Compound inhalation powder and method for preparing the same

Abstract

The application discloses a compound inhalation powder aerosol and a preparation method thereof. The compound inhalation powder aerosol 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 amount of the efficacy enhancing substance is 0.1-10 times the amount of the apremilast or the pharmaceutically acceptable salt thereof. In the compound inhalation powder aerosol, the drug exposure of apremilast is greatly improved under the action of nintedanib, and a significant enhancement effect is exhibited. Meanwhile, nintedanib further improves efficacy. The powder aerosol is used for pulmonary inhalation administration, and apremilast or the pharmaceutically acceptable salt thereof and nintedanib or the pharmaceutically acceptable salt thereof are used for treating lung diseases, so that the drugs can be directly delivered to effective sites, the administration dose can be further effectively reduced or the drug utilization rate can be improved, the deposition rate can be improved, and the treatment effect can be greatly improved.

Description

Technical Field

[0001] This invention relates to a compound inhaled powder and its preparation method. Background Technology

[0002] Interstitial lung disease (ILD) is a large group of diseases characterized by interstitial lung inflammation and fibrosis, affecting alveolar epithelium, capillary endothelium, and surrounding tissues. When lung injury triggers an abnormal healing response, it can lead to progressive fibrotic interstitial lung disease (PF-ILD). PF-ILD is characterized by the self-maintenance and development of fibrosis, independent of initial triggering factors, and is usually accompanied by a progressive decline in lung function and a poor prognosis. Among these, idiopathic pulmonary fibrosis (IPF) is the most common diffuse pulmonary fibrosis disease. Its etiology remains unknown, its pathogenesis is unclear, and there are no effective treatments; the median survival is only 3-5 years.

[0003] Apemilast (molecular formula C) 22 H 24 N2O7S (CAS No. 608141-41-9), as a phosphodiesterase 4 (PDE4) inhibitor, reduces inflammatory responses by regulating the release of inflammatory mediators. Studies have shown that apremilast can intervene in fibroblast proliferation and its transformation into myofibroblasts, inhibiting the fibrotic process and potentially improving the treatment of fibrotic diseases, providing a new treatment option for IPF. However, the concentrations of apremilast in the lungs and plasma after intrapulmonary administration are generally low. Increasing these concentrations could further expand its clinical application, enhancing its effectiveness and acceptance.

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

[0005] The technical problem this invention aims to solve is to overcome the shortcomings of apremilast as a treatment for IPF, which results in low concentrations in the lungs and plasma after administration and room for improvement in therapeutic efficacy. This invention provides a compound inhaled powder and its preparation method. In the compound inhaled powder provided by this invention, the drug exposure of apremilast is greatly enhanced by nintedanib, exhibiting a significant enhancement effect. Simultaneously, nintedanib itself is also an active pharmaceutical ingredient for treating pulmonary fibrosis, which can further improve efficacy. This invention administers the drug to the lungs via inhalation in the form of a powder, and simultaneously uses apremilast or its pharmaceutically acceptable salts and nintedanib or its pharmaceutically acceptable salts together to treat lung diseases. This allows for direct drug delivery to the effective site, further effectively reducing the dosage or increasing drug utilization, improving deposition rate, and significantly enhancing therapeutic efficacy.

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

[0007] This invention provides a compound inhaled powder formulation comprising apremilast or a pharmaceutically acceptable salt thereof, and a efficacy-enhancing substance, wherein the efficacy-enhancing substance is nintedanib or a pharmaceutically acceptable salt thereof; the amount of the efficacy-enhancing substance is 0.1-10 times the mass of the apremilast or a pharmaceutically acceptable salt thereof.

[0008] In this invention, the nintedanib is generally used in the form of nintedanib free alkali.

[0009] In this invention, the pharmaceutically acceptable salt of nintedanib can be nintedanib ethanesulfonate. The English name for nintedanib is Nintedanib, and its molecular formula is C2. 31 H 33 N5O4, CAS number 656247-17-5; nintedanib esylate, molecular formula C 31 H 33 N5O4·C2H6O3S, CAS number 656247-18-6.

