Indometacin inhalable dry particles as well as preparation method and application thereof

Abstract

The invention discloses indometacin dry particles and a preparation method and application thereof, and the indometacin inhalable dry particles comprise: L-amino acid; indometacin and / or a pharmaceutically acceptable derivative thereof; the mass ratio of the L-amino acid to the indometacin and / or the pharmaceutically acceptable derivative of the indometacin is 1.0: (0.1-1.0). The indometacin inhalable dry particles have excellent solubility and air properties, the deposition effect of indometacin in the lung can be effectively improved, and the effective deposition rate of the indometacin inhalation powder inhalation is effectively increased.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an indomethacin inhalable dry particle, its preparation method, and its application. Background Technology

[0002] Indomethacin is a widely used nonsteroidal anti-inflammatory drug (NSAID) in clinical practice. It has anti-inflammatory, antipyretic, and analgesic effects and can be used to treat a variety of conditions, including arthritis, soft tissue injuries and inflammation, migraines, postoperative analgesia, and acute and chronic fever. Indomethacin has also been shown to be used to treat specific and nonspecific asthmatic bronchitis.

[0003] Currently, indomethacin is mainly administered orally. However, oral indomethacin has many adverse reactions, such as: ① gastrointestinal adverse reactions such as indigestion, stomach pain, heartburn, gastric ulcer, and gastric bleeding; ② neurological symptoms such as headache, dizziness, anxiety, and insomnia; ③ kidney damage; ④ various types of skin rashes; ⑤ suppression of the hematopoietic system, leukopenia, or thrombocytopenia; ⑥ allergic reactions.

[0004] A pulmonary drug delivery system (PDDS) is a drug delivery system that delivers drugs to the lungs to produce local or systemic therapeutic effects. The human respiratory system has a unique dendritic structure, and the lungs have a large surface area (70–140 m²). 2 The alveolar epithelial cell layer is thin (0.5–1 μm), and capillaries and enzymes are abundant. These characteristics give PDDS (Prophylactic Differential Deficiency Drugs) a great advantage: PDDS can avoid the first-pass effect of oral administration, directly reach the lesion, take effect quickly, and reduce adverse reactions such as gastrointestinal problems.

[0005] Pharmaceutical formulations used in PDDS mainly include inhaled liquid formulations, inhaled sprays, inhaled aerosols, and dry powder inhalers (DPIs). Among them, dry powder inhalers are a novel PDDS dosage form that integrates powder science and particle engineering. Compared with other inhaled formulations, DPIs have the following characteristics: ① convenient to use and good patient compliance; ② no propellants, avoiding environmental pollution; ③ no preservatives or solvents such as ethanol, and no irritation to mucous membranes and lungs; ④ the drug is solid and has good stability.

[0006] Therefore, indomethacin inhalation powder for local lung administration can directly deliver the drug to the lungs, overcoming the first-pass effect and gastrointestinal adverse reactions of oral administration, and reducing the dosage.

[0007] However, there are several key bottlenecks in preparing indomethacin into an inhaled powder: first, indomethacin is a poorly soluble drug, which affects its absorption in the lungs; second, the prepared inhaled powder has poor aerodynamic properties, causing drug particles to be deposited prematurely in the oropharynx, reducing the efficiency of drug delivery to the lungs. Summary of the Invention

[0008] The present invention aims to at least solve one of the aforementioned technical problems existing in the prior art. Therefore, the object of the present invention is to provide indomethacin inhalable dry particles, a method for preparing the same, and their applications.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A first aspect of the present invention provides indomethacin inhalable dry particles, comprising:

[0011] Indomethacin and / or its pharmaceutically acceptable derivatives;

[0012] L-amino acids;

[0013] The mass ratio of indomethacin and / or its pharmaceutically acceptable derivatives to L-amino acids is 1.0:(0.1 to 1.0).

[0014] The L-amino acids of the present invention, in a specific mass ratio, effectively improve the solubility and aerodynamic properties of indomethacin dry particles by forming intermolecular forces and surface enrichment with indomethacin, thereby improving the deposition effect of indomethacin in the lungs after inhalation and increasing its effective deposition rate.

[0015] In some embodiments of the present invention, the mass ratio of indomethacin and / or its pharmaceutically acceptable derivatives to L-amino acids that achieves the purpose of the present invention is 1.0:(0.1 to 1.0), such as 1.0:(0.1 to 0.9), 1.0:(0.1 to 0.8), 1.0:(0.1 to 0.7), 1.0:(0.1 to 0.6), 1.0:(0.1 to 0.5), 1.0:(0.1 to 0.4), 1.0:(0.2 to 0.4), 1.0:(0.1 to 0.3), 1.0:(0.15 to 0.3), 1.0:1.0, 1.0:0.9, 1.0:0.8, 1.0:0.7, 1.0:0.6, 1.0:0.5, 1.0:0.4, 1.0:0.3, 1.0:0.2, 1.0:0.1, etc. In this invention, excessive use of L-amino acids will significantly reduce the drug loading of indomethacin, which is not conducive to the effective delivery of indomethacin; insufficient use will result in low drug deposition rate in the lungs, making it impossible to achieve high delivery efficiency.

[0016] In some embodiments of the present invention, the L-amino acid includes at least one of L-isoleucine, L-leucine, L-lysine, L-threonine, L-tryptophan, L-valine, L-methionine, L-phenylalanine, L-histidine, and L-arginine, or any of their polymorphs, comorphs, amorphous forms, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0017] In some embodiments of the present invention, the L-amino acid includes amorphous / partially crystalline / crystalline / polymorphic L-amino acids.

