Apremilast inhalation powder and its preparation method and application

Abstract

The invention discloses an apremilast inhalation powder and its preparation method and application, wherein the apremilast inhalation powder comprises an active ingredient and an excipient; the active ingredient is apremilast and / or its salt; the excipient comprises an amino acid surface modifier, a phospholipid excipient, a mixture of an amino acid surface modifier and a phospholipid excipient, a mixture of an amino acid surface modifier and a saccharide excipient, or a mixture of an amino acid surface modifier and a sugar alcohol excipient; and the preparation process of the apremilast inhalation powder is a spray drying process. The apremilast inhalation powder prepared by the invention is used for pulmonary administration, and is to administer apremilast in the form of a powder, and is also to use apremilast for the treatment of pulmonary diseases, and can directly deliver the drug to the effective part, effectively reduce the dosage, increase the deposition rate, reduce the systemic exposure and toxicity, and greatly improve the therapeutic effect.

Description

Technical Field

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

[0002] Pulmonary fibrosis is the final stage of a variety of interstitial lung diseases, characterized by the destruction of lung parenchyma and the deposition of extracellular matrix in the lung interstitium and alveolar cavity. This disease was once considered a chronic inflammatory process, but current evidence shows that the fibrotic reaction is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that stimulate the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, the attraction of circulating fibrocytes, and the transition of epithelial cells to mesenchymal cells. Fibroblast and myofibroblast foci secrete excessive extracellular matrix, mainly collagen, leading to scarring and destruction of lung structure. Idiopathic pulmonary fibrosis (IPF) is the most common diffuse pulmonary fibrosis disease. To date, the cause and pathogenesis are unclear, and there is a lack of effective treatment. The median survival period is only 3-5 years.

[0003] Currently, there are only two drugs on the market for this disease, namely Roche's pirfenidone and Boehringer Ingelheim's nintedanib, but neither can effectively improve the survival of patients, the cost of treatment is high, and the clinical needs are far from being met. Therefore, it is of great market value and medical value to clarify the occurrence and development mechanism of pulmonary fibrosis, explore new potential drug targets, and develop drugs with confirmed efficacy, relatively safe, and reasonably priced for pulmonary fibrosis.

[0004] Apremilast (CAS No.: 608141-41-9, molecular formula: C 22 H 24 N2O7S) is an oral selective phosphodiesterase 4 (PDE4) inhibitor originally developed by Celgene. Currently, the globally approved indications include: patients with plaque psoriasis, Behcet's syndrome, oral ulcers, psoriatic arthritis, and psoriasis. In addition, other therapeutic areas include: juvenile rheumatoid arthritis, viral infections, ankylosing spondylitis, aggregated acne, lichen planus, gynecological diseases, dermatomyositis, pruritus, alcoholism, dermatitis, eczema, vitiligo, ulcerative colitis, atopic dermatitis, oral lichen planus, uveitis, rheumatoid arthritis, gout, acne vulgaris, suppurative hidradenitis, prurigo, osteoarthritis, sarcoidosis, non-radiographic axial spondyloarthritis, vulvar pain, prostatitis, discoid lupus erythematosus, allergic contact dermatitis, etc.

[0005] The patents for the pharmaceutical compositions of Apremilast include oral preparations (WO2023089101A1, WO2019073331A2 (A3), WO2022075760A1, WO2019116386A1), oral delayed-release / specific site-release preparations (WO2019073477A1, CA3008471A1, etc.), and topical preparations (WO2021090301A1, CA3130882A1, WO2017216738A1, WO2020058992A1, etc.). Summary of the invention

[0006] The present invention overcomes the technical problem that there is no apremilast inhalation powder in the prior art, and there is no method of directly delivering the powder to the lungs for treating lung diseases, and provides an apremilast inhalation powder and a preparation method and application thereof. The apremilast inhalation powder has the advantages of being able to directly deliver the drug to the lungs and achieving a higher deposition rate in the lungs.

[0007] Inhalation preparations refer to liquid or solid preparations in which the raw drug is dissolved or dispersed in a suitable medium and delivered to the lungs in the form of aerosol or vapor to exert local or systemic effects. The inventor focused on studying inhalation powders prepared by different processes, such as spray drying processes, and explored inhalation powders with different preparation effects through prescriptions and processes. The pulmonary administration effects of the prepared drugs are not consistent and vary greatly. Through experimental studies, it is found that the preparations of the present invention and their preparation schemes have very good effects. The Apremilast inhalation powder of the present invention has the advantage of being able to directly deliver drugs to the lungs and achieve a higher deposition rate in the lungs. It is the first successful administration of Apremilast in the form of a powder for the treatment of lung diseases, which can achieve the purpose of directly delivering drugs to the effective site, effectively reducing the dosage, and increasing the deposition rate, thereby greatly improving the therapeutic effect.

[0008] The present invention is achieved through the following technical solutions.

[0009] In a first aspect, the present invention provides an apremilast inhalation powder, which comprises an active ingredient and an excipient; the active ingredient is apremilast and / or its salt; the excipient comprises any one of the following: an amino acid surface modifier, less than 50% of a phospholipid excipient, a mixture of an amino acid surface modifier and a phospholipid excipient, a mixture of an amino acid surface modifier and a sugar excipient, or a mixture of an amino acid surface modifier and a sugar alcohol excipient; the preparation process of the apremilast inhalation powder is a spray drying process, and the percentage is the mass percentage of each component in the apremilast inhalation powder.

[0010] In the present invention, the amino acid surface modifier is a pharmaceutical excipient in the art, and can be one or more of leucine, isoleucine, dileucine, trileucine, and glycine.

