WO2023056935A1 - 抗纤维化组合物 - Google Patents

抗纤维化组合物 Download PDF

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Publication number
WO2023056935A1
WO2023056935A1 PCT/CN2022/123811 CN2022123811W WO2023056935A1 WO 2023056935 A1 WO2023056935 A1 WO 2023056935A1 CN 2022123811 W CN2022123811 W CN 2022123811W WO 2023056935 A1 WO2023056935 A1 WO 2023056935A1
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weight
parts
optionally
hydrochloride
antioxidant
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PCT/CN2022/123811
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English (en)
French (fr)
Inventor
应侠
李建泽
郭朕
陈奕娜
郑艳艳
张英俊
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广东东阳光药业有限公司
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Publication of WO2023056935A1 publication Critical patent/WO2023056935A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention belongs to the field of medicines, and in particular relates to an anti-fibrosis composition.
  • Fibrosis can occur in many organs, and the main pathological changes are the increase of fibrous connective tissue and the decrease of parenchymal cells in organ tissues. Continuous progress can lead to organ function decline and eventual death. It is seen in end-stage liver disease, kidney disease, idiopathic Pulmonary fibrosis (IPF) and heart failure etc. seriously threaten human health and life. IPF is considered the most common and severe form of the disease, with a median survival of approximately three years, and the exact mechanisms driving fibrosis are currently unknown. Pirfenidone is the first anti-IPF drug approved by Japan in 2008 and the European Union in 2011 and developed by Shionogi in Japan.
  • Patent application WO 2014012360 A1 discloses a substituted pyrimidinone compound, specifically the compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H) - Ketone (compound shown in formula (I)), its activity is better than pirfenidone, meanwhile, it has good pharmacokinetic properties and safety.
  • Patent application WO 2018019166 A1 discloses salts of compounds represented by formula (I), such as hydrochloride, etc., wherein the hydrochloride has good stability and biological properties.
  • the studies of the aforementioned patent applications are still in the relatively early stage of preclinical research. In order to facilitate the development of clinical research, it is necessary to further study the properties of the drug and find a drug form suitable for human consumption.
  • the inventors of the present application on the basis of their own research and development of new drugs (compounds represented by formula (I) and pharmaceutically acceptable salts thereof), found through initial research that compounds represented by formula (I) or pharmaceutically acceptable salts thereof Salt such as hydrochloride has good stability, and no impurities will be generated or the content of impurities will not increase after long-term storage. But in the process of developing pharmaceutical preparations, the inventors have found that when the compound shown in formula (I) or its pharmaceutically acceptable salt such as hydrochloride is made into pharmaceutical preparations by conventional methods, the stability of the pharmaceutical preparations is not stable. Unexpectedly, it turned out to be poor.
  • the inventors tried to screen and proportion various pharmaceutical excipients, and found that when the compound shown in formula (I) or its pharmaceutically acceptable salt such as hydrochloride and antioxidant When combined, the stability of the pharmaceutical preparation can be maintained, especially when the compound or a pharmaceutically acceptable salt thereof such as hydrochloride is combined with an antioxidant of a free radical reaction type, the stability of the pharmaceutical preparation product is better good.
  • the present invention provides a composition with anti-fibrosis effect.
  • the composition of the present invention is based on 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (compound represented by formula (I)) or its
  • the pharmaceutically acceptable salt such as hydrochloride
  • the invention provides a composition.
  • the composition includes 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (formula (I) Shown compounds) or pharmaceutically acceptable salts thereof and antioxidants.
  • the composition uses 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition of the invention can effectively treat fibrotic diseases such as idiopathic pulmonary fibrosis and the like, and has high safety.
  • the above composition may further include at least one of the following additional technical features:
  • the pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is its hydrochloride.
  • the antioxidants described in the present invention include but are not limited to free radical reactive antioxidants and/or antioxidant synergists.
  • the antioxidant of the present invention is an antioxidant reactive with free radicals.
  • the antioxidants of the present invention include but are not limited to butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate or any combination thereof.
  • compositions described herein are oral formulations.
  • compositions described herein are oral solid formulations.
  • the oral solid preparation of the present invention is a capsule or a tablet.
  • compositions of the invention are capsules or tablets.
  • composition of the present invention further includes pharmaceutically acceptable excipients.
  • the excipients of the present invention include at least one selected from fillers, disintegrants, binders, anti-sticking agents, and lubricants.
  • the filler of the present invention can be selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, lactitol and maltose.
  • the disintegrating agent of the present invention may be selected from at least one of crospovidone, sodium starch glycolate, croscarmellose sodium and low-substituted hydroxypropyl cellulose.
  • the anti-sticking agent of the present invention may be selected from at least one of colloidal silicon dioxide and talc.
  • the lubricant of the present invention may be selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and glyceryl behenate.
  • the binder of the present invention may be selected from povidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, polyethylene glycol, ethylcellulose and methylcellulose at least one of the elements.
  • the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one salt The content of acid salt is 5.00 ⁇ 73.00 parts by weight (for example: 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, 20.00 parts by weight 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 the range value between any two point values).
  • the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride of the present invention is about 6.00 to 58.00 parts by weight.
  • the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride is about 9.00 ⁇ 58.00 or 11.00 to 58.00 parts by weight. In some embodiments, the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride is about 6.00 ⁇ 22.00 parts by weight.
  • the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride in the present invention is 9.00 ⁇ 35.00 or 12.00 ⁇ 35.00 parts by weight.
  • the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride in the present invention is 21.00 to 35.00 wt. share. or
  • the content of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride in the present invention is 9.00 to 22.00 or 12.00 to 22.00 parts by weight.
  • the antioxidant content of the present invention is 0.01 to 0.40 parts by weight (for example: 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 value between any two point values).
  • 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.
  • the antioxidant content of the present invention is 0.03-0.08 parts by weight.
  • the antioxidant content of the present invention is 0.03-0.05 parts by weight, 0.04-0.05 parts by weight or 0.05-0.08 parts by weight.
  • the filler content of the present invention is 22.00 to 91.00 parts by weight (for example: 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 weight parts, 45.00 weight parts, 50.00 weight parts, 55.00 weight parts, 55.50 weight parts, 60.00 weight parts, 60.36 weight parts, 65.00 weight parts, 65.60 weight parts, 65.63 weight parts, 67.00 weight parts, 68.10 weight parts, 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,
  • the filler content of the present invention is about 22.50-91.00 parts by weight, 29.00-82.00 parts by weight, 55.00-90.00 parts by weight, 60.00-76.00 parts by weight, 60.00-77.00 parts by weight, 60.00-69.00 parts by weight parts, 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.
  • the content of the anti-sticking agent of the present invention is 0.50 to 3.50 parts by weight (for example: 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 parts or a range value between any two point values).
  • the content of the anti-sticking agent in 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.
  • the content of the disintegrating agent of the present invention is 0.50 to 16.00 parts by weight (for example: 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 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 two points range between values).
  • the content of the disintegrating agent in 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.
  • the content of the lubricant of the present invention is 0.50-7.00, 0.50-6.00 or 0.50-5.00 parts by weight (for example: 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 a range value between any two point values).
  • the content of the lubricant of the present invention is 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 to 4.00 parts by weight.
  • the content of the binder of the present invention is 0 to 3.50 parts by weight (for example: 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 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 a range value between any two point values).
  • the content of the binder in the present invention is 0-3.00, 0-2.00, 0-2.50 or 2.00-3.00 parts by weight.
  • the composition of the present invention is a capsule; the capsule comprises 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4 (3H)-Kone hydrochloride, antioxidants, fillers, disintegrants, antisticking agents, lubricants and optionally binders.
  • the capsules of the present invention include: 5.00-73.00 or 21.00-35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine -4(3H)-ketone hydrochloride; 0.01-0.40, 0.02-0.10 or 0.04-0.09 parts by weight of antioxidant; 22.50-90.50 parts by weight of filler; 0.50-6.00 or 2.00-6.00 parts by weight of disintegration agent; 0.50-3.50 parts by weight of anti-sticking agent; 0.50-3.50 parts by weight of lubricant; and 0-2.50 parts by weight of adhesive.
  • the capsules of the present invention include: 5.00 to 73.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone hydrochloride; 0.01 to 0.40 parts by weight of antioxidant; 22.50 to 90.50 parts by weight of filler; 0.50 to 6.00 parts by weight of disintegrant; parts of lubricant; and 0-2.50 parts by weight of binder.
  • the capsules of the present invention include: 21.00 to 35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone hydrochloride; 0.02 to 0.10 parts by weight of antioxidant; 22.50 to 90.50 parts by weight of filler; 2.00 to 6.00 parts by weight of disintegrant; parts of lubricant; and 0-2.50 parts by weight of binder.
  • the capsules of the present invention include: 21.00 to 35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone hydrochloride; 0.05-0.08 parts by weight of antioxidant; 60.00-70.00 parts by weight of filler; 2.00-6.00 parts by weight of disintegrating agent; 0.50-3.00 parts by weight of anti-sticking agent; parts of lubricant; 0-2.50 parts by weight of binder.
  • the filler is optionally selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, lactose At least one of alcohol and maltose.
  • the disintegrant is optionally selected from crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl at least one of cellulose.
  • the anti-sticking agent is optionally selected from at least one of colloidal silicon dioxide and talc.
  • the lubricant is optionally selected from magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and glyceryl behenate at least one of the .
  • the binder is optionally selected from povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, ethylcellulose at least one of cellulose and methylcellulose.
  • the antioxidant 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, and the disintegrant is crospovidone Or carboxymethyl starch sodium, described antitack agent is colloidal silicon dioxide, and described lubricant is magnesium stearate.
  • the capsules of the present invention include: 13.00-58.00 or 34.00-34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine -4(3H)-ketone 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; Lipovidone; 0.50-2.50 or 0.50-1.50 parts by weight of colloidal silicon dioxide; and 0.50-3.00 or 1.50-2.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.03-0.20 or 0.04-0.06 parts by weight of butylated hydroxyanisole; and 0.03-0.10 or 0.04-0.06 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: 13.00 to 58.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 silicon dioxide ; 0.50-3.00 parts by weight of magnesium stearate; and 0.04-0.06 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: 34.00 to 34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 silicon dioxide and 1.50-2.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.04-0.06 parts by weight of butylated hydroxyanisole; and 0.04-0.06 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: 13.00 to 58.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 silicon dioxide and 0.50-3.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.03-0.20 parts by weight of butylated hydroxyanisole; and 0.03-0.10 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: about 34.00 to 34.50 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4( 3H)-ketone 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 silicon dioxide; 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 .
  • the capsules of the present invention include: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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; 4.00 ⁇ 6.00 or 4.00 ⁇ 5.50 parts by weight of sodium carboxymethyl starch; 0 ⁇ 2.00 parts by weight of hydroxypropyl methylcellulose; 2.00 to 3.00 parts by weight of colloidal silicon dioxide; and 2.00 to 3.50 or 2.50 to 3.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.03-0.10 or 0.04-0.06 parts by weight of butylated hydroxyanisole; and 0.02-0.10 or 0.02-0.05 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 methyl 2.00 to 3.00 parts by weight of colloidal silicon dioxide; 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 0.02-0.10 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 methyl 2.00-3.00 parts by weight of colloidal silicon dioxide; and 2.50-3.50 parts by weight of magnesium stearate; and at least one selected from the following: 0.04-0.06 parts by weight of butylated hydroxyanisole; and 0.02-0.05 parts by weight of butylated hydroxytoluene.
  • the capsules of the present invention include: 21.82 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H)- Ketone 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 starch glycolate; 0 to 2.00 parts by weight of hydroxypropyl methylcellulose; 2.50 parts by weight of colloidal silicon dioxide; 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.
  • the composition of the present invention is a tablet; the tablet comprises 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4( 3H)-ketone hydrochloride, antioxidants, fillers, disintegrants, antiadhesives, lubricants and optionally binders.
  • the above tablet may further include at least one of the following additional technical features:
  • the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one salt The mass ratio of the acid salt to the antioxidant is (6.00-22.00): (0.02-0.30).
  • the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one salt The mass ratio of the acid salt to the antioxidant is (9.00-22.00): (0.03-0.10).
  • the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one salt The mass ratio of the acid salt to the antioxidant is (9.00-22.00): (0.03-0.08).
  • the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one salt The mass ratio of salt to antioxidant is about (12.00-22.00): (0.03-0.08).
  • 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride and antioxidant The mass ratio is about (9.00-13.00): (0.03-0.05).
  • 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride and antioxidant The mass ratio is about (12.00 ⁇ 13.00):(0.03 ⁇ 0.05).
  • 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride and antioxidant The mass ratio is about (21.00 ⁇ 22.00):(0.04 ⁇ 0.10).
  • 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrochloride and antioxidant The mass ratio is about (21.00-22.00): (0.05-0.08).
  • the tablet of the present invention includes: 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-Dimethylpyrimidin-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 antioxidant; 55.00 ⁇ 90.00, 60.00 ⁇ 80.00, 60.00 ⁇ 78.00, 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 binder; 2.00 ⁇ 12.00, 3.00 ⁇ 10.00, 4.00 ⁇ 9.00, 4.00 to 8.00, 5.0 to 8.00 or 6.00 to 8.00 parts by weight of a disintegrant; 0.50 to 3.00 or 1.00 to 2.50 parts by weight of an anti-sticking agent; and 2.00 to 7.00, 2.50 to
  • the tablet of the present invention includes: 6.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone hydrochloride; 0.02 to 0.30 parts by weight of antioxidant; 55.00 to 90.00 parts by weight of filler; 0 to 3.50 parts by weight of binder; 2.00 to 12.00 parts by weight of disintegrant; 0.50 to 3.00 parts by weight 2.50-7.00 or 2.50-6.00 parts by weight of lubricant.
  • the tablet of the present invention includes: about 6.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4( 3H)-ketone hydrochloride; about 0.02 to 0.10 parts by weight of antioxidant; about 55.00 to 90.00 parts by weight of filler; about 0 to 3.50 parts by weight of binder; about 2.00 to 12.00 parts by weight of disintegrant ; about 0.50-3.00 parts by weight of an anti-sticking agent; and about 2.50-6.00 or 2.50-5.00 parts by weight of a lubricant.
  • the tablet of the present invention includes: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl Pyrimidin-4(3H)-one hydrochloride; about 0.02 to 0.10 parts by weight of 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 filler; about 0 to 3.50 parts by weight The binder of about 3.00 ⁇ 10.00 parts by weight; The disintegrant of about 1.00 ⁇ 2.50 parts by weight; And the lubricant of about 2.50 ⁇ 7.00, 2.50 ⁇ 6.00 or 3.00 ⁇ 4.00 parts by weight.
  • the tablet of the present invention includes: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl Pyrimidin-4(3H)-one hydrochloride; about 0.03 to 0.10 parts by weight of antioxidant; about 60.00 to 78.00, 60.00 to 76.00 or 60.00 to 77.00 parts by weight of filler; about 0 to 3.50 parts by weight of adhesive agent; about 3.00-10.00 parts by weight of disintegrant; about 1.00-2.50 parts by weight of anti-tack agent; and about 2.50-6.00 or 3.00-4.00 parts by weight of lubricant.
