Anti-fibrotic compositions

Abstract

This invention relates to an antifibrotic composition. The composition comprises: 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, and an antioxidant. This composition has advantages such as easy storage, stable and controllable quality, and high bioavailability. Furthermore, the composition is highly effective, has high safety, and exhibits good patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, and specifically relates to an anti-fibrotic composition. Background Technology

[0002] Fibrosis can occur in various organs, with the main pathological changes being an increase in fibrous connective tissue and a decrease in parenchymal cells within organ tissues. Continued progression can lead to organ dysfunction and eventual death. It is seen in end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure, seriously threatening human health and life. IPF is considered the most common and severe form of the disease, with a median survival of approximately three years. The exact mechanisms driving fibrosis are currently unclear. Pirfenidone, developed by Shionogi & Co., Ltd. in Japan, was the first drug for treating IPF approved in Japan in 2008 and in the European Union in 2011.

[0003] Patent application WO 2014012360 A1 discloses a substituted pyrimidinone compound, specifically 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (the compound shown in formula (I)), which exhibits superior activity compared to pirfenidone, along with excellent pharmacokinetic properties and safety. Patent application WO 2018019166 A1 discloses a salt of the compound shown in formula (I), such as a hydrochloride salt, wherein the hydrochloride salt possesses good stability and biological properties. However, the research in the aforementioned patent applications is still in the early stages of preclinical studies. To facilitate clinical research, further investigation into the properties of the drug is needed to identify a suitable form for human administration.

[0004] Summary of the Invention

[0005] Based on their existing research and development of a new drug (the compound shown in Formula (I) and its pharmaceutically acceptable salts), the inventors of this application discovered through initial research that the compound shown in Formula (I) or its pharmaceutically acceptable salts, such as hydrochloride, exhibits good stability and does not produce impurities or increase impurity content over long-term storage. However, during the development of the drug formulation, the inventors found that when the compound shown in Formula (I) or its pharmaceutically acceptable salts, such as hydrochloride, were prepared into a drug formulation using conventional methods, the stability of the drug formulation unexpectedly became very poor. To overcome the problem of poor stability in the drug formulation, the inventors attempted to screen and proportion various pharmaceutical excipients and found that when the compound shown in Formula (I) or its pharmaceutically acceptable salts, such as hydrochloride, were combined with antioxidants, the stability of the drug formulation could be maintained. In particular, when the compound or its pharmaceutically acceptable salts, such as hydrochloride, were combined with antioxidants that react with free radicals, the stability of the drug formulation product was even better.

[0006] Based on the above findings, the present invention provides a composition with anti-fibrotic activity. The composition of the present invention uses 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (the compound shown in formula (I)) or a pharmaceutically acceptable salt thereof (such as hydrochloride) as the active ingredient, combined with an antioxidant, effectively overcoming the problem of reduced composition stability.

[0007] On one hand, the present invention provides a composition. In some embodiments, the composition comprises 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (the compound shown in formula (I)) or a pharmaceutically acceptable salt thereof, and an antioxidant. The composition uses 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof as the active ingredient. The composition of the present invention is effective in treating fibrotic diseases such as idiopathic pulmonary fibrosis and has a high safety profile.

[0008] In some embodiments, the above composition may further include at least one of the following additional technical features:

[0009] In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is its hydrochloride salt.

[0010]

[0011] In some embodiments, the antioxidants described in this invention include, but are not limited to, antioxidants that react with free radicals and / or antioxidant synergists.

[0012] In some embodiments, the antioxidant described in this invention is a free radical-reactive antioxidant.

[0013] In some embodiments, the antioxidants of the present invention include, but are not limited to, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, or any combination thereof.

[0014] In some embodiments, the composition of the present invention is an oral formulation.

[0015] In some embodiments, the composition of the present invention is an oral solid dosage form.

[0016] In some embodiments, the oral solid dosage form of the present invention is a capsule or a tablet.

[0017] In some embodiments, the composition of the present invention is a capsule or a tablet.

[0018] In some embodiments, the compositions of the present invention further comprise pharmaceutically acceptable excipients.

[0019] In some embodiments, the excipients of the present invention include at least one selected from fillers, disintegrants, adhesives, anti-adhesives, and lubricants.

[0020] In some embodiments, the filler of the present invention may be selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dicalcium phosphate, sorbitol, sucrose, lactitol and maltose.

[0021] In some embodiments, the disintegrant of the present invention may be selected from at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0022] In some embodiments, the anti-adhesion agent of the present invention may be selected from at least one of colloidal silica and talc.

[0023] In some embodiments, the lubricant of the present invention may be selected from at least one of magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, and glyceryl behenate.

[0024] In some embodiments, the adhesive of the present invention may be selected from at least one of povidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methyl cellulose.

[0025] In some embodiments, the composition of the present invention contains 5.00 to 73.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride (e.g., 5.00 parts by weight, 6.00 parts by weight, 7.00 parts by weight, 8.00 parts by weight, 9.00 parts by weight, 11.00 parts by weight, 12.00 parts by weight, 12.12 parts by weight, 13.00 parts by weight). Parts by weight, 20.00 parts by weight, 21.00 parts by weight, 21.82 parts by weight, 22.00 parts by weight, 25.00 parts by weight, 28.00 parts by weight, 31.00 parts by weight, 34.00 parts by weight, 34.09 parts by weight, 35.00 parts by weight, 58.00 parts by weight, 60.00 parts by weight, 65.00 parts by weight, 70.00 parts by weight, 73.00 parts by weight, or any range between two point values).

[0026] In some embodiments, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride of the present invention is about 6.00 to 58.00 parts by weight.

[0027] In some embodiments, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride is about 9.00 to 58.00 or 11.00 to 58.00 parts by weight. In some embodiments, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride is about 6.00 to 22.00 parts by weight.

[0028] In some embodiments, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride of the present invention is 9.00 to 35.00 or 12.00 to 35.00 parts by weight.

[0029] Preferably, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride of the present invention is 21.00 to 35.00 parts by weight. Or

[0030] Preferably, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride of the present invention is 9.00-22.00 or 12.00-22.00 parts by weight.

[0031] In some embodiments, the antioxidant content of the present invention is 0.01 to 0.40 parts by weight (e.g., 0.01 parts by weight, 0.02 parts by weight, 0.03 parts by weight, 0.04 parts by weight, 0.05 parts by weight, 0.06 parts by weight, 0.07 parts by weight, 0.08 parts by weight, 0.09 parts by weight, 0.10 parts by weight, 0.15 parts by weight, 0.20 parts by weight, 0.25 parts by weight, 0.30 parts by weight, 0.40 parts by weight, or a range between any two point values).

[0032] In some embodiments, the antioxidant content of the present invention is 0.02-0.40, 0.01-0.30, 0.01-0.20, 0.02-0.30, 0.03-0.30, 0.03-0.20, 0.03-0.10, 0.05-0.20, 0.08-0.30, 0.08-0.20, 0.08-0.10, or 0.04-0.30 parts by weight.

[0033] In some embodiments, the antioxidant content of the present invention is 0.03 to 0.08 parts by weight. Preferably, the antioxidant content of the present invention is 0.03 to 0.05 parts by weight, 0.04 to 0.05 parts by weight, or 0.05 to 0.08 parts by weight.

[0034] In some embodiments, the filler content of the present invention is 22.00 to 91.00 parts by weight (e.g., 22.00 parts by weight, 22.50 parts by weight, 25.00 parts by weight, 29.00 parts by weight, 29.50 parts by weight, 30.00 parts by weight, 35.00 parts by weight, 40.00 parts by weight, 45.00 parts by weight, 50.00 parts by weight, 55.00 parts by weight, 55.50 parts by weight, 60.00 parts by weight, 60.36 parts by weight, 65.00 parts by weight, 65.60 parts by weight, 65.63 parts by weight, 67.00 parts by weight, 6...). 8.10 parts by weight, 68.13 parts by weight, 69.00 parts by weight, 70.00 parts by weight, 70.50 parts by weight, 71.00 parts by weight, 73.84 parts by weight, 74.00 parts by weight, 74.34 parts by weight, 74.50 parts by weight, 74.84 parts by weight, 75.34 parts by weight, 75.84 parts by weight, 76.00 parts by weight, 77.00 parts by weight, 80.00 parts by weight, 82.00 parts by weight, 86.00 parts by weight, 90.00 parts by weight, 90.50 parts by weight, 91.00 parts by weight, or any range between two point values).

[0035] In some embodiments, the filler content of the present invention is about 22.50 to 91.00 parts by weight, 29.00 to 82.00 parts by weight, 55.00 to 90.00 parts by weight, 60.00 to 76.00 parts by weight, 60.00 to 77.00 parts by weight, 60.00 to 69.00 parts by weight, 55.00 to 90.00 parts by weight, 65.00 to 77.00 parts by weight, 65.00 to 76.00 parts by weight, or 70.00 to 76.00 parts by weight.

[0036] In some embodiments, the content of the anti-adhesion agent of the present invention is 0.50 to 3.50 parts by weight (e.g., 0.50 parts by weight, 1.00 parts by weight, 1.50 parts by weight, 2.00 parts by weight, 2.50 parts by weight, 3.00 parts by weight, 3.50 parts by weight, or any range between two point values).

[0037] In some embodiments, the content of the anti-adhesion agent of the present invention is 0.50-2.50 parts by weight, 0.50-1.50 parts by weight, 1.00-2.50 parts by weight, or 1.00-2.00 parts by weight.

[0038] In some embodiments, the content of the disintegrant of the present invention is 0.50 to 16.00 parts by weight (e.g., 0.50 parts by weight, 1.00 parts by weight, 1.50 parts by weight, 2.00 parts by weight, 2.50 parts by weight, 3.00 parts by weight, 3.50 parts by weight, 4.00 parts by weight, 4.50 parts by weight, 5.00 parts by weight, 6.00 parts by weight, 7.00 parts by weight, 8.00 parts by weight, 9.00 parts by weight, 10.00 parts by weight, 12.00 parts by weight, 14.00 parts by weight, 16.00 parts by weight, or any range between two point values).