[0011] Wherein, the leucine can be L-leucine or D-leucine; further, it can be the natural amino acid L-leucine.

[0012] In the present invention, the selected amino acid surface modifier tends to occupy the surface of the droplets during spray drying, precipitate into shells, or form large and hollow particles, or form wrinkled particles, or form spherical particles with smooth surfaces, etc. Such particles generally reduce the aerodynamic particle size and improve the in vitro dispersion performance.

[0013] In the present invention, the phospholipid excipient is a pharmaceutical excipient in the art, and can be one or more of dipalmitoylphosphatidylcholine DPPC, distearoylphosphatidylcholine DSPC and lecithin.

[0014] In the present invention, the carbohydrate excipient is a pharmaceutical excipient in the art, and may be trehalose.

[0015] In the present invention, the sugar alcohol excipient is a pharmaceutical excipient in the art, and may be mannitol.

[0016] In the present invention, the sugar excipient and the sugar alcohol excipient can increase the wettability of the particles; trehalose itself has a high glass transition temperature (110-120° C.), and spray drying together with the drug can improve the powder properties.

[0017] In the present invention, the apremilast inhalation powder can also include an antistatic agent; the antistatic agent is a pharmaceutical excipient in the art, and can further be an alkaline earth metal salt and / or an alkali metal salt, specifically a divalent alkaline earth metal ion (such as calcium, magnesium) or a monovalent alkali metal salt, for example, one or more of calcium chloride, sodium chloride, sodium citrate and sodium metaphosphate. Generally speaking, it is used in combination with long-chain phospholipids, and the antistatic agent reduces the hydration of the head group, thereby increasing the phospholipid gel-liquid crystal phase transition and the wettability of the powder on the lung lining fluid, and the sodium salt can reduce the local static electricity on the particle surface, reduce the agglomeration of particles, improve the in vitro dispersion and process, and increase the spray-dried powder yield.

[0018] In the present invention, the excipient may further include one or more volatile salt excipients.

[0019] In the present invention, the volatile salt excipient is a pharmaceutical excipient in the art, which may be ammonium carbonate and / or ammonium bicarbonate. It can make the powder aerosol pore-forming, and may also be called a pore-forming agent. It may be used alone with the active ingredient, or in combination with an amino acid surface modifier, etc. The particles prepared using the volatile salt excipient are porous, have the characteristics of low density and large specific surface area, can improve the porosity, significantly increase the specific surface area of ​​the carrier particles, and improve the effective deposition rate of the drug in the inhaled powder aerosol.

[0020] In the present invention, the excipient can be any one of the following combinations: leucine, "leucine and calcium chloride", "leucine and sodium chloride", "leucine, trehalose and calcium chloride", "leucine, mannitol and calcium chloride", or "leucine, dipalmitoylphosphatidylcholine DPPC and calcium chloride".

[0021] In the present invention, the amount of the active ingredient can be 5wt%-95wt%, further can be 15wt%-80wt%, further can be 35wt%-65wt%, for example, 5wt%, 15wt%, 20wt%, 30wt%, 35wt%, 65wt%, 80wt%, 90wt%, or 95wt%.

[0022] In the present invention, the amount of the excipient can be 5wt%-95wt%, further can be 20wt%-85wt%, and further can be 35wt%-65wt%; for example, 2.5wt%, 5.9wt%, 10wt%, 17wt%, 17.5wt%, 18.4wt%, 29.5wt%, 32.25wt%, 42wt%, 59.5wt%, 64.5wt%, or 94.5wt%.

[0023] In the present invention, the amount of the amino acid surface modifier can be 5wt%-95wt%, further can be 20wt%-85wt%, and further can be 35wt%-65wt%, for example, 2.5wt%, 5.9wt%, 10wt%, 17wt%, 17.5wt%, 18.4wt%, 29.5wt%, 32.25wt%, 42wt%, 59.5wt%, 64.5wt%, or 94.5wt%; the amount of the carbohydrate excipient and / or sugar alcohol excipient can be 2wt%-42.5wt%, for example, 2wt%, 9.5wt%, 17wt%, 35wt%, or 42.5wt%.

[0024] In the present invention, in the mixture of the amino acid surface modifier and the phospholipid excipient, the amount of the phospholipid excipient can be within 90wt%, further can be 25wt%-60wt%, further can be 25wt%-45wt%; for example, 25wt%, 32.25wt%, 58.6wt%, or 46.1wt%.

[0025] In the present invention, the amount of the phospholipid excipient within 50wt% may be 2.5wt%-50wt%, and further may be 2.5wt%-50wt%, for example, 9.5wt% dipalmitoylphosphatidylcholine DPPC.

[0026] In the present invention, the amount of the antistatic agent can be 0.5wt%-4wt%; for example, 0.5wt% calcium chloride, or 1wt% sodium chloride.

[0027] In some specific embodiments, the excipient is any one of the following combinations: "94.5wt% leucine and 0.5wt% calcium chloride", "64.5wt% leucine and 0.5wt% calcium chloride", "10wt% leucine, 9.5wt% trehalose and 0.5wt% calcium chloride", "17wt% leucine, 17wt% trehalose and 1wt% sodium chloride", "2.5wt% leucine, 2wt% trehalose and 0.5wt% calcium chloride", "42wt% leucine, 42.5wt% trehalose and 0.5wt% calcium chloride", "59.5wt% leucine, 25wt% dipalmitoylphosphatidylcholine DPPC and 0.5wt% calcium chloride", or "9.5wt% dipalmitoylphosphatidylcholine DPPC".

