A pharmaceutical composition, preparation and preparation method comprising the compound SYN045

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically provides a pharmaceutical composition, a preparation and a preparation method thereof containing the compound SYN045. By using a mannitol and low-substituted hydroxypropyl cellulose composition with a fixed ratio, the preparation product prepared from the pharmaceutical composition of the present invention can effectively dissolve the active ingredient, reduce the generation of impurities at the same time, ensure the effectiveness and safety of the drug, and significantly improve the quality stability of the preparation during storage. The present invention adopts a dry direct compression process, and the preparation method is simple and fast, which is beneficial to industrial production and application.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition, a preparation and a preparation method thereof comprising the compound SYN045. Background Art

[0002] Pulmonary hypertension is a malignant disease mainly characterized by elevated pulmonary vascular resistance and pulmonary artery pressure caused by pulmonary artery lesions. In severe cases, it can lead to right heart failure and even death. Due to the rapid progression of the disease, with high fatality and disability rates, it is regarded as the "malignant tumor" in the cardiovascular field.

[0003] SYN045, whose chemical name is 6 - ((5,6 - diphenyl - 1,2,4 - triazin - 3 - yl)(isopropyl)amino) - N - (methylsulfonyl)hexanamide, is a small - molecule compound with a brand - new structure. SYN045 is a prostacyclin receptor (PGI2) - targeted drug. Pre - clinical studies have shown that it has prominent antihypertensive effects, can significantly improve the pulmonary hypertension - related symptoms in rats with pulmonary hypertension models, and at the same time increase the tolerance dose and survival rate of rats, with relatively high safety.

[0004] The SYN045 compound has poor solubility and strong hydrophobicity, is insoluble in water, which may affect the dissolution, absorption and bioavailability after drug administration, and thus restricts the drug efficacy. At the same time, during the formulation research of the new compound SYN045, it is found that its formulation has poor stability, is prone to generate impurities, resulting in a decrease in drug content, which poses a threat to the safety of drugs to a certain extent.

[0005] In view of the excellent activity of SYN045, there is an urgent need to develop a SYN045 pharmaceutical composition that has rapid in - vitro dissolution, quick onset of action, good bioavailability, is easy to prepare and has stable quality, to ensure the safety and effectiveness of clinical medications. Summary of the Invention

[0006] The object of the present invention is to provide a pharmaceutical composition of the compound SYN045 with good dissolution, high formulation stability and low impurity content, and its preparation method, aiming at the defects of the existing technology. By using a mannitol and low - substituted hydroxypropyl cellulose composition with a fixed ratio, the preparation products obtained from the pharmaceutical composition of the present invention can effectively dissolve the active ingredient, and at the same time reduce the generation of impurities, ensure the effectiveness and safety of the drug, and at the same time significantly improve the quality stability of the formulation during storage. The present invention adopts a dry - direct - compression process, and the preparation method is simple and fast.

[0007] To achieve the object of the present invention, the following technical solutions are adopted:

[0008] An object of the present invention is to provide a pharmaceutical composition comprising compound SYN045, the pharmaceutical composition comprising components in the following mass percentages: compound SYN045 0.07% - 1.5%, filler 90.0% - 96.0%, disintegrant 2.0% - 8.5% and lubricant 0.95% - 1.4%, wherein the filler is mannitol and the disintegrant is low-substituted hydroxypropyl cellulose.

[0009] Further, the filler is one or both of mannitol 100SD or mannitol 200SD, and more preferably mannitol 100SD.

[0010] Further, the lubricant is one or both of magnesium stearate or talc powder.

[0011] Further, the above pharmaceutical composition comprising compound SYN045 can be prepared into an oral solid preparation.

[0012] A second object of the present invention is to provide a preparation method one of the above pharmaceutical composition comprising compound SYN045, comprising the following steps: taking the prescription amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mixing them evenly to obtain a premix; taking the prescription amount of compound SYN045 and mannitol and mixing them evenly in a stepwise manner, sieving, adding the premix and continuing to mix to obtain a pharmaceutical composition comprising compound SYN045.

[0013] Further, the filler is one or both of mannitol 100SD or mannitol 200SD, and more preferably mannitol 100SD.

[0014] Further, the sieving is through a 60-mesh sieve.

[0015] Further, the time for the continued mixing is 5 - 15 min, preferably 10 min.

