A pharmaceutical composition and a method for quality control thereof

Abstract

This invention provides a pharmaceutical composition and a quality control method thereof, wherein the pharmaceutical composition comprises a compound of formula A or a salt thereof, and an antioxidant, wherein the structure of the compound of formula A is as follows: By mixing the pharmaceutical composition with one or more antioxidants, the safety of solid dosage forms is effectively addressed.

Description

A pharmaceutical composition and its quality control method Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition and a quality control method. Background Technology

[0002] Compound A is a histamine H1 receptor agonist with the following chemical structure: This drug increases blood flow to the inner ear and vestibular system, alleviating symptoms such as inner ear vertigo, a feeling of ear blockage, and tinnitus, making it a first-line treatment for otogenic vertigo. In addition, it dilates cardiovascular and cerebrovascular vessels, with a particularly pronounced effect on the pyloric arterial system, increasing blood flow to the heart, brain, and peripheral circulation, improving systemic circulation, lowering blood pressure, inhibiting platelet aggregation to prevent thrombosis, and having a mild diuretic effect. Clinically, it is mainly used to improve vertigo and dizziness associated with Meniere's disease, Meniere's syndrome, and vertigo. Currently, the active ingredient of this drug is available in two forms: hydrochloride and mesylate. The former is available in various dosage forms, including tablets, oral solutions, injections, and lyophilized products, while the latter is only available in tablet form.

[0003] Since the discovery and detection of the genotoxic impurity N-nitrosodimethylamine (NDMA) in valsartan active pharmaceutical ingredient (API) in July 2018, regulatory agencies in various countries have successively detected various nitrosamine impurities in other APIs. Nitrosamines are potent carcinogens, classified into different risk categories (Groups 1-5) using the Common Carcinogenicity Classification (CPCA) method. Carcinogenicity severity is determined based on acceptable intake and activation or inactivation characteristics defined by structural features. Due to the presence of a secondary amine structure, nitrosamine impurities may form in compound A (BH), which, according to the CPCA method, is classified as a Group 1 carcinogen. The chemical structure of the nitrosamine impurity also present in compound A is as follows:

[0004]

[0005] There is no literature reporting how to control the content of nitrosamine impurities in compound A drugs. Solving this problem has become a difficult problem and an urgent need for the pharmaceutical industry. Summary of the Invention

[0006] The pharmaceutical preparation of compound A will gradually generate nitrosamine impurities during storage, and the nitrosamine impurities will gradually increase with the extension of storage time.

[0007] The inventors discovered through research that the nitrosamine impurities in the existing hydrochloride tablets of compound A all exceed the permissible acceptable limit (0.375 ppm).

[0008]

[0009] Test results of the reference preparation of compound A mesylate tablets

[0010]

[0011] The domestically produced methanesulfonate tablets of Formula A (Minsilon®) were tested for nitrosamine impurities, and the content of nitrosamine impurities exceeded the permissible limit within their shelf life.

[0012] The purpose of this invention is to overcome the shortcomings of the prior art and provide a pharmaceutical composition containing a compound of formula A with excellent stability, as well as a quality control method and uses.

[0013] In a first aspect of the invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of formula A or a salt thereof, and an antioxidant, the structure of said compound of formula A being as follows:

[0014] .

[0015] In a second aspect of the invention, an oral solid dosage form is provided, characterized in that it comprises a compound of formula A or a salt thereof and a non-inorganic salt antioxidant, said compound A having the following structure:

[0016] .

[0017] In a third aspect, the present invention provides a method for controlling the content of nitrosamine impurities in a pharmaceutical composition comprising a compound of formula A or a salt thereof, characterized in that the method comprises mixing a compound of formula A or a salt thereof with one or more antioxidants, wherein the compound of formula A has the following structure: The nitrosamine impurity is: .

[0018] In a fourth aspect, the present invention provides the use of nitrosamine impurities in the quality control of pharmaceutical compositions comprising a compound of formula A, characterized in that the compound of formula A has the following structure: The structure of the nitrosamine impurity is as follows: ;

[0019] When the salt of compound A is hydrochloric acid, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm;

[0020] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm.

[0021] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0022] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0023] Figure 1 shows the growth trend of nitrosamine impurities in the hydrochloride preparation of compound A in Experimental Example 2;

[0024] Figure 2 shows the growth trend of nitrosamine impurities in the methanesulfonate preparation of compound A in Experimental Example 3;

[0025] Figure 3 shows the growth trend of nitrosamine impurities in Test Examples 2-3, 2-4, 2-5, 2-6 and 2-7 of the present invention under accelerated conditions of 40℃ / 75%RH. Detailed Implementation

[0026] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0027] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0028] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0029] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0030] In this article, the term "shelf life" generally refers to the period during which a medicine exists as a product sold to consumers and is suitable for patient use. The term "shelf life" also refers to the period during which a medicine can maintain its quality, safety, and effectiveness under specified storage conditions. Within this period, the medicine's ingredients, content, properties, etc., meet the requirements of national drug standards or drug registration standards and can be used safely and effectively. The shelf life of a medicine can be greater than 3 months, 6 months, 12 months, 18 months, or 24 months, preferably 36 months. Specified storage conditions for medicines include, for example, "a cool, dry place, protected from light, at a temperature not exceeding 25°C" or "stored in a light-protected, tightly closed container." Specifically, the shelf life of betahistine hydrochloride or mesylate is 36 months.

[0031] In this article, the term "antioxidant" generally refers to a substance that controls nitrosamine drug-related impurities (NDSRIs) and other impurities in a pharmaceutical composition to below acceptable levels.

[0032] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0033] In a first aspect, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a compound of formula A or a salt thereof, and an antioxidant, wherein the structure of the compound of formula A is: .

[0034] In a preferred embodiment of the present invention, the antioxidant is selected from water-soluble antioxidants or insoluble antioxidants; the water-soluble antioxidant is selected from cysteine ​​and / or cysteine ​​hydrochloride. Methionine, glutamic acid, and acetylcysteine ​​have the same effect as cysteine ​​or cysteine ​​hydrochloride as water-soluble antioxidants; the insoluble antioxidant is selected from one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tert-butylhydroquinone, tocopherol, ascorbyl palmitate, dilauryl thiodipropionate, or distearate thiodipropionate; preferably, the antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine ​​hydrochloride, and cysteine; more preferably, the antioxidant is selected from cysteine ​​hydrochloride and / or cysteine.