[0028] Wherein, the above percentage (%) is the mass percentage of each component in the apremilast inhalation powder.

[0029] In the present invention, the spray drying process may include the following steps according to the conventional art: dissolving or dispersing the active ingredient and the excipient in a solvent to obtain a spray drying precursor solution, and then spray drying to remove the solvent to obtain a powder.

[0030] The spray drying precursor solution refers to a solution in which drugs and excipients are dissolved and to be spray dried, and the form may be a solution, a suspension or an emulsion.

[0031] The solvent may be an organic phase or a mixture of an organic phase and an aqueous phase; for example, the organic phase is ethanol or a mixture of ethanol and acetone. The total solid concentration of the apremilast and the excipient may be 1 mg / g-100 mg / g, may be 5 mg / g-50 mg / g, and may further be 10 mg / g-50 mg / g, for example, 30 mg / g.

[0032] In the present invention, regarding the equipment used for spray drying, those skilled in the art know that when performing the spray drying step, the spray drying conditions are adaptively adjusted according to the size of the spray drying equipment used. For example, a small spray drying equipment (e.g., Buchi-B290) or a large factory-made spray drying equipment (GEA-PSD1, PSD4, etc.) can be used, wherein the largest model of the large spray drying equipment can be PSD-7.

[0033] In the present invention, the spray drying conditions can be the same regardless of the size of the model:

[0034] The inlet air temperature of the spray drying is 90-150°C, for example 110-120°C;

[0035] The outlet air temperature of the spray drying is 40-80°C, such as 55-60°C.

[0036] In some embodiments, when a small-scale spray drying device is used, such as Buchi-B290, the conditions of the small-scale spray drying may be further as follows:

[0037] The atomization pressure of the small-scale spray drying is 0.4-1.35 bar, for example 1.0-1.35 bar.

[0038] The feed rate of the small-scale spray drying is 3-30 ml / min, for example 6 ml / min.

[0039] In the present invention, the dosage form of the apremilast inhalation powder can be a single-dose capsule inhalation powder inhalation. The size of the single-dose capsule can generally be any of the following according to the conventional art: No. 0, No. 1, No. 2, No. 3 or No. 4 capsule.

[0040] The material of the single-dose capsule may be gelatin or hydroxypropyl methylcellulose (HPMC), preferably HPMC.

[0041] The particle size D of the Apremilast inhalation powder obtained by the present invention is 50 Generally, it can be 0.5μm to 5.0μm, and can be, for example, 0.99μm-2.39μm, or 1.28μm-1.59μm according to different batches; the in vitro drug deposition rate FPF can be 30%-95%, and can be, for example, 70%-93% for different preparation batches; the tap density can be 0.05-0.4g / ml, for example, 0.1-0.3g / ml; the numerical range of the median particle size MMAD can be within the range of ≤8μm, for example, within the range of ≤5μm, and further within the range of ≤3μm. Different preparation batches have been tested, and can be, for example, 1.31-2.72μm.

[0042] In a second aspect, the present invention also provides a method for preparing apremilast inhalation powder, which comprises the following steps: dissolving or dispersing the active ingredient and the excipient in a solvent to form a spray drying precursor solution, and then spray drying to remove the solvent to obtain a powder.

[0043] Preferably, the solvent is the solvent used in the aforementioned spray drying preparation process.

[0044] Preferably, the spray drying conditions are the same as those mentioned above.

[0045] In a third aspect, the present invention further provides a use of an apremilast inhalation powder in the preparation of a pulmonary fibrosis drug, wherein the apremilast inhalation powder adopts the aforementioned apremilast inhalation powder.

[0046] For example, the pulmonary fibrosis includes idiopathic pulmonary fibrosis.

[0047] 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.

[0048] The reagents and raw materials used in the present invention are commercially available.

[0049] The positive and progressive effects of the present invention are:

[0050] The apremilast inhalation powder prepared by the present invention is used for pulmonary administration, and is used to administer apremilast in the form of a powder. Apremilast is also used to treat lung diseases, and can directly deliver the drug to the effective part, effectively reduce the administration dosage, and improve the deposition rate. The FPF value reaches at least 50%, and the preferred solution can reach more than 92%, thereby greatly improving the treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is a scanning electron microscope image of the Apremilast inhalation powder prepared in Example 1.

[0052] Figure 2 This is a scanning electron microscope image of the Apremilast inhalation powder prepared in Example 7.

[0053] Figure 3 This is a scanning electron microscope image of the Apremilast inhalation powder prepared in Example 11.

[0054] Figure 4 This is a comparison chart of the deposition conditions of various levels of Apremilast inhalation powder APSD prepared in Examples 1, 2 and 11.

[0055] Figure 5 This is a statistical chart showing the effects of different dosing groups in Effect Example 3 on the body weight (g) of rats with pulmonary fibrosis.

[0056] Figure 6 This is a statistical diagram of the effects of different dosing groups in Example 3 on the degree of lesions in rats with pulmonary fibrosis.

[0057] Figure 7 This is a statistical chart showing the effects of different dosing groups on the degree of inflammatory cell infiltration in the lung tissue of rats with pulmonary fibrosis in Effect Example 3.

[0058] Figure 8 This is the average plasma concentration-time data graph of Apremilast in SD rats after IT, IV and PO routes in Effect Example 4. DETAILED DESCRIPTION

[0059] 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.

[0060] The technical solution of the present invention is further described below by specific examples. Those skilled in the art should understand that the embodiments are only used to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0061] 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.

[0062] The terms "including" and "having" 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.

