Pharmaceutical composition

Abstract

The invention provides a stable pharmaceutical composition containing [(1R, 5S, 6S)-6-(aminomethyl)-3-ethyl bicyclo [3.2. 0] hept-3-ene-6-yl] acetic acid or single benzene sulfonate thereof, and the pharmaceutical composition contains an effective amount of active substances and a stabilizer, and has excellent industrial application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a pharmaceutical composition. BACKGROUND

[0002] It has been proven that compounds exhibiting high affinity binding to voltage-dependent calcium channel subunit a2d can effectively treat a variety of diseases, such as neuropathic pain. Examples of known a2d ligand drugs include gabapentin and pregabalin, which can be used to treat epilepsy and neuropathic pain.

[0003] [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (hereinafter referred to as Compound I) and its monobenzene sulfonate are known a2d ligands, the chemical structure, preparation method and pharmacological activity of which are reported in detail in WO2009041453A1. Compound I has the chemical structure shown in Formula I:

[0004] .

[0005] Its monosulfonate structure is as follows:

[0006] .

[0007] Tarlige (minobactin benzene sulfonate) 2.5mg, 5mg, 10mg, 15mg tablets of Japanese pharmaceutical company Daiichi Sankyo have been approved in Japan for the treatment of peripheral neuropathic pain (PNP).

[0008] Previous studies have shown that formulations containing Compound I or its monobenzene sulfonate have obvious instability during long-term storage, and various related substances are easily produced, affecting the quality of the drug.

[0009] Daiichi Sankyo uses antioxidants such as sodium edetate, citric acid hydrate, dibutyl hydroxytoluene, propyl gallate, magnesium citrate (anhydrous), soybean lecithin tocopherol, tocopherol acetate and 8-cyclodextrin to reduce the content of impurities in the pharmaceutical composition containing [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzene sulfonate in CN107405322A. The experimental results show that tocopherol and β-cyclodextrin have better stability.

[0010] In subsequent patent application CN 111971036 A, the First Chemical Co., Ltd. provided a solid preparation with better stability, and used citric acid hydrate and α-tocopherol to provide particularly excellent stability effects, and applied the antioxidant combination in the marketed preparation product Tarlige. However, tocopherol is a viscous liquid, the storage conditions are relatively harsh, and it is not easy to mix uniformly with other raw and auxiliary materials in the preparation process of the solid preparation, thereby increasing the cost of industrial application.

[0011] Another study used malic acid. However, the compatibility experiment data of raw and auxiliary materials showed that there was a risk of increasing related substances in long-term contact of malic acid with the monobenzene sulfonate salt of compound I, and the unknown impurities increased significantly, thereby bringing uncertainty to the long-term quality stability of the product.

[0012] Although there are many studies on the stability of the product in the prior art, whether the stability can be further improved and the generation of too many impurities can be avoided as much as possible still needs to be further studied. SUMMARY

[0013] One of the purposes of the present application is to provide a long-term stable pharmaceutical composition, which has good stability of the drug through the combination of specific types and amounts of antioxidants.

[0014] Specifically, the present application provides a long-term stable pharmaceutical composition, which contains a therapeutically effective amount of active substance, stabilizer and organic acid, wherein the active substance is selected from compound I or the monobenzene sulfonate salt thereof shown in formula 1, the stabilizer is selected from the fatty acid ester of ascorbic acid, the fatty acid ester of ascorbic acid includes ascorbic acid palmitate, ascorbic acid isopalmitate, ascorbic acid stearate, ascorbic acid oleate, ascorbic acid laurate, ascorbic acid myristate; and the organic acid is selected from citric acid hydrate or / and tartaric acid.

[0015] .

[0016] In some embodiments, the fatty acid ester of ascorbic acid is selected from ascorbic acid palmitate.

[0017] In particular, in some embodiments, the mass ratio of the ascorbic acid palmitate to the active substance (calculated as the free base of compound I) is 0.5-20:25, in some embodiments, the mass ratio of the ascorbic acid palmitate to the active substance (calculated as the free base of compound I) is 1-10:25, preferably 1-5:25; for example, in some embodiments, the mass ratio of the ascorbic acid palmitate to the active substance (calculated as the free base of compound I) in the composition of the present application is 1:25 or 2:25 or 3:25.