[0035] In a preferred embodiment of the present invention, the pharmaceutical composition is an oral solid dosage form of compound A or a liquid dosage form of compound A; preferably, the oral solid dosage form is granules, tablets or capsules.

[0036] In a preferred embodiment of the present invention, the salt of compound A is a hydrochloride or a methanesulfonate.

[0037] In a preferred embodiment of the present invention, the antioxidant is present in a weight content of not less than 0.2% in the pharmaceutical composition.

[0038] In a preferred embodiment of the present invention, the antioxidant in the pharmaceutical composition has a weight content of not more than 10% w / w; preferably, the antioxidant in the pharmaceutical composition has a content range of 0.5% to 6.4% w / w.

[0039] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises an excipient selected from one or more of ① to ⑥:

[0040] ① Filler: The filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch and microcrystalline cellulose;

[0041] ② Adhesive: The adhesive is selected from one or more of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methylcellulose and gelatin;

[0042] ③ pH adjuster: The pH adjuster is selected from one or more of the following: tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate.

[0043] ④ Disintegrant: The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose and starch;

[0044] ⑤ Glide aid: The glide aid is selected from one or more of silica, talc, hydrogenated vegetable oil, calcium silicate and magnesium silicate;

[0045] ⑥ Lubricant: The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate.

[0046] In a preferred embodiment of the invention, the pharmaceutical composition satisfies one or more of a)-c);

[0047] a) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 3 months,

[0048] When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0049] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0050] b) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 6 months,

[0051] When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0052] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0053] c) The pharmaceutical composition containing compound A is within its shelf life.

[0054] When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0055] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the pharmaceutical composition has a white or off-white appearance.

[0056] In a preferred embodiment of the invention, the antioxidant is present in a content of not more than 10% w / w in the pharmaceutical composition; preferably, the antioxidant is present in a content ranging from 0.1% to 10% w / w in the pharmaceutical composition. In some embodiments, the antioxidant constitutes not less than 0.2% of the prescription weight (i.e., the weight of the oral solid dosage form of compound A), or 0.2% to 10%, 0.5% to 10%, or 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 6.4%, 7.0%, 7.2%, 8.0%, 9.0%, or 10%.

[0057] In a preferred embodiment of the present invention, the salt of compound A is a hydrochloride or a methanesulfonate.

[0058] In a preferred embodiment of the present invention, the excipient comprises one or more of the following excipients ① to ⑥:

[0059] ① Filler: The filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch and microcrystalline cellulose;

[0060] ② Adhesive: The adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methylcellulose and gelatin;

[0061] ③ pH adjuster: The pH adjuster is selected from one or more of the following: tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate.

[0062] ④ Disintegrant: The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose and starch;

[0063] ⑤ Glide aid: The glide aid is selected from one or more of silica, talc, hydrogenated vegetable oil, calcium silicate and magnesium silicate;

[0064] ⑥ Lubricant: The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate.

[0065] In some embodiments, the oral solid dosage form of the formula A compound comprises 0.1% to 10% by weight of an antioxidant, 2% to 10% by weight of the formula A compound or a salt thereof, 70% to 90% by weight of a filler, 1% to 3% by weight of a pH adjuster, 1% to 3% by weight of a flow aid, and 2% to 8% by weight of a lubricant.

[0066] In a preferred embodiment of the present invention, the pharmaceutical composition is a solid dosage form or a liquid dosage form; preferably, the solid dosage form is a granule, tablet, or capsule.

[0067] In a second aspect, the present invention provides an oral solid dosage form, characterized in that it comprises a compound of formula A or a salt thereof and a non-inorganic salt antioxidant, wherein the structure of the compound of formula A is as follows:

[0068] .

[0069] In a preferred embodiment of the present invention, the salt of compound A is a hydrochloride or a methanesulfonate.

[0070] In a preferred embodiment of the present invention, the antioxidant accounts for not less than 0.1% of the prescription weight.

[0071] In a preferred embodiment of the present invention, the non-inorganic salt antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine ​​hydrochloride, and cysteine.

[0072] In a preferred embodiment of the present invention, the oral solid dosage form comprises 0.1% to 10% by weight of a non-inorganic salt antioxidant, 2% to 10% by weight of a compound of formula A or a salt thereof, 70% to 90% by weight of a filler, 1% to 3% by weight of a pH adjuster, 1% to 3% by weight of a flow aid, and 2% to 8% by weight of a lubricant.

[0073] Optionally, the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose (anhydrous or hydrated), mannitol, dicalcium phosphate, starch, pregelatinized starch, and microcrystalline cellulose; preferably, it is microcrystalline cellulose and mannitol; and / or

[0074] The pH adjuster is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate; preferably, it is citric acid; and / or

[0075] The flow aid is selected from one or more of silica, talc, and hydrogenated vegetable oil; preferably, it is silica and talc; and / or

[0076] The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate; preferably, it is talc.

[0077] In a preferred embodiment of the present invention, the oral solid dosage form is prepared using a dry process or a wet process.

[0078] Thirdly, the present invention provides a method for controlling the content of nitrosamine impurities in a pharmaceutical composition comprising a compound of formula A or a salt thereof, characterized in that the method comprises mixing a compound of formula A or a salt thereof with one or more antioxidants, wherein the compound of formula A has the following structure: The nitrosamine impurity is: .

[0079] In a preferred embodiment of the present invention, the nitrosamine impurity is When the salt of compound A is a hydrochloride salt, the content of nitrosamine in the pharmaceutical composition is less than 0.375 ppm;

[0080] When the salt of compound A is a methanesulfonate, the content of nitrosamine in the pharmaceutical composition is less than 0.500 ppm.