[0063] Examples 1-23 and Comparative Examples 1-2

[0064] The active substance and excipients are dissolved or dispersed in a solvent to form a spray drying precursor (solution or suspension), and then the spray drying precursor is spray-dried on a spray dryer to obtain a powder to obtain apremilast inhalation powder.

[0065] The spray drying conditions are as follows: inlet air temperature 115°C, outlet air temperature 57°C, atomization pressure 1.35 bar, and feed rate 6 mL / min. The test results are shown in Table 1.

[0066] The percentages in the following examples are the mass percentages of the various components in the total amount of the Apremilast inhalation powder.

[0067] Example 1: 5% of Apremilast, 94.5% of L-leucine, and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0068] Comparative Example 1: 20% of Apremilast, 79.5% of DPPC, and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0069] Example 2: 35% of Apremilast, 64.5% of L-leucine, and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0070] Example 3: 35% of Apremilast, 29.5% of L-leucine, 35% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0071] Example 4: 65% of Apremilast, 17.5% of L-leucine, 17% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0072] Example 5: 80% of Apremilast, 10% of L-leucine, 9.5% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0073] Example 6: 65% of Apremilast, 17.5% of L-isoleucine, 17% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0074] Example 7: 65% of Apremilast, 17% of L-leucine, 17% of trehalose and 1% of sodium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0075] Example 8: 65% of Apremilast, 17.5% of L-leucine, 17% of trehalose and 0.5% of calcium chloride were dispersed in a solvent to obtain a spray drying precursor suspension, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0076] Comparative Example 2: 30% of Apremilast, 69.5% of DPPC and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. Evaluation of the powder under this condition

[0077] Example 9: 65% of Apremilast, 17.5% of L-leucine, 17% of mannitol and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0078] Example 10: 80% of Apremilast, 10% of L-leucine, 9.5% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, and a spray dryer was used to spray dry the solution to prepare a powder. The powder under this condition was evaluated. The spray drying conditions were: an inlet air temperature of 115°C, an outlet air temperature of 57°C, an atomization pressure of 1.35 bar, and a feed rate of 3 mL / min.

[0079] Example 11: 95% of Apremilast, 2.5% of L-leucine, 2% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, and a spray dryer was used to spray dry the solution to prepare a powder. The powder under this condition was evaluated. The spray drying conditions were: an inlet air temperature of 115°C, an outlet air temperature of 57°C, an atomization pressure of 0.41 bar, and a feed rate of 6 mL / min.

[0080] Example 12: 15% of Apremilast, 42% of L-leucine, 42.5% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0081] Example 13: 15% of Apremilast, 42% of L-leucine, 42.5% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0082] Example 14: 15% of Apremilast, 59.5% of L-leucine, 25% of DPPC and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0083] Example 15: 35% of Apremilast, 32.25% of L-leucine, 32.25% of DPPC and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0084] Example 16: 35% of Apremilast, 5.9% of L-leucine, 58.6% of DPPC and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0085] Example 17: 35% of Apremilast, 18.4% of L-leucine, 46.1% of DPPC and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0086] Example 18: 90% of Apremilast, 9.5% of DPPC and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0087] Example 19: 15% of Apremilast, 42% of dileucine, 42.5% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0088] Example 20: 15% of Apremilast, 42% of Trileucine, 42.5% of Trehalose and 0.5% of Calcium Chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare powder. The powder under this condition was evaluated.

[0089] Example 21: 15% of Apremilast, 42% of glycine, 42.5% of trehalose and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0090] Example 22: 15% of Apremilast, 42% of L-leucine, 42.5% of hydroxypropyl-β-cyclodextrin and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0091] Example 23: 15% of Apremilast, 42% of L-leucine, 37.5% of trehalose, 5% of ammonium bicarbonate and 0.5% of calcium chloride were dissolved in a solvent to obtain a spray drying precursor solution, which was spray dried using a spray dryer to prepare a powder. The powder under this condition was evaluated.

[0092] Effect Example 1 In vitro experimental test

[0093] The inhalation powders prepared in the above Examples 1-23 and Comparative Examples 1-2 were subjected to the following in vitro experimental effect tests.

[0094] 1. Particle size determination

[0095] Particle size: Geometric particle size distribution measurement method - laser particle size analysis

[0096] The dispersion pressure was 3.0 bar, the feed rate was 65%, and each sample was measured twice in parallel. The test results are summarized in Table 1.

[0097] 2. Aerodynamic Particle Size Distribution Determination

[0098] Aerodynamic Particle Size Distribution (APSD): The aerodynamic particle size distribution is determined using an Anderson cascade impactor.

[0099] (1) ACI installation

[0100] 1.1 Place appropriate filter paper (81mm diameter, 1μm pore size) in the F layer of ACI and press the sealing ring into it to seal it. Then install the corresponding layers step by step from bottom to top according to the flow rate required for the experiment, 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 on the surface of each collection plate and spread it evenly with a silicone spatula, and add 10ml of receiving liquid to the pre-separator.

[0101] 1.2 Connect the outlet of the ACI base to the flow controller, connect the flow controller to the vacuum pump, connect the L-type 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, and then remove the flow meter.

[0102] 1.3 Put the clamping device on the L-shaped connecting tube, 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.

[0103] 1.4 Set the flow controller to the number of particles to be sucked in the experiment (1 particle) and the time for each suction (4S). Wait for 5 seconds, turn off the vacuum pump, and remove the impactor (remove it step by step from top to bottom).

