Pharmaceutical composition comprising tricyclic compound

Abstract

The present application belongs to the technical field of pharmaceuticals, relates to a pharmaceutical composition comprising a tricyclic compound of formula I, a preparation method therefor, and use thereof, and particularly relates to use thereof in the treatment of respiratory diseases (e.g., COPD).

Description

Pharmaceutical compositions containing tricyclic rings Technical Field

[0001] This application belongs to the field of pharmaceutical technology and relates to pharmaceutical compositions containing tricyclic rings, their preparation methods and uses, specifically their use in the treatment of respiratory diseases (such as COPD). Background Technology

[0002] In principle, an inhibitor that inhibits both PDE3 and PDE4 will possess both the bronchodilatory effect of a β-adrenergic receptor agonist and the anti-inflammatory effect of an inhaled corticosteroid. This dual-targeting functional complementarity provides a theoretical basis for greater efficacy than single-targeting, achieving therapeutic effects currently only achievable through combination therapy. It overcomes the limitation of incomplete matching of the physicochemical properties of combination drugs, simplifies administration, and facilitates precise dosage. WO2020011254 discloses a compound of formula I, which simultaneously possesses good PDE3 / 4 inhibitory activity and is effective in treating respiratory disorders; it is typically administered via inhalation.

[0003] Dry powder drug formulations administered via dry powder inhalers (DPIs) can deliver an appropriate dose of active agent in an efficient manner. Effective formulations for DPIs typically deliver a high fine particle fraction (FPF, corresponding to the portion of the emission dose with a particle size less than 5 μm). There is a need to develop dry powder formulations that effectively deliver Formula I compounds. It is also desirable to prepare dry powder formulations capable of delivering doses of a variety of different Formula I compounds. Summary of the Invention

[0004] On the one hand, this application provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0005] On the one hand, this application provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and lactose.

[0006] On the other hand, this application provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and magnesium stearate. In some embodiments, the pharmaceutical composition further comprises lactose.

[0007] On the other hand, this application provides a pharmaceutical composition comprising: 1) a compound of formula I or a pharmaceutically acceptable salt thereof; 2) crude lactose granules; and 3) fine lactose granules.

[0008] On the other hand, this application provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof in a single dose of 5-5000 μg.

[0009] On the other hand, this application provides a solid pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0010] In some embodiments, the lactose is selected from lactose or its solvates. In some embodiments, the lactose is selected from lactose or its hydrates. In some embodiments, the lactose is selected from lactose or its monohydrate. In some embodiments, the lactose is selected from α-lactose or β-lactose, or their solvates. In some embodiments, the lactose is selected from α-lactose, β-lactose, or their monohydrates. In some embodiments, the lactose is selected from α-lactose monohydrate. In some embodiments, the lactose is selected from β-lactose monohydrate. In some embodiments, the lactose is selected from 4-O-β-D-galactopyranosyl-D-glucose monohydrate.

[0011] In some embodiments, the pharmaceutical composition further comprises magnesium stearate.

[0012] In some embodiments, magnesium stearate in the pharmaceutical composition is used to improve the flowability of inhaled powder formulations.

[0013] In some embodiments, the magnesium stearate in the pharmaceutical composition is used to improve the stability of a compound of formula I or a pharmaceutically acceptable salt thereof in an inhaled powder formulation.

[0014] In some embodiments, magnesium stearate in the pharmaceutical composition can improve the flowability of inhaled powder formulations.

[0015] In some embodiments, magnesium stearate in the pharmaceutical composition can improve the stability of compound I of formula or its pharmaceutically acceptable salt in inhaled powder formulations.

[0016] In some embodiments, the single dose of the pharmaceutical composition is 5-5000 μg, 5-3000 μg, or 10-2000 μg, or 5-1500 μg, or 15-1500 μg, or 5-1000 μg, or 20-1000 μg, or 25-750 μg, or 30-500 μg.

[0017] In some embodiments, the single dose of the compound I compound or its compound is 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95μg、100μg、105μg、110μg、115μg、120μg、125μg、130μg、135μg、140μg、145 μg、150μg、155μg、160μg、165μg、170μg、175μg、180μg、185μg、190μg、195μg、 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg ,305μg,310μg,315μg,320μg,325μg,330μg,335μg,340μg,345μg,350μg,355μg,360μg,365μg,370μg,375μg,380μg,385μg,390μg,395μg,400μg,405μg g, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490μg, 495μg, 500μg, 505μg, 510 μg、515μg、520μg、525μg、530μg、535μg、540μg、545μg、550μg、555μg、560μg 、565μg、570μg、575μg、580μg、585μg、590μg、595μg、600μg、605μg、610μg、61 5μg, 620μg, 625μg, 630μg, 635μg, 640μg, 645μg, 650μg, 655μg, 660μg, 665μg, 670μg, 675μg, 680μg, 685μg, 690μg, 695μg, 700μg, 705μg, 710μg, 715μg, 7 20μg, 725μg, 730μg, 735μg, 740μg, 745μg, 750μg, 755μg, 760μg, 765μg, 770μg, 775μg, 780μg, 785μg, 790μg, 795μg, 800μg, 805μg, 810μg, 815μg, 820μg,825μg, 830μg, 835μg, 840μg, 845μg, 850μg, 855μg, 860μg, 865μg, 870μg, 875μ g, 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 925μg, 93 0 μg, 935 μg, 940 μg, 945 μg, 950 μg, 955 μg, 960 μg, 965 μg, 970 μg, 975 μg, 980 μg, 985 μg, 990 μg, 995 μg, 1000 μg, 1200 μg, 1500 μg, 2000 μg, 3000 μg, or any range of the above values.

[0018] In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 125 μg to 1500 μg. In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 125 μg, 500 μg, 750 μg, 1000 μg, or 1500 μg. In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 750 μg or 1000 μg. In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 500 μg. In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 750 μg. In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1000 μg. In some embodiments, the single dose of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 1500 μg.

[0019] In some embodiments, the amount of compound I in the pharmaceutical composition is 125 μg to 1500 μg. In some embodiments, the amount of compound I in the pharmaceutical composition is 125 μg, 500 μg, 750 μg, 1000 μg, or 1500 μg. In some embodiments, the amount of compound I in the pharmaceutical composition is 750 μg or 1000 μg. In some embodiments, the amount of compound I in the pharmaceutical composition is 500 μg. In some embodiments, the amount of compound I in the pharmaceutical composition is 750 μg. In some embodiments, the amount of compound I in the pharmaceutical composition is 1000 μg. In some embodiments, the amount of compound I in the pharmaceutical composition is 1500 μg. In some embodiments, the pharmaceutical composition is in the form of a single-dose formulation.

[0020] In some embodiments, the content (by weight percentage) of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 50% to 0.005%, 25% to 0.05%, 21% to 0.04%, or 6% to 0.1%. In some embodiments, the content (by weight percentage) of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 20% to 0.01%, 18% to 0.02%, 15% to 0.1%, or 12% to 0.15%. In some embodiments, the content (by weight percentage) of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 12% to 0.15%, 7% to 4%, 10% to 6%, 3% to 0.2%, or 5.5% to 3%.

[0021] In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6.3%, 5%, 4.3%, 3.3%, 3%, 2%, 1%, 0.56%, 0.5%, 0.4%, 0.27%, 0.2%, 0.11%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%, or any range of the above values.

[0022] In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 17.6%, 12%, 9.6%, 6.7%, 6.3%, 4.3%, 3.3%, 2.4%, 2.3%, 1.0%, 0.88%, 0.87%, 0.83%, 0.73%, 0.72%, 0.56%, 0.27%, 0.18%, 0.11%, 0.036%, or 0.023%, or any range of the above values. In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 17.65%, 17.57%, 12%, 11.95%, 9.6%, 9.55%, 6.7%, 6.67%, 6.64%, 6.38%, 6.35%, 6.33%, 6.3%, 5.08%, 5.06%, 4.35%, 4.34%, 4.33%, 4.31%, 4.32%, and 4. 3%, 3.3%, 3.28%, 3.27%, 2.44%, 2.4%, 2.35%, 2.3%, 1.03%, 1.02%, 1.0%, 0.88%, 0.87%, 0.83%, 0.73%, 0.72%, 0.56%, 0.27%, 0.18%, 0.11%, 0.04%, 0.036%, 0.023%, 0.022%, or 0.02%, or a range consisting of any two of the above values.

[0023] In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 7% to 0.5%. In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 4.5% to 3%. In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 6.3%, 4.3%, or 3.3%, or any range of the foregoing values.

[0024] In some embodiments, the pharmaceutical composition contains, by weight percentage, a compound of formula I or a pharmaceutically acceptable salt thereof selected from 0.27%, 0.88%, 0.87%, 0.02%, 0.56%, 4.35%, 12%, 0.83%, 3.3%, 0.04%, 6.67%, 17.65%, 1.03%, 0.73%, 5.08%, 11.95%, 0.11%, 6.33%, 2.35%, 3.28%, 4.33%, 3.27%, 4.31%, 4.32%, 4.34%, 6.38%, 17.57%, 0.18%, 9.55%, 1.02%, 0.72%, 5.06%, or 6.64%, or a range consisting of any two of the above values.

[0025] In some embodiments, the lactose content (by weight percentage) in the pharmaceutical composition is selected from 99.99%–50%, 99.99%–60%, 99.99%–70%, or 99.99%–80%. In some embodiments, the lactose content, by weight percentage, in the pharmaceutical composition is selected from 99.9%–80%, 99.85%–81%, 99.8%–82%, 99.98%–82.02%, or 99.9%–88%. In some embodiments, the lactose content, by weight percentage, in the pharmaceutical composition is selected from 99.9%–88%, 99.8%–97.5%, 97%–94.5%, 96%–93%, or 94%–89%.

[0026] In some embodiments, the lactose content (by weight) in the pharmaceutical composition is selected from 99.98%, 99.96%, 99.8%, 99.73%, 99.6%, 99.5%, 99.48%, 99.47%, 99.44%, 99.34%, 99.3%, 99.27%, 99.17%, 99.12%, 99.02%, 98.99%, 98.97%, 98.94%, 98.8%, 98.7%, and 98%. 63%, 98.54%, 98.47%, 98.42%, 98.3%, 98.2%, 98.1%, 97.9%, 97.84%, 97.73%, 97.6%, 97.56%, 97.4%, 97.3%, 97.2%, 97.1%, 97.05%, 96.9%, 96.8%, 96.7%, 96.6%, 96.5%, 96.4%, 96.3%, 96.1%, 96%, 95.9%, 95.8% %, 95.7%, 95.65%, 95.5%, 95.4%, 95.3%, 95.2%, 95.1%, 95%, 94.9%, 94.83%, 94.7%, 94.6%, 94.5%, 94.4%, 94.3%, 94.2%, 94.1%, 93.9%, 93.8%, 93.7%, 93.6%, 93.5%, 93.4%, 93.33%, 93.2%, 93.1%, 93%, 92.9%, 92.83%, 92.7%, 92.6%, 92.5%, 92.4%, 92.3%, 92.2%, 92.1%, 91.5%, 91%, 90.5%, 90%, 89.5%, 89.17%, 88.5%, 88%, 87.61%, 87%, 86.5%, 86%, 85.5%, 85%, 84.5%, 84%, 83.5%, 83%, 82.35%, 82.02%, or any range of the above values.

[0027] In some embodiments, the lactose content (by weight) in the pharmaceutical composition is selected from 99.98%, 99.96%, 99.73%, 99.48%, 99.47%, 99.44%, 99.34%, 99.3%, 99.27%, 99.17%, 99.12%, 99.02%, 98.99%, 98.97%, 98.94%, 98%... 0.63%, 98.54%, 98.47%, 98.42%, 98.1%, 97.84%, 97.73%, 97.56%, 97.05%, 95.65%, 94.83%, 93.9%, 93.33%, 92.83%, 89.17%, 88%, 87.61%, 82.35%, 82.02%, or any range of the above values. In some embodiments, the lactose content in the pharmaceutical composition, by weight percentage, is selected from 99.98%, 99.96%, 99.73%, 99.48%, 99.47%, 99.44%, 99.34%, 99.3%, 99.27%, 99.17%, 99.12%, 99.02%, 98.99%, 98.97%, 98.94%, 98.63%, 98.54%, 98.47%, 98.42%, 98.1%, 97.84%, 97. 0.73%, 97.56%, 97.05%, 96.7%, 96.24%, 96.15%, 95.86%, 95.65%, 95.56%, 95.2%, 95.11%, 94.92%, 94.83%, 94.47%, 93.9%, 93.53%, 93.33%, 93.1%, 92.9%, 92.83%, 89.17%, 88%, 87.61%, 82.35%, 82.02%, or a range consisting of any two of the above values.

[0028] In some embodiments, the lactose content (by weight) in the pharmaceutical composition is selected from 99.5% to 91%. In some embodiments, the lactose content (by weight) in the pharmaceutical composition is selected from 99.5% to 92.1%. In some embodiments, the lactose content (by weight) in the pharmaceutical composition is selected from 98.0% to 94.0%.