  • the tablet of the present invention includes: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl Pyrimidin-4(3H)-one hydrochloride; about 0.04 to 0.08 parts by weight of antioxidant; about 65.00 to 76.00 or 65.00 to 77.00 parts by weight of filler; about 0 to 3.00 parts by weight of binder; about 4.00 -8.00 or 5.00-8.00 parts by weight of a disintegrant; about 1.00-2.50 parts by weight of an anti-sticking agent; and about 2.50-6.00 or 3.00-4.00 parts by weight of a lubricant.
  • the tablet of the present invention includes: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl Pyrimidin-4(3H)-one hydrochloride; about 0.03 to 0.05 parts by weight of antioxidant; about 65.00 to 76.00 or 65.00 to 77.00 parts by weight of filler; about 0 to 3.50 parts by weight of binder; about 4.00 -8.00 or 5.0-8.00 parts by weight of disintegrant; about 1.00-2.50 parts by weight of anti-sticking agent; and about 2.50-6.00 or 3.00-4.00 parts by weight of lubricant.
  • the filler is optionally selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, lactose At least one of alcohol and maltose.
  • the disintegrant is optionally selected from crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl at least one of cellulose.
  • the anti-adhesive agent is optionally selected from at least one of colloidal silicon dioxide and talc.
  • the lubricant is optionally selected from magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and glyceryl behenate at least one of the .
  • the binder is optionally selected from povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, ethylcellulose at least one of cellulose and methylcellulose.
  • the antioxidant 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, and the binder is povidone or hydroxy Propyl methyl cellulose, the disintegrating agent is crospovidone or sodium starch glycolate, the anti-sticking agent is colloidal silicon dioxide, and the lubricant is magnesium stearate or glycerin behenate ester.
  • the tablet of the present invention includes: 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 or 62.00 ⁇ 67.00 or 64.00 ⁇ 66.00 parts by weight of microcrystalline cellulose; 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 silicon dioxide; 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 at least one
  • the tablet of the present invention includes: 9.00-13.00 or 11.00-13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine -4(3H)-ketone 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 ; 4.00-12.00 parts by weight of crospovidone; 0.50-2.50 parts by weight of colloidal silicon dioxide; 2.50-4.50 parts by weight of magnesium stearate, or 5.00-7.00 parts by weight of glyceryl behenate; and At least one selected from the following: 0.03-0.05 parts by weight of butylated hydroxytoluene; and 0.03-0.05 parts by weight of butylated hydroxyanisole.
  • the tablet of the present invention includes: 9.00-13.00 or 12.00-13.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine -4(3H)-ketone hydrochloride; 9.00 to 10.00 parts by weight of pregelatinized starch; 64.00 to 66.00 or 64.00 to 67.00 parts by weight of microcrystalline cellulose; 2.00 to 3.00 parts by weight of povidone or hydroxypropyl Methylcellulose; 4.00-8.00 or 6.00-8.00 parts by weight of crospovidone; 1.00-2.00 parts by weight of colloidal silicon dioxide; 3.00-4.00 parts by weight of magnesium stearate, or 5.00-7.00 parts by weight Glyceryl behenate; and at least one selected from the following: 0.03-0.04 parts by weight of butylated hydroxytoluene; and 0.03-0.05 parts by weight of butylated hydroxyanisole.
  • the tablet of the present invention includes: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone hydrochloride; 20.00 to 25.00 or 23.00 to 24.00 parts by weight of pregelatinized starch; 40.00 to 50.00 or 43.00 to 47.00 parts by weight of microcrystalline cellulose; 0 to 3.00 or 0 to 2.00 parts by weight of hydroxypropyl Methyl cellulose; 4.00 ⁇ 5.50 or 4.50 ⁇ 5.00 parts by weight of sodium starch glycolate; 2.00 ⁇ 3.00 parts by weight of colloidal silicon dioxide; and 2.00 ⁇ 4.00 or 2.50 ⁇ 3.50 parts by weight of magnesium stearate; and optional 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.
  • the tablet of the present invention includes: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 carboxy sodium starch glycolate; 2.00 to 3.00 parts by weight of colloidal silicon dioxide; 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 0.02-0.05 parts by weight of butylated hydroxytoluene.
  • the tablet of the present invention includes: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone 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 carboxy sodium starch glycolate; 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 following: 0.04 to 0.06 parts by weight of butylated hydroxyanisole; and 0.02-0.04 parts by weight of butylated hydroxytoluene.
  • the tablet further comprises a coating material; optionally, the coating material is a film coating premix.
  • the weight of the coating material is 2.0-4.0% of the weight of the plain tablet of the tablet.
  • first and second are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the quantity of indicated technical features. Thus, a feature defined as “first” and “second” may explicitly or implicitly include one or more of these features. Further, in the description of the present invention, unless otherwise specified, "plurality" means two or more.
  • the term "about” or “approximately” refers to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, Within 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05%.
  • composition of the present invention includes an optional binder, which means that the composition may or may not contain a binder.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith.
  • pharmaceutically acceptable in the present invention refers to those approved by federal regulatory agencies or national governments, or listed in the US Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, especially humans.
  • pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as documented in Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.
  • the pharmaceutically acceptable salts described in the present invention include but are not limited to hydrochloride, besylate, p-toluenesulfonate, sulfate, hydrobromide and the like.
  • the pharmaceutically acceptable salt of the present invention is hydrochloride.
  • compositions or preparations provided by the present invention can be administered to patients alone, or co-administered or combined with other active agents.
  • co-administration and “combination” include simultaneous or sequential administration of two or more therapeutic agents without specific time limits.
  • the agents are present in a cell or in an individual at the same time, or exert a biological or therapeutic effect at the same time.
  • each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in a different composition or unit dosage form.
  • active ingredient refers to a substance used in therapy (eg, human therapy, veterinary therapy), including prophylactic and therapeutic treatments. Active ingredients include any substance used as a medicament for the treatment, prevention, delay, alleviation or amelioration of a disease, condition or disorder.
  • oral preparation refers to a preparation form that is administered orally and the drug is absorbed into the blood in the gastrointestinal tract, including tablets, granules, capsules, oral solutions, and the like.
  • solid oral dosage form refers to tablet, dispersible tablet, fast-dissolving tablet, fast-melting tablet, fast-melting tablet, mouth-melting tablet, mouth-melting tablet, orodispersible tablet, lyophilized unit, porous tablet, conventional tablet, coated tablet , uncoated tablet, gastro-resistant tablet, effervescent tablet, soluble tablet, chewable tablet, oral lyophilizate, powder, oral powder, pill, capsule and/or granule.
  • the solid oral dosage form is a capsule.
  • the solid oral dosage form is a tablet.
  • parts by weight refers to the number of parts by mass obtained after comparing the mass of a certain component of the composition with the mass of other components.
  • the content of the antioxidant is 0.01-0.40 parts by weight, which means that the antioxidant and other components of the composition
  • the mass parts obtained after comparing the masses are 0.01-0.40 parts by weight.
  • the weight data of each component may be enlarged or omitted or replaced by the same amount according to the proportion.
  • the specific value or decimal point may be calculated according to the molecular weight or the quantitative relationship between the mass of each component itself. digits or digits accurate to different decimal points, including but not limited to, within the pharmaceutically understandable range or in the case of scientific notation, further deduced according to the rules of rounding, for example, the content of fillers is 80.00 parts by weight, the content is equivalent or interchangeable with the contents of 79.95 parts by weight, 80.01 parts by weight, and 80.35 parts by weight, and other components can be deduced by analogy.
  • antioxidant enhancer refers to inhibiting the formation of free radicals and synergizing with other antioxidant systems.
  • the present invention proposes a composition, the compound has anti-fibrosis effect, and can be used for treating fibrotic diseases such as liver fibrosis, pulmonary fibrosis such as idiopathic pulmonary fibrosis and the like.
  • the composition includes 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (formula (I) compound) or a pharmaceutically acceptable salt thereof and an antioxidant.
  • the composition is formulated as 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one or a pharmaceutically acceptable Salts such as hydrochloride are active ingredients.
  • the inventors have found through a large number of tests that the problem of reduced stability of the composition can be well overcome by combining the active ingredient with an antioxidant.
  • the composition effectively reduces the formation of impurities during storage, and has the advantages of easy storage, stable and controllable quality, high bioavailability, and the like.
  • the composition prepared by the present invention has strong drug efficacy, high safety, and good compliance of patients taking it.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is its hydrochloride.
  • the composition of the present invention contains the hydrochloride salt of the compound represented by formula (I) as an active ingredient.
  • the antioxidants described in the present invention include but are not limited to free radical-reactive antioxidants and/or antioxidant synergists.
  • the antioxidant of the present invention is an antioxidant reactive with free radicals; optionally, the antioxidant reactive with free radicals may be selected from butylated hydroxyanisole, butylated hydroxytoluene (also known as di Butylated hydroxytoluene) and at least one of propyl gallate.
  • Antioxidants reacting with free radicals 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 a large number of experiments that the effect of using this type of antioxidants is better.
  • compositions described herein are oral formulations.
  • compositions described herein are oral solid formulations.
  • the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof and the antioxidant is prepared into an oral solid preparation, which has a good stability effect.
  • the oral solid preparation of the present invention is a capsule or a tablet.
  • compositions of the invention are capsules or tablets.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt and antioxidant is made into capsules and/or tablets, and the stability effect is better.
  • the composition of the present invention contains an appropriate amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the appropriate amount is an effective dose of the compound, which is safe and effective.
  • the content of the compound represented by formula (I) can be 4.00 to 70.00 parts by weight; optionally, in the composition, the content of the compound represented by formula (I) can be 4.50 to 67.00 parts parts by weight; optionally, in the composition, the content of the compound shown in formula (I) can be 20.00 to 32.00 parts by weight; optionally, in the composition, the content of the compound shown in formula (I) can be 8.00 to 32.00 parts by weight; optionally, in the composition, the content of the compound represented by formula (I) can be 11.00 to 32.00 parts by weight; optionally, in the composition, the compound represented by formula (I) The content of the compound may be 8.00-20.00 parts by weight; optionally, in the composition, the content of the compound represented by formula (I) may be 11.00-20.00 parts by weight
  • the composition of the present invention uses a pharmaceutically acceptable salt of the compound represented by formula (I) as an active ingredient.
  • the composition of the present invention can use the hydrochloride salt of the compound represented by formula (I) as an active ingredient.
  • the content of the hydrochloride salt of the compound represented by the formula (I) is 5.00 to 73.00 parts by weight; optionally, the compound represented by the formula (I)
  • the content of the hydrochloride is about 6.00 to 58.00 parts by weight; optionally, the content of the hydrochloride of the compound represented by the formula (I) is about 9.00 to 58.00 parts by weight; optionally, the compound represented by the formula (I)
  • the content of the hydrochloride salt of the compound shown is about 11.00 to 58.00 parts by weight; optionally, the content of the hydrochloride salt of the compound shown in the formula (I) is about 12.00 to 58.00 parts by weight; optionally, the formula
  • the content of the hydrochloride of the compound shown in (I) is about 13.00 to 58.00 parts by weight; optionally, the content of the hydrochloride of the compound shown in the formula (I) is about 9.00 to 35.00 parts by weight; optionally , the content of the hydrochlorlor
  • the antioxidant content is 0.01 to 0.40 parts by weight; optionally, the antioxidant content is 0.02 to 0.40 parts by weight; optionally, the antioxidant content 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 The content is 0.03-0.30 parts by weight; optionally, the content of the antioxidant is 0.03-0.20 parts by weight; optionally, the content of the antioxidant is 0.03-0.10 parts by weight; optionally, the antioxidant The content of the antioxidant is 0.05 to 0.20 parts by weight; optionally, the content of the antioxidant is 0.08 to 0.30 parts by weight; optionally, the content of the antioxidant is 0.08 to 0.20 parts by weight; optionally, the antioxidant The content of the oxygen agent is 0.08 to 0.10 parts by weight; optionally, the content of the antioxidant is 0.04 to 0.30 parts by weight; optionally, the content of the antioxidant is 0.03 to 0.08 parts by weight; optionally, the
  • the inventors have found through a large number of tests that controlling the content of the antioxidant at 0.01 to 0.4 parts by weight, especially 0.03 to 0.10 parts by weight, can effectively reduce the amount and rate of impurities generated during the storage of the composition, and improve the composition. Stability, convenient storage of the composition.
  • the composition further includes pharmaceutically acceptable excipients.
  • the stability of the composition can be further improved by adding auxiliary materials.
  • the excipients of the present invention include at least one selected from fillers, disintegrants, binders, anti-sticking agents and lubricants.
  • the stability of the composition can be further improved by adding the above-mentioned types of auxiliary materials.
  • the filler of the present invention can be selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, lactitol and maltose.
  • the disintegrating agent of the present invention can be selected from at least one of crospovidone, sodium starch glycolate, croscarmellose sodium and low-substituted hydroxypropyl cellulose.
  • the anti-sticking agent of the present invention may be selected from at least one of colloidal silicon dioxide and talc.
  • the lubricant of the present invention may be selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and glyceryl behenate.
  • the binder of the present invention may be selected from povidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, polyethylene glycol, ethylcellulose and methylcellulose at least one of the elements.
  • the content of the filler is 22.00-91.00 parts by weight.
  • the content of the filler is 22.50 to 91.00 parts by weight; optionally, the content of the filler is about 29.00 to 82.00 parts by weight; optionally, the content of the filler is about 55.00 to 90.00 parts parts by weight; optionally, the content of the filler is about 55.00 to 82.00 parts by weight; optionally, the content of the filler is about 70.00 to 76.00 parts by weight; optionally, the content of the filler is About 65.00 to 77.00 parts by weight; Optionally, the content of the filler is about 65.00 to 76.00 parts by weight; Optionally, the content of the filler is about 60.00 to 77.00 parts by weight; Optionally, the filler The content of the filler is 60.00-76.00 parts by weight; optionally, the content of the filler is about 60.00-69.00 parts by weight.
  • the content of the anti-sticking agent in the present invention is 0.50-3.50 parts by weight.
  • the content of the anti-sticking agent is 0.50 to 2.50 parts by weight;
  • the content of the anti-sticking agent is 0.50 to 1.50 parts by weight;
  • the content of the anti-sticking agent is 1.00 to 1.50 parts by weight 2.50 parts by weight; optionally, the content of the anti-sticking agent is 1.00-2.00 parts by weight.
  • the content of the disintegrant of the present invention is 0.50-16.00 parts by weight.
  • the content of the disintegrating agent is 1.50 to 12.00 parts by weight; optionally, the content of the disintegrating agent is 2.00 to 10.00 parts by weight; optionally, the content of the disintegrating agent is 3.00 to 10.00 parts by weight; Optionally, the content of the disintegrating agent is 0.50 to 6.00 parts by weight; Optionally, the content of the disintegrating agent is 1.50 to 6.00 parts by weight;
  • the content of the disintegrating agent The content is 2.50-5.00 parts by weight; optionally, the content of the disintegrating agent is 4.00-9.00 parts by weight; optionally, the content of the disintegrating agent is 4.00-8.00 parts by weight; optionally, the The content of the disintegrating agent is 1.50-3.50 parts by weight; optionally, the content of the disintegrating agent is 2.50-6.00 parts by weight; optionally, the content of the disintegrating agent is 2.50-8.00 parts by weight.