[0104] (2) Sample cleaning and recovery

[0105] The capsule, dosing device, L-shaped connecting tube, pre-separator, grading plate, collection plate, and filter paper were washed into a volumetric flask of appropriate volume in sequence, diluted to an appropriate multiple, and filtered before sampling. The test results are summarized in Table 1.

[0106] At the same time, the APSD deposition conditions of the Apremilast inhalation powder prepared in Examples 1, 2 and 11 were compared. The results are as follows: Figure 4 shown.

[0107] 3. Determination of active ingredient content

[0108] Content determination method: Determined by high performance liquid chromatography (General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia).

[0109] (1) Sample processing

[0110] Test solution: Take an appropriate amount of the product, weigh accurately, add an appropriate amount of acetonitrile-water (6:4) to dissolve and Quantitative dilution Each 1 ml of solution contains approximately 0.01 mg of Apremilast.

[0111] Reference solution: Take an appropriate amount of Apremilast reference substance, weigh accurately, add an appropriate amount of acetonitrile-water (6:4) to dissolve and quantitatively dilute to make a solution containing approximately 0.01 mg per 1 ml.

[0112] (2) Chromatographic conditions

[0113] Octadecylsilane bonded silica gel was used as filler (Welch Ultimate Plus C18, 4.6 mm × 150 mm, 3.5 μm or a chromatographic column with equivalent performance); potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate was dissolved in 1000 ml of water, and the pH value was adjusted to 2.8 with phosphoric acid) and acetonitrile were used as mobile phases with a flow rate of 1.0 ml per minute; the column temperature was 30°C; the detection wavelength was 230 nm; and the injection volume was 20 μl.

[0114] (3) System suitability requirements: In the chromatogram of the reference solution, the theoretical plate number calculated based on the apremilast peak shall be no less than 3000.

[0115] (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 1.

[0116] 4. Determination of related substances

[0117] Determination method for related substances: Determined according to high performance liquid chromatography (General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia).

[0118] (1) Test solution

[0119] Take an appropriate amount of this product, weigh it accurately, add an appropriate amount of acetonitrile-water (3:7) to dissolve it and quantitatively dilute it to make a solution containing about 0.1 mg of Apremilast per 1 ml.

[0120] (2) Chromatographic conditions

[0121] Use octadecylsilane bonded silica gel as filler (Welch Ultimate Plus C18, 4.6mm×150mm, 3.5μm or chromatographic column with equivalent performance); use potassium dihydrogen phosphate solution (take 1.36g of potassium dihydrogen phosphate, add 1000ml of water to dissolve, and adjust the pH value to 2.8 with phosphoric acid) as mobile phase A, acetonitrile as mobile phase B, and perform linear gradient elution as shown in the table below; flow rate is 1.0ml per minute; column temperature is 35℃; injector temperature is 8℃; detection wavelength is 230nm; injection volume is 20μl. As shown in the table below:

[0122]

[0123]

[0124] (3) System suitability requirements: In the chromatogram of the test solution, the separation between the main peak and the adjacent impurity peaks should be greater than 1.5.

[0125] (4) Determination method: Accurately measure the test sample solution and inject it into the liquid chromatograph, and record the chromatogram.

[0126] (5) Limit: If there are impurity peaks in the chromatogram of the test solution, calculate using the area normalization method.

[0127] 5. Determination of bulk density

[0128] Weigh an appropriate amount of preparation powder and place it in a 1ml precision syringe. Record the initial volume v0 of the powder. The bulk density of the powder is ρ b =m / v0.

[0129] According to the above test method, the Apremilast inhalation powder samples prepared in the examples and comparative examples were characterized and evaluated. The test results are summarized in Table 1.

[0130] Table 1

[0131]

[0132]

[0133] 6. Stability analysis

[0134] The stability of the Apremilast inhalation powder obtained in Examples 7 and 12 was investigated. The investigation conditions were 0 day, 40°C / RH75%1M, 40°C / RH75%2M, and 40°C / RH75%3M. The test results are summarized in Table 2 below.

[0135] Table 2 Stability results of samples with different drug loading

[0136]

[0137] The stability of Apremilast inhalation powder samples with API to excipient mass ratios of 65:35 and 15:85 was investigated. The results showed that the API content and FPF of Apremilast inhalation powder samples could be maintained in a relatively stable range under accelerated conditions.

[0138] 7. Effect data analysis

[0139] (1) The apremilast inhalation powder samples with different drug loading ratios prepared in Examples 3, 5, 7 and Example 12 were characterized or evaluated. As shown in Table 3, the results showed that the powder yields with different drug loading ratios were all above 57%; the overall particle size distribution was relatively stable, all concentrated between 1.28 μm and 1.59 μm; the in vitro drug deposition rate was good, and the drug could be effectively delivered to the lung tissue.

[0140] (2) The test data of the Apremilast inhalation powder prepared in Example 4 and Example 6 are shown in Table 1. The only difference between Example 4 and Example 6 is that the amino acid excipients are leucine and isoleucine, respectively, and the effects are basically the same: the powder yield of the Apremilast inhalation powder is above 52%, and the overall particle size distribution is relatively stable, all concentrated between 1.26 μm and 1.28 μm, and the FPF values ​​are relatively high, indicating that the powder dispersion performance is good.

[0141] (3) The test data of the Apremilast inhalation powder prepared in Example 4 and Example 9 are shown in Table 1. The only difference between Example 4 and Example 9 is that the carbohydrate excipients are trehalose and mannitol, respectively. The test results show that the Apremilast inhalation powder prepared in Example 4 and Example 9 perform well in terms of yield, content and particle size distribution.

