Pharmaceutical composition containing a dipeptidyl peptidase small molecule inhibitor

Abstract

A pharmaceutical composition comprising compound A, a dipeptidyl peptidase 1 (DPP1) small molecule inhibitor, a method for preparing the same, and the use of the pharmaceutical composition in the treatment of diseases or conditions associated with fibrotic bronchiectasis: TIFF2026510407000021.tif37170(A).

Description

Technical Field

[0001] The present invention relates to the technical field of formulations containing chemical agents, and particularly to a pharmaceutical composition containing compound A, a small molecule inhibitor of dipeptidyl peptidase, for treating diseases associated with fibrotic bronchiectasis, and a method for preparing the same.

Background Art

[0002] Non-cystic fibrotic bronchiectasis is a disease that causes repeated damage and / or obstruction of the medium-sized bronchi and bronchioles due to recurrent purulent infections caused by various etiologies, thereby damaging the structure of the bronchial wall and causing the bronchi to abnormally and continuously dilate. Clinically, the main symptoms are chronic cough, a large amount of sputum, and / or intermittent hemoptysis, with or without dyspnea or respiratory failure, and the severity of the symptoms varies widely. Any factor that damages the structure of the bronchial wall, such as infectious diseases, immunodeficiency, rheumatism, bronchial asthma, chronic obstructive pulmonary disease, etc., can cause bronchiectasis. The most common and typical symptoms are chronic cough and sputum with mucopurulent secretions. Symptoms such as dyspnea, fatigue, and hemoptysis may also appear due to the progression of the disease and / or the decline of lung function. In recent years, an increase in the incidence and prevalence of bronchiectasis has been reported internationally. According to statistics, the incidence and prevalence of bronchiectasis in the UK population have increased to 31.1 per 100,000 and 525.8 per 100,000, respectively, as of 2013. The incidence of bronchiectasis in the Spanish population was approximately 48.1 per 100,000 in 2012, and the prevalence of bronchiectasis in adults in the United States was approximately 139 per 100,000.

[0003] Acute lung injury / acute respiratory distress syndrome (ARDS) is hypoxic respiratory failure or respiratory failure resulting from diffuse interstitial and alveolar edema caused by damage to pulmonary capillary endothelial cells and alveolar epithelial cells during the course of non-cardiogenic diseases such as severe infection, shock, trauma, and burns. Its pathophysiological features include decreased lung volume, reduced lung compliance, and severe ventilation / perfusion mismatch. Clinical symptoms include progressive hypoxemia and dyspnea, and heterogeneous exudative lesions are observed on lung imaging. Due to differing definitions and the heterogeneity of the disease, it is difficult to accurately determine the incidence and mortality of ARDS. According to a 2007 review by Rubenfeld and Herridge, the incidence of ARDS is 13.5–58.7 cases per 100,000 population per year, and the mortality rate is approximately 34%–57.9%.

[0004] Compound A, disclosed in WO2022 / 042591A1, is a potent and highly selective small molecule inhibitor of dipeptidyl peptidase (dipeptidyl peptidase 1, DPP1). This compound is used in the treatment of bronchiectasis (including non-cystic fibrotic bronchiectasis and cystic fibrotic bronchiectasis) and lower respiratory tract diseases resulting from acute lung injury / acute respiratory distress syndrome. In preclinical studies, compound A significantly inhibited NE enzyme activity in rat bone marrow and mitigated LPS-induced acute lung injury in mice, demonstrating favorable pharmacological effects. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2022 / 042591 [Modes for carrying out the invention]

[0006] Disclosure of the invention The object of the present invention is to provide a pharmaceutical composition of compound A, comprising compound A and a pharmaceutically acceptable excipient. The composition according to the present invention has stable quality, good stability, high bioavailability, and rapid dissolution. When formulated as an immediate-release tablet, the composition according to the present invention has advantages such as stable quality, accurate dosage, ease of transport, and low manufacturing cost. After administration, the drug is rapidly released and absorbed into the body.

[0007] The present invention provides a pharmaceutical composition comprising compound A and a pharmaceutically acceptable excipient. The structure of compound A is shown below:

[0008] [ka] (A).

[0009] The present invention provides a pharmaceutical composition in which the pharmaceutically acceptable excipient comprises one or more of the following: fillers, disintegrants, lubricants, antioxidants, binders, flavoring agents, colorants, and coating materials.

[0010] The present invention provides a pharmaceutical composition comprising compound A and a filler.

[0011] The present invention provides a pharmaceutical composition comprising compound A, a filler, and a disintegrant.

[0012] The present invention provides a pharmaceutical composition comprising compound A, a filler, a disintegrant, and a lubricant.

[0013] The present invention provides a pharmaceutical composition comprising compound A, a filler, a disintegrant, a lubricant, and a coating material.

[0014] The present invention provides an orally administered pharmaceutical composition comprising compound A and a pharmaceutically acceptable excipient, the composition specifically comprising (1) compound A, (2) a filler, (3) a lubricant, (4) a disintegrant, and (5) a coating material, wherein compound A has the following structure:

[0015] [Chem.] (A).