[0039] In some embodiments, the content of the disintegrant of the present invention is 0.05-6.00, 1.50-6.00, 2.50-5.00, 3.00-10.00, 4.00-9.00, 4.00-8.00 or 2.50-8.00 parts by weight.

[0040] In some embodiments, the lubricant of the present invention is present in a content of 0.50–7.00, 0.50–6.00, or 0.50–5.00 parts by weight (e.g., 0.50 parts by weight, 1.00 parts by weight, 1.50 parts by weight, 2.00 parts by weight, 2.50 parts by weight, 3.00 parts by weight, 3.50 parts by weight, 4.00 parts by weight, 4.50 parts by weight, 5.00 parts by weight, 6.00 parts by weight, 7.00 parts by weight, or any range between two point values).

[0041] In some embodiments, the lubricant of the present invention is present in parts by weight of 1.00–7.00, 1.00–6.00, 1.00–5.00, 2.00–7.00, 2.00–6.00, 2.00–3.00, 3.00–6.00, 5.00–7.00, 3.00–4.00, or 2.00–4.00.

[0042] In some embodiments, the adhesive of the present invention is present in a content of 0 to 3.50 parts by weight (e.g., 0.01 parts by weight, 0.02 parts by weight, 0.03 parts by weight, 0.04 parts by weight, 0.05 parts by weight, 0.06 parts by weight, 0.08 parts by weight, 1.00 parts by weight, 1.50 parts by weight, 2.00 parts by weight, 2.50 parts by weight, 3.00 parts by weight, 3.50 parts by weight, or any range between two point values).

[0043] In some embodiments, the adhesive of the present invention is present in a content of 0-3.00, 0-2.00, 0-2.50, or 2.00-3.00 parts by weight.

[0044] In some embodiments, the composition of the present invention is a capsule; the capsule comprises 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride, an antioxidant, a filler, a disintegrant, an anti-adhesive, a lubricant, and optionally a binder.

[0045] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant in the capsules of the present invention is (5.00-73.00):(0.01-0.40).

[0046] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant in the capsules of the present invention is (21.00-35.00):(0.03-0.08).

[0047] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant in the capsules of the present invention is (21.00-35.00):(0.05-0.08).

[0048] In some embodiments, in the capsules of the present invention, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is (21.00-22.00):(0.05-0.08).

[0049] In some embodiments, in the capsules of the present invention, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is (34.00-35.00):(0.05-0.08).

[0050] In some embodiments, the capsules of the present invention comprise: 5.00 to 73.00 or 21.00 to 35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.01 to 0.40, 0.02 to 0.10 or 0.04 to 0.09 parts by weight of an antioxidant; 22.50 to 90.50 parts by weight of a filler; 0.50 to 6.00 or 2.00 to 6.00 parts by weight of a disintegrant; 0.50 to 3.50 parts by weight of an anti-adhesive; 0.50 to 3.50 parts by weight of a lubricant; and 0 to 2.50 parts by weight of a binder.

[0051] In some embodiments, the capsules of the present invention comprise: 5.00 to 73.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.01 to 0.40 parts by weight of an antioxidant; 22.50 to 90.50 parts by weight of a filler; 0.50 to 6.00 parts by weight of a disintegrant; 0.50 to 3.50 parts by weight of an anti-adhesive; 0.50 to 3.50 parts by weight of a lubricant; and 0 to 2.50 parts by weight of a binder.

[0052] In some embodiments, the capsule formulation of the present invention comprises: 21.00 to 35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.02 to 0.10 parts by weight of an antioxidant; 22.50 to 90.50 parts by weight of a filler; 2.00 to 6.00 parts by weight of a disintegrant; 0.50 to 3.50 parts by weight of an anti-adhesive; 0.50 to 3.50 parts by weight of a lubricant; and 0 to 2.50 parts by weight of an adhesive.

[0053] In some embodiments, the capsule formulation of the present invention comprises: 21.00 to 35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.05 to 0.08 parts by weight of an antioxidant; 60.00 to 70.00 parts by weight of a filler; 2.00 to 6.00 parts by weight of a disintegrant; 0.50 to 3.00 parts by weight of an anti-adhesive; 1.50 to 3.50 parts by weight of a lubricant; and 0 to 2.50 parts by weight of an adhesive.

[0054] In some embodiments, the filler in the capsules of the present invention is optionally selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dicalcium phosphate, sorbitol, sucrose, lactitol, and maltose.

[0055] In some embodiments, the disintegrant in the capsules of the present invention is optionally selected from at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0056] In some embodiments, the anti-adhesive in the capsules of the present invention is optionally selected from at least one of colloidal silica and talc.

[0057] In some embodiments, the lubricant in the capsules of the present invention is optionally selected from at least one of magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, and glyceryl behenate.

[0058] In some embodiments, the binder in the capsules of the present invention is optionally selected from at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methylcellulose.

[0059] In some embodiments, the antioxidant in the capsules of the present invention includes at least one selected from butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0060] In some embodiments, the capsules of the present invention include, as follows: the filler comprises at least one selected from mannitol, microcrystalline cellulose and pregelatinized starch; the disintegrant is crospovidone or sodium carboxymethyl starch; the anti-adhesive is colloidal silica; and the lubricant is magnesium stearate.

[0061] In some embodiments, the capsule formulation of the present invention comprises: 13.00–58.00 or 34.00–34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 20.00–55.00 or 40.00–41.00 parts by weight of mannitol; 9.00–28.00 or 20.00–21.00 parts by weight of pregelatinized starch; 1.5 0 to 3.50 or 2.00 to 3.00 parts by weight of crospovidone; 0.50 to 2.50 or 0.50 to 1.50 parts by weight of colloidal silica; and 0.50 to 3.00 or 1.50 to 2.50 parts by weight of magnesium stearate; and at least one of the following: 0.03 to 0.20 or 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.03 to 0.10 or 0.04 to 0.06 parts by weight of butylated hydroxytoluene.

[0062] In some embodiments, the capsule formulation of the present invention comprises: 13.00 to 58.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 20.00 to 55.00 parts by weight of mannitol; 9.00 to 28.00 parts by weight of pregelatinized starch; 1.50 to 3.50 parts by weight of crospovidone; 0.50 to 2.50 parts by weight of colloidal silica; 0.50 to 3.00 parts by weight of magnesium stearate; and 0.04 to 0.06 parts by weight of butylated hydroxytoluene.

[0063] In some embodiments, the capsule formulation of the present invention comprises: 34.00 to 34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 40.00 to 41.00 parts by weight of mannitol; 20.00 to 21.00 parts by weight of pregelatinized starch; 2.00 to 3.00 parts by weight of crospovidone; 0.50 to 1.50 parts by weight of colloidal silica; and 1.50 to 2.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.04 to 0.06 parts by weight of butylated hydroxytoluene.

[0064] In some embodiments, the capsule formulation of the present invention comprises: 13.00 to 58.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 20.00 to 55.00 parts by weight of mannitol; 9.00 to 28.00 parts by weight of pregelatinized starch; 1.50 to 3.50 parts by weight of crospovidone; 0.50 to 2.50 parts by weight of colloidal silica; and 0.50 to 3.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.03 to 0.20 parts by weight of butylated hydroxyanisole; and 0.03 to 0.10 parts by weight of butylated hydroxytoluene.

[0065] In some embodiments, the capsule formulation of the present invention comprises: about 34.00 to 34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; about 40.00 to 41.00 parts by weight of mannitol; about 20.00 to 21.00 parts by weight of pregelatinized starch; about 2.00 to 3.00 parts by weight of crospovidone; about 0.50 to 1.50 parts by weight of colloidal silica; and about 1.50 to 2.50 parts by weight of magnesium stearate; and at least one selected from the following: about 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and about 0.04 to 0.06 parts by weight of butylated hydroxytoluene.

[0066] In some embodiments, the capsule formulation of the present invention comprises: 21.00–22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 43.00–47.00 parts by weight of microcrystalline cellulose; 20.00–23.00 or 21.00–23.00 parts by weight of pregelatinized starch; and 4.00–6.00 or 4.00–5.50 parts by weight of... The following are components by weight: sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.00 to 3.00 parts by weight of colloidal silica; and 2.00 to 3.50 or 2.50 to 3.50 parts by weight of magnesium stearate; and at least one of the following: 0.03 to 0.10 or 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02 to 0.10 or 0.02 to 0.05 parts by weight of butylated hydroxytoluene.

[0067] In some embodiments, the capsule formulation of the present invention comprises: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 20.00 to 23.00 parts by weight of pregelatinized starch; 4.00 to 6.00 parts by weight of sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.00 to 3.00 parts by weight of colloidal silica; and 2.00 to 3.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.03 to 0.10 parts by weight of butylated hydroxyanisole; and 0.02 to 0.10 parts by weight of butylated hydroxytoluene.

[0068] In some embodiments, the capsule formulation of the present invention comprises: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 21.00 to 23.00 parts by weight of pregelatinized starch; 4.00 to 5.50 parts by weight of sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.00 to 3.00 parts by weight of colloidal silica; and 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02 to 0.05 parts by weight of butylated hydroxytoluene.

[0069] In some embodiments, the capsule formulation of the present invention comprises: 21.82 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 22.00 parts by weight of pregelatinized starch; 4.50 to 5.00 parts by weight of sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.50 parts by weight of colloidal silica; and 3.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.05 parts by weight of butylated hydroxyanisole; and 0.03 parts by weight of butylated hydroxytoluene.

[0070] In some embodiments, the composition of the present invention is a tablet; the tablet comprises 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride, an antioxidant, a filler, a disintegrant, an anti-adhesive, a lubricant, and optionally a binder.