[0142] (4) The test data of the Apremilast inhalation powder prepared in Example 4 and Example 7 are shown in Table 1. The only difference between Example 4 and Example 7 is that the alkali metal salt excipients are calcium chloride and sodium chloride, respectively. It shows that the Apremilast inhalation powder prepared in Example 4 and Example 7 both show good yield and high content, and have smaller particle size and higher in vitro drug deposition rate performance, respectively.

[0143] (5) The test data of the Apremilast inhalation powder prepared in Example 5 and Example 11 are shown in Table 1. The results show that as the atomization pressure increases, the solution is dispersed into smaller droplets, and the powder particle size after hot air drying becomes smaller.

[0144] (6) The test data of the Apremilast inhalation powder prepared in Example 4 and Example 8 are shown in Table 1. The results show that the transition from the solution to the suspension state slightly reduces the particle size of the particles and reduces the in vitro drug deposition rate performance, indicating that the state of the precursor liquid has a certain influence on the preparation process of the inhalation powder.

[0145] (7) The apremilast inhalation powders prepared in Examples 14-17 differ in the ratio of the excipients leucine and DPPC. However, within this ratio range, although the yields are slightly different, they all have good in vitro drug deposition rate performance.

[0146] (8) The Apremilast inhalation powder prepared in Example 12 was tested using three sets of devices 1, 2, and 3 with different flow resistances commonly used in the art. The obtained FPF and MMAD effect data are shown in Table 1, indicating that delivery using devices with different flow resistances can all show excellent delivery performance.

[0147] (9) Comparison of the APSD deposition of the Apremilast inhalation powder prepared in Examples 1, 2 and 11. Figure 4 As shown, products with different drug loadings have higher FPF and can be better deposited in the lungs.

[0148] Effect Example 2 Scanning electron microscope photo

[0149] The scanning electron microscope was used to photograph the Apremilast inhalation powder prepared in Examples 1, 7 and 11, and the results were as follows: Figure 1-3 shown.

[0150] It can be seen from the figure that as the proportion of leucine in the formula increases, the degree of wrinkling of the particles becomes increasingly obvious, and the specific surface area of ​​Example 11 is 2.17 m 2 / g, Example 1 is 53.98m 2 / g; SSA (specific surface area) increased significantly.

[0151] Effect Example 3 Preliminary efficacy test in animal experiments

[0152] A preliminary study on the efficacy of apremilast inhalation powder in rats with pulmonary fibrosis

[0153] 1. Materials and Reagents

[0154] Thirty-two 6-8 week old Sprague-Dawley rats were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., with a body weight of 200-250 g. Bleomycin hydrochloride for injection (Hanhui Pharmaceutical Co., Ltd.), pirfenidone capsules (Beijing Contini Pharmaceutical Co., Ltd.), and a Japanese Olympus BX51-32000 microscope.

[0155] 2. Test methods

[0156] 1. Model construction: The animals in the D1 model group were given bleomycin (2 mg / kg, 1 mL / kg, once in the morning and afternoon, twice in total) by intra-airway nebulization for model construction, and the animals in the normal control group were given sodium chloride injection (1 mL / kg, once in the morning and afternoon, twice in total) by intra-airway nebulization.

[0157] 2. Method of administration

[0158] Group 1: Normal control group, no medication

[0159] Group 2 to Group 4: Inhalation of powder aerosol in the airway, 2 times / day, planned for 10 consecutive days (D8-D17). Group 2 is the model control group, given a blank preparation; Groups 3-4 are apremilast inhalation powder aerosol groups.

[0160] Group 5: intragastric administration, once a day, for 14 consecutive days (D8-D21).

[0161] Data analysis: This experiment used statistical software IBM SPSS Statistics 28.0 and / or GraphPadPrism 8 to process the data. All statistical analyses were performed using two-tailed analysis, and the statistical level was set at P ≤ 0.05. All indicators were expressed as "mean ± standard deviation" and analyzed according to the following process: First, the data were tested for homogeneity using Levene's Test. If the data were homogeneous (P> 0.05), a one-way analysis of variance (ANOVA) was performed.

[0162] 3. Results

[0163] During the experiment, the weight of the animals after being given the modeling reagent was significantly lower than that of the normal control group. As the experimental period prolonged, the average weight of the animals in each group increased steadily. At the same time, compared with the model control group, as the number of times the animals were given the test or control substances increased, the weight of the animals in each group increased steadily. The weight changes of each group are shown in the attached Figure 5 .

[0164] The inhalation powder prepared in Example 12 was selected as the low-dose group of Apremilast, and the inhalation powder prepared in Example 5 was selected as the high-dose group of Apremilast.

[0165] After testing, compared with the model control group, the lung and bronchial fibrosis levels of the low-dose Apremilast group, the high-dose Apremilast group, and the commercial control group were lower, among which the high-dose Apremilast group had the lowest fibrosis level, indicating that the high-dose Apremilast treatment effect was the best. At the same time, the low-dose Apremilast group and the high-dose Apremilast group were better than the commercial control group. For specific results, see Figure 6 , the corresponding data are shown in Table 3 below:

[0166] Table 3

[0167]

[0168]

[0169] The degree and incidence of inflammatory cell infiltration in the model control group and the commercial control group were similar. Compared with the model control group, the degree of inflammatory cell infiltration in the lungs and bronchial canal was lower in the low-dose and high-dose Apremilast groups, and the incidence and degree of lesions in the high-dose Apremilast group were the lowest, indicating that the high-dose Apremilast treatment had the best effect. The microscopic pathological changes related to the test article were observed in the euthanized animals at the end of the administration. For specific results, see Figure 7 , the corresponding data are shown in Table 4 below:

[0170] Table 4

[0171]

[0172] It can be seen that under the experimental conditions, intra-airway aerosolized bleomycin induced lung fibrosis in SD rats. After that, the experimental animals were given the test substance (Apremilast) by inhalation of powder aerosol aerosol in the airway. The results of microscopic examination showed that the incidence and degree of lung lesions (inflammatory cell infiltration and fibrosis) in the high-dose Apremilast group were the lowest, indicating that high-dose Apremilast had the best therapeutic effect.