[0010] In this invention, the amount of the efficacy-enhancing substance may be 0.1-2 times the mass of the apremilast or its pharmaceutically acceptable salt, preferably 0.2-1 times, for example 0.1 times, 0.2 times, 0.8 times, 1 time or 2 times.

[0011] In this 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%, where the above percentages are the mass percentages of apremilast or its pharmaceutically acceptable salt in the compound inhalation powder.

[0012] In this invention, the amount 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%, where the above percentages are the mass percentages of the efficacy-enhancing substance in the compound inhaled powder.

[0013] In this invention, the sum of the amounts of apremilast or its pharmaceutically acceptable salts and the efficacy-enhancing substances can 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 salts and the efficacy-enhancing substances in the compound inhaled powder.

[0014] In this invention, the compound inhalation powder may also contain excipients.

[0015] The excipient may 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 may be selected from one or more of leucine, isoleucine, dileucine, trileucine, and glycine; the leucine is preferably L-leucine.

[0017] The amount of the amino acid surface modifier can be 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%.

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

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

[0020] The sugar excipient can be selected from trehalose.

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

[0022] The amount of the sugar excipient or the sugar alcohol excipient may be 30wt%-40wt%, for example 30wt%, 35wt% or 39.5wt%.

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

[0024] The amount of the volatile salt excipient can be 10wt%-50wt%, for example, 10wt% or 47wt%.

[0025] The antistatic agent 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 amount of the antistatic agent can be 0.5wt%-4wt%, preferably 0.5wt%-1wt, for example 0.5wt% or 1wt%.

[0027] The percentages mentioned above represent the percentage of each component by mass in the compound inhalation powder.

[0028] In some preferred embodiments, the excipient is a mixture of amino acid surface modifier, phospholipid excipient and antistatic agent, wherein 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 amino acid surface modifier, sugar excipient and antistatic agent, wherein the mass ratio of the amino acid surface modifier to the sugar excipient is 1:(0-5), preferably 1:(0-3), for example 1:1.

[0030] In some preferred embodiments, the excipient is a mixture of amino acid surface modifier, sugar alcohol excipient and 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.

[0031] In some preferred embodiments, the excipient is a mixture of amino acid surface modifier, volatile salt excipient and 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.

[0032] In some preferred embodiments, the excipient is a mixture of amino acid surface modifiers, sugar alcohol excipients, volatile salt excipients, and antistatic agents, 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 may be selected from any 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] 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%, where the above percentages are the mass percentage of the excipient in the compound inhalation powder.

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

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

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

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

[0039] The excipient comprises any one of the following:

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

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

[0042] c. A mixture of the amino acid surface modifier, the sugar excipient, and the antistatic agent, wherein the mass ratio of the amino acid surface modifier to the sugar excipient is 1:(0-3);

[0043] d. A mixture of the amino acid surface modifier, the sugar alcohol excipient, and the 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 contains an active ingredient, an excipient, and an antistatic agent;

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

[0046] The excipient comprises any one of the following:

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

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

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

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

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

[0052] In one specific embodiment, the compound inhalation powder is composed of 15 wt% aprestinum, 12.5 wt% nintedanib free base, 15 wt% leucine, 57 wt% DPPC and 0.5 wt% calcium chloride.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0068] The capsule may be made of gelatin or hydroxypropyl methylcellulose (HPMC).

[0069] The capsules can be selected from capsules No. 0, No. 1, No. 2, No. 3 or No. 4.

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

[0071] In this invention, the mass median aerodynamic diameter (MMAD) of the apremilast or its pharmaceutically acceptable salt can 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... Pharmaceutically acceptable salts have a mass median aerodynamic diameter (MMAD) of 1 μm to 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] This invention provides a method for preparing the above-mentioned compound inhalation powder, which includes the following steps: dissolving the apremilast or its pharmaceutically acceptable salt and the efficacy-enhancing substance in an organic phase or an aqueous phase respectively; mixing the aqueous phase and the organic phase to obtain a spray-drying precursor liquid; and obtaining the powder by spray drying.

[0073] In this invention, the apremilast or its pharmaceutically acceptable salt, as well as the efficacy-enhancing substance, are dissolved in the organic phase or the aqueous phase, respectively. Those skilled in the art will know that the substances to be dissolved can be selectively dissolved in the organic phase or the aqueous phase, respectively, based on their solubility.