[0016] In certain embodiments, the amount of Compound A in the pharmaceutical composition of the present invention is 1% to 40% by mass of the whole composition. In certain embodiments, the amount of Compound A is 1% to 20% by mass of the whole composition. In certain embodiments, the amount of Compound A is 2.5% to 10% by mass of the whole composition. In certain embodiments, the amount of Compound A is 5% to 10% by mass of the whole composition. In certain embodiments, the amount of Compound A is 5% by mass of the whole composition.

[0017] The present invention provides a pharmaceutical composition in which the particle size distribution d(0.9) of Compound A is 150 μm or less, preferably 100 μm or less, more preferably 85 μm or less.

[0018] In the pharmaceutical composition of the present invention, the processing method of Compound A is one or more of sieving, mechanical grinding, and air jet grinding.

[0019] In the pharmaceutical composition of the present invention, the filler can be selected from one or more of lactose, microcrystalline cellulose, sucrose, glucose, powdered cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, aluminum silicate, dextrin, starch (including corn starch, potato starch, or amylopectin), pregelatinized starch, sodium chloride, potassium chloride, mannitol, and sorbitol.

[0020] In certain embodiments of the pharmaceutical composition according to the present invention, the filler is selected from one or more of lactose, microcrystalline cellulose, and mannitol.

[0021] In certain embodiments, the amount of the filler in the pharmaceutical composition of the present invention is 67% to 99% by mass of the whole composition. In certain embodiments, the amount of the filler is 70% to 99% by mass of the whole composition. In certain embodiments, the amount of the filler is 80% to 90% by mass of the whole composition. In certain embodiments, the amount of the filler is 89% by mass of the whole composition.

[0022] In certain embodiments of the pharmaceutical composition according to the present invention, the filler is mannitol and microcrystalline cellulose, and the mass ratio of mannitol to microcrystalline cellulose is 5:1 to 1:1. In certain embodiments, the mass ratio of mannitol to microcrystalline cellulose is 4:1 to 1:1. In certain embodiments, the mass ratio of mannitol to microcrystalline cellulose is 3:1 to 1:1. In certain embodiments, the mass ratio of mannitol to microcrystalline cellulose is 2:1 to 1:1. In certain embodiments, the mass ratio of mannitol to microcrystalline cellulose is 1:1.

[0023] In certain embodiments of the pharmaceutical composition according to the present invention, the filler is lactose and microcrystalline cellulose, and the mass ratio of lactose to microcrystalline cellulose is 5:1 to 1:1. In certain embodiments, the mass ratio of lactose to microcrystalline cellulose is 4:1 to 1:1. In certain embodiments, the mass ratio of lactose to microcrystalline cellulose is 3:1 to 1:1. In certain embodiments, the mass ratio of lactose to microcrystalline cellulose is 2:1 to 1:1. In certain embodiments, the mass ratio of lactose to microcrystalline cellulose is 3:1.

[0024] In the pharmaceutical composition of the present invention, the disintegrant can be selected from one or more of starch, pregelatinized starch, sodium carboxymethyl starch, crospovidone, and croscarmellose sodium.

[0025] In certain embodiments, the amount of disintegrant in the pharmaceutical composition of the present invention is 0.5% to 10% by mass of the total composition. In certain embodiments, the amount of disintegrant is 1% to 10% by mass of the total composition. In certain embodiments, the amount of disintegrant is 2% to 9% by mass of the total composition. In certain embodiments, the amount of disintegrant is 3% to 8% by mass of the total composition. In certain embodiments, the amount of disintegrant is 3% to 7% by mass of the total composition. In certain embodiments, the amount of disintegrant is 5% by mass of the total composition.

[0026] In certain embodiments, the disintegrant in the pharmaceutical composition of the present invention is cross-linked povidone.

[0027] In certain embodiments, the amount of cross-linked povidone in the pharmaceutical composition of the present invention is 0.5% to 10% by mass of the total composition. In certain embodiments, the amount of cross-linked povidone is 1% to 7% by mass of the total composition. In certain embodiments, the amount of cross-linked povidone is 3% to 7% by mass of the total composition. In certain embodiments, the amount of cross-linked povidone is 3% to 5% by mass of the total composition. In certain embodiments, the amount of cross-linked povidone in the pharmaceutical composition of the present invention is 5% by mass of the total composition.

[0028] In the pharmaceutical composition of the present invention, the lubricant may be selected from one or more of the following: stearic acid, magnesium stearate, calcium stearate, aluminum stearate, palmitic acid, glyceryl behenate, polyethylene glycol having various molecular weights, hydrogenated castor oil, or sodium stearyl fumarate.

[0029] In certain embodiments, the amount of lubricant in the pharmaceutical composition of the present invention is 0.25% to 2% by mass of the total composition. In certain embodiments, the amount of lubricant is 0.5% to 1.5% by mass of the total composition. In certain embodiments, the amount of lubricant is 1% to 1.5% by mass of the total composition. In certain embodiments, the amount of lubricant is 1% by mass of the total composition.