[0173] Effect Example 4

[0174] Comparison of IT, IV and PO administration of apremilast - rats

[0175] 1. Experimental animals: 27 SD rats. Animal dosing and grouping were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd., with the experimental animal use license number: SYXK (Shanghai) 2023-0011.

[0176] 2. Animal dosing grouping: 27 SD rats were randomly divided into 3 groups, 9 rats in each group, and Apremilast (the inhalation powder prepared in Example 14) was administered intravenously, orally and intratracheally. Blood was collected for plasma sample analysis at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 8 h after administration, and HPLC-MS was used for detection.

[0177] 3. HPLC-MS blood sample test results are shown in the following table and Figure 8 As shown:

[0178] Dosage Intravenous (IV) Airway (IT) Oral (PO) Dosage (mg / kg) 1 1 5 Peak time (h) 0.08 0.08 0.83 Peak concentration (ng / mL) 561 262 111 Half-life (h) 0.27 0.46 1.96 Area under the curve (h*ng / mL) 241 141 455 Bioavailability % 242 144 493 Dosage (mg / kg) / 60％ 41％

[0179] Figure 8 It can be seen that Apremilast is rapidly absorbed after IT intratracheal administration of 1 mg / kg, with Cmax detected 5 minutes after administration, a plasma half-life of approximately 0.46 hr, and linear elimination in plasma.

[0180] Figure 8Combined with the above table, it can be seen that the half-life ratio of the three administration methods is approximately: IV:IT:PO=1:2:8; the bioavailability after IT administration is 60%, which is higher than the bioavailability of oral administration (40%). The PK characteristics of Apremilast after airway administration (1 mg / kg) are closer to IV administration (1 mg / kg), with a slightly lower Cmax and a longer half-life; the absorption characteristics of oral administration are different from IT or IV, with a slower absorption rate and a longer process.

Claims

1. An apremilast inhalation powder, characterized in that: The invention comprises an active ingredient and an excipient; the active ingredient is apremilast and / or its salt; the excipient comprises any one of the following: an amino acid surface modifier, a phospholipid excipient within 50 wt%, a mixture of an amino acid surface modifier and a phospholipid excipient, a mixture of an amino acid surface modifier and a sugar excipient, or a mixture of an amino acid surface modifier and a sugar alcohol excipient; the preparation process of the apremilast inhalation powder is a spray drying process; The amino acid surface modifier is one or more of leucine, isoleucine, trileucine, and glycine; The phospholipid excipient is one or more of dipalmitoylphosphatidylcholine DPPC, distearoylphosphatidylcholine DSPC and lecithin; The carbohydrate excipient is trehalose; The sugar alcohol excipient is mannitol; The apremilast inhalation powder also includes an anti-static agent; the anti-static agent is an alkaline earth metal salt and / or an alkali metal salt; The active ingredient is used in an amount of 5wt%-95wt%; The amount of the excipient is 2.5wt% or 5wt%-95wt%; The amount of the amino acid surface modifier is 2.5wt% or 5wt%-95wt%; The amount of the carbohydrate excipient and / or sugar alcohol excipient is 2wt%-42.5wt%; In the mixture of the amino acid surface modifier and the phospholipid excipient, the amount of the phospholipid excipient is within 90wt%; The amount of the phospholipid excipient within 50wt% is 2.5wt%-50wt%; The amount of the antistatic agent is 0.5wt%-4wt%; The percentages are the mass percentages of each component in the apremilast inhalation powder.

2. The Apremilast inhalation powder according to claim 1, characterized in that: The leucine is L-leucine.

3. The Apremilast inhalation powder according to claim 1, characterized in that: The antistatic agent is one or more of calcium chloride, sodium chloride, sodium citrate and sodium metaphosphate.

4. Apremilast inhalation powder according to claim 1, characterized in that, The excipient is any one of the following combinations: leucine, "leucine and calcium chloride", "leucine and sodium chloride", "leucine, trehalose and calcium chloride", "leucine, mannitol and calcium chloride", or "leucine, dipalmitoylphosphatidylcholine DPPC and calcium chloride".

5. The Apremilast inhalation powder according to any one of claims 1 to 4, characterized in that: The apremilast inhalation powder meets one or more of the following conditions: a. The amount of the active ingredient is 15wt%-80wt%; b. The amount of the excipient is 20wt%-85wt%; c. The amount of the amino acid surface modifier is 20wt%-85wt%; d. In the mixture of the amino acid surface modifier and the phospholipid excipient, the amount of the phospholipid excipient is 25wt%-60wt%; e. The amount of the phospholipid excipient within 50wt% is 2.5wt%-50wt%; f. The antistatic agent is 0.5wt% calcium chloride or 1wt% sodium chloride; The above percentages are the mass percentages of each component in the Apremilast inhalation powder.