[0071] In some embodiments, the tablet may further include at least one of the following additional technical features:

[0072] In some embodiments, the mass ratio of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to the antioxidant in the tablets of the present invention is (6.00-22.00):(0.02-0.30).

[0073] In some embodiments, the mass ratio of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to the antioxidant in the tablets of the present invention is (9.00-22.00):(0.03-0.10).

[0074] In some embodiments, the mass ratio of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to the antioxidant in the tablets of the present invention is (9.00-22.00):(0.03-0.08).

[0075] In some embodiments, in the tablets of the present invention, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is about (12.00 to 22.00):(0.03 to 0.08).

[0076] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is about (9.00 to 13.00): (0.03 to 0.05).

[0077] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is about (12.00-13.00):(0.03-0.05).

[0078] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is about (21.00-22.00):(0.04-0.10).

[0079] In some embodiments, the mass ratio of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride to antioxidant is about (21.00-22.00):(0.05-0.08).

[0080] In some embodiments, the tablets of the present invention comprise: 6.00–22.00, 9.00–22.00, 9.00–13.00, or 12.00–22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.02–0.30, 0.03–0.10, 0.04–0.08, 0.05–0.08, or 0.03–0.05 parts by weight of an antioxidant; and 55.00–90.00, 60.00–80.00, 60.00–78.00, or 60.00– 76.00, 60.00–77.00, 65.00–77.00 or 65.00–76.00 parts by weight of filler; 0–3.50 parts by weight of adhesive; 2.00–12.00, 3.00–10.00, 4.00–9.00, 4.00–8.00, 5.0–8.00 or 6.00–8.00 parts by weight of disintegrant; 0.50–3.00 or 1.00–2.50 parts by weight of anti-adhesive; and 2.00–7.00, 2.50–6.00, 2.50–5.00 or 3.00–4.00 parts by weight of lubricant.

[0081] In some embodiments, the tablets of the present invention comprise: 6.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.02 to 0.30 parts by weight of an antioxidant; 55.00 to 90.00 parts by weight of a filler; 0 to 3.50 parts by weight of a binder; 2.00 to 12.00 parts by weight of a disintegrant; 0.50 to 3.00 parts by weight of an anti-adhesive; and 2.50 to 7.00 or 2.50 to 6.00 parts by weight of a lubricant.

[0082] In some embodiments, the tablets of the present invention comprise: about 6.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; about 0.02 to 0.10 parts by weight of an antioxidant; about 55.00 to 90.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 2.00 to 12.00 parts by weight of a disintegrant; about 0.50 to 3.00 parts by weight of an anti-adhesive; and about 2.50 to 6.00 or 2.50 to 5.00 parts by weight of a lubricant.

[0083] In some embodiments, the tablets of the present invention comprise: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; about 0.02 to 0.10 parts by weight of an antioxidant; about 60.00 to 80.00, 60.00 to 78.00, 60.00 to 76.00 or 60.00 to 77.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 3.00 to 10.00 parts by weight of a disintegrant; about 1.00 to 2.50 parts by weight of an anti-adhesive; and about 2.50 to 7.00, 2.50 to 6.00 or 3.00 to 4.00 parts by weight of a lubricant.

[0084] In some embodiments, the tablets of the present invention comprise: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; about 0.03 to 0.10 parts by weight of an antioxidant; about 60.00 to 78.00, 60.00 to 76.00 or 60.00 to 77.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 3.00 to 10.00 parts by weight of a disintegrant; about 1.00 to 2.50 parts by weight of an anti-adhesive; and about 2.50 to 6.00 or 3.00 to 4.00 parts by weight of a lubricant.

[0085] In some embodiments, the tablets of the present invention comprise: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; about 0.04 to 0.08 parts by weight of an antioxidant; about 65.00 to 76.00 or 65.00 to 77.00 parts by weight of a filler; about 0 to 3.00 parts by weight of a binder; about 4.00 to 8.00 or 5.00 to 8.00 parts by weight of a disintegrant; about 1.00 to 2.50 parts by weight of an anti-adhesive; and about 2.50 to 6.00 or 3.00 to 4.00 parts by weight of a lubricant.

[0086] In some embodiments, the tablets of the present invention comprise: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; about 0.03 to 0.05 parts by weight of an antioxidant; about 65.00 to 76.00 or 65.00 to 77.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 4.00 to 8.00 or 5.00 to 8.00 parts by weight of a disintegrant; about 1.00 to 2.50 parts by weight of an anti-adhesive; and about 2.50 to 6.00 or 3.00 to 4.00 parts by weight of a lubricant.

[0087] In some embodiments, the filler in the tablets of the present invention is optionally selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dicalcium phosphate, sorbitol, sucrose, lactitol, and maltose.

[0088] In some embodiments, the disintegrant in the tablets of the present invention is optionally selected from at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0089] In some embodiments, the anti-adhesion agent in the tablets of the present invention is optionally selected from at least one of colloidal silica and talc.

[0090] In some embodiments, the lubricant in the tablets of the present invention is optionally selected from at least one of magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, and glyceryl behenate.

[0091] In some embodiments, the binder in the tablets of the present invention is optionally selected from at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, ethylcellulose, and methylcellulose.

[0092] In some embodiments, the antioxidant in the tablets of the present invention comprises at least one selected from butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0093] In some embodiments, the tablets of the present invention include a filler comprising at least one selected from mannitol, microcrystalline cellulose, and pregelatinized starch; a binder comprising povidone or hydroxypropyl methylcellulose; a disintegrant comprising crospovidone or sodium carboxymethyl starch; an anti-adhesion agent comprising colloidal silica; and a lubricant comprising magnesium stearate or glyceryl behenate.

[0094] In some embodiments, the tablets of the present invention comprise: 9.00–13.00, 11.00–13.00, or 12.00–13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 9.00–10.50 or 9.00–10.00 parts by weight of pregelatinized starch; 60.00–70.00, 62.00–67.00, or 64.00–66.00 parts by weight of microcrystalline cellulose; and 1.00–4.00 or 2.00–3.00 parts by weight of povidone or hydroxypropyl methylcellulose. ; 4.00–12.00, 4.00–9.00, 5.00–9.00, 4.00–8.00 or 6.00–8.00 parts by weight of crospovidone; 0.50–2.50 or 1.00–2.00 parts by weight of colloidal silica; 2.50–4.50 or 3.00–4.00 parts by weight of magnesium stearate, or 5.00–7.00 parts by weight of glyceryl behenate; and selected from at least one of the following: 0.03–0.05 or 0.03–0.04 parts by weight of butylated hydroxytoluene; and 0.03–0.08 or 0.03–0.05 parts by weight of butylated hydroxyanisole.

[0095] In some embodiments, the tablets of the present invention comprise: 9.00 to 13.00 or 11.00 to 13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 9.00 to 10.50 parts by weight of pregelatinized starch; 60.00 to 70.00 parts by weight of microcrystalline cellulose; 1.00 to 4.00 parts by weight of povidone or hydroxypropyl methylcellulose; 4.00 to 12.00 parts by weight of crospovidone; 0.50 to 2.50 parts by weight of colloidal silica; 2.50 to 4.50 parts by weight of magnesium stearate, or 5.00 to 7.00 parts by weight of glyceryl behenate; and at least one selected from the following: 0.03 to 0.05 parts by weight of butylated hydroxytoluene; and 0.03 to 0.05 parts by weight of butylated hydroxyanisole.

[0096] In some embodiments, the tablets of the present invention comprise: 9.00–13.00 or 12.00–13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 9.00–10.00 parts by weight of pregelatinized starch; 64.00–66.00 or 64.00–67.00 parts by weight of microcrystalline cellulose; and 2.00–3.00 parts by weight of... The following are components: povidone or hydroxypropyl methylcellulose; 4.00 to 8.00 or 6.00 to 8.00 parts by weight of cross-linked povidone; 1.00 to 2.00 parts by weight of colloidal silica; 3.00 to 4.00 parts by weight of magnesium stearate, or 5.00 to 7.00 parts by weight of glyceryl behenate; and at least one of the following: 0.03 to 0.04 parts by weight of butylated hydroxytoluene; and 0.03 to 0.05 parts by weight of butylated hydroxyanisole.

[0097] In some embodiments, the tablets of the present invention comprise: 21.00–22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 20.00–25.00 or 23.00–24.00 parts by weight of pregelatinized starch; 40.00–50.00 or 43.00–47.00 parts by weight of microcrystalline cellulose; and 0–3.00 or 0–2.00 parts by weight of... Hydroxypropyl methylcellulose; 4.00–5.50 or 4.50–5.00 parts by weight of sodium carboxymethyl starch; 2.00–3.00 parts by weight of colloidal silica; and 2.00–4.00 or 2.50–3.50 parts by weight of magnesium stearate; and at least one of the following: 0.04–0.08 or 0.04–0.06 parts by weight of butylated hydroxyanisole; and 0.02–0.05 or 0.02–0.04 parts by weight of butylated hydroxytoluene.

[0098] In some embodiments, the tablets of the present invention comprise: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 20.00 to 25.00 parts by weight of pregelatinized starch; 40.00 to 50.00 parts by weight of microcrystalline cellulose; 0 to 3.00 parts by weight of hydroxypropyl methylcellulose; 4.00 to 5.50 parts by weight of sodium carboxymethyl starch; 2.00 to 3.00 parts by weight of colloidal silica; and 2.00 to 4.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.04 to 0.08 parts by weight of butylated hydroxyanisole; and 0.02 to 0.05 parts by weight of butylated hydroxytoluene.

[0099] In some embodiments, the tablets of the present invention comprise: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 23.00 to 24.00 parts by weight of pregelatinized starch; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 4.50 to 5.00 parts by weight of sodium carboxymethyl starch; 2.00 to 3.00 parts by weight of colloidal silica; and 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02 to 0.04 parts by weight of butylated hydroxytoluene.

[0100] In some embodiments, the tablet further comprises a coating material; optionally, the coating material is a film-coating premix.