[0029] In some embodiments, the lactose content in the pharmaceutical composition, by weight percentage, is selected from 99.98%, 99.73%, 99.44%, 95.65%, 88%, 99.17%, 96.7%, 99.12%, 99.96%, 93.33%, 82.35%, 98.97%, 99.27%, 94.92%, 99.3%, 99.48%, 98.94%, 87.61%, 99.34%, 98%, etc. 0.54%, 92.83%, 98.1%, 93.9%, 96.24%, 95.2%, 95.86%, 94.83%, 95.56%, 93.53%, 99.47%, 98.63%, 82.02%, 99.02%, 97.73%, 98.42%, 89.17%, 97.05%, 97.84%, 98.47%, 94.47%, or 92.9%, or a range consisting of any two of the above values.

[0030] In some embodiments, the magnesium stearate content (by weight) in the pharmaceutical composition is selected from 20% to 0%, 10% to 0%, 5% to 0.05%, or 4% to 0.1%. In some embodiments, the magnesium stearate content, by weight percentage, in the pharmaceutical composition is selected from 5% to 0.01%, 4.5% to 0.02%, 4.5% to 0.05%, 4% to 0.05%, 3% to 0.02%, 2.8% to 0.04%, 2.6% to 0.05%, 2.4% to 0.06%, 2.3% to 0.07%, 2.2% to 0.08%, 3.76% to 0.09%, or 2.1% to 0.09%. In some embodiments, the magnesium stearate content in the pharmaceutical composition, by weight percentage, is selected from 4.5% to 0.05%, 4% to 0.1%, 1% to 0.4%, 1% to 0.1%, or 1.5% to 0.09%.

[0031] In some embodiments, the magnesium stearate content (by weight) in the pharmaceutical composition is selected from 5%, 4.5%, 4%, 3.76%, 3%, 2.5%, 2.08%, 1.41%, 1.4%, 1.34%, 1.27%, 1.14%, 0.9%, 0.86%, 0.84%, 0.81%, 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.49%, 0.44%, 0.43%, 0.41%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, 0.05%, 0%, or any combination of the above values. In some embodiments, the magnesium stearate content in the pharmaceutical composition, by weight percentage, is selected from 5%, 4.5%, 4%, 3.76%, 3%, 2.5%, 2.08%, 1.41%, 1.4%, 1.34%, 1.27%, 1.14%, 0.94%, 0.92%, 0.9%, 0.87%, 0.86%, 0.84%, 0.81%, 0%, and 0%, respectively. 0.75%, 0.7%, 0.65%, 0.6%, 0.55%, 0.5%, 0.49%, 0.48%, 0.47%, 0.46%, 0.44%, 0.43%, 0.41%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, 0.09%, 0.05%, 0%, or a range consisting of any two of the above values.

[0032] In some embodiments, the magnesium stearate content (by weight) in the pharmaceutical composition is selected from 3.76%, 2.08%, 1.41%, 1.4%, 1.34%, 1.27%, 1.14%, 0.9%, 0.86%, 0.84%, 0.81%, 0.5%, 0.49%, 0.44%, 0.43%, 0.41%, 0.1%, 0%, or any range of the above values. In some embodiments, the magnesium stearate content (by weight) in the pharmaceutical composition is selected from 0.2% to 4%, or 0.2% to 0.9%, or 0.4% to 0.8%.

[0033] In some embodiments, the magnesium stearate content in the pharmaceutical composition, by weight percentage, is selected from 0%, 0.43%, 0.5%, 0.49%, 0.44%, 0.1%, 0.9%, 0.84%, 1.34%, 3.76%, 0.48%, 0.87%, 0.86%, 0.09%, 0.41%, 1.4%, 1.41%, 1.27%, 2.08%, 1.14%, 0.81%, 0.55%, 0.56%, 0.57%, 0.47%, or 0.46%, or a range of any two of the above values.

[0034] In some embodiments, the weight ratio of lactose to the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from (5000–1):1, (4500–3):1, (2000–5):1, or (1800–250):1. In some embodiments, the weight ratio of lactose to the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 4500:1 to 4:1, 4400:1 to 4.6:1, or 2800:1 to 7:1.

[0035] In some embodiments, the content (weight ratio) of lactose to the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is selected from 5000:1, 4500:1, 4400:1, 3500:1, 2800:1, 2400:1, 2300:1, 2200:1, 2100:1, 2000:1, 1900:1, 1800:1, 1750:1, 1700:1, 1650:1, 1600:1, 1550:1, 1500:1, 1450:1, 1400:1, 1350:1, 1300:1, 1250:1, 1200:1, 1150:1, 1100:1, 1000:1, 950:1, 900:1, 880:1, 85 0:1, 800:1, 750:1, 700:1, 650:1, 600:1, 560:1, 550:1, 500:1, 450:1, 400:1, 368:1, 350:1, 300:1, 250:1, 200:1, 176:1, 150:1, 136:1, 120:1, 112:1, 10 0:1, 96:1, 90:1, 80:1, 70:1, 60:1, 50:1, 44:1, 40:1, 30:1, 29:1, 22:1, 20:1, 15:1, 14:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1, or a range of any of the above values.

[0036] In some embodiments, the content (by weight) of lactose to the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 4400:1, 2800:1, 880:1, 560:1, 368:1, 176:1, 136:1, 120:1, 112:1, 96:1, 40:1, 22:1, 15:1, 14:1, 9:1, 7:1, 5:1, or any range of the above values. In some embodiments, the content (by weight) of lactose to the compound of Formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 176:1 to 14:1, or from 29:1 to 22:1.

[0037] In some embodiments, the weight ratio of lactose to the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is selected from 4400:1, 176:1, 22:1, 7.3:1, 7.4:1, 120:1, 368:1, 29.3:1, 29.4:1, 2800:1, 112:1, 14:1, 4.6:1, 4.7:1, 96:1, 136:1, 880:1, 14.6:1, 14.7:1, 40:1, 18.6:1, 18.7:1, 560:1, 9.3:1, or 9.4:1, or a range consisting of any two of the above values.

[0038] In some embodiments, the content (weight ratio) of magnesium stearate to the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is selected from (50 to 0.001):1, (30 to 0.01):1, (25 to 0.01):1 or (22 to 0.02):1.

[0039] In some embodiments, the content (by weight) ratio of magnesium stearate to the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is selected from 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9.5:1, 9:1, 8.5:1, 8:1, 7.5:1, 7:1, 6.5: 1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.4:1, 2:1, 1.6:1, 1.1:1, 0.88:1, 0.8:1, 0.7:1, 0.56:1, 0.4:1, 0.3:1, 0.2:1, 0.18:1, 0.13:1, 0.11:1, 0.09:1, 0.08:1, 0.07:1, 0.06:1, 0.05:1, 0.04:1 or 0.02:1, or any range of the above values. In some embodiments, the weight ratio of magnesium stearate to the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 20:1 to 0.005:1, 18:1 to 0.008:1, 16:1 to 0.01:1, or 14:1 to 0.014:1.

[0040] In some embodiments, the content (weight ratio) of magnesium stearate to the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is selected from 22:1, 14:1, 8:1, 2.4:1, 1.6:1, 1.1:1, 0.88:1, 0.56:1, 0.2:1, 0.18:1, 0.17:1, 0.13:1, 0.11:1, 0.09:1, 0.04:1, or 0.02:1, or any range of the above values.

[0041] In some embodiments, the content (weight ratio) of magnesium stearate to the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is selected from 2:1 to 0.02:1, or from 1.6:1 to 0.11:1.

[0042] In some embodiments, the pharmaceutical composition comprises magnesium stearate, wherein the weight ratio of magnesium stearate to the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 2:1, 0.88:1, 0.036:1, 0.037:1, 0.176:1, 1.6:1, 8:1, 0.13:1, 0.14:1, 2.4:1, 0.15:1, 0.26:1, 0.27:1, 0.11:1, 0.2:1, 0.022:1, 0.014:1, 0.015:1, 14:1, 0.56:1, 0.023:1, 0.024:1, 0.112:1, 1.12:1, 0.093:1, 0.094:1, 0.17:1, or 0.07:1, or a range consisting of any two of the above values.

[0043] In some embodiments, the pharmaceutical composition comprises lactose and magnesium stearate.

[0044] In some embodiments, the ratio (by weight) of lactose to magnesium stearate in the pharmaceutical composition is selected from (5000–10):1, (3000–20):1, (2000–30):1, (1000–40):1, (300–100):1, or (150–100):1. In some embodiments, the weight ratio of lactose to magnesium stearate in the pharmaceutical composition is selected from 2000:1 to 20:1, 1500:1 to 22:1, or 1000:1 to 25:1.

[0045] In some embodiments, the ratio of lactose to magnesium stearate (by weight) in the pharmaceutical composition is selected from 2000:1, 1500:1, 1000:1, 950:1, 900:1, 850:1, 800:1, 750:1, 700:1, 650:1, 600:1, 550:1, 500:1, 450:1, 400:1, 350:1, 300:1, 250:1, 230:1, 200:1, 17... 0:1, 150:1, 140:1, 130:1, 121:1, 120:1, 110:1, 100:1, 90:1, 86:1, 80:1, 73:1, 70:1, 60:1, 50:1, 47:1, 40:1, 30:1, 25:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1, or any range of the above values.

[0046] In some embodiments, the ratio (by weight) of lactose to magnesium stearate in the pharmaceutical composition is selected from 1000:1, 230:1, 200:1, 121:1, 110:1, 86:1, 73:1, 70:1, 47:1, or 25:1, or any range of the above values.

[0047] In some embodiments, the ratio (by weight) of lactose to magnesium stearate in the pharmaceutical composition is selected from 400:1 to 100:1.

[0048] In some embodiments, the weight ratio of lactose to magnesium stearate in the pharmaceutical composition is selected from 200:1, 1000:1, 110:1, 73.3:1, 73.4:1, 25:1, 230:1, 70:1, 46.6:1, 46.7:1, 85.7:1, 85.8:1, 121.4:1, 169:1, or 121.5:1, or a range consisting of any two of the above values.

[0049] In some embodiments, the pharmaceutical composition comprises coarse lactose particles. In some embodiments, the pharmaceutical composition comprises fine lactose particles. In some embodiments, the pharmaceutical composition comprises a mixture of coarse and fine lactose particles. As those skilled in the art will understand, there may be some overlap between the particle size distributions of the coarse and fine particles.

[0050] In some embodiments, the lactose in the pharmaceutical composition has a particle size distribution (Dv90) of 5–500 μm; or, Dv90 of 10–300 μm; or, Dv90 of 15–250 μm; or, Dv90 of 15–200 μm; or, Dv90 of 18–194 μm; or, Dv90 of 50–250 μm; or, Dv90 of 50–220 μm; or, Dv90 of 50–210 μm.

[0051] In some embodiments, the lactose particle size distribution (Dv90) in the pharmaceutical composition is 60–200 μm, 65–195 μm, or 65–194 μm. In some embodiments, the lactose particle size distribution (Dv90) in the pharmaceutical composition is 65–140 μm.

[0052] In some embodiments, the lactose in the pharmaceutical composition has a particle size distribution (Dv50) of 1–200 μm; or, Dv50 of 5–180 μm; or, Dv50 of 5–150 μm; or, Dv50 of 5–120 μm; or, Dv50 of 8–100 μm; or, Dv50 of 15–120 μm; or, Dv50 of 15–120 μm; or, Dv50 of 15–110 μm.

[0053] In some embodiments, the lactose particle size distribution (Dv50) in the pharmaceutical composition is 15–110 μm, 20–100 μm, 20–70 μm, or 20–66 μm. In some embodiments, the lactose particle size distribution (Dv50) in the pharmaceutical composition is 20–60 μm.

[0054] In some embodiments, the lactose in the pharmaceutical composition has a particle size Dv10 of 0.5–100 μm; or Dv10 of 1–80 μm; or Dv10 of 1–70 μm; or Dv10 of 1–60 μm; or Dv10 of 1–53 μm; or Dv10 of 1–40 μm; or Dv10 of 1–30 μm; or Dv10 of 1–20 μm.

[0055] In some embodiments, the lactose particle size distribution (Dv10) in the pharmaceutical composition is 1–70 μm, 1–60 μm, 1–55 μm, or 1–53 μm. In some embodiments, the lactose particle size distribution (Dv10) in the pharmaceutical composition is 1–6 μm.

[0056] In some embodiments, the lactose in the pharmaceutical composition has a particle size distribution of Dv90 of 5–500 μm, Dv50 of 1–200 μm, and Dv10 of 0.5–100 μm; or, Dv90 of 10–300 μm, Dv50 of 5–180 μm, and Dv10 of 1–80 μm; or, Dv90 of 15–250 μm, Dv50 of 5–150 μm, and Dv10 of 1–70 μm; or, Dv90 of 15–200 μm, Dv50 of 5–120 μm, and Dv10 of 0.5–100 μm. v10 is 1–60 μm; or, Dv90 is 18–194 μm, Dv50 is 8–100 μm, and Dv10 is 1–53 μm; or, Dv90 is 50–250 μm, Dv50 is 15–120 μm, and Dv10 is 1–40 μm; or, Dv90 is 50–220 μm, Dv50 is 15–120 μm, and Dv10 is 1–30 μm; or, Dv90 is 50–210 μm, Dv50 is 15–110 μm, and Dv10 is 1–20 μm.