[0016] A third object of the present invention is to provide a preparation method two of the above pharmaceutical composition comprising compound SYN045, comprising the following steps: taking the prescription amount of compound SYN045 and mannitol and mixing them evenly in a stepwise manner, adding the prescription amount of low-substituted hydroxypropyl cellulose and mixing evenly, sieving, and then adding the prescription amount of magnesium stearate and continuing to mix to obtain a pharmaceutical composition comprising compound SYN045.

[0017] Further, the filler is one or both of mannitol 100SD or mannitol 200SD, and more preferably mannitol 100SD.

[0018] Further, the sieving is through a 60-mesh sieve.

[0019] Further, the continuous mixing time is 5 - 15 min, preferably 10 min.

[0020] The fourth object of the present invention is to provide a pharmaceutical preparation, which comprises the above-mentioned pharmaceutical composition comprising compound SYN045.

[0021] Further, the dosage form of the pharmaceutical preparation is tablet, capsule, granule or dry suspension.

[0022] Further, the tablet can be an ordinary tablet or a coated tablet.

[0023] Further, the pharmaceutical preparation can also contain other excipients.

[0024] Further, the coated tablet can also contain a coating agent.

[0025] Further, the coated tablet comprises the following components in mass percentage: based on the total mass of the coated tablet, compound SYN045 0.07% - 0.69%, filler 88% - 95%, disintegrant 2.3% - 7.9%, lubricant 0.92% - 1.38% and coating agent 1.0% - 2.9%.

[0026] Further, the coating agent is one or more of cellulose derivatives, vinyl compounds, acrylate resins, etc., preferably Opadry gastro-resistant coating agent.

[0027] Further, the dry suspension can also contain a flavoring agent and a suspending agent.

[0028] Further, the dry suspension comprises the following components in mass percentage: based on the total mass of the dry suspension, compound SYN045 0.07% - 0.69%, filler 90% - 96%, disintegrant 2.3% - 8.1%, lubricant 0.94% - 1.39%, flavoring agent 0.02% - 0.05% and suspending agent 0.14% - 0.41%.

[0029] Further, the flavoring agent is one or more of citric acid, malic acid, aspartame or orange essence, preferably orange essence.

[0030] Further, the suspending agent is one or more of xanthan gum, gum arabic, sodium alginate or chitosan, preferably xanthan gum.

[0031] The fifth object of the present invention is to provide a preparation method of the above-mentioned pharmaceutical composition comprising compound SYN045 for preparing ordinary tablets, coated tablets, capsules, granules and dry suspensions, which comprises the following steps: tableting the pharmaceutical composition comprising compound SYN045, and packaging to obtain SYN045 tablets; tableting the pharmaceutical composition comprising compound SYN045, coating the obtained tablet core, and packaging to obtain SYN045 coated tablets; filling the pharmaceutical composition comprising compound SYN045 into capsules, and packaging to obtain SYN045 capsules; granulating and filling the pharmaceutical composition comprising compound SYN045, and packaging to obtain SYN045 granules; adding suspending agent and flavoring agent according to the prescription amount to the pharmaceutical composition comprising compound SYN045, mixing evenly, filling and packaging to obtain SYN045 dry suspension.

[0032] In the screening study of the formulation prescription, it was found that after granulating with insoluble excipients such as microcrystalline cellulose and corn starch, the dissolution of the formulation was slow and incomplete. While fully mixing and contacting the instant-soluble prescription such as mannitol and lactose with the raw material was helpful to improve the hydrophilicity of the raw material, which could significantly increase the dissolution rate of the raw material and the dissolution was complete. However, after choosing lactose, the stability of the formulation was poor, there were many impurities, and the dissolution was slow. Mannitol had better stability for the formulation, and less impurities were generated. Among them, the effect of mannitol 100SD was more significant. The dosage of low-substituted hydroxypropyl cellulose needed to be controlled. If the dosage was too high, the dissolution rate in the stability test would decrease instead because of excessive disintegration of the formulation, resulting in accumulation and affecting the dissolution of the active ingredient. If the dosage was too low, the tablets would crack and the dissolution would be too fast. Selecting other disintegrants such as crospovidone, etc., the dissolution rate would decrease in the stability test. The synergistic effect of the dosage of mannitol and low-substituted hydroxypropyl cellulose solved the problem of decreased dissolution during the storage of the product. The coating operation had no obvious influence on the dissolution, content, related substances and stability of the formulation.