[0101] In some embodiments, the coating material is 2.0% to 4.0% of the weight of the uncoated tablet.

[0102] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Detailed Implementation

[0103] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0104] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0105] Detailed description of the invention

[0106] Definitions and General Terms

[0107] Before describing the invention in more detail, it should be understood that the invention is not limited to the specific embodiments described herein, as such embodiments can vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications and patents referenced herein are incorporated herein by reference in their entirety.

[0108] In the context of this invention, all figures disclosed herein are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, or 10%, etc. Whenever a figure with a value of N is disclosed, any figure having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction. Whenever a lower limit (DL) and an upper limit (DU) of a numerical range are disclosed, any value within that disclosed range is explicitly disclosed.

[0109] Where numerical ranges are provided, it should be understood that, unless the context clearly indicates otherwise, interpolated values ​​between the upper and lower limits of the range, and any other stated or interpolated values ​​within the range, are covered within the invention, up to one-tenth of the upper and lower limits. The upper and lower limits of these smaller ranges may be independently included within the smaller range and are also covered within the invention, subject to any specific exclusion restrictions within the range. Where the range includes one or both of the limits, ranges excluding any one or both of the limits are also included in the invention.

[0110] Certain ranges of values ​​previously referred to by the term "about" are provided herein. The term "about" is used herein to provide textual support for precise numerical values ​​and values ​​that are close to or approximate the value preceding the term. In determining whether a numerical value is close to or approximates a specifically stated numerical value, the close or approximate unstated numerical value can be a value that, in the context in which it is provided, provides a substantial equivalent to the specifically stated numerical value. The term "about" or "approximately" refers to an acceptable error for a particular value as determined by those skilled in the art, depending in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0111] The terms “optionally,” “optionally,” or “optionally” mean that the event or condition described below may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur. For example, the composition of the present invention contains an optional adhesive, meaning that the composition may or may not contain an adhesive.

[0112] The term "pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutical acceptable" as used herein means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0113] The term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in Berge et al., "describe pharmaceutically acceptable salts in detail" in J. Pharmacol Sci, 1997, 66, 1-19. In some embodiments, the pharmaceutically acceptable salts of this invention include, but are not limited to, hydrochloride salts, benzenesulfonates, p-toluenesulfonates, sulfates, hydrobromates, etc. Preferably, the pharmaceutically acceptable salts of this invention are hydrochloride salts.

[0114] For reference on these and other pharmaceutically acceptable excipients or processes mentioned in this article, please refer to the extensive literature on the subject, specifically Handbook of Pharmaceutical Excipients, 3rd edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete, edited by HP Fiedler, 4th edition, edited by Cantor, Aulendorf and earlier editions.

[0115] The compositions or formulations provided by this invention can be administered to a patient alone, or co-administered or combined with other active agents. The terms "co-administered" and "combined" include the simultaneous or sequential administration of two or more therapeutic agents without a specific time limit. In one embodiment, the agents are simultaneously present in cells or within an individual, or exert biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in different compositions or unit dosage forms. In some implementations, the first agent is administered before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the second therapeutic agent.

[0116] The term "active ingredient" or "active agent" refers to a substance intended for treatment (e.g., human treatment, veterinary treatment) (including preventative and therapeutic treatment). Active ingredients include any substance used as a medicine to treat, prevent, delay, alleviate, or improve a disease, symptom, or disorder.

[0117] The term "oral preparation" refers to a form of drug that is administered orally and absorbed into the bloodstream through the gastrointestinal tract, including tablets, granules, capsules, oral solutions, etc.

[0118] The term "solid oral dosage form" refers to tablets, dispersible tablets, instant-dissolving tablets, fast-dissolving tablets, quick-melting tablets, orally dissolving tablets, orally dispersible tablets, lyophilized units, porous tablets, conventional tablets, coated tablets, uncoated tablets, enteric-coated tablets (gastro-resistant tablets), effervescent tablets, soluble tablets, chewable tablets, oral lyophilized products, powders, oral powders, pills, capsules, and / or granules. In some embodiments, the solid oral dosage form is a capsule. In some embodiments, the solid oral dosage form is a tablet.

[0119] The term "parts by weight" refers to the number of parts by weight obtained by comparing the mass of a certain component of the composition with the mass of other components. For example, the antioxidant content of 0.01 to 0.40 parts by weight means that the antioxidant content is 0.01 to 0.40 parts by weight after comparing the mass of the antioxidant with the mass of other components of the composition.

[0120] In formulation preparation, the weight data of each component may be amplified, omitted, or substituted proportionally. In this invention, the weight data of each component may be extended based on the metric relationship between their molecular weight or mass, either to specific values ​​or decimal places, or to different decimal places. This extension may include, but is not limited to, further analogy based on rounding rules within a pharmaceutically understandable range or in the case of scientific counting. For example, if the content of the filler is 80.00 parts by weight, this content is equivalent to or interchangeable with contents of 79.95 parts by weight, 80.01 parts by weight, 80.35 parts by weight, etc., and other components can be analogized accordingly.

[0121] The term "antioxidant enhancer" refers to an agent that inhibits the formation of free radicals and enhances the effects of other antioxidant systems.

[0122] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0123] Composition

[0124] In one aspect of the invention, a composition is provided that has anti-fibrotic activity and can be used to treat fibrotic diseases such as liver fibrosis and pulmonary fibrosis such as idiopathic pulmonary fibrosis. In some embodiments, the composition comprises 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (the compound shown in formula (I)) or a pharmaceutically acceptable salt thereof, and an antioxidant.

[0125] In some embodiments, the composition uses 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, such as hydrochloride, as the active ingredient. Through extensive testing, the inventors have found that combining the active ingredient with an antioxidant effectively overcomes the problem of decreased composition stability. This composition effectively reduces impurity formation during storage and has advantages such as easy storage, stable and controllable quality, and high bioavailability. Furthermore, the inventors have also found that the composition prepared according to this invention has strong efficacy, high safety, and good patient compliance.

[0126] In some embodiments, a pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is its hydrochloride salt. The compositions of the present invention comprise the hydrochloride salt of the compound represented by formula (I) as the active ingredient.

[0127]

[0128] In some embodiments, the antioxidants of the present invention include, but are not limited to, antioxidants that react with free radicals and / or antioxidant synergists.

[0129] In some embodiments, the antioxidant described in this invention is a free radical reactive antioxidant; optionally, the free radical reactive antioxidant may be selected from at least one of butylated hydroxyanisole, butylated hydroxytoluene (also known as dibutylhydroxytoluene), and propyl gallate. Free radical reactive antioxidants are a class of antioxidants capable of reacting with free radicals, which can block the chain reaction of the oxidation process. The inventors have found through extensive experimentation that the use of this type of antioxidant is more effective.

[0130] In some embodiments, the composition of the present invention is an oral formulation.

[0131] In some embodiments, the compositions of the present invention are oral solid dosage forms. Oral solid dosage forms containing compounds of formula (I) or pharmaceutically acceptable salts thereof and antioxidants exhibit good stability. Optionally, the oral solid dosage forms of the present invention are capsules or tablets.

[0132] In some embodiments, the compositions of the present invention are capsules or tablets. The stability is further enhanced when the compound of formula (I) or its pharmaceutically acceptable salts and antioxidants are formulated into capsules and / or tablets.

[0133] In some embodiments, the composition of the present invention contains a suitable amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The suitable amount is an effective dose of the compound, which is safe and effective. Preferably, the content of the compound represented by formula (I) in the composition may be 4.00 to 70.00 parts by weight; optionally, the content of the compound represented by formula (I) in the composition may be 4.50 to 67.00 parts by weight; optionally, the content of the compound represented by formula (I) in the composition may be 20.00 to 32.00 parts by weight; optionally, the content of the compound represented by formula (I) in the composition may be 8.00 to 32.00 parts by weight; optionally, the content of the compound represented by formula (I) in the composition may be 11.00 to 32.00 parts by weight; optionally, the content of the compound represented by formula (I) in the composition may be 8.00 to 20.00 parts by weight; optionally, the content of the compound represented by formula (I) in the composition may be 11.00 to 20.00 parts by weight. Optionally, when the active ingredient in the composition is a pharmaceutically acceptable salt of the compound of formula (I), the content of the salt can be calculated based on the ratio of the molecular weight of the free compound to that of the corresponding salt.

[0134] In some embodiments, the compositions of the present invention use a pharmaceutically acceptable salt of the compound shown in formula (I) as the active ingredient. Preferably, the compositions of the present invention may use the hydrochloride salt of the compound shown in formula (I) as the active ingredient.

[0135] In some embodiments, the composition of the present invention contains 5.00 to 73.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); optionally, the hydrochloride salt content of the compound represented by formula (I) is about 6.00 to 58.00 parts by weight; optionally, the hydrochloride salt content of the compound represented by formula (I) is about 9.00 to 58.00 parts by weight; optionally, the hydrochloride salt content of the compound represented by formula (I) is about 11.00 to 58.00 parts by weight; optionally... Optionally, the content of the hydrochloride salt of the compound shown in formula (I) is about 12.00 to 58.00 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is about 13.00 to 58.00 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is about 9.00 to 35.00 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is about 12.00 to 35.00 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is about 12.00 to 35.00 parts by weight. The content of hydrochloride is about 6.00 to 22.00 parts by weight; optionally, the content of hydrochloride of the compound shown in formula (I) is about 9.00 to 22.00 parts by weight; optionally, the content of hydrochloride of the compound shown in formula (I) is about 21.00 to 35.00 parts by weight; optionally, the content of hydrochloride of the compound shown in formula (I) is about 12.0 to 22.0 parts by weight; optionally, the content of hydrochloride of the compound shown in formula (I) is 12.12 to 34 parts by weight. 0.9 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is 12.12 to 21.82 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is 21.82 to 34.09 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is about 9, 12, 22 or 34 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in formula (I) is 9.09, 12.12, 21.82 or 34.09 parts by weight.