  • the content of the lubricant of the present invention is 0.50-7.00 parts by weight.
  • the content of the lubricant is 0.50-5.00 parts by weight;
  • the content of the lubricant is 1.00-7.00 parts by weight;
  • the content of the lubricant is 1.00-6.00 parts by weight ;
  • the content of the lubricant is 1.00 to 5.00 parts by weight;
  • the content of the lubricant is 2.00 to 7.00 parts by weight;
  • the content of the lubricant is 2.00 to 6.00 parts by weight parts;
  • the content of the lubricant is 2.00 to 4.00 parts by weight;
  • the content of the lubricant is 2.00 to 3.00 parts by weight;
  • the content of the lubricant is 3.00 to 6.00 parts parts by weight;
  • the content of the lubricant is 3.00 to 4.00 parts by weight;
  • the content of the lubricant is 2.00 to 3.50 parts by
  • the content of the binder in the present invention is 0-3.50 parts by weight.
  • the content of the binder is 0 to 3.00 parts by weight; optionally, the content of the binder is 0 to 2.50 parts by weight; optionally, the content of the binder is 0 to 3.00 parts by weight; 2.00 parts by weight; optionally, the content of the binder is 2.00-3.00 parts by weight; optionally, the content of the binder is 2.50 parts by weight.
  • the present invention provides a capsule.
  • the capsule comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, an antioxidant, a filler, a disintegrant, an anti-sticking agent, a lubricant and an optional binder .
  • the "optional binder” means that the capsule may or may not contain a binder.
  • the mass ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to the antioxidant is about (4.00-77.00): (0.01-0.40).
  • the inventors have found through experiments that the use of the above ratio can reduce the amount and rate of impurities generated during the storage of the capsules, improve the stability of the capsules, and facilitate the storage of the capsules.
  • the active ingredient is the hydrochloride salt of the compound represented by formula (I).
  • the mass ratio of the hydrochloride of the compound represented by formula (I) to the antioxidant is (5.00-73.00): (0.01-0.40).
  • the inventor has found through a large number of tests that the capsules prepared within the above proportioning range have less impurity content and high stability during storage.
  • the mass ratio of the hydrochloride 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 of the compound shown in formula (I) to the antioxidant is (21.00 ⁇ 35.00): (0.03 ⁇ 0.10); optionally, the hydrochloride of the compound shown in formula (I) and the antioxidant The mass ratio of is (21.00 ⁇ 35.00): (0.03 ⁇ 0.80); Optionally, the mass ratio of the hydrochloride of the compound shown in formula (I) and antioxidant is (21.00 ⁇ 35.00): (0.05 ⁇ 0.80) Optionally, the mass ratio of the hydrochloride of the compound shown in formula (I) to the antioxidant is (21.00 ⁇ 22.00): (0.05 ⁇ 0.08); Optionally, the hydrochloric acid of the compound shown in formula (I) The mass ratio of salt to antioxidant is (34.00-35.00): (0.05-0.08).
  • the capsules of the present invention include: 5.00-73.00 or 21.00-35.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine -4(3H)-ketone hydrochloride; 0.01-0.40, 0.02-0.10 or 0.04-0.09 parts by weight of antioxidant; 22.50-90.50 parts by weight of filler; 0.50-6.00 or 2.00-6.00 parts by weight of disintegration agent; 0.50-3.50 parts by weight of anti-sticking agent; 0.50-3.50 parts by weight of lubricant; 0-2.50 parts by weight of adhesive.
  • the capsules of the present invention include: 5.00 to 73.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 0.01 to 0.40 parts by weight of an antioxidant; 22.50 to 90.50 parts by weight of a filler ; 0.50-6.00 parts by weight of a disintegrant; 0.50-3.50 parts by weight of an anti-sticking agent; 0.50-3.50 parts by weight of a lubricant; and/or, 0-2.50 parts by weight of a binder.
  • the antioxidant is an antioxidant that reacts with free radicals; optionally, the antioxidant that reacts with free radicals can be selected from butylated hydroxyanisole, butyl At least one of hydroxytoluene and propyl gallate.
  • the filler is optionally selected from mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, lactose At least one of alcohol and maltose.
  • the disintegrant is optionally selected from crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl at least one of cellulose.
  • the anti-sticking agent is optionally selected from at least one of colloidal silicon dioxide and talc.
  • the lubricant is optionally selected from magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and glyceryl behenate at least one of the .
  • the binder is optionally selected from povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, ethylcellulose at least one of cellulose and methylcellulose.
  • the antioxidant is butylated hydroxyanisole, butylated hydroxytoluene and/or propyl gallate
  • the filler is mannitol, microcrystalline cellulose and/or pre- Gelatinized starch
  • the disintegrant is crospovidone or sodium starch glycolate
  • the anti-sticking agent is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • the capsules of the present invention include: 13.00 to 58.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 20.00 to 55.00 parts by weight of mannitol; 9.00 to 28.00 parts by weight of pregelatinized starch; 1.50-3.50 parts by weight of crospovidone; 0.50-1.50 parts by weight of colloidal silicon dioxide; and 0.50-2.00 parts by weight of magnesium stearate; and at least one selected from the following: 0.05- 0.20 parts by weight of butylated hydroxyanisole; and 0.03-0.10 parts by weight of butylated hydroxytoluene.
  • the capsules include: about 34.00-34.50 parts by weight of the hydrochloride salt of the compound represented by formula (I); about 40.00-41.00 parts by weight of mannitol; about 20.00-21.00 parts by weight of pregelatin starch; about 2.00 to 2.50 parts by weight of crospovidone; about 1.00 to 1.50 parts by weight of colloidal silicon dioxide; and about 1.50 to 2.00 parts by weight of magnesium stearate; and at least one selected from the following : about 0.05-0.20 parts by weight of butylated hydroxyanisole; and about 0.03-0.10 parts by weight of butylated hydroxytoluene.
  • the capsules include: 21.00 to 22.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 43.00 to 47.00 parts by weight of microcrystalline cellulose; 20.00 to 22.00 parts by weight of pregelatinized Starch; 4.00-5.00 parts by weight of sodium carboxymethyl starch; 0-2.00 parts by weight of hydroxypropyl methylcellulose; 2.00-3.00 parts by weight of colloidal silicon dioxide; and 2.50-3.50 parts by weight of magnesium stearate and, at least one selected from the following: 0.05 parts by weight of butylated hydroxyanisole; and 0.03-0.05 parts by weight of butylated hydroxytoluene.
  • the hydrochloride salt of the compound represented by formula (I) 43.00 to 47.00 parts by weight of microcrystalline cellulose
  • 20.00 to 22.00 parts by weight of pregelatinized Starch 4.00-5.00 parts by weight of sodium carboxymethyl starch
  • 0-2.00 parts by weight of hydroxypropyl methylcellulose 2.00-3.00 parts by weight of colloidal silicon
  • the capsules include: 21.82 parts by weight of the hydrochloride salt of the compound shown in 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 0-2.00 parts by weight of hydroxypropyl methylcellulose; 2.50 parts by weight of colloidal silicon dioxide; 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 to 0.05 parts by weight of butylated hydroxytoluene.
  • the inventor has found through a large number of tests that the capsules prepared by adopting the above formula have better stability.
  • the present invention proposes a tablet.
  • the composition is a tablet, wherein the tablet comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, an antioxidant, a filler, a disintegrant, and an antiadherent , a lubricant and an optional binder.
  • the mass ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to the antioxidant is (6.00-22.00): (0.02-0.30).
  • the tablet of the present invention uses the hydrochloride of the compound shown in formula (I) as an active ingredient, optionally, the mass ratio of the hydrochloride of the compound shown in formula (I) to the antioxidant It is (6.00 ⁇ 22.00): (0.02 ⁇ 0.30).
  • the inventor found through a large number of tests that the tablet prepared by adopting the above proportion has less impurity content and high stability during storage.
  • the mass ratio of the hydrochloride of the compound represented by the formula (I) to the antioxidant is about (9.00-22.00): (0.03-0.10); optionally Preferably, the mass ratio of the hydrochloride of the compound represented by the formula (I) to the antioxidant is about (9.00-22.00): (0.03-0.08); optionally, the compound represented by the formula (I)
  • the mass ratio of hydrochloride and antioxidant is about (12.00 ⁇ 22.00): (0.03 ⁇ 0.08);
  • the mass ratio of hydrochloride and antioxidant of the compound shown in the formula (I) is about (9.00 ⁇ 22.00): (0.03 ⁇ 0.05);
  • the mass ratio of the hydrochloride of the compound represented by the formula (I) to the antioxidant is about (9.00 ⁇ 13.00): (0.03 ⁇ 0.05);
  • the mass ratio of the hydrochloride of the compound represented by the formula (I) to the antioxidant is about (12.00-13.00): (0.03-0.05); optionally, the The mass ratio of the mass ratio of the mass ratio of the hydrochloride of
  • the tablet of the present invention includes: 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-Dimethylpyrimidin-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 antioxidant; 55.00 ⁇ 90.00, 60.00 ⁇ 80.00, 60.00 ⁇ 78.00, 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 binder; 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 agent; and 2.00 ⁇ 7
  • the tablet of the present invention includes: about 6.00-22.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); about 0.02-0.10 parts by weight of antioxidant; about 55.00-90.00 parts by weight A filler; about 0-3.50 parts by weight of a binder; about 2.00-12.00 parts by weight of a disintegrant; about 0.50-3.00 parts by weight of an anti-tack agent; and about 2.50-7.00 parts by weight of a lubricant.
  • the tablet of the present invention includes: about 6.00-22.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); about 0.02-0.30 parts by weight of antioxidant; about 55.00-90.00 parts by weight 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-sticking agent; parts of lubricant.
  • the tablet of the present invention includes: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl Pyrimidin-4(3H)-one hydrochloride; about 0.02 to 0.10 parts by weight of 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 filler; about 0 to 3.50 parts by weight The binder of about 3.00 ⁇ 10.00 parts by weight; The disintegrant of about 1.00 ⁇ 2.50 parts by weight; And the lubricant of about 2.50 ⁇ 7.00, 2.50 ⁇ 6.00 or 3.00 ⁇ 4.00 parts by weight.
  • the tablet of the present invention includes: about 9.00 to 22.00 or 12.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl Pyrimidin-4(3H)-one hydrochloride; about 0.04 to 0.08 parts by weight of antioxidant; about 65.00 to 76.00 or 65.00 to 77.00 parts by weight of filler; about 0 to 3.00 parts by weight of binder; about 4.00 -8.00 or 5.00-8.00 parts by weight of a disintegrant; about 1.00-2.50 parts by weight of an anti-sticking agent; and about 2.50-6.00 or 3.00-4.00 parts by weight of a lubricant.
  • the antioxidant of the present invention is an antioxidant reactive with free radicals; optionally, the antioxidant reactive with free radicals may be selected from butylated hydroxyanisole, butylated hydroxytoluene and gall at least one of propyl esters.
  • the filler of the present invention is optionally selected from at least one of mannitol, pregelatinized starch, microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, lactitol and maltose one.
  • the disintegrant of the present invention is optionally selected from at least one of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low-substituted hydroxypropyl cellulose one.
  • the anti-sticking agent of the present invention is optionally selected from at least one of colloidal silicon dioxide and talc.
  • the lubricant of the present invention is optionally selected from at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate and glyceryl behenate.
  • the binder of the present invention is optionally selected from povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, ethylcellulose, and methylcellulose at least one of the .
  • the antioxidant of the present invention includes at least one selected from butylated hydroxyanisole, butylated hydroxytoluene and propyl gallate
  • the filler includes selected from mannitol, microcrystalline cellulose and pregelatin
  • the binder is povidone or hydroxypropyl methylcellulose
  • the disintegrant is crospovidone or sodium carboxymethyl starch
  • the anti-sticking agent is colloidal silicon dioxide
  • the lubricant is The agent is magnesium stearate.
  • the tablet of the present invention includes: 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 or 62.00 ⁇ 67.00 or 64.00 ⁇ 66.00 parts by weight of microcrystalline cellulose; 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 silicon dioxide; 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 at least one
  • the tablet of the present invention includes: 9.00-13.00 or 11.00-13.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 9.00-10.50 parts by weight of pregelatinized starch; 60.00-70.00 parts by weight Parts by weight of microcrystalline cellulose; 1.00-4.00 parts by weight of povidone or hydroxypropyl methylcellulose; 4.00-12.00 parts by weight of crospovidone; 0.50-2.50 parts by weight of colloidal silicon dioxide; 3.50-4.50 parts by weight of magnesium stearate, or 5.00-7.00 parts by weight of glyceryl behenate; and at least one selected from the following: 0.03-0.05 parts by weight of butylated hydroxytoluene; and 0.03-0.05 parts by weight of Butylated hydroxyanisole.
  • the tablet of the present invention includes: 9.00-13.00 or 12.00-13.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 9.00-10.00 parts by weight of pregelatinized starch; 64.00-67.00 parts by weight Or 64.00 ⁇ 66.00 parts by weight of microcrystalline cellulose; 2.00 ⁇ 3.00 parts by weight of povidone or hydroxypropyl methylcellulose; 4.00 ⁇ 8.00 or 6.00 ⁇ 8.00 parts by weight of crospovidone; 1.00 ⁇ 2.00 parts by weight 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 the following: 0.03 to 0.04 parts by weight of butylated hydroxy toluene; and 0.03-0.05 parts by weight of butylated hydroxyanisole.
  • the tablet of the present invention includes: 21.00 to 22.00 parts by weight of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine-4(3H )-ketone hydrochloride; 20.00 to 25.00 or 23.00 to 24.00 parts by weight of pregelatinized starch; 40.00 to 50.00 or 43.00 to 47.00 parts by weight of microcrystalline cellulose; 0 to 3.00 or 0 to 2.00 parts by weight of hydroxypropyl Methyl cellulose; 4.00 ⁇ 5.50 or 4.50 ⁇ 5.00 parts by weight of sodium starch glycolate; 2.00 ⁇ 3.00 parts by weight of colloidal silicon dioxide; and 2.00 ⁇ 4.00 or 2.50 ⁇ 3.50 parts by weight of magnesium stearate; and optional 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.
  • the tablet of the present invention includes: 21.00 to 22.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 20.00 to 25.00 parts by weight of pregelatinized starch; 40.00 to 50.00 parts by weight of Crystalline cellulose; 0-3.00 parts by weight of hydroxypropyl methylcellulose; 4.00-5.50 parts by weight of sodium starch glycolate; 2.00-3.00 parts by weight of colloidal silicon dioxide; and 2.00-4.00 parts by weight of stearin and at least one selected from the following: 0.04-0.08 parts by weight of butylated hydroxyanisole; and 0.02-0.05 parts by weight of butylated hydroxytoluene.