[0033] After experimental investigation, by using a fixed ratio composition of mannitol and low-substituted hydroxypropyl cellulose, especially selecting mannitol 100SD, a pharmaceutical composition comprising SYN045 with excellent processing performance was obtained. And for the oral solid preparation made from this pharmaceutical composition, the dissolution rate of SYN045 was fast and complete, and the dissolution degree at 20 min was above 90% in all cases, having good bioavailability. At the same time, the compatibility between the drug and the excipients was good, the stability of the formulation was good, the dissolution would not decrease, the impurity content was low. After accelerating for 6 months, the total impurities were less than 1.5%, the maximum impurity was less than 0.5%, and other single impurities were not higher than 0.1%. The product quality was good, ensuring the safety and effectiveness of clinical medication.

[0034] The present invention adopts a dry preparation process, which produces fewer impurities and has better dissolution than the wet granulation process. Furthermore, the process is optimized by controlling the mixing method of raw and auxiliary materials to reduce impurity generation and improve the stability of the preparation, enhance product quality, and the preparation method is simple and fast. Detailed implementation manners

[0035] The present invention will be further described in detail below through specific implementation manners, but it is only used to help understand the present invention, enabling those skilled in the art to implement or use the present invention, and does not constitute any limitation to the present invention.

[0036] Example 1

[0037] Preparation of SYN045 tablets (1000 tablets)

[0038] A kind of SYN045 tablet, comprising components in the following mass percentages:

[0039] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Mannitol 100SD 134.4 95.32％ Low-substituted hydroxypropyl cellulose 4.2 2.98％ Magnesium stearate 1.4 0.99％ Total 141 100.00％

[0040] Preparation method:

[0041] 1. Take the prescribed amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mix them in advance, and take the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal amount. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and magnesium stearate and continue to mix for 10 minutes;

[0042] 2. Compress the mixed powder after total mixing, and package it to obtain SYN045 tablets.

[0043] Example 2

[0044] Preparation of SYN045 tablets (1000 tablets)

[0045] A kind of SYN045 tablet, comprising components in the following mass percentages:

[0046] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 0.1 0.07％ Mannitol 100SD 134.4 90.87％ Low-substituted hydroxypropyl cellulose 12 8.11％ Magnesium stearate 1.4 0.95％ Total 147.9 100.00％

[0047] Preparation method:

[0048] 1. Take the prescribed amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mix them in advance, and take the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal amount. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and magnesium stearate and continue to mix for 10 minutes;

[0049] 2. Compress the mixed powder after total mixing, and package it to obtain SYN045 tablets.

[0050] Example 3

[0051] Preparation of SYN045 Tablets (1000 tablets)

[0052] A SYN045 tablet, comprising components in the following mass percentages:

[0053] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.23％ Mannitol 100SD 413 96.05％ Low-substituted hydroxypropyl cellulose 10 2.33％ Magnesium stearate 6 1.40％ Total 430 100.00％

[0054] Preparation method:

[0055] 1. Take the prescribed amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mix them in advance. Take the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and magnesium stearate and continue to mix for 10 min;

[0056] 2. Compress the mixed powder after total mixing, package it, and obtain SYN045 tablets.

[0057] Example 4

[0058] Preparation of SYN045 Tablets (1000 tablets)

[0059] A SYN045 tablet, comprising components in the following mass percentages:

[0060] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 2 1.43％ Mannitol 200SD 132.4 94.57％ Low-substituted hydroxypropyl cellulose 4.2 3.00％ Magnesium stearate 1.4 1.00％ Total 140 100.00％

[0061] Preparation method:

[0062] 1. Take the prescribed amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mix them in advance. Take the prescribed amount of SYN045 and mannitol 200SD and mix them in a stepwise manner. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and magnesium stearate and continue to mix for 10 min;

[0063] 2. Compress the mixed powder after total mixing, package it, and obtain SYN045 tablets.

[0064] Example 5

[0065] Preparation of SYN045 Capsules (1000 capsules)

[0066] A SYN045 capsule, comprising components in the following mass percentages:

[0067] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Mannitol 100SD 134.4 95.32％ Low-substituted hydroxypropyl cellulose 4.2 2.98％ Magnesium stearate 1.4 0.99％ Total 141 100.00％

[0068] Preparation method:

[0069] 1. Weigh out the prescribed amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mix them evenly in advance. Then, weigh out the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal increments. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and magnesium stearate and continue to mix for 10 minutes;

[0070] 2. Fill the total mixed powder into capsules and package them to obtain SYN045 capsules.