[0081] In a preferred embodiment of the present invention

[0082] The pharmaceutical composition of formula A satisfies one or more of a)-c);

[0083] a) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 3 months,

[0084] When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0085] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance;

[0086] b) After the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 6 months,

[0087] When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0088] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance;

[0089] c) The pharmaceutical composition containing compound A is within its shelf life.

[0090] When the salt of compound A is a hydrochloride salt, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance.

[0091] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the pharmaceutical composition has a white or off-white appearance.

[0092] In a preferred embodiment of the present invention, the pharmaceutical composition is an oral solid dosage form or liquid dosage form of formula A; preferably, the oral solid dosage form is granules, tablets or capsules.

[0093] In a preferred embodiment of the present invention, the antioxidant is selected from water-soluble antioxidants and / or insoluble antioxidants; the water-soluble antioxidant is selected from cysteine ​​and / or cysteine ​​hydrochloride. Methionine, glutamic acid, and acetylcysteine ​​have the same effect as cysteine ​​or cysteine ​​hydrochloride as water-soluble antioxidants; the insoluble antioxidant is selected from one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tert-butylhydroquinone, tocopherol, ascorbyl palmitate, dilauryl thiodipropionate, or distearate thiodipropionate; preferably, the antioxidant is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin C, ascorbyl palmitate, cysteine ​​hydrochloride, and cysteine. More preferably, the antioxidant is selected from one or two of cysteine ​​hydrochloride and cysteine.

[0094] In a preferred embodiment of the invention, the antioxidant is present in a content of not more than 10% w / w in the pharmaceutical composition; preferably, the antioxidant is present in a content ranging from 0.1% to 10% w / w in the pharmaceutical composition. In some embodiments, the antioxidant constitutes not less than 0.2% of the prescription weight (i.e., the weight of the oral solid dosage form of compound A), or 0.2% to 10%, 0.5% to 10%, or 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 6.4%, 7.0%, 7.2%, 8.0%, 9.0%, or 10%.

[0095] In a preferred embodiment of the present invention, the salt of compound A is a hydrochloride or a methanesulfonate.

[0096] In a preferred embodiment of the present invention, the method comprises mixing a compound of formula A or a salt thereof with one or more antioxidants and excipients, wherein the excipients comprise one or more of the following excipients ① to ⑥:

[0097] ① Filler: The filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch and microcrystalline cellulose;

[0098] ② Adhesive: The adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methylcellulose and gelatin;

[0099] ③ pH adjuster: The pH adjuster is selected from one or more of the following: tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate.

[0100] ④ Disintegrant: The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose and starch;

[0101] ⑤ Glide aid: The glide aid is selected from one or more of the following: silica, talc, hydrogenated vegetable oil, calcium silicate, and magnesium silicate;

[0102] ⑥ Lubricant: The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate.

[0103] In some embodiments, the oral solid dosage form of the formula A compound comprises 0.1% to 10% by weight of an antioxidant, 2% to 10% by weight of the formula A compound or a salt thereof, 70% to 90% by weight of a filler, 1% to 3% by weight of a pH adjuster, 1% to 3% by weight of a flow aid, and 2% to 8% by weight of a lubricant.

[0104] In a preferred embodiment of the present invention, the pharmaceutical composition is a solid dosage form or a liquid dosage form; preferably, the solid dosage form is a granule, tablet, or capsule.

[0105] Fourthly, the present invention provides the use of nitrosamine impurities in the quality control of pharmaceutical compositions comprising formula A, characterized in that the structure of said compound A is as follows: The structure of the nitrosamine impurity is as follows: ;

[0106] When the salt of compound A is hydrochloric acid, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm;

[0107] When the salt of compound A is a methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm.

[0108] Fifthly, the present invention provides a method for preparing a pharmaceutical composition according to the first or second aspect of the present invention. The preparation method is a dry preparation process, specifically involving direct mixing of powders or dry granulation followed by the addition of excipients for direct packaging into powders / granules, or direct filling into capsules, or compression into tablets. Specifically, the preparation method includes the following steps:

[0109] a) The compound of formula A or its salt, antioxidants and other excipients are sieved separately;

[0110] b) Pour the active pharmaceutical ingredient and all excipients into a mixer for mixing, or perform dry granulation after mixing;

[0111] c) Add auxiliary materials to the powder or granules obtained in step b) to obtain total powder or total granules;

[0112] d) The total powder or total particles are directly packaged into powder / granules, or directly filled into capsules, or compressed into tablets;

[0113] In some embodiments, the preparation process includes the following steps:

[0114] a) Raw material processing: Pass the glidant through an 80-mesh sieve, grind the pH adjuster and pass it through an 80-mesh sieve, then take the fine powder that passes through the sieve for later use.

[0115] b) Premixing: The pH adjuster and filler are mixed evenly in a mixer in equal increments to form powder ①; the antioxidant and flow aid are mixed first, then compound A or its salt is added and mixed, then the filler is added and mixed evenly in a mixer to form powder ②; powder ① is added to powder ② and mixed evenly in a mixer, then the flow aid and lubricant are added and mixed evenly to obtain powder ③;

[0116] c) Total mixing: Add the powder ③ to the mixer, add the flow aid and lubricant to obtain the total powder;

[0117] d) Finished product preparation: The total powder preparation is packaged into powder, or filled into capsules, or directly compressed into tablets.

[0118] In the above preparation process, the antioxidant used is a non-water-soluble stabilizer, which is selected from one or more of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and ascorbyl palmitate. Preferably, the antioxidant is ascorbyl palmitate.

[0119] In some embodiments, the preparation process includes the following steps:

[0120] a) Raw material processing: Pass the glidant through an 80-mesh sieve, grind the pH adjuster and pass it through an 80-mesh sieve, then take the fine powder that passes through the sieve for later use.

[0121] b) Premixing: The pH adjuster and filler are mixed evenly in a mixer in equal increments to form powder ①; the antioxidant and flow aid are mixed first, then compound A or its salt is added and mixed, then the filler is added and mixed evenly in a mixer to form powder ②; powder ① is added to powder ② and mixed evenly in a mixer, then the flow aid and lubricant are added and mixed evenly to obtain powder ③;

[0122] c) Granulation: The mixed powder ③ is put into a dry granulator for granulation to obtain drug-containing granules;

[0123] d) Total mixture: Add silica and talc to the drug-containing granules and then compress them into tablets to obtain compound A tablets.