[0057] In some specific embodiments, the lactose in the pharmaceutical composition has a particle size distribution (Dv90) of 115–170 μm, a particle size distribution (Dv50) of 75–95 μm, and a particle size distribution (Dv10) of 20–50 μm.

[0058] In some specific embodiments, the lactose in the pharmaceutical composition has a particle size distribution of Dv90 of 120–160 μm, Dv50 of 50–100 μm, and Dv10 of 5–15 μm.

[0059] In some specific embodiments, the lactose in the pharmaceutical composition has a particle size distribution (Dv90) of 124–194 μm, a Dv50 of 37–61 μm, and a Dv10 of 3–7 μm.

[0060] In some specific embodiments, the lactose in the pharmaceutical composition has a particle size distribution (Dv90) of 65–140 μm, a particle size distribution (Dv50) of 20–60 μm, and a particle size distribution (Dv10) of 1–6 μm.

[0061] In some specific embodiments, the lactose particles in the pharmaceutical composition have a Dv90 of 65–140 μm, a Dv50 of 20–66 μm, and a Dv10 of 1–53 μm. In some specific embodiments, the lactose particles in the pharmaceutical composition have a Dv90 of 65–140 μm, a Dv50 of 20–50 μm, and a Dv10 of 1–6 μm. In some specific embodiments, the lactose particles in the pharmaceutical composition have a Dv90 of 75–106 μm, a Dv50 of 53–66 μm, and a Dv10 of 19–53 μm.

[0062] In some embodiments, the lactose in the pharmaceutical composition is selected from LH206 lactose, LH200 lactose, ML001 lactose, ML003 lactose, SV003 lactose, LH300 lactose, Inhalac230 lactose, Inhalac180 lactose, Inhalac140 lactose, Inhalac145 lactose, or Inhalac 500 lactose (commercially available).

[0063] In some embodiments, the magnesium stearate in the pharmaceutical composition has a particle size distribution (Dv90) of 10–100 μm; or, a Dv90 of 10–50 μm; or, a Dv90 of 15–35 μm.

[0064] In some embodiments, the magnesium stearate in the pharmaceutical composition has a particle size distribution (Dv50) of 5–50 μm; or a Dv50 of 5–20 μm; or a Dv50 of 5–15 μm.

[0065] In some embodiments, the magnesium stearate in the pharmaceutical composition has a particle size distribution (Dv10) of 1–20 μm; or, a Dv10 of 1–10 μm; or, a Dv10 of 1.5–6 μm.

[0066] In some embodiments, the magnesium stearate particles in the pharmaceutical composition have a particle size distribution (Dv90) of 10–100 μm; a particle size distribution (Dv50) of 5–50 μm; a particle size distribution (Dv10) of 1–20 μm; or, a particle size distribution (Dv90) of 10–50 μm; a particle size distribution (Dv50) of 5–20 μm; a particle size distribution (Dv10) of 1–10 μm; or, a particle size distribution (Dv90) of 15–35 μm; a particle size distribution (Dv50) of 5–15 μm; a particle size distribution (Dv10) of 1.5–6 μm.

[0067] In some specific embodiments, the magnesium stearate particles in the pharmaceutical composition have a particle size distribution (Dv90) of 18–28 μm, a particle size distribution (Dv50) of 8–11 μm, and a particle size distribution (Dv10) of 2.5–4 μm.

[0068] In some embodiments, the pharmaceutical composition contains a particle size Dv50 ≤ 5 μm for the compound of formula I or a pharmaceutically acceptable salt thereof; or, Dv50 ≤ 4 μm; or, Dv50 ≤ 2 μm; or, 0.5 μm < Dv50 ≤ 2 μm; or, 0.8 μm < Dv50 ≤ 2 μm; or, 1 μm < Dv50 ≤ 1.5 μm. In some embodiments, the pharmaceutical composition contains a particle size 1 μm < Dv50 ≤ 3 μm for the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains a particle size 1 μm < Dv50 ≤ 2 μm for the compound of formula I or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the pharmaceutical composition may also additionally contain excipients.

[0070] This application also provides a dry powder inhaler that contains the (dry powder) pharmaceutical composition of this application.

[0071] In some embodiments, this application relates to the following pharmaceutical compositions:

[0072] Compound of Formula I, 7% to 0.5% by weight

[0073] Lactose 99.5%–91% by weight

[0074] Magnesium stearate 0% to 4% by weight.

[0075] In some embodiments, this application relates to the following pharmaceutical compositions:

[0076] Compound of Formula I, 500 mg, 750 mg or 1000 mg

[0077] Lactose 99.5%–91% by weight

[0078] Magnesium stearate 0% to 4% by weight.

[0079] In some embodiments, this application relates to the following pharmaceutical compositions:

[0080] Compound of Formula I, 500 μg to 1500 μg

[0081] Lactose 15mg~22mg

[0082] Magnesium stearate 0.11mg~0.3mg.

[0083] In some embodiments, this application relates to the following pharmaceutical compositions:

[0084] Compound of Formula I, 500 μg to 1000 μg

[0085] Lactose 15mg~22mg

[0086] Magnesium stearate 0.11mg~0.3mg.

[0087] In some embodiments, this application relates to the following pharmaceutical compositions:

[0088] Compound of Formula I, 500 μg to 1000 μg

[0089] Lactose 5mg~46mg

[0090] Magnesium stearate 0.014 mg to 0.3 mg.

[0091] In some embodiments, this application relates to the following pharmaceutical compositions:

[0092] Compound of Formula I, 500 μg, 750 μg or 1000 μg

[0093] Lactose 5mg, 12mg, 14mg, 15mg, 17mg, 22mg or 46mg

[0094] Magnesium stearate in the following doses: 0.3 mg, 0.2 mg, 0.13 mg, 0.14 mg, 0.11 mg, 0.07 mg, 0.022 mg, or 0.014 mg.

[0095] In some embodiments, the particle size, content, and ratio of the Formula I compound, lactose, and magnesium stearate are as described in this application. In some embodiments, the pharmaceutical composition is administered by inhalation. In some embodiments, the pharmaceutical composition is a solid inhalation formulation. In some embodiments, the pharmaceutical composition is a dry powder pharmaceutical composition. In some embodiments, the pharmaceutical composition is a dry powder pharmaceutical composition administered by inhalation (e.g., an inhaled powder aerosol).

[0096] The Dv50 (as well as Dv10 and Dv90) values ​​described in this application were measured using a NeoPatek laser particle size analyzer.

[0097] The pharmaceutical compositions of this application are generally suitable for administration via a dry powder inhaler. For example, the dry powder pharmaceutical compositions may be suitable for administration via a capsule dry powder inhaler, a blister dry powder inhaler, or a reservoir dry powder inhaler. For example, the dry powder pharmaceutical compositions may be capsule dry powder, blister dry powder, or reservoir dry powder.

[0098] The pharmaceutical compositions of this application can be prepared using standard formulation methods. Optionally, the dry powder pharmaceutical composition can be prepared by a method comprising mixing granules of a compound of formula I or a pharmaceutically acceptable salt thereof with lactose granules, optionally including mixing with magnesium stearate granules. A high-shear mixer can be used to mix the components. Specifically, this includes sieving lactose and mixing it with a compound of formula I or a pharmaceutically acceptable salt thereof. Alternatively, lactose can be mixed with magnesium stearate to obtain a carrier. The resulting carrier is then mixed with a compound of formula I or a pharmaceutically acceptable salt thereof. The mixing can be performed using a hopper mixer or a high-shear mixer (PCM, MPM, QMM, PMA, or TRV series mixers, such as TRV25 or TRV65) or a low-shear tumbler mixer or a Cyclomix mixer.

[0099] In some embodiments, the mixing speed is 50-1000 rpm, or 120-800 rpm, or 120-300 rpm, or 120-150 rpm, or 100-150 rpm.

[0100] In some implementations, the mixing speed is 80-800 rpm, or 80-300 rpm, or 80-200 rpm.

[0101] In some implementations, the mixing speed is approximately 100 rpm, 120 rpm, 150 rpm, 170 rpm, 300 rpm, or 800 rpm.

[0102] In some implementations, the mixing time is 1-10 minutes or 2-5 minutes.

[0103] In some implementations, the mixing speed is 120-800 rpm and the mixing time is 2-5 min.

[0104] In some embodiments, the mixing is performed under the following conditions: mixing at 100 rpm for 2 minutes, mixing at 100 rpm for 5 minutes, mixing at 120 rpm for 2 minutes, mixing at 120 rpm for 5 minutes, mixing at 150 rpm for 2 minutes, mixing at 150 rpm for 5 minutes, mixing at 170 rpm for 5 minutes, mixing at 300 rpm for 5 minutes, or mixing at 800 rpm for 5 minutes.

[0105] The resulting mixture can be packaged in hydroxypropyl methylcellulose (HPMC) capsules or blister packs.

[0106] This application provides a dry powder inhaler (DPI) comprising the pharmaceutical composition described herein. The DPI may be a blister DPI, a capsule DPI, or a reservoir-type DPI. DPIs are well known to those skilled in the art, and many such devices are commercially available. Representative dry powder inhalers include Aerolizer™ (Novartis), Airmax™ (IV AX), ClickHaler™ (Innovata Biomed), Diskhaler™ (GlaxoSmithKline), Diskus™ or Accuhaler™ (GlaxoSmithKline), Easyhaler™ (Orion Pharma), Eclipse™ (Aventis), FlowCaps™ (Hovione), Handihaler™ (Boehringer Ingelheim), Pulvinal™ (Chiesi), Rotahaler™ (GlaxoSmithKline), SkyeHaler™ or Certihaler™ (SkyePharma), Twisthaler™ (Schering-Plough), Turbuhaler™ (AstraZeneca), Ultrahaler™ (Aventis), and Plasciape. RS01 dry powder inhaler (RPC), Powdair (Hovione), MRX003 (Merxin), and MRX001 (Merxin).

[0107] This application also provides the (dry powder) pharmaceutical composition of the present invention for treating human or animal bodies.

[0108] The pharmaceutical composition described in this application is used to treat human or animal bodies.

[0109] Typically, the emission dose from a DPI containing the pharmaceutical composition described in this application is 70% to 95% of the quantitatively set dose.

[0110] Typically, the pharmaceutical composition of this application is administered to the patient by inhaling a DPI 1 to 8 times daily. For example, the pharmaceutical composition may be administered to the patient by inhaling 1 or 2 times daily, up to a maximum of four times daily.

[0111] Fine particle fraction (FPF) is a portion of the emission dose of a Formula I compound or its pharmaceutically acceptable salt particles having an aerodynamic particle size of less than or equal to 5 μm. The emission dose is the total amount of Formula I compound or its pharmaceutically acceptable salt particles emitted by a dry powder inhaler device containing the pharmaceutical composition described in this application.

[0112] This application also provides a pharmaceutical composition of the present application for a method of treating a disease or disease state as defined herein, the method comprising inhaling (or actuating) a dry powder inhaler containing the dry powder pharmaceutical composition, wherein, after inhalation (or actuation), the fine particle fraction of the Formula I compound or its pharmaceutically acceptable salt is at least 20%. After inhalation, the fine particle fraction of the Formula I compound or its pharmaceutically acceptable salt particles is generally at least 30%, preferably at least 35%. The fine particle fraction may be at least 40%. The fine particle fraction may be at least 50%.

[0113] In some embodiments, the pulmonary deposition rate of the compound of formula I or its pharmaceutically acceptable salt in the pharmaceutical composition is not less than 20%, preferably not less than 30%, more preferably not less than 35%, further preferably not less than 40%, and even more preferably not less than 50%.

[0114] In some embodiments, the pulmonary deposition rate of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is not less than 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 4 7%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%, or any range of the above values.

[0115] In some embodiments, the pharmaceutical composition, when administered by inhalation, contains a fine particle fraction of not less than 20%, preferably not less than 30%, more preferably not less than 35%, further preferably not less than 40%, and even more preferably not less than 50%.

[0116] In some embodiments, the pharmaceutical composition, after administration by inhalation, contains a fine particle fraction of not less than 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, or 46%. 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%, or any range of the above values.

[0117] This application provides a method for treating or preventing a disease, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition described herein.

[0118] On the other hand, this disclosure provides compositions of the medicaments described herein for the treatment or prevention of diseases.

[0119] On the other hand, this disclosure provides the use of the pharmaceutical composition in the preparation of medicaments for treating or preventing diseases.

[0120] On the other hand, this disclosure provides for the use of the pharmaceutical composition in the treatment or prevention of disease.

[0121] On the other hand, this disclosure provides a kit containing the pharmaceutical composition, and instructions for use of the pharmaceutical composition for treating or preventing diseases.

[0122] In some embodiments, the disease is selected from lung diseases; in some embodiments, the treatment or prevention of the disease is selected from anti-inflammatory or bronchodilatory effects.

[0123] In some embodiments, the lung disease is selected from respiratory diseases and inflammatory diseases; in other embodiments, the lung disease is selected from COPD or asthma.