[0071] Example 6

[0072] Preparation of SYN045 granules (1000 bags)

[0073] A SYN045 granule, comprising the following components in mass percentage:

[0074] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Mannitol 100SD 134.4 95.32％ Low-substituted hydroxypropyl cellulose 4.2 2.98％ Talc powder 1.4 0.99％ Total 141 100.00％

[0075] Preparation method:

[0076] 1. Weigh out the prescribed amount of low-substituted hydroxypropyl cellulose and talc powder and mix them evenly in advance. Then, weigh out the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal increments. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and talc powder and continue to mix for 10 minutes;

[0077] 2. Fill the total mixed powder into granules and package them to obtain SYN045 granules.

[0078] Example 7

[0079] Preparation of SYN045 tablets (1000 tablets)

[0080] A SYN045 tablet, comprising the following components in mass percentage:

[0081] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.69％ Mannitol 100SD 134.4 92.56％ Low-substituted hydroxypropyl cellulose 4.2 2.89％ Talc powder 1.4 0.96％ Opadry enteric coating agent 4.2 2.89％ Total 145.2 100.00％

[0082] Preparation method:

[0083] 1. Weigh out the prescribed amount of low-substituted hydroxypropyl cellulose and talc powder and mix them evenly in advance. Then, weigh out the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal increments. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and talc powder and continue to mix for 10 minutes;

[0084] 2. Press the total mixed powder into tablets, and coat the obtained tablet cores with Opadry enteric coating powder and package them to obtain SYN045 coated tablets.

[0085] Example 8

[0086] Preparation of SYN045 tablets (1000 tablets)

[0087] A SYN045 tablet, comprising components in the following mass percentages:

[0088] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 0.1 0.07％ Mannitol 100SD 134.4 88.36％ Low-substituted hydroxypropyl cellulose 12 7.89％ Talc powder 1.4 0.92％ Opadry enteric coating agent 4.2 2.76％ Total 152.1 100.00％

[0089] Preparation method:

[0090] 1. Take the prescribed amounts of low-substituted hydroxypropyl cellulose and talc powder and mix them in advance. Take the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal increments. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and talc powder and continue to mix for 5 minutes;

[0091] 2. Compress the total mixed powder into tablets. Coat the obtained tablet cores with Opadry enteric coating powder, and package to obtain SYN045 coated tablets.

[0092] Example 9

[0093] Preparation of SYN045 tablets (1000 tablets)

[0094] A SYN045 tablet, comprising components in the following mass percentages:

[0095] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.23％ Mannitol 100SD 413 95.12％ Low-substituted hydroxypropyl cellulose 10 2.30％ Talc powder 6 1.38％ Opadry enteric coating agent 4.2 0.97％ Total 434.2 100.00％

[0096] Preparation method:

[0097] 1. Take the prescribed amounts of low-substituted hydroxypropyl cellulose and talc powder and mix them in advance. Take the prescribed amount of SYN045 and mannitol 100SD and mix them in a stepwise manner by equal increments. After mixing, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose and talc powder and continue to mix for 15 minutes;

[0098] 2. Compress the total mixed powder into tablets. Coat the obtained tablet cores with Opadry enteric coating powder, and package to obtain SYN045 coated tablets.

[0099] Example 10

[0100] Preparation of SYN045 dry suspension (1000 bags)

[0101] A SYN045 dry suspension, comprising components in the following mass percentages:

[0102] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.69％ Mannitol 100SD 137.6 94.98％ Low-substituted hydroxypropyl cellulose 4.2 2.90％ Magnesium stearate 1.4 0.97％ Xanthan gum 0.6 0.41％ Orange flavor essence 0.07 0.05％ Total 144.87 100.00％

[0103] Preparation method:

[0104] 1. Weigh out the prescribed amounts of low-substituted hydroxypropyl cellulose, magnesium stearate, xanthan gum, and orange flavor essence, and mix them evenly in advance. Then, weigh out the prescribed amount of SYN045 and mannitol 100SD, and mix them in a stepwise manner by equal increments. After mixing evenly, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose, magnesium stearate, xanthan gum, and orange flavor essence, and continue to mix for 10 minutes;

[0105] 2. Fill and package the total mixed powder into a dry suspension to obtain the SYN045 dry suspension.