[0030] In certain embodiments, the lubricant in the pharmaceutical composition of the present invention is magnesium stearate.

[0031] In certain embodiments, the amount of magnesium stearate in the pharmaceutical composition of the present invention is 0.25% to 2% by mass of the total composition. In certain embodiments, the amount of magnesium stearate is 0.5% to 1.5% by mass of the total composition. In certain embodiments, the amount of magnesium stearate is 1% to 1.5% by mass of the total composition. In certain embodiments, the amount of magnesium stearate is 1% by mass of the total composition.

[0032] In certain embodiments, the pharmaceutical composition of the present invention further comprises a binder. The binder may be selected from one or more of the following: starch slurry, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, sodium carboxymethylcellulose, xanthan gum, gum arabic, gelatin, guar gum, or carbomer.

[0033] In certain embodiments, the amount of binder in the pharmaceutical composition of the present invention is 0.1% to 10% by mass of the total composition. In certain embodiments, the amount of binder is 3% to 10% by mass of the total composition. In certain embodiments, the amount of binder is 3% to 7% by mass of the total composition. In certain embodiments, the amount of binder is 7% by mass of the total composition.

[0034] In certain embodiments, the binder in the pharmaceutical composition of the present invention is selected from povidone.

[0035] In certain embodiments, the binder in the pharmaceutical composition of the present invention is selected from povidone, and its amount is 0.1% to 10% by mass of the total composition. In certain embodiments, the amount of povidone is 3% to 10% by mass of the total composition. In certain embodiments, the amount of povidone is 3% to 7% by mass of the total composition. In certain embodiments, the amount of povidone is 7% by mass of the total composition.

[0036] In certain embodiments, the pharmaceutical composition of the present invention further comprises a coating material. The coating material may be selected from a film coating premix (gastricly soluble) or a mixture of one or more of the following coating materials: polyvinyl alcohol, hydroxypropyl methylcellulose, talc, polyethylene glycol, polyethylene glycol-polyvinyl alcohol copolymer, titanium dioxide, glyceryl mono- and dicaprylate, and lake.

[0037] In certain embodiments, the target coating weight increase in the pharmaceutical composition of the present invention is 0.5% to 10% by mass of the tablet core. In certain embodiments, the target coating weight increase is 1% to 6% by mass of the tablet core. In certain embodiments, the target coating weight increase is 2% to 4% by mass of the tablet core.

[0038] In certain embodiments, the coating material in the pharmaceutical composition of the present invention is selected from a film coating premix (gastricly soluble).

[0039] In certain embodiments, the coating material in the pharmaceutical composition of the present invention is selected from a film coating premix (gastricly soluble), and the target coating weight increase is 0.5% to 10% by mass of the tablet core. In certain embodiments, the target coating weight increase is 1% to 6% by mass of the tablet core. In certain embodiments, the target coating weight increase is 2% to 4% by mass of the tablet core.

[0040] The pharmaceutical composition of the present invention can be prepared in the form of tablets, capsules, granules, or powders.

[0041] The present invention also relates to a pharmaceutical composition comprising (1) compound A, (2) a filler, (3) a lubricant, (4) a disintegrant, and (5) a coating material.

[0042] The present invention further relates to a pharmaceutical composition comprising: (1) Compound A in an amount of 1% to 20% by mass of the total composition, preferably 2.5% to 10% by mass, more preferably 5% by mass; (2) Filler in an amount of 70% to 99% by mass of the total composition, preferably 80% to 90% by mass, more preferably 89% by mass; (3) The lubricant shall be added in an amount of 0.25% to 2% by mass of the total composition, preferably 0.5% to 1.5% by mass, more preferably 1% by mass; (4) The disintegrant shall be in an amount of 0.5% to 10% by mass of the total composition, preferably 3% to 7% by mass, more preferably 5% by mass; (5) Coating material: The target coating weight increase is 0.5% to 10% by mass of the tablet core, preferably 1% to 6% by mass, and more preferably 2% to 4% by mass.

[0043] The present invention further relates to a pharmaceutical composition comprising: (1) Compound A in an amount of 1% to 20% by mass of the total composition, preferably 2.5% to 10% by mass, more preferably 5% by mass; (2) Filler: The filler contains mannitol and microcrystalline cellulose in a mass ratio of 3:1 to 1:1, preferably 1:1, and the amount of the filler is 70% to 99% by mass of the total composition, preferably 80% to 90% by mass, more preferably 89% by mass; (3) Lubricant: The lubricant is magnesium stearate, in an amount of 0.25% to 2% by mass, preferably 0.5% to 1.5% by mass, and more preferably 1% by mass of the total composition; (4) Disintegrant: The disintegrant is cross-linked povidone, in an amount of 0.5% to 10% by mass of the total composition, preferably 3% to 7% by mass, and more preferably 5% by mass; (5) Coating material: The coating powder is a film coating premix (gastricly soluble), and the target coating weight increase is 0.5% to 10% by mass of the tablet core, preferably 1% to 6% by mass, and more preferably 2% to 4% by mass.