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

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

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

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

[0078] In this invention, spray drying is a drying technology that transforms liquid materials into powder or granular solids by atomizing them into fine droplets and rapidly drying them in a hot air stream. The process typically includes the following steps: Atomization: The liquid material is atomized into fine droplets using an atomizer (such as a pressure, centrifugal, or airflow atomizer). Drying: The atomized droplets rapidly evaporate moisture in the hot air stream, forming dried powder or granules. Collection: The dried powder or granules are collected using equipment such as a cyclone separator or a bag filter. In this invention, the spray drying can employ conventional spray drying parameters, or, as those skilled in the art know, the raw materials can be dissolved or suspended for spray drying to obtain the final product. The inlet air temperature for spray drying can be 90-150℃, preferably 110-125℃, for example, 110℃, 120℃, or 125℃. The outlet air temperature of the spray dryer can be 40-80℃, preferably 50-60℃, such as 51℃, 55℃, 56℃, 57℃, 58℃, 59℃ or 60℃.

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

[0080] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0081] The reagents and raw materials used in this invention are all commercially available.

[0082] The positive and progressive effects of this invention are as follows:

[0083] 1. The compound inhaled powder provided by this invention significantly enhances the drug exposure of apremilast under the action of nintedanib, demonstrating a remarkable enhancement effect; at the same time, nintedanib itself is also an active pharmaceutical ingredient for treating pulmonary fibrosis, which can further improve efficacy.

[0084] Meanwhile, in cell experiments, the combined administration showed a more significant inhibitory effect on fibrosis-related RNA in human pulmonary fibrosis cells compared to the positive control group, the control group using apremilast alone, and the control group using nintedanib alone.

[0085] 2. The compound inhaled powder provided by this invention can maintain the fine particle fraction (FPF) within a good range, with the preferred FPF value reaching 70%-95%. When administered via inhalation in the form of a powder, it combines apremilast or its pharmaceutically acceptable salts with nintedanib or its pharmaceutically acceptable salts for the treatment of lung diseases. This allows for direct delivery of the drug to the effective site, further reducing the dosage or increasing drug utilization, improving deposition rate, and significantly enhancing therapeutic efficacy. Attached Figure Description

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

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

[0088] Figure 3 XRD characterization images of the API, blank formulation, and compound inhalation powder prepared in Example 5 at 0 days and after 1 minute acceleration.

[0089] Figure 4 The image shows the scanning electron microscope (SEM) characterization 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 The APSD distribution of nintedanib ethsulfate in the compound inhalation powder prepared in Example 1 at 0 days and after accelerated 3M is shown in the figure.

[0092] Figure 7 The APSD distribution of the compound inhalation powder prepared in Example 1 at 0 days and after 3M acceleration is shown in the figure. Detailed Implementation

[0093] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0094] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and the terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0095] The terms "comprising," "including," and "having," and any variations thereof, are intended to cover non-exclusive inclusion. "A plurality of" as used herein refers to two or more. "And / or" describes the relationship between related 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 each component in the total amount of the compound inhalation powder.