[0018] In certain embodiments, the ascorbyl palmitate is present in the pharmaceutical composition in an amount of 0.05% to 2% by weight, particularly in an amount of 0.1% to 1% by weight, preferably in an amount of 0.1% to 0.5% or 0.1% to 0.3% by weight; for example, in certain embodiments, the ascorbyl palmitate is present in the pharmaceutical composition in an amount of 0.1% or 0.2% or 0.3% by weight.

[0019] In certain embodiments, the organic acid is selected from L(+)-tartaric acid.

[0020] In certain embodiments, the organic acid is present in the pharmaceutical composition in an amount of 1.5% to 5% by weight, further selected from 2.5% to 5% by weight, more further selected from 2.5% to 4% by weight, and also selected from 2.5% to 3% by weight; for example, the organic acid can be present in an amount of 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 5% by weight.

[0021] In certain embodiments, the mass ratio of the organic acid to the active substance (calculated as the free base of Compound I) in the pharmaceutical composition of the present application is 3 to 10:5, preferably 5 to 6:5, for example, the mass ratio of the organic acid to the active substance (calculated as the free base of Compound I) is 3:5, 4:5, 5:5, 6:5, 7:5, 8:5 or 10:5.

[0022] In certain embodiments, the pharmaceutical composition of the present application further comprises one or more of a filler, a disintegrant, a lubricant, and a sorbent; further, the filler is selected from mannitol and microcrystalline cellulose; the disintegrant is selected from carboxymethylcellulose; the lubricant is selected from magnesium stearate and sodium stearyl fumarate; and the sorbent is selected from magnesium metasilicate aluminate.

[0023] In certain embodiments, the filler is present in an amount of 77% to 82% by weight of the total weight of the composition; the disintegrant is present in an amount of 8% to 12% by weight of the total weight of the composition; and the lubricant is present in an amount of 1.0% to 2.0% by weight.

[0024] In certain embodiments, the disintegrant is present in an amount of 10% or 12% by weight of the total weight of the composition; and the lubricant is present in an amount of 1.5% by weight.

[0025] The amount of Compound I (calculated as the free form) used in the pharmaceutical composition of the present application is the minimum effective dose to achieve its clinical therapeutic purpose, which can be adjusted according to clinical needs combined with conventional technical means in the field of formulation, for example, it can be 0.5 to 40% by weight, or 0.5 to 25% by weight, or 0.5 to 10% by weight, or 0.5 to 5% by weight, or 1.0 to 5% by weight.

[0026] In certain embodiments, the monobenzenesulfonic acid salt of Compound I is present in the pharmaceutical composition in an amount of 4.39% by weight of the total weight.

[0027] In certain embodiments, the stabilizer is present in the pharmaceutical composition in an amount of 0.1-0.3% by weight, the organic acid is present in the pharmaceutical composition in an amount of 2.5-4% by weight, the filler is present in an amount of 77-82% by weight of the total weight of the composition, the disintegrant is present in an amount of 8-12% by weight of the total weight of the composition, and the lubricant is present in an amount of 1.0-2.0% by weight, and Compound I is present in a conventional amount known in the art.

[0028] The foregoing percentages by weight are based on the uncoated core tablet.

[0029] In certain embodiments, the pharmaceutical composition of the present application further comprises a coating agent.

[0030] In certain embodiments, the pharmaceutical composition of the present application is a solid formulation.

[0031] In certain embodiments, the pharmaceutical composition of the present application is a tablet, which can be a coated or uncoated tablet.

[0032] The present inventors have found that a new related substance, a compound of Formula Ia (hereinafter "Impurity Ia"), is generated in a pharmaceutical composition comprising Compound I during long-term storage, which is not generally present in the raw material product of Compound I. In particular, the content of this impurity increases dramatically under long-term storage or certain specific storage conditions, which is significantly higher than the limit of the control of a single impurity in the pharmacopoeia (not more than 0.2%). The present inventors have found, by long-term experiments, that ascorbyl palmitate can effectively inhibit the generation of related substances in the composition, and in particular, has a significant inhibitory effect on the content of Impurity Ia. Although it has been confirmed in experiments that tocopherol can also reduce the content of related substances in the pharmaceutical composition to a certain extent, its effect is not as good as that of ascorbyl palmitate. In addition, tocopherol is a viscous oily liquid, which is slowly oxidized in the air, and needs to be stored in a gas-tight container under inert gas protection, in the dark and in a cool and dry place. Tocopherol needs to be frequently opened during use, which may affect its physicochemical properties and its own stability. In addition, tocopherol is used in a small amount as a stabilizer, and the remaining excipients are all solid powders. The addition of the viscous oily liquid is not convenient for the production process, and may lead to uneven mixing of the excipients, which is difficult for the process. Ascorbyl palmitate does not have the above problems, and is beneficial for industrial mass production.