[0044] In a particular embodiment, the unit dose in the pharmaceutical composition formulation of the present invention is calculated based on active compound A and is selected from 1 mg to 100 mg, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, and 100 mg.

[0045] In certain embodiments, the pharmaceutical composition of the present invention is a tablet.

[0046] In a particular embodiment of the pharmaceutical composition according to the present invention, the dose per unit formulation of the tablet is calculated based on the active compound A and is selected from 1 mg to 100 mg, preferably from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, and 100 mg.

[0047] In the pharmaceutical composition of the present invention, compound A, which is the active substance, is present in an amount of 1 to 100 mg. In some embodiments, compound A, which is the active substance, is present in an amount of 2 to 80 mg; in some embodiments, it is present in an amount of 2 to 60 mg; in some embodiments, it is present in an amount of 2 to 50 mg; in some embodiments, it is present in an amount of 5 to 50 mg; in some embodiments, it is present in an amount of 5 to 40 mg; in some embodiments, it is present in an amount of 5 to 30 mg; in some embodiments, it is present in an amount of 5 to 20 mg; in some embodiments, it is present in an amount of 5 to 10 mg; in some embodiments, it is present in an amount of 10 to 80 mg; in some embodiments, it is present in an amount of 10 to 60 mg; in some embodiments, it is present in an amount of 10 to 50 mg; in some embodiments, it is present in an amount of 20 to 80 mg; in some embodiments, it is present in an amount of 20 to 60 mg; in some embodiments, it is present in an amount of 20 to 50 mg; and in some embodiments, it is present in an amount of 30 to 50 mg.

[0048] The pharmaceutical composition of the present invention is a tablet or capsule, and the active substance is present in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In certain embodiments, the active substance is present in an amount of 5 mg, 10 mg, or 20 mg. In certain embodiments, the active substance is present in an amount of 5 mg or 20 mg.

[0049] The present invention also provides a method for preparing a pharmaceutical composition formulation, comprising one or more of a dry granulation process, a wet granulation process, and a direct powder compression process.

[0050] In certain embodiments, a unit formulation of the pharmaceutical composition of the present invention comprises 5 mg of compound A, 44.5 mg of mannitol, 44.5 mg of microcrystalline cellulose, 3 mg of coating powder, 5 mg of cross-linked povidone, and 1 mg of magnesium stearate, or a unit formulation of the pharmaceutical composition comprises 20 mg of compound A, 178 mg of mannitol, 178 mg of microcrystalline cellulose, 20 mg of cross-linked povidone, 4 mg of magnesium stearate, and 12 mg of coating powder.

[0051] The present invention also provides a method for preparing a pharmaceutical composition formulation, comprising the following steps: (1) Grind compound A; (2) Put compound A, the filler, and the disintegrant into the mixer and premix them; (3) The lubricant is added to the mixer and thoroughly mixed with the pre-mixed powder, the mixture is compressed into tablets, film coated and packaged.

[0052] Examples of mixer devices include, but are not limited to, one or more mixers that mix materials by driving stirring blades or cutting blades at high speed, such as wet mixing granulators or high-energy mixers, or mixers that mix materials in a container by rotating the device container, such as three-dimensional mixers or hopper mixers.

[0053] In the pharmaceutical preparation process of the present invention, a wet mixing granulator is employed to premix the starting material or auxiliary material. This optimizes the mixing process, reduces mixing steps in conventional mixing processes, such as uniform incremental addition and multi-stage mixing, shortens the mixing time, has high mixing efficiency, and provides better material mixing uniformity than conventional mixing methods.

[0054] The present invention also provides the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with fibrotic bronchiectasis, wherein the disease associated with fibrotic bronchiectasis is selected from bronchiectasis (including non-cystic fibrotic bronchiectasis and cystic fibrotic bronchiectasis) and lower respiratory tract diseases resulting from acute lung injury / acute respiratory distress syndrome.

[0055] Unless otherwise specified, the term "amount" of each component in this invention refers to the mass percentage of that substance relative to the total mass of the composition. In the case of formulations such as tablets or capsules, the mass percentage of each component refers to the mass percentage of that component in the contents of the tablet or capsule (including the activator and excipients).

[0056] The pharmaceutical composition formulations provided in the present invention have good stability and bioavailability. [Examples]

[0057] The present invention will be described in further detail below with reference to examples. Unless otherwise specified, the examples were carried out according to the conventional conditions of the experimental method. The examples are provided to better illustrate the scope of the present invention and should not be understood as limiting the scope of the present invention. With respect to the above disclosure of the present invention, those skilled in the art can improve and modify the embodiments without departing from the spirit of the invention. These improved or modified technical solutions remain within the scope of protection of the present invention.

[0058] Unless otherwise specified, all materials used in the embodiments of this invention are commercially available.