  • the tablet of the present invention includes: 21.00 to 22.00 parts by weight of the hydrochloride salt of the compound represented by formula (I); 23.00 to 24.00 parts by weight of pregelatinized starch; 43.00 to 47.00 parts by weight of Crystalline cellulose; 0-2.00 parts by weight of hydroxypropyl methylcellulose; 4.50-5.00 parts by weight of sodium starch glycolate; 2.00-3.00 parts by weight of colloidal silicon dioxide; and 2.50-3.50 parts by weight of stearin and at least one selected from the following: 0.04-0.06 parts by weight of butylated hydroxyanisole; and 0.02-0.04 parts by weight of butylated hydroxytoluene.
  • the tablet further comprises a coating material; optionally, the weight of the coating material is 2.00-4.00% of the weight of the plain tablet of the tablet.
  • Plain tablet refers to the total substance wrapped in the coating material in the tablet.
  • the impurity content of the samples in each embodiment of the present invention or comparative examples is measured with reference to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition general rule 0512), specifically as follows:
  • Need testing solution get need testing (for example, capsule of the present invention, tablet or the reference substance in the comparative example of the present invention), add methanol extraction and dilute to make every 1mL contain about 2.5mg formula (I ) solution of the compound shown in ) (the tablet needs to be disintegrated with a small amount of water before extraction), and then diluted with 60% methanol-water into a solution containing about 1 mg of the compound shown in formula (I) per 1 mL.
  • Reference substance solution take an appropriate amount of reference substance (such as the hydrochloride of the compound shown in formula (I)), accurately weighed, add 60% methanol-water to dissolve and be diluted to contain about 5 ⁇ g of the compound shown in formula (I) per 1 mL solution.
  • reference substance such as the hydrochloride of the compound shown in formula (I)
  • Sensitivity solution accurately measure an appropriate amount of the reference substance solution, and quantitatively dilute it with 60% methanol-water to form a solution containing about 0.5 ⁇ g of the compound represented by formula (I) per 1 mL.
  • System suitability solution get reference substance (as the hydrochloride of the compound shown in formula (I)) appropriate amount, weigh, add 60% methanol-water to dissolve and be diluted to every 1mL about containing 1mg compound shown in formula (I) solution.
  • Chromatographic conditions chromatographic column with octylsilane bonded silica gel as filler (such as Phenomenex kinetex C8 100A, 4.6 ⁇ 100mm, 2.6 ⁇ m or equivalent chromatographic column); with 0.01mol/L ammonium acetate-acetonitrile (9 : 1) mobile phase A, methanol-acetonitrile (75:25) mobile phase B, gradient elution according to the program in the table below, the detection wavelength is 266nm, and the injection volume is 10 ⁇ L.
  • the active ingredients were prepared into capsules and tested for dissolution.
  • preparation method is as follows:
  • antioxidants can also be added in step 3.
  • the binder can also be added after preparing the binder solution in step 2, and/or the antioxidant can also be added in step 3.
  • capsule samples A1 and A2 were prepared according to method A above, 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 A-C below.
  • N/A stands for “none” in this application.
  • Adopt the dissolution rate determination method (Chinese Pharmacopoeia 2020 edition general rule 0931 first method), with 900mL, 0.1M HCl as the dissolution medium, 100rpm, for the above-mentioned capsule samples, measure the dissolution rate according to law, the acceptable standard of dissolution rate is 45min ⁇ 80 %.
  • Results The results of the dissolution test showed that the dissolution rate of each sample was greater than 80% in 45 minutes.
  • the active ingredient was prepared into tablets and tested for dissolution.
  • preparation method is as follows:
  • antioxidants can also be added in step 3.
  • the binder can also be added after preparing the binder solution in step 2, and/or the antioxidant can also be added in step 3.
  • the above-mentioned coating material is a film coating premix, and the dosage is 3.0 ⁇ 1.0% of the weight of the plain tablet.
  • tablet samples B1-B2 and B5-B17 were prepared according to the third method above, and samples B3 and B4 were prepared according to the second method.
  • the composition of each sample element sheet is shown in Tables D, E and F1-F6 below.
  • Adopt dissolution test method Choinese Pharmacopoeia 2020 edition general rule 0931 second method
  • the potassium hydrogen phthalate buffer solution +1.5% Tween 80 of 900mL, pH3.0 as dissolution medium, 75rpm, to above-mentioned tablet sample
  • the dissolution rate was determined according to the law, and the acceptable standard for the dissolution rate was 45min ⁇ 80%.
  • results The results of the dissolution test showed that the dissolution rate of each sample was greater than 80% at 45 minutes, and the dissolution rate of most samples was greater than 90% at 45 minutes.
  • the capsules and tablet samples without antioxidants were prepared as reference substances. Specifically, according to the method B and method C of Example 1, the capsule reference substances C1 and C2 without antioxidants were respectively prepared; according to the second method and the third method of Example 2, the tablet comparisons without antioxidants were respectively prepared. Products C3 and C4.
  • the specific composition of each reference substance is shown in Tables G1 and G2 below.
  • the capsules and tablets of the present invention have substantially no change in the total impurity content during the experiment, and are significantly lower than the total impurity content of the control sample; especially after long-term storage, the total impurity content of each sample has no significant difference. Changes, and much lower than the total impurity content of the control sample. It can be seen that when preparing capsules or tablets, adding an antioxidant can reduce the amount and rate of impurities generated during storage and improve the stability of the tablet.

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Abstract

一种抗纤维化组合物，包括3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮或其药学上可接受的盐和抗氧剂。该组合物具有易储存、质量稳定可控、生物利用度高等优点，并且该组合物药效强、安全性高，且患者服用该组合物的顺应性好。

Description

抗纤维化组合物 技术领域
本发明属于药物领域，具体涉及一种抗纤维化组合物。
背景技术
纤维化(fibrosis)可发生于多种器官，主要病理改变为器官组织内纤维结缔组织增多，实质细胞减少，持续进展可致器官功能衰退和最终死亡，见于终末期肝病、肾脏疾病、特发性肺纤维化(IPF)和心力衰竭等，严重威胁人类健康和生命。IPF被认为是该疾病最常见和最严重的形式，中位生存期约为三年，目前驱动纤维化的确切机制尚未明确。吡非尼酮是2008年经日本和2011年经欧盟批准、由日本盐野义研发的用于抗IPF的首款药物。
专利申请WO 2014012360 A1公开了一种取代的嘧啶酮化合物，具体公开了化合物3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)，其活性优于吡非尼酮，同时，具有很好的药代动力学特性及安全性。专利申请WO 2018019166 A1公开了式(I)所示化合物的盐，如盐酸盐等，其中所述盐酸盐具有良好的稳定性和生物学性质。但前述专利申请的研究均还处于较前期的临床前研究，为了助于临床研究的开展，需要进一步的对该药物的性质进行研究，寻找适合人类服用的药物形式。
Figure PCTCN2022123811-appb-000001
发明内容
本申请的发明人在自有研发新药(式(I)所示化合物及其药学上可接受的盐)的基础上，通过初期研究发现，式(I)所示化合物或其药学上可接受的盐如盐酸盐的稳定性好，长期放置不会产生杂质或杂质含量不会升高。但在开发药物制剂的过程中，发明人发现，当将式(I)所示化合物或其药学上可接受的盐如盐酸盐通过常规方法制成药物制剂后，药物制剂的稳定性却出乎意料地变得很差。发明人为了克服药物制剂的稳定性差的问题，尝试对多种药物辅料进行筛选和配比，发现，当式(I)所示化合物或其药学上可接受的盐如盐酸盐与抗氧剂进行组合时，能够保持药物制剂的稳定性，尤其是当所述化合物或其药学上可接受的盐如盐酸盐和与自由基反应类的抗氧剂组合时，药物制剂产品的稳定性更好。
基于上述发现，本发明提供了一种具有抗纤维化作用的组合物。本发明的组合物以3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)或其药学上可接受的盐(如盐酸盐)为活性成分，与抗氧剂进行组合，很好地克服了组合物稳定性降低的问题。
一方面，本发明提供了一种组合物。在一些实施方案中，所述组合物包括3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)或其药学上可接受的盐以及抗氧剂。该组合物以3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮或其药学上可接受的盐为活性成分。本发明所述的组合物可有效治疗纤维化疾病如特发性肺纤维化等，且安全性高。
在一些实施方案中，上述组合物还可以进一步包括如下附加技术特征中的至少之一：
在一些实施方案中，本发明所述式(I)所示化合物的药学上可接受的盐为其盐酸盐。
Figure PCTCN2022123811-appb-000002
在一些实施方案中，本发明所述抗氧剂包括但不限于与自由基反应类抗氧剂和/或抗氧增效剂。
在一些实施方案中，本发明所述抗氧剂为与自由基反应类抗氧剂。
在一些实施方案中，本发明所述抗氧剂包括但不限于丁羟茴醚、丁羟甲苯、没食子酸丙酯或它们的任意组合。
在一些实施方案中，本发明所述组合物为口服制剂。
在一些实施方案中，本发明所述组合物为口服固体制剂。
在一些实施方案中，本发明所述口服固体制剂为胶囊剂或片剂。
在一些实施方案中，本发明所述组合物为胶囊剂或片剂。
在一些实施方案中，本发明所述组合物进一步包括药学上可接受的辅料。
在一些实施方案中，本发明所述辅料包括选自填充剂、崩解剂、粘合剂、抗黏剂、润滑剂中的至少之一。
在一些实施方案中，本发明所述填充剂可选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少之一。
在一些实施方案中，本发明所述崩解剂可选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠和低取代羟丙基纤维素中的至少之一。
在一些实施方案中，本发明所述抗黏剂可选自胶态二氧化硅和滑石粉中的至少之一。
在一些实施方案中，本发明所述润滑剂可选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一。
在一些实施方案中，本发明所述粘合剂可选自聚维酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
在一些实施方案中，本发明所述组合物中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为5.00～73.00重量份(例如：5.00重量份、6.00重量份、7.00重量份、8.00重量份、9.00重量份、11.00重量份、12.00重量份、12.12重量份、13.00重量份、20.00重量份、21.00重量份、21.82重量份、22.00重量份、25.00重量份、28.00重量份、31.00重量份、34.00重量份、34.09重量份、35.00重量份、58.00重量份、60.00重量份、65.00重量份、70.00重量份、73.00重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为约6.00～58.00重量份。