[0018] In some embodiments of the present invention, the L-amino acid includes at least one of L-leucine, L-arginine, or any of its polymorphs, comorphs, amorphous forms, hydrates, solvates, or pharmaceutically acceptable salts. In this invention, L-arginine forms an amorphous form with indomethacin, which facilitates efficient pulmonary delivery of indomethacin; L-leucine improves the dispersibility of indomethacin dry particles, thereby enhancing its pulmonary deposition.

[0019] In some embodiments of the present invention, the L-amino acid includes at least one of L-leucine, L-arginine, or any polymorph, comorph, or amorphous form thereof. In the present invention, the crystalline compounds of L-leucine and L-arginine may be partially or completely converted into an amorphous form; when partially converted, the L-amino acid includes any polymorph and amorphous form of L-leucine and L-arginine.

[0020] In some embodiments of the present invention, the L-amino acid includes amorphous L-leucine and / or amorphous L-arginine.

[0021] In some embodiments of the present invention, the L-amino acid includes amorphous L-leucine and amorphous L-arginine; the mass ratio of L-arginine to L-leucine is (1.0 to 1.5):1, such as (1.1 to 1.4):1, (1.2 to 1.4):1, 1.2:1, 1.3:1, 1.4:1, etc.

[0022] In some embodiments of the present invention, the indomethacin and / or its pharmaceutically acceptable derivatives include at least one of indomethacin and / or its polymorph, its eutectic form, its amorphous form, its hydrate, its solvate, or its pharmaceutically acceptable salt. In this invention, the amount of its pharmaceutically acceptable derivatives is calculated based on the amount of indomethacin.

[0023] In some embodiments of the present invention, the indomethacin and / or its pharmaceutically acceptable derivatives comprise at least one amorphous / partially crystalline / crystalline / polymorphic indomethacin. In the present invention, polymorphic indomethacin may be partially or completely converted to an amorphous form; when partially converted, the indomethacin and / or its pharmaceutically acceptable derivatives comprise both polymorphic and amorphous indomethacin.

[0024] In some embodiments of the present invention, the indomethacin and / or its pharmaceutically acceptable derivatives include amorphous indomethacin.

[0025] In some embodiments of the present invention, the polymorphs of indomethacin include at least one of α-crystalline indomethacin and γ-crystalline indomethacin.

[0026] In some embodiments of the present invention, the indomethacin inhalable dry particles comprise:

[0027] Amorphous indomethacin;

[0028] Amorphous L-leucine and / or amorphous L-arginine.

[0029] In some embodiments of the present invention, the indomethacin inhalable dry particles comprise:

[0030] Amorphous indomethacin;

[0031] Amorphous L-arginine;

[0032] The mass ratio of indomethacin to L-arginine is 1.0:(0.1-1.0), such as 1.0:(0.1-0.9), 1.0:(0.1-0.8), 1.0:(0.1-0.7), 1.0:(0.1-0.6), 1.0:(0.1-0.5), 1.0:(0.1-0.4), 1.0:(0.2-0.4), 1.0:(0.1-0.3), 1.0:(0.15-0.3), 1.0:1.0, 1.0:0.9, 1.0:0.8, 1.0:0.7, 1.0:0.6, 1.0:0.5, 1.0:0.4, 1.0:0.3, 1.0:0.2, 1.0:0.1, etc.

[0033] In some embodiments of the present invention, the indomethacin inhalable dry particles comprise:

[0034] Amorphous indomethacin;

[0035] Amorphous L-leucine and amorphous L-arginine;

[0036] The mass ratio of indomethacin, L-arginine, and L-leucine is 1.0:(0.08-0.6):(0.02-0.4), such as 1.0:(0.1-0.5):(0.08-0.3), 1.0:(0.1-0.4):(0.08-0.25), 1.0:(0.1-0.3):(0.1-0.25), 1.0:(0.1-0.28):(0.1-0.20), etc.

[0037] In some embodiments of the present invention, the indomethacin-inhalable dry particles are spherical. In this invention, the spherical shape reduces friction between particles, which is beneficial for delivery. In this invention, the morphology of the dry particles is observed using scanning electron microscopy.

[0038] In some embodiments of the present invention, the average particle size (D) of the indomethacin inhalable dry particles 50 The particle size ranges from 0.5 to 8.0 μm. In this invention, the particle size is determined by dry method using a laser particle size analyzer, with reference to standards ISO-13320 and GB / T19077.

[0039] In some embodiments of the present invention, the particle size distribution of the indomethacin inhalable dry particles is 0.5 μm ≤ D. V10 ≤1.0μm; 1.5μm≤D V50 ≤5.0μm; 3.0μm≤D V90 ≤9.0μm.

[0040] In some embodiments of the present invention, the particle size distribution of the indomethacin inhalable dry particles is 0.60 μm ≤ D. V10 ≤0.95μm; 1.8μm≤D V50 ≤2.8μm; 3.2μm≤D V90 ≤6.0μm.

[0041] In some embodiments of the present invention, the particle size distribution of the indomethacin inhalable dry particles is 0.60 μm ≤ D. V10 ≤0.95μm; 1.8μm≤D V50 ≤2.7μm; 3.4μm≤D V90 ≤5.8μm.