[0106] Example 11

[0107] Preparation of SYN045 Dry Suspension (1000 Bags)

[0108] A SYN045 dry suspension, comprising the following components in mass percentage:

[0109] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 0.1 0.07％ Mannitol 100SD 134.4 90.46％ Low-substituted hydroxypropyl cellulose 12 8.08％ Magnesium stearate 1.4 0.94％ Xanthan gum 0.6 0.40％ Orange flavor essence 0.07 0.05％ Total 148.57 100.00％

[0110] Preparation method:

[0111] 1. Weigh out the prescribed amounts of low-substituted hydroxypropyl cellulose, magnesium stearate, xanthan gum, and orange flavor essence, and mix them evenly in advance. Then, weigh out the prescribed amount of SYN045 and mannitol 100SD, and mix them in a stepwise manner by equal increments. After mixing evenly, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose, magnesium stearate, xanthan gum, and orange flavor essence, and continue to mix for 10 minutes;

[0112] 2. Fill and package the total mixed powder into a dry suspension to obtain the SYN045 dry suspension.

[0113] Example 12

[0114] Preparation of SYN045 Dry Suspension (1000 Bags)

[0115] A SYN045 dry suspension, comprising the following components in mass percentage:

[0116] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.23％ Mannitol 100SD 413 95.90％ Low-substituted hydroxypropyl cellulose 10 2.32％ Magnesium stearate 6 1.39％ Xanthan gum 0.6 0.14％ Orange flavor essence 0.07 0.02％ Total 430.67 100.00％

[0117] Preparation method:

[0118] 1. Weigh out the prescribed amounts of low-substituted hydroxypropyl cellulose, magnesium stearate, xanthan gum, and orange flavor essence, and mix them evenly in advance. Then, weigh out the prescribed amount of SYN045 and mannitol 100SD, and mix them in a stepwise manner by equal increments. After mixing evenly, continue to pass through a 60-mesh sieve, and add the pre-mixed low-substituted hydroxypropyl cellulose, magnesium stearate, xanthan gum, and orange flavor essence, and continue to mix for 10 minutes;

[0119] 2. Fill and package the total mixed powder into a dry suspension to obtain the SYN045 dry suspension.

[0120] Example 13

[0121] Preparation of SYN045 Tablets (1000 tablets)

[0122] A SYN045 tablet, comprising the following components in mass percentage:

[0123] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Mannitol 100SD 134.4 95.32％ Low-substituted hydroxypropyl cellulose 4.2 2.98％ Magnesium stearate 1.4 0.99％ Total 141 100.00％

[0124] Preparation method:

[0125] 1. Take the prescribed amount of SYN045 and mannitol 100SD, mix them in equal increments, add low-substituted hydroxypropyl cellulose after mixing, continue to mix and pass through a 60-mesh sieve, and then add magnesium stearate externally and continue to mix for 10 min;

[0126] 2. Compress the total mixed powder into tablets and package to obtain SYN045 tablets.

[0127] Comparative Example 1

[0128] Preparation of SYN045 Tablets (1000 tablets)

[0129] A SYN045 tablet, comprising the following components in mass percentage:

[0130] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Mannitol 100SD 134.4 95.32％ Crospovidone 4.2 2.98％ Magnesium stearate 1.4 0.99％ Total 141 100.00％

[0131] The preparation method is the same as that of Example 1, except that the low-substituted hydroxypropyl cellulose in Example 1 is replaced with crospovidone, and the types and dosages of other raw and auxiliary materials are the same.

[0132] Comparative Example 2

[0133] Preparation of SYN045 Tablets (1000 tablets)

[0134] A SYN045 tablet, comprising the following components in mass percentage:

[0135] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.62％ Mannitol 100SD 139.6 86.17％ Low-substituted hydroxypropyl cellulose 20 12.35％ Magnesium stearate 1.4 0.86％ Total 162 100.00％

[0136] The preparation method is the same as that of Example 1, except that the dosages of the auxiliary materials are different, especially the mass ratio of low-substituted hydroxypropyl cellulose is increased.

[0137] Comparative Example 3

[0138] Preparation of SYN045 Tablets (1000 tablets)

[0139] A SYN045 tablet, comprising the following components in mass percentage:

[0140] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.70％ Mannitol 100SD 139.6 97.28％ Low-substituted hydroxypropyl cellulose 1.5 1.05％ Magnesium stearate 1.4 0.98％ Total 143.5 100.00％

[0141] The preparation method is the same as that of Example 1, except for the different amounts of excipients, especially the mass ratio of low-substituted hydroxypropyl cellulose is reduced.

[0142] Control Example 4

[0143] Preparation of SYN045 Tablets (1000 tablets)

[0144] A SYN045 tablet, comprising the following components in mass percentages:

[0145] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Lactose 134.4 95.32％ Low-substituted hydroxypropyl cellulose 4.2 2.98％ Magnesium stearate 1.4 0.99％ Total 141 100.00％

[0146] The preparation method is the same as that of Example 1, except that mannitol 100SD in Example 1 is replaced with lactose, and the types and amounts of other raw and auxiliary materials are the same.