在一些实施方案中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为约9.00～58.00或11.00～58.00重量份。在一些实施方案中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶 -4(3H)-酮盐酸盐的含量为约6.00～22.00重量份。
在一些实施方案中，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为9.00～35.00或12.00～35.00重量份。
优选地，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为21.00～35.00重量份。或
优选地，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为9.00～22.00或12.00～22.00重量份。
在一些实施方案中，本发明所述抗氧剂含量为0.01～0.40重量份(例如：0.01重量份、0.02重量份、0.03重量份、0.04重量份、0.05重量份、0.06重量份、0.07重量份、0.08重量份、0.09重量份、0.10重量份、0.15重量份、0.20重量份、0.25重量份、0.30重量份、0.40重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述的抗氧剂含量为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或0.04～0.30重量份。
在一些实施方案中，本发明所述抗氧剂含量为0.03～0.08重量份。优选地，本发明所述抗氧剂含量为0.03～0.05重量份、0.04～0.05重量份或0.05～0.08重量份。
在一些实施方案中，本发明所述填充剂的含量为22.00～91.00重量份(例如：22.00重量份、22.50重量份、25.00重量份、29.00重量份、29.50重量份、30.00重量份、35.00重量份、40.00重量份、45.00重量份、50.00重量份、55.00重量份、55.50重量份、60.00重量份、60.36重量份、65.00重量份、65.60重量份、65.63重量份、67.00重量份、68.10重量份、68.13重量份、69.00重量份、70.00重量份、70.50重量份、71.00重量份、73.84重量份、74.00重量份、74.34重量份、74.50重量份、74.84重量份、75.34重量份、75.84重量份、76.00重量份、77.00重量份、80.00重量份、82.00重量份、86.00重量份、90.00重量份、90.50重量份、91.00重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述填充剂的含量为约22.50～91.00重量份、29.00～82.00重量份、55.00～90.00重量份、60.00～76.00重量份、60.00～77.00重量份、60.00～69.00重量份、55.00～90.00重量份、65.00～77.00重量份、65.00～76.00重量份或70.00～76.00重量份。
在一些实施方案中，本发明所述抗黏剂的含量为0.50～3.50重量份(例如：0.50重量份、1.00重量份、1.50重量份、2.00重量份、2.50重量份、3.00重量份、3.50重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述抗黏剂的含量为0.50～2.50重量份、0.50～1.50重量份、1.00～2.50重量份或1.00～2.00重量份。
在一些实施方案中，本发明所述崩解剂的含量为0.50～16.00重量份(例如：0.50重量份、1.00重量份、1.50重量份、2.00重量份、2.50重量份、3.00重量份、3.50重量份、4.00重量份、4.50重量份、5.00重量份、6.00重量份、7.00重量份、8.00重量份、9.00重量份、10.00重量份、12.00重量份、14.00重量份、16.00重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述崩解剂的含量为0.05～6.00、1.50～6.00、2.50～5.00、3.00～10.00、4.00～9.00、4.00～8.00或2.50～8.00重量份。
在一些实施方案中，本发明所述润滑剂的含量为0.50～7.00、0.50～6.00或0.50～5.00重量份(例如： 0.50重量份、1.00重量份、1.50重量份、2.00重量份、2.50重量份、3.00重量份、3.50重量份、4.00重量份、4.50重量份、5.00重量份、6.00重量份、7.00重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述润滑剂的含量为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或2.00～4.00重量份。
在一些实施方案中，本发明所述粘合剂的含量为0～3.50重量份(例如：0.01重量份、0.02重量份、0.03重量份、0.04重量份、0.05重量份、0.06重量份、0.08重量份、1.00重量份、1.50重量份、2.00重量份、2.50重量份、3.00重量份、3.50重量份或任意两个点值之间的范围值)。
在一些实施方案中，本发明所述粘合剂的含量为0～3.00、0～2.00、0～2.50或2.00～3.00重量份。
在一些实施方案中，本发明所述的组合物为胶囊剂；所述胶囊剂包含3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐、抗氧剂、填充剂、崩解剂、抗黏剂、润滑剂和任选的粘合剂。
在一些实施方案中，本发明所述胶囊剂中，3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(5.00～73.00)：(0.01～0.40)。
在一些实施方案中，本发明所述胶囊剂中，3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(21.00～35.00)：(0.03～0.08)。
在一些实施方案中，本发明所述胶囊剂中，3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(21.00～35.00)：(0.05～0.08)。
在一些实施例中，本发明所述胶囊剂中，3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(21.00～22.00)：(0.05～0.08)。
在一些实施例中，本发明所述胶囊剂中，3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(34.00～35.00)：(0.05～0.08)。
在一些实施方案中，本发明所述胶囊剂包括：5.00～73.00或21.00～35.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.01～0.40、0.02～0.10或0.04～0.09重量份的抗氧剂；22.50～90.50重量份的填充剂；0.50～6.00或2.00～6.00重量份的崩解剂；0.50～3.50重量份的抗黏剂；0.50～3.50重量份的润滑剂；和0～2.50重量份的粘合剂。
在一些实施方案中，本发明所述胶囊剂包括：5.00～73.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.01～0.40重量份的抗氧剂；22.50～90.50重量份的填充剂；0.50～6.00重量份的崩解剂；0.50～3.50重量份的抗黏剂；0.50～3.50重量份的润滑剂；和0～2.50重量份的粘合剂。
在一些实施例中，本发明所述胶囊剂包括：21.00～35.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.02～0.10重量份的抗氧剂；22.50～90.50重量份的填充剂；2.00～6.00重量份的崩解剂；0.50～3.50重量份的抗黏剂；0.50～3.50重量份的润滑剂；和0～2.50重量份的粘合剂。
在一些实施例中，本发明所述胶囊剂包括：21.00～35.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.05～0.08重量份的抗氧剂；60.00～70.00重量份的填充剂；2.00～6.00重量份的崩解剂；0.50～3.00重量份的抗黏剂；1.50～3.50重量份的润滑剂；0～2.50重量份的粘合剂。
在一些实施方案中，本发明所述胶囊剂中，所述填充剂任选地选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述崩解剂任选地选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠和低取代羟丙基纤维素中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述抗黏剂任选地选自胶态二氧化硅和滑石粉中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述润滑剂任选地选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述粘合剂任选地选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述抗氧剂包括选自丁羟茴醚、丁羟甲苯和没食子酸丙酯中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述填充剂包括选自甘露醇、微晶纤维素和预胶化淀粉中的至少之一，所述崩解剂为交联聚维酮或羧甲淀粉钠，所述抗黏剂为胶态二氧化硅，所述润滑剂为硬脂酸镁。
在一些实施方案中，本发明所述胶囊剂包括：13.00～58.00或34.00～34.50重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；20.00～55.00或40.00～41.00重量份的甘露醇；9.00～28.00或20.00～21.00重量份的预胶化淀粉；1.50～3.50或2.00～3.00重量份的交联聚维酮；0.50～2.50或0.50～1.50重量份的胶态二氧化硅；和0.50～3.00或1.50～2.50重量份的硬脂酸镁；以及选自下列的至少之一：0.03～0.20或0.04～0.06重量份的丁羟茴醚；和0.03～0.10或0.04～0.06重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：13.00～58.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；20.00～55.00重量份的甘露醇；9.00～28.00重量份的预胶化淀粉；1.50～3.50重量份的交联聚维酮；0.50～2.50重量份的胶态二氧化硅；0.50～3.00重量份的硬脂酸镁；和0.04～0.06重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：34.00～34.50重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；40.00～41.00重量份的甘露醇；20.00～21.00重量份的预胶化淀粉；2.00～3.00重量份的交联聚维酮；0.50～1.50重量份的胶态二氧化硅；和1.50～2.50重量份的硬脂酸镁；以及选自下列的至少之一：0.04～0.06重量份的丁羟茴醚；和0.04～0.06重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：13.00～58.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；20.00～55.00重量份的甘露醇；9.00～28.00重量份的预胶化淀粉；1.50～3.50重量份的交联聚维酮；0.50～2.50重量份的胶态二氧化硅；和0.50～3.00重量份的硬脂酸镁；以及，选自下列的至少之一：0.03～0.20重量份的丁羟茴醚；和0.03～0.10重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：约34.00～34.50重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约40.00～41.00重量份的甘露醇；约20.00～21.00重量份的预胶化淀粉；约2.00～3.00重量份的交联聚维酮；约0.50～1.50重量份的胶态二氧化硅；和约1.50～2.50重量份的硬脂酸镁；以及，选自下列的至少之一：约0.04～0.06重量份的丁羟茴醚；和约0.04～0.06重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6- 二甲基嘧啶-4(3H)-酮盐酸盐；43.00～47.00重量份的微晶纤维素；20.00～23.00或21.00～23.00重量份的预胶化淀粉；4.00～6.00或4.00～5.50重量份的羧甲淀粉钠；0～2.00重量份的羟丙基甲基纤维素；2.00～3.00重量份的胶态二氧化硅；和2.00～3.50或2.50～3.50重量份的硬脂酸镁；以及，选自下列的至少之一：0.03～0.10或0.04～0.06重量份的丁羟茴醚；和0.02～0.10或0.02～0.05重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；43.00～47.00重量份的微晶纤维素；20.00～23.00重量份的预胶化淀粉；4.00～6.00重量份的羧甲淀粉钠；0～2.00重量份的羟丙基甲基纤维素；2.00～3.00重量份的胶态二氧化硅；和2.00～3.50重量份的硬脂酸镁；以及，选自下列的至少之一：0.03～0.10重量份的丁羟茴醚；和0.02～0.10重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；43.00～47.00重量份的微晶纤维素；21.00～23.00重量份的预胶化淀粉；4.00～5.50重量份的羧甲淀粉钠；0～2.00重量份的羟丙基甲基纤维素；2.00～3.00重量份的胶态二氧化硅；和2.50～3.50重量份的硬脂酸镁；以及，选自下列的至少之一：0.04～0.06重量份的丁羟茴醚；和0.02～0.05重量份的丁羟甲苯。
在一些实施方案中，本发明所述胶囊剂包括：21.82重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；43.00～47.00重量份的微晶纤维素；22.00重量份的预胶化淀粉；4.50～5.00重量份的羧甲淀粉钠；0～2.00重量份的羟丙基甲基纤维素；2.50重量份的胶态二氧化硅；和3.00重量份的硬脂酸镁；以及，选自下列的至少之一：0.05重量份的丁羟茴醚；和0.03重量份的丁羟甲苯。
在一些实施方案中，本发明所述组合物为片剂；所述片剂包含3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐、抗氧剂、填充剂、崩解剂、抗黏剂、润滑剂和任选的粘合剂。
在一些实施方案中，上述片剂还可以进一步包括如下附加技术特征至少之一：
在一些实施方案中，本发明所述片剂中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与所述抗氧剂的质量比为(6.00～22.00)：(0.02～0.30)。
在一些实施方案中，本发明所述片剂中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与所述抗氧剂的质量比为(9.00～22.00)：(0.03～0.10)。
在一些实施方案中，本发明所述片剂中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与所述抗氧剂的质量比为(9.00～22.00)：(0.03～0.08)。
在一些实施例中，本发明所述片剂中，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为约(12.00～22.00)：(0.03～0.08)。
在一些实施例中，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为约(9.00～13.00)：(0.03～0.05)。
在一些实施例中，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为约(12.00～13.00)：(0.03～0.05)。
在一些实施例中，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为约(21.00～22.00)：(0.04～0.10)。
在一些实施例中，本发明所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为约(21.00～22.00)：(0.05～0.08)。
在一些实施方案中，本发明所述片剂包括：6.00～22.00、9.00～22.00、9.00～13.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.02～0.30、0.03～0.10、0.04～0.08、0.05～0.08或0.03～0.05重量份的抗氧剂；55.00～90.00、60.00～80.00、60.00～78.00、60.00～76.00、60.00～77.00、65.00～77.00或65.00～76.00重量份的填充剂；0～3.50重量份的粘合剂；2.00～12.00、3.00～10.00、4.00～9.00、4.00～8.00、5.0～8.00或6.00～8.00重量份的崩解剂；0.50～3.00或1.00～2.50重量份的抗黏剂；和2.00～7.00、2.50～6.00、2.50～5.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：6.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.02～0.30重量份的抗氧剂；55.00～90.00重量份的填充剂；0～3.50重量份的粘合剂；2.00～12.00重量份的崩解剂；0.50～3.00重量份的抗黏剂；2.50～7.00或和2.50～6.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约6.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.02～0.10重量份的抗氧剂；约55.00～90.00重量份的填充剂；约0～3.50重量份的粘合剂；约2.00～12.00重量份的崩解剂；约0.50～3.00重量份的抗黏剂；和约2.50～6.00或2.50～5.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.02～0.10重量份的抗氧剂；约60.00～80.00、60.00～78.00、60.00～76.00或60.00～77.00重量份的填充剂；约0～3.50重量份的粘合剂；约3.00～10.00重量份的崩解剂；约1.00～2.50重量份的抗黏剂；和约2.50～7.00、2.50～6.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.03～0.10重量份的抗氧剂；约60.00～78.00、60.00～76.00或60.00～77.00重量份的填充剂；约0～3.50重量份的粘合剂；约3.00～10.00重量份的崩解剂；约1.00～2.50重量份的抗黏剂；和约2.50～6.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.04～0.08重量份的抗氧剂；约65.00～76.00或65.00～77.00重量份的填充剂；约0～3.00重量份的粘合剂；约4.00～8.00或5.00～8.00重量份的崩解剂；约1.00～2.50重量份的抗黏剂；和约2.50～6.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.03～0.05重量份的抗氧剂；约65.00～76.00或65.00～77.00重量份的填充剂；约0～3.50重量份的粘合剂；约4.00～8.00或5.0～8.00重量份的崩解剂；约1.00～2.50重量份的抗黏剂；和约2.50～6.00或3.00～4.00重量份的润滑剂。