[0042] In some embodiments of the present invention, the particle size distribution of the indomethacin inhalable dry particles is 0.60 μm ≤ D. V10 ≤0.95μm; 1.8μm≤D V50 ≤2.7μm; 3.4μm≤D V90 ≤5.0μm.

[0043] In some embodiments of the present invention, the particle size distribution of the indomethacin inhalable dry particles is 0.60 μm ≤ D. V10 ≤0.95μm; 1.8μm≤D V50 ≤2.7μm; 3.4μm≤D V90 ≤4.5μm.

[0044] In some embodiments of the present invention, the particle size distribution of the indomethacin inhalable dry particles is 0.60 μm ≤ D. V10 ≤0.95μm; 1.8μm≤D V50 ≤2.7μm; 3.4μm≤D V90 ≤4.0μm.

[0045] In some embodiments of the present invention, the drug loading of the indomethacin inhalable dry particles is at least 50 wt%, such as at least 60 wt%, at least 65 wt%, at least 70 wt%, at least 75 wt%, or at least 80 wt%. In this invention, "drug loading" refers to the mass percentage of indomethacin in the inhalable dry particles. In this invention, high-performance liquid chromatography (HPLC) is used to determine the drug loading.

[0046] In some embodiments of the invention, the mass median aerodynamic diameter (MMAD) of the indomethacin inhalable dry particles is less than about 10 μm, less than about 5 μm, about 1 μm to about 10 μm, about 1 μm to about 5 μm, about 1 μm to about 4 μm, about 2 μm to about 4 μm, about 2.0 μm to about 3.5 μm, about 2.5 μm to about 3.5 μm, or smaller.

[0047] In some embodiments of the invention, at least about 30%, at least about 40%, preferably at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70% of the indomethacin inhalable dry particles may have a particle size fraction (FPF) of less than about 5.0 μm.

[0048] In some embodiments of the invention, the fine particle fraction (FPF) % of the indomethacin inhalable dry particles is 40% to 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 65%, or about 50% to about 60%.

[0049] In some embodiments of the present invention, the fine particle dose of the indomethacin inhalable dry particles is 1.0–3.0 mg; such as 1.2–2.9 mg, 1.3–2.8 mg, 1.4–2.5 mg, 1.4–2.1 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, etc.

[0050] In some embodiments of the present invention, the water or solvent content of the indomethacin inhalable dry particles may be less than about 15 wt% of the dry particles, such as less than about 15 wt%, less than about 13 wt%, less than about 11.5 wt%, less than about 10 wt%, less than about 9 wt%, less than about 8 wt%, less than about 7 wt%, less than about 6 wt%, less than about 5 wt%, less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, less than about 1 wt%, or anhydrous.

[0051] In some embodiments of the present invention, the water or solvent content of the indomethacin inhalable dry particles may be less than about 6% and greater than about 1 wt%, less than about 5.5 wt% and greater than about 1.5 wt%, less than about 5 wt% and greater than about 2 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, or about 5 wt%.

[0052] A second aspect of the present invention provides a method for preparing the indomethacin inhalable dry particles, comprising the following steps:

[0053] S1: Dissolve L-amino acids and indomethacin and / or their pharmaceutically acceptable derivatives in a solvent in proportion to obtain a mixed solution;

[0054] S2: The indomethacin inhalable dry particles are obtained by drying the mixed solution.

[0055] In some embodiments of the present invention, the L-amino acid includes at least one of L-isoleucine, L-leucine, L-lysine, L-threonine, L-tryptophan, L-valine, L-methionine, L-phenylalanine, L-histidine, and L-arginine, or any of their polymorphs, comorphs, amorphous forms, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0056] In some embodiments of the present invention, the L-amino acid includes polymorphs of L-leucine and / or L-arginine.

[0057] In some embodiments of the present invention, the indomethacin and / or its pharmaceutically acceptable derivatives include at least one of indomethacin and / or its polymorph, its eumorph, its amorphous form, its hydrate, its solvate, or its pharmaceutically acceptable salt.

[0058] In some embodiments of the present invention, the indomethacin and / or its pharmaceutically acceptable derivatives include polymorphs of indomethacin.

[0059] In some embodiments of the present invention, the polymorph of indomethacin includes at least one of α-crystalline indomethacin and γ-crystalline indomethacin.

[0060] In some embodiments of the present invention, the solvent includes at least one of water, methanol, ethanol, isopropanol, acetone, and toluene, such as a mixed solvent of water and ethanol; more specifically, a mixed solvent of water and ethanol in a volume ratio of 1:(5-12), such as a volume ratio of 1:(6-10), 1:(7-9), 1:7, 1:8, 1:9, etc.

[0061] In some embodiments of the present invention, the total concentration of L-amino acid and indomethacin and / or its pharmaceutically acceptable derivatives in the mixed solution is (8-12) mg / mL, such as (9-11) mg / mL or 10 mg / mL.

[0062] The drying method of the present invention can employ conventional drying methods in the art, such as solvent evaporation, heating drying, spray drying, spray freeze drying, freeze drying, and vacuum drying.

[0063] In some embodiments of the present invention, the drying includes at least one of spray drying and freeze drying.

[0064] Suitable spray drying techniques are described, for example, by K. Masters in “Spray Drying Handbook,” John Wiley & Sons, New York (1984). Generally, during spray drying, heat from a hot gas (such as heated air or nitrogen) is used to evaporate the solvent from droplets formed by atomizing a continuous liquid feed. If desired, spray drying or other instruments (e.g., jet milling instruments) used to prepare dry particles may include an in-line geometric particle size classifier that measures the geometric diameter of inhalable dry particles during preparation, and / or an in-line aerodynamic particle size classifier that measures the aerodynamic diameter of inhalable dry particles during preparation.

