to the scale with solvent, then measure 5.0 mL to a 100 mL volumetric flask, dilute to the scale with solvent to make a solution containing approximately 0.01 mg of apremilast and 0.01 mg of nintedanib per 1 mL.

[0156] (2) Chromatographic conditions

[0157] Octadecylsilane bonded silica gel was used as the filler (Agilent ZOBAX SB-C18, 4.6 mm × 150 mm, 3.5 μm or a chromatographic column with equivalent performance); 0.1% trifluoroacetic acid solution (1 mL of trifluoroacetic acid was diluted to 1000 mL with water) was used as the mobile phase A, and acetonitrile was used as the mobile phase B; gradient elution was performed according to Table 3 below, with a flow rate of 1.0 mL per minute; the column temperature was 35 °C; the detection wavelengths were 230 nm (for detection of apremilast) and 390 nm (for detection of nintedanib); the injection volume was 10 μL.

[0158] Table 3 Gradient elution parameters for content determination

[0159]

[0160] (3) System suitability requirements: In the chromatogram of the reference solution, the tailing factors of the two main peaks of apremilast and nintedanib should not be greater than 1.5, and the number of theoretical plates should not be less than 3000.

[0161] (4) Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the peak area according to the external standard method. The test results are statistically shown in Table 4.

[0162] 4. Fine particle dose measurement

[0163] According to the method for determining the aerodynamic characteristics of fine particles of inhalation preparations (General Rules 0951 Device 2 of Part IV of the 2020 edition of the Chinese Pharmacopoeia):

[0164] Solvent: methanol-water (70:30)

[0165] Test solution: Connect the device (leakage detection is required before using the device). Before use, evenly coat the pre-separator base and the level-1~F collection plates with a coating agent, and add appropriate solvent to the pre-separator. Adjust the flow rate to 60L per minute, take 1 capsule of this product, place it in the inhalation device, remove static electricity from the capsule and the inhalation device, press the button on the device with your fingers, puncture both sides of the capsule, connect the adapter, turn on the vacuum pump, pump for 4 seconds, turn off the pump, and wait for 5 seconds. Dismantle the device, carefully remove the filter paper, clean the nozzle adapter, L-shaped connecting tube and pre-separator with solvent, and quantitatively dilute to an appropriate volume; quantitatively extract the drugs on the inner wall of each level and the corresponding collection plate or filter paper with solvent and quantitatively dilute to a certain volume.

[0166] The reference solution, chromatographic conditions, system suitability requirements and determination methods are the same as those under the above determination of active ingredient content.

[0167] According to the above test method, the inhalation powder samples prepared in Examples 1-16 and Comparative Examples 1-2 were characterized and evaluated. The test results are summarized in Table 4.

[0168] Table 4 In vitro test results

[0169]

[0170] Note: * D 50 It is the geometric particle size at which the cumulative particle size distribution percentage reaches 50% as measured by laser particle size measurement.

[0171] From Table 4, we can see that:

[0172] (1) According to the comparison between Example 1 and Example 2, it can be seen that the use of nintedanib or a pharmaceutically acceptable salt of nintedanib can achieve good in vitro drug deposition rate performance.

[0173] (2) According to the comparison between Example 1 and Example 3, when the ratio of nintedanib to apremilast is increased, the in vitro drug deposition rate performance is improved to a certain extent.

[0174] (3) According to the comparison between Example 4 and Example 5, it can be seen that using calcium chloride or sodium chloride as the antistatic agent can achieve good in vitro drug deposition rate performance.

[0175] (4) According to the comparison between Example 1, Example 6 and Example 10, when the phospholipid excipients are replaced with "sugar alcohol excipients and volatile salt excipients" or trehalose, the in vitro drug deposition rate performance is improved to a certain extent.

[0176] (5) According to the comparison between Example 9 and Example 12, when the drug loading amount and the content of the amino acid surface modifier are the same, the yield is reduced after the phospholipid excipient is replaced by a volatile salt excipient, but the in vitro drug deposition rate performance becomes higher.

[0177] (6) According to the comparison between Example 4, Example 14 and Example 15, it can be seen that if the excipient does not contain an amino acid surface modifier and only contains a phospholipid excipient or a sugar alcohol excipient, the in vitro drug deposition rate performance is reduced.

[0178] (7) According to the comparison of Example 4, Example 7 and Example 16, when the ratio of the amino acid surface modifier to the phospholipid excipient is within 1:(0-11), the in vitro drug deposition rate performance is better.

[0179] Effect Example 5 Stability Test

[0180] Example 1 was stored at 40° C. / 75% RH for 3 months, and the aerodynamic particle size distribution (APSD) test was performed on the compound inhalation powder stored for 0 days and 3 months.