在一些实施例中，本发明所述片剂中，所述填充剂任选地选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少之一。
在一些实施方案中，本发明所述片剂中，所述崩解剂任选地选自交联聚维酮、羧甲基淀粉钠、交联 羧甲基纤维素钠和低取代羟丙基纤维素中的至少之一。
在一些实施方案中，本发明所述片剂中，所述抗黏剂任选地选自胶态二氧化硅和滑石粉中的至少之一。
在一些实施方案中，本发明所述片剂中，所述润滑剂任选地选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一。
在一些实施方案中，本发明所述片剂中，所述粘合剂任选地选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
在一些实施方案中，本发明所述片剂中，所述抗氧剂包括选自丁羟茴醚、丁羟甲苯和没食子酸丙酯中的至少之一。
在一些实施方案中，本发明所述片剂中，所述填充剂包括选自甘露醇、微晶纤维素和预胶化淀粉中的至少之一，所述粘合剂为聚维酮或羟丙基甲基纤维素，所述崩解剂为交联聚维酮或羧甲淀粉钠，所述抗黏剂为胶态二氧化硅，所述润滑剂为硬脂酸镁或山嵛酸甘油酯。
在一些实施方案中，本发明所述片剂包括：9.00～13.00、11.00～13.00或12.00～13.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；9.00～10.50或9.00～10.00重量份的预胶化淀粉；60.00～70.00或62.00～67.00或64.00～66.00重量份的微晶纤维素；1.00～4.00或2.00～3.00重量份的聚维酮或羟丙基甲基纤维素；4.00～12.00、4.00～9.00、5.00～9.00、4.00～8.00或6.00～8.00重量份的交联聚维酮；0.50～2.50或1.00～2.00重量份的胶态二氧化硅；2.50～4.50或3.00～4.00重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及选自下列的至少之一：0.03～0.05或0.03～0.04重量份的丁羟甲苯；和0.03～0.08或0.03～0.05重量份的丁羟茴醚。
在一些实施方案中，本发明所述片剂包括：9.00～13.00或11.00～13.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；9.00～10.50重量份的预胶化淀粉；60.00～70.00重量份的微晶纤维素；1.00～4.00重量份的聚维酮或羟丙基甲基纤维素；4.00～12.00重量份的交联聚维酮；0.50～2.50重量份的胶态二氧化硅；2.50～4.50重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及选自下列的至少之一：0.03～0.05重量份的丁羟甲苯；和0.03～0.05重量份的丁羟茴醚。
在一些实施方案中，本发明所述片剂包括：9.00～13.00或12.00～13.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；9.00～10.00重量份的预胶化淀粉；64.00～66.00或64.00～67.00重量份的微晶纤维素；2.00～3.00重量份的聚维酮或羟丙基甲基纤维素；4.00～8.00或6.00～8.00重量份的交联聚维酮；1.00～2.00重量份的胶态二氧化硅；3.00～4.00重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及选自下列的至少之一：0.03～0.04重量份的丁羟甲苯；和0.03～0.05重量份的丁羟茴醚。
在一些实施方案中，本发明所述片剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；20.00～25.00或23.00～24.00重量份的预胶化淀粉；40.00～50.00或43.00～47.00重量份的微晶纤维素；0～3.00或0～2.00重量份的羟丙基甲基纤维素；4.00～5.50或4.50～5.00重量份的羧甲淀粉钠；2.00～3.00重量份的胶态二氧化硅；和2.00～4.00或2.50～3.50重量份的硬脂酸镁；以及选自下列的至少之一：0.04～0.08或0.04～0.06重量份的丁羟茴醚；和0.02～0.05或0.02～0.04重量份的丁羟甲苯。
在一些实施方案中，本发明所述片剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；20.00～25.00重量份的预胶化淀粉；40.00～50.00重量份的微晶纤维素；0～3.00重量份的羟丙基甲基纤维素；4.00～5.50重量份的羧甲淀粉钠；2.00～3.00重量份的胶态二氧化硅；和2.00～4.00重量份的硬脂酸镁；以及，选自下列的至少之一：0.04～0.08重量份的丁羟茴醚；和0.02～0.05重量份的丁羟甲苯。
在一些实施方案中，本发明所述片剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；23.00～24.00重量份的预胶化淀粉；43.00～47.00重量份的微晶纤维素；0～2.00重量份的羟丙基甲基纤维素；4.50～5.00重量份的羧甲淀粉钠；2.00～3.00重量份的胶态二氧化硅；和2.50～3.50重量份的硬脂酸镁；以及，选自下列的至少之一：0.04～0.06重量份的丁羟茴醚；和0.02～0.04重量份的丁羟甲苯。
在一些实施方案中，所述片剂进一步包含包衣材料；任选地，所述包衣材料为薄膜包衣预混剂。
在一些实施方案中，所述包衣材料的重量为所述片剂的素片重量的2.0～4.0％。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
需要说明的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地，在本发明的描述中，除非另有说明，“多个”的含义是两个或两个以上。
本发明详细说明
定义及一般术语
在更详细地描述本发明之前，应理解，本发明不限于本文中描述的特定实施方式，因为这样的实施方式可以变化。还应理解，本文中使用的术语仅用于描述特定实施方式的目的，并且术语不用于限制。除非另有规定，本文使用的所有技术和科学术语具有本领域技术人员普遍理解的相同含义。本文参照的所有出版物和专利均通过引用将其全部内容并入本文。
在本发明的上下文中，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％、2％、5％、7％、8％或10％等差异。每当公开一个具有N值的数字时，任何具有N+/-1％、N+/-2％、N+/-3％、N+/-5％、N+/-7％、N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。每当公开一个数值范围中的一个下限、DL和一个上限、DU时，任何处于该公开了的范围之内的数值会被明确地公开。
在提供数值范围的情况下，应理解，除非上下文另有明确指出，至上下限单位的十分之一，该范围上下限之间的插入值和在所述范围中的任何其他陈述或插入的值被涵盖在本发明内。这些较小范围的上下限可以独立地包括在该较小范围内并且也涵盖在本发明中，经过在所述范围内的任何具体地排除限 制。在所述范围包括所述界限之一或两个的情况下，排除那些包括界限的任一个或二者的范围也包括在本发明中。
某些范围以前面用术语“约”的数值提供在本文中。术语“约”在本文中用来对精确数值以及接近或近似之前有该术语的数值提供文字支持。在确定数值是否接近或近似具体陈述的数值中，该接近或近似的未陈述数值可以是这样的数值，在提供其的上下文中，其提供该具体陈述数值的实质性等同。术语“约”或“大约”是指由本领域技术人员确定的对于特定值可接受的误差，其部分取决于如何测量或确定该值。在某些实施方案中，术语“约”或“大约”指在1、2、3或4个标准偏差之内。在某些实施方案中，术语“约”或“大约”指在给定值或范围的30％、25％、20％、15％、10％、9％、8％、7％、6％、5％、4％、3％、2％、1％、0.5％、0.1％或0.05％之内。
术语“任选地”，“任选的”或“任选”是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。例如，本发明所述组合物包含任选的粘合剂，代表所述组合物可以包含粘合剂，也可以不包含粘合剂。
术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地，本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。在一些实施方案中，本发明所述的药学上可接受的盐包括但不限于盐酸盐、苯磺酸盐、对甲苯磺酸盐、硫酸盐、氢溴酸盐等。优选地，本发明所述的药学上可接受的盐为盐酸盐。
对本文所提及的这些和其他药学上可接受的辅料或工艺可参考关于此主题的大量文献，具体而言参见Handbook of Pharmaceutical Excipients，第3版，Arthur H.Kibbe编辑，American Pharmaceutical Association,Washington,USA和Pharmaceutical Press,London；以及Lexikon der Hilfsstoffe für Pharmazie、Kosmetik和angrenzende Gebiete，H.P.Fiedler编辑，第4版，编辑Cantor、Aulendorf和早期版本。
本发明所提供的组合物或制剂可单独给予患者，也可与其他活性制剂共同给予或联合给药。术语“共同给予”和“联合”包括在没有具体时限的情况下同时或顺序给予两种或多种治疗剂。在一个实施方案中，试剂同时存在于细胞中或个体体内，或者同时发挥生物或治疗效果。在一个实施方案中，各治疗剂在同一组合物或单位剂型中。在其他实施方案中，各治疗剂在不同的组合物或单位剂型中。在某些实施方案中，在给予第二治疗剂之前(例如，5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周前)、同时或之后(例如，5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周后)给予第一种试剂。
术语“活性成分”或“活性剂”是指用于治疗(如，人治疗，兽医治疗)(包括预防性和治疗性治疗)的物质。活性成分包括用作药物的任何物质，该药物用于治疗、预防、延迟、减轻或改善疾病、病症或障碍。
术语“口服制剂”是指经口给予，且药物在胃肠道内吸收入血的制剂形式，包括片剂、颗粒剂、胶囊剂、口服溶液剂等。
术语“固体口服制剂”是指片剂、分散片、速溶片、快溶片、速融片、口溶片、口融片、口腔分散片、冻干单位、多孔片、常规片、包衣片、未包衣片、肠溶片(gastro-resistant tablet)、泡腾片、可溶片、咀嚼片、口服冻干物、散剂、口服散剂、丸剂、胶囊剂和/或颗粒剂。在一些实施例中，所述固体口服制剂为胶囊。在一些实施例中，所述固体口服制剂为片剂。
术语“重量份”是指组合物某一成分质量与其他成分质量对比后获得的质量份数，例如所述抗氧剂含量为0.01～0.40重量份，是指抗氧剂与组合物的其他成分的质量进行对比后获得的质量份数为0.01～0.40重量份。
在制剂制备中，各组分重量数据存在依据比例放大或略省或等量替换的情况，在本发明中，可依据各组分本身的分子量或质量之间的计量关系，在具体数值或小数点位数上或精确到不同小数点的位数上进行延伸，包括但不限于，在药学上可理解的范围内或在科学计数的情况下，依据四舍五入的规则进一步类推，例如，填充剂的含量为80.00重量份，该含量与79.95重量份、80.01重量份、80.35重量份等含量之间是相等效果或可相互替换的，其他组分可以此类推。
术语“抗氧增强剂”是指阻碍自由基形成、与其他抗氧剂系统增效。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
组合物
在本发明的一个方面，本发明提出了一种组合物，所述化合物具有抗纤维化作用，可以用于治疗纤维化疾病如肝纤维化、肺纤维化如特发性肺纤维化等。在一些实施方案中，该组合物包括3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)或其药学上可接受的盐以及抗氧剂。
在一些实施方案中，该组合物以3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮或其药学上可接受的盐如盐酸盐为活性成分。发明人通过大量试验发现，通过所述活性成分与抗氧剂组合，很好地克服了组合物稳定性降低的问题。该组合物在储存过程中有效地减少了杂质的生成，具有易储存、质量稳定可控、生物利用度高等优点。并且，发明人还发现，本发明制得的组合物的药效强、安全性高，且患者服用的顺应性好。
在一些实施方案中，本发明所述式(I)所示化合物的药学上可接受的盐为其盐酸盐。本发明所述组合物包含以式(I)所示化合物的盐酸盐作为活性成分。
Figure PCTCN2022123811-appb-000003
在一些实施例中，本发明所述抗氧剂包含但不限于与自由基反应类抗氧剂和/或抗氧增效剂。
在一些实施方案中，本发明所述抗氧剂为与自由基反应类抗氧剂；任选地，与自由基反应类抗氧剂可选自丁羟茴醚、丁羟甲苯(又称二丁基羟基甲苯)和没食子酸丙酯中的至少之一。与自由基反应类抗氧剂是一类能够与自由基反应的抗氧剂，其能够阻断氧化过程的连锁反应，发明人通过大量试验发现， 采用该类抗氧剂的效果更佳。
在一些实施方案中，本发明所述组合物为口服制剂。
在一些实施方案中，本发明所述组合物为口服固体制剂。将式(I)所示化合物或其药学上可接受的盐和抗氧剂制成口服固体制剂的稳定性的效果好。任选地，本发明所述口服固体制剂为胶囊剂或片剂。
在一些实施方案中，本发明所述组合物为胶囊剂或片剂。将式(I)所示化合物或其药学上可接受的盐和抗氧剂制成胶囊剂和/或片剂，其稳定性的效果更好。
在一些实施方案中，本发明所述组合物中含有合适量的式(I)所示化合物或其药学上可接受的盐。所述合适量为所述化合物的有效剂量，所述有效剂量是安全有效的。优选地，所述组合物中，式(I)所示化合物的含量可以为4.00～70.00重量份；任选地，所述组合物中，式(I)所示化合物的含量可以为4.50～67.00重量份；任选地，所述组合物中，式(I)所示化合物的含量可以为20.00～32.00重量份；任选地，所述组合物中，式(I)所示化合物的含量可以为8.00～32.00重量份；任选地，所述组合物中，式(I)所示化合物的含量可以为11.00～32.00重量份；任选地，所述组合物中，式(I)所示化合物的含量可以为8.00～20.00重量份；任选地，所述组合物中，式(I)所示化合物的含量可以为11.00～20.00重量份。任选地，当所述组合物中的活性成分为式(I)所述化合物的药学上可接受的盐时，所述盐的含量可以根据游离化合物与相应盐的分子量之比进行换算。
在一些实施方案中，本发明所述组合物以式(I)所示化合物的药学上可接受的盐为活性成分。优选地，本发明所述组合物可以以式(I)所示化合物的盐酸盐为活性成分。
在一些实施方案中，本发明所述组合物中，所述式(I)所示化合物的盐酸盐的含量为5.00～73.00重量份；任选地，所述式(I)所示化合物的盐酸盐含量为约6.00～58.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约9.00～58.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约11.00～58.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约12.00～58.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约13.00～58.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约9.00～35.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约12.00～35.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约6.00～22.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约9.00～22.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约21.00～35.00重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约12.0～22.0重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为12.12～34.09重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为12.12～21.82重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为21.82～34.09重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为约9、12、22或34重量份；任选地，所述式(I)所示化合物的盐酸盐的含量为9.09、12.12、21.82或34.09重量份。
在一些实施方案中，所述组合物中，抗氧剂含量为0.01～0.40重量份；任选地，所述抗氧剂含量为0.02～0.40重量份；任选地，所述抗氧剂含量为0.01～0.30重量份；任选地，所述抗氧剂含量为0.01～0.20重量份；任选地，所述抗氧剂含量为0.02～0.30重量份；任选地，所述抗氧剂含量为0.03～0.30重量份；任选地，所述抗氧剂含量为0.03～0.20重量份；任选地，所述抗氧剂含量为0.03～0.10重量份；任选地，所述抗氧剂含量为0.05～0.20重量份；任选地，所述抗氧剂含量为0.08～0.30重量份；任选地，所述抗氧 剂含量为0.08～0.20重量份；任选地，所述抗氧剂含量为0.08～0.10重量份；任选地，所述抗氧剂含量为0.04～0.30重量份；任选地，所述抗氧剂含量为0.03～0.08重量份；任选地，所述抗氧剂含量为0.03～0.05重量份；任选地，所述抗氧剂含量为0.04～0.05重量份；任选地，所述抗氧剂含量为0.05～0.08重量份。
发明人通过大量试验发现，将抗氧剂的含量控制在0.01～0.4重量份，特别是在0.03～0.10重量份，可有效降低组合物储存过程中杂质的生成量和生成速率，提高组合物的稳定性，方便组合物的储存。
在一些实施方案中，该组合物进一步包括药学上可接受的辅料。通过辅料的加入，能够进一步提高组合物的稳定性。
在一些实施方案中，本发明所述辅料包括选自填充剂、崩解剂、粘合剂、抗黏剂和润滑剂中的至少之一。通过加入上述类型的辅料，能够进一步提高组合物的稳定性。
在一些实施方案中，本发明所述填充剂可选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少一种。
在一些实施方案中，本发明所述崩解剂可选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠和低取代羟丙基纤维素中的至少一种。
在一些实施方案中，本发明所述抗黏剂可选自胶态二氧化硅和滑石粉中的至少之一。
在一些实施方案中，本发明所述润滑剂可选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一。
在一些实施方案中，本发明所述粘合剂可选自聚维酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
