Pharmaceutical composition of pyridone derivative and use thereof

Abstract

A pharmaceutical composition of a pyridone derivative and use thereof. Specifically disclosed is a sustained-release composition, the sustained-release composition comprising an active pharmaceutical ingredient, a sustained-release material, and an excipient. The active pharmaceutical ingredient is compound 1 or a pharmaceutically acceptable salt thereof. The sustained-release composition can prolong the in vivo release time while reducing the occurrence of adverse reactions.

Description

A pharmaceutical composition of pyridone derivatives and its application

[0001] This application claims priority to Chinese Patent Application No. 2024103954585, filed on April 2, 2024, and Chinese Patent Application No. 2024112371928, filed on September 4, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to a pharmaceutical composition of a pyridone derivative and application thereof. Background Art

[0003] Idiopathic pulmonary fibrosis (IPF) is a typical chronic, progressive, and fatal fibrosing interstitial pneumonia characterized by progressive dyspnea and declining lung function, which can quickly lead to respiratory failure and death. The five-year survival rate for IPF is approximately 20%-25%, a mortality rate far higher than many cancers, earning it the nickname "the cancer that isn't cancer." Potential risk factors include occupational exposures and environmental contaminants such as metals, animals, wood dust, smoking, and smog. The pathogenesis of IPF is complex, generally believed to involve an interaction between proinflammatory and profibrotic pathways, but the precise mechanisms remain largely unknown. In 2014, Roche's pirfenidone and Boehringer Ingelheim's nintedanib were first approved in the United States. Currently, IPF has a poor prognosis and limited treatment options. The launch of these two new drugs has provided some confidence in the progression of IPF. However, the main side effects of pirfenidone are phototoxicity and gastrointestinal reactions, and long-term medication compliance is poor, compromising the drug's clinical effectiveness. Currently, there are still unmet medical needs for the majority of patients, so the development of better new IPF drugs is receiving increasing attention.

[0004] Patent WO2017177974A1 discloses Compound 1, which can be used to treat IPF and has better efficacy than pirfenidone. Patent WO2019072236A1 discloses a crystalline form of Compound 1 and its preparation method, as well as its use in the preparation of a drug for treating fibrosis-related diseases. However, no research has been conducted on the pharmaceutical composition and side effects of Compound 1. Summary of the Invention

[0005] The present invention provides a pharmaceutical composition of a pyridone derivative and its application. The pharmaceutical composition of the pyridone derivative can prolong the in vivo release time and reduce the occurrence of adverse reactions.

[0006] The first aspect of the present invention provides a sustained-release composition comprising an active pharmaceutical ingredient, a sustained-release material, and an additive; the active pharmaceutical ingredient is Compound 1 or a pharmaceutically acceptable salt thereof;

[0007] In some embodiments of the present invention, the sustained-release composition consists of Compound 1 or a pharmaceutically acceptable salt thereof, a sustained-release material, and an additive.

[0008] In some embodiments of the present invention, the sustained-release material is a sustained-release matrix material.

[0009] In some embodiments of the present invention, the active pharmaceutical ingredient is Compound 1.

[0010] In some embodiments of the present invention, based on the compound 1, the content of the compound 1 or its pharmaceutically acceptable salt as the active ingredient in a unit sustained-release composition is 10 mg-200 mg, specifically 10 mg, 50 mg, 100 mg, 150 mg or 200 mg.

[0011] In some embodiments of the present invention, based on Compound 1, the content of Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient in a unit sustained-release composition is 50 mg or 150 mg.

[0012] In some embodiments of the present invention, the content of the active pharmaceutical ingredient is 3.33wt%-50.00wt%, preferably 6.67wt%-50.00wt%, more preferably 10.00wt%-50.00wt%, 13.33wt%-50.00wt%, 16.67wt%-50.00wt%, 20.00wt%-50.00wt%, 26.67%-50.00wt%, 6.67wt%-33.33wt%, 10wt%-33.33wt%, 13.33wt%-33.33wt%, 16.67wt%-33.33wt%, 20wt%-33.33wt% or 26.67wt%-33.33wt%.

[0013] In some embodiments of the present invention, the content of the active pharmaceutical ingredient is 10.00 wt%-50.00 wt%, for example, 10.00 wt%, 13.33 wt%, 16.67 wt%, 20.00 wt%, 26.67 wt%, 33.33 wt% or 50.00 wt%.

[0014] In some embodiments of the present invention, the sustained-release material is a hydrophilic polymer.

[0015] In some embodiments of the present invention, the hydrophilic polymer is one or more of a cellulose derivative, povidone, and carbomer.

[0016] In some embodiments of the present invention, the hydrophilic polymer is a cellulose derivative.

[0017] In some embodiments of the present invention, the cellulose derivative is one or more of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose and sodium hydroxymethyl cellulose.

[0018] In some embodiments of the present invention, the cellulose derivative is one or more of hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.

[0019] In some embodiments of the present invention, the cellulose derivative is one or more of hydroxyethyl cellulose and hydroxypropyl methyl cellulose.

[0020] In some embodiments of the present invention, the cellulose derivative is hydroxypropyl methylcellulose.

[0021] In some embodiments of the present invention, the cellulose derivative is hydroxypropyl methylcellulose K4M CR.

[0022] In some embodiments of the present invention, the viscosity of the hydrophilic polymer is 1000-150000 mPa.s, preferably 2000-10000 mPa.s, more preferably 2000-8000 mPa.s, further preferably 2663-4379 mPa.s, for example 4000 mPa.s.

[0023] In some embodiments of the present invention, the hydrophilic polymer is a cellulose derivative with a viscosity of 1000-150000 mPa.s, preferably a cellulose derivative with a viscosity of 2000-10000 mPa.s, more preferably a cellulose derivative with a viscosity of 2000-8000 mPa.s, further preferably a cellulose derivative with a viscosity of 2663-4379 mPa.s, and even more preferably a cellulose derivative with a viscosity of 4000 mPa.s.

[0024] In some embodiments of the present invention, the hydrophilic polymer is hydroxypropyl methylcellulose having a viscosity of 1000-150000 mPa.s, preferably hydroxypropyl methylcellulose having a viscosity of 2000-10000 mPa.s, more preferably hydroxypropyl methylcellulose having a viscosity of 2000-8000 mPa.s, further preferably hydroxypropyl methylcellulose having a viscosity of 2663-4379 mPa.s, and even more preferably hydroxypropyl methylcellulose having a viscosity of 4000 mPa.s.

[0025] In some embodiments of the present invention, the content of the sustained-release material is 18.00 wt%-35.00 wt%, preferably 18.00 wt%-30.00 wt%, more preferably 18.00 wt%-28.00 wt%, and further preferably 18.00 wt%-25.00 wt%.

[0026] In some embodiments of the present invention, the content of the sustained-release material is 18.00 wt%-35.00 wt%, for example, 18.00 wt%, 20.00 wt%, 22.00 wt%, 25.00 wt%, 28.00 wt% or 35% wt%.

[0027] In some embodiments of the present invention, the additives include diluents and lubricants.

[0028] In some embodiments of the present invention, the diluent is a water-soluble diluent and a water-insoluble diluent.

[0029] In some embodiments of the present invention, the water-soluble diluent is one or more of lactose, mannitol, sorbitol, sucrose, povidone and copovidone.

[0030] In some embodiments of the present invention, the water-soluble diluent is one or more of lactose, mannitol, sorbitol and sucrose.

[0031] In some embodiments of the present invention, the water-insoluble diluent is one or more of pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, and hydroxypropyl methylcellulose (≤50 cps).

[0032] In some embodiments of the present invention, the water-insoluble diluent is one or more of pregelatinized starch, microcrystalline cellulose and calcium hydrogen phosphate.

[0033] In some embodiments of the present invention, the diluent is lactose and / or microcrystalline cellulose.

[0034] In some embodiments of the present invention, the content of the diluent is 29.00 wt%-62.33 wt%, for example, 29.00 wt%, 31.00 wt%, 43.67 wt%, 54.33 wt%, 57.33 wt%, 60.33 wt%, 60.67 wt% or 62.33 wt%.

[0035] In some embodiments of the present invention, the lubricant is a hydrophobic lubricant or a hydrophilic lubricant, preferably a hydrophobic lubricant.

[0036] In some embodiments of the present invention, the hydrophobic lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate and talc, preferably one or more of magnesium stearate, sodium stearyl fumarate and talc, more preferably magnesium stearate.

[0037] In some embodiments of the present invention, the content of the lubricant is 0.5wt%-5wt%, for example 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt% or 5.0wt%.

[0038] In some embodiments of the present invention, the content of the lubricant is 1.0 wt %.

[0039] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt%-50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt%-35.00 wt% of a sustained-release material, 29.00 wt%-62.33 wt% of a diluent, and 0.5 wt%-5 wt% of a lubricant.

[0040] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt%-50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt%-35.00 wt% of a sustained-release material, 29.00 wt%-62.33 wt% of a diluent, and 1.00 wt% of a lubricant.

[0041] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt%-50.00 wt% of Compound 1, 18.00 wt%-35.00 wt% of sustained-release material, 29.00 wt%-62.33 wt% of diluent, and 0.5 wt%-5 wt% of lubricant.

[0042] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt%-50.00 wt% of Compound 1, 18.00 wt%-35.00 wt% of sustained-release material, 29.00 wt%-62.33 wt% of diluent and 1.00 wt% of lubricant.

[0043] In some embodiments of the present invention, the sustained-release composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, lactose and magnesium stearate.

[0044] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt%-50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt%-35.00 wt% of hydroxypropyl methylcellulose, 29.00 wt%-62.33 wt% of lactose and 0.5 wt%-5 wt% of magnesium stearate.

[0045] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt%-50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt%-35.00 wt% of hydroxypropyl methylcellulose, 29.00 wt%-62.33 wt% of lactose and 1.00 wt% of magnesium stearate.

[0046] In some embodiments of the present invention, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt % of hydroxypropyl methylcellulose (4000 mPa.s), 62.33 wt % of lactose and 1.00 wt % of magnesium stearate.

[0047] In some embodiments of the present invention, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 22.00 wt % of hydroxypropyl methylcellulose (4000 mPa.s), 60.33 wt % of lactose and 1.00 wt % of magnesium stearate.

[0048] In some embodiments of the present invention, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 25.00 wt % of hydroxypropyl methylcellulose (4000 mPa.s), 57.33 wt % of lactose and 1.00 wt % of magnesium stearate.

[0049] In some embodiments of the present invention, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 28.00 wt % of hydroxypropyl methylcellulose (4000 mPa.s), 54.33 wt % of lactose and 1.00 wt % of magnesium stearate.

[0050] In some embodiments of the present invention, the sustained-release composition comprises 33.33 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 22.00 wt % of hydroxypropyl methylcellulose (4000 mPa.s), 43.67 wt % of lactose and 1.00 wt % of magnesium stearate.

[0051] In some embodiments of the present invention, the sustained-release composition comprises 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 29.00 wt% of lactose and 1.00 wt% of magnesium stearate.

[0052] In some embodiments of the present invention, the sustained-release composition comprises 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 31.00 wt% of lactose and 1.00 wt% of magnesium stearate.

[0053] In some embodiments of the present invention, the sustained-release composition comprises 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 31.00 wt% of microcrystalline cellulose and 1.00 wt% of magnesium stearate.

[0054] In some embodiments of the present invention, the sustained-release composition comprises 3.33 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 35.00 wt % of hydroxypropyl methylcellulose (4000 mPa.s), 60.67 wt % of lactose and 1.00 wt % of magnesium stearate.

[0055] In some embodiments of the present invention, the sustained-release composition comprises 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 29.00 wt% of lactose and 1.00 wt% of magnesium stearate.

[0056] In some embodiments of the present invention, the sustained-release composition comprises an inner phase and an outer phase, wherein the inner phase is composed of the compound 1 or a pharmaceutically acceptable salt thereof, a sustained-release material, a diluent and a lubricant, and the outer phase is composed of the lubricant;

[0057] The content of the inner phase is 95 wt%-99.9 wt%, and the content of the outer phase is 0.1 wt%-5.00 wt%.

[0058] In some embodiments of the present invention, the content of the inner phase is 99.50 wt %, and the content of the outer phase is 0.50 wt %.

[0059] In some embodiments of the present invention, the content of the lubricant in the internal phase is 0.00 wt%-2.00 wt%, preferably 0.50 wt%.