[0033] In particular, we found that the further addition of an organic acid such as citric acid hydrate or tartaric acid, especially L(+)-tartaric acid, to the pharmaceutical composition containing ascorbyl palmitate leads to a further significant improvement in the stability of the pharmaceutical composition, which is very surprising and leads to a breakthrough in the quality control of the formulation of Compound I and its monobenzenesulfonate salt.

[0034] The structure of the impurity la compound found in the present application is as follows:

[0035]

[0036] a) 1 The H-NMR spectrum shows 11 groups of proton signals, and according to the integral area ratio, it can be known that the sample contains 16 hydrogen atoms. Including 1 hydrogen signal H-5 (δ H 5.384-5.380, s, 1H) on 1 double bond; 2 hydrogen signals H-1 (δ H 3.125-3.121, s, 1H), H-2 (δ H 2.191-2.179, m, 1H) on 2 methine groups; 10 hydrogen signals H-11 (δ H 3.508-3.488, dd, 2H), H-3 (δ H 2.846-2.831, m, 1H) / (δ H 2.487-2.472, m, 1H), H-8 (δ H 2.391-2.358, m, 2H), H-9 (δ H 2.191-2.179, m, 2H), H-7 (δ H 2.073-2.040, m, 1H) / (δ H 1.696-1.681, dd, 1H); 3 hydrogen signals H-10 (δ H 1.107-1.092, t, 3H) on 1 methyl group.

[0037] b) 13 The C-NMR spectrum shows that the sample contains 12 groups of signals of 12 carbons in total, including 1 amide carbon signal C-12 (δ C 178.709); 2 double bond carbon signals C-4 (δ C 149.429), C-5 (δ C 121.726); 1 quaternary carbon signal C-6 (δ C 31.128); 2 methine carbon signals C-1 (δ C 39.408), C-2 (δC 23.914); 5 methylene carbon signals C-11 (δ C 55.409), C-7 (δ C 54.693), C-8 (δ C 45.490), C-3 (δ C 41.872), C-9 (δ C 38.159); 1 methyl carbon signal C-10 (δ C 11.448).

[0038] The present application further provides a pharmaceutical composition comprising Compound 1 or its monobenzene sulfonate, pharmaceutically acceptable excipients, and no more than 2% of Compound Ia; preferably, the pharmaceutical composition contains no more than 1.5% of Compound Ia; more preferably, the pharmaceutical composition contains no more than 1% or no more than 0.5% or no more than 0.2% or no more than 0.1% of Compound Ia.

[0039] In some embodiments of the present application, the pharmaceutical composition with low content of Compound Ia has the following excipient prescription.

[0040] The pharmaceutical composition of the present application can comprise pharmaceutically acceptable excipients. Specifically, the pharmaceutical composition of the present application can comprise fillers such as mannitol, microcrystalline cellulose; disintegrants such as carboxymethyl cellulose; lubricants such as magnesium stearate, sodium stearyl fumarate; adsorbents such as magnesium metasilicate.

[0041] In the pharmaceutical composition of the present application, the amount of the filler is 77%-82% of the total weight of the composition, the amount of the disintegrant is 8-12%, such as 10% or 12%, of the total weight of the composition, and the amount of the lubricant is 1.0%-2.0%, such as 1.5%, of the total weight of the composition.

[0042] The present application provides a long-term stable pharmaceutical composition, characterized in that it comprises:

[0043] Monobenzene sulfonate of Compound I 4.39%

[0044] D-mannitol 78.21%,

[0045] Carboxymethyl cellulose 12%

[0046] Microcrystalline cellulose 0.9%

[0047] Ascorbyl palmitate 0.2%

[0048] L(+)-tartaric acid 2.5%

[0049] Magnesium metasilicate 0.3%

[0050] Magnesium stearate or sodium stearyl fumarate 1.5%.

[0051] or

[0052] Monobenzoate salt of Compound I 4.39%

[0053] D-mannitol 79.81%,

[0054] Carboxymethylcellulose 10%

[0055] Microcrystalline cellulose 0.9%

[0056] Ascorbyl palmitate 0.2%

[0057] L(+)-Tartaric acid 3%

[0058] Magnesium aluminium silicate 0.2%

[0059] Magnesium stearate or sodium stearyl fumarate 1.5%.