[0124] This application provides a method for treating or preventing respiratory and inflammatory diseases (e.g., COPD), comprising administering a therapeutically effective amount of the pharmaceutical composition described in this application to a subject.

[0125] On the other hand, this disclosure provides pharmaceutical compositions described herein for the treatment or prevention of respiratory and inflammatory diseases (such as COPD).

[0126] On the other hand, this disclosure provides the use of the pharmaceutical composition in the preparation of medicaments for treating or preventing respiratory and inflammatory diseases (e.g., COPD).

[0127] On the other hand, this disclosure provides the use of the pharmaceutical composition in the treatment or prevention of respiratory and inflammatory diseases (e.g., COPD). Furthermore, this disclosure provides a kit containing the pharmaceutical composition, along with instructions for use of the pharmaceutical composition for the treatment or prevention of respiratory and inflammatory diseases (e.g., COPD).

[0128] In some implementations, the respiratory and inflammatory diseases include symptoms such as insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration.

[0129] This disclosure provides a method for improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung disease, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition described in this application.

[0130] On the other hand, this disclosure provides a pharmaceutical composition as described in this application for improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung diseases.

[0131] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in the preparation of a medicament for improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung diseases.

[0132] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung diseases.

[0133] In some embodiments, in the methods or uses described in this disclosure, the pharmaceutical composition of this application is used to exert at least one of bronchodilatory and anti-inflammatory effects.

[0134] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, and instructions for use of the salt of the pharmaceutical composition to improve or eliminate symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited activity, cough, or expectoration in patients with lung diseases.

[0135] Furthermore, this disclosure provides the use of the kit of this disclosure in the preparation of medicaments for improving or eliminating symptoms of insomnia, lack of energy, dyspnea, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung diseases.

[0136] This disclosure provides a method for improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung disease, comprising administering a therapeutically effective amount of the kit of this disclosure to an individual in need.

[0137] This disclosure provides the use of the kit disclosed herein in improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung disease.

[0138] This disclosure provides a kit for improving or eliminating symptoms of insomnia, lack of energy, difficulty breathing, wheezing, chest tightness, fatigue, limited mobility, cough, or expectoration in patients with lung disease.

[0139] This disclosure provides a method for improving sleep quality in patients with lung disease caused by lung disease, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition described in this application.

[0140] On the other hand, this disclosure provides a pharmaceutical composition as described in this application for improving symptoms of reduced sleep quality in patients with lung disease caused by lung disease.

[0141] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in the preparation of a medicament for improving symptoms of reduced sleep quality in patients with lung disease caused by lung disease.

[0142] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in improving symptoms of reduced sleep quality in patients with lung disease caused by lung disease.

[0143] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, and instructions for use of the pharmaceutical composition described in this application to improve the symptoms of reduced sleep quality in patients with lung disease caused by lung disease.

[0144] Furthermore, this disclosure provides the use of the kit of this disclosure in the preparation of a medicament to improve the symptoms of reduced sleep quality in patients with lung disease caused by lung disease.

[0145] This disclosure provides a method for improving symptoms of reduced sleep quality in patients with lung disease, which includes administering a therapeutically effective amount of the kit of this disclosure to an individual in need.

[0146] This disclosure provides the use of the kit disclosed herein in improving sleep quality in patients with lung disease caused by lung disease.

[0147] This disclosure provides a kit for improving sleep quality in patients with lung disease caused by lung disease.

[0148] On the other hand, this disclosure provides a pharmaceutical composition for improving sleep quality in patients with lung disease caused by lung disease, comprising the pharmaceutical composition described in this application.

[0149] In some embodiments of this disclosure, the pharmaceutical composition is packaged in a kit, which further includes instructions for using the pharmaceutical composition of this application to improve sleep quality in patients with lung disease caused by lung disease.

[0150] In some implementations, the methods, uses, compositions, and kits may also include administering a therapeutically effective amount of one or more other drugs to a patient.

[0151] In some embodiments, the methods, uses, compositions, and kits further include administering a therapeutically effective amount of a single- or dual-bronchodilator to a patient; in some embodiments, an anti-inflammatory drug is further included; and in some embodiments, ICS is further included. In some embodiments, the anti-inflammatory drug is selected from ICS.

[0152] In some embodiments, the methods, uses, compounds, compositions, and kits further include administering a therapeutically effective amount of LABA, LAMA, and / or ICS to a patient. In some embodiments, the methods, uses, compounds, compositions, and kits further include administering a therapeutically effective amount of one, two, or three of LABA, LAMA, or ICS to a patient.

[0153] In some implementations, the method, use, compound, composition, and kit may further include administering a therapeutically effective amount of LABA to a patient.

[0154] In some implementations, the methods, uses, compounds, compositions, and kits may further include administering a therapeutically effective amount of LAMA to a patient.

[0155] In some embodiments, the methods, uses, compounds, compositions, and kits may further include administering therapeutically effective amounts of LABA and LAMA to a patient.

[0156] In some embodiments, the methods, uses, compounds, compositions, and kits may further include administering therapeutically effective amounts of LABA, LAMA, and ICS to a patient.

[0157] In some implementations, the methods, uses, compounds, compositions, and kits may further include administering therapeutically effective amounts of LABA and ICS to a patient.

[0158] In some embodiments, the single- or dual-bronchodilator is used as background treatment for lung disease. In some embodiments, the single- or dual-bronchodilator, used as background treatment for lung disease, further includes ICS (intracytoplasmic sinusoids) as background treatment.

[0159] In some implementations, the LABA, LAMA, or ICS are used as background treatment for lung diseases.

[0160] On the other hand, this disclosure provides for the combination (or combination) of the pharmaceutical composition described in this application with one or more other pharmaceuticals.

[0161] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in the preparation of a medicament for the treatment or prevention of lung diseases in combination with one or more other drugs.

[0162] On the other hand, this disclosure provides the use of one or more other drugs in the preparation of a medicament for the treatment or prevention of lung diseases in combination with the pharmaceutical composition described in this application.

[0163] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in the preparation of a medicament for treating or preventing lung diseases, wherein the treatment or prevention further comprises administering one or more other medicaments.

[0164] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in combination with one or more other drugs in the preparation of a medicament for treating or preventing lung diseases.

[0165] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, and instructions for use of the pharmaceutical composition described in this application in combination with one or more other drugs for the treatment or prevention of lung diseases.

[0166] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, and instructions for use of the pharmaceutical composition for treating or preventing lung diseases treated with one or more other drugs as a background.

[0167] Furthermore, this disclosure provides the use of the kit disclosed herein in the preparation of a medicament for the treatment or prevention of lung diseases in combination with one or more other drugs.

[0168] In another aspect, this disclosure provides the use of the kit of this disclosure in the preparation of a medicament for the treatment or prevention of lung diseases, wherein the treatment or prevention further comprises administering one or more other medicaments.

[0169] Furthermore, this disclosure provides the use of the kit disclosed herein in the preparation of medicaments for treating or preventing lung diseases treated in the background of one or more other drugs.

[0170] This disclosure provides a method for treating or preventing lung diseases treated in the background with one or more other drugs, comprising administering a therapeutically effective amount of the kit of this disclosure to an individual in need.

[0171] This disclosure provides the use of the kit of this disclosure in the treatment or prevention of lung diseases treated in the background of one or more other drugs.

[0172] This disclosure provides a kit for treating or preventing lung diseases treated in the presence of one or more other drugs.

[0173] In some embodiments of this disclosure, the pharmaceutical composition is packaged in a kit that also includes instructions for using the pharmaceutical composition of this application to treat or prevent lung diseases treated with one or more other drugs in the background.

[0174] This application provides a method for treating or preventing lung disease, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition described in this application and one or more other pharmaceuticals.

[0175] On the other hand, this disclosure provides a combination of the pharmaceutical composition described in this application and one or more other pharmaceuticals for the treatment or prevention of lung diseases.

[0176] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application and a combination of one or more other pharmaceuticals in the preparation of a medicament for treating or preventing lung diseases.

[0177] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application and combinations of one or more other pharmaceuticals in the treatment or prevention of lung diseases.

[0178] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, as well as instructions for use of the pharmaceutical composition described in this application and one or more other drugs for the treatment or prevention of lung diseases.

[0179] In some implementations, the other drugs are used as background treatment.

[0180] In some embodiments, the other drugs are selected from bronchodilators. In some embodiments, the other drugs further comprise anti-inflammatory drugs.

[0181] In some implementations, the other drugs are selected from single-breast vasodilators, dual-breast vasodilators, or anti-inflammatory drugs.

[0182] In some implementations, the other drugs are selected from single-bronchodilator drugs, dual-bronchodilator drugs, or triple therapy drugs containing anti-inflammatory components.

[0183] In some embodiments, the other drugs are selected from one, two, or three of LABA, LAMA, or ICS.

[0184] In some embodiments, the other drugs are selected from LABA and / or LAMA.

[0185] In some implementations, the other drug is LABA.

[0186] In some implementations, the other drug is LAMA.

[0187] In some implementations, the other drug is LABA / LAMA.

[0188] In some implementations, the other drugs are LABA / LAMA / ICS.

[0189] In some embodiments, the LAMA is selected from tiotropium bromide, omeprazole bromide, adecyl bromide, glycopyrronium, refenazine, darotropium, or glycopyrronium bromide; the LABA is selected from salmeterol, formoterol, afortrol, indacaterol, vilanterol, olodaterol, abeteterol, or carmoterol; and / or the ICS is selected from beclomethasone (e.g., beclomethasone propionate), budesonide, fluticasone (fluticasone propionate, fluticasone furoate), cicsolone, or mometasone.

[0190] In some embodiments, the LABA / LAMA is selected from umeclidinium / vilanterol, indacaterol / glycopyrronium bromide, tiotropium bromide / olodaterol, glycopyrronium bromide / formoterol, budesonide / formoterol, ademethorphanium bromide / formoterol, or salmeterol / ticasone.

[0191] In some embodiments, the LABA / LAMA / ICS is selected from budesonide / formoterol / glycopyrronium bromide, fluticasone / umetromex / vilanterol, or beclomethasone propionate / formoterol fumarate / glycopyrronium bromide.

[0192] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in the preparation of a medicament for the treatment or prevention of lung diseases when used in combination with a single or dual bronchodilator.

[0193] On the other hand, this disclosure provides the use of single- or dual-bronchodilator drugs in the preparation of medicaments for use in combination with the pharmaceutical compositions described in this application to treat or prevent lung diseases.

[0194] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in the preparation of a medicament for treating or preventing lung diseases, wherein the treatment or prevention further comprises administering a single- or dual-bronchodilator drug.

[0195] On the other hand, this disclosure provides the use of the pharmaceutical composition described in this application in combination with a single- or dual-bronchodilator drug in the preparation of a medicament for the treatment or prevention of lung diseases.

[0196] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, and instructions for use of the pharmaceutical composition described in this application in combination with a single- or dual-bronchodilator drug for the treatment or prevention of lung diseases.

[0197] On the other hand, this disclosure provides a kit containing the pharmaceutical composition described in this application, and instructions for use of the pharmaceutical composition for treating or preventing lung diseases treated with a single or dual bronchodilator as background therapy.

[0198] Furthermore, this disclosure provides the use of the kit disclosed herein in the preparation of medicaments for the treatment or prevention of lung diseases in combination with single or dual bronchodilators.

[0199] In another aspect, this disclosure provides the use of the kit of this disclosure in the preparation of a medicament for the treatment or prevention of lung diseases, wherein the treatment or prevention further comprises administering a single- or dual-bronchodilator drug.

[0200] Furthermore, this disclosure provides the use of the kit of this disclosure in the preparation of medicaments for the treatment or prevention of lung diseases treated with a single or dual bronchodilator as a background therapy.

[0201] This disclosure provides a method for treating or preventing lung diseases treated with a single or dual bronchodilator as background therapy, comprising administering a therapeutically effective amount of the kit of this disclosure to an individual in need.

[0202] This disclosure provides the use of the kits disclosed herein in the treatment or prevention of lung diseases treated with a single or dual bronchodilation agent as background therapy.

[0203] This disclosure provides a kit for treating or preventing lung diseases treated with a single or dual bronchodilation drug as a background treatment.

[0204] In some embodiments of this disclosure, the pharmaceutical composition is packaged in a kit, which further includes instructions for using the pharmaceutical composition of this application to treat or prevent lung diseases treated with a single or dual bronchodilator as background therapy.

[0205] In some embodiments, the treatment or prevention of lung disease includes improving lung function, or improving or eliminating one or more of the following symptoms in patients with lung disease: insomnia, dyspnea, wheezing, chest tightness, fatigue, limited activity, cough, or expectoration. In some embodiments, the treatment or prevention of lung disease includes improving or eliminating recurrent acute exacerbations in patients with lung disease. In some embodiments, the treatment or prevention of lung disease includes improving sleep quality in patients with lung disease due to lung disease. In some embodiments, improving or eliminating the symptoms of insomnia, lack of energy, dyspnea, wheezing, chest tightness, fatigue, limited activity, cough, or expectoration in patients with lung disease can be one or more of these symptoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9).