[0098] Example 1: 15 wt% of apremilast and 54.5 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 15 wt% of nintedanib ethanesulfonate, 15 wt% of leucine, and 0.5 wt% of calcium chloride were dissolved in water to prepare an aqueous phase; the aqueous phase was added to the organic phase under stirring and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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: 15 wt% of apremilast and 57 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 12.5 wt% of nintedanib free base (this is the pharmaceutical presentation of nintedanib as the active ingredient, as known to those skilled in the art), 15 wt% of leucine, and 0.5 wt% of calcium chloride were dissolved in water to prepare an aqueous phase; under stirring conditions, the aqueous phase was slowly added to the organic phase and mixed to obtain a spray-drying precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder, obtaining 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: 5 wt% of apremilast and 54.5 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 10 wt% of nintedanib ethanesulfonate, 30 wt% of leucine, and 0.5 wt% of calcium chloride were dissolved in water to prepare an aqueous phase; the aqueous phase was added to the organic phase under stirring and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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: 54.5 wt% of apremilast and 36 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 5.5 wt% of nintedanib ethanesulfonate, 3.5 wt% of leucine, and 0.5 wt% of calcium chloride were dissolved in water to prepare an aqueous phase; the aqueous phase was added to the organic phase under stirring and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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: 54.5 wt% of apremilast and 19.5 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 5.5 wt% of nintedanib ethanesulfonate, 19.5 wt% of leucine, and 1 wt% of sodium chloride were dissolved in water to prepare an aqueous phase; the aqueous phase was added to the organic phase under stirring and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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 prepare 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 prepare an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, obtaining 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: An organic phase was prepared by dissolving 50 wt% apremilast and 10 wt% DPPC in an ethanol solution; an aqueous phase was prepared by dissolving 10 wt% nintedanib ethanesulfonate, 29.5 wt% leucine, and 0.5 wt% calcium chloride in water; the aqueous phase was then added to the organic phase under stirring to obtain a spray-drying precursor solution. The precursor solution was spray-dried using a spray dryer to prepare a powder, resulting in 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 prepare 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 prepare an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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 prepare 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 prepare an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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 prepare 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 prepare an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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 prepare 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 prepare an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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: 2.5 wt% of apremilast and 47 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 2.5 wt% of nintedanib ethanesulfonate, 47.5 wt% of leucine, and 0.5 wt% of calcium chloride were dissolved in water to prepare an aqueous phase; under stirring conditions, the aqueous phase was added to the organic phase and mixed to obtain a spray-drying precursor liquid. The precursor liquid was spray-dried using a spray dryer to prepare a powder, thus obtaining 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 prepare 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 prepare an aqueous phase; the aqueous phase was added to the organic phase under stirring and mixed to obtain a spray-drying precursor solution. The precursor solution was spray-dried to prepare powder. The spray-drying conditions were an inlet air temperature of 120°C and an outlet air temperature of 55°C.

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

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

[0113] Example 16: An organic phase was prepared by dissolving 54.5 wt% of apremilast and 37.6 wt% of DPPC in an ethanol solution; an aqueous phase was prepared by dissolving 5.5 wt% of nintedanib ethanesulfonate, 1.9 wt% of leucine, and 0.5 wt% of calcium chloride in water; the aqueous phase was then added to the organic phase under stirring to obtain a spray-drying precursor solution. The precursor solution was spray-dried to prepare 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: 5 wt% of apremilast and 60.75 wt% of DPPC were dissolved in an ethanol solution to prepare an organic phase; 33.75 wt% of leucine and 0.5 wt% of calcium chloride were dissolved in water to prepare an aqueous phase; the aqueous phase was added to the organic phase under stirring and mixed to obtain a spray-drying precursor solution. The precursor solution was spray-dried to prepare powder. The spray-drying conditions were an inlet air temperature of 120℃ and an outlet air temperature of 55℃.

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

[0116] 10 mg of the powder prepared in Examples 1-16 and Comparative Examples 1-2 was filled into a hydroxypropyl methylcellulose (HPMC) empty capsule to prepare an inhalation powder.

[0117] Example 1: Cellular Experimental Drug Efficacy Detection

[0118] Comparison of intrapulmonary and plasma exposures of apremilast, nintedanib, and combination intratracheal administration in rats

[0119] 1. Experimental animals: 27 SD rats. Animals were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd., Laboratory Animal Use License No.: 20241119Aa220619000995.

[0120] 2. Animal drug administration grouping: 27 SD rats were randomly divided into 3 groups of 9 each. Each group was administered apremilast (using the inhaled powder prepared in Comparative Example 1), nintedanib (using the inhaled powder prepared in Comparative Example 2), and a combination of apremilast and nintedanib (using the inhaled powder prepared in Example 3) via the airway. Blood and lung samples were collected at 5 min, 1 h, and 4 h after drug administration for analysis, and the results were detected by HPLC-MS.

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

[0122] Table 1. Concentrations of Apstar monotherapy or combination therapy in rat lungs and plasma.

[0123]

[0124] Table 2. Concentrations of nintedanib in rat lungs and plasma after administration of nintedanib alone or in combination.