[0060] In some embodiments of the present invention, the content of the lubricant in the external phase is 0.50 wt%-3.00 wt%, preferably 0.50 wt%.

[0061] In some embodiments of the present invention, the sustained-release composition consists of an inner phase and an outer phase, the inner phase consisting of 3.33wt%-50.00wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00wt%-35.00wt% of a sustained-release material, 29.00wt%-62.33wt% of a diluent and 0.50wt% of a lubricant, and the outer phase consists of 0.50wt% of a lubricant.

[0062] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase comprising Compound 1 or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, lactose and magnesium stearate, and the external phase comprising magnesium stearate.

[0063] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase comprising 3.33wt%-50.00wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00wt%-35.00wt% of hydroxypropyl methylcellulose, 29.00wt%-62.33wt% of lactose and 0.50wt% of magnesium stearate, and the external phase comprising 0.50wt% of magnesium stearate.

[0064] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 16.67 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 62.33 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0065] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 16.67 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 22.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 60.33 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0066] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 16.67 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 25.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 57.33 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0067] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 16.67 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 28.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 54.33 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0068] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 33.33 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 22.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 43.67 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0069] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 29.00 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0070] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 31.00 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0071] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 31.00 wt% of microcrystalline cellulose and 0.50 wt% of magnesium stearate, and the external phase consists of 0.50 wt% of magnesium stearate.

[0072] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 3.33 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 35.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 60.67 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0073] In some embodiments of the present invention, the sustained-release composition consists of an internal phase and an external phase, the internal phase consisting of 50.00 wt% of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt% of hydroxypropyl methylcellulose (4000 mPa.s), 29.00 wt% of lactose and 0.50 wt% of magnesium stearate, and the external phase consisting of 0.50 wt% of magnesium stearate.

[0074] The second aspect of the present invention provides a film-coated sustained-release preparation, which comprises the sustained-release composition as described in the first aspect of the present invention and a coating coated on the surface of the sustained-release composition.

[0075] In some embodiments of the present invention, the coating coated on the surface of the sustained-release composition is prepared using a film coating premix, and the mass ratio of the film coating premix to the sustained-release composition is (0.015-0.045):1, preferably (0.02-0.04):1, and more preferably 0.03:1.

[0076] In some embodiments of the present invention, the film coating premix is ​​a gastric-soluble film coating premix, such as an HMPC film coating premix or a PVA film coating premix.

[0077] In some embodiments of the present invention, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is a tablet.

[0078] In some embodiments of the present invention, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention comprises 10-150 mg (eg, 50 or 100 mg) of Compound 1 per unit dosage form.

[0079] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release rate within 1 hour of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is 15% to 40%, preferably 15% to 36%, more preferably 20% to 35%, further preferably 23% to 35%, and even more preferably 24% to 32%.

[0080] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention within 1 hour is 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35% or 36%, preferably 15%, 23%, 24%, 27%, 28%, 29%, 30%, 32%, 34% or 35%.

[0081] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release rate of 24% to 60% within 2 hours, preferably 30% to 50%, more preferably 35% to 50%, and even more preferably 40% to 50%.

[0082] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release within 2 hours of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is 24%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%, preferably 24%, 37%, 39%, 41%, 44%, 46% or 49%.

[0083] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5° C. and a paddle speed of 50 rpm, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release rate of 40% to 60% within 3 hours, preferably 40% to 55%, and more preferably 45% to 55%.

[0084] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention within 3 hours is 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60%, preferably 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55% or 57%.

[0085] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release rate of 39% to 80% within 4 hours, preferably 50% to 70%, more preferably 50% to 65%, and further preferably 50% to 60%.

[0086] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention within 4 hours is 39%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 67% or 68%, preferably 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 67% or 68%.

[0087] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release rate of ≥63% within 8 hours, preferably ≥75%, more preferably ≥80%, and further preferably ≥82%.

[0088] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C. and a paddle speed of 50 rpm, the cumulative release rate of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention within 8 hours is 63%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or 96%, preferably 63%, 70%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or 96%, more preferably 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% or 93%.

[0089] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release rate of ≥80% within 10 hours, preferably ≥85%, more preferably ≥90%, further preferably ≥92%, and even more preferably ≥94%.

[0090] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C. and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention within 10 hours is 80%, 82%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, preferably 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, more preferably 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

[0091] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition as described in the first aspect of the present invention or the film-coated sustained-release preparation as described above is 15% to 40% within 1 hour, the cumulative release within 2 hours is 24% to 60%, the cumulative release within 4 hours is 39%-80%, and the cumulative release within 8 hours is ≥63%; preferably, the sustained-release composition as described in the first aspect of the present invention or the film-coated sustained-release preparation as described in the second aspect of the present invention is 15% to 40% within 1 hour. The cumulative release within 1 hour is 15% to 36%, the cumulative release within 2 hours is 24% to 50%, the cumulative release within 4 hours is 39% to 70%, and the cumulative release within 8 hours is ≥63%; more preferably, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release within 1 hour of 15% to 35%, the cumulative release within 2 hours is 30% to 50%, the cumulative release within 4 hours is 50% to 70%, and the cumulative release within 8 hours is ≥75%.

[0092] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5° C. and a paddle speed of 50 rpm, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; preferably, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; more preferably, the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 49% to 57% within 3 hours, and a cumulative release of ≥92% within 10 hours.

[0093] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C maxThe concentration of the oligonucleotide is 1202-7828 ng / mL, preferably 1718-6022 ng / mL, more preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, and further preferably 3870 ng / mL.

[0094] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-t The molecular weight of the present invention is 7319-40253 ng*h / mL, preferably 10456-30964 ng*h / mL, more preferably 16568-24852 ng*h / mL, 17603-23816 ng*h / mL, 18639-22781 ng*h / mL, 19674-21745 ng*h / mL, 20295-21124 ng*h / mL or 20502-20917 ng*h / mL, and further preferably 20710 ng*h / mL.

[0095] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ The molecular weight of the present invention is 7387-40253 ng*h / mL, preferably 10554-30964 ng*h / mL, more preferably 16607-24910 ng*h / mL, 18683-22834 ng*h / mL, 19721-21796 ng*h / mL, 20343-21174 ng*h / mL or 20551-20966 ng*h / mL, and further preferably 20759 ng*h / mL.

[0096] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, T max The operating time is 3.6-7.4h, preferably 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, more preferably 5.5h.

[0097] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, T 1 / 2The time is 0.6-7.1h, preferably 0.9-5.5h, more preferably 2.56-3.84h, 2.88-3.52h or 3.04-3.36h, further preferably 3.2h.

[0098] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max 1202-7828 ng / mL, AUC 0-t 7319-40253 ng*h / mL, AUC 0-∞ 7387-40253 ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.6-7.1h.

[0099] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max 1718-6022 ng / mL, AUC 0-t 10456-30964 ng*h / mL, AUC 0-∞ 10554-30964ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.9-5.5h.

[0100] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max 3870 ng / mL, AUC 0-t 20710 ng*h / mL, AUC 0-∞ 20759ng*h / mL, T max 5.5h, T 1 / 2 3.2h.

[0101] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C maxThe concentration of the oligonucleotide is 170.42-774.46 ng / mL, preferably 243.46-595.74 ng / mL, more preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, and further preferably 419.60 ng / mL.

[0102] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, the AUC 0-t The molecular weight of the present invention is 1062.68-4646.28 ng*h / mL, preferably 1518.12-3574.06 ng*h / mL, more preferably 2036.87-3055.20 ng*h / mL, 2291.48-2800.70 ng*h / mL, 2418.78-2673.39 ng*h / mL or 2495.17-2597.01 ng*h / mL, and further preferably 2546.09 ng / mL.

[0103] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, the AUC 0-∞ The molecular weight of the present invention is 1049.31-4849.65 ng*h / mL, preferably 1499.02-3730.50 ng*h / mL, more preferably 2091.81-3137.71 ng*h / mL, 2353.28-2876.24 ng*h / mL, 2484.02-2745.50 ng*h / mL or 2562.46-2667.06 ng*h / mL, and further preferably 2614.76 ng / mL.

[0104] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max The time is 1.4-7.8h, preferably 2-6h, more preferably 4-6h, 4.5-5.5h or 4.9-5.1h, further preferably 5h.

[0105] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T 1 / 2The time is 1.60-5.84 h, preferably 2.29-4.49 h, more preferably 2.71-4.07 h, 3.05-3.73 h or 3.22-3.56 h, for example 3.39 h.

[0106] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 170.42-774.46 ng / mL, AUC 0-t 1062.68-4646.28 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 1.4-7.8h, T 1 / 2 1.60-5.84h.

[0107] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 243.46-595.74 ng / mL, AUC 0-t 1518.12-3574.06 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 2-6h, T 1 / 2 2.29-4.49h.

[0108] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 419.60 ng / mL, AUC 0-t 2546.09 ng / mL, AUC 0-∞ was 2614.76 ng / mL, T max 5h, T 1 / 2 It is 3.39h.

[0109] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C maxThe concentration of the soluble amino acid in the ethanol is 423.20-1705.12 ng / mL, preferably 604.57-1311.63 ng / mL, more preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, and further preferably 958.10 ng / mL.

[0110] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, the AUC 0-t The molecular weight of the alcohol is 2394.79-9868.31 ng*h / mL, preferably 4192.55-7591.01 ng*h / mL, more preferably 4713.42-7070.14 ng*h / mL, 5302.60-6480.96 ng*h / mL or 5597.19-6186.37 ng*h / mL, and further preferably 5891.78 ng*h / mL.

[0111] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, the AUC 0-∞ The molecular weight of the active ingredient is 2969.63-10001.46 ng*h / mL, preferably 4242.33-7693.43 ng*h / mL, more preferably 4774.14-7161.22 ng*h / mL, 5370.91-6564.45 ng*h / mL or 5669.30-6266.06 ng*h / mL, and further preferably 5967.68 ng*h / mL.

[0112] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max The time is 2.8-7.8h, preferably 4-6h, more preferably 5-6h, and further preferably 6h.

[0113] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T 1 / 2 The operating time is 0.83-5.14 h, preferably 2.75-3.95 h, more preferably 3.01-3.69 h or 3.18-3.52 h, further preferably 3.35 h.

[0114] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 423.20-1705.12 ng / mL, AUC 0-t 2394.79-9868.31 ng*h / mL, AUC 0-∞ 2969.63-10001.46 ng*h / mL, T max 2.8-7.8h, T 1 / 2 0.83-5.14h.

[0115] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 604.57-1311.63 ng / mL, AUC 0-t 4192.55-7591.01 ng*h / mL, AUC 0-∞ 4242.33-7693.43 ng*h / mL, T max 4-6h, T 1 / 2 2.75-3.95h.

[0116] In some embodiments of the present invention, when the sustained-release composition according to the first aspect of the present invention or the film-coated sustained-release preparation according to the second aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 958.10 ng / mL, AUC 0-t 5891.78 ng*h / mL, AUC 0-∞ is 5967.68ng*h / mL, T max 6h, T 1 / 2 It is 3.35h.

[0117] In a third aspect, the present invention provides a sustained-release composition or film-coated sustained-release preparation, wherein, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as a dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition or film-coated sustained-release preparation has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 24% to 60% within 2 hours, a cumulative release of 39% to 80% within 4 hours, and a cumulative release of ≥63% within 8 hours;

[0118] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0119] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0120] In a fourth aspect, the present invention provides a sustained-release composition or a film-coated sustained-release preparation, wherein, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as a dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours;

[0121] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0122] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0123] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release rate of the sustained-release composition or film-coated sustained-release preparation as described in the third aspect or the fourth aspect of the present invention within 1 hour is 15% to 36%, preferably 20% to 35%, more preferably 23% to 35%, and even more preferably 24% to 32%.

[0124] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the third aspect or the fourth aspect of the present invention within 1 hour is 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35% or 36%, preferably 15%, 23%, 24%, 27%, 28%, 29%, 30%, 32%, 34% or 35%.

[0125] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the third aspect of the present invention within 2 hours is 30% to 50%, more preferably 35% to 50%, and even more preferably 40% to 50%.

[0126] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the third aspect of the present invention within 2 hours is 24%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%, preferably 24%, 37%, 39%, 41%, 44%, 46% or 49%.

[0127] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the fourth aspect of the present invention within 3 hours is 40% to 55%, preferably 45% to 55%.