[0206] In some embodiments, the pharmaceutical composition of this disclosure is an inhalation formulation. In some embodiments, the pharmaceutical composition of this disclosure is a solid inhalation formulation. In some embodiments, the pharmaceutical composition of this disclosure is a dry powder formulation for inhalation. In some embodiments, the pharmaceutical composition of this disclosure is an inhaled powder aerosol.

[0207] Lung diseases

[0208] In some implementations, the lung disease is selected from chronic obstructive pulmonary disease (COPD).

[0209] In some implementations, the COPD is selected from moderate or severe COPD.

[0210] In some implementations, the COPD is selected from moderate COPD.

[0211] In some implementations, the COPD is selected from severe COPD.

[0212] In some implementations, the COPD is selected from moderate to severe COPD.

[0213] In some implementations, the COPD is not a life-threatening COPD.

[0214] In some implementations, the treatment or prevention of COPD is selected from maintenance therapy for COPD.

[0215] In some implementations, the COPD is selected from COPD diagnosed according to the GOLD criteria.

[0216] In some implementations, the COPD is selected from COPD diagnosed according to the 2023 or 2024 GOLD criteria.

[0217] In some implementations, the COPD is COPD diagnosed according to the 2023 or 2024 GOLD criteria.

[0218] In some implementation schemes, COPD patients have previously received (or are currently receiving) treatment with single or dual bronchodilation drugs.

[0219] In some implementation schemes, COPD patients receive maintenance therapy with single or dual bronchodilation drugs.

[0220] In some implementations, COPD patients may or may not receive background treatment. In some implementations, the background treatment includes a single or dual bronchodilator. In some implementations, the background treatment further includes an anti-inflammatory drug. In some implementations, the anti-inflammatory drug is selected from ICS (Intracytoplasmic Surgery). In some implementations, the background treatment includes one or more of LAMA, LABA, or ICS. In some implementations, the COPD patient has previously received (or is currently receiving) LABA, LAMA, and / or ICS treatment.

[0221] In some implementation schemes, COPD patients receive maintenance therapy with LABA, LAMA, and / or ICS.

[0222] In some implementation schemes, COPD patients use LABA, LAMA, and / or ICS as background medications.

[0223] In some implementations, COPD patients are selected from COPD patients undergoing background treatment during the washout period. In some implementations, COPD patients are subjects who have not previously been diagnosed with life-threatening COPD.

[0224] In some embodiments, the COPD patient is receiving background medication treatment prior to administration of the pharmaceutical composition. The background medication is selected from background inhaled medications. In some embodiments, the background medication treatment is maintained for 4 weeks prior to screening.

[0225] In some implementations, the COPD patient receives the pharmaceutical composition prior to the administration of background drug treatment.

[0226] In some implementations, the drug composition is administered to COPD patients after background drug treatment.

[0227] In some implementations, the pharmaceutical composition is administered to COPD patients concurrently with background drug treatment.

[0228] In some embodiments, the background medication includes a single- or dual-bronchodilator. In some embodiments, the background medication is selected from single- or dual-bronchodilator formulations (further including or not including inhaled corticosteroids (ICS)). In some embodiments, the background medication includes or further includes an anti-inflammatory drug. In some embodiments, the background medication further includes an ICS drug. In some embodiments, the background medication is selected from one or more (in combination or in combination) of long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS). In some embodiments, the background medication is LAMA, LABA, LAMA / LABA, LAMA / LABA / ICS, or LABA / ICS (LAMA / LABA indicates the combined use of both or a combination of both; other similar expressions in the context have similar meanings; for example, LAMA / LABA / ICS indicates the combined use of LAMA, LABA, and ICS or a combination of all three).

[0229] In some embodiments, the single-bronchial vasodilator is selected from LABA or LAMA; in some embodiments, the single-bronchial vasodilator does not include ICS. In some embodiments, the single-bronchial vasodilator further includes an anti-inflammatory drug (e.g., ICS). In some embodiments, the dual-bronchial vasodilator is selected from LABA and / or LAMA; in some embodiments, the dual-bronchial vasodilator is a LABA / LAMA (LAMA / LABA combination); in some embodiments, the dual-bronchial vasodilator further includes an anti-inflammatory drug (e.g., ICS); in some embodiments, the dual-bronchial vasodilator does not further include ICS. In some embodiments, the single-bronchial vasodilator or dual-bronchial vasodilator further includes ICS.

[0230] In some implementations, the patient has not received background medication prior to administration of the above-described pharmaceutical composition. For example, the patient may not be taking a background medication, such as a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), or an inhaled corticosteroid (ICS).

[0231] In some embodiments, the LAMA is selected from tiotropium bromide, umeclidinium bromide, adecyl bromide, glycopyrronium, refenazine, darotropium, or glycopyrronium bromide.

[0232] In some implementations, the LABA is selected from salmeterol, formoterol, afortrol, indaterol, vilanterol, adaterol, abetero, or carmoterol.

[0233] In some embodiments, the ICS is selected from beclomethasone, budesonide, fluticasone propionate, cyclosonepine, mometasone, or fluticasone furoate.

[0234] In some embodiments, the LABA / LAMA is selected from umeclidinium / vilanterol, indacaterol / glycopyrronium bromide, tiotropium bromide / olodaterol, glycopyrronium bromide / formoterol, budesonide / formoterol, ademethorphanium bromide / formoterol, or salmeterol / ticasone.

[0235] In some embodiments, the LABA / LAMA / ICS is selected from budesonide / formoterol / glycopyrronium bromide, fluticasone / umetromex / vilanterol, or beclomethasone propionate / formoterol fumarate / glycopyrronium bromide.

[0236] In some embodiments, the LABA / LAMA is selected from umeclidinium / vilanterol inhalation powder, indacaterol / glycopyrronium bromide inhalation powder, tiotropium bromide / olodaterol inhalation spray, or glycopyrronium bromide / formoterol inhalation aerosol.

[0237] In some embodiments, the LABA / LAMA is administered once or twice daily at a dose of 2.5 μg to 110 μg per administration.

[0238] In some embodiments, the LABA / LAMA is selected from umebromide / vilanterol inhalation powder, and is administered once daily at a dose of 62.5 μg / 25 μg per inhalation.

[0239] In some embodiments, the LABA / LAMA is selected from indacaterol / glycopyrronium bromide inhalation powder, and is administered once daily at a dose of 110 μg / 50 μg per capsule.

[0240] In some embodiments, the LABA / LAMA is selected from tiotropium bromide / olodaterol inhalation spray, and is administered once daily at a dose of 2.5 μg / 2.5 μg per actuation.

[0241] In some embodiments, the LABA / LAMA is selected from glycopyrronium bromide / formoterol inhalation aerosol, and is administered twice daily at a dose of 7.2 μg / 5 μg per actuation.

[0242] In some implementations, the COPD patients are selected from subjects who are able to undergo acceptable and repeatable pulmonary function tests.

[0243] In some implementations, after a patient inhales a bronchodilator (e.g., 4 drops of salbutamol), 30% of predicted value ≤ FEV1 ≤ 70% of predicted value, and FEV1 / FVC < 0.7; in other implementations, after a subject inhales a bronchodilator (e.g., 4 drops of salbutamol), 30% of predicted value ≤ FEV1 < 80% of predicted value, and FEV1 / FVC < 0.7; or, 40% of predicted value ≤ FEV1 < 80% of predicted value, and FEV1 / FVC < 0.7. Airway reversibility is observed after inhalation of a bronchodilator (e.g., 4 drops of salbutamol): the absolute improvement in FEV1 is greater than 100 mL.

[0244] In some implementations, the COPD is selected from 30% predicted value ≤ FEV1 ≤ 70% predicted value after the application of a bronchodilator (e.g., salbutamol 4 drops), and the FEV1 / FVC ratio < 0.7.

[0245] In some implementations, the COPD patient is selected from subjects with clinically stable COPD.

[0246] In some implementations, the COPD patients are selected from subjects with a modified UK Medical Research Council (mMRC) Dyspnea Scale score ≥2.

[0247] During the study, salbutamol aerosol was administered as an emergency medication and used as needed when symptoms worsened.

[0248] In some implementations, the patient's FEV1 is ≥ 40% of predicted value.

[0249] In some implementations, the patient's FEV1 is ≤ 80% of the predicted value.

[0250] In some implementations, the patient's FEV1 / FVC ≤ 0.7.

[0251] In some embodiments, the patient has 30% predicted value ≤ FEV1 < 80% predicted value. In some embodiments, the patient has 30% predicted value ≤ FEV1 < 80% predicted value, and FEV1 / FVC ≤ 0.7. In some embodiments, the patient has 40% predicted value ≤ FEV1 ≤ 80% predicted value, and FEV1 / FVC ≤ 0.7.

[0252] In some implementations, the pharmaceutical composition is typically used as maintenance therapy.

[0253] In some embodiments, the pharmaceutical composition is typically used as maintenance therapy and is particularly effective in increasing lung function in subjects with COPD. In particular, it can improve morning lung function in COPD patients, which is especially beneficial for COPD patients who are prone to sleep disturbances (e.g., due to the presence of comorbidities affecting sleep).

[0254] In some embodiments, the treatment or prevention of COPD includes improving morning lung function in patients with COPD. In some embodiments, the treatment or prevention of COPD includes increasing the trough lung function in patients with COPD.

[0255] In some embodiments, the use, method, kit, or pharmaceutical composition further includes a use or method to increase the trough value of lung function in patients with COPD.

[0256] In some implementations, the COPD patient is a subject susceptible to sleep disturbances. The method may include increasing the morning trough of lung function (i.e., the trough of lung function after sleep). As part of maintenance therapy, morning lung function can be measured by determining the patient's FEV1 shortly before administering the drug composition in the morning. For example, FEV1 can be measured less than one hour before administering the drug composition in the morning. The morning trough of FEV1 can be FEV1 measured between 11.5 and 12 hours after taking the medication the previous night. Improved lung function can improve sleep in COPD patients. This is particularly important for patients prone to sleep disturbances. Patients susceptible to sleep disturbances often have conditions that directly affect sleep ability (e.g., insomnia or sleep apnea) or indirectly cause sleep difficulties (e.g., skin conditions such as psoriasis, which irritate the skin and cause sleep disturbances, making it harder for patients to fall asleep or remain asleep).

[0257] "Subjects susceptible to sleep disorders" are typically subjects suffering from one or more of the following diseases or conditions: obesity, insomnia, sleep apnea, narcolepsy, restless legs syndrome, REM sleep behavior disorder, circadian rhythm sleep disorder, parasomnia, depression, anxiety, psoriasis, dermatitis, eczema, or urticaria. For example, the pharmaceutical composition can be used to treat COPD in patients with both COPD and sleep apnea. The pharmaceutical composition can also be used to treat COPD in patients with both COPD and skin conditions such as psoriasis, dermatitis, eczema, or urticaria.

[0258] In some implementations, the patient may be using a beta-receptor agonist (such as salbutamol) as a rescue (emergency) medication.

[0259] In some embodiments, the use, method, or pharmaceutical composition further includes reducing the frequency and / or severity of acute exacerbations of COPD (AECOPD) in patients with COPD.

[0260] This further includes increasing the time to the first COPD exacerbation in patients with COPD. Therefore, a patient may not have yet experienced a COPD exacerbation, and the pharmaceutical composition can increase the time until the patient experiences their first COPD exacerbation (i.e., the first COPD exacerbation is delayed). Therefore, the pharmaceutical composition can reduce the risk of COPD exacerbations in patients with COPD.

[0261] In some implementations, the patients are prone to acute exacerbations of COPD.

[0262] In some implementations, the patient is sensitive to acute exacerbations of COPD.

[0263] Subjects may experience two or fewer (e.g., one or zero) COPD exacerbations per year. The number of COPD exacerbations experienced per year during treatment with the pharmaceutical composition may be one to three fewer than the number of COPD exacerbations experienced per year before treatment with the compound.

[0264] An acute exacerbation of COPD typically includes one or more of the following: difficulty breathing, worsening cough, increased sputum volume, purulent sputum, wheezing, sore throat, cold-like symptoms, and fever. Purulent sputum refers to spontaneously coughed-up sputum that changes color from colorless to yellowish-green. An acute exacerbation of COPD can last for at least one or two days.

[0265] COPD exacerbations (acute exacerbations) may include an worsening of two or more of the following primary symptoms for at least two consecutive days: dyspnea, sputum volume, and purulent sputum; or any primary symptom along with an worsening of any of the following minor symptoms for at least two consecutive days: sore throat, cold (runny nose and / or nasal congestion), fever without other cause (oral temperature >37.5°C), and increased cough. For example, an acute exacerbation of COPD may include an worsening of two or more primary symptoms (dyspnea, sputum volume, and purulent sputum) for at least two consecutive days.

[0266] An acute exacerbation of COPD can be either a moderate acute exacerbation or a severe acute exacerbation of COPD.

[0267] A moderate exacerbation is defined as a worsening of COPD symptoms (as described above) requiring at least three days of oral / systemic corticosteroid and / or antibiotic treatment. A severe exacerbation is defined as a worsening of COPD symptoms requiring hospitalization (as described above). The pharmaceutical composition can reduce the severity of acute exacerbations of COPD in patients, and therefore can be used to prevent severe acute exacerbations of COPD in patients. For example, a patient may not experience a severe acute exacerbation of COPD within one year of the first administration of the pharmaceutical composition.