[0124] In some embodiments, the present invention provides a method for preparing the pharmaceutical composition of the first or second aspect of the present invention, wherein the preparation method is a wet preparation process.

[0125] During the research process, the inventors discovered that when using a dry preparation process to prepare formulations of compound A, the high hygroscopicity of compound A makes it easy for uneven dispersion to occur due to the aggregation of compound A during the scale-up production of the formulation, resulting in yellow spots on the tablet surface.

[0126] In large-scale production, the wet preparation process can dissolve compound A, greatly improving the uniformity of compound A distribution in the formulation and avoiding the yellow spots caused by uneven API dispersion due to moisture absorption of compound A, which occurs in the dry preparation process. In the wet preparation process, nitrosamine impurities will gradually form when compound A hydrochloride and methanesulfonate are in aqueous solution, and these impurities will gradually increase with prolonged storage time. To avoid the growth of nitrosamine impurities, water-soluble antioxidants are preferred. The water-soluble antioxidants are selected from one or more of cysteine, cysteine ​​hydrochloride, methionine, glutamic acid, acetylcysteine, ascorbic acid, oxalic acid, tartaric acid, propionic acid, malonic acid, thiopropionic acid, glucuronic acid, galacturonic acid, or sorbitol; specifically, cysteine ​​hydrochloride or cysteine ​​is preferred.

[0127] Specifically, in a preferred embodiment of the present invention, the wet preparation process includes the following steps:

[0128] (1) Premixing

[0129] The active pharmaceutical ingredient of formula A is mixed with an antioxidant and some pharmaceutical excipients;

[0130] (2) Granulation

[0131] Wet granulation is used to granulate the product, which is then dried and granulated.

[0132] (3) Total Mixing

[0133] Add the granules obtained in step (2) to a flow aid or lubricant and mix thoroughly.

[0134] (4) Tablets or canned capsules

[0135] The mixture prepared in step (3) is tableted or directly packaged.

[0136] In some specific embodiments, the preparation process includes the following steps:

[0137] (1) Dissolving the active pharmaceutical ingredient:

[0138] The hydrochloride salt of compound A, an antioxidant, and a pH adjuster are dissolved in water to obtain a liquid.

[0139] (2) Granulation

[0140] The filler is placed in a wet granulator and mixed evenly. The liquid from step (1) is added for wet granulation. After drying, the granules are sized.

[0141] (3) Total Mixing

[0142] In step (2), add the dry granules to a flow aid or lubricant and mix thoroughly.

[0143] (4) Tablets or canned capsules

[0144] The mixture prepared in step (3) is tableted or directly packaged.

[0145] In the above wet preparation process, the antioxidant used is preferably a water-soluble antioxidant, which is selected from one or more of vitamin C, cysteine ​​hydrochloride, and cysteine; preferably, the water-soluble antioxidant is selected from one or two of cysteine ​​hydrochloride and cysteine.

[0146] Detection of genotoxic impurities and nitrosamine impurities

[0147] Testing instrument: Agilent 6470QQQ liquid chromatography-mass spectrometry system.

[0148] The determination was performed by high performance liquid chromatography and mass spectrometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapters 0512 and 0431).

[0149] Solvent: water-acetonitrile (10:90).

[0150] The test solution should be freshly prepared before use. Take an appropriate amount of this product, accurately weigh it, dissolve it in solvent, and quantitatively dilute it to prepare a solution containing approximately 0.2 mg per ml.

[0151] Take an appropriate amount of nitrosamine impurity reference standard, accurately weigh it, dissolve it in solvent and quantitatively dilute it to prepare a solution containing approximately 0.075 ng of nitrosamine impurity per 1 ml.

[0152] Chromatographic conditions: HlLICC was used as the packing material (e.g., ACQUITYUPLCBEHHlLICC 1.7μm, 2.1×50mm or equivalent column); water-acetonitrile-formic acid (10:90:0.1) (containing 5mmol / L ammonium formate) was used as the mobile phase; the flow rate was 0.2ml per minute; the column temperature was 35℃; the injection volume was 5μl; and the sample tray temperature was 4℃.

[0153] Mass spectrometry conditions (reference instrument model: Agilent 6470QQQ LC-MS / MS, parameters can be adjusted according to specific instruments to meet detection requirements): ESI+, MRM mode, ion pair 166→93, Dwell 200, Fragmentor 60 (V), CCollision Energy 10 (V), Cell Accelerator Voltage 5 (V), carrier gas temperature 300℃, carrier gas flow rate 10 L / min, nebulizer pressure 45 psi, sheath gas temperature 250℃, sheath gas flow rate 11 L / min, capillary voltage 3500 V, nozzle voltage 500 V.

[0154] Switching valve:

[0155]

[0156] The test solution and the reference solution are precisely measured and injected into the liquid chromatograph separately, and the mass spectra are recorded.

[0157] If impurity peaks are present in the mass spectrum of the test sample solution, the nitrosamine impurities in the hydrochloride preparation of compound A shall not exceed 0.0000375% by peak area, calculated using the external standard method. The nitrosamine impurities in the methanesulfonate preparation of compound A shall not exceed 0.00005%.

[0158] Experimental Example 1

[0159] Experimental Example 1-1

[0160] Prepare 1000 tablets according to the prescription in the table below.

[0161] Table 1-1

[0162]

[0163] Preparation process of Experimental Example 1-1:

[0164] (1) Dissolving the active pharmaceutical ingredient: Dissolve the hydrochloride and citric acid of compound A in water as a wetting agent for granulation;

[0165] (2) Microcrystalline cellulose, mannitol, and ascorbate palmitate are placed in a wet granulator and mixed evenly. Wetting agent is added for wet granulation.

[0166] (3) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0167] (4) Add the dry granules obtained in step (3) to silica and talc, and mix;

[0168] (5) Compress the tablets to form compound A hydrochloride tablets.

[0169] Experimental Examples 1-2 to 1-4

[0170] Prepare 1000 tablets according to the prescription in the table below.