[0060] or

[0061] Monobenzoate salt of Compound I 4.39%

[0062] D-mannitol 79.71%,

[0063] Carboxymethylcellulose 10%

[0064] Microcrystalline cellulose 0.9%

[0065] Ascorbyl palmitate 0.2%

[0066] L(+)-Tartaric acid 3.0%

[0067] Magnesium aluminium silicate 0.3%

[0068] Magnesium stearate or sodium stearyl fumarate 1.5%.

[0069] or

[0070] Monobenzoate salt of Compound I 4.39%

[0071] D-mannitol 79.61%,

[0072] Carboxymethylcellulose 10%

[0073] Microcrystalline cellulose 0.9%

[0074] Ascorbyl palmitate 0.3%

[0075] L(+)-Tartaric acid 3.0%

[0076] Magnesium aluminium silicate 0.3%

[0077] Magnesium stearate or sodium stearyl fumarate 1.5%.

[0078] or

[0079] Monobenzene sulfonate salt of compound I 4.39%

[0080] D-mannitol 78.71%

[0081] E-carboxymethyl cellulose 10%

[0082] F-microcrystalline cellulose 0.9%

[0083] Ascorbyl palmitate 0.2%

[0084] L(+)-tartaric acid 4.0%

[0085] Magnesium silicate 0.3%

[0086] Magnesium stearate or sodium stearyl fumarate 1.5%.

[0087] In another aspect of the present application, there is further provided a method for detecting compound Ia in the solid preparation of compound I, wherein the stationary phase is selected from a C18 column, and the mobile phase is selected from an ammonium bicarbonate buffer as mobile phase A, and acetonitrile as mobile phase B, and the gradient elution program is as follows:

[0088] .

[0090] In certain embodiments, the detection wavelength is 205 nm.

[0091] In certain embodiments, the concentration of the ammonium bicarbonate buffer is 0.001M-0.1M; further selected from 0.005M-0.05M; for example, 0.005M, 0.01M, 0.02M, 0.03M, 0.04M, 0.05M, etc. can be selected.

[0092] In another aspect of the present application, there is further provided a method for reducing impurities in compound I or its monobenzene sulfonate salt, wherein a stabilizer and an organic acid are added in compound I or its monobenzene sulfonate salt, or a solid preparation containing compound I or its monobenzene sulfonate salt, wherein the active substance is selected from compound I or its monobenzene sulfonate salt shown in formula 1, the stabilizer is selected from a fatty acid ester of ascorbic acid, the fatty acid ester of ascorbic acid includes ascorbyl palmitate, ascorbyl isopalmitate, ascorbyl stearate, ascorbyl oleate, ascorbyl laurate, ascorbyl myristate; the organic acid is selected from citric acid hydrate or / and tartaric acid;

[0093] .

[0094] In certain embodiments, the impurities at least include impurity Ia

[0095] .

[0096] In some embodiments, reducing impurities also includes reducing the total impurity content.

[0097] The kind and amount of the stabilizer, organic acid are as described above.

[0098] The "reducing impurities" in the present application includes preventing, reducing or / and delaying the formation of impurities, or / and reducing the kind of impurities.

[0099] The method for preparing the solid preparation in the present application can use the conventional preparation technology in the art, for example, the common methods for preparing the tablet containing Compound I or its benzenesulfonate salt include:

[0100] (1) direct compression of powder, mixing the active ingredient with the filler, binder and other excipients, and then compressing the tablet by using the tablet press;

[0101] (2) tabletting after wet granulation, mixing the active ingredient with the filler, disintegrant and other excipients, adding the wetting agent or binder for granulation, obtaining the dry granules, adding the lubricant, and then compressing the tablet by using the tablet press;

[0102] (3) tabletting after dry granulation, mixing the active ingredient with the filler, disintegrant, binder and other excipients for granulation, obtaining the dry granules, adding the lubricant, and then compressing the tablet by using the tablet press.

[0103] In the present application, the direct compression of powder is preferred for preparing the tablet.