[0268] The drug composition can prolong the duration of acute exacerbations of COPD. For example, it may extend the time before the condition worsens by two months or more.

[0269] Patients are generally prone to COPD exacerbations. Typically, a "patient prone to COPD exacerbations" is someone with one or more comorbidities (in addition to COPD). Such patients usually have one or more of the following conditions or illnesses: asthma, pulmonary hypertension, bronchiectasis, allergy, lung cancer, chest infection, cystic fibrosis, pulmonary fibrosis, pneumonia, hay fever, allergic rhinitis, bronchitis, emphysema, adult respiratory distress syndrome (ARDS), interstitial lung disease, or tuberculosis, optionally including allergic asthma, steroid-resistant asthma, severe asthma, or childhood asthma. Patients prone to COPD exacerbations may have a chronic bronchitis as an underlying cause, may have impaired lung function (e.g., an expected FEV1 of 30% to 70%), or may have COPD symptoms despite treatment with a long-acting muscarinic receptor antagonist (LAMA) or long-acting medication.

[0270] Other risk factors for COPD exacerbations include: high serum immunoglobulin (Ig), a history of tuberculosis, severe airflow obstruction, chest infection, and one or more hospitalizations in the previous year due to COPD exacerbations.

[0271] In some cases, a patient may have experienced one or more COPD exacerbations within one year prior to the first administration of the drug composition. For example, a patient may have experienced two or more COPD exacerbations within one year prior to the first administration of the drug composition. For example, a patient may have had at least one severe COPD exacerbation (i.e., requiring hospitalization) in the previous year. A patient may have experienced one or more COPD exacerbations within six months prior to the first administration of the drug composition, or within one month prior to the first administration of the drug composition.

[0272] In some embodiments, for the methods, uses, kits, or pharmaceutical compositions described herein, FEV1 is significantly increased. For example, peak FEV1 changes (increases) by 100–350 mL from baseline; 100–300 mL; or 150–280 mL. For example, mean FEV1 changes by 30–200 mL from baseline; or 59–150 mL.

[0273] In some embodiments, the method, use, or pharmaceutical composition may further include administering a therapeutically effective amount of other therapeutic agents to the subject, including but not limited to LABA, LAMA, and / or ICS.

[0274] In some embodiments, the method, use, or pharmaceutical composition further includes administering a therapeutically effective amount of salbutamol to the subject.

[0275] In some implementations, the COPD subjects are selected from those clinically diagnosed with stable moderate to severe COPD according to the GOLD guidelines (2024).

[0276] In some implementations, the COPD subjects are selected from those whose FEV1 / FVC is <0.7 after inhalation of a bronchodilator; and whose FEV1 is ≤40% of the predicted value ≤80%.

[0277] In some implementations, the COPD subjects are selected from those whose airways are reversible after inhaling salbutamol aerosol.

[0278] In some implementations, the COPD subject is selected from those whose absolute FEV1 value improved by more than 100 mL after inhaling salbutamol aerosol.

[0279] Dosing regimen

[0280] In some implementations, the dosage administered to the subject (e.g., COPD) is selected from 10 μg to 2250 μg per dose (e.g., 125 μg per dose).

[0281] In some embodiments, the prescribed dosage (for example, COPD) is 10μg、15μg、20μg、25μg、30μg、35μg、40μg、45μg、50μg、55μg、60μg、65μg、70μg、75μg、80μg、85μg、90μg、95μg、 100μg、105μg、110μg、115μg、120μg、125μg、130μg、135μg、140μg、145μg、15 0μg、155μg、160μg、165μg、170μg、175μg、180μg、185μg、190μg、195μg、200μg ,205μg,210μg,215μg,220μg,225μg,230μg,235μg,240μg,245μg,250μg,255μg,260μg,265μg,270μg,275μg,280μg,285μg,290μg,295μg,300μg,305μg g、310μg、315μg、320μg、325μg、330μg、335μg、340μg、345μg、350μg、355μg、 360μg、365μg、370μg、375μg、380μg、385μg、390μg、395μg、400μg、405μg、410 μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490μg, 495μg, 500μg, 505μg, 510μg, 51 5μg, 520μg, 525μg, 530μg, 535μg, 540μg, 545μg, 550μg, 555μg, 560μg, 565μg, 570μg, 575μg, 580μg, 585μg, 590μg, 595μg, 600μg, 605μg, 610μg, 615μg, 6 20μg, 625μg, 630μg, 635μg, 640μg, 645μg, 650μg, 655μg, 660μg, 665μg, 670μg, 675μg, 680μg, 685μg, 690μg, 695μg, 700μg, 705μg, 710μg, 715μg, 720μg, 725μg, 730μg, 735μg, 740μg, 745μg, 750μg, 755μg, 760μg, 765μg, 770μg, 775μg, 780μg, 785μg, 790μg, 795μg, 800μg, 805μg, 810μg, 815μg, 820μg, 825μg,830μg, 835μg, 840μg, 845μg, 850μg, 855μg, 860μg, 865μg, 870μg, 875μg, 880μg, 885μg, 890μg, 895μg, 900μg, 905μg, 910μg, 915μg, 920μg, 925μg, 930μg g、935μg、940μg、945μg、950μg、955μg、960μg、965μg、970μg、975μg、980μg、 985μg、990μg、995μg、1000μg、1005μg、1010μg、1015μg、1020μg、1025μg、10 30μg, 1035μg, 1040μg, 1045μg, 1050μg, 1055μg, 1060μg, 1065μg, 1070μg, 1075μg, 1080μg, 1085μg, 1090μg, 1095μg, 1100μg, 1105μg, 1110μg, 1115μg, 1120μg, 1125μg, 1130μg, 1135μg, 1140μg, 1145μg, 1150μg, 1155μg, 1160μg, 1165μg, 1170μg, 1175μg, 1180μg, 1185μg, 1190μg, 1195μg, 1200μg, 1205μg ,1210μg,1215μg,1220μg,1225μg,1230μg,1235μg,1240μg,1245μg,1250μg,1255μg,1260μg,1265μg,1270μg,1275μg,1280μg,1285μg,1290μg,1295 μg, 1300μg, 1305μg, 1310μg, 1315μg, 1320μg, 1325μg, 1330μg, 1335μg, 1340μg, 1345μg, 1350μg, 1355μg, 1360μg, 1365μg, 1370μg, 1375μg, 1380μg, 138 5μg, 1390μg, 1395μg, 1400μg, 1405μg, 1410μg, 1415μg, 1420μg, 1425μg, 1430μg, 1435μg, 1440μg, 1445μg, 1450μg, 1455μg, 1460μg, 1465μg, 1470μg, 1 475μg, 1480μg, 1485μg, 1490μg, 1495μg, 1500μg, 1505μg, 1510μg, 1515μg, 1520μg, 1525μg, 1530μg, 1535μg, 1540μg, 1545μg, 1550μg, 1555μg, 1560μg,1565μg, 1570μg, 1575μg, 1580μg, 1585μg, 1590μg, 1595μg, 1600μg, 1605μg, 1610μg, 1615μg, 1620μg, 1625μg, 1630μg, 1635μg, 1640μg, 1645μg, 165 0μg, 1655μg, 1660μg, 1665μg, 1670μg, 1675μg, 1680μg, 1685μg, 1690μg, 1695μg, 1700μg, 1705μg, 1710μg, 1715μg, 1720μg, 1725μg, 1730μg, 1735μg, 1740μg, 1745μg, 1750μg, 1755μg, 1760μg, 1765μg, 1770μg, 1775μg, 1780μg, 1785μg, 1790μg, 1795μg, 1800μg, 1805μg, 1810μg, 1815μg, 1820μg, 18 25μg, 1830μg, 1835μg, 1840μg, 1845μg, 1850μg, 1855μg, 1860μg, 1865μg, 1870μg, 1875μg, 1880μg, 1885μg, 1890μg, 1895μg, 1900μg, 1905μg, 1910μg ,1915μg,1920μg,1925μg,1930μg,1935μg,1940μg,1945μg,1950μg,1955μg,1960μg,1965μg,1970μg,1975μg,1980μg,1985μg,1990μg,1995μg,20 00μg, 2005μg, 2010μg, 2015μg, 2020μg, 2025μg, 2030μg, 2035μg, 2040μg, 2045μg, 2050μg, 2055μg, 2060μg, 2065μg, 2070μg, 2075μg, 2080μg, 2085μg 、2090μg、2095μg、2100μg、2105μg、2110μg、2115μg、2120μg、2125μg、2130 μg、2135μg、2140μg、2145μg、2150μg、2155μg、2160μg、2165μg、2170μg、21 75μg、2180μg、2185μg、2190μg、2195μg、2200μg、2205μg、2210μg、2215μg、 2220μg、2225μg、2230μg、2235μg、2240μg、2245μg、2250μg、or the above-mentioned arbitrary value composition range。、

[0282] In some embodiments, the dosage (per dose) administered to the subject is selected from 750 μg or 1000 μg. In some embodiments, the dosage (daily) administered to the subject is selected from 1500 μg, 2000 μg, or 3000 μg. In some embodiments, the dosage (daily) administered to the subject is selected from 1500 μg or 2000 μg.

[0283] In some embodiments, the subject is given the medication once or twice daily. In some embodiments, the subject is given the medication twice daily. In some embodiments, the subject is given the medication continuously for 4 weeks. In some embodiments, the pharmaceutical composition is typically used as maintenance therapy.

[0284] In some embodiments, the pharmaceutical composition is administered to the subject daily for 1 to 52 weeks or longer; or for 4, 16, 24, 48, 52 weeks or longer, or any range of the above values.

[0285] In some embodiments, the pharmaceutical composition is administered daily for approximately 1 to 7 days, approximately 1 to 3 weeks, approximately 3 to 6 weeks, approximately 6 to 9 weeks, or approximately 12 weeks. Alternatively, it may be administered for approximately 12 weeks, approximately 12 to 15 weeks, or approximately 15 to 18 weeks, or approximately 15 to 52 weeks, or for longer periods.

[0286] In some embodiments, the pharmaceutical composition is administered by inhalation at the same time (±1 hour) daily. In some embodiments, it is administered twice daily. In some embodiments, it is administered continuously for 12-52 weeks or longer. In some embodiments, it is administered continuously for 12 weeks, 16 weeks, 24 weeks, 52 weeks or longer.

[0287] In some embodiments, the pharmaceutical composition is administered to the subject by inhalation.

[0288] In some embodiments, the pharmaceutical composition is administered to the subject via an inhalation device. In some embodiments, the inhalation device is selected from SnnyHaler DPI-C5 (capsule type) or DPI-M3 (vesicle type).

[0289] In some embodiments, the pharmaceutical composition is administered by inhalation twice daily (e.g., once in the morning and once in the evening), at a dose of 750 μg or 1000 μg each time.

[0290] In some embodiments, the pharmaceutical composition is administered once daily by inhalation, at a dose of 1500 μg or 2000 μg. In some embodiments, the pharmaceutical composition is available in strengths of 750 μg or 1000 μg.

[0291] Technical effect

[0292] The disclosed compound has good efficacy against COPD, effectively relieving COPD-related symptoms, including but not limited to: worsening shortness of breath, accompanied by wheezing, chest tightness, increased cough, increased sputum volume, changes in sputum color and / or viscosity, and fever, as well as other possible symptoms such as tachycardia, general malaise, insomnia, drowsiness, fatigue, depression, and mental disturbances. The disclosed compound can improve symptoms of reduced sleep quality caused by COPD in COPD patients.

[0293] The compound of Formula I or a pharmaceutical composition thereof, or a pharmaceutically acceptable salt thereof, possesses at least one or more of the following properties: significant dual PDE3 and PDE4 inhibitory activity, and significant inhibitory activity against TNF-α in human peripheral blood mononuclear cells (hPBMCs); it also exhibits excellent anti-inflammatory activity in an LPS (lipopolysaccharide)-induced rat model of acute lung injury; it has high in vivo plasma clearance, low oral plasma systemic exposure, and low oral bioavailability, with good safety profile when administered via the local route; it has low inhibitory activity against the five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450, with no risk of drug-drug interactions; it reduces the total number of white blood cells in BALF, exhibits significant anti-inflammatory effects, and has a low onset dose; it reduces the airway resistance index (Penh). It demonstrates good COPD control in humans.

[0294] After 0-12 hours, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks or more (e.g., 24 weeks), peak FEV1 was significantly improved from baseline. In patients with moderate to severe COPD, FEV1 reached 40%-80% of predicted value after inhalation of the bronchodilator, and FEV1 / FVC < 0.7. The bronchodilatory effect reached peak FEV1 at approximately 2 hours. Regarding the duration of efficacy, the 6 mg-Bid group showed better efficacy than other groups 6 hours after administration, maintaining a bronchodilatory effect of over 100 mL. Regarding symptom improvement, numerical improvements in CAT scores from baseline were observed in the 1.5 mg-QD, 3 mg-QD-BID, 3 mg-QD, and 6 mg-QD groups. The compound described in this application can improve sleep in COPD patients or increase morning trough lung function (i.e., trough lung function after sleep).