[0181] Figure 6 The deposition amount of nintedanib at various levels of the compound inhalation powder prepared in Example 1 is shown. Figure 7 The deposition amount of Apremilast at each level of the compound inhalation powder prepared in Example 1 is shown. Figure 6 and Figure 7 It can be seen that the samples have good stability under accelerated conditions and no significant changes in in vitro distribution occur. It can be determined that the compound inhalation powder prepared by the present invention has good stability.

[0182] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A compound inhalation powder, characterized in that: It comprises Apremilast or a pharmaceutically acceptable salt thereof, and an efficacy enhancing substance, wherein the efficacy enhancing substance is Nintedanib or a pharmaceutically acceptable salt thereof; The dosage of the efficacy enhancing substance is 0.1-10 times the mass of the dosage of Apremilast or its pharmaceutically acceptable salt.

2. The compound inhalation powder as claimed in claim 1, characterized in that: The compound inhalation powder meets one or more of the following conditions: a. The use form of nintedanib is nintedanib free base; b. The pharmaceutically acceptable salt of nintedanib is nintedanib ethanesulfonate; c. The amount of the efficacy enhancing substance is 0.1-2 times the amount of Apremilast or a pharmaceutically acceptable salt thereof by mass, preferably 0.2-1 times, for example 0.1 times, 0.2 times, 0.8 times, 1 times or 2 times; d. The amount of Apremilast or a pharmaceutically acceptable salt thereof is 2wt%-80wt%, preferably 4.2wt%-30wt%, for example 2.5wt%, 4.2wt%, 5wt%, 5.5wt%, 15wt%, 25wt%, 30wt%, 40wt%, 50wt%, 54.5wt% or 79.2wt%, wherein the above percentages are the mass percentages of Apremilast or a pharmaceutically acceptable salt thereof in the compound inhalation powder; e. The amount of the efficacy enhancing substance is 0.5wt%-55wt%, preferably 0.8wt%, 2.5wt%, 5wt%, 5.5wt%, 10wt%, 12.5wt%, 15wt%, 15.8wt%, 30wt%, 40wt% or 54.5wt%, the above percentage is the mass percentage of the efficacy enhancing substance in the compound inhalation powder; f. The sum of the amounts of Apremilast or its pharmaceutically acceptable salt, and the efficacy enhancing substance is 5wt%-95wt%, preferably 5wt%-80wt%, more preferably 5wt%-60wt%, for example 5wt%, 15wt%, 20wt%, 27wt%, 27.5wt%, 28wt%, 30wt%, 60wt%, 80wt%, 90wt% or 95wt%, where the percentage is the sum of the amounts of Apremilast or its pharmaceutically acceptable salt, and the efficacy enhancing substance in the mass percentage of the compound inhalation powder; g. The compound inhalation powder further comprises an excipient; h. The preparation process of the compound inhalation powder is a spray drying process; i. The compound inhalation powder is used to prepare a drug for treating pulmonary fibrosis; the pulmonary fibrosis may be idiopathic pulmonary fibrosis.

3. The compound inhalation powder as claimed in claim 2, characterized in that: The compound inhalation powder meets one or more of the following conditions: a. The excipient is selected from one or more of an amino acid surface modifier, a phospholipid excipient, a carbohydrate excipient, a sugar alcohol excipient, a volatile salt excipient and an antistatic agent; preferably a mixture of an amino acid surface modifier and an antistatic agent, a mixture of an amino acid surface modifier, a phospholipid excipient and an antistatic agent, a mixture of an amino acid surface modifier, a carbohydrate excipient and an antistatic agent, a mixture of an amino acid surface modifier, a sugar alcohol excipient and an antistatic agent, a mixture of an amino acid surface modifier, a volatile salt excipient and an antistatic agent, or a mixture of an amino acid surface modifier, a sugar alcohol excipient, a volatile salt excipient and an antistatic agent; b. The amount of the excipient is 4wt%-95wt%, preferably 20wt%-95wt%, more preferably 39wt%-70wt%, for example 4.5wt%, 19.5wt%, 39wt%, 39.5wt%, 69.5wt%, 72wt%, 84.5wt%, 89.5wt% or 94.5wt%, wherein the above percentages are the mass percentages of the excipient in the compound inhalation powder.