[0128] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation according to the fourth aspect of the present invention within 3 hours is 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60%, preferably 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55% or 57%.

[0129] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the third aspect of the present invention within 4 hours is 50% to 70%, preferably 50% to 65%, and more preferably 50% to 60%.

[0130] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation according to the third aspect of the present invention within 4 hours is 39%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 67% or 68%, preferably 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 67% or 68%.

[0131] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the third aspect of the present invention within 8 hours is ≥75%, preferably ≥80%, and more preferably ≥82%.

[0132] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation according to the third aspect of the present invention within 8 hours is 63%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135 %, 90%, 91%, 92%, 93%, 94%, 95% or 96%, preferably 63%, 70%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or 96%, more preferably 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%.

[0133] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation as described in the fourth aspect of the present invention within 10 hours is ≥85%, more preferably ≥90%, further preferably ≥92%, and even more preferably ≥94%.

[0134] In some embodiments of the present invention, with 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C, a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation according to the fourth aspect of the present invention within 10 hours is 80%, 82%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, preferably 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, more preferably 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

[0135] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition or film-coated sustained-release preparation as described in the third aspect of the present invention has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 24% to 50% within 2 hours, a cumulative release of 39% to 70% within 4 hours, and a cumulative release of ≥63% within 8 hours; preferably, the sustained-release composition or film-coated sustained-release preparation as described in the third aspect of the present invention has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 30% to 50% within 2 hours, a cumulative release of 50% to 70% within 4 hours, and a cumulative release of ≥75% within 8 hours.

[0136] In some embodiments of the present invention, using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition or film-coated sustained-release preparation as described in the fourth aspect of the present invention has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; preferably, the sustained-release composition or film-coated sustained-release preparation as described in the fourth aspect of the present invention has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 49% to 57% within 3 hours, and a cumulative release of ≥92% within 10 hours.

[0137] The fifth aspect of the present invention provides a sustained-release composition or film-coated sustained-release preparation, wherein when the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of the compound 1 after a meal, C max 1202-7828 ng / mL;

[0138] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0139] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0140] The sixth aspect of the present invention provides a sustained-release composition or film-coated sustained-release preparation, wherein when the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of the compound 1 after a meal, T max 3.6-7.4h;

[0141] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0142] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0143] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max The concentration of the oligonucleotide is 1718-6022 ng / mL, preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, and more preferably 3870 ng / mL.

[0144] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max The concentration of the oligonucleotide is 1202-7828 ng / mL, preferably 1718-6022 ng / mL, more preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, and further preferably 3870 ng / mL.

[0145] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth or sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-tThe molecular weight of the present invention is 7319-40253 ng*h / mL, preferably 10456-30964 ng*h / mL, more preferably 16568-24852 ng*h / mL, 17603-23816 ng*h / mL, 18639-22781 ng*h / mL, 19674-21745 ng*h / mL, 20295-21124 ng*h / mL or 20502-20917 ng*h / mL, and further preferably 20710 ng*h / mL.

[0146] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth or sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ The molecular weight of the present invention is 7387-40253 ng*h / mL, preferably 10554-30964 ng*h / mL, more preferably 16607-24910 ng*h / mL, 18683-22834 ng*h / mL, 19721-21796 ng*h / mL, 20343-21174 ng*h / mL or 20551-20966 ng*h / mL, and further preferably 20759 ng*h / mL.

[0147] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, T max The operating time is 3.6-7.4h, preferably 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, more preferably 5.5h.

[0148] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, T max It is 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, preferably 5.5h.

[0149] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth or sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, T 1 / 2 The time is 0.6-7.1h, preferably 0.9-5.5h, more preferably 2.56-3.84h, 2.88-3.52h or 3.04-3.36h, further preferably 3.2h.

[0150] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth or sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max 1202-7828 ng / mL, AUC 0-t 7319-40253 ng*h / mL, AUC 0-∞ 7387-40253 ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.6-7.1h.

[0151] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth or sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max 1718-6022 ng / mL, AUC 0-t 10456-30964 ng*h / mL, AUC 0-∞ 10554-30964ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.9-5.5h.

[0152] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the fifth or sixth aspect of the present invention is orally administered to beagle dogs at a dose of 150 mg of Compound 1 after a meal, C max 3870 ng / mL, AUC 0-t 20710 ng*h / mL, AUC 0-∞ 20759ng*h / mL, T max 5.5h, T 1 / 2 3.2h.

[0153] In a seventh aspect of the present invention, a sustained-release composition or film-coated sustained-release preparation is provided. When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of the compound 1 after a meal, C max 170.42-774.46 ng / mL;

[0154] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0155] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0156] In an eighth aspect of the present invention, a sustained-release composition or film-coated sustained-release preparation is provided. When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of the compound 1 after a meal, T max 1.4-7.8h;

[0157] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0158] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0159] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max The concentration of the oligonucleotide is 243.46-595.74 ng / mL, preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, and more preferably 419.60 ng / mL.

[0160] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max The concentration of the oligonucleotide is 170.42-774.46 ng / mL, preferably 243.46-595.74 ng / mL, more preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, and further preferably 419.60 ng / mL.

[0161] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh or eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, the AUC 0-t The molecular weight of the present invention is 1062.68-4646.28 ng*h / mL, preferably 1518.12-3574.06 ng*h / mL, more preferably 2036.87-3055.20 ng*h / mL, 2291.48-2800.70 ng*h / mL, 2418.78-2673.39 ng*h / mL or 2495.17-2597.01 ng*h / mL, and further preferably 2546.09 ng / mL.

[0162] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh or eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, the AUC 0-∞ The molecular weight of the present invention is 1049.31-4849.65 ng*h / mL, preferably 1499.02-3730.50 ng*h / mL, more preferably 2091.81-3137.71 ng*h / mL, 2353.28-2876.24 ng*h / mL, 2484.02-2745.50 ng*h / mL or 2562.46-2667.06 ng*h / mL, and further preferably 2614.76 ng / mL.

[0163] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max The time is 1.4-7.8h, preferably 2-6h, more preferably 4-6h, 4.5-5.5h or 4.9-5.1h, further preferably 5h.

[0164] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max The time is 2-6 hours, preferably 4-6 hours, 4.5-5.5 hours or 4.9-5.1 hours, more preferably 5 hours.

[0165] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh or eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T 1 / 2 The time is 1.60-5.84 h, preferably 2.29-4.49 h, more preferably 2.71-4.07 h, 3.05-3.73 h or 3.22-3.56 h, for example 3.39 h.

[0166] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh or eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 170.42-774.46 ng / mL, AUC 0-t 1062.68-4646.28 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 1.4-7.8h, T 1 / 21.60-5.84h.

[0167] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh or eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 243.46-595.74 ng / mL, AUC 0-t 1518.12-3574.06 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 2-6h, T 1 / 2 2.29-4.49h.

[0168] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the seventh or eighth aspect of the present invention is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 419.60 ng / mL, AUC 0-t 2546.09 ng / mL, AUC 0-∞ was 2614.76 ng / mL, T max 5h, T 1 / 2 It is 3.39h.

[0169] The ninth aspect of the present invention provides a sustained-release composition or film-coated sustained-release preparation, wherein when the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of the compound 1 after a meal, C max 423.20-1705.12 ng / mL;

[0170] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0171] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0172] The tenth aspect of the present invention provides a sustained-release composition or film-coated sustained-release preparation, wherein when the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of the compound 1 after a meal, T max 2.8-7.8h;

[0173] The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition;

[0174] The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof;

[0175] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max The concentration of the oligonucleotide is 604.57-1311.63 ng / mL, preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, and more preferably 958.10 ng / mL.

[0176] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max The concentration of the soluble amino acid in the ethanol is 423.20-1705.12 ng / mL, preferably 604.57-1311.63 ng / mL, more preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, and further preferably 958.10 ng / mL.

[0177] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth or tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-t The molecular weight of the alcohol is 2394.79-9868.31 ng*h / mL, preferably 4192.55-7591.01 ng*h / mL, more preferably 4713.42-7070.14 ng*h / mL, 5302.60-6480.96 ng*h / mL or 5597.19-6186.37 ng*h / mL, and further preferably 5891.78 ng*h / mL.

[0178] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth or tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞The molecular weight of the active ingredient is 2969.63-10001.46 ng*h / mL, preferably 4242.33-7693.43 ng*h / mL, more preferably 4774.14-7161.22 ng*h / mL, 5370.91-6564.45 ng*h / mL or 5669.30-6266.06 ng*h / mL, and further preferably 5967.68 ng*h / mL.

[0179] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max The time is 2.8-7.8h, preferably 4-6h, more preferably 5-6h, and further preferably 6h.

[0180] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max The time is 4-6 hours, preferably 5-6 hours, more preferably 6 hours.

[0181] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth or tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T 1 / 2 The operating time is 0.83-5.14 h, preferably 2.75-3.95 h, more preferably 3.01-3.69 h or 3.18-3.52 h, further preferably 3.35 h.

[0182] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth or tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 423.20-1705.12 ng / mL, AUC 0-t 2394.79-9868.31 ng*h / mL, AUC 0-∞ 2969.63-10001.46 ng*h / mL, T max 2.8-7.8h, T 1 / 2 0.83-5.14h.

[0183] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth or tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 604.57-1311.63 ng / mL, AUC 0-t4192.55-7591.01 ng*h / mL, AUC 0-∞ 4242.33-7693.43 ng*h / mL, T max 4-6h, T 1 / 2 2.75-3.95h.

[0184] In some embodiments of the present invention, when the sustained-release composition or film-coated sustained-release preparation according to the ninth or tenth aspect of the present invention is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 958.10 ng / mL, AUC 0-t 5891.78 ng*h / mL, AUC 0-∞ is 5967.68ng*h / mL, T max 6h, T 1 / 2 It is 3.35h.

[0185] In some embodiments of the present invention, the coating coated on the surface of the sustained-release composition as described in the third, fourth, fifth, sixth, seventh, eighth, ninth or tenth aspects of the present invention is prepared using a film coating premix, and the mass ratio of the film coating premix to the sustained-release composition is (0.015-0.045):1, preferably (0.02-0.04):1, and more preferably 0.03:1. The film coating premix is ​​preferably a gastric-soluble film coating premix, such as an HMPC film coating premix or a PVA film coating premix.

[0186] In some embodiments of the present invention, the sustained-release composition as described in the third, fourth, fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention or the film-coated sustained-release preparation as described in the second aspect of the present invention is a tablet.

[0187] In some embodiments of the present invention, in the sustained-release composition or film-coated sustained-release preparation as described in the third aspect, fourth aspect, fifth aspect, sixth aspect, seventh aspect, eighth aspect, ninth aspect or tenth aspect of the present invention, each unit dosage form contains 10-150 mg (e.g., 50 or 100 mg) of the compound 1.

[0188] The eleventh aspect of the present invention provides a method for preparing a sustained-release composition, comprising the following steps: (1) premixing an active pharmaceutical ingredient, a sustained-release material, and a portion of an additive;

[0189] (2) granulating the premix obtained in step (1) using a dry granulator;

[0190] (3) mixing the dry particles obtained in step (2) with the remaining amount of the additive;

[0191] (4) tableting the total mixed material obtained in step (3);

[0192] The active pharmaceutical ingredient is Compound 1 or a pharmaceutically acceptable salt thereof;

[0193] In the method for preparing the sustained-release composition, preferably, the amount of the active pharmaceutical ingredient is 3.33wt%-50.00wt%, preferably 6.67wt%-50wt%, for example 10.00wt%, 13.33wt%, 16.67wt%, 20.00wt%, 26.67wt% or 33.33wt%.

[0194] In the method for preparing the sustained-release composition, preferably, the sustained-release material is a hydrophilic polymer.

[0195] In the method for preparing the sustained-release composition, preferably, the hydrophilic polymer is one or more of a cellulose derivative, povidone and carbomer.

[0196] In the method for preparing the sustained-release composition, preferably, the hydrophilic polymer is a cellulose derivative.

[0197] In the method for preparing the sustained-release composition, preferably, the cellulose derivative is one or more of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose and sodium carboxymethyl cellulose, preferably hydroxypropyl methyl cellulose, more preferably hydroxypropyl methyl cellulose K4M CR.

[0198] In the method for preparing the sustained-release composition, preferably, the viscosity of the hydrophilic polymer is 1000-150000 mPa.s, preferably 2000-10000 mPa.s, more preferably 2000-8000 mPa.s, further preferably 2663-4379 mPa.s, for example 4000 mPa.s.