[0136] In some embodiments, the composition contains 0.01 to 0.40 parts by weight of antioxidant; optionally, the antioxidant content is 0.02 to 0.40 parts by weight; optionally, the antioxidant content is 0.01 to 0.30 parts by weight; optionally, the antioxidant content is 0.01 to 0.20 parts by weight; optionally, the antioxidant content is 0.02 to 0.30 parts by weight; optionally, the antioxidant content is 0.03 to 0.30 parts by weight; optionally, the antioxidant content is 0.03 to 0.20 parts by weight; optionally, the antioxidant content is 0.03 to 0.10 parts by weight; optionally, the antioxidant content is... The antioxidant content is 0.05 to 0.20 parts by weight; optionally, the antioxidant content is 0.08 to 0.30 parts by weight; optionally, the antioxidant content is 0.08 to 0.20 parts by weight; optionally, the antioxidant content is 0.08 to 0.10 parts by weight; optionally, the antioxidant content is 0.04 to 0.30 parts by weight; optionally, the antioxidant content is 0.03 to 0.08 parts by weight; optionally, the antioxidant content is 0.03 to 0.05 parts by weight; optionally, the antioxidant content is 0.04 to 0.05 parts by weight; optionally, the antioxidant content is 0.05 to 0.08 parts by weight.

[0137] Through extensive experiments, the inventors discovered that controlling the antioxidant content to 0.01–0.4 parts by weight, especially 0.03–0.10 parts by weight, can effectively reduce the amount and rate of impurity formation during the storage of the composition, improve the stability of the composition, and facilitate its storage.

[0138] In some embodiments, the composition further includes pharmaceutically acceptable excipients. The addition of excipients can further improve the stability of the composition.

[0139] In some embodiments, the excipients of the present invention include at least one selected from fillers, disintegrants, binders, anti-adhesives, and lubricants. The addition of excipients of the above types can further improve the stability of the composition.

[0140] In some embodiments, the filler of the present invention may be selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dicalcium phosphate, sorbitol, sucrose, lactitol and maltose.

[0141] In some embodiments, the disintegrant of the present invention may be selected from at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0142] In some embodiments, the anti-adhesion agent of the present invention may be selected from at least one of colloidal silica and talc.

[0143] In some embodiments, the lubricant of the present invention may be selected from at least one of magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, and glyceryl behenate.

[0144] In some embodiments, the adhesive of the present invention may be selected from at least one of povidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methyl cellulose.

[0145] In some embodiments, the filler content in the composition of the present invention is 22.00 to 91.00 parts by weight. Optionally, the filler content is 22.50 to 91.00 parts by weight; optionally, the filler content is about 29.00 to 82.00 parts by weight; optionally, the filler content is about 55.00 to 90.00 parts by weight; optionally, the filler content is about 55.00 to 82.00 parts by weight; optionally, the filler content is about 70.00 to 76.00 parts by weight; optionally, the filler content is about 65.00 to 77.00 parts by weight; optionally, the filler content is about 65.00 to 76.00 parts by weight; optionally, the filler content is about 60.00 to 77.00 parts by weight; optionally, the filler content is 60.00 to 76.00 parts by weight; optionally, the filler content is about 60.00 to 69.00 parts by weight.

[0146] In some embodiments, the content of the anti-adhesion agent of the present invention is 0.50 to 3.50 parts by weight. Optionally, the content of the anti-adhesion agent is 0.50 to 2.50 parts by weight; optionally, the content of the anti-adhesion agent is 0.50 to 1.50 parts by weight; optionally, the content of the anti-adhesion agent is 1.00 to 2.50 parts by weight; optionally, the content of the anti-adhesion agent is 1.00 to 2.00 parts by weight.

[0147] In some embodiments, the content of the disintegrant of the present invention is 0.50 to 16.00 parts by weight. Optionally, the content of the disintegrant is 1.50 to 12.00 parts by weight; optionally, the content of the disintegrant is 2.00 to 10.00 parts by weight; optionally, the content of the disintegrant is 3.00 to 10.00 parts by weight; optionally, the content of the disintegrant is 0.50 to 6.00 parts by weight; optionally, the content of the disintegrant is 1.50 to 6.00 parts by weight; optionally, the content of the disintegrant is 2.50 to 5.00 parts by weight; optionally, the content of the disintegrant is 4.00 to 9.00 parts by weight; optionally, the content of the disintegrant is 4.00 to 8.00 parts by weight; optionally, the content of the disintegrant is 1.50 to 3.50 parts by weight; optionally, the content of the disintegrant is 2.50 to 6.00 parts by weight; optionally, the content of the disintegrant is 2.50 to 8.00 parts by weight.

[0148] In some embodiments, the lubricant of the present invention comprises 0.50 to 7.00 parts by weight. Optionally, the lubricant comprises 0.50 to 5.00 parts by weight; optionally, the lubricant comprises 1.00 to 7.00 parts by weight; optionally, the lubricant comprises 1.00 to 6.00 parts by weight; optionally, the lubricant comprises 1.00 to 5.00 parts by weight; optionally, the lubricant comprises 2.00 to 7.00 parts by weight; optionally, the lubricant comprises 2.00 to 6.00 parts by weight; optionally, the lubricant comprises... 2.00 to 4.00 parts by weight; optionally, the content of the lubricant is 2.00 to 3.00 parts by weight; optionally, the content of the lubricant is 3.00 to 6.00 parts by weight; optionally, the content of the lubricant is 3.00 to 4.00 parts by weight; optionally, the content of the lubricant is 2.00 to 3.50 parts by weight; optionally, the content of the lubricant is 2.00 to 4.00 parts by weight; optionally, the content of the lubricant is 5.00 to 7.00 parts by weight.

[0149] In some embodiments, the adhesive content of the present invention is 0 to 3.50 parts by weight. Optionally, the adhesive content is 0 to 3.00 parts by weight; optionally, the adhesive content is 0 to 2.50 parts by weight; optionally, the adhesive content is 0 to 2.00 parts by weight; optionally, the adhesive content is 2.00 to 3.00 parts by weight; optionally, the adhesive content is 2.50 parts by weight.

[0150] Capsules

[0151] In another aspect of the invention, a capsule is provided. In some embodiments, the capsule comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, an antioxidant, a filler, a disintegrant, an anti-adhesive, a lubricant, and optionally a binder. The term "optional binder" means that the capsule may or may not contain a binder.

[0152] Through extensive experimentation, the inventors discovered that capsules prepared using the above formula have fewer impurities and better dissolution during storage, and can also improve the stability and safety of the capsules.

[0153] In some embodiments, the mass ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the antioxidant in the capsules of this invention is approximately (4.00–77.00):(0.01–0.40). The inventors have found through experiments that using the above ratio can reduce the amount and rate of impurity formation during capsule storage, improve the stability of the capsules, and facilitate capsule storage.

[0154] In some embodiments, the active ingredient in the capsules of the present invention is the hydrochloride salt of the compound shown in formula (I).

[0155] In some embodiments, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant in the capsules of this invention is (5.00–73.00):(0.01–0.40). Through extensive testing, the inventors have found that capsules prepared within the above ratio range exhibit low impurity content and high stability during storage.

[0156] In some embodiments, in the capsules of the present invention, the mass ratio of the hydrochloride salt of the compound represented by formula (I) to the antioxidant is (13.00–58.00):(0.03–0.30); optionally, the mass ratio of the hydrochloride salt of the compound represented by formula (I) to the antioxidant is (21.00–35.00):(0.03–0.10); optionally, the mass ratio of the hydrochloride salt of the compound represented by formula (I) to the antioxidant is (21.00–35.00):(0.03–0.10). 3~0.80); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is (21.00~35.00):(0.05~0.80); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is (21.00~22.00):(0.05~0.08); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is (34.00~35.00):(0.05~0.08).

[0157] In some embodiments, the capsules of the present invention comprise: 5.00–73.00 or 21.00–35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.01–0.40, 0.02–0.10 or 0.04–0.09 parts by weight of an antioxidant; 22.50–90.50 parts by weight of a filler; 0.50–6.00 or 2.00–6.00 parts by weight of a disintegrant; 0.50–3.50 parts by weight of an anti-adhesive; 0.50–3.50 parts by weight of a lubricant; and 0–2.50 parts by weight of an adhesive.

[0158] In some embodiments, the capsules of the present invention comprise: 5.00 to 73.00 parts by weight of the hydrochloride salt of the compound of formula (I); 0.01 to 0.40 parts by weight of an antioxidant; 22.50 to 90.50 parts by weight of a filler; 0.50 to 6.00 parts by weight of a disintegrant; 0.50 to 3.50 parts by weight of an anti-adhesive; 0.50 to 3.50 parts by weight of a lubricant; and / or 0 to 2.50 parts by weight of a binder.

[0159] In some embodiments, the antioxidant in the capsules of the present invention is a free radical reactive antioxidant; optionally, the free radical reactive antioxidant may be selected from at least one of butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0160] Through extensive experimentation, the inventors discovered that capsules prepared using the above formula have fewer impurities and better dissolution during storage, and can also improve the stability and safety of the capsules.

[0161] In some embodiments, the filler in the capsules of the present invention is optionally selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dicalcium phosphate, sorbitol, sucrose, lactitol, and maltose.

[0162] In some embodiments, the disintegrant in the capsules of the present invention is optionally selected from at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0163] In some embodiments, the anti-adhesive in the capsules of the present invention is optionally selected from at least one of colloidal silica and talc.

[0164] In some embodiments, the lubricant in the capsules of the present invention is optionally selected from at least one of magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, and glyceryl behenate.

[0165] In some embodiments, the binder in the capsules of the present invention is optionally selected from at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methylcellulose.

[0166] In some embodiments, the antioxidant in the capsules of this invention is butylated hydroxyanisole, butylated hydroxytoluene, and / or propyl gallate; the filler is mannitol, microcrystalline cellulose, and / or pregelatinized starch; the disintegrant is crospovidone or sodium carboxymethyl starch; the anti-adhesive is colloidal silica; and the lubricant is magnesium stearate. The inventors have found through experiments that capsules made from the above-mentioned raw materials have fewer impurities generated during storage and possess advantages such as easy storage and good stability.