[0171] Table 1-2

[0172]

[0173] Preparation process of Experimental Examples 1-2 to 1-4:

[0174] (1) Citrate is ground and passed through an 80-mesh sieve, silica is passed through an 80-mesh sieve, and compound A hydrochloride and other excipients are passed through a 60-mesh sieve for later use;

[0175] (2) Mix all the components after sieving evenly, compress into tablets, and make compound A hydrochloride tablets.

[0176] Experimental Examples 1-5 to 1-6

[0177] Prepare 1000 tablets according to the prescription in the table below.

[0178] Table 1-3

[0179]

[0180] Preparation process of Experimental Examples 1-5 to 1-6:

[0181] (1) Citrate is ground and passed through an 80-mesh sieve, silica is passed through an 80-mesh sieve, and compound A hydrochloride and other excipients are passed through a 60-mesh sieve for later use;

[0182] (2) Mix all the components used for dry granulation after sieving evenly, and put them into a dry granulator to obtain granules;

[0183] (3) The obtained granules are mixed with silica and talc in the prescription ratio and then compressed into tablets.

[0184] Experimental Examples 1-7 to 1-8

[0185] Prepare tablets in batches of 1000 tablets according to the prescription in the table below.

[0186] Table 1-4

[0187]

[0188] Preparation process of Experimental Examples 1-7:

[0189] (1) Mix the compound A methanesulfonate, microcrystalline cellulose, mannitol and cross-linked polyvinylpyrrolidone in a wet granulator, add a wetting agent and perform wet granulation;

[0190] (2) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0191] (3) Add the dry granules obtained in step (3) to silica, calcium stearate and lemon flavoring, and mix;

[0192] (4) Compress the tablets to form compound A methanesulfonate tablets.

[0193] Preparation process of Experimental Examples 1-8:

[0194] (1) Mix the compound A methanesulfonate, microcrystalline cellulose, mannitol, crospovidone and ascorbate palmitate in a wet granulator, add a wetting agent and perform wet granulation;

[0195] (2) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0196] (3) Add the dry granules obtained in step (3) to silica, calcium stearate and lemon flavoring, and mix;

[0197] (4) Compress the tablets to form compound A methanesulfonate tablets.

[0198] Test Examples 1-9 to 1-10

[0199] Prepare tablets in batches of 1000 tablets according to the prescription in the table below.

[0200] Table 1-5

[0201]

[0202] Preparation process of Experimental Examples 1-9 to 1-10:

[0203] (1) Silicate is passed through an 80-mesh sieve, and compound A methanesulfonate and other excipients are passed through a 60-mesh sieve for later use;

[0204] (2) Mix all the components after sieving evenly, compress into tablets, and make compound A mesylate tablets.

[0205] Stability Study

[0206] (1) Acceleration stability study and influencing factors and conditions study

[0207] The changes in nitrosamine impurities of the Compound A hydrochloride tablets and Compound A methanesulfonate tablets obtained in Experiments 1-1 to 1-10 were investigated under the conditions of 40℃ and 60℃, respectively, as shown in Table 1-6. The changes in nitrosamine impurities of Experiments 1-5, 1-9 and the reference formulation of Compound A tablets under accelerated conditions of 40℃ / 75%RH are shown in Table 1-7.

[0208] Table 1-6 Changes in nitrosamine impurities in Compound A tablets under high temperature conditions

[0209]

[0210] Table 1-7 Changes in nitrosamine impurities in selected test cases and reference formulations under accelerated conditions.

[0211]

[0212] The results of the nitrosamine impurity test in the table above show that:

[0213] When an antioxidant is added to the formulation of compound A tablets, the tablets can be stored at high temperatures of 40°C and 60°C for 30 days, which can significantly inhibit the growth of nitrosamine impurities, or even prevent the growth trend.

[0214] Experimental Example 2

[0215] Prepare 1000 tablets of compound A hydrochloride according to the prescription in the table below.

[0216]

[0217] Comparative Example 2-1

[0218] (1) Dissolving the active pharmaceutical ingredient: Dissolve the hydrochloride and citric acid of compound A in water as a wetting agent for granulation;

[0219] (2) Mix microcrystalline cellulose and mannitol evenly in a wet granulator, add wetting agent and perform wet granulation;

[0220] (3) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0221] (4) Add the dry granules obtained in step (3) to silica and talc and mix.

[0222] (5) Compress the tablets to form compound A hydrochloride tablets.

[0223] Experimental Example 2-1

[0224] (1) Dissolving the active pharmaceutical ingredient: Dissolve the hydrochloride and citric acid of compound A in water as a wetting agent for granulation;

[0225] (2) Microcrystalline cellulose, mannitol and ascorbate palmitate are mixed evenly in a wet granulator and a wetting agent is added for wet granulation.

[0226] (3) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0227] (4) Add the dry granules obtained in step (3) to silica and talc and mix.

[0228] (5) Compress the tablets to form compound A hydrochloride tablets.

[0229] Experimental Example 2-2

[0230] (1) Dissolving the active pharmaceutical ingredient: Dissolve the hydrochloride, citric acid and vitamin C of compound A in water as a wetting agent for granulation;

[0231] (2) Mix microcrystalline cellulose and mannitol evenly in a wet granulator, add wetting agent and perform wet granulation;

[0232] (3) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0233] (4) Add the dry granules obtained in step (3) to silica and talc and mix.

[0234] (5) Compress the tablets to form compound A hydrochloride tablets.

[0235] Experimental Examples 2-3 to 2-8

[0236] The method is the same as in Experiment 2-2, except that vitamin C is replaced with the appropriate amount of cysteine ​​hydrochloride.

[0237] Experimental Examples 2-9

[0238] Refer to the method in Example 2-2, except that vitamin C is replaced with the appropriate amount of cysteine.

[0239] Stability Study

[0240] (1) Acceleration stability study and influencing factors and conditions study

[0241] The changes in nitrosamine impurities were investigated by placing the hydrochloride tablets of compound A obtained in Experiment 2 at 40°C and 60°C, respectively, as shown in Table 2-2. The changes in nitrosamine impurities in Experiments 2-3, 2-4, and 2-5 under accelerated conditions of 40°C / 75%RH are shown in Tables 2-2 and 2-3, and Figures 1 and 3.