4. The compound inhalation powder as claimed in claim 3, characterized in that: The compound inhalation powder meets one or more of the following conditions: a. The amino acid surface modifier is selected from one or more of leucine, isoleucine, dileucine, trileucine and glycine; the leucine is preferably L-leucine; b. The amino acid surface modifier is used in an amount of 1wt%-50wt%, preferably 29wt%-50wt%, for example 1.9wt%, 3.5wt%, 4.5wt%, 15wt%, 19.5wt%, 29.5wt%, 30wt%, 34.5wt%, 39.5wt% or 47.5wt%; c. The phospholipid excipient is selected from one or more of dipalmitoylphosphatidylcholine DPPC, distearoylphosphatidylcholine DSPC and lecithin; d. The amount of the phospholipid excipient is 0wt%-60wt%, preferably 0wt%-55wt%, for example 10wt%, 19.5wt%, 36wt%, 37.6wt%, 47wt%, 54.5wt% or 57wt%; e. The carbohydrate excipient is selected from trehalose; f. The sugar alcohol excipient is selected from mannitol; g. The carbohydrate excipient or the sugar alcohol excipient is used in an amount of 30wt%-40wt%, for example 30wt%, 35wt% or 39.5wt%; h. The volatile salt excipient is selected from ammonium carbonate and / or ammonium bicarbonate; i. The volatile salt excipient is used in an amount of 10wt%-50wt%, for example 10wt% or 47wt%; j. The static removing agent is selected from alkaline earth metal salts and / or alkali metal salts, preferably calcium chloride, sodium chloride, sodium citrate and sodium metaphosphate in one or more; k. The amount of the antistatic agent is 0.5wt%-4wt%, preferably 0.5wt%-1wt%, for example 0.5wt% or 1wt%; The above percentages are the mass percentages of each component in the compound inhalation powder.

5. The compound inhalation powder according to claim 3 or 4, characterized in that: The compound inhalation powder meets one or more of the following conditions: a. The excipient is a mixture of an amino acid surface modifier, a phospholipid excipient and an antistatic agent, and the mass ratio of the amino acid surface modifier to the phospholipid excipient is 1:(0-20), preferably 1:(0.3-10.3), for example 1:0.3, 1:1, 1:1.8, 1:3.6, 1:3.8, 1:10.3 or 1:19.8; b. The excipient is a mixture of an amino acid surface modifier, a carbohydrate excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier to the carbohydrate excipient is 1:(0-5), preferably 1:(0-3), for example 1:1; c. The excipient is a mixture of an amino acid surface modifier, a sugar alcohol excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier to the sugar alcohol excipient is 1:(0-5), preferably 1:(0-3), for example 1:1; d. The excipient is a mixture of an amino acid surface modifier, a volatile salt excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier to the volatile salt excipient is 1:(0-5), preferably 1:(0-3), for example 1:1; e. The excipient is a mixture of an amino acid surface modifier, a sugar alcohol excipient, a volatile salt excipient and an antistatic agent, wherein the mass ratio of the amino acid surface modifier to the sugar alcohol excipient is 1:(0-5), preferably 1:(0-3), for example 1:1; the mass ratio of the amino acid surface modifier to the volatile salt excipient is 1:(0-5), preferably 1:(0-3), for example 1:0.

3.

6. The compound inhalation powder as claimed in claim 5, characterized in that: The excipients are selected from any one of the following combinations: "leucine and calcium chloride", "isoleucine and calcium chloride", "leucine, dipalmitoylphosphatidylcholine DPPC and calcium chloride", "leucine, dipalmitoylphosphatidylcholine DPPC and sodium chloride", "leucine, trehalose and calcium chloride", "leucine, mannitol and calcium chloride", "leucine, ammonium carbonate and calcium chloride" or "leucine, mannitol, ammonium carbonate and calcium chloride".

7. The compound inhalation powder according to claim 1, characterized in that: The compound inhalation powder meets one or more of the following conditions: a. The geometric particle size D of the compound inhalation powder 50 1μm-5μm; b. The mass median aerodynamic diameter (MMAD) of the apremilast or a pharmaceutically acceptable salt thereof is 1 μm-5 μm; the mass median aerodynamic diameter (MMAD) of the nintedanib or a pharmaceutically acceptable salt thereof is 1 μm-5 μm.

8. A method for preparing the compound inhalation powder according to any one of claims 1 to 7, characterized in that: The method comprises the following steps: dissolving the apremilast or a pharmaceutically acceptable salt thereof and the efficacy enhancing substance in an organic phase or an aqueous phase respectively, mixing the aqueous phase with the organic phase to obtain a spray drying precursor solution; and obtaining a powder by spray drying; Preferably, the apremilast is dissolved in the organic phase, and the pharmaceutically acceptable salt of apremilast, the nintedanib or a pharmaceutically acceptable salt thereof is dissolved in the aqueous phase; the aqueous phase and the organic phase are mixed to obtain a spray drying precursor solution; and the powder is obtained by spray drying.

9. The method for preparing the compound inhalation powder as claimed in claim 8, characterized in that: The compound inhalation powder meets one or more of the following conditions: a. The organic phase is ethanol, or a mixture of ethanol and acetone; b. The organic phase further comprises the phospholipid excipient; c. The aqueous phase further comprises one or more of the carbohydrate excipient, the sugar alcohol excipient, the volatile salt excipient and the antistatic agent.

10. A compound inhalation powder inhalation preparation, which is prepared according to the preparation method of the compound inhalation powder inhalation preparation according to claim 8 or 9.

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