[0167] In some embodiments, the capsules of the present invention comprise: 13.00 to 58.00 parts by weight of the hydrochloride salt of the compound of formula (I); 20.00 to 55.00 parts by weight of mannitol; 9.00 to 28.00 parts by weight of pregelatinized starch; 1.50 to 3.50 parts by weight of crospovidone; 0.50 to 1.50 parts by weight of colloidal silica; and 0.50 to 2.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.05 to 0.20 parts by weight of butylated hydroxyanisole; and 0.03 to 0.10 parts by weight of butylated hydroxytoluene.

[0168] In some embodiments, the capsule comprises: about 34.00 to 34.50 parts by weight of the hydrochloride salt of the compound of formula (I); about 40.00 to 41.00 parts by weight of mannitol; about 20.00 to 21.00 parts by weight of pregelatinized starch; about 2.00 to 2.50 parts by weight of crospovidone; about 1.00 to 1.50 parts by weight of colloidal silica; and about 1.50 to 2.00 parts by weight of magnesium stearate; and at least one selected from the following: about 0.05 to 0.20 parts by weight of butylated hydroxyanisole; and about 0.03 to 0.10 parts by weight of butylated hydroxytoluene.

[0169] In some embodiments, the capsule comprises: 21.00 to 22.00 parts by weight of the hydrochloride salt of the compound of formula (I); 43.00 to 47.00 parts by weight of microcrystalline cellulose; 20.00 to 22.00 parts by weight of pregelatinized starch; 4.00 to 5.00 parts by weight of sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.00 to 3.00 parts by weight of colloidal silica; and 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the group consisting of: 0.05 parts by weight of butylated hydroxyanisole; and 0.03 to 0.05 parts by weight of butylated hydroxytoluene.

[0170] In some embodiments, the capsule comprises: 21.82 parts by weight of the hydrochloride salt of the compound of formula (I); 43.00 to 47.00 parts by weight of microcrystalline cellulose; 22.00 parts by weight of pregelatinized starch; 4.50 parts by weight of sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.50 parts by weight of colloidal silica; and 3.00 parts by weight of magnesium stearate; and at least one selected from the group consisting of: 0.05 parts by weight of butylated hydroxyanisole; and 0.03 to 0.05 parts by weight of butylated hydroxytoluene.

[0171] Through numerous experiments, the inventors discovered that the capsules prepared using the above formula have good stability.

[0172] Furthermore, those skilled in the art will understand that the features and advantages described above for the composition also apply to the capsule formulation, and will not be repeated here.

[0173] tablet

[0174] In another aspect of the invention, a tablet is provided. In some embodiments, the composition is a tablet, wherein the tablet comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, an antioxidant, a filler, a disintegrant, an anti-adhesive, a lubricant, and optionally a binder.

[0175] Through extensive testing, the inventors discovered that tablets prepared using the above formula have lower impurity content and better dissolution during storage, and can improve the stability and safety of the tablets.

[0176] In some embodiments, the mass ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the antioxidant in the tablets of this invention is (6.00–22.00):(0.02–0.30). Through extensive experimentation, the inventors have found that using the above ratio can reduce the amount and rate of impurity formation during tablet storage, improve tablet stability, and facilitate tablet storage.

[0177] In some embodiments, the tablets of the present invention use the hydrochloride salt of the compound shown in formula (I) as the active ingredient. Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is (6.00–22.00):(0.02–0.30). Through extensive testing, the inventors have found that tablets prepared using the above ratio have low impurity content and high stability during storage.

[0178] In some embodiments, in the tablets of the present invention, the mass ratio of the hydrochloride salt of the compound represented by formula (I) to the antioxidant is about (9.00–22.00):(0.03–0.10); optionally, the mass ratio of the hydrochloride salt of the compound represented by formula (I) to the antioxidant is about (9.00–22.00):(0.03–0.08); optionally, the mass ratio of the hydrochloride salt of the compound represented by formula (I) to the antioxidant is about (12.00–22.00):(0.03–0.08); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (9.00–22.00):(0.03–0.05); optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (9.00–13.00):(0.03–0.05); optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (12.00–13.00):(0.03–0.05); optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (12.00–13.00):(0.03–0.05); optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (9.00–22.00):(0.03–0.05). The mass ratio of the salt to the antioxidant is about (12.00–22.00):(0.04–0.08); optionally, the mass ratio of the hydrochloride salt to the antioxidant of the compound shown in formula (I) is about (21.00–22.00):(0.04–0.10); optionally, the mass ratio of the hydrochloride salt to the antioxidant of the compound shown in formula (I) is about (21.00–22.00):(0.03–0.08); optionally, the mass ratio of the hydrochloride salt to the antioxidant of the compound shown in formula (I) is about ( 21.00~22.00):(0.05~0.08); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (21.00~22.00):(0.03~0.05); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (9.00~22.00):(0.04); Optionally, the mass ratio of the hydrochloride salt of the compound shown in formula (I) to the antioxidant is about (12.00~22.00):(0.04).

[0179] In some embodiments, the tablets of the present invention comprise: 6.00–22.00, 9.00–22.00, 9.00–13.00, or 12.00–22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 0.02–0.30, 0.03–0.10, 0.03–0.08, 0.04–0.08, 0.05–0.08, or 0.03–0.05 parts by weight of an antioxidant; and 55.00–90.00, 60.00–80.00, 60.00–78.00, or 6... 0.00–76.00, 60.00–77.00, 65.00–77.00 or 65.00–76.00 parts by weight of filler; 0–3.50 parts by weight of adhesive; 2.00–12.00, 3.00–10.00, 4.00–9.00, 4.00–8.00, 5.0–8.00 or 6.00–8.00 parts by weight of disintegrant; 0.50–3.00 or 1.00–2.50 parts by weight of anti-adhesive; and 2.00–7.00, 2.50–6.00, 2.50–5.00 or 3.00–4.00 parts by weight of lubricant.

[0180] In some embodiments, the tablets of the present invention comprise: about 6.00 to 22.00 parts by weight of the hydrochloride salt of the compound of formula (I); about 0.02 to 0.10 parts by weight of an antioxidant; about 55.00 to 90.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 2.00 to 12.00 parts by weight of a disintegrant; about 0.50 to 3.00 parts by weight of an anti-adhesive; and about 2.50 to 7.00 parts by weight of a lubricant.

[0181] In some embodiments, the tablets of the present invention comprise: about 6.00 to 22.00 parts by weight of the hydrochloride salt of the compound of formula (I); about 0.02 to 0.30 parts by weight of an antioxidant; about 55.00 to 90.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 2.00 to 12.00 parts by weight of a disintegrant; about 0.50 to 3.00 parts by weight of an anti-adhesive; and about 2.50 to 7.00, 2.50 to 6.00, or 2.50 to 5.00 parts by weight of a lubricant.

[0182] In some embodiments, the tablets of the present invention comprise: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; about 0.02 to 0.10 parts by weight of an antioxidant; about 60.00 to 80.00, 60.00 to 78.00, 60.00 to 76.00 or 60.00 to 77.00 parts by weight of a filler; about 0 to 3.50 parts by weight of a binder; about 3.00 to 10.00 parts by weight of a disintegrant; about 1.00 to 2.50 parts by weight of an anti-adhesive; and about 2.50 to 7.00, 2.50 to 6.00 or 3.00 to 4.00 parts by weight of a lubricant.

[0183] In some embodiments, the tablets of the present invention comprise: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; about 0.04 to 0.08 parts by weight of an antioxidant; about 65.00 to 76.00 or 65.00 to 77.00 parts by weight of a filler; about 0 to 3.00 parts by weight of a binder; about 4.00 to 8.00 or 5.00 to 8.00 parts by weight of a disintegrant; about 1.00 to 2.50 parts by weight of an anti-adhesive; and about 2.50 to 6.00 or 3.00 to 4.00 parts by weight of a lubricant.

[0184] In some embodiments, the antioxidant of the present invention is a free radical reactive antioxidant; optionally, the free radical reactive antioxidant may be selected from at least one of butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0185] Through extensive testing, the inventors discovered that tablets prepared using the above formula have lower impurity content and better dissolution during storage, and can improve the stability and safety of the tablets.

[0186] In some embodiments, the filler of the present invention is optionally selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dicalcium phosphate, sorbitol, sucrose, lactitol and maltose.

[0187] In some embodiments, the disintegrant of the present invention is optionally selected from at least one of crospovidone, sodium carboxymethyl starch, sodium crospovidone carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0188] In some embodiments, the anti-adhesion agent of the present invention is optionally selected from at least one of colloidal silica and talc.

[0189] In some embodiments, the lubricant of the present invention is optionally selected from at least one of magnesium stearate, sodium stearate fumarate, stearic acid, calcium stearate, and glyceryl behenate.

[0190] In some embodiments, the adhesive of the present invention is optionally selected from at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methylcellulose.

[0191] In some embodiments, the antioxidant of the present invention includes at least one selected from butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate; the filler includes at least one selected from mannitol, microcrystalline cellulose, and pregelatinized starch; the binder is povidone or hydroxypropyl methylcellulose; the disintegrant is crospovidone or sodium carboxymethyl starch; the anti-adhesive is colloidal silica; and the lubricant is magnesium stearate. Through extensive experiments, the inventors have found that tablets made from the above-mentioned raw materials exhibit low impurity formation during storage and possess advantages such as easy storage and good stability.