[0147] Control Example 5

[0148] Preparation of SYN045 Tablets (1000 tablets)

[0149] A SYN045 tablet, comprising the following components in mass percentages:

[0150] Names of raw and auxiliary materials Mass (g) Mass percentage (%) SYN045 1 0.71％ Microcrystalline cellulose 134.4 95.32％ Low-substituted hydroxypropyl cellulose 4.2 2.98％ Magnesium stearate 1.4 0.99％ Total 141 100.00％

[0151] The preparation method is the same as that of Example 1, except that mannitol 100SD in Example 1 is replaced with microcrystalline cellulose, and the types and amounts of other raw and auxiliary materials are the same.

[0152] Control Example 6

[0153] Preparation of SYN045 Tablets (1000 tablets)

[0154] A SYN045 tablet, comprising the following components in mass percentages:

[0155]

[0156]

[0157] Preparation method:

[0158] 1. Take the prescribed amount of SYN045 and mannitol, mix them in equal increments, add polyvinylpyrrolidone K30 and low-substituted hydroxypropyl cellulose, mix well and pass through a 60-mesh sieve;

[0159] 2. Add the mixed powder to a wet granulator, premix for 10 min, add the wetting agent purified water for wet granulation, dry and pass through a 14-mesh sieve for sizing;

[0160] 3. Add magnesium stearate externally to the granules obtained by wet granulation, and mix well for 10 min;

[0161] 4. Compress and package the mixed granules after total mixing to obtain SYN045 tablets.

[0162] Test Example 1 Stability Study

[0163] To investigate the stability of the products, accelerated tests were conducted on the samples prepared in Examples 1 - 13 and Comparative Examples 1 - 6. Each of the above products was placed under accelerated conditions (40°C ± 2°C, relative humidity 75% ± 5%) in the same packaging. Samples were taken at 0 months and 6 months respectively, and the changes in content, dissolution, and related substances were compared. The results are shown in Table 1.

[0164] Content Detection Method:

[0165] Determined according to the high - performance liquid chromatography method (General Rules 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0166] Solvent: Methanol - water (80:20)

[0167] Test Solution: Take 10 tablets of this product, place them in a 100 - ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve, then dilute to the mark with solvent, shake well, and filter.

[0168] Reference Solution: Take an appropriate amount of SYN045 reference substance, weigh accurately, dissolve it by sonication with solvent and quantitatively dilute to prepare a solution containing about 60 μg per 1 ml, and shake well. The preparation of the SYN045 reference substance of the compound refers to Patent CN202410701022.4.

[0169] Chromatographic Conditions: Use octadecylsilane - bonded silica gel as the filler; use 0.2% (v / v) formic acid aqueous solution - methanol (20:80) as the mobile phase; the flow rate is 1 ml per minute; the column temperature is 30°C; the detection wavelength is 280 nm; the injection volume is 20 μl.

[0170] Determination Method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate by the external standard method based on the peak area.

[0171] Related Substances Detection Method:

[0172] Determined according to the high - performance liquid chromatography method (General Rules 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0173] Test Solution: Take an appropriate amount of this product or its contents, weigh accurately, dissolve it with the mobile phase and quantitatively dilute to prepare a solution containing about 0.5 mg of compound SYN045 per 1 mL, filter, and take the subsequent filtrate.

[0174] Chromatographic Conditions: Chromatographic column: Welchrom - C 18Chromatographic column (4.6 mm x 200 mm, 5 μm); Mobile phase: 0.1 mol / L sodium dihydrogen phosphate solution (adjusted to pH 4.0 with phosphoric acid) - acetonitrile (55:45); Flow rate: 1.0 mL / min; Detection wavelength: 280 nm; Injection volume: 20 μL.

[0175] Determination method: Accurately measure the test solution and inject it into the liquid chromatograph, and record the chromatogram.

[0176] Limit: If there are impurity peaks in the chromatogram of the test solution, calculated by the area normalization method, the total amount of impurities shall not exceed 1.5%, the single largest impurity shall not exceed 0.5%, and each individual other impurity shall not exceed 0.2%.

[0177] Dissolution test method:

[0178] Determined according to the dissolution and release determination method (General Chapter 0931, Method 2, Four Parts of Chinese Pharmacopoeia 2020 Edition) and high performance liquid chromatography (General Chapter 0512, Four Parts of Chinese Pharmacopoeia 2020 Edition).