[0242] Table 2-2 Changes in nitrosamine impurities under high temperature conditions in Experiment Example 2

[0243]

[0244] Table 2-3 Stability of nitrosamine impurities under accelerated conditions of 40℃ / 75%RH

[0245]

[0246] Both vitamin C and ascorbyl palmitate can inhibit the growth of nitrosamine impurities in tablets, but the appearance and color of tablets prepared from vitamin C and ascorbyl palmitate change significantly.

[0247] Cysteine ​​hydrochloride and cysteine ​​can inhibit the growth of nitrosamine impurities while maintaining no significant change in the appearance of the tablets.

[0248] When tablets are stored at 40°C / 75%RH for 6 months, if the amount of cysteine ​​hydrochloride is too low, there is a risk that the nitrosamine impurity will exceed 0.375 ppm; if the amount of cysteine ​​hydrochloride is too high, the tablets will tend to turn pale yellow.

[0249] Cysteine ​​hydrochloride, in the range of 0.5–16 mg / tablet (0.5%–6.4% w / w relative to total tablet weight), can effectively inhibit the growth of nitrosamine impurities.

[0250] As shown in Figure 3, the results indicate that when the hydrochloride tablets of compound A were placed under accelerated testing conditions (40℃ / 75%RH) for 6 months, there was no significant change in nitrosamine impurities, and all met the quality control limits.

[0251] The nitrosamine impurities in compound A are significantly affected by temperature and humidity, increasing rapidly under high temperature and high humidity conditions. However, in tests 2-3, 2-4, and 2-5, after 6 months of high temperature and humidification, the nitrosamine impurities showed no significant change compared to the initial 0-month period and remained below the limit. Furthermore, Table 1-7 shows that the reference formulation exhibited a multi-fold increase in nitrosamine impurities under accelerated conditions. Based on the nitrosamine impurity growth trend of this product, it can be concluded that after exposing the drug composition to 40℃ / 75%RH for 6 months and throughout the entire 36-month shelf life, the amount of nitrosamine impurities is less than 0.375 ppm. The nitrosamine impurity content still meets the requirements.

[0252] The results demonstrated that the formulations of test examples 2-3, 2-4, 2-5, and 2-7 could effectively control the growth of nitrosamine impurities, especially under accelerated conditions, the test example formulations were superior to the reference formulation.

[0253] Experimental Example 3

[0254] Prepare 1000 tablets of compound A mesylate according to the prescription in the table below.

[0255] Table 3-1

[0256]

[0257] Comparative Example 3-1

[0258] (1) Mix the methanesulfonate, microcrystalline cellulose and hydroxypropyl methylcellulose in a wet granulator, and add a wetting agent to perform wet granulation.

[0259] (2) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0260] (3) Add the dry granules obtained in step (3) to silica, talc and calcium stearate and mix.

[0261] (4) Compress the tablets to form compound A methanesulfonate tablets.

[0262] Experimental Example 3-1

[0263] (1) Mix the compound A methanesulfonate, microcrystalline cellulose, hydroxypropyl methylcellulose and ascorbate palmitate in a wet granulator, add a wetting agent and perform wet granulation.

[0264] (2) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0265] (3) Add the dry granules obtained in step (3) to silica, talc and calcium stearate, and mix.

[0266] (4) Compress the tablets to form compound A methanesulfonate tablets.

[0267] Experimental Example 3-2

[0268] (1) Dissolution of active pharmaceutical ingredient: Dissolve compound A methanesulfonate and cysteine ​​hydrochloride in water as a wetting agent for granulation;

[0269] (2) Place microcrystalline cellulose and hydroxypropyl methylcellulose in a wet granulator and mix them evenly. Add a wetting agent and perform wet granulation.

[0270] (3) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0271] (4) Add the dry granules obtained in step (3) to silica, talc and calcium stearate, and mix.

[0272] (5) Compress the tablets to form compound A methanesulfonate tablets.

[0273] Experimental Examples 3-3 to 3-4

[0274] The method is the same as in Experiment 3-2, except that the amount of cysteine ​​hydrochloride is different.

[0275] Table 3-2 Results of the Experiment on Influencing Factors

[0276]

[0277] The stability results of Experiment 3 are shown in Table 3-2 and Figure 2. Similar to the results of the study on Compound A hydrochloride tablets, ascorbate palmitate can inhibit the growth of nitrosamine impurities in Compound A methanesulfonate tablets, but it is unstable at high temperatures and easily oxidizes, turning yellow and significantly altering the tablet's appearance. However, cysteine ​​hydrochloride and cysteine ​​can inhibit the growth of nitrosamine impurities while maintaining the tablet's appearance.

[0278] Cysteine ​​hydrochloride can effectively inhibit the growth of nitrosamine impurities in the range of 2-6 mg / tablet (1.0%-3.0% w / w relative to the total tablet weight).

[0279] When the reference formulation was placed under accelerated study conditions (40℃ / 75%RH) and long-term study conditions (30℃ / RH65%) for drug stability studies, the content of nitrosamine impurities in the tablets increased further over time, as shown in Table 4-1.

[0280] Table 4-1 Growth of nitrosamine impurities in the reference formulation of compound A tablets during stability studies.

[0281]

[0282] When compounds A hydrochloride and methanesulfonate are present in aqueous solution, they gradually generate nitrosamine impurities, and the nitrosamine impurities gradually increase with the storage time. The results of the study on the growth rate are shown in Table 4-2.

[0283] Table 4-2 Stability of API test solutions at room temperature

[0284]

[0285] Comparative Example 1:

[0286] Compound A hydrochloride tablets were prepared according to Example 1 of patent CN111249237A. The preparation process is as follows:

[0287] (1) Dissolving the active pharmaceutical ingredient: Dissolve the hydrochloride and citric acid of compound A in water as a wetting agent for granulation;

[0288] (2) Mix microcrystalline cellulose and mannitol evenly in a wet granulator, add wetting agent and perform wet granulation;

[0289] (3) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 55°C until the moisture content does not exceed 3.0%, and then granulated.