6. The Apremilast inhalation powder according to claim 5, characterized in that: The apremilast inhalation powder meets one or more of the following conditions: a. The amount of the active ingredient is 35wt%-65wt%; b. The amount of the excipient is 35wt%-65wt%; c. The amount of the amino acid surface modifier is 35wt%-65wt%; d. In the mixture of the amino acid surface modifier and the phospholipid excipient, the amount of the phospholipid excipient is 25wt%-45wt%; e. The phospholipid excipient within 50wt% is 9.5wt% dipalmitoylphosphatidylcholine DPPC.

7. The Apremilast inhalation powder according to claim 5, characterized in that: The apremilast inhalation powder meets one or more of the following conditions: a. The amount of the active ingredient is 5wt%, 15wt%, 20wt%, 30wt%, 35wt%, 65wt%, 80wt%, 90wt%, or 95wt%; b. The amount of the excipient is 5.9wt%, 10wt%, 17wt%, 17.5wt%, 18.4wt%, 29.5wt%, 32.25wt%, 42wt%, 59.5wt%, 64.5wt%, or 94.5wt%; c. The amount of the amino acid surface modifier is 5.9wt%, 10wt%, 17wt%, 17.5wt%, 18.4wt%, 29.5wt%, 32.25wt%, 42wt%, 59.5wt%, 64.5wt%, or 94.5wt%; The amount of the carbohydrate excipient and / or sugar alcohol excipient is 2wt%, 9.5wt%, 17wt%, 35wt%, or 42.5wt%; d. In the mixture of the amino acid surface modifier and the phospholipid excipient, the amount of the phospholipid excipient is 25wt%, 32.25wt%, 58.6wt%, or 46.1wt%.

8. The Apremilast inhalation powder according to claim 5, characterized in that: The excipient is any one of the following combinations: "94.5wt% leucine and 0.5wt% calcium chloride", "64.5wt% leucine and 0.5wt% calcium chloride", "10wt% leucine, 9.5wt% trehalose and 0.5wt% calcium chloride", "17wt% leucine, 17wt% trehalose and 1wt% sodium chloride", "2.5wt% leucine, 2wt% trehalose and 0.5wt% calcium chloride", "42wt% leucine, 42.5wt% trehalose and 0.5wt% calcium chloride", "59.5wt% leucine, 25wt% dipalmitoylphosphatidylcholine DPPC and 0.5wt% calcium chloride", or "9.5wt% dipalmitoylphosphatidylcholine DPPC"; The above percentages are the mass percentages of each component in the Apremilast inhalation powder.

9. The Apremilast inhalation powder according to claim 1, characterized in that: The spray drying process comprises the following steps: dissolving or dispersing the active ingredient and the excipient in a solvent to obtain a spray drying precursor solution, and then spray drying to remove the solvent to obtain a powder.

10. The Apremilast inhalation powder according to claim 9, characterized in that: The solvent is a mixture of an organic phase and an aqueous phase; And / or, the spray drying precursor liquid is a solution, a suspension or an emulsion; the spray drying conditions meet one or more of the following conditions: a. Inlet air temperature is 90-150℃; b. The air outlet temperature is 40-80℃.

11. The Apremilast inhalation powder according to claim 10, characterized in that: The organic phase is ethanol or a mixture of ethanol and acetone; and / or, in the spray drying precursor solution, the total solid concentration of the apremilast and the excipient is 1 mg / g-100 mg / g; And / or, the inlet air temperature of the spray drying is 110-120°C; And / or, the outlet air temperature of the spray drying is 55-60°C.

12. The Apremilast inhalation powder according to claim 10, characterized in that: In the spray drying precursor solution, the total solid concentration of the apremilast and the excipient is 5 mg / g-50 mg / g; and / or, the inlet air temperature of the spray drying is 115°C; And / or, the outlet air temperature of the spray drying is 57°C.

13. The Apremilast inhalation powder according to claim 10, characterized in that: In the spray drying precursor solution, the total solid concentration of the apremilast and the excipient is 10 mg / g-50 mg / g.

14. The Apremilast inhalation powder according to claim 1, characterized in that: The dosage form of the apremilast inhalation powder is a capsule; wherein the capsule size is any one of the following: capsule size 0, 1, 2, 3 or 4; the capsule material is gelatin or HPMC; Apremilast inhalation powder D 50 The particle size is 0.5 μm to 5.0 μm; the in vitro drug deposition rate FPF is 70% to 93%; the tap density is 0.05 g / ml to 0.4 g / ml; and the median particle size MMAD has a numerical range of ≤8 μm.

15. The Apremilast inhalation powder according to claim 14, characterized in that: The Apremilast inhalation powder: D 50 0.99μm-2.39μm, or 1.28μm-1.59μm; Tap density 0.1g / ml-0.3g / ml; The value range of the median particle size MMAD is ≤5μm.

16. The Apremilast inhalation powder according to claim 14, characterized in that: The apremilast inhalation powder has a median particle size (MMAD) value in the range of ≤3 μm.

17. A method for preparing the apremilast inhalation powder according to any one of claims 1 to 16, characterized in that: The method comprises the following steps: dissolving or dispersing the active ingredient and the excipient in a solvent to obtain a spray drying precursor solution, and then removing the solvent by spray drying to obtain a powder; wherein the solvent is further the solvent as described in any one of claims 9 to 11; and the spray drying conditions are further the spray drying conditions as described in any one of claims 9 to 13.

18. Use of the apremilast inhalation powder according to any one of claims 1 to 16 in the preparation of a medicament for pulmonary fibrosis.

19. Use of the Apremilast inhalation powder according to claim 18 in preparing a pulmonary fibrosis drug, characterized in that: The pulmonary fibrosis is idiopathic pulmonary fibrosis.

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