[0192] In some embodiments, the tablets of the present invention comprise: 9.00–13.00, 11.00–13.00, or 12.00–13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride; 9.00–10.50 or 9.00–10.00 parts by weight of pregelatinized starch; 60.00–70.00, 62.00–67.00, or 64.00–66.00 parts by weight of microcrystalline cellulose; and 1.00–4.00 or 2.00–3.00 parts by weight of povidone or hydroxypropyl methylcellulose. ; 4.00–12.00, 4.00–9.00, 5.00–9.00, 4.00–8.00 or 6.00–8.00 parts by weight of crospovidone; 0.50–2.50 or 1.00–2.00 parts by weight of colloidal silica; 2.50–4.50 or 3.00–4.00 parts by weight of magnesium stearate, or 5.00–7.00 parts by weight of glyceryl behenate; and selected from at least one of the following: 0.03–0.05 or 0.03–0.04 parts by weight of butylated hydroxytoluene; and 0.03–0.08 or 0.03–0.05 parts by weight of butylated hydroxyanisole.

[0193] In some embodiments, the tablets of the present invention comprise: 9.00 to 13.00 or 11.00 to 13.00 parts by weight of the hydrochloride of the compound of formula (I); 9.00 to 10.50 parts by weight of pregelatinized starch; 60.00 to 70.00 parts by weight of microcrystalline cellulose; 1.00 to 4.00 parts by weight of povidone or hydroxypropyl methylcellulose; 4.00 to 12.00 parts by weight of crospovidone; 0.50 to 2.50 parts by weight of colloidal silica; 3.50 to 4.50 parts by weight of magnesium stearate, or 5.00 to 7.00 parts by weight of glyceryl behenate; and at least one selected from the following: 0.03 to 0.05 parts by weight of butylated hydroxytoluene; and 0.03 to 0.05 parts by weight of butylated hydroxyanisole.

[0194] In some embodiments, the tablets of the present invention comprise: 9.00 to 13.00 or 12.00 to 13.00 parts by weight of the hydrochloride of the compound of formula (I); 9.00 to 10.00 parts by weight of pregelatinized starch; 64.00 to 67.00 or 64.00 to 66.00 parts by weight of microcrystalline cellulose; 2.00 to 3.00 parts by weight of povidone or hydroxypropyl methylcellulose; 4.00 to 8.00 or 6.00 to 8.00 parts by weight of crospovidone; 1.00 to 2.00 parts by weight of colloidal silica; and 3.00 to 4.00 parts by weight of magnesium stearate, or 5.00 to 7.00 parts by weight of glyceryl behenate; and at least one selected from: 0.03 to 0.04 parts by weight of butylated hydroxytoluene; and 0.03 to 0.05 parts by weight of butylated hydroxyanisole.

[0195] In some embodiments, the tablets of the present invention comprise: 21.00–22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)-one hydrochloride; 20.00–25.00 or 23.00–24.00 parts by weight of pregelatinized starch; 40.00–50.00 or 43.00–47.00 parts by weight of microcrystalline cellulose; and 0–3.00 or 0–2.00 parts by weight of... Hydroxypropyl methylcellulose; 4.00–5.50 or 4.50–5.00 parts by weight of sodium carboxymethyl starch; 2.00–3.00 parts by weight of colloidal silica; and 2.00–4.00 or 2.50–3.50 parts by weight of magnesium stearate; and at least one of the following: 0.04–0.08 or 0.04–0.06 parts by weight of butylated hydroxyanisole; and 0.02–0.05 or 0.02–0.04 parts by weight of butylated hydroxytoluene.

[0196] In some embodiments, the tablets of the present invention comprise: 21.00 to 22.00 parts by weight of the hydrochloride salt of the compound of formula (I); 20.00 to 25.00 parts by weight of pregelatinized starch; 40.00 to 50.00 parts by weight of microcrystalline cellulose; 0 to 3.00 parts by weight of hydroxypropyl methylcellulose; 4.00 to 5.50 parts by weight of sodium carboxymethyl starch; 2.00 to 3.00 parts by weight of colloidal silica; and 2.00 to 4.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.04 to 0.08 parts by weight of butylated hydroxyanisole; and 0.02 to 0.05 parts by weight of butylated hydroxytoluene.

[0197] In some embodiments, the tablets of the present invention comprise: 21.00 to 22.00 parts by weight of the hydrochloride salt of the compound shown in formula (I); 23.00 to 24.00 parts by weight of pregelatinized starch; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 4.50 to 5.00 parts by weight of sodium carboxymethyl starch; 2.00 to 3.00 parts by weight of colloidal silica; and 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02 to 0.04 parts by weight of butylated hydroxytoluene. Through extensive experimentation, the inventors have found that tablets prepared using the above formulation can further improve tablet stability and efficacy.

[0198] In some embodiments, the tablet further comprises a coating material; optionally, the weight of the coating material is 2.00 to 4.00% of the weight of the uncoated tablet. The uncoated tablet refers to the total substance in the tablet encapsulated within the coating material.

[0199] Furthermore, those skilled in the art will understand that the features and advantages described above for the composition also apply to the tablet, and will not be repeated here.

[0200] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or in accordance with the product manual.

[0201] The impurity content of the samples in the various embodiments or comparative examples of this invention was determined by high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia 2020), as detailed below:

[0202] Test solution: Take the test sample (e.g., the capsules, tablets or the reference standard in the comparative examples of the present invention), extract with methanol and dilute to prepare a solution containing about 2.5 mg of the compound of formula (I) per 1 mL (for tablets, a small amount of water should be added to disintegrate them before extraction), and then dilute with 60% methanol-water to prepare a solution containing about 1 mg of the compound of formula (I) per 1 mL.

[0203] Reference solution: Weigh an appropriate amount of reference standard (such as the hydrochloride salt of the compound shown in formula (I) accurately, dissolve and dilute it with 60% methanol-water to prepare a solution containing about 5 μg of the compound shown in formula (I) per 1 mL.

[0204] Sensitivity solution: Accurately measure an appropriate amount of the reference solution and dilute it quantitatively with 60% methanol-water to prepare a solution containing approximately 0.5 μg of the compound shown in formula (I) per 1 mL.

[0205] System suitability solution: Weigh an appropriate amount of reference standard (such as the hydrochloride salt of the compound shown in formula (I), dissolve and dilute it in 60% methanol-water to prepare a solution containing approximately 1 mg of the compound shown in formula (I) per 1 mL.

[0206] Chromatographic conditions: Use a column packed with octylsilane-bonded silica gel (such as Phenomenex Kinetex C8100A, 4.6×100mm, 2.6μm or equivalent column); use 0.01mol / L ammonium acetate-acetonitrile (9:1) as mobile phase A and methanol-acetonitrile (75:25) as mobile phase B, and perform gradient elution according to the program in the table below. The detection wavelength is 266nm and the injection volume is 10μL.

[0207] Time (min) Mobile phase A Mobile phase B 0 42 58 6 33 67 25 33 67 35 13 87 50 13 87 50.5 42 58 55 42 58

[0208] Calculation: The principal component external standard plus correction factor method was used for calculation.

[0209] Acceptable standard: If there are impurity peaks in the chromatogram of the test solution, the total impurities shall not exceed 1.5%.

[0210] Taking the hydrochloride crystal form I of the compound shown in formula (I) disclosed in patent application WO2018019166A1 as an example, the technical solution of the present invention will be explained, that is, the composition is prepared by using the hydrochloride crystal form I of the compound shown in formula (I) as the active ingredient.

[0211] Example 1

[0212] The active ingredients were prepared into capsules, and their dissolution rate was determined.

[0213] The preparation method is as follows:

[0214] Method A:

[0215] ① Mix the active ingredient with filler, disintegrant, anti-adhesive, binder (if any) and antioxidant evenly to obtain a premix; ② Then mix the lubricant and premix evenly to obtain a total powder; ③ Fill the total powder into a suitable hollow capsule shell to obtain a capsule.

[0216] Method B:

[0217] ① Mix the active ingredient with filler, disintegrant, anti-adhesive, binder (if applicable), lubricant, and antioxidant until homogeneous to obtain a premix; ② Perform dry granulation on the premix to obtain granulated particles; ③ Premix the granulated particles with filler (if applicable), disintegrant, and anti-adhesive to obtain premixed particles; ④ Mix the lubricant with the premixed particles until homogeneous to obtain total mixed particles; ⑤ Fill the total mixed particles into suitable hollow capsule shells. Optionally, an antioxidant may also be added in step ③.

[0218] Method C:

[0219] ① Mix the active ingredient with filler, disintegrant, binder (if applicable), and antioxidant evenly to obtain a premix; ② Perform wet granulation on the premix and dry it to obtain dried granules; ③ Premix the dried granules with filler, disintegrant, and anti-adhesion agent to obtain premixed granules; ④ Mix the lubricant with the premixed granules evenly to obtain total mixed granules; ⑤ Fill the total mixed granules into suitable hollow capsule shells. Optionally, the binder may also be added after being prepared into a binder solution in step ②, and / or the antioxidant may also be added in step ③.

[0220] Specifically, capsule samples A1 and A2 were prepared according to method A, samples A3 and A4 were prepared according to method B, and samples A5 and A6 were prepared according to method C. The composition of each sample is shown in Tables AC below.

[0221] Table A

[0222]

[0223] In this application, "N / A" represents "None".

[0224] Table B

[0225]

[0226]

[0227] Table C

[0228]

[0229] The dissolution rate was determined using the method of General Chapter 0931, Method I, of the Chinese Pharmacopoeia 2020 Edition, with 900 mL of 0.1 M HCl as the dissolution medium and 100 rpm. The dissolution rate of the above-mentioned capsule samples was determined in accordance with the method. The acceptable standard for dissolution rate is ≥80% at 45 min.

[0230] Results: The dissolution test results showed that the dissolution rate of each sample was greater than 80% at 45 min.

[0231] Example 2

[0232] The active ingredient was prepared into tablets, and its dissolution rate was measured.

[0233] The preparation method is as follows:

[0234] Method 1:

[0235] ① Mix the active ingredient with filler, disintegrant, anti-adhesive, binder (if any) and antioxidant evenly to obtain a premix; ② Then mix the lubricant and premix evenly to obtain a total powder; ③ Compress the total powder into tablets to obtain uncoated tablets; ④ Coat the uncoated tablets to obtain coated tablets.