[0059] [Preparation of Compound A] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (compound A)

[0060] [ka]

[0061] Step 1: (S)-tert-butyl(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamate (1B) 1A (0.29 g, 0.85 mmol, synthesized according to WO2016 / 016242A1) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL). Intermediate 2a (0.35 g, 1.27 mmol, synthesized according to WO2016 / 016242A1), potassium carbonate (0.24 g, 1.70 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (70 mg, 0.09 mmol) were added. After the additions were complete, the mixture was reacted at 90°C for 3 hours. The reaction mixture was cooled to room temperature and saturated sodium chloride aqueous solution (20 mL) was added. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA(v / v)=4:1) to obtain compound 1B (white solid, 0.34 g, 99.0%) as indicated in the title. LC-MS(ESI): m / z = 412.1[M+H] + .

[0062] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)propannitrile (1C) Compound 1B (0.34 g, 0.83 mmol) was dissolved in formic acid (5 mL). After the addition was complete, the mixture was reacted at room temperature overnight. The reaction product was concentrated to dryness, and ethyl acetate (25 mL) was added. Subsequently, saturated sodium bicarbonate aqueous solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 1C (pale yellow solid, 0.21 g, 69.5%). LC-MS(ESI): m / z = 312.1[M+H] + .

[0063] Step 3: (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepan-4-carboxylate(1D) 1C (0.21 g, 0.60 mmol) was dissolved in DMF (10 mL), and DIPEA (0.23 g, 1.80 mmol), HATU (0.34 g, 0.90 mmol), and INT-3 (0.22 g, 0.90 mmol, prepared according to WO2015 / 110826) were added. After the additions were complete, the mixture was reacted overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride aqueous solution dropwise, and saturated brine (30 mL) was added. The mixture was extracted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (25 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound 1D (pale yellow solid, 0.32 g, yield 99.0%). This was used directly in the next step. LC-MS(ESI): m / z = 483.1[M-57+H] + .

[0064] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-yl)phenyl)ethyl)-1,4-oxazepan-2-carboxamide (compound A) 1D (0.32 g, 0.59 mmol) was dissolved in formic acid (2.5 mL). After the addition was complete, the mixture was reacted at 50°C for 10 minutes. The reaction product was concentrated to dryness, and ethyl acetate (20 mL) was added. Subsequently, saturated sodium bicarbonate aqueous solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated, and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain compound 1 (0.15 g, yield 58.0%).

[0065] LC-MS(ESI): m / z = 439.1[M+H] + . 1 H-NMR(400MHz, CDCl3):δ 7.43-7.22(m,5H), 7.12(d,1H), 5.19(dd,1H), 4.18-4.04(m,1H), 4.05-3.95(m,1 H), 3.78(m,1H), 3.46(s,3H), 3.41-3.17(m,3H), 3.03-2.87(m,3H), 1.88(m,2H).

[0066] [Examples 1-3] Table 1 shows the formulations for Examples 1-3. The preparation steps are as follows: (1) Compound A was mechanically pulverized. (2) Compound A, lactose, microcrystalline cellulose, povidone, and cross-linked povidone were placed in a wet mixing granulator, and the agitator (500 rpm) and shear blades (2000 rpm) were turned ON to thoroughly mix the materials. (3) With the agitator and shear blades turned ON, an appropriate amount of purified water was added to the granulator to prepare a suitable soft material, which was then granulated by passing it through a 20-mesh sieve. The wet granules were dried at a temperature below 60°C. (4) The dried granules were sieved through a 20-mesh screen and mixed with magnesium stearate until homogeneous. This material was compressed into tablets using a 6.5 mm round punch to obtain uncoated tablets. (5) Water was added to Colorcon's film coating premix (gastric soluble) under stirring to prepare a coating solution with a solid content of 30%. The uncoated tablets were placed in a high-efficiency coating machine and coated by spraying the coating solution. The target coating weight increase was 2% to 4% relative to the weight of the tablet core. Film-coated tablets were obtained.

[0067] Table 1: Composition and elution rates of Examples 1-3

[0068] [Table 1]

[0069] Conclusion: By using 3% to 7% cross-linked polyvinylpyrrolidone as a disintegrant, the product can be rapidly disintegrated and almost completely eluted.

[0070] [Examples 4 and 5] The formulations for Examples 4 and 5 are shown in Table 2. The preparation steps are the same as in Examples 1-3.

[0071] Table 2: Composition and elution rates of Examples 4 and 5

[0072] [Table 2]

[0073] Conclusion: When combined with the elution results shown in Example 2, using 0.5% to 1.5% magnesium stearate, all products rapidly disintegrate and dissolve, providing sufficient lubrication during the manufacturing process.

[0074] [Examples 6-8] Table 3 shows the formulations for Examples 6-8. The preparation steps are as follows: (1) Compound A was mechanically pulverized. (2) Compound A, mannitol, microcrystalline cellulose, and cross-linked povidone were placed in a wet mixing granulator, and the agitator and shear blades were turned ON to thoroughly mix the materials. (3) The above mixture was placed in a hopper mixer. Magnesium stearate was added and mixed thoroughly. The mixed material was compressed into tablets to obtain the product.