[0199] In the method for preparing the sustained-release composition, preferably, the hydrophilic polymer is hydroxypropyl methylcellulose with a viscosity of 2663-4379 mPa.s, preferably hydroxypropyl methylcellulose with a viscosity of 4000 mPa.s.

[0200] In the method for preparing the sustained-release composition, preferably, the content of the sustained-release material is 18.00 wt%-35.00 wt%, such as 20.00 wt%, 22.00 wt%, 25.00 wt% or 28.00 wt%.

[0201] In the method for preparing the sustained-release composition, preferably, the additives include a diluent and a lubricant.

[0202] In the method for preparing the sustained-release composition, preferably, the diluent is a water-soluble diluent and a water-insoluble diluent. The water-soluble diluent is preferably one or more of lactose, mannitol, sorbitol, sucrose, povidone, and copovidone. The water-insoluble diluent is preferably one or more of pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, and hydroxypropyl methylcellulose (≤50 cps).

[0203] In the method for preparing the sustained-release composition, preferably, the diluent is lactose and / or microcrystalline cellulose.

[0204] In the method for preparing the sustained-release composition, preferably, the amount of the diluent used is 29.00 wt%-62.33 wt%, such as 31.00 wt%, 43.67 wt%, 54.33 wt%, 57.33 wt%, 60.33 wt% or 60.67 wt%.

[0205] In the method for preparing the sustained-release composition, preferably, the weight ratio of the additives in step (1) and step (3) is (59-122.33):1, for example, 59:1, 63:1, 88.33:1, 109.67:1, 115.67:1, 121.67:1, 125.67:1 or 122.33:1.

[0206] In the method for preparing the sustained-release composition, preferably, the lubricant is a hydrophobic lubricant or a hydrophilic lubricant, preferably a hydrophobic lubricant. The hydrophobic lubricant is preferably one or more of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate and talc, more preferably one or more of magnesium stearate, sodium stearyl fumarate and talc, such as magnesium stearate.

[0207] In the preparation method of the sustained-release composition, preferably, the amount of the lubricant is 0.5wt%-5wt%, preferably 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt% or 5.0wt%, more preferably 1.0wt%.

[0208] The twelfth aspect of the present invention further provides a sustained-release composition, which is prepared by the preparation method as described in the eleventh aspect of the present invention.

[0209] In the thirteenth aspect of the present invention, there is provided a use of a substance X in the preparation of a medicament for preventing or treating diseases related to fibrosis, wherein the substance X is a sustained-release composition as described in the first or twelfth aspect of the present invention, a film-coated sustained-release preparation as described in the second aspect of the present invention, or a sustained-release composition or film-coated sustained-release preparation as described in the third, fourth, fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention.

[0210] In some embodiments of the present invention, the fibrosis-related disease is idiopathic pulmonary fibrosis.

[0211] In a fourteenth aspect, the present invention provides a method for treating a disease associated with fibrosis, comprising administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. The disease associated with fibrosis is preferably idiopathic pulmonary fibrosis.

[0212] In some embodiments of the present invention, the Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0213] In some embodiments of the present invention, the Compound 1 or a pharmaceutically acceptable salt thereof is orally administered after a meal.

[0214] In some embodiments of the present invention, Compound 1 or a pharmaceutically acceptable salt thereof can be prepared into the sustained-release composition or the film-coated sustained-release formulation. In the sustained-release composition or the film-coated pre-release formulation, each unit dosage form contains 10-150 mg (e.g., 50 or 100 mg) of Compound 1.

[0215] In some embodiments of the present invention, the total daily dosage of Compound 1 is 200-400 mg, for example, 300 mg.

[0216] In some embodiments of the present invention, the administration frequency of Compound 1 is once a day or twice a day, preferably twice a day.

[0217] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0218] The reagents and raw materials used in the present invention are commercially available.

[0219] The positive progress of the present invention is that the sustained-release composition or film-coated sustained-release preparation of Compound 1 provided by the present invention can control the release rate and blood concentration of Compound 1 in the body, reduce the occurrence of adverse reactions, increase the exposure of the drug in the body, and improve the patient's compliance with medication.

[0220] definition

[0221] The section headings as used in this section and the overall disclosure are not intended to be limiting.

[0222] The term "additives" refers to other pharmaceutically acceptable carriers besides sustained-release materials, such as diluents, fillers, binders, wetting agents, surfactants or surface active carriers, buffers, lubricants, glidants, thickeners, sweeteners, flavorings, colorants and coating materials.

[0223] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts. Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like. Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts (e.g., lithium, sodium, potassium, cesium, magnesium, calcium salts, etc.), salts with organic bases, for example, primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, hydrazine salts and salts with amino acids, such as, for example, arginine, lysine, etc. Conversely, the salt form can be converted into the free acid form by treatment with an acid.

[0224] The term "subject" refers to a human subject, such as a healthy adult subject.

[0225] The terms "treating" and "treatment" refer to ameliorating, inhibiting, eradicating, reducing the severity of, decreasing the frequency of, preventing, reducing the risk of, slowing the progression of damage caused by, or delaying the onset of a disorder, or improving the quality of life of a patient suffering from the disorder.

[0226] The term "wt%" refers to the ratio of the weight of the corresponding component to the total weight of the sustained-release composition or film-coated sustained-release preparation.

[0227] The term "cumulative release" is determined using the second method (paddle method) for dissolution and release determination in Part IV of the Chinese Pharmacopoeia (2020 Edition). 900 mL of 50 mM pH 6.8 phosphate buffer solution is used as the dissolution medium. The dissolution medium temperature is 37 ± 0.5°C, the paddle speed is 50 rpm, and a sinker is added. To calculate the cumulative release, the cumulative release amount at each time point (concentration * volume + concentration of the drug solution in the dissolution medium removed * volume of the dissolution medium removed) is compared with the labeled amount of the test preparation to obtain the cumulative release at that time point.

[0228] The term "150 mg of Compound 1" means that the active ingredient in the administered composition or preparation is 150 mg in terms of the content of Compound 1, and the active ingredient can be provided by a single composition or preparation administered to the subject, or by multiple compositions or preparations administered to the subject at the same time.

[0229] The term "100 mg of Compound 1 dose" means that the active ingredient in the administered composition or preparation is 100 mg in terms of the content of Compound 1, and the active ingredient can be provided by a single composition or preparation administered to the subject, or by multiple compositions or preparations administered to the subject at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0230] FIG1 is a comparison of in vitro dissolution / release curves of Examples 1-10.

[0231] FIG2 is a comparison of the in vitro dissolution / release curves of Example 11 and Comparative Example 1.

[0232] Figure 3 shows the blood drug concentration-time curves of beagle dogs after oral administration of different preparations.

[0233] Figure 4 shows the blood concentration-time curves of different oral preparations. DETAILED DESCRIPTION

[0234] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0235] Compound 1 was provided by Guangzhou Jiayue Pharmaceutical Technology Co., Ltd. or can be prepared according to the method disclosed in WO2017177974A1. In the following examples, Form A of Compound 1 was used as the starting material, and Form A was prepared according to the method of Example 2 in patent WO2019072236A1;

[0236] Hydroxypropyl methylcellulose (4000mPa.s), trade name and model: Methocel TMK4M Premium CR; Manufacturer: Nutrition&Biosciences USA 1, LLC.

[0237] Example 1-4: Preparation of 50 mg / tablet sustained-release formulation of Compound 1

[0238] A 50 mg / tablet sustained-release formulation of Compound 1 was prepared by the following method: 1) weighing a batch of Compound 1 and various excipients according to the formulation in Table 1; 2) sieving and mixing Compound 1 and the excipients in the internal phase except magnesium stearate; adding the internal phase magnesium stearate, continuing to mix, preparing a premix and dry granulating; 3) adding the external phase excipients to the prepared premix, mixing, and preparing the final mixture; and 4) tableting using a punch die.

[0239] Table 1 Composition of 50 mg / tablet sustained-release preparation of Compound 1

[0240] Example 5-8: Preparation of 100 mg / tablet and 150 mg / tablet sustained-release formulations of Compound 1

[0241] The formulation in Table 2 was used and the preparation was carried out according to the method of Examples 1-4.

[0242] Table 2 Composition of 100 mg / tablet and 150 mg / tablet sustained-release formulations of Compound 1

[0243] Examples 9-11: Preparation of film-coated premixed sustained-release formulations

[0244] The preparation steps of the uncoated tablets of Examples 9-11 were the same as those of Examples 1-4. The film coating process included: 1) preparing a coating solution with a solid content of 15% (HPMC type, model: 03K1310023; manufacturer: Shanghai Colorcon Coating Technology Co., Ltd.) or 20% (PVA type, model: 321A140065-CN; manufacturer: Shanghai Colorcon Coating Technology Co., Ltd.) using a film coating premix and water. After the tablet cores were fully preheated, the tablet cores were evenly coated with a layer of film coating using a tablet coating apparatus.

[0245] Table 3 Prescription composition of film-coated premixed sustained-release preparations

[0246] Example 12 Preparation of Dry Granulated Sustained Release Formulation

[0247] A sustained-release preparation was prepared by dry granulation using the following method: 1) weighing a batch of Compound 1 and various excipients according to the formulation in Table 4; 2) sieving and mixing Compound 1 and the excipients in the internal phase except magnesium stearate; adding magnesium stearate to the internal phase and continuing to mix to prepare a premix; 3) granulating the premixed excipients in step 2) using a dry granulator; 4) adding the external phase excipients to the dry granules prepared in step 3), mixing, and preparing the final mixture; and 5) tableting using a die.

[0248] Table 4 Prescription composition of dry granulation sustained-release preparation

[0249] Example 13 Preparation of 200 mg total weight sustained-release tablets

[0250] A sustained-release preparation was prepared by dry granulation using the following method: 1) weighing a batch of Compound 1 and various excipients according to the formulation in Table 5; 2) sieving and mixing Compound 1 and the excipients in the internal phase except magnesium stearate; adding magnesium stearate to the internal phase and continuing to mix to prepare a premix; 3) granulating the premixed excipients in step 2) using a dry granulator; 4) adding the external phase excipients to the dry granules prepared in step 3), mixing, and preparing the final mixture; and 4) tableting using a die.

[0251] Table 5 Composition of 200 mg total weight sustained-release preparation

[0252] Comparative Example 1 Preparation of Ordinary Tablets

[0253] Ordinary tablets were prepared by wet granulation using the following method: 1) weighing a batch of Compound 1 and various excipients according to the formulation in Table 6; 2) sieving and mixing Compound 1 and the excipients except magnesium stearate in the internal phase; adding an appropriate amount of water to carry out wet granulation, wet granulation, drying, and granulation; 3) adding magnesium stearate from the external phase to the dry granules prepared in step 2), and mixing to form the total mixed material; 4) tableting using a die to obtain uncoated tablet cores.

[0254] The film coating process includes: 1) preparing a coating solution with a solid content of 15% using a film coating premix (HPMC type: 03K520034-CN, manufactured by Shanghai Colorcon Coating Technology Co., Ltd.) and water. After the tablet cores are fully preheated, a film coating is evenly applied to the tablet cores using a tablet coating device according to conventional coating parameters.

[0255] Table 6 Composition of common tablet prescription

[0256] Effect Example 1 Dissolution Test of Tablets of Examples 1-10

[0257] The dissolution of the sustained-release tablets of Compound 1 prepared in Example 1-10 was investigated. The second method (paddle method) of the dissolution and release determination method in Part IV of the Chinese Pharmacopoeia (2020 Edition) was adopted, and 900 mL of 50 mM pH 6.8 phosphate buffer solution was used as the dissolution medium. The dissolution medium temperature was 37 ± 0.5 ° C, the paddle speed was 50 rpm, and a sinker was added. The dissolution test results of the tablets of each prescription in Example 1-10 are shown in Table 7, and the dissolution curves are shown in Figure 1. The results show that the sustained-release tablets prepared in Example 1-10 dissolve smoothly, and a significant slow release effect can be achieved.