[0295] Average C max The AUC(0-t) increases with increasing dose, and the increase rate of AUC(0-t) is close to the dose-increase ratio. Lung deposition studies show that this product is mainly absorbed into the systemic circulation via the lungs. The disclosed compound is rapidly absorbed and eliminated, with no significant accumulation.

[0296] The disclosed compounds have good safety and tolerability, with a low incidence of adverse reactions and no serious adverse events.

[0297] The disclosed compound is well-tolerated, has a rapid onset of action, and a long duration of action (e.g., rapid onset within 3 hours and lasting for 12 hours).

[0298] The disclosed compounds showed a significant increase in FEV1 in patients with moderate and severe COPD, with a particularly significant increase observed in the treatment of patients with moderate COPD.

[0299] The disclosed compound can effectively prolong the time to first deterioration (i.e. reduce the risk of deterioration) and reduce the frequency of COPD deterioration.

[0300] Compared to Ensifentrine, a drug targeting the same target in clinical trials, the compound in this application has higher target binding capacity, stronger downstream airway dilation and anti-inflammatory effects, and better efficacy in animal disease models.

[0301] The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt possesses at least one or more of the following properties: good stability, no growth of impurities, exhibiting pharmaceutically acceptable levels of impurities; good dispersibility and kinetic stability, including no significant particle sedimentation and no particle size growth, within the range required for effective delivery of an approved inhalation product. Additionally, the composition has uniform and moderate particle size and rapid absorption. It exhibits good delivery rate, accurate dosage, a high proportion of inhalable aerosol particles, and a high dose of fine particles. It demonstrates favorable pharmacokinetic parameters in animals or humans.

[0302] Compared to suspensions, the formulation of this application has higher delivery efficiency, lower onset dose, better pharmacokinetic properties, and higher safety.

[0303] The pharmaceutical composition of this application has a fine particulate fraction (FPF) in the aerodynamic spectrum that can reach greater than 30%; and it also has good chemical stability. The pharmaceutical composition of this application exhibits good human safety and tolerability, pharmacokinetic properties, and pharmacodynamic properties as expected. After administration to subjects, the peak FEV1 value shows the expected change from baseline (e.g., the change is greater than 100 mL, greater than 200 mL, or higher), the trough FEV1 value changes as expected from baseline (e.g., the change is greater than 100 mL, greater than 150 mL, or higher), and the change in the area under the curve of the mean FEV1 0-12 hours curve from baseline is as expected (e.g., the change is greater than 100 mL, greater than 180 mL, or higher).

[0304] Terminology Explanation

[0305] Unless otherwise required by this application, throughout the specification and the claims, the words “comprise” or “comprising” and their English variations such as “comprises” and “comprising” or equivalents shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”, implying that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be covered.

[0306] Throughout this specification, the terms "one or some embodiments," "implementation," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in one or some embodiments," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0307] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this specification and appended claims includes plural objects unless expressly stated otherwise; in other words, singular terms encompass plural terms herein, and vice versa. Thus, a reaction involving “catalyst,” for example, includes one catalyst, or two or more catalysts. It should also be understood that the term “or” is generally used in its meaning including “and / or” unless expressly stated otherwise.

[0308] As used herein, the terms “subject” or “patient” refer to any animal (e.g., a mammal) that is a recipient of a particular treatment, including but not limited to humans, non-human primates, canines, felines, rodents, such as monkeys, mice, pigs, cattle, goats, sheep, rabbits, rats, guinea pigs, hamsters, or horses. A subject may be a human.

[0309] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0310] (i) Suppress the disease or disease state, that is, curb its development;

[0311] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0312] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0313] In this document, the pharmaceutical composition is administered or contained in a dosage form at an effective amount or therapeutically effective amount. As used herein, the terms "effective amount," "therapeutically effective amount," or "effective dose" are used. The term "therapeutically effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeuticly effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the contents of this disclosure (e.g., the individual circumstances of the subject, the severity of the disease, sex, age, weight, and route of administration).

[0314] Generally, particle size is quantified by measuring the characteristic equivalent sphere diameter (called volume diameter) through laser diffraction, for example, by using a laser particle size analyzer.

[0315] This application uses volume diameter (VD) to represent particle size distribution.

[0316] This application describes particle size by referring to the Dv50 value, which is the median particle size of the volume distribution. Therefore, half the volume of particles has a diameter smaller than the Dv50 value, and half the volume of particles has a diameter larger than the Dv50 value. The particle size distribution of a sample can also be characterized using the parameters Dv10 and Dv90. 10% of the volume of particles has a diameter smaller than the Dv10 value. 90% of the volume of particles has a diameter smaller than the Dv90 value. The technique used to measure the Dv50 (and Dv10 and Dv90) values ​​described in this application is typically laser diffraction.

[0317] In this document, unless otherwise stated, all parameter values ​​(including 2θ values ​​and reaction conditions) are considered to be modified by the term “about” to reflect measurement errors, such as ±5% error relative to a given value.

[0318] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0319] abbreviations

[0320] FEV1 / FVC ratio: The ratio of forced expiratory volume in one second to forced vital capacity;

[0321] FEV1: Forced expiratory volume in the first second;

[0322] FEV1 predicted value: The normal value of lung function calculated according to the predicted formula based on the age, sex, height and weight of healthy individuals;

[0323] FVC: Forced vital capacity;

[0324] GOLD: Global Initiative for Chronic Obstructive Lung Disease;

[0325] ICS: Inhaled corticosteroids;

[0326] LABA: a long-acting β2-receptor agonist;

[0327] LAMA: Long-acting anticholinergic drug;

[0328] SABA: a short-acting β2-receptor agonist;

[0329] SAMA: Short-acting anticholinergic drug;

[0330] SD: Standard deviation;

[0331] SGRQ: St. George's Respiratory Questionnaire;

[0332] FEV1 peak: The maximum value of FEV1 measured after medication;

[0333] The CAT questionnaire is mainly used to assess the impact of COPD on patients' health and daily quality of life. The CAT has 8 questions, and each question is scored from 0 to 5 points. The higher the score, the more severe the symptoms.

[0334] SGRQ: A standardized self-assessment tool for evaluating the quality of life of patients with chronic respiratory diseases. It comprehensively reflects the impact of the disease on patients' daily lives by quantifying the degree of impairment in symptoms, activity levels, and psychosocial adaptation. Detailed Implementation

[0335] The lactose and magnesium stearate used in the embodiments of this article have the following particle size characteristics:

[0336] Lactose codes: LH206 (lactose 1), LH200 (lactose 2), ML001 (lactose 3), ML003 (lactose 4), SV003 (lactose 5), Lactose 6

[0337] Example 1: Compatibility study of Formula I compound with inhaled excipients

[0338] Lactose 2 and compound I were sieved and mixed thoroughly. The weight ratio of compound I to lactose was controlled at 1:200 to obtain sample 1.

[0339] Magnesium stearate and compound I were sieved and mixed thoroughly. The weight ratio of compound I to magnesium stearate was controlled at 1:200 to obtain sample 2.

[0340] Lactose 2 is mixed with magnesium stearate, controlling the weight ratio of lactose to magnesium stearate at 1:0.003. This mixing can be performed using a hopper mixer, a high-shear mixer (PCM, MPM, QMM, PMA, or TRV series mixers, such as TRV25 or TRV65), a low-shear tumbler mixer, or a Cyclomix mixer to obtain the carrier. Compound I is then sieved and mixed with the carrier, controlling the weight ratio of compound I to the carrier at 1:200, to obtain sample 3.

[0341] The samples and active pharmaceutical ingredients (i.e., compounds of formula I) prepared above were placed in a 60°C thermostatic incubator for 30 days. Before and after the incubation period, impurity profiles were determined by high-performance liquid chromatography.

[0342] Experimental results show that samples 3 and 2 have good chemical stability, which is better than that of sample 1.

[0343] Example 2: Prescription Product

[0344] Preparation method: According to the formulations in Tables 1 and 2, sieve the lactose monohydrate and then mix it with the compound of formula I. Mix at a speed of 100-150 rpm. A hopper mixer, a high-shear mixer (PCM, MPM, QMM, PMA or TRV series mixers, such as TRV25 or TRV65), a low-shear tumbler mixer, or a Cyclomix mixer can be used to obtain the mixture.

[0345] The mixture powder can be filled into hydroxypropyl methylcellulose (HPMC) capsules in equal portions to obtain the prescription product shown in Table 1.

[0346] Table 1

[0347] The mixed powder can be transferred to a blister pack (average amount per blister) typically used to provide dry powder for inhalation, and then the blister pack can be sealed in the usual manner to obtain the prescription product in Table 2.

[0348] Table 2

[0349] Example 3

[0350] According to the formulations in Tables 3 and 4, lactose and magnesium stearate are mixed using a hopper mixer or a high-shear mixer (PCM, MPM, QMM, PMA or TRV series mixers, such as TRV25 or TRV65) or a low-shear tumbler mixer or a Cyclomix mixer to obtain the carrier.

[0351] The compound of formula I is mixed with the carrier at a mixing speed of 100-150 rpm. A hopper mixer, a high-shear mixer (PCM, MPM, QMM, PMA or TRV series mixers, such as TRV25 or TRV65), a low-shear tumble mixer, or a Cyclomix mixer can be used to obtain a mixture.

[0352] The mixture powder was divided into equal portions and filled into hydroxypropyl methylcellulose (HPMC) capsules to obtain the product formulation shown in Table 3.

[0353] Table 3

[0354] The mixture powder is transferred to a blister pack typically used to provide dry powder for inhalation (average amount per blister pack is shown in the table below), and then the blister pack is sealed in the usual manner to obtain the formulation in Table 4.

[0355] Table 4

[0356] Example 4

[0357] Preparation method: According to the formulations in Table 5, lactose and magnesium stearate are mixed using a hopper mixer, a high-shear mixer (PCM, MPM, QMM, PMA or TRV series mixers, such as TRV25 or TRV65), a low-shear tumble mixer, or a Cyclomix mixer to obtain the carrier.

[0358] The compound of formula I can be mixed with the carrier using a hopper mixer or a high-shear mixer (PCM, MPM, QMM, PMA or TRV series mixers, such as TRV25 or TRV65) or a low-shear tumble mixer or a Cyclomix mixer to obtain a mixture.

[0359] The mixture powder was divided into equal portions and filled into hydroxypropyl methylcellulose (HPMC) capsules.

[0360] The mixing homogeneity (relative standard deviation RSD) and aerodynamic spectrum of the formulation were evaluated. The aerodynamic spectrum was characterized using fine particle fraction (FPF).

[0361] It was found that formulations obtained by mixing the carrier and drug at a lower mixing rate had a higher FPF. Therefore, a lower drug loading rate was selected as the preferred mixing parameter. See Table 5.

[0362] Table 5

[0363] Example 1: Evaluation of Inhalation Properties

[0364] Delivery effectiveness measurement method:

[0365] Aerodynamic spectra were characterized using fine particle fraction (FPF). Measurements were performed according to the method for determining the dose-aerodynamic properties of fine particles in inhaled formulations (Chinese Pharmacopoeia 2020, Part IV, General Chapter 0951, Apparatus 3).

[0366] Refer to the operation of the delivery dose uniformity test device under the "Inhalation Powder" section of Part IV, "0111 Inhalation Preparations," in the 2020 edition of the Chinese Pharmacopoeia. Take the inhalation device and insert the adapter. Turn on the vacuum pump, open the two-way flux valve, and adjust the flow control valve to achieve a pressure difference (P1) of 4.0 kPa across the inhalation device. Remove the inhalation device, connect a flow meter to the device inlet, and measure the volumetric flow rate Q exiting the flow meter. out .

[0367] Using a new generation impactor (NGI) to Q out The aerodynamic spectra of each sample were measured at a flow rate of [value missing], and the fine particle fraction (FPF) was used for characterization. The data are shown in Tables 6-7.

[0368] Table 6

[0369] Table 7

[0370] The test results show that the pharmaceutical composition of this application has good inhalation properties, such as the fine particulate fraction (FPF) property in terms of aerodynamic spectrum. Formulations 19-28, 30, 170-171, 49-60, 175-176, 71-110, 181-200, 121-150, 205-210, and 220-249 can all achieve an FPF greater than 30%.

[0371] Stability Study of Experiment Example 2

[0372] Formulated products from Examples 1-4 (e.g., formulations of Formula 24, Formula 50, Formula 100, Formula 145, Formula 175, Formula 101, Formula 146, etc.) were placed in polyester / aluminum polyethylene pharmaceutical aluminum foil bags and sealed. They were then placed in a stability test chamber (accelerated conditions: 40℃±2℃, 75% RH±5% RH; long-term conditions: 30℃±2℃, 65% RH±5% RH). Samples were taken at different time points, and impurity profiles were determined using high-performance liquid chromatography (HPLC).

[0373] Experimental results show that the pharmaceutical compositions of each formulation in Examples 1-4 of this application (e.g., formulations 24, 50, 100, 145, 175, 101, 146, 220-249, etc.) exhibit good chemical stability in accelerated stability and long-term stability tests (the content of total impurities, single impurities, and major impurities hardly changes).