[0125]

[0126] As shown in Table 1, apremilast monotherapy was rapidly absorbed after intratracheal administration, with the highest concentration detected 5 minutes after administration. The pulmonary concentration of apremilast and nintedanib combination was higher than that of apremilast monotherapy, with exposure increasing by 30%-236%. The plasma exposure of apremilast monotherapy and the combination was similar.

[0127] As can be seen from Table 2, when nintedanib is administered alone in the airway, it is absorbed rapidly, with a higher pulmonary exposure and a longer exposure time than apremilast. When nintedanib is administered alone, or in combination with apremilast or nintedanib, the pulmonary and plasma exposures are similar.

[0128] This confirms that the drug exposure of apremilast is greatly enhanced by nintedanib, demonstrating a significant enhancing effect.

[0129] Example 2: Cellular Experimental Drug Efficacy Detection

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

[0131] Detection method: Human lung fibrosis cells were seeded in 6-well plates, with 5 × 10⁶ cells per well. 5 Cells were cultured for 24 hours. 50 ng / mL of recombinant Transforming Growth Factor β1 (TGFβ1) protein was added, followed by the addition of 1 μM apremilast solution (A), 0.1 μM nintedanib ethanesulfonate solution (B), and 1 μM apremilast solution and 0.1 μM nintedanib solution, respectively. After washing the cells three times with pre-cooled phosphate-buffered saline (PBS), 1 mL of Trizol was added to each cell. Intracellular ribonucleic acid (RNA) was extracted, dissolved in 50 μL of diethyl pyrocarbonate (DEPC) water, and the concentration was detected using nanodrop. The results were then analyzed using a quantitative PCR (qPCR) system. Data collected by the instrument were analyzed.

[0132] Test results are as follows Figure 1 As shown in the figure, A represents 1 μM apremilast solution and B represents 0.1 μM nintedanib solution. The figure reveals that TGFβ1 induces fibrosis in human cells, promoting cellular fibrosis and increasing the RNA expression of pulmonary fibrosis-related proteins such as α-SMA, fibronectin, and collagen I. After adding apremilast solution, nintedanib solution, and a mixture of apremilast and nintedanib, the results showed that apremilast or nintedanib alone did not significantly inhibit the RNA expression of α-SMA and collagen I. However, combined incubation with both significantly inhibited the RNA expression of these two proteins, demonstrating a synergistic effect. Apremilast solution, nintedanib solution, and the mixture of apremilast and nintedanib all significantly inhibited fibronectin RNA expression, with the mixture of apremilast and nintedanib showing the best inhibitory effect.

[0133] Example 3: XRD and SEM characterization

[0134] The API, blank formulation, and the compound inhalation powder prepared in Example 4, as well as the API, blank formulation, and the compound inhalation powder prepared in Example 5, were characterized by XRD, and the results are as follows. Figure 2 and Figure 3 As shown. Among them, the API is a mixture of 50 wt% apremilast and 50 wt% nintedanib, the blank formulation is a mixture of 50 wt% leucine and 50 wt% DPPC, and the accelerated 1M is the 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 As can be seen, API exists in an amorphous form; the blank formulation shows characteristic peaks of DPPC and leucine; the drug-containing formulations (Examples 4 and 5) mainly show excipient peaks; under accelerated conditions, the drug-containing formulations did not undergo crystallization. It can be seen that API can still maintain an amorphous state under high temperature and high humidity conditions, and has good stability.

[0136] The compound inhalation powder prepared in Examples 7 and 14 were characterized by SEM, and the results are as follows: Figures 4-5 As shown.

[0137] from Figures 4-5 As can be seen, in Example 7, a mixture of leucine and DPPC was used as an excipient, and the resulting drug particles were mainly hollow and wrinkled. In Example 14, only DPPC was used as an excipient, without the addition of leucine, and the resulting drug particles had a smoother surface.

[0138] Example 4: In vitro experimental testing

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

[0140] 1. Particle size determination

[0141] Geometric particle size distribution determination method - laser particle size analysis: dispersion pressure 3.0 bar, feed rate 65%, each sample was measured twice in parallel. The test results are summarized in Table 4.