[0258] Table 7 Dissolution test results of each prescription tablet of Examples 1-10

[0259] Effect Example 2 Tablet Dissolution Test of Examples 11-13 and Comparative Example 1

[0260] The sustained-release tablets of compound 1 prepared in Example 11-13 and the ordinary tablets prepared in Comparative Example 1 were subjected to dissolution investigation. The sustained-release tablets of Example 11-13 adopt the second method (paddle method) of the dissolution and release determination method in Part IV of the Chinese Pharmacopoeia (2020 Edition), using 900mL of 50mM pH 6.8 phosphate buffer solution as the dissolution medium, the dissolution medium temperature 37±0.5°C, the paddle speed 50rpm, and a sinker. The ordinary tablets of Comparative Example 1 adopt the second method paddle method of the dissolution determination method of the Chinese Pharmacopoeia (2020 Edition), using 900mL of 50mM pH 6.8 phosphate buffer solution as the dissolution medium, the dissolution medium temperature 37±0.5°C, and the paddle speed 50rpm. The dissolution test results of Example 11-13 sustained-release tablets and Comparative Example 1 ordinary tablets are shown in Table 8, and the dissolution curves of Example 11 and Comparative Example 1 are shown in Figure 2. The results showed that compared with the ordinary tablets of Comparative Example 1, the sustained-release tablets prepared in Examples 11-13 dissolve more slowly and can achieve a significant slow-release effect.

[0261] Table 8 Dissolution test results of sustained-release tablets of Examples 11-13 and ordinary tablets of Comparative Example 1

[0262] Effect Example 3 Pharmacokinetic Study in Dogs

[0263] Four male beagle dogs (8-11 kg) were divided into two groups and administered orally after meals in two cycles (overnight fasting, feeding 30 minutes before morning administration) with the compound 1 preparation prepared in Example 6 and Comparative Example 1. The dose was 150 mg. The blood was collected before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h after administration. About 0.5 mL of blood was collected from the forelimb vein at the above set time points, placed in an EDTA-K2 test tube, centrifuged at 11000 rpm for 5 min, and the plasma was separated and frozen in a -70 ° C refrigerator for testing. A standard curve of the appropriate range was established based on the sample concentration, and the concentration of compound 1 in the plasma sample was determined for quantitative analysis and calculation of pharmacokinetic parameters. The results are as follows:

[0264] Table 9

[0265] Clinical observation after administration revealed that obvious vomiting reaction was observed in the comparative example 1 group within 2 hours after administration, while no vomiting reaction was observed in the example 6 group after administration.

[0266] The results in Table 9 and Figure 3 show that the sustained-release preparation of the present invention reduces C max , significantly improved T 1 / 2 and T max , has obvious sustained-release characteristics, and at the same time, the sustained-release preparation of the present invention can significantly reduce or avoid the occurrence of adverse reactions such as vomiting.

[0267] Effect Example 4 Pharmacokinetic Study in Humans

[0268] (1) Comparative Example 1 Tablet

[0269] This study was a single-center, randomized, double-blind, placebo-controlled trial designed to evaluate the tolerability, pharmacokinetic characteristics, and food-induced pharmacokinetic characteristics of the common tablets of Compound 1 obtained in Comparative Example 1 in healthy adult volunteers after single and repeated dosing. Both single-dose and repeated-dose groups were designed. In the single-dose group, each subject received a single dose of the common tablets of Compound 1 obtained in Comparative Example 1 or a placebo. In the repeated-dose group, each subject received a single dose of the common tablets of Compound 1 obtained in Comparative Example 1 or a placebo. In the repeated-dose group, each subject received a twice-daily dose (BID, morning and evening) on ​​Days 1 to 6, and a single dose of the Comparative Example 1 tablet or placebo on Day 7.

[0270] The single-dose grouping and administration are as follows:

[0271] 50 mg on an empty stomach, 3 cases, each subject was given a single 50 mg dose of the comparative example 1 tablet on an empty stomach (50 mg × 1 tablet);

[0272] 150 mg on an empty stomach, 7 cases, each subject was given a single dose of 150 mg of the comparative example 1 tablet (50 mg × 3 tablets) on an empty stomach;

[0273] 300 mg on an empty stomach, 7 cases, each subject was given a single 300 mg tablet of Comparative Example 1 (50 mg × 6 tablets) on an empty stomach;

[0274] 150 mg after meal, 8 cases, each subject was given a single dose of 150 mg tablet of Comparative Example 1 after meal (50 mg×3 tablets).

[0275] The multiple dose groups and administration schedules are as follows:

[0276] 200 mg after meals, 8 cases, each subject was given 100 mg tablet of comparative example 1 (50 mg × 2 tablets) twice a day (BID, once in the morning and once in the evening) after meals on days 1 to 6, and 100 mg tablet of comparative example 1 (50 mg × 2 tablets) was given once after meals on the morning of day 7;

[0277] 400 mg after meals, 8 cases, each subject was given 200 mg (50 mg × 4 tablets) of comparative example 1 tablet twice a day (BID, once in the morning and once in the evening) after meals on days 1 to 6, and 200 mg (50 mg × 4 tablets) of comparative example 1 tablet was given once after meals on the morning of day 7.

[0278] The HPLC-MS / MS method was used to determine the blood concentration of compound 1 at different times after administration to obtain the corresponding pharmacokinetic parameters of each group and record the occurrence of adverse reactions in each subject after administration.

[0279] (2) Example 11 Tablets

[0280] This single-center, open-label study evaluated the tolerability and pharmacokinetic characteristics of sustained-release Compound 1 tablets obtained in Example 11 after repeated dosing in healthy adult volunteers. The doses used in the repeated dosing study were 200 mg / day (8 subjects, 100 mg, 50 mg × 2 tablets, bid), 300 mg / day (8 subjects, 150 mg, 50 mg × 3 tablets, bid), and 400 mg / day (8 subjects, 200 mg, 50 mg × 4 tablets, bid). Each subject was screened and enrolled in the study and administered the tablets after meals for 7 consecutive days (once in the morning on days 1 and 7, and twice daily on days 2-6). HPLC-MS / MS was used to determine Compound 1 plasma concentrations at different times post-dose to obtain pharmacokinetic parameters for each group, and adverse reactions were recorded for each subject.

[0281] The pharmacokinetic parameters of the main dose groups are shown in Table 10 and Figure 4 below, and the occurrence of major adverse events / reactions are shown in Tables 11 and 12 below.

[0282] Table 10 Main pharmacokinetic parameters after first dose of 200 mg and 300 mg tablets of Example 11 (Mean ± SD)

[0283] Note: a. 200 mg and 300 mg are daily doses (BID), and single doses are 100 mg and 150 mg respectively;

[0284] b. The format is - median (minimum, maximum)

[0285] Table 11 Adverse events (AEs) in each dosage group of Example 11 tablets

[0286] Table 12 TEAEs with ≥2 cases / times in each group of Example 11 tablets

[0287] The results showed that compared with the tablets of Comparative Example 1, the tablets of Example 11 could significantly reduce the max and / or delay T max and T 1 / 2 , has obvious sustained-release characteristics, and can significantly increase the exposure of compound 1 in the body. At the same dosage, compared with the administration of comparative example 1 tablets, the TEAEs (Treatment-emergent adverse events) after administration of Example 11 tablets were significantly reduced. For example, in the multiple-dose study, the incidence of TEAEs of 100 mg comparative example 1 tablets twice a day and 100 mg example 11 tablets twice a day were 100% and 25%, respectively. At the same dosage, compared with the administration of comparative example 1 tablets, the incidence of adverse reactions such as gastrointestinal diseases (such as nausea, gastroesophageal reflux, abdominal distension, vomiting, diarrhea) and nervous system diseases (such as dizziness, headache, drowsiness) after administration of Example 11 tablets was reduced. In particular, when the dosage of compound 1 was 100 mg / time or 150 mg / time, the incidence of adverse reactions after administration of Example 11 tablets was significantly reduced compared with the administration of comparative example 1 tablets. Therefore, compared with conventional preparations, the sustained-release preparation of the present invention has obvious sustained-release characteristics, which can increase the exposure of the active ingredient in the body. At the same time, the sustained-release preparation of the present invention can reduce, significantly reduce or avoid the occurrence of adverse reactions such as gastrointestinal diseases (such as nausea, gastroesophageal reflux, abdominal distension, vomiting, diarrhea) and nervous system diseases (such as dizziness, headache, drowsiness).

[0288] Although specific embodiments of the present invention have been described above, those skilled in the art will appreciate that these are merely examples and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention.

Claims

1. A sustained-release composition, characterized in that The sustained-release composition comprises an active pharmaceutical ingredient, a sustained-release material, and an additive; the active pharmaceutical ingredient is Compound 1 or a pharmaceutically acceptable salt thereof; 2. The sustained-release composition according to claim 1, wherein The sustained-release composition satisfies one or more of the following conditions: (1) The active pharmaceutical ingredient is Compound 1; (2) The content of Compound 1 or a pharmaceutically acceptable salt thereof as the active ingredient in a unit sustained-release composition is 10 mg to 200 mg, for example, 10 mg, 50 mg, 100 mg, 150 mg or 200 mg, calculated as Compound 1; (3) the content of the active pharmaceutical ingredient is 3.33wt%-50.00wt%, preferably 6.67wt%-50.00wt%, more preferably 10.00wt%-50.00wt%, 13.33wt%-50.00wt%, 16.67wt%-50.00wt%, 20.00wt%-50.00wt%, 26.67%-50.00wt%, 6.67wt%-33.33wt%, 10wt%-33.33wt%, 13.33wt%-33.33wt%, 16.67wt%-33.33wt%, 20wt%-33.33wt% or 26.67wt%-33.33wt%; (4) The sustained-release material is a hydrophilic polymer; preferably one or more of a cellulose derivative, povidone, and carbomer; more preferably a cellulose derivative; (5) The content of the sustained-release material is 18.00 wt%-35.00 wt%, preferably 18.00 wt%-30.00 wt%, more preferably 18.00 wt%-28.00 wt%, and further preferably 18.00 wt%-25.00 wt%.

3. The sustained-release composition according to claim 2, wherein The cellulose derivative is one or more of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose and sodium hydroxymethyl cellulose; preferably one or more of hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; more preferably one or more of hydroxyethyl cellulose and hydroxypropyl methyl cellulose; further preferably hydroxypropyl methyl cellulose; and even more preferably hydroxypropyl methyl cellulose K4M CR.

4. The sustained-release composition according to claim 2, wherein The viscosity of the hydrophilic polymer is 1000-150000 mPa.s, preferably 2000-10000 mPa.s, more preferably 2000-8000 mPa.s, further preferably 2663-4379 mPa.s, for example 4000 mPa.s.

5. The sustained-release composition according to claim 2, wherein The hydrophilic polymer is a cellulose derivative with a viscosity of 1000-150000 mPa.s, preferably a cellulose derivative with a viscosity of 2000-10000 mPa.s, more preferably a cellulose derivative with a viscosity of 2000-8000 mPa.s, further preferably a cellulose derivative with a viscosity of 2663-4379 mPa.s, and even more preferably a cellulose derivative with a viscosity of 4000 mPa.s.

6. The sustained-release composition according to claim 5, wherein The hydrophilic polymer is hydroxypropyl methylcellulose with a viscosity of 1000-150000 mPa.s, preferably hydroxypropyl methylcellulose with a viscosity of 2000-10000 mPa.s, more preferably hydroxypropyl methylcellulose with a viscosity of 2000-8000 mPa.s, further preferably hydroxypropyl methylcellulose with a viscosity of 2663-4379 mPa.s, and even more preferably hydroxypropyl methylcellulose with a viscosity of 4000 mPa.s.

7. The sustained-release composition according to any one of claims 1 to 6, wherein The additives include diluents and lubricants.

8. The sustained-release composition according to claim 7, wherein The additive meets one or more of the following conditions: (1) The diluent is preferably a water-soluble diluent and a water-insoluble diluent; the water-soluble diluent is preferably one or more of lactose, mannitol, sorbitol, sucrose, povidone and copovidone; the water-insoluble diluent is one or more of pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate and hydroxypropyl methylcellulose; (2) the content of the diluent is 29.00 wt% to 62.33 wt%, for example, 29.00 wt%, 31.00 wt%, 43.67 wt%, 54.33 wt%, 57.33 wt%, 60.33 wt%, 60.67 wt% or 62.33 wt%; (3) The lubricant is a hydrophobic lubricant or a hydrophilic lubricant; the hydrophobic lubricant is preferably one or more of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate and talc, more preferably one or more of magnesium stearate, sodium stearyl fumarate and talc, further preferably magnesium stearate; (4) the content of the lubricant is 0.5 wt% to 5 wt%, for example, 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt% or 5.0 wt%; (5) The sustained-release composition is a tablet.