[0075] Table 3: Composition and content uniformity of tablets in Examples 6-8

[0076] [Table 3]

[0077] Conclusion: When microcrystalline cellulose is used alone, or in combination with mannitol (in a ratio of approximately 3:1 to 1:1), the tablets exhibit uniform content, good compressibility, and stable quality.

[0078] [Example 9] Compound A was uniformly mixed with lactose, microcrystalline cellulose, and mannitol in a ratio of 1:5 each. The mixture was placed in a wide-mouthed glass container of appropriate size.

[0079] The above mixtures were placed under the following conditions: 60°C in a sealed container, 92.5% RH (relative humidity) open, 40°C / 75% RH in a sealed container, and 40°C / 75% RH open. After two weeks, changes in impurities were measured.

[0080] Table 4: Stability of Compound A when mixed with different fillers

[0081] [Table 4]

[0082] Conclusion: Based on the results after two weeks of standing, compound A maintained good stability even after being mixed with various fillers. In particular, when compound A was mixed with mannitol or microcrystalline cellulose, it showed less increase in impurities and better stability.

[0083] [Example 10] The composition of the formulation in Example 10 is shown in Table 5. The preparation steps are the same as in Examples 6-8.

[0084] Table 5: Composition of Example 10

[0085] [Table 5]

[0086] Tablets with different hardness levels were prepared. As shown in Table 6 below, all of them dissolved relatively completely.

[0087] Table 6: Dissolution rates of tablets with different hardness in Examples 8 and 10

[0088] [Table 6]

[0089] The hardness of the tablets within the investigated range did not affect the dissolution profile. The product has an elegant appearance and good mechanical strength.

[0090] Products 8 and 10 were packaged in double aluminum blisters and left in a test environment of 40°C and 75% RH for 6 months. Compared to the results at 0 months, the elution rate and content remained unchanged at 6 months, and the total amount of impurities increased only slightly, suggesting good stability. The specific results are shown in Table 7 below.

[0091] Table 7: Stability of Examples 8 and 10

[0092] [Table 7]

[0093] [Examples 11-14] Compound A was processed to various particle sizes by different means. The composition of the formulations was the same as in Example 10, and the preparation steps were as described in Examples 6-8. The effect of differences in the particle size of Compound A on the mixing uniformity of the formulations and the dissolution profile of the tablets was investigated.

[0094] Table 8: Content measurement results

[0095] [Table 8]

[0096] Table 9: Tablet dissolution profile results

[0097] [Table 9]

[0098] As a result, when the particle size d(0.9) of the starting material was in the range of 7.349 μm to 82.334 μm, the prepared total mixed powder and tablets had good content uniformity, and the dissolution profile of the formulation was basically consistent.

[0099] [Examples 15-16] The formulation composition was the same as in Example 10, and the preparation steps were the same as in Examples 6-8. Uncoated tablets were prepared and film-coated using a film-coating premix (gastricly soluble). Dissolution profiles were measured for samples with different coating weight increases.

[0100] Table 10: Dissolution profiles of tablets with different coating weight increases

[0101] [Table 10]

[0102] Differences in coating weight increase within the scope of this study do not significantly affect the tablet dissolution profile.

[0103] [Example 17] The samples from Example 8 and Example 15 were packaged in either a double aluminum blister (a solid, cold-pressed composite rigid sheet of polyamide / aluminum / polyvinyl chloride, pharmaceutical-grade aluminum foil) or a PVDC blister (polyvinyl chloride / polyvinylidene chloride, pharmaceutical-grade aluminum foil), and left under accelerated conditions (40°C / 75%RH) for 6 months. The stability of the samples under different packaging conditions was investigated. The results are shown below. After 6 months, the stability of the samples packaged in double aluminum blisters was significantly better than that of the samples packaged in PVDC blisters.

[0104] Table 11: Sample stability in different packaging

[0105] [Table 11]

[0106] [Examples 18-19] The composition of the formulation was the same as in Example 10. Compound A, mannitol, microcrystalline cellulose, and cross-linked povidone were placed in a wet mixing granulator, and the materials were mixed with the agitator and shear blades turned ON. After different mixing times, samples were taken to confirm the uniformity of the content of the mixture.

[0107] Table 11: Content homogeneity of samples after different mixing times

[0108] [Table 12]

[0109] Using a wet mixing granulator, the materials were homogeneously mixed within a short processing time, achieving excellent mixing uniformity. Furthermore, the mixing uniformity of the materials remained good for different mixing times within the test range.