[0065] For spray drying, a solution, emulsion, or suspension containing the components of the dry particles to be prepared in a suitable solvent is dispensed into a drying container via an atomizing device. For example, a nozzle or rotary atomizer can be used to dispense the solution or suspension into the drying container. For example, a rotary atomizer with a 4-blade or 24-blade wheel can be used. Examples of suitable spray dryers that can be equipped with a rotary atomizer or nozzle include portable miniature spray dryers or the PSD-1 model spray dryer, both manufactured by GEA Group (Niro, Denmark). Actual spray drying conditions will vary to some extent depending on the composition of the solution or suspension to be sprayed and the flow rate of the material. Those skilled in the art will be able to determine appropriate conditions based on the composition of the solution, emulsion, or suspension to be sprayed, the desired particle characteristics, and other factors.

[0066] In some embodiments of the present invention, the process parameters for spray drying include: an inlet air temperature of 90–130°C, such as 100–120°C, 105–115°C, or 110°C; and a feed rate of 1.0–5.0 mL / min, such as 2.0–4.0 mL / min, 2.5–4.0 mL / min, 3.0–4.0 mL / min, 3.1 mL / min, 3.2 mL / min, 3.3 mL / min, 3.4 mL / min, or 3.5 mL / min. The flow rates are 3.6 mL / min, 3.7 mL / min, 3.8 mL / min, 3.9 mL / min, etc.; the atomizing airflow rate is 200–500 L / h, such as 250–450 L / h, 300–400 L / h, 310 L / h, 320 L / h, 330 L / h, 340 L / h, 350 L / h, 360 L / h, 370 L / h, 380 L / h, 390 L / h, 400 L / h; the airflow velocity is 20–50 m / s. 3 / h, such as 25-45m 3 / h, 30~40m 3 / h、31m 3 / h、32m 3 / h、33m 3 / h、34m 3 / h, 35m 3 / h、36m 3 / h、37m 3 / h, 38m 3 / h、39m 3 / h, etc. If necessary, the generated inhalable dry particles can be separated by volume fractionation, for example using a sieve, or by aerodynamic particle size fractionation, for example using a cyclone separator, and / or further separated by density using techniques known to those skilled in the art.

[0067] A third aspect of the present invention provides an indomethacin inhalable dry powder, comprising the indomethacin inhalable dry particles.

[0068] A fourth aspect of the present invention provides an indomethacin inhalation powder, comprising the indomethacin inhalable dry particles and / or the indomethacin inhalable dry powder, and an inhaler.

[0069] In this invention, the indomethacin inhalable dry powder can be used in any type of inhaler. The unit dosage container can be a capsule (e.g., size 000, 00, 0E, 0, 1, 2, 3, and 4, corresponding to volumes of 1.37 mL, 950 μL, 770 μL, 680 μL, 480 μL, 360 μL, 270 μL, and 200 μL).

[0070] In some embodiments of the present invention, the indomethacin inhalation powder includes: a capsule containing the indomethacin inhalable dry powder.

[0071] Different inhaled powders have different pre-administration dosages. Taking No. 3 capsule as an example, the loading of indomethacin inhalable dry powder in the capsule is 8-12 mg / capsule, such as 10±0.2 mg / capsule.

[0072] In some embodiments of the present invention, the capsule may be a hard gelatin capsule, a starch capsule, or a cellulose capsule, such as a hydroxypropyl methylcellulose capsule.

[0073] In some embodiments of the present invention, the indomethacin inhalation powder may also include other pharmaceutically acceptable excipients.

[0074] For example, pharmaceutically acceptable excipients include any standard carbohydrates and sugar alcohols known in the art, alone or in any desired combination, as useful for inhalation therapy. These excipients are generally relatively free-flowing particles that do not thicken or aggregate upon contact with water, are toxicologically harmless when inhaled as dispersible powders, and do not significantly interact with the therapeutic agent in a manner that adversely affects the desired physiological effect. Carbohydrate excipients useful in this regard include monosaccharides and polysaccharides. Representative monosaccharides include carbohydrate excipients such as dextrose (anhydrous and monohydrate; also known as glucose and glucose monohydrate), galactose, mannitol, D-mannose, sorbitol, etc. Representative disaccharides include lactose, maltose, sucrose, trehalose, etc. Representative trisaccharides include raffinose, etc. Other carbohydrate excipients include maltodextrin and cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin may be used as needed.

[0075] In some embodiments of the invention, pharmaceutically acceptable excipients may be present in amounts less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 17.5%, less than about 15%, less than about 12.5%, less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%, all percentages being based on the weight of indomethacin inhalation powder.

[0076] A fifth aspect of the present invention provides the use of the indomethacin inhalable dry particles, the indomethacin inhalable dry powder, or the indomethacin inhalation powder in the preparation of medicaments for the prevention and / or treatment of diseases.

[0077] In some embodiments of the present invention, the drug includes at least one of anti-inflammatory, antipyretic, and analgesic drugs.

[0078] In some embodiments of the present invention, the disease includes at least one of acute rheumatoid arthritis, chronic rheumatoid arthritis, gouty arthritis, bursitis, tenosynovitis, joint bursitis, thrombosis, fever, cough, specific asthmatic bronchitis, nonspecific asthmatic bronchitis, postoperative pain, cancer pain, biliary colic, migraine, and menstrual pain.