9. The sustained-release composition according to claim 7, wherein The sustained-release composition comprises 3.33wt%-50.00wt% of compound 1 or a pharmaceutically acceptable salt thereof, 18.00wt%-35.00wt% of a sustained-release material, 29.00wt%-62.33wt% of a diluent and 0.5wt%-5wt% of a lubricant; preferably, the sustained-release composition comprises 3.33wt%-50.00wt% of compound 1 or a pharmaceutically acceptable salt thereof, 18.00wt%-35.00wt% of a sustained-release material, 29.00wt%-62.33wt% of a diluent and 1.00wt% of a lubricant.

10. The sustained-release composition according to claim 7, wherein The sustained-release composition comprises 3.33wt%-50.00wt% of compound 1, 18.00wt%-35.00wt% of sustained-release material, 29.00wt%-62.33wt% of diluent and 0.5wt%-5wt% of lubricant; preferably, the sustained-release composition comprises 3.33wt%-50.00wt% of compound 1, 18.00wt%-35.00wt% of sustained-release material, 29.00wt%-62.33wt% of diluent and 1.00wt% of lubricant.

11. The sustained-release composition according to claim 7, wherein The sustained-release composition comprises the compound 1 or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, lactose and magnesium stearate; preferably, the sustained-release composition comprises 3.33wt%-50.00wt% of the compound 1 or a pharmaceutically acceptable salt thereof, 18.00wt%-35.00wt% of hydroxypropyl methylcellulose, 29.00wt%-62.33wt% of lactose and 0.5wt%-5wt% of magnesium stearate; more preferably, the sustained-release composition comprises 3.33wt%-50.00wt% of the compound 1 or a pharmaceutically acceptable salt thereof, 18.00wt%-35.00wt% of hydroxypropyl methylcellulose, 29.00wt%-62.33wt% of lactose and 1.00wt% of magnesium stearate.

12. The sustained-release composition according to claim 9, wherein The sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt % of hydroxypropyl methylcellulose, 62.33 wt % of lactose, and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 22.00 wt % of hydroxypropyl methylcellulose, 60.33 wt % of lactose, and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 25.00 wt % of hydroxypropyl methylcellulose, 57.33 wt % of lactose, and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 16.67 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 28.00 wt % of hydroxypropyl methylcellulose, 54.33 wt % of lactose, and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 33.33 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 22.00 wt % of hydroxypropyl methylcellulose, 43.67 wt % of lactose, and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 50.00 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt % of hydroxypropyl methylcellulose, 29.00 wt % of lactose and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 50.00 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt % of hydroxypropyl methylcellulose, 31.00 wt % of lactose, and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 50.00 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 18.00 wt % of hydroxypropyl methylcellulose, 31.00 wt % of microcrystalline cellulose and 1.00 wt % of magnesium stearate; Or, the sustained-release composition comprises 3.33 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 35.00 wt % of hydroxypropyl methylcellulose, 60.67 wt % of lactose, and 1.00 wt % of magnesium stearate; Alternatively, the sustained-release composition comprises 50.00 wt % of Compound 1 or a pharmaceutically acceptable salt thereof, 20.00 wt % of hydroxypropyl methylcellulose, 29.00 wt % of lactose and 1.00 wt % of magnesium stearate.

13. The sustained-release composition according to any one of claims 1 to 11, wherein The sustained-release composition satisfies one or more of the following conditions: (1) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5 ° C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition within 1 hour is 15% to 40%, preferably 15% to 36%, more preferably 20% to 35%, further preferably 23% to 35%, and even more preferably 24% to 32%; (2) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition within 2 hours is 24% to 60%, preferably 30% to 50%, more preferably 35% to 50%, and even more preferably 40% to 50%; (3) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition within 3 hours is 40% to 60%, preferably 40% to 55%, and more preferably 45% to 55%; (4) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition within 4 hours is 39% to 80%, preferably 50% to 70%, more preferably 50% to 65%, and even more preferably 50% to 60%; (5) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition within 8 hours is ≥63%, preferably ≥75%, more preferably ≥80%, and even more preferably ≥82%; (6) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition within 10 hours is ≥80%, preferably ≥85%, more preferably ≥90%, further preferably ≥92%, and even more preferably ≥94%.

14. The sustained-release composition according to any one of claims 1 to 11, wherein Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5° C. and a paddle speed of 50 rpm, the sustained-release composition has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 24% to 60% within 2 hours, a cumulative release of 39% to 80% within 4 hours, and a cumulative release of ≥63% within 8 hours; preferably, the sustained-release composition has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 24% to 50% within 2 hours, a cumulative release of 39% to 70% within 4 hours, and a cumulative release of ≥63% within 8 hours; more preferably, the sustained-release composition has a cumulative release of 15% to 35% within 1 hour, a cumulative release of 30% to 50% within 2 hours, a cumulative release of 50% to 70% within 4 hours, and a cumulative release of ≥75% within 8 hours.

15. The sustained-release composition according to claim 1, wherein Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; preferably, the sustained-release composition has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; more preferably, the sustained-release composition has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 49% to 57% within 3 hours, and a cumulative release of ≥92% within 10 hours.

16. The sustained-release composition according to any one of claims 1 to 11, wherein The sustained-release composition satisfies one or more of the following conditions: (1) When the sustained-release composition of Compound 1 is orally administered to beagle dogs at a dose of 150 mg after a meal, C max 1202-7828 ng / mL, preferably 1718-6022 ng / mL, more preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, further preferably 3870 ng / mL; (2) When the sustained-release composition of compound 1 was orally administered to beagle dogs at a dose of 150 mg after a meal, the AUC 0-t 7319-40253 ng*h / mL, preferably 10456-30964 ng*h / mL, more preferably 16568-24852 ng*h / mL, 17603-23816 ng*h / mL, 18639-22781 ng*h / mL, 19674-21745 ng*h / mL, 20295-21124 ng*h / mL or 20502-20917 ng*h / mL, further preferably 20710 ng*h / mL; (3) When the sustained-release composition of compound 1 was orally administered to beagle dogs at a dose of 150 mg after a meal, the AUC 0-∞ 7387-40253 ng*h / mL, preferably 10554-30964 ng*h / mL, more preferably 16607-24910 ng*h / mL, 18683-22834 ng*h / mL, 19721-21796 ng*h / mL, 20343-21174 ng*h / mL or 20551-20966 ng*h / mL, further preferably 20759 ng*h / mL; (4) When the sustained-release composition of Compound 1 was orally administered to beagle dogs at a dose of 150 mg after a meal, T max 3.6-7.4h, preferably 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, more preferably 5.5h; (5) When the sustained-release composition of Compound 1 was orally administered to beagle dogs at a dose of 150 mg after a meal, T 1 / 2 The time is 0.6-7.1h, preferably 0.9-5.5h, more preferably 2.56-3.84h, 2.88-3.52h or 3.04-3.36h, further preferably 3.2h.

17. The sustained-release composition according to any one of claims 1 to 11, wherein When the sustained-release composition is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1202-7828 ng / mL, AUC 0-t 7319-40253 ng*h / mL, AUC 0-∞ 7387-40253 ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.6-7.1h; preferably, when the sustained-release composition is orally administered to beagles at a dose of 150 mg of compound 1 after a meal, C max 1718-6022 ng / mL, AUC 0-t 10456-30964 ng*h / mL, AUC 0-∞ 10554-30964ng*h / mL, T max 3.6-7.4h, T 1 / 2 More preferably, when the sustained-release composition is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 3870 ng / mL, AUC 0-t 20710 ng*h / mL, AUC 0-∞ 20759ng*h / mL, T max 5.5h, T 1 / 2 3.2h.

18. The sustained-release composition according to any one of claims 1 to 11, wherein The sustained-release composition satisfies one or more of the following conditions: (1) When the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 170.42-774.46 ng / mL, preferably 243.46-595.74 ng / mL, more preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, further preferably 419.60 ng / mL; (2) When the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0-t 1062.68-4646.28 ng*h / mL, preferably 1518.12-3574.06 ng*h / mL, more preferably 2036.87-3055.20 ng*h / mL, 2291.48-2800.70 ng*h / mL, 2418.78-2673.39 ng*h / mL or 2495.17-2597.01 ng*h / mL, further preferably 2546.09 ng / mL; (3) When the sustained-release composition is administered orally to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0-∞ 1049.31-4849.65 ng*h / mL, preferably 1499.02-3730.50 ng*h / mL, more preferably 2091.81-3137.71 ng*h / mL, 2353.28-2876.24 ng*h / mL, 2484.02-2745.50 ng*h / mL or 2562.46-2667.06 ng*h / mL, further preferably 2614.76 ng / mL; (4) When the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max 1.4-7.8h, preferably 2-6h, more preferably 4-6h, 4.5-5.5h or 4.9-5.1h, further preferably 5h; (5) When the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, T 1 / 2 The time is 1.60-5.84 h, preferably 2.29-4.49 h, more preferably 2.71-4.07 h, 3.05-3.73 h or 3.22-3.56 h, for example 3.39 h.

19. The sustained-release composition according to any one of claims 1 to 11, wherein When the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 170.42-774.46 ng / mL, AUC 0-t 1062.68-4646.28 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 1.4-7.8h, T 1 / 2 1.60-5.84h; preferably, when the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 243.46-595.74 ng / mL, AUC 0-t 1518.12-3574.06 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 2-6h, T 1 / 2 More preferably, when the sustained-release composition is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 419.60 ng / mL, AUC 0-t 2546.09 ng / mL, AUC 0-∞ was 2614.76 ng / mL, T max 5h, T 1 / 2 It is 3.39h.

20. The sustained-release composition according to any one of claims 1 to 11, wherein The sustained-release composition satisfies one or more of the following conditions: (1) When the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 423.20-1705.12 ng / mL, preferably 604.57-1311.63 ng / mL, more preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, further preferably 958.10 ng / mL; (2) When the sustained-release composition is administered orally to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-t 2394.79-9868.31 ng*h / mL, preferably 4192.55-7591.01 ng*h / mL, more preferably 4713.42-7070.14 ng*h / mL, 5302.60-6480.96 ng*h / mL or 5597.19-6186.37 ng*h / mL, further preferably 5891.78 ng*h / mL; (3) When the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ 2969.63-10001.46 ng*h / mL, preferably 4242.33-7693.43 ng*h / mL, more preferably 4774.14-7161.22 ng*h / mL, 5370.91-6564.45 ng*h / mL or 5669.30-6266.06 ng*h / mL, further preferably 5967.68 ng*h / mL; (4) When the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, T max 2.8-7.8h, preferably 4-6h, more preferably 5-6h, further preferably 6h; (5) When the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, T 1 / 2 The operating time is 0.83-5.14 h, preferably 2.75-3.95 h, more preferably 3.01-3.69 h or 3.18-3.52 h, further preferably 3.35 h.

21. The sustained-release composition according to claim 1, wherein When the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 423.20-1705.12 ng / mL, AUC 0-t 2394.79-9868.31 ng*h / mL, AUC 0-∞ 2969.63-10001.46 ng*h / mL, T max 2.8-7.8h, T 1 / 2 0.83-5.14h; preferably, when the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 604.57-1311.63 ng / mL, AUC 0-t 4192.55-7591.01 ng*h / mL, AUC 0-∞ 4242.33-7693.43 ng*h / mL, T max 4-6h, T 1 / 2 More preferably, when the sustained-release composition is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 958.10 ng / mL, AUC 0-t 5891.78 ng*h / mL, AUC 0-∞ is 5967.68ng*h / mL, T max 6h, T 1 / 2 It is 3.35h.

22. A film-coated sustained-release preparation, characterized in that: The invention comprises the sustained-release composition according to any one of claims 1 to 21 and a coating coated on the surface of the sustained-release composition.

23. The film-coated sustained-release preparation according to claim 22, wherein The coating coated on the surface of the sustained-release composition is prepared using a film coating premix, and the mass ratio of the film coating premix to the sustained-release composition is (0.015-0.045):1, preferably (0.02-0.04):1, and more preferably 0.03:

1.