[0110] [Biological assay of compound A] 1. In vitro DPP1 enzyme activity assay Recombinant human DPP1 enzyme (R&D Systems, model number: 1071-CY) at a final concentration of 100 μg / mL was mixed with recombinant human cathepsin L (R&D Systems, model number: 952-CY) at a final concentration of 20 μg / mL. The mixture was incubated at room temperature for 1 hour to activate the DPP1 enzyme. The activated DPP1 enzyme was diluted 100-fold. 5 μL of the compounds at different concentrations and 5 μL of the diluted DPP1 enzyme were added to a 384-well plate and incubated at room temperature for 30 minutes. 10 μL of the substrate Gly-Arg-AMC (bachem, model number: I-1215) at a concentration of 20 μM was added, and incubation was continued at room temperature for 60 minutes. Fluorescence intensity was detected using a microplate reader at an excitation wavelength of 380 nm and an emission wavelength of 460 nm. IC 50 The values ​​were calculated using Origin2019 software equipped with the DosResp function.

[0111] Test results: The compound of the present invention showed inhibitory activity against the DPP1 receptor. The compound of the example showed IC1c activity against the DPP1 receptor. 50 The value was less than 100 nM. The test results for some of the examples are shown in Table 8.

[0112] Table 8: Inhibitory activity against DPP1

[0113] [Table 13]

[0114] Conclusion: Compound A of the present invention showed high inhibitory activity against the DPP1 receptor.

[0115] 2. Pharmacokinetic experiments in rats 1.1 Test animals: Male SD rats, approximately 220g, 6-8 weeks old, 6 rats / compound. The rats were purchased from CHENGDU DOSSY EXPERIMENTAL ANIMALS CO.,LTD. 1.2 Study Design: On the day of the study, six SD rats were randomly divided into groups according to their body weight. The rats were fasted for 12-14 hours the day before administration, but water was available for free. They were fed 4 hours after administration.

[0116] Table 9: Administration Information

[0117] [Table 14]

[0118] Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% physiological saline; Vehicle for oral administration: 0.5% MC; Control compound INS1007 is compound 2 of patent WO2015 / 110826A1, which was prepared according to the method described in the said patent.

[0119] Rats were anesthetized with isoflurane before and after administration. Blood (0.1 mL) was collected by orbital sampling and placed in an EDTAK2 centrifuge tube. Blood samples were centrifuged at 4°C and 5000 rpm for 10 minutes to obtain plasma. Blood sampling times for the intravenous administration group: 0 min, 5 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours; blood sampling times for the oral administration group: 0 min, 5 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. All samples were stored at -80°C until analysis and detection.

[0120] Table 10: Pharmacokinetic parameters of test compounds in rat plasma

[0121] [Table 15]

[0122] Conclusion: The compounds of the present invention have good bioavailability and pharmacokinetic profiles.

[0123] 3. 14-day repeated oral toxicity study in rats SD rats were randomly divided into the following groups according to body weight: a vehicle control group (0.5% MC), an INS1007 group (30, 100, and 300 mg / kg), and a compound A group (30, 100, and 300 mg / kg). Each treatment group contained 16 rats, and the vehicle control group contained 10 rats, with an equal number of male and female rats. The corresponding concentrations of the drug and vehicle were administered orally daily for 14 consecutive days. The rats were given a 7-day recovery period. During the administration period, the general condition, body weight, and food intake were measured for each group. After the completion of the administration and recovery periods, hematological, serological, and gross anatomical examinations were performed for each group.

[0124] Conclusion: At the same dosage, compound A of the present invention is less toxic and safer than INS1007.

Claims

1. A pharmaceutical composition comprising compound A and an excipient, wherein compound A has the following structure: 【Chemistry 1】 (A).

2. The pharmaceutical composition according to claim 1, wherein the amount of compound A in the pharmaceutical composition is 1% to 20% by mass of the total composition, preferably 2.5% to 10% by mass, and more preferably 5% by mass.

3. The pharmaceutical composition according to claim 1 or 2, wherein the particle size distribution d(0.9) of compound A is 150 μm or less, preferably 100 μm or less, and more preferably 85 μm or less.

4. The pharmaceutical composition according to claim 3, wherein the processing method for compound A is one or more of sieving, mechanical grinding, and air-jet grinding.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the excipient comprises, as a filler, one or more selected from lactose, microcrystalline cellulose, sucrose, glucose, powdered cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, aluminum silicate, dextrin, starch, pregelatinized starch, sodium chloride, potassium chloride, mannitol, or sorbitol, preferably one or more selected from lactose, microcrystalline cellulose, or mannitol.

6. The pharmaceutical composition according to claim 5, wherein the filler is mannitol and microcrystalline cellulose, and the mass ratio of mannitol to microcrystalline cellulose is 3:1 to 1:1, preferably 1:

1.

7. The pharmaceutical composition according to claim 5, wherein the filler is lactose and microcrystalline cellulose, and the mass ratio of lactose to microcrystalline cellulose is 3:1 to 1:1, preferably 3:

1.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the excipient further comprises a disintegrant.

9. The pharmaceutical composition according to claim 8, wherein the disintegrant is one or more of starch, pregelatinized starch, carboxymethyl starch sodium, cross-linked povidone, or croscarmellose sodium, preferably cross-linked povidone.

10. The pharmaceutical composition according to claim 9, wherein the amount of the cross-linked povidone is 0.5% to 10% by mass of the total composition, preferably 3% to 7% by mass, and more preferably 5% by mass.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the excipient further comprises a lubricant.