[0079] The indomethacin dry particles described above exhibit excellent deposition effects in the lungs, making them particularly suitable for the prevention and treatment of specific asthmatic bronchitis and non-specific asthmatic bronchitis.

[0080] The beneficial effects of this invention are:

[0081] The indomethacin inhalable dry particles of the present invention have excellent solubility and air properties, which can effectively improve the deposition effect of indomethacin in the lungs and effectively increase the effective drug deposition rate of indomethacin inhalation powder.

[0082] The indomethacin inhalation powder of the present invention can directly deliver the drug to the lungs, effectively reducing the dosage and overcoming the disadvantage of traditional oral formulations having greater adverse reactions.

[0083] The method for preparing indomethacin inhalable dry particles of the present invention is simple and suitable for industrial mass production. Attached Figure Description

[0084] Figure 1 This is a crystal form diagram of the indomethacin inhalable dry powder of Example 1 of the present invention.

[0085] Figure 2 This is a crystal form diagram of the indomethacin inhalable dry powder of Example 3 of the present invention.

[0086] Figure 3 This is a SEM image of indomethacin in Example 1 of the present invention.

[0087] Figure 4 This is a SEM image of L-arginine in Example 1 of the present invention.

[0088] Figure 5 This is a SEM image of L-leucine in Example 3 of the present invention.

[0089] Figure 6 The images show SEM images of indomethacin inhalable dry powder particles F1, F2, F3, and F4 with different mass ratios in Example 1 of this invention.

[0090] Figure 7 The images show SEM images of indomethacin inhalable dry powder particles F5 and F6 with different mass ratios in Example 3 of this invention.

[0091] Figure 8 The results show the in vitro atomization performance test results of indomethacin inhalation powder with different mass ratios in Example 2 of this invention.

[0092] Figure 9 The results are from the in vitro atomization performance tests of indomethacin inhalation powder with different mass ratios in Example 4 of this invention. Detailed Implementation

[0093] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments and comparative examples are all available from conventional commercial sources or can be obtained by existing technical methods. Unless otherwise specified, the test or experimental methods are conventional methods in the art.

[0094] The term "pharmaceutical acceptable" means that a drug is chemically or physically compatible with other components that make up a drug dosage form and is physiologically compatible with receptors.

[0095] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt formed by a compound or its stereoisomer with an inorganic acid, organic acid, or base, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained through separation and purification during compound preparation, or by mixing the aforementioned compound or its stereoisomer with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may precipitate in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compound.

[0096] As used herein, the term "dry powder" refers to a composition containing inhalable dry particles that can be dispersed in an inhalation device and subsequently inhaled by a subject. Such dry powder may contain up to about 25%, up to about 20%, or up to about 15% water or other solvents, or be substantially free of water or other solvents, or be anhydrous.

[0097] As used herein, the term "dry particles" refers to inhalable particles that may contain up to about 25%, up to about 20%, or up to about 15% water or other solvents, or are substantially free of water or other solvents or anhydrous.

[0098] As used herein, the term "inhalable" refers to dry particles or powders suitable for delivery to a subject's respiratory tract by inhalation (e.g., lung delivery).

[0099] Particle size distribution can be measured using laser diffraction (e.g., with a Malvern Mastersizer 2000S instrument). D... 10 D 50 and D 90 The value is used to represent particle size distribution. The particle size distribution is represented by the value D. 50 The median is defined as the micrometer-sized particle size that divides the distribution in two. Detection results obtained from laser diffraction more accurately describe the volume distribution, and therefore the D obtained using this method... 50 The value is more meaningfully called Dv 50 The Dv value (median of the volume distribution). As used in this paper, the Dv value refers to the particle size distribution detected using laser diffraction. Similarly, the Dv value used in the context of laser diffraction... 10 and D 90 The value is considered to refer to Dv 10 and Dv 90 The values, and respectively refer to the 10% of the distribution below D. 10 The particle size is low, and 90% of the distribution is below D.90 value.

[0100] Experimentally, aerodynamic diameter can be determined using time-of-flight (TOF) measurements. For example, an instrument such as the Model 3225 Aerosizer DSP particle size analyzer (Amherst Process Instrument, Inc., Amherst, MA) can be used to measure the aerodynamic diameter. The Aerosizer measures the time it takes for each inhalable dry particle to pass between two fixed laser beams.

[0101] Aerodynamic diameter can also be determined experimentally using conventional gravity sedimentation methods, which measure the time required for a sample of inhalable dry particles to settle a certain distance. Indirect methods for measuring the mass median aerodynamic diameter include the two-stage impactor and the Andersen Cascade Impactor (ACI) method. Another method for measuring aerodynamic diameter is using the Next Generation Impactor (NGI). The NGI operates based on an inertial impact principle similar to that of the ACI. The NGI consists of seven stages and can be calibrated at flow rates of 30, 60, and 100 LPM. Unlike the stacked stages of the ACI impact sampler, the stages of the NGI are all in a single plane. A collection cup is used to collect particles below each stage of the NGI. US Patent No. 8,614,255, regarding the method and instrumentation for measuring the aerodynamic diameter of particles, is well known in the art. The above test methods specifically refer to the relevant provisions of General Chapter 0951 of the Chinese Pharmacopoeia 2020 edition, "Determination of Aerodynamic Properties of Fine Particles in Inhaled Preparations," which are incorporated herein by reference.