[0179] Use 900 ml of 0.3% SDS hydrochloric acid solution with pH 1.0 as the dissolution medium, and the rotation speed is 50 revolutions per minute. Samples are taken at 5 min, 10 min, 15 min, 20 min, and 30 min respectively. Take the test solution and the reference solution, and determine the content at a wavelength of 280 nm, and calculate the dissolution of each tablet at different times respectively. The dissolution requirement is 20 min > 80%.

[0180] Table 1 Stability study test data

[0181]

[0182]

[0183] Test conclusion:

[0184] Through experimental research, it is found that the samples prepared in Examples 1-13 have high drug content and low impurity content. After 6 months of accelerated test, less impurities are generated, the preparation has good stability, the total impurities are less than 1.5%, the largest impurity is less than 0.5%, and each individual other impurity is not higher than 0.1%. And there is no problem of significant decrease in dissolution. The dissolution at 20 min is above 90%, meeting the requirement that the dissolution at 20 min is greater than 80%, and the product quality is well guaranteed.

[0185] In Example 4, mannitol 200SD was used, and its preparation stability was slightly worse than that of Examples 1-3 and Examples 5-8 using mannitol 100SD. In comparison, the dissolution reduction in Example 4 was slightly more obvious at 6 months of accelerated test. The dissolution at 20 min was only 90.2%, but greater than 80%, which also met the dissolution requirements; the content reduction was slightly more obvious, and at the same time, the impurities increased slightly more obviously. The content decreased from 104.2% to 101.5% at 6 months with a slightly larger decrease, and the increases in total impurities, the maximum single impurity, and other single impurities were slightly larger, but all met the quality requirements.

[0186] In Example 7, film coating was performed on the tablet core, and the film coating operation had no obvious effect on the dissolution, content, related substances, and its stability of the preparation, and all met the quality requirements. Examples 8 and 9 achieved the same effect as Example 7; Examples 11 and 12 achieved the same effect as Example 10.

[0187] The mixing steps of the raw and auxiliary materials used in Example 13 were different from those in Examples 1-12. In Examples 1-12, magnesium stearate and other auxiliary materials such as low-substituted hydroxypropyl cellulose were pre-mixed first, and then further mixed with the mixture of SYN045 and mannitol; in Example 13, SYN045 and mannitol were mixed evenly, low-substituted hydroxypropyl cellulose was added and mixed evenly, and then magnesium stearate was added externally and mixed evenly. Example 13 produced more impurities than Examples 1-12, with a low content and high impurities at 0 month. After 6 months of accelerated test, the content decreased slightly more obviously, and the total impurities, the maximum single impurity, and other single impurities increased slightly more obviously, but it also met the quality requirements.

[0188] In Comparative Example 1, crospovidone was used as the disintegrant, and the dissolution was not ideal. The dissolution at 20 min was 88.5% at 0 month, and the dissolution decreased significantly after the accelerated test. The dissolution at 20 min decreased to 79.3% at 6 months, lower than the lower limit of 80% required by the quality standard, and the quality was difficult to guarantee.

[0189] In Comparative Example 2, the dosage of low-substituted hydroxypropyl cellulose used was too high, and the dissolution decreased significantly after the accelerated test. The dissolution at 20 min was 89.5% at 0 month and decreased significantly to 78.5% at 6 months.

[0190] In Comparative Example 3, the dosage of low-substituted hydroxypropyl cellulose used was too low, and it was found that the tablets cracked during tableting and the dissolution rate was too fast. The dissolution at 10 min reached 89.1% at 0 month, and the dissolution at 15 min was 92.5%.

[0191] In Comparative Example 4, lactose was used as the diluent, the dissolution rate was slightly slower, and there were many impurities. The total impurities were 1.21% at 0 month, and the preparation stability was poor. After 6 months of accelerated test, the total impurities increased to 1.63%, with an obvious increase, exceeding 1.5%, and the product quality could not be guaranteed.

[0192] In Comparative Example 5, microcrystalline cellulose was used as the diluent, and the dissolution rate was slow and insufficient. The dissolution rate at 20 min was only 82.3% at 0 month, and the dissolution decreased significantly after the accelerated 6-month test. The dissolution rate at 20 min decreased to 70.1%, which was much lower than the 80% required by the dissolution standard, not meeting the quality standard requirements, and serious problems occurred in the drug quality. At the same time, the impurity content of the preparation was high, the total impurities at 0 month were 1.36%, and the stability of the preparation was poor. After the accelerated 6-month test, the total impurities increased to 1.87%, showing a significant increase and exceeding 1.5%.