12. The pharmaceutical composition according to claim 11, wherein the lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, aluminum stearate, palmitic acid, glyceryl behenate, polyethylene glycol having various molecular weights, hydrogenated castor oil, and sodium stearyl fumarate, preferably magnesium stearate.

13. The pharmaceutical composition according to claim 12, wherein the amount of magnesium stearate is 0.25% to 2% by mass of the total composition, preferably 0.5% to 1.5% by mass, and more preferably 1% by mass.

14. A pharmaceutical composition according to any one of claims 5 to 13, further comprising a binder.

15. The pharmaceutical composition according to claim 14, wherein the binder is selected from one or more of the following: starch slurry, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, sodium carboxymethylcellulose, xanthan gum, gum arabic, gelatin, guar gum, or carbomer, preferably povidone, and the amount of povidone is 0.1% to 10% by mass of the total composition, preferably 3% to 7% by mass, more preferably 7% by mass.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the dosage form of the pharmaceutical composition is a tablet, a capsule, granules, or a powder.

17. The pharmaceutical composition according to claim 16, wherein the dosage form of the pharmaceutical composition is a tablet.

18. The pharmaceutical composition according to claim 17, wherein the tablet further comprises a film coating layer; the tablet is coated with a gastrosoluble film coating premix or coating material, the coating material being selected from polyvinyl alcohol, hydroxypropyl methylcellulose, talc, polyethylene glycol, polyethylene glycol-polyvinyl alcohol copolymer, titanium dioxide, glyceryl mono- and dicaprylocate, and lake; preferably, the tablet is coated with a gastrosoluble film coating premix; where the target coating weight increase is 0.5% to 10% by mass of the tablet core, preferably 1% to 6% by mass, more preferably 2% to 4% by mass.

19. A pharmaceutical composition comprising compound A, a filler, a lubricant, a disintegrant, and a coating material.

20. The amount of compound A is 1% to 20% by mass of the total composition, preferably 2.5% to 10% by mass, more preferably 5% by mass; The amount of the filler is 70% to 99% by mass of the total composition, preferably 80% to 90% by mass, and more preferably 89% by mass; The amount of the lubricant is 0.25% to 2% by mass of the total composition, preferably 0.5% to 1.5% by mass, and more preferably 1% by mass; The amount of the disintegrant is 0.5% to 10% by mass of the total composition, preferably 3% to 7% by mass, and more preferably 5% by mass; The pharmaceutical composition according to claim 19, wherein the target coating weight increase for the coating material is 0.5% to 10% by mass of the tablet core, preferably 1% to 6% by mass, and more preferably 2% to 4% by mass.

21. The pharmaceutical composition according to claim 19 or 20, wherein the filler is mannitol and microcrystalline cellulose, and the mass ratio of mannitol to microcrystalline cellulose is 3:1 to 1:1, preferably 1:1; the lubricant is magnesium stearate; the disintegrant is cross-linked povidone; and the coating material is a gastric-soluble film coating premix.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the unit dose of the formulation is calculated based on the mass of the active substance and is selected from 1 mg to 500 mg, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, or 200 mg.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein the unit formulation of the pharmaceutical composition comprises 5 mg of compound A, 44.5 mg of mannitol, 44.5 mg of microcrystalline cellulose, 5 mg of cross-linked povidone, 1 mg of magnesium stearate, and 3 mg of coating powder; or the pharmaceutical composition according to any one of claims 1 to 22, wherein the unit formulation of the pharmaceutical composition comprises 20 mg of compound A, 178 mg of mannitol, 178 mg of microcrystalline cellulose, 20 mg of cross-linked povidone, 4 mg of magnesium stearate, and 12 mg of coating powder.

24. A method for preparing a pharmaceutical composition according to any one of claims 1 to 23, wherein the preparation process is one or more of a dry granulation process, a wet granulation process, and a direct powder compression process.

25. A method for preparing a pharmaceutical composition according to any one of claims 18 to 23, comprising the following steps: (1) Grind compound A; (2) Compound A, the filler, and the disintegrant are placed in a mixer and pre-mixed; (3) Add the lubricant to the mixer and mix thoroughly with the pre-mixed powder, compress the mixture into tablets, coat with film and package.

26. The preparation method according to claim 25, wherein the mixer includes one or more of the following: a mixer that mixes materials by driving stirring blades or cutting blades at high speed, preferably a wet mixing granulator or a high-energy mixer; or a mixer that mixes materials in a container by rotating the device container, preferably a three-dimensional mixer or a hopper mixer.

27. Use of the pharmaceutical composition according to any one of claims 1 to 23 in the manufacture of a pharmaceutical for treating diseases associated with fibrotic bronchiectasis.

28. The use according to claim 27, wherein the disease associated with fibrotic bronchiectasis is selected from lower respiratory tract diseases resulting from bronchiectasis, and acute lung injury or acute respiratory distress syndrome.

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