[0104] After using the specific proportion of the fatty acid ester of ascorbic acid and the citric acid hydrate or tartaric acid in the pharmaceutical composition of the present application, the formation of impurity Ia and total impurities in the solid preparation of Compound I can be effectively inhibited. In the long-term stability experiment, the pharmaceutical composition of the present application can maintain a relatively low impurity level for a long time, and the stability is obviously superior to the pharmaceutical composition disclosed in the prior art. DETAILED DESCRIPTION

[0105] The following only exemplifies the pharmaceutical composition of the present application to facilitate the understanding of the present application. Those skilled in the art should understand that the following examples are not a limitation of the present application, and any technical solution within the scope of the description of the present application is part of the present application.

[0106] In the present application, the high performance liquid chromatography is used to detect the content of related substances, and the chromatographic conditions are as follows

[0107] Column: Kromasil 100-5-C18, 4.6 mm x 150 mm, 5 µm

[0108] Column temperature: 30℃ ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0109] Flow rate: 1.0 ml / min

[0110] Injection volume: 10 μl

[0111] Detector: UV detector

[0112] Detection wavelength: 205 nm

[0113] Mobile phase: 0.01 M ammonium bicarbonate buffer (0.79 g ammonium bicarbonate was weighed, dissolved in water and diluted to 1000 ml) as mobile phase A, and acetonitrile as mobile phase B, gradient elution was performed according to the following table.

[0114]

[0115] Experimental Example 1

[0116] The prescription ratio of Table 1-1 was used to weigh mannitol, monobenzenesulfonate of compound 1 (Sichuan Ren'an Pharmaceutical Co., Ltd.) and stabilizer, which were mixed and then magnesium stearate was added to obtain a total mixed powder. The total mixed powder was tabletted by using a rotary tablet machine to obtain round tablets with a tablet weight of about 200 mg. The tablets were placed in an open container at 50°C and 75% RH for 30 days, and the amount of related substances was detected. The results are shown in Table 1-2.

[0117] Table 1-1

[0118]

[0119] Note: The content of the raw and auxiliary materials in the table is percentage content, and the same below.

[0120] Table 1-2

[0121]

[0122] Results of raw material compatibility experiment

[0123] The organic acid and monobenzenesulfonate of compound 1 were mixed in a mass ratio of 1:1, and then placed in an open container at 50°C and 75% RH for 30 days, and the content of related substances was detected. The results are as follows:

[0124] Table 1-3

[0125]

[0126] The results of the raw material compatibility experiment showed that citric acid hydrate, succinic acid, fumaric acid and L(+)-tartaric acid had a certain inhibitory effect on impurity Ia, and among them, succinic acid, fumaric acid and L(+)-tartaric acid could effectively inhibit the growth of other unknown impurities; but DL-malic acid, L-malic acid and maleic acid had no obvious inhibitory effect on impurity Ia and would cause a large amount of unknown impurities.

[0127] Example 2

[0128] Tablet was prepared according to the prescription in Table 2. Compound 1 monobenzenesulfonate salt (Sichuan Ren'an Pharmaceutical Co., Ltd.), and the auxiliary ingredients except magnesium stearate in the prescription were weighed, mixed, and then magnesium stearate was added to obtain the total mixed powder. The total mixed powder was tabletted by using a rotary tablet press to obtain capsule-shaped tablets with a tablet weight of about 200 mg. The obtained tablets were placed in an open container at 50°C and 75% RH for 30 days, and the content of related substances was detected. The results are shown in Table 3.

[0129] Table 2

[0130]

[0131] Table 3

[0132]

[0133] Example 3

[0134] Tablet was prepared according to the prescription in Table 4. Compound 1 monobenzenesulfonate salt (Sichuan Ren'an Pharmaceutical Co., Ltd.), and the auxiliary ingredients except magnesium stearate in the prescription were weighed, mixed, and then magnesium stearate was added to obtain the total mixed powder. The total mixed powder was tabletted by using a rotary tablet press to obtain capsule-shaped tablets with a tablet weight of about 200 mg. The obtained tablets were placed in an open container at 50°C and 75% RH for 30 days, and the content of related substances was detected. The results are shown in Table 5.

[0135] Table 4

[0136]

[0137] Table 5

[0138]

[0139] Example 4

[0140] Tablet was prepared according to the prescription in Table 6. Compound 1 monobenzenesulfonate salt (Sichuan Ren'an Pharmaceutical Co., Ltd.), and the auxiliary ingredients except magnesium stearate in the prescription were weighed, mixed, and then magnesium stearate was added to obtain the total mixed powder. The total mixed powder was tabletted by using a rotary tablet press to obtain capsule-shaped tablets with a tablet weight of about 200 mg. The obtained tablets were placed in an open container at 50°C and 75% RH for 30 days, and the content of related substances was detected. The results are shown in Table 7.