[0142] 2. Aerodynamic particle size distribution (APSD) determination

[0143] Aerodynamic particle size distribution was determined using the Andersen cascade impactor (ACI):

[0144] (1) ACI installation

[0145] S1. Place suitable filter paper (81 mm in diameter, 1 μm in pore size) into the F stage of ACI and press it into the sealing ring to seal. Then, according to the required flow rate, install the corresponding stages from bottom to top, and then connect the pre-separator, fixing it with three spring clips. Finally, connect the L-shaped connecting tube to ensure the system's airtightness. For each collection tray, drop 1-2 drops of coating solution onto its surface and spread it evenly with a silicone spatula. Add 10 mL of receiving solution 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 airtightness, turn on the vacuum pump, adjust the flow rate to reach the required flow rate Q=60L / min, and then remove the flow meter.

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

[0148] S4. Set the number of particles to be aspirated in the experiment (1 particle) and the aspiration time for each aspiration (4S) on the flow controller. Wait 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, drug delivery device, L-shaped connecting tube, pre-separator, staged plate and collection plate, and filter paper were sequentially washed into volumetric flasks of appropriate volume, diluted to the appropriate factor, and filtered before injection. The test results are summarized in Table 4.

[0151] 3. Determination of active ingredient content

[0152] The content was determined according to high performance liquid chromatography (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020 Edition):

[0153] (1) Sample processing

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

[0155] Reference solution: Weigh approximately 20 mg each of apremilast and nintedanib reference standards, place them in a 100 mL volumetric flask, add 4 mL of acetonitrile and sonicate to dissolve, add 6 mL of water, dilute to the mark with solvent, and then measure 5.0 mL into a 100 mL volumetric flask and dilute to the mark with solvent to prepare a solution containing approximately 0.01 mg apremilast and 0.01 mg nintedanib per mL.

[0156] (2) Chromatographic conditions

[0157] The column was packed with octadecylsilane-bonded silica gel (Agilent ZOBAX SB-C18, 4.6 mm × 150 mm, 3.5 μm or equivalent performance column); mobile phase A was 0.1% trifluoroacetic acid solution (1 mL of trifluoroacetic acid diluted with water to 1000 mL), and mobile phase B was acetonitrile; gradient elution was performed according to Table 3, with a flow rate of 1.0 mL per minute; column temperature was 35 °C; detection wavelengths were 230 nm (for detecting apromisc) and 390 nm (for detecting nintedanib); 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 factor of the two main peaks of Apmisate and Nintanib is not greater than 1.5, and the theoretical plate number is not less than 3000.

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

[0162] 4. Fine particle dosimetry

[0163] The following measurements were taken according to the method for determining the aerodynamic properties of fine particles in inhaled preparations (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0951, Apparatus 2):

[0164] Solvent: Methanol-Water (70:30)

[0165] Test solution: Connect the device (leakage detection is required before use). Before use, evenly coat the pre-separator base and the collection plates of stages -1 to F with a film-coating agent. Add an appropriate solvent to the pre-separator. Adjust the flow rate to 60 L / min. Take one capsule of this product and place it in the inhalation device. After destaticating the capsule and inhalation device, press the button on the device with your finger to puncture both sides of the capsule. Connect the adapter, turn on the vacuum pump, evacuate for 4 seconds, turn off the pump, and wait for 5 seconds. Disassemble the device, carefully remove the filter paper, and clean the nozzle adapter, L-shaped connecting tube, and pre-separator with solvent. Dilute quantitatively to an appropriate volume. Quantitatively extract the drug from the inner wall of each stage and the corresponding collection plate or filter paper, and dilute quantitatively to a certain volume.

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

[0167] The inhaled powder samples prepared in Examples 1-16 and Comparative Examples 1-2 were characterized and evaluated according to the test methods described above. The test results are summarized in Table 4.

[0168] Table 4 In vitro experimental test results

[0169]

[0170] Note: *D 50 It is the geometric particle size measured using laser particle size distribution method, with a cumulative particle size distribution percentage reaching 50%.

[0171] As shown in Table 4:

[0172] (1) Based on the comparison between Example 1 and Example 2, it can be seen that good in vitro drug deposition rate performance can be achieved by using nintedanib or a pharmaceutically acceptable salt of nintedanib.