[0236] Method 2:

[0237] ① Mix the active ingredient with filler, disintegrant, anti-adhesive, binder (if applicable), lubricant, and antioxidant until homogeneous to obtain a premix; ② Perform dry granulation on the premix to obtain granulated particles; ③ Premix the granulated particles with filler (if applicable), disintegrant, and anti-adhesive to obtain premixed particles; ④ Mix the lubricant with the premixed particles until homogeneous to obtain total mixed particles; ⑤ Compress the total mixed particles to obtain unmixed tablets; ⑥ Coat the unmixed tablets to obtain coated tablets. Optionally, an antioxidant may also be added in step ③.

[0238] Method 3:

[0239] ① Mix the active ingredient with filler, disintegrant, binder (if applicable), and antioxidant evenly to obtain a premix; ② Perform wet granulation on the premix and dry it to obtain dried granules; ③ Premix the dried granules with filler, disintegrant, and anti-adhesion agent to obtain premixed granules; ④ Mix the lubricant (e.g., purified water) with the premixed granules evenly to obtain total mixed granules; ⑤ Compress the total mixed granules to obtain unmixed tablets; ⑥ Coat the unmixed tablets to obtain coated tablets. Optionally, the binder may also be added after preparing the binder solution in step ②, and / or the antioxidant may also be added in step ③.

[0240] The coating material is a film coating premix, and the amount used is 3.0 ± 1.0% of the weight of the uncoated tablets.

[0241] Specifically, tablet samples B1-B2 and B5-B17 were prepared according to Method 3, and samples B3 and B4 were prepared according to Method 2. The composition of the uncoated tablets for each sample is shown in Tables D, E, and F1-F6 below.

[0242] Table D

[0243]

[0244] Table E

[0245]

[0246]

[0247] Table F1

[0248]

[0249] Table F2

[0250]

[0251] Table F3

[0252]

[0253]

[0254] Table F4

[0255]

[0256] Table F5

[0257]

[0258]

[0259] Table F6

[0260]

[0261] The dissolution rate was determined using the method (General Chapter 0931, Method II, Chinese Pharmacopoeia 2020 Edition). The dissolution medium was 900 mL of potassium hydrogen phthalate buffer solution (pH 3.0) + 1.5% Tween 80. The dissolution rate was determined at 75 rpm for the above tablet samples. The acceptable dissolution rate was ≥80% at 45 min.

[0262] Results: The dissolution test results showed that the dissolution rate of each sample was greater than 80% at 45 min, and the dissolution rate of most samples was greater than 90% at 45 min.

[0263] Comparative Example

[0264] Following the aforementioned methods for capsules and tablets, antioxidant-free capsule and tablet samples were prepared without the addition of antioxidants, serving as reference standards. Specifically, antioxidant-free capsule reference standards C1 and C2 were prepared according to methods B and C of Example 1, respectively; antioxidant-free tablet reference standards C3 and C4 were prepared according to methods two and three of Example 2, respectively. The specific compositions of each reference standard are shown in Tables G1 and G2 below.

[0265] Table G1 Capsule Reference Standard

[0266]

[0267]

[0268] Table G2 Tablet Reference Standard

[0269]

[0270] Example 3

[0271] Following the guidelines for stability testing of active pharmaceutical ingredients and preparations in the 2015 edition of the Chinese Pharmacopoeia, Volume IV, section 9001, the stability of the capsule and tablet products of this invention, as well as control samples C1-C4, was investigated. Specific experimental methods are as described in this invention, and the experimental results are shown in Table H below.

[0272] Table H

[0273]

[0274]

[0275] As shown in the table above, the total impurity content of the control sample increased significantly after one month of experimentation, and exceeded the acceptable limit after 3-4 months; indicating poor stability of the control sample. In contrast, the total impurity content of the capsules and tablets described in this invention remained essentially unchanged during the experiment and was significantly lower than that of the control sample; especially after long-term storage, the total impurity content of each sample showed virtually no significant change and was far lower than that of the control sample. Therefore, adding antioxidants during the preparation of capsules or tablets can reduce the amount and rate of impurity formation during storage, thereby improving tablet stability.

[0276] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0277] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A composition in the form of a capsule, characterized in that, 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3 H )-one hydrochloride, an antioxidant, a filler, a disintegrant, an antiadherent, and a lubricant, or, 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3 H )-one hydrochloride, an antioxidant, a filler, a disintegrant, an antiadherent, a lubricant, and a binder, wherein: The mass ratio of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3 H )-one hydrochloride to the antioxidant is (21.00~35.00):(0.05~0.08), The antioxidant is butylated hydroxyanisole and / or butylated hydroxytoluene.

2. The composition of claim 1, wherein, The filler is at least one selected from the group consisting of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, sorbitol, sucrose, lactitol, and maltose.

3. The composition of claim 1, wherein, The disintegrant is at least one selected from the group consisting of cross-linked polyplasdone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

4. The composition of claim 1, wherein, The anti-adherent is at least one selected from the group consisting of colloidal silicon dioxide and talc.

5. The composition of claim 1, wherein The lubricant is at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, and glyceryl behenate.

6. The composition of claim 1, wherein, The binder is at least one selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methyl cellulose.

7. The composition of claim 1, wherein, The content of the filler is 60.00 to 69.00 parts by weight.

8. The composition of claim 1, wherein, The content of the anti-adherent is 1.00 to 2.50 parts by weight.

9. The composition of claim 1, wherein, The content of the disintegrant is 2.50 to 5.00 parts by weight.

10. The composition of claim 1, wherein, The content of the lubricant is 2.00 to 3.00 parts by weight.

11. The composition of claim 1, wherein, The content of the binder is 0 to 2.00 parts by weight.

12. The composition of claim 1, wherein, The capsule includes: 34.00~34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3 H )-Keto hydrochloride; 40.00 to 41.00 parts by weight of mannitol; 20.00 to 21.00 parts by weight of pregelatinized starch; 2.00 to 3.00 parts by weight of cross-linked polyplasdone; 0.50 to 1.50 parts by weight of colloidal silicon dioxide; and 1.50 to 2.50 parts by weight of magnesium stearate; and at least one selected from the group consisting of: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.04 to 0.06 parts by weight of butylated hydroxytoluene.

13. The composition of claim 1, wherein, The capsule includes: 21.00~22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3 H )-Keto hydrochloride; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 20.00 to 23.00 parts by weight of pregelatinized starch; 4.00 to 6.00 or 4.00 to 5.50 parts by weight of sodium carboxymethyl starch; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.00 to 3.00 parts by weight of colloidal silicon dioxide; 2.00 to 3.50 or 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the group consisting of: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02 to 0.05 parts by weight of butylated hydroxytoluene.

14. A composition in the form of a tablet, characterized in that 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3 H )-one hydrochloride, an antioxidant, a filler, a disintegrant, an anti-tacking agent, a lubricant, or, 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3 H )-one hydrochloride, an antioxidant, a filler, a disintegrant, an anti-tacking agent, a lubricant, and a binder, wherein: The mass ratio of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3 H )-one hydrochloride and the antioxidant is (9.00~22.00): (0.03~0.10), The antioxidant is butylated hydroxyanisole and / or butylated hydroxytoluene.

15. The composition of claim 14, wherein, The filler is at least one selected from the group consisting of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, sorbitol, sucrose, lactitol, and maltose.

16. The composition of claim 14, wherein, The disintegrant is at least one selected from the group consisting of cross-linked polyplasdone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

17. The composition of claim 14, wherein, The anti-adherent is at least one selected from the group consisting of colloidal silicon dioxide and talc.

18. The composition of claim 14, wherein, The lubricant is at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, and glyceryl behenate.

19. The composition of claim 14, wherein, The binder is at least one selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, and methyl cellulose.

20. The composition of claim 14, wherein, The tablet includes: 9.00~22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3 H )-Keto hydrochloride; 0.03 to 0.10 parts by weight of an antioxidant; 60.00 to 77.00 parts by weight of a filler; 0 to 3.50 parts by weight of a binder; 3.00 to 10.00 parts by weight of a disintegrant; 0.50 to 3.00 parts by weight of an anti-tacking agent; and 2.50 to 6.00 parts by weight of a lubricant.

21. The composition of claim 14, wherein, The tablet comprises: 9.00~13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3 H )-Keto hydrochloride; 9.00 to 10.50 parts by weight of pregelatinized starch; 62.00 to 67.00 parts by weight of microcrystalline cellulose; 2.00 to 3.00 parts by weight of povidone or hydroxypropyl methylcellulose; 6.00 to 8.00 parts by weight of cross-linked povidone; 0.50 to 2.50 parts by weight of colloidal silicon dioxide; and 2.50 to 4.50 parts by weight of magnesium stearate, or 5.00 to 7.00 parts by weight of glyceryl behenate; and at least one selected from the group consisting of: 0.03 to 0.04 parts by weight of butylated hydroxytoluene; and 0.03 to 0.05 parts by weight of butylated hydroxyanisole.

22. The composition of claim 14, wherein, The tablet comprises: 21.00~22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3 H )-Keto hydrochloride; 20.00 to 25.00 parts by weight of pregelatinized starch; 43.00 to 47.00 parts by weight of microcrystalline cellulose; 0 to 3.00 parts by weight of hydroxypropyl methylcellulose; 4.50 to 5.00 parts by weight of sodium carboxymethyl starch; 2.00 to 3.00 parts by weight of colloidal silicon dioxide; and 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the group consisting of: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02 to 0.04 parts by weight of butylated hydroxytoluene.

23. The composition of any one of claims 14-22, wherein, The tablet further comprises a coating material, the weight of which is 2.0% to 4.0% of the weight of the tablet core of the tablet. The tablet further comprises a coating material, the weight of which is 2.0% to 4.0% of the weight of the tablet core of the tablet.

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