[0141] Table 6

[0142]

[0143] Table 7

[0144]

[0145] Example 5

[0146] The monobenzenesulfonate salt of compound 1 (Sichuan Ren'an Pharmaceutical Co., Ltd.), and the auxiliary ingredient except magnesium stearate in the prescription were weighed according to the prescription in Table 8, and then mixed. After that, magnesium stearate was added and mixed to obtain a total mixed powder. The total mixed powder was compressed into a capsule-shaped tablet with a tablet weight of about 200 mg by using a rotary tablet press. The obtained tablet was placed in an open condition at 50°C and 75% RH for 30 days, and the content of related substances was detected. The results are shown in Table 9.

[0147] Table 8

[0148]

[0149] Table 9

[0150]

[0151] Example 6

[0152] The monobenzenesulfonate salt of compound 1 (Sichuan Ren'an Pharmaceutical Co., Ltd.), and the auxiliary ingredient except magnesium stearate in the prescription were weighed according to the prescription in Table 10, and then mixed. After that, magnesium stearate or sodium stearyl fumarate was added and mixed again to obtain a total mixed powder. The total mixed powder was compressed into a capsule-shaped tablet with a tablet weight of about 200 mg by using a rotary tablet press. The obtained tablet was placed in an aluminum plastic package and then placed in an accelerated condition at 40°C and 75% RH for 3 months, and the content of related substances was detected. The total impurities and impurity Ia content of the pharmaceutical composition of the application were significantly lower than those of the original research marketed product (total impurity content 0.90% and impurity Ia content 0.63% after 3 months of acceleration), and the stability was better.

[0153] Table 10-1

[0154]

[0155] Table 10-2

[0156]

[0157] *: original research marketed

[0158] The dissolution curve or dissolution degree of the composition of the application in pH 1.2, pH 4.0, and pH 6.8 media was determined according to the dissolution and release test method (Chinese Pharmacopoeia 2020 edition four general rules 0931 second method) (paddle method). The cumulative dissolution was calculated by high performance liquid chromatography. The cumulative dissolution of the pharmaceutical composition of the application reached more than 95% at 10 min, which was consistent with the original research reference preparation.

Claims

1. A long-term stable pharmaceutical composition comprising a therapeutically effective amount of an active substance, a stabilizer and an organic acid, wherein the active substance is selected from the group consisting of Compound I or its monobenzene sulfonate salt of Formula I, the stabilizer is selected from the group consisting of fatty acid esters of ascorbic acid, the fatty acid esters of ascorbic acid including ascorbyl palmitate, ascorbyl isopalmitate, ascorbyl stearate, ascorbyl oleate, ascorbyl laurate, ascorbyl myristate; and the organic acid is selected from the group consisting of citric acid hydrate and / or tartaric acid; 。 2. The pharmaceutical composition according to claim 1, wherein, the stabilizer is selected from ascorbyl palmitate.

3. The pharmaceutical composition of claim 1, wherein, the organic acid is selected from L(+)-tartaric acid.

4. The pharmaceutical composition according to claim 1 or 2, wherein, The mass ratio of the stabilizer and the active substance is 0.5-20:25, calculated as the free base of Compound I; further, the mass ratio is selected from 1-10:25; preferably, the mass ratio is 1-5:

25.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The mass ratio of the organic acid and the active substance is 3-10:5, calculated as the free base of Compound I; further, the mass ratio is selected from 5-6:

5.

6. The pharmaceutical composition according to claim 1 or 4, wherein, The mass percentage of the stabilizer in the pharmaceutical composition is 0.05%-2%; further, the mass percentage of the stabilizer in the pharmaceutical composition is 0.1%-1%; preferably, the mass percentage of the stabilizer in the pharmaceutical composition is 0.1%-0.3%.

7. The pharmaceutical composition of claim 6, wherein the mass percentage of ascorbyl palmitate in the pharmaceutical composition is 0.1% or 0.2% or 0.3%.

8. The pharmaceutical composition according to claim 1 or 5, wherein, The mass percentage of the organic acid in the pharmaceutical composition is 1.5%-5%, further selected from 2.5%-5%; more further selected from 2.5%-4%.