[0193] In Comparative Example 6, the wet granulation process was used, with many impurities. The total impurities at 0 month were 1.30%, and the stability of the preparation was poor. After the 6-month accelerated test, the impurities increased to 1.78%, showing an obvious increase and exceeding 1.5%, and the product quality could not be guaranteed. At the same time, the dissolution effect was not ideal. The dissolution rate at 20 min at 0 month was 89.3%, and the dissolution rate decreased significantly after the accelerated test. The dissolution rate at 20 min at 6 months decreased to 77.8%, lower than the lower limit of 80% required by the quality standard, and the quality was difficult to guarantee.

[0194] In summary, the preparation prepared from the composition of the present invention has a high content, few impurities, and high dissolution. At the same time, the preparation has better stability. After the accelerated test, the content of the preparation decreases less, the impurities increase less, and there will be no problem of obvious decrease in the dissolution rate. After the accelerated 6-month test, the total impurities are lower than 1.5%, the maximum impurity is lower than 0.5%, and other single impurities are not higher than 0.1%. Moreover, the dissolution rate at 20 min is above 90%, meeting the requirement that the dissolution rate at 20 min is greater than 80%, improving the bioavailability, ensuring the safety and effectiveness of clinical medication, and greatly improving the product quality. In addition, its preparation process is simple, using the dry preparation process, which is conducive to industrial production and application.

[0195] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition comprising compound SYN045, said pharmaceutical composition comprising components in the following mass percentages: compound SYN045 0.07% - 1.5%, filler 90.0% - 96.0%, disintegrant 2.0% - 8.5% and lubricant 0.95% - 1.4%; Among them, The filler is mannitol, and the disintegrant is low-substituted hydroxypropyl cellulose; The compound SYN045 is 6 - ((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methanesulfonyl)hexanamide.

2. The pharmaceutical composition comprising the compound SYN045 according to claim 1, wherein The filler is one or both of mannitol 100SD or mannitol 200SD; and / or The lubricant is one or both of magnesium stearate or talc powder.

3. A method for preparing a pharmaceutical composition comprising the compound SYN045 according to any one of claims 1-2, characterized in that, It includes the following steps: Take the prescribed amount of low-substituted hydroxypropyl cellulose and magnesium stearate and mix them evenly to obtain a premix; Take the prescribed amount of compound SYN045 and mannitol and mix them in a stepwise manner in equal amounts, pass through a sieve, and add the premix and continue to mix to obtain a pharmaceutical composition comprising compound SYN045.

4. A method for preparing a pharmaceutical composition comprising the compound SYN045 according to any one of claims 1-2, characterized in that, It includes the following steps: Take the prescribed amount of compound SYN045 and mannitol and mix them in a stepwise manner in equal amounts, add the prescribed amount of low-substituted hydroxypropyl cellulose and mix evenly, pass through a sieve, and then add the prescribed amount of magnesium stearate and continue to mix to obtain a pharmaceutical composition comprising compound SYN045.

5. A pharmaceutical preparation, characterized in that, It includes the pharmaceutical composition comprising compound SYN045 as claimed in claim 1 or 2.

6. The pharmaceutical preparation according to claim 5, characterized in that, The dosage form of the pharmaceutical preparation is tablets, capsules, granules or dry suspensions.

7. The pharmaceutical preparation according to claim 6, characterized in that, The tablets comprise components in the following mass percentages: compound SYN045 0.07% - 0.69%, filler 88% - 95%, disintegrant 2.3% - 7.9%, lubricant 0.92% - 1.38% and coating agent 1.0% - 2.9%.

8. The pharmaceutical preparation according to claim 7, wherein, The coating agent is Opadry enteric coating agent.

9. The pharmaceutical preparation according to claim 7, wherein The lubricant is one or both of magnesium stearate or talc powder.

10. The pharmaceutical preparation according to claim 6, characterized in that, The dry suspension comprises components in the following mass percentages: compound SYN045 0.07% - 0.69%, filler 90% - 96%, disintegrant 2.3% - 8.1%, lubricant 0.94% - 1.39%, flavoring agent 0.02% - 0.05% and suspending agent 0.14% - 0.41%.

11. The pharmaceutical preparation according to claim 10, wherein The suspending agent is one or more of xanthan gum, gum arabic, sodium alginate or chitosan; and / or The lubricant is one or both of magnesium stearate or talc powder.

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