24. The film-coated sustained-release preparation according to claim 23, wherein The film-coated sustained-release preparation meets one or more of the following conditions: (1) The film coating premix is ​​a gastric soluble film coating premix, such as an HMPC film coating premix or a PVA film coating premix; (2) The film coating premix is ​​a tablet; (3) In the film-coated premix, each unit dosage form contains 10-150 mg of the compound 1, preferably 50 or 100 mg of the compound 1.

25. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein The film-coated sustained-release preparation meets one or more of the following conditions: (1) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 40%, preferably 15% to 36%, more preferably 20% to 35%, further 23% to 35%, and even more preferably 24% to 32%; (2) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 2 hours is 24% to 60%, preferably 30% to 50%, more preferably 35% to 50%, and even more preferably 40% to 50%; (3) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 3 hours is 40% to 60%, preferably 40% to 55%, and more preferably 45% to 55%; (4) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 4 hours is 39% to 80%, preferably 50% to 70%, more preferably 50% to 65%, and even more preferably 50% to 60%; (5) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 8 hours is ≥63%, preferably ≥75%, more preferably ≥80%, and even more preferably ≥82%; (6) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 10 hours is ≥80%, preferably ≥85%, more preferably ≥90%, further preferably ≥92%, and even more preferably ≥94%.

26. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 40%, the cumulative release within 2 hours is 24% to 60%, the cumulative release within 4 hours is 39% to 80%, and the cumulative release within 8 hours is ≥63%; preferably, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 36%, the cumulative release within 2 hours is 24% to 50%, the cumulative release within 4 hours is 39% to 70%, and the cumulative release within 8 hours is ≥63%; more preferably, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 35%, the cumulative release within 2 hours is 30% to 50%, the cumulative release within 4 hours is 50% to 70%, and the cumulative release within 8 hours is ≥75%.

27. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 40%, the cumulative release within 3 hours is 40% to 60%, and the cumulative release within 10 hours is ≥80%; preferably, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 36%, the cumulative release within 3 hours is 40% to 60%, and the cumulative release within 10 hours is ≥80%; more preferably, the cumulative release of the film-coated sustained-release preparation within 1 hour is 15% to 36%, the cumulative release within 3 hours is 49% to 57%, and the cumulative release within 10 hours is ≥92%.

28. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein The film-coated sustained-release preparation meets one or more of the following conditions: (1) When the film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1202-7828 ng / mL, preferably 1718-6022 ng / mL, more preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, further preferably 3870 ng / mL; (2) When the film-coated sustained-release preparation was orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-t 7319-40253 ng*h / mL, preferably 10456-30964 ng*h / mL, more preferably 16568-24852 ng*h / mL, 17603-23816 ng*h / mL, 18639-22781 ng*h / mL, 19674-21745 ng*h / mL, 20295-21124 ng*h / mL or 20502-20917 ng*h / mL, further preferably 20710 ng*h / mL; (3) When the film-coated sustained-release preparation was orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ 7387-40253 ng*h / mL, preferably 10554-30964 ng*h / mL, more preferably 16607-24910 ng*h / mL, 18683-22834 ng*h / mL, 19721-21796 ng*h / mL, 20343-21174 ng*h / mL or 20551-20966 ng*h / mL, further preferably 20759 ng*h / mL; (4) When the film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T max 3.6-7.4h, preferably 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, more preferably 5.5h; (5) When the film-coated sustained-release preparation was orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T 1 / 2 The time is 0.6-7.1h, preferably 0.9-5.5h, more preferably 2.56-3.84h, 2.88-3.52h or 3.04-3.36h, further preferably 3.2h.

29. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein When the film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after meals, C max 1202-7828 ng / mL, AUC 0-t 7319-40253 ng*h / mL, AUC 0-∞ 7387-40253 ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.6-7.1h; preferably, when the film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1718-6022 ng / mL, AUC 0-t 10456-30964 ng*h / mL, AUC 0-∞ 10554-30964ng*h / mL, T max 3.6-7.4h, T 1 / 2 More preferably, when the film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 3870 ng / mL, AUC 0-t 20710 ng*h / mL, AUC 0-∞ 20759ng*h / mL, T max 5.5h, T 1 / 2 3.2h.

30. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein The film-coated sustained-release preparation meets one or more of the following conditions: (1) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 170.42-774.46 ng / mL, preferably 243.46-595.74 ng / mL, more preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, further preferably 419.60 ng / mL; (2) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0- t 1062.68-4646.28 ng*h / mL, preferably 1518.12-3574.06 ng*h / mL, more preferably 2036.87-3055.20 ng*h / mL, 2291.48-2800.70 ng*h / mL, 2418.78-2673.39 ng*h / mL or 2495.17-2597.01 ng*h / mL, further preferably 2546.09 ng / mL; (3) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0- ∞ 1049.31-4849.65 ng*h / mL, preferably 1499.02-3730.50 ng*h / mL, more preferably 2091.81-3137.71 ng*h / mL, 2353.28-2876.24 ng*h / mL, 2484.02-2745.50 ng*h / mL or 2562.46-2667.06 ng*h / mL, further preferably 2614.76 ng / mL; (4) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max 1.4-7.8h, preferably 2-6h, more preferably 4-6h, 4.5-5.5h or 4.9-5.1h, further preferably 5h; (5) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T 1 / 2 The time is 1.60-5.84 h, preferably 2.29-4.49 h, more preferably 2.71-4.07 h, 3.05-3.73 h or 3.22-3.56 h, for example 3.39 h.

31. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 170.42-774.46 ng / mL, AUC 0-t 1062.68-4646.28 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 1.4-7.8h, T 1 / 2 1.60-5.84h; preferably, when the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 243.46-595.74 ng / mL, AUC 0-t 1518.12-3574.06 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 2-6h, T 1 / 2 More preferably, when the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 419.60 ng / mL, AUC 0-t 2546.09 ng / mL, AUC 0-∞ was 2614.76 ng / mL, T max 5h, T 1 / 2 It is 3.39h.

32. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein The film-coated sustained-release preparation meets one or more of the following conditions: (1) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 423.20-1705.12 ng / mL, preferably 604.57-1311.63 ng / mL, more preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, further preferably 958.10 ng / mL; (2) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0- t 2394.79-9868.31 ng*h / mL, preferably 4192.55-7591.01 ng*h / mL, more preferably 4713.42-7070.14 ng*h / mL, 5302.60-6480.96 ng*h / mL or 5597.19-6186.37 ng*h / mL, further preferably 5891.78 ng*h / mL; (3) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0- ∞ 2969.63-10001.46 ng*h / mL, preferably 4242.33-7693.43 ng*h / mL, more preferably 4774.14-7161.22 ng*h / mL, 5370.91-6564.45 ng*h / mL or 5669.30-6266.06 ng*h / mL, further preferably 5967.68 ng*h / mL; (4) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max 2.8-7.8h, preferably 4-6h, more preferably 5-6h, further preferably 6h; (5) When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T 1 / 2 The operating time is 0.83-5.14 h, preferably 2.75-3.95 h, more preferably 3.01-3.69 h or 3.18-3.52 h, further preferably 3.35 h.

33. The film-coated sustained-release preparation according to any one of claims 22 to 24, wherein When the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after meals, C max 423.20-1705.12 ng / mL, AUC 0-t 2394.79-9868.31 ng*h / mL, AUC 0-∞ 2969.63-10001.46 ng*h / mL, T max 2.8-7.8h, T 1 / 2 0.83-5.14h; preferably, when the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 604.57-1311.63 ng / mL, AUC 0-t 4192.55-7591.01 ng*h / mL, AUC 0-∞ 4242.33-7693.43 ng*h / mL, T max 4-6h, T 1 / 2 More preferably, when the film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 958.10 ng / mL, AUC 0-t 5891.78 ng*h / mL, AUC 0-∞ is 5967.68ng*h / mL, T max 6h, T 1 / 2 It is 3.35h.

34. A sustained-release composition or film-coated sustained-release preparation, characterized in that: Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition or film-coated sustained-release preparation has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 24% to 60% within 2 hours, a cumulative release of 39% to 80% within 4 hours, and a cumulative release of ≥63% within 8 hours; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 35. The sustained-release composition or film-coated sustained-release preparation according to claim 34, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 1 hour is 15% to 36%, preferably 20% to 35%, more preferably 23% to 35%, and even more preferably 24% to 32%; (2) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 2 hours is 30% to 50%, more preferably 35% to 50%, and even more preferably 40% to 50%; (3) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 4 hours is 50% to 70%, preferably 50% to 65%, and more preferably 50% to 60%; (4) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 8 hours is ≥75%, more preferably ≥80%, and even more preferably ≥82%.

36. The sustained-release composition or film-coated sustained-release preparation according to claim 34, wherein Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition or film-coated sustained-release preparation has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 24% to 50% within 2 hours, a cumulative release of 39% to 70% within 4 hours, and a cumulative release of ≥63% within 8 hours; preferably, the sustained-release composition or film-coated sustained-release preparation has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 30% to 50% within 2 hours, a cumulative release of 50% to 70% within 4 hours, and a cumulative release of ≥75% within 8 hours.

37. A sustained-release composition or film-coated sustained-release preparation, characterized in that: Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition has a cumulative release of 15% to 40% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 38. The sustained-release composition or film-coated sustained-release preparation according to claim 37, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 1 hour is 15% to 36%, preferably 20% to 35%, more preferably 23% to 35%, and even more preferably 24% to 32%; (2) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37 ± 0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 3 hours is 40% to 55%, preferably 45% to 55%; (3) Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the cumulative release of the sustained-release composition or film-coated sustained-release preparation within 10 hours is ≥85%, more preferably ≥90%, further preferably ≥92%, and even more preferably ≥94%.

39. The sustained-release composition or film-coated sustained-release preparation according to claim 37, wherein Using 900 mL of 50 mM pH 6.8 phosphate buffer solution as the dissolution medium, at 37±0.5°C and a paddle speed of 50 rpm, the sustained-release composition or film-coated sustained-release preparation has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 40% to 60% within 3 hours, and a cumulative release of ≥80% within 10 hours; preferably, the sustained-release composition or film-coated sustained-release preparation has a cumulative release of 15% to 36% within 1 hour, a cumulative release of 49% to 57% within 3 hours, and a cumulative release of ≥92% within 10 hours.

40. A sustained-release composition or film-coated sustained-release preparation, characterized in that: When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1202-7828 ng / mL; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 41. The sustained-release composition or film-coated sustained-release preparation according to claim 40, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1718-6022 ng / mL, preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, more preferably 3870 ng / mL; (2) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-t 7319-40253 ng*h / mL, preferably 10456-30964 ng*h / mL, more preferably 16568-24852 ng*h / mL, 17603-23816 ng*h / mL, 18639-22781 ng*h / mL, 19674-21745 ng*h / mL, 20295-21124 ng*h / mL or 20502-20917 ng*h / mL, further preferably 20710 ng*h / mL; (3) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ 7387-40253 ng*h / mL, preferably 10554-30964 ng*h / mL, more preferably 16607-24910 ng*h / mL, 18683-22834 ng*h / mL, 19721-21796 ng*h / mL, 20343-21174 ng*h / mL or 20551-20966 ng*h / mL, further preferably 20759 ng*h / mL; (4) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T max 3.6-7.4h, preferably 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, more preferably 5.5h; (5) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T 1 / 2 The time is 0.6-7.1h, preferably 0.9-5.5h, more preferably 2.56-3.84h, 2.88-3.52h or 3.04-3.36h, further preferably 3.2h.

42. The sustained-release composition or film-coated sustained-release preparation according to claim 40, wherein When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1202-7828 ng / mL, AUC 0- t 7319-40253 ng*h / mL, AUC 0-∞ 7387-40253 ng*h / mL, T max 3.6-7.4h, T 1 / 2 0.6-7.1h; preferably, when the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1718-6022 ng / mL, AUC 0-t 10456-30964 ng*h / mL, AUC 0-∞ 10554-30964ng*h / mL, T max 3.6-7.4h, T 1 / 2 More preferably, when the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 3870 ng / mL, AUC 0-t 20710 ng*h / mL, AUC 0-∞ 20759ng*h / mL, T max 5.5h, T 1 / 2 3.2h.