在一些实施方案中，本发明所述组合物中，所述填充剂的含量为22.00～91.00重量份。任选地，所述填充剂的含量为22.50～91.00重量份；任选地，所述填充剂的含量为约29.00～82.00重量份；任选地，所述填充剂的含量为约55.00～90.00重量份；任选地，所述填充剂的含量为约55.00～82.00重量份；任选地，所述填充剂的含量为约70.00～76.00重量份；任选地，所述填充剂的含量为约65.00～77.00重量份；任选地，所述填充剂的含量为约65.00～76.00重量份；任选地，所述填充剂的含量为约60.00～77.00重量份；任选地，所述填充剂的含量为60.00～76.00重量份；任选地，所述填充剂的含量为约60.00～69.00重量份。
在一些实施方案中，本发明所述抗黏剂的含量为0.50～3.50重量份。任选地，所述抗黏剂的含量为0.50～2.50重量份；任选地，所述抗黏剂的含量为0.50～1.50重量份；任选地，所述抗黏剂的含量为1.00～2.50重量份；任选地，所述抗黏剂的含量为1.00～2.00重量份。
在一些实施方案中，本发明所述崩解剂的含量为0.50～16.00重量份。任选地，所述崩解剂的含量为1.50～12.00重量份；任选地，所述崩解剂的含量为2.00～10.00重量份；任选地，所述崩解剂的含量为3.00～10.00重量份；任选地，所述崩解剂的含量为0.50～6.00重量份；任选地，所述崩解剂的含量为1.50～6.00重量份；任选地，所述崩解剂的含量为2.50～5.00重量份；任选地，所述崩解剂的含量为4.00～9.00重量份；任选地，所述崩解剂的含量为4.00～8.00重量份；任选地，所述崩解剂的含量为1.50～3.50重量份；任选地，所述崩解剂的含量为2.50～6.00重量份；任选地，所述崩解剂的含量为2.50～8.00重量份。
在一些实施方案中，本发明所述润滑剂的含量为0.50～7.00重量份。任选地，所述润滑剂的含量为 0.50～5.00重量份；任选地，所述润滑剂的含量为1.00～7.00重量份；任选地，所述润滑剂的含量为1.00～6.00重量份；任选地，所述润滑剂的含量为1.00～5.00重量份；任选地，所述润滑剂的含量为2.00～7.00重量份；任选地，所述润滑剂的含量为2.00～6.00重量份；任选地，所述润滑剂的含量为2.00～4.00重量份；任选地，所述润滑剂的含量为2.00～3.00重量份；任选地，所述润滑剂的含量为3.00～6.00重量份；任选地，所述润滑剂的含量为3.00～4.00重量份；任选地，所述润滑剂的含量为2.00～3.50重量份；任选地，所述润滑剂的含量为2.00～4.00重量份；任选地，所述润滑剂的含量为5.00～7.00重量份。
在一些实施方案中，本发明所述粘合剂的含量为0～3.50重量份。任选地，所述粘合剂的含量为0～3.00重量份；任选地，所述粘合剂的含量为0～2.50重量份；任选地，所述粘合剂的含量为0～2.00重量份；任选地，所述粘合剂的含量为2.00～3.00重量份；任选地，所述粘合剂的含量为2.50重量份。
胶囊剂
在本发明的又一方面，本发明提出了一种胶囊剂。在一些实施方案中，该胶囊剂包含式(I)所示化合物或其药学上可接受的盐、抗氧剂、填充剂、崩解剂、抗黏剂、润滑剂和任选的粘合剂。其中，所述“任选的粘合剂”是指，所述胶囊剂中可以包含粘合剂，也可以不含有粘合剂。
发明人通过大量试验发现，采用上述配方制得的胶囊剂，其储存过程中的杂质含量少、溶出度好，并且，可提高该胶囊剂的稳定性和安全性。
在一些实施方案中，本发明所述胶囊剂中，式(I)所示化合物或其药学上可接受的盐与抗氧剂的质量比约为(4.00～77.00)：(0.01～0.40)。发明人通过试验发现，采用上述配比，可降低胶囊剂储存过程中杂质的生成量和生成速率，提高胶囊剂的稳定性，方便胶囊剂的储存。
在一些实施方案中，本发明所述胶囊剂中，活性成分为式(I)所示化合物的盐酸盐。
在一些实施方案中，本发明所述的胶囊剂中，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(5.00～73.00)：(0.01～0.40)。发明人通过大量试验发现，上述配比范围内制得的胶囊剂在储存过程中的杂质含量少、稳定性高。
在一些实施方案中，本发明所述的胶囊剂中，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(13.00～58.00)：(0.03～0.30)；任选地，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(21.00～35.00)：(0.03～0.10)；任选地，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(21.00～35.00)：(0.03～0.80)；任选地，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(21.00～35.00)：(0.05～0.80)；任选地，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(21.00～22.00)：(0.05～0.08)；任选地，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(34.00～35.00)：(0.05～0.08)。
在一些实施方案中，本发明所述胶囊剂包括：5.00～73.00或21.00～35.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.01～0.40、0.02～0.10或0.04～0.09重量份的抗氧剂；22.50～90.50重量份的填充剂；0.50～6.00或2.00～6.00重量份的崩解剂；0.50～3.50重量份的抗黏剂；0.50～3.50重量份的润滑剂；0～2.50重量份的粘合剂。
在一些实施方案中，本发明所述胶囊剂包括：5.00～73.00重量份的式(I)所示化合物的盐酸盐；0.01～0.40重量份的抗氧剂；22.50～90.50重量份的填充剂；0.50～6.00重量份的崩解剂；0.50～3.50重量份 的抗黏剂；0.50～3.50重量份的润滑剂；和/或，0～2.50重量份的粘合剂。
在一些实施方案中，本发明所述胶囊剂中，所述抗氧剂为与自由基反应类抗氧剂；任选地，与自由基反应类抗氧剂可选自丁羟茴醚、丁羟甲苯和没食子酸丙酯中的至少之一。
发明人通过大量试验发现，采用上述配方制得的胶囊剂，其储存过程中的杂质含量少、溶出度好，并且，可提高该胶囊剂的稳定性和安全性。
在一些实施方案中，本发明所述胶囊剂中，所述填充剂任选地选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述崩解剂任选地选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠和低取代羟丙基纤维素中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述抗黏剂任选地选自胶态二氧化硅和滑石粉中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述润滑剂任选地选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述粘合剂任选地选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
在一些实施方案中，本发明所述胶囊剂中，所述抗氧剂为丁羟茴醚、丁羟甲苯和/或没食子酸丙酯，填充剂为甘露醇、微晶纤维素和/或预胶化淀粉，崩解剂为交联聚维酮或羧甲淀粉钠，抗黏剂为胶态二氧化硅，润滑剂为硬脂酸镁。发明人通过试验发现，采用上述原料制得的胶囊剂，在储存过程中的杂质生成量少，具有易储存和稳定性好等优点。
在一些实施方案中，本发明所述胶囊剂包括：13.00～58.00重量份的式(I)所示化合物的盐酸盐；20.00～55.00重量份的甘露醇；9.00～28.00重量份的预胶化淀粉；1.50～3.50重量份的交联聚维酮；0.50～1.50重量份的胶态二氧化硅；和0.50～2.00重量份的硬脂酸镁；以及，选自下列的至少之一：0.05～0.20重量份的丁羟茴醚；和0.03～0.10重量份的丁羟甲苯。
在一些实施方案中，所述胶囊剂包括：约34.00～34.50重量份的式(I)所示化合物的盐酸盐；约40.00～41.00重量份的甘露醇；约20.00～21.00重量份的预胶化淀粉；约2.00～2.50重量份的交联聚维酮；约1.00～1.50重量份的胶态二氧化硅；和约1.50～2.00重量份的硬脂酸镁；以及，选自下列的至少之一：约0.05～0.20重量份的丁羟茴醚；和约0.03～0.10重量份的丁羟甲苯。
在一些实施方案中，所述胶囊剂包括：21.00～22.00重量份的式(I)所示化合物的盐酸盐；43.00～47.00重量份的微晶纤维素；20.00～22.00重量份的预胶化淀粉；4.00～5.00重量份的羧甲淀粉钠；0～2.00重量份的羟丙基甲基纤维素；2.00～3.00重量份的胶态二氧化硅；和2.50～3.50重量份的硬脂酸镁；以及，选自下列的至少之一：0.05重量份的丁羟茴醚；和0.03～0.05重量份的丁羟甲苯。
在一些实施方案中，所述胶囊剂包括：21.82重量份的式(I)所示化合物的盐酸盐；43.00～47.00重量份的微晶纤维素；22.00重量份的预胶化淀粉；4.50重量份的羧甲淀粉钠；0～2.00重量份的羟丙基甲基纤维素；2.50重量份的胶态二氧化硅；和3.00重量份的硬脂酸镁；以及，选自下列的至少之一：0.05重量份的丁羟茴醚；和0.03～0.05重量份的丁羟甲苯。
发明人通过大量试验发现，采用上述配方制得的胶囊剂的稳定性较好。
另外，本领域技术人员能够理解的是，前面针对组合物所描述的特征和优点同样适用于该胶囊剂，在此不再赘述。
片剂
在本发明的另一方面，本发明提出了一种片剂。在一些实施方案中，该组合物为片剂，其中，所述片剂包含式(I)所示化合物或其药学上可接受的盐、抗氧剂、填充剂、崩解剂、抗黏剂、润滑剂和任选的粘合剂。
发明人通过大量试验发现，采用上述配方制得的片剂，其储存过程中的杂质含量少、溶出度好，并且，可提高该片剂的稳定性和安全性。
在一些实施方案中，本发明所述片剂中，式(I)所示化合物或其药学上可接受的盐与抗氧剂的质量比为(6.00～22.00)：(0.02～0.30)。发明人通过大量试验发现，采用上述配比，可降低片剂储存过程中杂质的生成量和生成速率，提高片剂的稳定性，方便片剂的储存。
在一些实施方案中，本发明所述片剂以式(I)所示化合物的盐酸盐为活性成分，任选地，式(I)所示化合物的盐酸盐与抗氧剂的质量比为(6.00～22.00)：(0.02～0.30)。发明人通过大量试验发现，采用上述配比制得的片剂的在储存过程中的杂质含量少、稳定性高。
在一些实施方案中，本发明所述片剂中，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(9.00～22.00)：(0.03～0.10)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(9.00～22.00)：(0.03～0.08)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(12.00～22.00)：(0.03～0.08)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(9.00～22.00)：(0.03～0.05)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(9.00～13.00)：(0.03～0.05)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(12.00～13.00)：(0.03～0.05)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(12.00～22.00)：(0.04～0.08)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(21.00～22.00)：(0.04～0.10)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(21.00～22.00)：(0.03～0.08)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(21.00～22.00)：(0.05～0.08)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(21.00～22.00)：(0.03～0.05)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(9.00～22.00)：(0.04)；任选地，所述式(I)所示化合物的盐酸盐与抗氧剂的质量比为约(12.00～22.00)：(0.04)。
在一些实施方案中，本发明所述片剂包括：6.00～22.00、9.00～22.00、9.00～13.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；0.02～0.30、0.03～0.10、0.03～0.08、0.04～0.08、0.05～0.08或0.03～0.05重量份的抗氧剂；55.00～90.00、60.00～80.00、60.00～78.00、60.00～76.00、60.00～77.00、65.00～77.00或65.00～76.00重量份的填充剂；0～3.50重量份的粘合剂；2.00～12.00、3.00～10.00、4.00～9.00、4.00～8.00、5.0～8.00或6.00～8.00重量份的崩解剂；0.50～3.00或1.00～2.50重量 份的抗黏剂；和2.00～7.00、2.50～6.00、2.50～5.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约6.00～22.00重量份的式(I)所示化合物的盐酸盐；约0.02～0.10重量份的抗氧剂；约55.00～90.00重量份的填充剂；约0～3.50重量份的粘合剂；约2.00～12.00重量份的崩解剂；约0.50～3.00重量份的抗黏剂；和约2.50～7.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约6.00～22.00重量份的式(I)所示化合物的盐酸盐；约0.02～0.30重量份的抗氧剂；约55.00～90.00重量份的填充剂；约0～3.50重量份的粘合剂；约2.00～12.00重量份的崩解剂；约0.50～3.00重量份的抗黏剂；和约2.50～7.00、2.50～6.00或2.50～5.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.02～0.10重量份的抗氧剂；约60.00～80.00、60.00～78.00、60.00～76.00或60.00～77.00重量份的填充剂；约0～3.50重量份的粘合剂；约3.00～10.00重量份的崩解剂；约1.00～2.50重量份的抗黏剂；和约2.50～7.00、2.50～6.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述片剂包括：约9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；约0.04～0.08重量份的抗氧剂；约65.00～76.00或65.00～77.00重量份的填充剂；约0～3.00重量份的粘合剂；约4.00～8.00或5.00～8.00重量份的崩解剂；约1.00～2.50重量份的抗黏剂；和约2.50～6.00或3.00～4.00重量份的润滑剂。
在一些实施方案中，本发明所述抗氧剂为与自由基反应类抗氧剂；任选地，所述与自由基反应类抗氧剂可选自丁羟茴醚、丁羟甲苯和没食子酸丙酯中的至少之一。
发明人通过大量试验发现，采用上述配方制得的片剂，其储存过程中的杂质含量少、溶出度好，并且，可提高该片剂的稳定性和安全性。
在一些实施例中，本发明所述填充剂任选地选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少之一。
在一些实施方案中，本发明所述崩解剂任选地选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠和低取代羟丙基纤维素中的至少之一。
在一些实施方案中，本发明所述抗黏剂任选地选自胶态二氧化硅和滑石粉中的至少之一。
在一些实施方案中，本发明所述润滑剂任选地选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一。
在一些实施方案中，本发明所述粘合剂任选地选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
在一些实施方案中，本发明所述抗氧剂包括选自丁羟茴醚、丁羟甲苯和没食子酸丙酯中的至少之一，填充剂包括选自甘露醇、微晶纤维素和预胶化淀粉中的至少之一，粘合剂为聚维酮或羟丙基甲基纤维素，崩解剂为交联聚维酮或羧甲淀粉钠，抗黏剂为胶态二氧化硅，润滑剂为硬脂酸镁。发明人通过大量实验发现，采用上述原料制得的片剂，在储存过程中的杂质生成量少，具有易储存和稳定性好等优点。
在一些实施方案中，本发明所述片剂包括：9.00～13.00、11.00～13.00或12.00～13.00重量份的3-(4-(二 己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；9.00～10.50或9.00～10.00重量份的预胶化淀粉；60.00～70.00或62.00～67.00或64.00～66.00重量份的微晶纤维素；1.00～4.00或2.00～3.00重量份的聚维酮或羟丙基甲基纤维素；4.00～12.00、4.00～9.00、5.00～9.00、4.00～8.00或6.00～8.00重量份的交联聚维酮；0.50～2.50或1.00～2.00重量份的胶态二氧化硅；2.50～4.50或3.00～4.00重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及选自下列的至少之一：0.03～0.05或0.03～0.04重量份的丁羟甲苯；和0.03～0.08或0.03～0.05重量份的丁羟茴醚。
在一些实施方案中，本发明所述片剂包括：9.00～13.00或11.00～13.00重量份的式(I)所示化合物的盐酸盐；9.00～10.50重量份的预胶化淀粉；60.00～70.00重量份的微晶纤维素；1.00～4.00重量份的聚维酮或羟丙基甲基纤维素；4.00～12.00重量份的交联聚维酮；0.50～2.50重量份的胶态二氧化硅；3.50～4.50重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及选自下列的至少之一：0.03～0.05重量份的丁羟甲苯；和0.03～0.05重量份的丁羟茴醚。
在一些实施方案中，本发明所述片剂包括：9.00～13.00或12.00～13.00重量份的式(I)所示化合物的盐酸盐；9.00～10.00重量份的预胶化淀粉；64.00～67.00或64.00～66.00重量份的微晶纤维素；2.00～3.00重量份的聚维酮或羟丙基甲基纤维素；4.00～8.00或6.00～8.00重量份的交联聚维酮；1.00～2.00重量份的胶态二氧化硅；和3.00～4.00重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及选自下列的至少之一：0.03～0.04重量份的丁羟甲苯；和0.03～0.05重量份的丁羟茴醚。
在一些实施方案中，本发明所述片剂包括：21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；20.00～25.00或23.00～24.00重量份的预胶化淀粉；40.00～50.00或43.00～47.00重量份的微晶纤维素；0～3.00或0～2.00重量份的羟丙基甲基纤维素；4.00～5.50或4.50～5.00重量份的羧甲淀粉钠；2.00～3.00重量份的胶态二氧化硅；和2.00～4.00或2.50～3.50重量份的硬脂酸镁；以及选自下列的至少之一：0.04～0.08或0.04～0.06重量份的丁羟茴醚；和0.02～0.05或0.02～0.04重量份的丁羟甲苯。