[0102] "Nominal dose" or "nominal powder dose" refers to the percentage of API present in the total mass of particles contained in the container.

[0103] "Pre-dosage dose" (hereinafter also referred to as "MD") refers to the mass of powder composition loaded into a device (inhaler) for inhaling the powder composition via aerosol. This composition is typically loaded into cartridges or hard capsules;

[0104] "Ejection dose" (hereinafter also referred to as "ED") means the amount of pre-administered dose that is expelled by the inhaler after the inhalation action.

[0105] The portion of a pharmaceutical formulation that falls within a certain size range is usually referred to as the fine particle fraction (FPF).

[0106] Unless otherwise stated, the term "FPF" or "fine particle fraction" refers to the fraction of dry particulate samples with an aerodynamic diameter of less than 5.0 μm, and may also be referred to as "FPF (<5.0)," "FPF (<5.0 μm)," and "fine particle fraction less than 5.0 μm."

[0107] The term “fine particle dose” as used in this article is defined as the mass of a dry particle sample with an aerodynamic diameter of less than 5.0 μm.

[0108] Emitted fraction (EF) refers to the ratio of the expelled dose to the pre-administered dose.

[0109] The term "spherical" encompasses both approximately spherical and spherical particles. Approximately spherical particles have the same size in each of the x, y, and z dimensions, differing by ±20%, more preferably ±10%; for example, when the size is 1.0 μm, the difference is ±0.2 μm, more preferably ±0.2 μm.

[0110] The dry particle and dry powder compositions disclosed herein can be prepared using any suitable method. Many suitable methods for preparing dry powders and dry particles are conventional in the art, including spray drying, milling (e.g., jet milling), blending, solvent extraction, solvent evaporation, phase separation, simple and complex agglomeration, interfacial polymerization, freeze drying, suitable methods involving the use of supercritical carbon dioxide (CO2), co-micronization, and other suitable methods. Dry particles can be prepared using methods known in the art for preparing microspheres or microcapsules. These methods can be used under conditions that result in the formation of dry particles with desired aerodynamic properties (e.g., aerodynamic diameter and geometric diameter) and unexpected stability as disclosed herein. If desired, suitable methods, such as sieving, can be used to select dry particles with desired properties, such as size and density.

[0111] Capsules are solid dosage forms in which drugs are encapsulated within a hard or soft soluble container or "shell." The shell is typically formed from gelatin; however, they can also be made from starch (such as hydroxypropyl methylcellulose (HPMC)) or other suitable substances.

[0112] Unless otherwise stated, the term "about" as used herein means ±10% of the value following the term "about".

[0113] Example 1

[0114] This embodiment prepares an indomethacin inhalable dry powder, the specific process of which is as follows:

[0115] Indomethacin and L-arginine were dissolved in ethanol-water (volume ratio 9:1) at different mass ratios (50.0:50.0, 67.5:32.5, 80.5:19.5, 86.0:14.0) to prepare mixed solutions with a total concentration of 10.0 mg / mL. The mixed solutions were then spray-dried using a spray dryer to prepare indomethacin / L-arginine dry powder.

[0116] The spray drying conditions are as follows: inlet air temperature is 110℃, feed rate is 3.6 mL / min, atomizing air flow rate is 357 L / h, and airflow velocity is 35 m / s. 3 / h.

[0117] The indomethacin inhalable dry powders prepared with indomethacin and L-arginine in mass ratios of 50.0:50.0, 67.5:32.5, 80.5:19.5, and 86.0:14.0 were labeled as F1, F2, F3, and F4, respectively.

[0118] Example 2

[0119] This embodiment prepares an indomethacin inhalation powder, the specific process of which is as follows:

[0120] The indomethacin inhalable dry powder prepared in Example 1 was filled into HPMC capsules No. 3 (10±0.2mg / capsule) to obtain indomethacin inhalation powder.

[0121] Example 3

[0122] This embodiment prepares an indomethacin inhalable dry powder, the specific process of which is as follows:

[0123] Indomethacin, L-arginine powder, and L-leucine powder were dissolved in ethanol-water (volume ratio 9:1) at different mass ratios (70.0:17.1:12.9, 77.9:12.6:9.5) to prepare mixed solutions with a total concentration of 10.0 mg / mL. The mixed solutions were then spray-dried using a spray dryer to prepare indomethacin / L-arginine / L-leucine dry powder.

[0124] The spray drying conditions are as follows: inlet air temperature is 110℃, feed rate is 3.6 mL / min, atomizing air flow rate is 357 L / h, and airflow velocity is 35 m / s. 3 / h.

[0125] Indomethacin inhalable dry powder prepared with mass ratios of indomethacin, L-arginine powder, and L-leucine powder of 70.0:17.1:12.9 and 77.9:12.6:9.5 respectively is designated as F5 and F6.

[0126] Example 4

[0127] This embodiment prepares an indomethacin inhalation powder, the specific process of which is as follows:

[0128] The indomethacin inhalable dry powder prepared in Example 3 was filled into HPMC capsules No. 3 (10±0.2mg / capsule) to obtain indomethacin inhalation powder.

[0129] Test case

[0130] This experimental example characterizes the indomethacin inhalable dry powder prepared in the previous examples. The specific process is as follows:

[0131] (1) Particle size determination: The particle size of indomethac inhalable dry powder was determined by dry method using a laser particle size analyzer (RODOS dispersion module of German Newpatek laser particle size analyzer). The dispersion pressure was 2.0 bar, and each sample was measured in parallel 3 times.