[0374] Experimental Example 3: Drug Efficacy and Safety Test

[0375] Selection criteria

[0376] 1. Patients clinically diagnosed with stable moderate to severe COPD according to the GOLD guidelines (2024) at the time of screening: FEV1 / FVC < 0.7 after inhalation of bronchodilators during the screening period; 40% ≤ FEV1 ≤ 80% of predicted value;

[0377] 2. During screening, after inhaling 4 puffs of salbutamol aerosol, there was some airway reversibility: the absolute value of FEV1 improved by more than 100 mL;

[0378] 3. Patients who can adjust their current COPD treatment or are treatment-naïve with COPD may discontinue prescribed bronchodilators, including LAMA and / or LABA inhaled medications, during the screening period after signing an informed consent form;

[0379] 4. Subjects were able to discontinue SABA for at least 6 hours and SAMA for at least 8 hours;

[0380] 5. Subjects were able to undergo repeatable FEV1 lung function testing according to the ATS / ERS2005 criteria during screening.

[0381] Experimental drug:

[0382] Compound I powder inhalation (wherein, Compound I: Lactose: Magnesium Stearate = (0.125-1.5):22:(0.13-0.2)), specifications: 25μg-750μg, 1000μg, 1500μg / capsule; single or multiple administration, twice a day, inhalation administration, dose 125μg-2250μg / time, for example 750μg, 1000μg or 1500μg each time.

[0383] Formulations for some specifications of Formula I compound powder aerosols:

[0384] The weight ratio of each component in the 125μg specification is: Compound I: Lactose: Magnesium Stearate = 0.125:22:(0.13-0.2).

[0385] The weight ratio of each component in the 750μg specification is: Compound I: Lactose: Magnesium Stearate = 0.75:22:(0.13-0.2).

[0386] The weight ratio of each component in the 1000μg specification is: Compound I: Lactose: Magnesium Stearate = 1:22:(0.13-0.2).

[0387] The weight ratio of each component in the 1500μg specification is: Compound I: Lactose: Magnesium stearate = 1.5:22:(0.13-0.2).

[0388] Salbutamol inhalation aerosol (trade name: ), manufactured by GlaxoSmithKline Australia Pty Ltd, supplied by Chia Tai Tianqing Pharmaceutical Group Co., Ltd., specification: 100μg / spoon, 200spoons.

[0389] Evaluation indicators:

[0390] Adverse events;

[0391] Pharmacokinetic (PK) and pharmacodynamic (PD) characteristics after inhalation of powder inhaler. These include, but are not limited to: PK characteristic blood drug concentrations, pulmonary function test indicators (changes in FEV1, including changes in FEV1, peak FEV1, and trough FEV1 relative to baseline), and CAT score.

[0392] PK index: peak plasma concentration (C max Peak time (T) max Steady-state peak plasma concentration (C) ss-max Steady-state peak time (T) ss- max ), steady-state plasma trough concentration (C ss-min), area under the steady-state plasma concentration-time curve (AUC) 0–τ Steady-state AUC from time zero to 24 hours after administration ss 0-24 terminal half-life (t) 1 / 2 ); The area under the concentration-time curve (AUC) extrapolated from time zero to infinity 0-∞ The area under the plasma concentration-time curve (AUC) from time zero to the time when the final measurable concentration is reached. 0–t ), and AUC from time zero to 12 hours after administration. 0–12 C max The cumulative ratio (Rac[C) max ], Day 9, C max With C on day 1 max (ratio); AUC 0-12 The cumulative ratio (Rac[AUC)) 0-12 The estimated AUC for day 9 is [missing information]. 0-12 (Ratio to Day 1).

[0393] PD index:

[0394] (1) FEV1 peak value change.

[0395] The change in peak FEV1 after a single dose on day 1 from baseline (baseline for a single dose is defined as the value measured within 1 hour before administration on day 1).

[0396] The change in FEV1 peak value on day 9 from baseline (for multiple dosing, the baseline is defined as the value measured within 1 hour before dosing on day 3).

[0397] Changes in valence FEV1 (1 hour before administration) on the morning of day 9 compared to baseline.

[0398] Changes in mean FEV1 within 12 hours after administration on the morning of day 1 and day 9 compared to baseline.

[0399] First, compare the change in mean FEV1 within 3 hours after medication on the morning of day 9 with baseline.

[0400] Changes in FEV1 at each time point within 12 hours after administration on the morning of Day 1 and Day 9 compared to baseline.

[0401] The changes in peak FEV1 (defined as the maximum value measured after administration) and mean FEV1 over 3 hours were evaluated on day 9 compared to day 3 (after the first dose of multiple-dose regimens).

[0402] Changes in glutar FEV1 from baseline before administration on day 6.

[0403] The change in peak FEV1 from baseline after 4 weeks of treatment.

[0404] Compared with baseline, the changes in peak, trough, and mean FEV1 AUC (area under the curve) within 3 hours and 12 hours after morning administration at 1 day, 2 weeks, and 4 weeks of treatment.

[0405] (2) Chronic obstructive pulmonary disease score (CAT) assessment, such as the change in symptom score (CAT assessment) on day 9 compared with baseline;

[0406] Changes in CAT assessment at 2 and 4 weeks after treatment compared to baseline.

[0407] (3) Changes in the St. George Respiratory Questionnaire (SGRQ), such as changes in the St. George Respiratory Questionnaire (SGRQ) after 2 weeks and 4 weeks of treatment.

[0408] (4) The number of times salbutamol was used during multiple administrations compared to the placebo group.

[0409] Test results

[0410] Sixty subjects were enrolled in a dose escalation trial with an average of six dose groups (125 μg, 250 μg, 500 μg, 750 μg, 1000 μg and 1500 μg), and another 12 subjects were enrolled in a placebo control group.

[0411] In the 1000 μg dose group (single dose of 1000 μg twice daily), the change from baseline to peak FEV1 (adjusted for placebo) was 290.63 mL (95CI: 188.59, 392.66) on day 1 after administration. On day 9 of treatment, the change from baseline to peak FEV1 (adjusted for placebo) was 377.19 mL (95CI: 255.02, 499.35).

[0412] Regarding the area under the curve for mean FEV1 0–12 hours, the change from baseline on day 1 (adjusted for placebo) in the 1000 μg dose group was 192.75 mL (95CI: 95.59, 289.90). On day 9, the change from baseline (adjusted for placebo) was 279.99 mL (95CI: 178.14, 381.84).

[0413] Regarding glutar FEV1, the change from baseline (corrected for placebo) in the 1000 μg dose group before day 9 was 167.95 mL (95 CI: 81.73, 254.16).

[0414] The experimental results showed that the bronchodilation effect of the 1000 μg and 1500 μg dose groups was significantly better than that of other dose groups, and the 1000 μg dose group was also better than the 1500 μg dose group. All dose groups showed good safety and tolerability.

[0415] The prescription products in Examples 1-4 of this application exhibit good human safety, pharmacokinetic properties, and pharmacodynamic properties as expected.

Claims

1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and lactose.

2. The pharmaceutical composition of claim 1, wherein the lactose is selected from lactose or its solvates; Alternatively, the lactose may be selected from lactose or its hydrate; Alternatively, the lactose may be selected from lactose or its monohydrate; Alternatively, the lactose is selected from α-lactose or β-lactose, or their solvates; Alternatively, the lactose may be selected from α-lactose, β-lactose, or their monohydrates.

3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition further comprises magnesium stearate.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the content (by weight percentage) of the compound of formula I or its pharmaceutically acceptable salt is selected from 50% to 0.005%, 25% to 0.05%, 21% to 0.04%, or 6% to 0.1%; or 20% to 0.01%, 18% to 0.02%, 15% to 0.1%, or 12% to 0.15%.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the lactose content (by weight percentage) in the pharmaceutical composition is selected from 99.99%–50%, 99.99%–60%, 99.99%–70%, or 99.99%–80%; or 99.9%–80%, 99.85%–81%, 99.8%–82%, 99.98%–82.02%, or 99.9%–88%.

6. The pharmaceutical composition according to any one of claims 3-5, wherein the magnesium stearate content (by weight) in the pharmaceutical composition is selected from 20% to 0%, 10% to 0%, 5% to 0.05%, or 4% to 0.1%; or 5% to 0.01%, 4.5% to 0.02%, 4.5% to 0.05%, 4% to 0.05%, 3% to 0.02%, 2.8% to 0.04%, 2.6% to 0.05%, 2.4% to 0.06%, 2.3% to 0.07%, 2.2% to 0.08%, 3.76% to 0.09%, or 2.1% to 0.09%.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the content (weight ratio) of lactose to the compound of formula I or its pharmaceutically acceptable salt is selected from (5000-1):1, (4500-3):1, (2000-5):1 or (1800-250):1; or 4500:1 to 4:1, 4400:1 to 4.6:1 or 2800:1 to 7:

1.

8. The pharmaceutical composition according to any one of claims 3-7, wherein the content (weight ratio) of magnesium stearate to the compound of formula I or its pharmaceutically acceptable salt is selected from (50-0.001):1, (30-0.01):1, (25-0.01):1 or (22-0.02):1; or 20:1 to 0.005:1, 18:1 to 0.008:1, 16:1 to 0.01:1, or 14:1 to 0.014:

1.

9. The pharmaceutical composition according to any one of claims 3-8, wherein the ratio (by weight) of lactose to magnesium stearate in the pharmaceutical composition is selected from (5000-10):1, (3000-20):1, (2000-30):1, (1000-40):1, (300-100):1 or (150-100):1; or 2000:1 to 20:1, 1500:1 to 22:1, or 1000:1 to 25:

1.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the particle size Dv90 of the lactose in the pharmaceutical composition is 5-500 μm; Alternatively, Dv90 is 10–300 μm; Alternatively, Dv90 is 15–250 μm; Alternatively, Dv90 is 15–200 μm; Alternatively, Dv90 is 18–194 μm; Alternatively, Dv90 is 50–250 μm; Alternatively, Dv90 is 50–220 μm; Alternatively, Dv90 is 50–210 μm; or In the pharmaceutical composition, the particle size Dv50 of the lactose is 1–200 μm; Alternatively, Dv50 is 5–180 μm; Alternatively, Dv50 is 5–150 μm; Alternatively, Dv50 is 5–120 μm; Alternatively, Dv50 is 8–100 μm; Alternatively, Dv50 is 15–120 μm; Alternatively, Dv50 is 15–120 μm; Alternatively, Dv50 is 15–110 μm; or In the pharmaceutical composition, the lactose has a particle size distribution (Dv10) of 0.5–100 μm; or a Dv10 of 1–80 μm. Alternatively, Dv10 is 1–70 μm; Alternatively, Dv10 is 1–60 μm; Alternatively, Dv10 is 1–53 μm; Alternatively, Dv10 is 1–40 μm; Alternatively, Dv10 is 1–30 μm; Alternatively, Dv10 is 1–20 μm; or In the pharmaceutical composition, the particle size Dv90 of the lactose is 60–200 μm, 65–195 μm, or 65–194 μm.

11. The pharmaceutical composition according to any one of claims 3-10, wherein the magnesium stearate has a particle size Dv90 of 10-100 μm; Alternatively, Dv90 is 10–50 μm; Alternatively, Dv90 is 15–35 μm; or In the pharmaceutical composition, the magnesium stearate has a particle size distribution (Dv50) of 5–50 μm; or a Dv50 of 5–20 μm. Alternatively, Dv50 is 5–15 μm; or In the pharmaceutical composition, the particle size Dv10 of the magnesium stearate is 1-20 μm; Alternatively, Dv10 is 1–10 μm; or Dv10 is 1.5–6 μm; or In the pharmaceutical composition, the magnesium stearate particles have a Dv90 of 10–100 μm, a Dv50 of 5–50 μm, and a Dv10 of 1–20 μm. Alternatively, Dv90 is 10–50 μm; Dv50 is 5–20 μm; Dv10 is 1–10 μm; Alternatively, Dv90 is 15–35 μm; Dv50 is 5–15 μm; Dv10 is 1.5–6 μm; or Dv90 is 18–28 μm; Dv50 is 8–11 μm; and Dv10 is 2.5–4 μm.

12. The pharmaceutical composition according to any one of claims 1-11, wherein the pharmaceutical composition is administered by inhalation; Alternatively, the pharmaceutical composition may be a dry powder pharmaceutical composition; Alternatively, the pharmaceutical composition may be a dry powder pharmaceutical composition administered by inhalation; Alternatively, the pharmaceutical composition may be an inhaled powder.

13. The pharmaceutical composition according to any one of claims 1-12, wherein the pulmonary deposition rate of the compound of formula I or its pharmaceutically acceptable salt is not less than 20%, preferably not less than 30%, more preferably not less than 35%, further preferably not less than 40%, and even more preferably not less than 50%.

14. The pharmaceutical composition according to any one of claims 1-13, wherein, The amount of the compound of formula I is 5-3000 μg or 125 μg-1500 μg.

15. A pharmaceutical composition according to any one of claims 1-14 for the treatment or prevention of respiratory and inflammatory diseases.

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