[0173] (2) According to the comparison between Example 1 and Example 3, when the ratio of nintedanib and apremilast is increased, the in vitro drug deposition rate 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 an antistatic agent can achieve good in vitro drug deposition rate performance.

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

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

[0177] (6) According to the comparison of Examples 4, 14 and 15, if the excipient does not contain amino acid surface modifiers and only contains phospholipid excipients or sugar alcohol excipients, the in vitro drug deposition rate performance is reduced.

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

[0179] Example 5: Stability Test

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

[0181] Figure 6 The deposition amount of nintedanib in each stage of the compound inhalation powder prepared in Example 1 is shown. Figure 7 The deposition rates of the compound inhalation powder prepared in Example 1 are shown at various levels of Aprepitant deposition. From Figure 6 and Figure 7 As can be seen from the results, the samples exhibit good stability under accelerated conditions, and their in vitro distribution did not change significantly. Therefore, it can be determined that the compound inhalation powder prepared in this invention has superior stability.

[0182] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A compound inhalation powder, characterized in that, It contains apremilast or a pharmaceutically acceptable salt thereof, a potency enhancer, and an excipient, wherein the potency enhancer is nintedanib or a pharmaceutically acceptable salt thereof; The amount of the efficacy-enhancing substance is 0.1-2 times the mass of the apremilast or its pharmaceutically acceptable salt; the amount of the apremilast or its pharmaceutically acceptable salt is 2wt%-80wt%, and the amount of the efficacy-enhancing substance is 0.5wt%-55wt%. The excipient is a mixture of an amino acid surface modifier, a phospholipid excipient, and an antistatic agent, wherein the amino acid surface modifier is leucine, the phospholipid excipient is dipalmitoylphosphatidylcholine (DPPC), the mass ratio of the amino acid surface modifier to the phospholipid excipient is 1:(0.3-10.3), the amount of the amino acid surface modifier is 1wt%-50wt%, and the amount of the phospholipid excipient is 10wt%-60wt%. The antistatic agent is calcium chloride or sodium chloride, and the amount of the antistatic agent used is 0.5wt%-4wt%. The percentages mentioned above represent the percentage of each component by mass in the compound inhalation powder.

2. The compound inhalation powder as described in claim 1, characterized in that, The compound inhalation powder meets one or more of the following conditions: a. The nintedanib is used in the form of nintedanib free alkali; b. The pharmaceutically acceptable salt of nintedanib is nintedanib ethanesulfonate; c. The sum of the amounts of the apremilast or its pharmaceutically acceptable salts and the efficacy-enhancing substances is 5wt%-95wt%, where the percentage is the sum of the amounts of the apremilast or its pharmaceutically acceptable salts and the efficacy-enhancing substances as a percentage of the mass of the compound inhaled powder. d. The preparation process of the compound inhalation powder is a spray drying process; e. The compound inhaled powder is used to prepare a drug for treating pulmonary fibrosis.

3. The compound inhalation powder as described in claim 2, characterized in that, The compound inhalation powder meets one or more of the following conditions: a. The amount of the efficacy-enhancing substance is 0.2-1 times the mass of the apremilast or its pharmaceutically acceptable salt; b. The amount of the apremilast or its pharmaceutically acceptable salt used is 4.2 wt% to 30 wt%; c. The amount of the efficacy-enhancing substance is 0.8wt%, 2.5wt%, 5wt%, 5.5wt%, 10wt%, 12.5wt%, 15wt%, 15.8wt%, 30wt%, 40wt%, or 54.5wt%; d. The sum of the amounts of the apremilast or its pharmaceutically acceptable salt and the efficacy-enhancing substance is 5wt%-80wt%; e. The pulmonary fibrosis mentioned is idiopathic pulmonary fibrosis.