[0132] (2) Determination of drug loading: Accurately weigh an appropriate amount of indomethacin inhalable dry powder from each formulation, dissolve and quantitatively dilute with anhydrous ethanol, and perform high performance liquid chromatography (Agilent Eclipse Plus column) to determine the drug loading. The content of indomethacin in the dry powder was determined and the drug loading was calculated using a C18 column (4.6×150mm, 5μm), with acetonitrile-0.1mol / L glacial acetic acid solution (65:35) as the mobile phase, a flow rate of 1.0mL / min, a detection wavelength of 320nm, a column temperature of 27℃, an injection volume of 20μL, and a retention time of approximately 3.6–4.0min.

[0133] The results are shown in Table 1. The results show that the dry powder D of the formulation in the example V50 All are less than 4μm, D V90 All particles are less than 7.5 μm. Most of the drug particles in indomethacin inhalable dry powder F3 to F6 are around 5 μm, which is more conducive to drug delivery to the lungs.

[0134] Table 1

[0135] Group <![CDATA[D V10 (μm)]]> <![CDATA[D V50 (μm)]]> <![CDATA[D V90 (μm)]]> Drug loading (wt%) F1 0.78±0.00 2.93±0.02 6.11±0.02 50.65 F2 0.96±0.02 3.12±0.02 7.16±0.02 67.40 F3 0.69±0.02 1.96±0.04 3.83±0.11 81.12 F4 0.91±0.01 2.44±0.02 5.54±0.08 87.50 F5 0.77±0.06 2.04±0.13 3.98±0.43 70.38 F6 0.91±0.02 2.51±0.02 5.11±0.02 77.87

[0136] (3) Crystal form evaluation: The crystal form of indomethacin inhalable dry powder was determined using X-ray powder diffraction, and the results are as follows: Figure 1 , Figure 2 As shown in the figure. The results show that indomethacin, L-arginine, and L-leucine powders were all crystalline before spray drying, and all were amorphous after spray drying.

[0137] (4) Particle morphology: The microscopic surface morphology of indomethacin, L-arginine, L-leucine, and indomethacin inhalable dry powder particles was captured using a Hitachi SU1000 scanning electron microscope (SEM). The sample powder was evenly spread on a sample stage coated with conductive adhesive, and then placed in a gold spraying apparatus. Under vacuum conditions, the surface was uniformly covered with gold powder to enhance the conductivity of the sample. The gold spraying current was 8-10 mA, the vacuum degree was 6-8 Pa, and the gold spraying time was 60 s.

[0138] SEM images of indomethacin, L-arginine, L-leucine, and the indomethacin inhalable dry powder from Examples 1 and 2 are shown in the following figures. Figures 3 to 7 As shown, where, Figure 6 SEM images of F1, F2, F3, and F4 are provided; Figure 7 SEM images of F5 and F6 are provided. Indomethacin powder exhibits an irregular flake-like morphology under SEM; L-arginine powder exhibits a block-like morphology; L-leucine powder exhibits a flake-like morphology; indomethacin inhalable dry powder of different mass ratios all exhibit a spherical structure. The spherical structure of the powder particles has less friction between them, which is advantageous when the dry powder is delivered to the lungs.

[0139] (5) In vitro nebulization performance: The indomethacin inhalation powder prepared in Examples 2 and 4 was tested for aerodynamic particle size using a Next Generation Impactor (NGI, see Chinese Pharmacopoeia 2020 General Chapter 0951, Apparatus 3 for the Determination of Aerodynamic Characteristics of Fine Particles in Inhaled Preparations). According to the requirements of the Chinese Pharmacopoeia 2020, data was analyzed using Copley inhaler test data analysis software version 3.10 to calculate the fine particle fraction (FPF), fine particle dose (FPD), emitted fraction (EF), and mass median aerodynamic diameter (MMAD). FPF is the most intuitive parameter for evaluating the pulmonary drug delivery efficiency of inhaled powder, referring to the percentage of drug deposited in the lungs relative to the total drug released from the device. FPD reflects the fine particle dose delivered to the lungs. The specific test method is as follows:

[0140] The inhalation device was used for testing. To reduce secondary particle collisions, the S1-S7 stages and the microorifice collector (MOC) were coated with a 1% (v / v) Tween 80 ethanol solution and dried before testing. One capsule of the indomethacin inhalation powder was placed in the inhalation device, and the bottom of the capsule was punctured by pressing the button at the bottom of the device. The vacuum pump was turned on, and the gas flow rate was set to 60 L / min (determined by the inherent internal resistance of the inhalation device). The inhalation device was connected to the adapter and an artificial larynx was inserted. After aspiration for 4 seconds, the inhalation device was removed, and a new capsule was inserted. A total of 6 capsules were aspirated in this way, and each sample was tested in triplicate. All samples were tested 3 times, with 2 capsules each time, and then the Agilent Eclipse Plus was used. Quantitative analysis was performed using a C18 (4.6×150mm, 5μm) column with a mobile phase of 0.1mol / L glacial acetic acid solution-acetonitrile (35:65).

[0141] FPF = S3-S7 and the amount of drug deposited in MOC divided by the excretion dose.

[0142] FPD = S3-S7 and the amount of drug deposition in MOC.