[0290] (4) Add the dry granules obtained in step (3) to silica and talc and mix.

[0291] (5) Compress the tablets to form compound A hydrochloride tablets.

[0292] The weights of the raw materials and excipients used to prepare the above 1000 tablets of compound A are shown in the table below:

[0293] Table 5

[0294]

[0295] Comparative Example 2:

[0296] According to Example 1 of patent CN101797237A, the orally disintegrating tablets of compound A (methanesulfonate) were prepared using the following process:

[0297] (1) Crush the methanesulfonate of formula A and all other excipients into fine powder with a fineness of 80 mesh or higher;

[0298] (2) Mix all the pulverized components evenly, compress into tablets, and make compound A mesylate orally disintegrating tablets.

[0299] The weights of the raw materials and excipients used to prepare the above 1000 tablets of compound A are shown in the table below:

[0300] Table 6

[0301]

[0302] The changes in nitrosamine impurities were investigated by placing the hydrochloride tablets and methanesulfonate tablets of compound A obtained in Comparative Examples 1-2 at 40°C and 60°C, respectively. The results are shown in the table below.

[0303] Table 7

[0304]

[0305] Comparative Examples 3-5

[0306] Prepare 1000 tablets according to the prescription in the table below.

[0307] Table 8

[0308]

[0309] Preparation process of Comparative Examples 3-5:

[0310] (1) The compound A hydrochloride, microcrystalline cellulose, mannitol, citric acid and optional antioxidant (sodium metabisulfite or butylated hydroxytoluene) are placed in a wet granulator and mixed evenly. A wetting agent is added for wet granulation.

[0311] (2) The wet granules obtained in step (2) are dried in a fluidized bed with an air inlet temperature of 60°C until the moisture content does not exceed 1.5%, and then granulated.

[0312] (3) Add the dry granules obtained in step (3) to silica and talc, and mix.

[0313] (4) Compress the tablets to form compound A hydrochloride tablets.

[0314] The results of the experiments on the influencing factors for each comparative example are shown in the table below.

[0315] Table 9

[0316]

[0317] Formulations prepared using sodium metabisulfite or butylated hydroxytoluene showed a significant increase in nitrosamine impurities after being stored at 60°C for 30 days, exceeding quality control requirements. Adjusting the amount of pH adjuster also failed to inhibit the increase of nitrosamine impurities in the formulation.

[0318] Comparative Examples 6-9:

[0319] The following table shows the weights of raw materials and excipients used to prepare 1000-tablet packs of Compound A hydrochloride tablets, using glycerol and linoleic acid as antioxidants:

[0320] Table 10

[0321]

[0322] Preparation process of Comparative Example 6:

[0323] (1) Microcrystalline cellulose and mannitol are premixed after being passed through a 50-mesh sieve;

[0324] (2) Preparation of wetting agent: Weigh out the raw material of compound A hydrochloride and citric acid, add purified water and stir to dissolve;

[0325] (3) Preparation of glycerol solution: Weigh the prescribed amount of glycerol, add anhydrous ethanol and stir to dissolve;

[0326] (4) Manual wet granulation: First, add a wetting agent for wet granulation, then add an ethanol solution of glycerol. After granulation, the soft material is passed through a 20-mesh steel wire sieve for granulation and then dried in an oven at 60 ℃.

[0327] (5) The dried granules are granulated, and talc and silica are added in proportion and mixed evenly to obtain a total powder.

[0328] (6) Tableting.

[0329] Preparation process of Comparative Example 7:

[0330] (1) Microcrystalline cellulose and mannitol are premixed after being passed through a 50-mesh sieve;

[0331] (2) Preparation of wetting agent: Weigh out the raw material of compound A hydrochloride and citric acid, add purified water and stir to dissolve;

[0332] (3) Preparation of conjugated linoleic acid solution: Weigh the prescribed amount of conjugated linoleic acid, add anhydrous ethanol and stir to dissolve;

[0333] (4) Manual wet granulation: First, add a wetting agent for wet granulation, then add an ethanol solution of conjugated linoleic acid. After granulation, the soft material is passed through a 20-mesh steel wire sieve for granulation and then dried in an oven at 60 ℃.

[0334] (5) The dried granules are granulated, and talc and silica are added in proportion and mixed evenly to obtain a total powder.

[0335] (6) Tableting.

[0336] Preparation process of Comparative Examples 8-9:

[0337] (1) Microcrystalline cellulose and mannitol are premixed after being passed through a 50-mesh sieve;

[0338] (2) Preparation of wetting agent: Weigh out the raw material of compound A hydrochloride and citric acid, add purified water and stir to dissolve;

[0339] (3) Preparation of conjugated linoleic acid and glycerol solution: Weigh the prescribed amount of conjugated linoleic acid and glycerol, add anhydrous ethanol and stir to dissolve;

[0340] (4) Manual wet granulation: First, add a wetting agent for wet granulation, then add an ethanol solution of conjugated linoleic acid and glycerol. After granulation, the soft material is passed through a 20-mesh steel wire sieve for granulation and then dried in an oven at 60 ℃.

[0341] (5) The dried granules are granulated, and talc and silica are added in proportion and mixed evenly to obtain a total powder.

[0342] (6) Tableting.

[0343] The results of the comparative experiments on influencing factors for Examples 6-9 are shown in the table below.

[0344] Table 11

[0345]

[0346] Solid particles prepared using conjugated linoleic acid have poor flowability, low bulk density, and poor compressibility, making them unsuitable for preparing solid tablets.

[0347] The results showed that the addition of conjugated linoleic acid had no significant inhibitory effect on the nitrosamine impurity content in the hydrochloride tablets of compound A. The nitrosamine impurities in the 0-day sample exceeded the limit, and there was a significant increasing trend after being placed at a high temperature of 60°C for 5 days. In addition, the appearance of the tablets changed from the initial white to off-white to light yellow.

[0348] Meanwhile, conjugated linoleic acid is insoluble in water. To prepare a solution, it is necessary to add an ethanol solution with a concentration greater than 70% to achieve good dispersion or dissolution. It is impossible to prepare a clear solution using 10% ethanol.