在一些实施方案中，本发明所述片剂包括：21.00～22.00重量份的式(I)所示化合物的盐酸盐；20.00～25.00重量份的预胶化淀粉；40.00～50.00重量份的微晶纤维素；0～3.00重量份的羟丙基甲基纤维素；4.00～5.50重量份的羧甲淀粉钠；2.00～3.00重量份的胶态二氧化硅；和2.00～4.00重量份的硬脂酸镁；以及，选自下列的至少之一：0.04～0.08重量份的丁羟茴醚；和0.02～0.05重量份的丁羟甲苯。
在一些实施方案中，本发明所述片剂包括：21.00～22.00重量份的式(I)所示化合物的盐酸盐；23.00～24.00重量份的预胶化淀粉；43.00～47.00重量份的微晶纤维素；0～2.00重量份的羟丙基甲基纤维素；4.50～5.00重量份的羧甲淀粉钠；2.00～3.00重量份的胶态二氧化硅；和2.50～3.50重量份的硬脂酸镁；以及，选自下列的至少之一：0.04～0.06重量份的丁羟茴醚；和0.02～0.04重量份的丁羟甲苯。发明人通过大量试验发现，采用上述配方配比制得的片剂，可进一步提高片剂的稳定性和药效。
在一些实施方案中，所述片剂进一步包含包衣材料；任选地，所述包衣材料的重量为片剂的素片重量的2.00～4.00％。素片是指片剂中包裹于包衣材料内部的总物质。
另外，本领域技术人员能够理解的是，前面针对组合物所描述的特征和优点同样适用于该片剂，在此不再赘述。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。
本发明各实施例或对比例中的样品的杂质含量参照高效液相色谱法(中国药典2020版通则0512)进行测定，具体如下：
供试品溶液：取供试品(例如，本发明所述的胶囊、片剂或本发明所述对比例中的对照品)，加甲醇提取并稀释制成每1mL约含2.5mg式(I)所示化合物的溶液(片剂需先加少量水崩解后再提取)，再用60％甲醇-水稀释成每1mL约含1mg式(I)所示化合物的溶液。
对照品溶液：取对照品(如式(I)所示化合物的盐酸盐)适量，精密称定，加60％甲醇-水溶解并稀释成每1mL约含5μg式(I)所示化合物的溶液。
灵敏度溶液：精密量取对照品溶液适量，用60％甲醇-水定量稀释成每1mL约含0.5μg式(I)所示化合物的溶液。
系统适用性溶液：取对照品(如式(I)所示化合物的盐酸盐)适量，称定，加60％甲醇-水溶解并稀释成每1mL约含1mg式(I)所示化合物的溶液。
色谱条件：以辛烷基硅烷键合硅胶为填充剂的色谱柱(如Phenomenex kinetex C8 100A，4.6×100mm，2.6μm或与之相当的色谱柱)；以0.01mol/L醋酸铵-乙腈(9:1)为流动相A，甲醇-乙腈(75:25)位流动相B，按下表中程序进行梯度洗脱，检测波长为266nm，进样体积10μL。
时间(min) 流动相A 流动相B
0 42 58
6 33 67
25 33 67
35 13 87
50 13 87
50.5 42 58
55 42 58
计算：采用主成分外标加校正因子法进行计算。
可接受标准：供试品溶液色谱图中如有杂质峰，总杂不得超过1.5％。
以专利申请WO2018019166A1公开的式(I)所示化合物的盐酸盐晶型I为例，对本发明的技术方案进行解释，即，以式(I)所示化合物的盐酸盐晶型I为活性成分进行组合物制备。
实施例1
将活性成分制备为胶囊剂，并测定溶出度。
其中，制备方法如下所述：
方法A：
①将活性成分与填充剂、崩解剂、抗黏剂、粘合剂(如有)和抗氧剂混合均匀，得到预混物；②然后将润滑剂和预混物混合均匀，得到总混粉末；③将总混粉末填充到合适的空心胶囊壳中，制得胶囊剂。
方法B：
①将活性成分与填充剂、崩解剂、抗黏剂、粘合剂(如有)、润滑剂和抗氧剂混合均匀，得到预混物；②将预混物进行干法制粒，得制粒颗粒；③将制粒颗粒和填充剂(如有)、崩解剂、抗黏剂进行预混，得预混颗粒；④将润滑剂与预混颗粒混合均匀，得到总混颗粒；⑤将总混颗粒填充到合适的空心胶囊壳中。任选地，抗氧剂也可在步骤③中加入。
方法C：
①将活性成分与填充剂、崩解剂、粘合剂(如有)和抗氧剂混合均匀，得到预混物；②将预混物进行湿法制粒，干燥，得干燥颗粒；③将干燥颗粒和填充剂、崩解剂、抗黏剂进行预混，得预混颗粒；④将润滑剂与预混颗粒混合均匀，得到总混颗粒；⑤将总混颗粒填充到合适的空心胶囊壳中。任选地，粘合剂也可在步骤②中配成粘合剂溶液后加入，和/或抗氧剂也可在步骤③中加入。
具体地，按照上述方法A制得胶囊剂样品A1和A2，按照方法B制得样品A3和A4，按照方法C制得样品A5和A6。各样品的组成如下表A-C所示。
表A
Figure PCTCN2022123811-appb-000004
本申请中“N/A”代表“无”。
表B
Figure PCTCN2022123811-appb-000005
Figure PCTCN2022123811-appb-000006
表C
Figure PCTCN2022123811-appb-000007
采用溶出度测定法(中国药典2020版通则0931第一法)，以900mL、0.1M的HCl为溶出介质，100rpm，对上述的胶囊样品，依法测定溶出度，溶出度可接受标准为45min≥80％。
结果：溶出度试验结果表明，各样品在45min的溶出度均大于80％。
实施例2
将活性成分制备成片剂，并测定溶出度。
其中，制备方法如下所示：
方法一：
①将活性成分与填充剂、崩解剂、抗黏剂、粘合剂(如有)和抗氧剂混合均匀，得到预混物；②然后将润滑剂和预混物混合均匀，得到总混粉末；③将总混粉末压片，得到素片；④将素片进行包衣，得到包衣片。
方法二：
①将活性成分与填充剂、崩解剂、抗黏剂、粘合剂(如有)、润滑剂和抗氧剂混合均匀，得到预混物；②将预混物进行干法制粒，得制粒颗粒；③将制粒颗粒和填充剂(如有)、崩解剂、抗黏剂进行预 混，得预混颗粒；④将润滑剂与预混颗粒混合均匀，得到总混颗粒；⑤将总混颗粒进行压片，得到素片；⑥将素片进行包衣，得到包衣片。任选地，抗氧剂也可在步骤③中加入。
方法三：
①将活性成分与填充剂、崩解剂、粘合剂(如有)和抗氧剂混合均匀，得到预混物；②将预混物进行湿法制粒，干燥，得干燥颗粒；③将干燥颗粒和填充剂、崩解剂、抗黏剂进行预混，得预混颗粒；④将润滑剂(如纯化水)与预混颗粒混合均匀，得到总混颗粒；⑤将总混颗粒进行压片，得到素片；⑥将素片进行包衣，得到包衣片。任选地，粘合剂也可在步骤②中配成粘合剂溶液后加入，和/或抗氧剂也可在步骤③中加入。
其中，上述包衣材料为薄膜包衣预混剂，用量为素片重量的3.0±1.0％。
具体地，按照上述方法三制得片剂样品B1-B2和B5-B17，按照方法二制得样品B3和B4。各样品素片的组成如下表D、E和F1-F6所示。
表D
Figure PCTCN2022123811-appb-000008
表E
Figure PCTCN2022123811-appb-000009
Figure PCTCN2022123811-appb-000010
表F1
Figure PCTCN2022123811-appb-000011
表F2
Figure PCTCN2022123811-appb-000012
表F3
Figure PCTCN2022123811-appb-000013
Figure PCTCN2022123811-appb-000014
表F4
Figure PCTCN2022123811-appb-000015
表F5
Figure PCTCN2022123811-appb-000016
Figure PCTCN2022123811-appb-000017
表F6
Figure PCTCN2022123811-appb-000018
采用溶出度测定法(中国药典2020版通则0931第二法)，以900mL、pH3.0的邻苯二甲酸氢钾缓冲溶液+1.5％吐温80为溶出介质，75rpm，对上述片剂样品，依法测定溶出度，溶出度可接受标准为45min≥80％。
结果：溶出度试验结果表明，各样品在45min的溶出度均大于80％，大部分样品在45min的溶出度大于90％。
对比例
按照前述胶囊剂和片剂的方法，通过不添加抗氧剂的方式，制得不含抗氧剂的胶囊剂和片剂样品，作为对照品。具体地，按照实施例1方法B和方法C分别制得不含抗氧剂的胶囊剂对照品C1和C2；按照实施例2方法二和方法三分别制得不含抗氧剂的片剂对照品C3和C4。各对照品的具体组成如下表G1和G2所示。
表G1 胶囊剂对照品
Figure PCTCN2022123811-appb-000019
Figure PCTCN2022123811-appb-000020
表G2 片剂对照品
Figure PCTCN2022123811-appb-000021
实施例3
参照《中国药典2015版四部》9001原料药物与制剂稳定性试验指导原则，对本发明的胶囊剂和片剂产品，以及对照样品C1-C4的稳定性进行考察。具体实验方法如本发明所述，实验结果如下表H所示。
表H
Figure PCTCN2022123811-appb-000022
Figure PCTCN2022123811-appb-000023
由上表可知，对照样品在实验1个月后总杂含量明显升高，3-4个月后总杂含量已超出可接受的限度；可见对照样品的稳定差。而本发明所述的胶囊剂和片剂在实验过程中，总杂含量基本无变化，且明显低于对照样品的总杂含量；特别是在长期存放后，各样品的总杂含量基本无明显变化，且远低于对照样品的总杂含量。可见，制备胶囊剂或片剂时，加入抗氧剂，可以降低储存过程中杂质的生成量和生成速率，提高片剂的稳定性。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (19)

  1. 一种组合物，其特征在于，包括3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮或其药学上可接受的盐以及抗氧剂。
  2. 根据权利要求1所述的组合物，其特征在于，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮的药学上可接受的盐是其盐酸盐。
  3. 根据权利要求1-2任意一项所述的组合物，其特征在于，所述抗氧剂为与自由基反应类抗氧剂。
  4. 根据权利要求1-3任意一项所述的组合物，其特征在于，所述抗氧剂为丁羟茴醚、丁羟甲苯、没食子酸丙酯或它们的任意组合。
  5. 根据权利要求1-4任意一项所述的组合物，其特征在于，所述组合物为口服固体制剂；
    任选地，所述口服固体制剂为胶囊剂或片剂。
  6. 根据权利要求1-5任意一项所述的组合物，其特征在于，进一步包括药学上可接受的辅料；
    任选地，所述辅料包括选自填充剂、崩解剂、粘合剂、润滑剂和抗黏剂中的至少之一。
  7. 根据权利要求6所述组合物，其特征在于，所述填充剂任选地选自甘露醇、预胶化淀粉、微晶纤维素、乳糖、淀粉、磷酸氢钙、山梨醇、蔗糖、乳糖醇和麦芽糖中的至少之一；
    所述崩解剂任选地选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠和低取代羟丙基纤维素中的至少之一；
    所述抗黏剂任选地选自胶态二氧化硅和滑石粉中的至少之一；
    所述润滑剂任选地选自硬脂酸镁、硬脂富马酸钠、硬脂酸、硬脂酸钙和山嵛酸甘油酯中的至少之一；
    所述粘合剂任选地选自聚维酮、羟丙基甲基纤维素、羟丙基纤维素、聚乙二醇、乙基纤维素和甲基纤维素中的至少之一。
  8. 根据权利要求1-7任意一项所述的组合物，其特征在于，所述抗氧剂含量为0.01～0.40、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、0.04～0.30、0.03～0.08、0.03～0.05、0.04～0.05或0.05～0.08重量份。
  9. 根据权利要求1-8任意一项所述的组合物，其特征在于，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐的含量为5.00～73.00、6.00～58.00、9.00～58.00、11.00～58.00、9.00～35.00、12.00～35.00、6.00～22.00、9.00～22.00、21.00～35.00或12.00～22.00重量份。
  10. 根据权利要求6-9任意一项所述的组合物，其特征在于，所述填充剂的含量为22.50～91.00、29.00～82.00、60.00～77.00、60.00～76.00、60.00～69.00、55.00～90.00、65.00～77.00、65.00～76.00或70.00～76.00重量份；
    任选地，所述抗黏剂的含量为0.50～3.50、0.50～2.50、0.50～1.50、1.00～2.50或1.00～2.00重量份；
    任选地，所述崩解剂的含量为0.50～16.00、0.05～6.00、1.50～6.00、2.50～5.00、3.00～10.00、4.00～9.00、4.00～8.00或2.50～8.00重量份；
    任选地，所述润滑剂的含量为0.50～7.00、0.50～5.00、1.00～6.00、1.00～5.00、2.00～6.00、2.00～3.00、3.00～6.00、3.00～4.00或2.00～4.00重量份；
    任选地，所述粘合剂的含量为0～3.50、0～3.00、0～2.00或2.00～3.00重量份。
  11. 根据权利要求2-10任意一项所述的组合物，其特征在于，所述组合物为胶囊剂，其包含3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐、抗氧剂、填充剂、崩解剂、抗黏剂、润滑剂以及任选的粘合剂；
    任选地，3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(5.00～73.00)：(0.01～0.40)或(21.00～35.00)：(0.05～0.08)。
  12. 根据权利要求11所述的组合物，其特征在于，所述胶囊剂包括：
    5.00～73.00或21.00～35.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；
    0.01～0.40或0.02～0.10重量份的抗氧剂；
    22.5～90.50重量份的填充剂；
    0.50～6.00或2.00～6.00重量份的崩解剂；
    0.50～3.50重量份的抗黏剂；
    0.50～3.50重量份的润滑剂；
    0～2.50重量份的粘合剂。
  13. 根据权利要求11-12任意一项所述的组合物，其特征在于，所述胶囊剂包括：
    13.00～58.00或34.00～34.50重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；
    20.00～55.00或40.00～41.00重量份的甘露醇；
    9.00～28.00或20.00～21.00重量份的预胶化淀粉；
    1.50～3.50或2.00～3.00重量份的交联聚维酮；
    0.50～2.50或0.50～1.50重量份的胶态二氧化硅；和
    0.50～3.00或1.50～2.50重量份的硬脂酸镁；以及
    选自下列的至少之一：
    0.03～0.20或0.04～0.06重量份的丁羟茴醚；和
    0.03～0.10或0.04～0.06重量份的丁羟甲苯。
  14. 根据权利要求11-12任意一项所述的组合物，其特征在于，所述胶囊剂包括：
    21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；
    43.00～47.00重量份的微晶纤维素；
    20.00～23.00重量份的预胶化淀粉；
    4.00～6.00或4.00～5.50重量份的羧甲淀粉钠；
    0～2.00重量份的羟丙基甲基纤维素；
    2.00～3.00重量份的胶态二氧化硅；
    2.00～3.50或2.50～3.50重量份的硬脂酸镁；以及
    选自下列的至少之一：
    0.03～0.10或0.04～0.06重量份的丁羟茴醚；和
    0.02～0.10或0.02～0.05重量份的丁羟甲苯。
  15. 根据权利要求2-10任意一项所述的组合物，其特征在于，所述组合物为片剂，其包含3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐、抗氧剂、填充剂、崩解剂、抗黏剂、润滑剂以及任选的粘合剂；
    任选地，所述3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐与抗氧剂的质量比为(6.00～22.00)：(0.02～0.30)或(9.00～22.00)：(0.03～0.10)或(12.00～22.00)：(0.03～0.08)。
  16. 根据权利要求15所述的组合物，其特征在于，所述片剂包括：
    6.00～22.00、9.00～22.00或12.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；
    0.02～0.30、0.03～0.10或0.04～0.08重量份的抗氧剂；
    55.00～90.00、60.00～76.00、60.00～77.00或65.00～76.00重量份的填充剂；
    0～3.50重量份的粘合剂；
    2.00～12.00或3.00～10.00重量份的崩解剂；
    0.50～3.00或1.00～2.50重量份的抗黏剂；和
    2.50～6.00或2.50～5.00或3.00～4.00重量份的润滑剂。
  17. 根据权利要求15-16任意一项所述的组合物，其特征在于，所述片剂包括：
    9.00～13.00或11.00～13.00或12.00～13.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；
    9.00～10.50或9.00～10.00重量份的预胶化淀粉；
    60.00～70.00或62.00～67.00或64.00～66.00重量份的微晶纤维素；
    1.00～4.00或2.00～3.00重量份的聚维酮或羟丙基甲基纤维素；
    4.00～12.00、4.00～9.00、5.00～9.00或6.00～8.00重量份的交联聚维酮；
    0.50～2.50或1.00～2.00重量份的胶态二氧化硅；和
    2.50～4.50或3.00～4.00重量份的硬脂酸镁，或5.00～7.00重量份的山嵛酸甘油酯；以及
    选自下列的至少之一：
    0.03～0.05或0.03～0.04重量份的丁羟甲苯；和
    0.03～0.08或0.03～0.05重量份的丁羟茴醚。
  18. 根据权利要求15-16任意一项所述的组合物，其特征在于，所述片剂包括：
    21.00～22.00重量份的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮盐酸盐；
    20.00～25.00或23.00～24.00重量份的预胶化淀粉；
    40.00～50.00或43.00～47.00重量份的微晶纤维素；
    0～3.00或0～2.00重量份的羟丙基甲基纤维素；
    4.00～5.50或4.50～5.00重量份的羧甲淀粉钠；
    2.00～3.00重量份的胶态二氧化硅；和
    2.00～4.00或2.50～3.50重量份的硬脂酸镁；以及
    选自下列的至少之一：
    0.04～0.08或0.04～0.06重量份的丁羟茴醚；和
    0.02～0.05或0.02～0.04重量份的丁羟甲苯。
  19. 根据权利要求15-18任意一项所述的组合物，其特征在于，所述片剂进一步包含包衣材料；
    任选地，所述包衣材料的重量为所述片剂的素片重量的2.0～4.0％。
PCT/CN2022/123811 2021-10-09 2022-10-08 抗纤维化组合物 WO2023056935A1 (zh)

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