4. The compound inhalation powder as described in claim 2, characterized in that, The compound inhalation powder meets one or more of the following conditions: a. The amount of the efficacy-enhancing substance is 0.1 times, 0.2 times, 0.8 times, 1 time, or 2 times the mass of the apremilast or its pharmaceutically acceptable salt; b. The amount of the apremilast or its pharmaceutically acceptable salt is 2.5 wt%, 4.2 wt%, 5 wt%, 5.5 wt%, 15 wt%, 25 wt%, 30 wt%, 40 wt%, 50 wt%, 54.5 wt%, or 79.2 wt%; c. The sum of the amounts of the apremilast or its pharmaceutically acceptable salt and the efficacy-enhancing substance is 5wt%-60wt%.

5. The compound inhalation powder as described in claim 2, characterized in that, The sum of the amounts of the apremilast or its pharmaceutically acceptable salt and the efficacy-enhancing substance is 5 wt%, 15 wt%, 20 wt%, 27 wt%, 27.5 wt%, 28 wt%, 30 wt%, 60 wt%, 80 wt%, 90 wt%, or 95 wt%.

6. The compound inhalation powder as described in claim 2, characterized in that, The amount of excipients in the compound inhalation powder is 4wt%-95wt%, where the above percentages are the mass percentages of the excipients in the compound inhalation powder.

7. The compound inhalation powder as described in claim 6, characterized in that, In the compound inhalation powder, the amount of excipient is 20wt%-95wt%.

8. The compound inhalation powder as described in claim 7, characterized in that, The amount of the excipient is 39wt%-70wt%.

9. The compound inhalation powder as described in claim 6, characterized in that, The excipients are used in amounts of 4.5 wt%, 19.5 wt%, 39 wt%, 39.5 wt%, 69.5 wt%, 72 wt%, 84.5 wt%, 89.5 wt%, or 94.5 wt%.

10. The compound inhalation powder as described in claim 6, characterized in that, In the compound inhalation powder, the amount of the phospholipid excipient is 10wt%, 19.5wt%, 36wt%, 37.6wt%, 47wt%, 54.5wt%, or 57wt%. The percentages mentioned above represent the percentage of each component by mass in the compound inhalation powder.

11. The compound inhalation powder as described in claim 10, characterized in that, The compound inhalation powder meets one or more of the following conditions: a. The leucine in question is L-leucine; b. The amount of the amino acid-based surface modifier used is 29wt%-50wt%; c. The amount of the antistatic agent used is 0.5wt%-1wt%.

12. The compound inhalation powder as described in claim 10, characterized in that, The compound inhalation powder meets one or more of the following conditions: a. The amount of the amino acid-based surface modifier is 1.9wt%, 3.5wt%, 4.5wt%, 15wt%, 19.5wt%, 29.5wt%, 30wt%, 34.5wt%, 39.5wt%, or 47.5wt%; b. The amount of the antistatic agent is 0.5 wt% or 1 wt%.

13. The compound inhalation powder as described in claim 1, characterized in that, In the compound inhalation powder, the mass ratio of the amino acid surface modifier to the phospholipid excipient is 1:0.3, 1:1, 1:1.8, 1:3.6, 1:3.8 or 1:10.

3.

14. The compound inhalation powder as described in claim 1, characterized in that, The compound inhalation powder meets one or more of the following conditions: a. The geometric particle size D50 of the compound inhalation powder is 1μm-5μm; b. The median mass aerodynamic diameter (MMAD) of the apremilast or its pharmaceutically acceptable salt is 1 μm-5 μm; the median mass aerodynamic diameter (MMAD) of the nintedanib or its pharmaceutically acceptable salt is 1 μm-5 μm.

15. A method for preparing a compound inhalation powder as described in any one of claims 1-14, characterized in that, It includes the following steps: dissolving the apremilast or its pharmaceutically acceptable salt, the efficacy enhancer and the excipient in an organic phase or an aqueous phase respectively; mixing the aqueous phase and the organic phase to obtain a spray-drying precursor solution; and obtaining a powder by spray drying.

16. The method for preparing the compound inhalation powder as described in claim 15, characterized in that, The apremilast is dissolved in the organic phase, and a pharmaceutically acceptable salt of the 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 a powder is obtained by spray drying.

17. The method for preparing the compound inhalation powder as described in claim 15, characterized in that, The preparation method satisfies 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 also contains the antistatic agent.

18. A compound inhaled powder, prepared by any one of claims 15-17.

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