[0349] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0350] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound of formula A or a salt thereof, and an antioxidant, wherein the structure of the compound of formula A is as follows: The antioxidant is selected from water-soluble antioxidants and / or non-water-soluble antioxidants; the water-soluble antioxidant is selected from cysteine ​​and / or cysteine ​​hydrochloride; the non-water-soluble antioxidant is butylated hydroxyanisole and / or propyl gallate; the salt of compound A is hydrochloride or methanesulfonate; when the antioxidant is cysteine ​​and / or cysteine ​​hydrochloride, the antioxidant content in the pharmaceutical composition ranges from 0.5% to 7.2% w / w.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is an oral solid dosage form of compound A or a liquid dosage form of compound A; the oral solid dosage form is granules, tablets or capsules.

3. The pharmaceutical composition according to claim 1, characterized in that, The antioxidant is present in the pharmaceutical composition at a concentration ranging from 0.5% to 6.4% w / w.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further comprises other excipients selected from one or more of ① to ⑥: ① Filler: the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch, and microcrystalline cellulose; ② Binder: the binder is selected from one or more of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, starch, carbomer, methylcellulose, and gelatin; ③ pH adjuster: the pH adjuster is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate; ④ Disintegrant: The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, calcium carboxymethyl cellulose and starch; ⑤ Glide aid: The glide aid is selected from one or more of silica, talc, hydrogenated vegetable oil, calcium silicate and magnesium silicate; ⑥ Lubricant: The lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate and sodium docusate.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition satisfies one or more of a)-c); a) after the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 3 months, when the salt of compound A is hydrochloride, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; when the salt of compound A is methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance; b) after the pharmaceutical composition containing compound A is exposed to 40°C / 75%RH for 6 months, when the salt of compound A is hydrochloride, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; when the salt of compound A is methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm. ppm; and the pharmaceutical composition has a white or off-white appearance; c) During the shelf life of the pharmaceutical composition containing compound A, when the salt of compound A is hydrochloride, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; when the salt of compound A is methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the pharmaceutical composition has a white or off-white appearance; the structure of the nitrosamine impurity is: 。 6. An oral solid dosage form, characterized in that, It includes a compound of formula A or its salt and a non-inorganic salt antioxidant, wherein the structure of the compound of formula A is as follows: The non-inorganic salt antioxidant is selected from one or more of propyl gallate, butylated hydroxyanisole, cysteine ​​hydrochloride, and cysteine; the salt of compound A is a hydrochloride or methanesulfonate; when the inorganic salt antioxidant is cysteine ​​and / or cysteine ​​hydrochloride, the content of the inorganic salt antioxidant in the pharmaceutical composition ranges from 0.5% to 7.2% w / w.

7. The oral solid dosage form according to claim 6, characterized in that, The oral solid dosage form comprises 0.5% to 7.2% by weight of a non-inorganic salt antioxidant, 2% to 10% by weight of a compound of formula A or a salt thereof, 70% to 90% by weight of a filler, 1% to 3% by weight of a pH adjuster, 1% to 3% by weight of a flow aid, and 2% to 8% by weight of a lubricant; wherein the filler is selected from one or more of starch, dextrin, maltodextrin, sucrose, lactose, mannitol, dicalcium phosphate, starch, pregelatinized starch, and microcrystalline cellulose; and / or the p The H-regulator is selected from one or more of tartaric acid, malic acid, fumaric acid, acetic acid, sodium acetate, concentrated ammonia solution, hydrochloric acid, lactic acid, sodium bicarbonate, sodium carbonate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, citric acid, and sodium citrate; and / or the flow aid is selected from one or more of silica, talc, and hydrogenated vegetable oil; and / or the lubricant is selected from one or more of magnesium stearate, talc, calcium stearate, stearic acid, sodium stearate fumarate, glyceryl behenate, and sodium docusate.

8. The oral solid dosage form according to any one of claims 6 or 7, characterized in that, The oral solid dosage form is prepared using either a dry process or a wet process.

9. A method for controlling the content of nitrosamine impurities in a pharmaceutical composition comprising a compound of formula A or a salt thereof, characterized in that, The method includes mixing a compound of formula A or a salt thereof with one or more antioxidants, wherein the compound of formula A has the following structure: The nitrosamine impurity is: The antioxidant is selected from water-soluble antioxidants and / or non-water-soluble antioxidants; the water-soluble antioxidant is selected from cysteine ​​and / or cysteine ​​hydrochloride; the non-water-soluble antioxidant is butylated hydroxyanisole and / or propyl gallate; the salt of compound A is hydrochloride or methanesulfonate; when the antioxidant is cysteine ​​and / or cysteine ​​hydrochloride, the antioxidant content in the pharmaceutical composition ranges from 0.5% to 7.2% w / w.

10. The method according to claim 9, characterized in that, When the salt of compound A is a hydrochloride salt, the content of nitrosamine in the pharmaceutical composition is less than 0.375 ppm; when the salt of compound A is a methanesulfonate salt, the content of nitrosamine in the pharmaceutical composition is less than 0.500 ppm.

11. The method according to claim 10, characterized in that, The pharmaceutical composition containing compound A satisfies one or more of a)-c); a) after exposure to 40°C / 75%RH for 3 months, when the salt of compound A is hydrochloride, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; when the salt of compound A is methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm; and the pharmaceutical composition has a white or off-white appearance; b) after exposure to 40°C / 75%RH for 6 months, when the salt of compound A is hydrochloride, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition has a white or off-white appearance; when the salt of compound A is methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm. ppm; and the pharmaceutical composition is white or off-white in appearance; c) During the shelf life of the pharmaceutical composition containing compound A, when the salt of compound A is hydrochloride, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.375 ppm; and the pharmaceutical composition is white or off-white in appearance; when the salt of compound A is methanesulfonate, the content of nitrosamine impurities in the pharmaceutical composition is less than 0.500 ppm, and the pharmaceutical composition is white or off-white in appearance.

12. The method according to claim 9, characterized in that, The antioxidant is present in the pharmaceutical composition at a weight range of 0.5%-6.4% w / w.

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