[0143] EF = The percentage of the total amount of indomethacin inhalable dry powder emitted from the device relative to the total amount of indomethacin inhalable dry powder collected.

[0144] The results are shown in Table 2 and Figure 8 , Figure 9 As shown.

[0145] Table 2

[0146]

[0147] When the mass ratio of indomethacin to L-arginine was 50.0:50.0 (F1), the Fasting Productivity (FPF) was only 29.94% and the FPD was only 0.89 mg. However, when the mass ratio was 86.0:14.0 (F4), the FPF significantly increased to 60.32%, and the FPD increased to 1.99 mg. This indicates that adjusting the amount of L-arginine added can enhance the delivery efficiency of indomethacin inhalable dry powder in the lungs; further addition of L-leucine can further improve FPF and FPD.

[0148] (6) Equilibrium solubility determination: The solubility of excess indomethacin inhalable dry powder in aqueous solution was determined by a constant temperature shaker. The temperature was set at 37℃, the shaker speed was 104 r / min, and the measurement was performed for 36 h. Each sample was measured in triplicate. The results are shown in Table 3.

[0149] Table 3

[0150]

[0151]

[0152] The results showed that L-arginine / L-leucine significantly improved the solubility of indomethacin in water.

[0153] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An indomethacin-inhalable dry particle, characterized in that: include: Indomethacin and / or its pharmaceutically acceptable derivatives; L-amino acids; The mass ratio of indomethacin and / or its pharmaceutically acceptable derivatives to L-amino acids is 1.0:(0.1 to 1.0).

2. The indomethacin inhalable dry particles according to claim 1, characterized in that: The L-amino acids include at least one of L-isoleucine, L-leucine, L-lysine, L-threonine, L-tryptophan, L-valine, L-methionine, L-phenylalanine, L-histidine, and L-arginine, or any of their polymorphs, comorphs, amorphous forms, hydrates, solvates, or pharmaceutically acceptable salts thereof.

3. The indomethacin inhalable dry particles according to claim 1, characterized in that: The L-amino acids include amorphous L-leucine and / or amorphous L-arginine.

4. The indomethacin inhalable dry particles according to claim 3, characterized in that: The L-amino acids include amorphous L-leucine and amorphous L-arginine; the mass ratio of L-arginine to L-leucine is (1.0 to 1.5):

1.

5. The indomethacin inhalable dry particles according to claim 1, characterized in that: The indomethacin and / or its pharmaceutically acceptable derivatives include at least one of indomethacin and / or its polymorph, its eumorph, its amorphous form, its hydrate, its solvate, or its pharmaceutically acceptable salt.

6. The indomethacin inhalable dry particles according to claim 1, characterized in that: The indomethacin inhalable dry particles include: Amorphous indomethacin; Amorphous L-arginine; The mass ratio of indomethacin to L-arginine is 1.0:(0.1-1.0).

7. The indomethacin inhalable dry particles according to claim 1, characterized in that: The indomethacin inhalable dry particles include: Amorphous indomethacin; Amorphous L-leucine and amorphous L-arginine; The mass ratio of indomethacin, L-arginine, and L-leucine is 1.0:(0.08-0.6):(0.02-0.4).

8. The indomethacin inhalable dry particles according to any one of claims 1 to 7, characterized in that: The indomethacin inhalable dry particles meet at least one of the following conditions: (I) The average particle size of the indomethacin inhalable dry particles is 0.5–8.0 μm; (II) The particle size distribution of the indomethacin inhalable dry particles is 0.5 μm ≤ D V10 ≤1.0μm; 1.5μm≤D V50 ≤5.0μm; 3.0μm≤D V90 ≤9.0μm; (III) The drug loading of the indomethacin inhalable dry particles is at least 50 wt%.

9. The indomethacin inhalable dry particles according to any one of claims 1 to 7, characterized in that: The indomethacin inhalable dry particles meet at least one of the following conditions: (I) The median aerodynamic diameter of the indomethacin inhalable dry particles is less than about 10 μm; (II) The fine particle fraction of the indomethacin inhalable dry particles is 40% to 90%.

10. A method for preparing indomethacin inhalable dry particles according to any one of claims 1 to 9, characterized in that: Includes the following steps: S1: Dissolve L-amino acids and indomethacin and / or their pharmaceutically acceptable derivatives in a solvent in proportion to obtain a mixed solution; S2: The indomethacin inhalable dry particles are obtained by drying the mixed solution.

11. The method for preparing indomethacin inhalable dry particles according to claim 10, characterized in that: The drying process includes at least one of spray drying and freeze drying.

12. The method for preparing indomethacin inhalable dry particles according to claim 11, characterized in that: The spray drying process parameters include: inlet air temperature of 90–130℃; feed rate of 1.0–5.0 mL / min; atomizing air flow rate of 200–500 L / h; and airflow velocity of 20–50 m / min. 3 / h.

13. An indomethacin inhalable dry powder, characterized in that: Including the indomethacin inhalable dry particles as described in any one of claims 1 to 9.

14. An indomethacin inhalation powder, characterized in that: Includes indomethacin inhalable dry particles as described in any one of claims 1 to 9 and / or indomethacin inhalable dry powder as described in claim 13, and an inhaler.

15. The use of indomethacin inhalable dry particles according to any one of claims 1 to 9, indomethacin inhalable dry powder according to claim 13, or indomethacin inhalation powder according to claim 14 in the preparation of medicaments for the prevention and / or treatment of diseases.

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