43. A sustained-release composition or film-coated sustained-release preparation, characterized in that: When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T max 3.6-7.4h; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 44. The sustained-release composition or film-coated sustained-release preparation according to claim 43, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, C max 1202-7828 ng / mL, preferably 1718-6022 ng / mL, more preferably 3096-4644 ng / mL, 3483-4257 ng / mL, 3676-4063 ng / mL, 3763-3967 ng / mL or 3831-3908 ng / mL, further preferably 3870 ng / mL; (2) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-t 7319-40253 ng*h / mL, preferably 10456-30964 ng*h / mL, more preferably 16568-24852 ng*h / mL, 17603-23816 ng*h / mL, 18639-22781 ng*h / mL, 19674-21745 ng*h / mL, 20295-21124 ng*h / mL or 20502-20917 ng*h / mL, further preferably 20710 ng*h / mL; (3) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ 7387-40253 ng*h / mL, preferably 10554-30964 ng*h / mL, more preferably 16607-24910 ng*h / mL, 18683-22834 ng*h / mL, 19721-21796 ng*h / mL, 20343-21174 ng*h / mL or 20551-20966 ng*h / mL, further preferably 20759 ng*h / mL; (4) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T max 4.4-6.6h, 4.95-6.05h, 5.23-5.78h or 5.39-5.61h, preferably 5.5h; (5) When the sustained-release composition or film-coated sustained-release preparation is orally administered to beagle dogs at a dose of 150 mg of compound 1 after a meal, T 1 / 2 The time is 0.6-7.1h, preferably 0.9-5.5h, more preferably 2.56-3.84h, 2.88-3.52h or 3.04-3.36h, further preferably 3.2h.

45. A sustained-release composition or film-coated sustained-release preparation, characterized in that: When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 170.42-774.46 ng / mL; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 46. ​​The sustained-release composition or film-coated sustained-release preparation according to claim 45, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 243.46-595.74 ng / mL, preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, more preferably 419.60 ng / mL; (2) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0-t 1062.68-4646.28 ng*h / mL, preferably 1518.12-3574.06 ng*h / mL, more preferably 2036.87-3055.20 ng*h / mL, 2291.48-2800.70 ng*h / mL, 2418.78-2673.39 ng*h / mL or 2495.17-2597.01 ng*h / mL, further preferably 2546.09 ng / mL; (3) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0-∞ 1049.31-4849.65 ng*h / mL, preferably 1499.02-3730.50 ng*h / mL, more preferably 2091.81-3137.71 ng*h / mL, 2353.28-2876.24 ng*h / mL, 2484.02-2745.50 ng*h / mL or 2562.46-2667.06 ng*h / mL, further preferably 2614.76 ng / mL; (4) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max 1.4-7.8h, preferably 2-6h, more preferably 4-6h, 4.5-5.5h or 4.9-5.1h, further preferably 5h; (5) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T 1 / 2 The time is 1.60-5.84 h, preferably 2.29-4.49 h, more preferably 2.71-4.07 h, 3.05-3.73 h or 3.22-3.56 h, for example 3.39 h.

47. The sustained-release composition or film-coated sustained-release preparation according to claim 45, wherein When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 170.42-774.46 ng / mL, AUC 0-t 1062.68-4646.28 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 1.4-7.8h, T 1 / 2 1.60-5.84h; preferably, when the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 243.46-595.74 ng / mL, AUC 0-t 1518.12-3574.06 ng*h / mL, AUC 0-∞ 1049.31-4849.65ng*h / mL, T max 2-6h, T 1 / 2 More preferably, when the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, C max 419.60 ng / mL, AUC 0-t 2546.09 ng / mL, AUC 0-∞ was 2614.76 ng / mL, T max 5h, T 1 / 2 It is 3.39h.

48. A sustained-release composition or film-coated sustained-release preparation, characterized in that: When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max 1.4-7.8h; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 49. The sustained-release composition or film-coated sustained-release preparation according to claim 48, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, C max 170.42-774.46 ng / mL, preferably 243.46-595.74 ng / mL, more preferably 335.68-503.52 ng / mL, 377.64-461.56 ng / mL, 398.62-440.58 ng / mL or 411.20-427.99 ng / mL, further preferably 419.60 ng / mL; (2) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0-t 1062.68-4646.28 ng*h / mL, preferably 1518.12-3574.06 ng*h / mL, more preferably 2036.87-3055.20 ng*h / mL, 2291.48-2800.70 ng*h / mL, 2418.78-2673.39 ng*h / mL or 2495.17-2597.01 ng*h / mL, further preferably 2546.09 ng / mL; (3) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of compound 1 after a meal, the AUC 0-∞ 1049.31-4849.65 ng*h / mL, preferably 1499.02-3730.50 ng*h / mL, more preferably 2091.81-3137.71 ng*h / mL, 2353.28-2876.24 ng*h / mL, 2484.02-2745.50 ng*h / mL or 2562.46-2667.06 ng*h / mL, further preferably 2614.76 ng / mL; (4) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T max 2-6h, preferably 4-6h, 4.5-5.5h or 4.9-5.1h, more preferably 5h; (5) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 100 mg of Compound 1 after a meal, T 1 / 2 The time is 1.60-5.84 h, preferably 2.29-4.49 h, more preferably 2.71-4.07 h, 3.05-3.73 h or 3.22-3.56 h, for example 3.39 h.

50. A sustained-release composition or film-coated sustained-release preparation, characterized in that: When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 423.20-1705.12 ng / mL; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 51. The sustained-release composition or film-coated sustained-release preparation according to claim 50, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 604.57-1311.63 ng / mL, preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, more preferably 958.10 ng / mL; (2) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-t 2394.79-9868.31 ng*h / mL, preferably 4192.55-7591.01 ng*h / mL, more preferably 4713.42-7070.14 ng*h / mL, 5302.60-6480.96 ng*h / mL or 5597.19-6186.37 ng*h / mL, further preferably 5891.78 ng*h / mL; (3) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ 2969.63-10001.46 ng*h / mL, preferably 4242.33-7693.43 ng*h / mL, more preferably 4774.14-7161.22 ng*h / mL, 5370.91-6564.45 ng*h / mL or 5669.30-6266.06 ng*h / mL, further preferably 5967.68 ng*h / mL; (4) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max 2.8-7.8h, preferably 4-6h, more preferably 5-6h, further preferably 6h; (5) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T 1 / 2 The operating time is 0.83-5.14 h, preferably 2.75-3.95 h, more preferably 3.01-3.69 h or 3.18-3.52 h, further preferably 3.35 h.

52. The sustained-release composition or film-coated sustained-release preparation according to claim 50, wherein When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 423.20-1705.12 ng / mL, AUC 0-t 2394.79-9868.31 ng*h / mL, AUC 0-∞ 2969.63-10001.46 ng*h / mL, T max 2.8-7.8h, T 1 / 2 0.83-5.14h; preferably, when the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 604.57-1311.63 ng / mL, AUC 0-t 4192.55-7591.01 ng*h / mL, AUC 0-∞ 4242.33-7693.43 ng*h / mL, T max 4-6h, T 1 / 2 More preferably, when the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, C max 958.10 ng / mL, AUC 0- t 5891.78 ng*h / mL, AUC 0-∞ is 5967.68ng*h / mL, T max 6h, T 1 / 2 It is 3.35h.

53. A sustained-release composition or film-coated sustained-release preparation, characterized in that: When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max 2.8-7.8h; The film-coated sustained-release preparation comprises the sustained-release composition and a coating coated on the surface of the sustained-release composition; The active pharmaceutical ingredient in the sustained-release composition or film-coated sustained-release preparation is Compound 1 or a pharmaceutically acceptable salt thereof; 54. The sustained-release composition or film-coated sustained-release preparation according to claim 53, wherein The sustained-release composition or film-coated sustained-release preparation meets one or more of the following conditions: (1) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, C max 423.20-1705.12 ng / mL, preferably 604.57-1311.63 ng / mL, more preferably 766.48-1149.72 ng / mL, 862.29-1053.91 ng / mL or 910.10-1006.01 ng / mL, further preferably 958.10 ng / mL; (2) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-t 2394.79-9868.31 ng*h / mL, preferably 4192.55-7591.01 ng*h / mL, more preferably 4713.42-7070.14 ng*h / mL, 5302.60-6480.96 ng*h / mL or 5597.19-6186.37 ng*h / mL, further preferably 5891.78 ng*h / mL; (3) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of compound 1 after a meal, the AUC 0-∞ 2969.63-10001.46 ng*h / mL, preferably 4242.33-7693.43 ng*h / mL, more preferably 4774.14-7161.22 ng*h / mL, 5370.91-6564.45 ng*h / mL or 5669.30-6266.06 ng*h / mL, further preferably 5967.68 ng*h / mL; (4) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T max 4-6h, preferably 5-6h, more preferably 6h; (5) When the sustained-release composition or film-coated sustained-release preparation is orally administered to adult subjects at a dose of 150 mg of Compound 1 after a meal, T 1 / 2 The operating time is 0.83-5.14h, preferably 2.75-3.95h, more preferably 3.01-3.69h or 3.18-3.52h, further preferably 3.35h.

55. A method for preparing a sustained-release composition, characterized in that: The method comprises the following steps: (1) premixing the active pharmaceutical ingredient, the sustained-release material and part of the additive; (2) granulating the premix obtained in step (1) using a dry granulator; (3) mixing the dry particles obtained in step (2) with the remaining amount of the additive; (4) tableting the total mixed material obtained in step (3); The active pharmaceutical ingredient is Compound 1 or a pharmaceutically acceptable salt thereof; 56. The method for preparing the sustained-release composition according to claim 55, wherein: The preparation method satisfies one or more of the following conditions: (1) The amount of the active pharmaceutical ingredient is 3.33 wt% to 50.00 wt%, preferably 6.67 wt% to 50 wt%, for example, 10.00 wt%, 13.33 wt%, 16.67 wt%, 20.00 wt%, 26.67 wt% or 33.33 wt%; (2) The sustained-release material is a hydrophilic polymer, preferably one or more of a cellulose derivative, povidone, and carbomer, more preferably a cellulose derivative; (3) the content of the sustained-release material is 18.00 wt% to 35.00 wt%, for example, 20.00 wt%, 22.00 wt%, 25.00 wt% or 28.00 wt%; (4) The additives include diluents and lubricants.

57. The method for preparing the sustained-release composition according to claim 56, wherein: The preparation method satisfies one or more of the following conditions: (1) The cellulose derivative is one or more of methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose and sodium carboxymethyl cellulose, preferably hydroxypropyl methyl cellulose, more preferably hydroxypropyl methyl cellulose K4M CR; (2) The viscosity of the hydrophilic polymer is 1000-150000 mPa.s, preferably 2000-10000 mPa.s, more preferably 2000-8000 mPa.s, further preferably 2663-4379 mPa.s, for example 4000 mPa.s; (3) The diluent is a water-soluble diluent and a water-insoluble diluent; the water-soluble diluent is preferably one or more of lactose, mannitol, sorbitol, sucrose, povidone and copovidone; the water-insoluble diluent is preferably one or more of pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate and hydroxypropyl methylcellulose; (4) the diluent is used in an amount of 29.00 wt% to 62.33 wt%, such as 31.00 wt%, 43.67 wt%, 54.33 wt%, 57.33 wt%, 60.33 wt% or 60.67 wt%; (5) The weight ratio of the additives in step (1) to step (3) is (59-122.33):1, for example, 59:1, 63:1, 88.33:1, 109.67:1, 115.67:1, 121.67:1, 125.67:1 or 122.33:1; (6) The lubricant is a hydrophobic lubricant or a hydrophilic lubricant; the hydrophobic lubricant is preferably one or more of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate and talc, more preferably one or more of magnesium stearate, sodium stearyl fumarate and talc, such as magnesium stearate; (7) The amount of the lubricant is 0.5wt%-5wt%, preferably 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 2.5wt%, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt% or 5.0wt%, more preferably 1.0wt%.

58. The method for preparing the sustained-release composition according to claim 56, wherein: The hydrophilic polymer is hydroxypropyl methylcellulose with a viscosity of 2663-4379 mPa.s, preferably hydroxypropyl methylcellulose with a viscosity of 4000 mPa.s.

59. A sustained-release composition, characterized in that It is prepared by the preparation method described in any one of claims 55 to 58.

60. Use of a substance X in the preparation of a medicament for preventing or treating a disease associated with fibrosis, wherein the substance X is the sustained-release composition according to claim 1 or 59, the film-coated sustained-release preparation according to any one of claims 22 to 33, or the sustained-release composition or film-coated sustained-release preparation according to any one of claims 34 to 54.

61. The use according to claim 60, wherein The fibrosis-related disease is idiopathic pulmonary fibrosis.

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