9. The pharmaceutical composition of claim 1 or 8, wherein the mass percentage of the organic acid in the pharmaceutical composition is 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 5%.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein, one or more of a filler, a disintegrant, a lubricant, and an adsorbent; further, the filler is selected from mannitol and microcrystalline cellulose; the disintegrant is selected from carboxymethyl cellulose; the lubricant is selected from magnesium stearate and sodium stearyl fumarate; and the adsorbent is selected from magnesium aluminum metasilicate.

11. The pharmaceutical composition of claim 10, wherein, The amount of the filler is 77%-82% of the total weight of the composition; the amount of the disintegrant is 8%-12% of the total weight of the composition; and the amount of the lubricant is 1.0%-2.0%.

12. The pharmaceutical composition of claim 11, wherein the amount of the disintegrant is 10% or 12% of the total weight of the composition; and the amount of the lubricant is 1.5%.

13. The pharmaceutical composition of claim 1, wherein, The monobenzene sulfonate salt of Compound I in the pharmaceutical composition is 4.39% of the total weight.

14. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises the following components in the following mass percentages: the monobenzene sulfonate salt of Compound I 4.39%, D-mannitol 78.21%, carboxymethyl cellulose 12%, microcrystalline cellulose 0.9%, ascorbyl palmitate 0.2%, L(+)-tartaric acid 2.5%, magnesium aluminum metasilicate 0.3%, magnesium stearate or sodium stearyl fumarate 1.5%; or the monobenzene sulfonate salt of Compound I 4.39%, D-mannitol 79.81%, carboxymethyl cellulose 10%, microcrystalline cellulose 0.9%, ​ Ascorbyl palmitate 0.2%, L(+)-tartaric acid 3.0%, magnesium aluminum silicate 0.2%, magnesium stearate or sodium stearyl fumarate 1.5%; or Monobenzenesulfonate salt of Compound I 4.39%, D-mannitol 79.71%, carboxymethylcellulose 10%, microcrystalline cellulose 0.9%, Ascorbyl palmitate 0.2%, L(+)-tartaric acid 3.0%, magnesium aluminum silicate 0.2%, magnesium stearate or sodium stearyl fumarate 1.5%; or Monobenzenesulfonate salt of Compound I 4.39%, D-mannitol 79.61%, carboxymethylcellulose 10%, microcrystalline cellulose 0.9%, Ascorbyl palmitate 0.3%, L(+)-tartaric acid 3.0%, magnesium aluminum silicate 0.3%, magnesium stearate or sodium stearyl fumarate 1.5%; or Monobenzenesulfonate salt of Compound I 4.39%, D-mannitol 78.71%, carboxymethylcellulose 10%, microcrystalline cellulose 0.9%, Ascorbyl palmitate 0.2%, L(+)-tartaric acid 4.0%, magnesium aluminum silicate 0.3%, magnesium stearate or sodium stearyl fumarate 1.5%.

15. The pharmaceutical composition according to any one of claims 1-14, wherein, The pharmaceutical composition is a solid preparation.

16. The pharmaceutical composition according to any one of claims 1-14, wherein, The pharmaceutical composition is a tablet.

17. A pharmaceutical composition, comprising Compound I or a monobenzenesulfonate salt thereof, pharmaceutically acceptable excipients, ； and not more than 2% of Compound Ia; further, not more than 1.5% of Compound Ia; preferably, not more than 1% or not more than 0.5% or not more than 0.2% or not more than 0.1% of Compound Ia 。 18. A method of detecting Compound la in a solid formulation of Compound I, wherein, The stationary phase is selected from a C18 column, and the mobile phase is selected from ammonium bicarbonate buffer as mobile phase A and acetonitrile as mobile phase B, and the gradient elution program is as follows: 。 19. A method of reducing impurities in Compound I or its monobenzene sulfonate salt, wherein, In Compound I or a monobenzenesulfonate salt thereof, or a solid preparation containing Compound I or a monobenzenesulfonate salt thereof, a stabilizer and an organic acid are added, wherein the active substance is selected from Compound I or a monobenzenesulfonate salt thereof shown in Formula I, the stabilizer is selected from a fatty acid ester of ascorbic acid, the fatty acid ester of ascorbic acid includes ascorbyl palmitate, ascorbyl isopalmitate, ascorbyl stearate, ascorbyl oleate, ascorbyl laurate, ascorbyl myristate; and the organic acid is selected from citric acid hydrate or / and tartaric acid; ; further, the impurities comprise at least impurity la 。

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