Pharmaceutical composition, preparation and preparation method thereof comprising compound SYN045

Abstract

The present invention belongs to the field of pharmaceutical preparation technology and specifically provides a pharmaceutical composition comprising the compound SYN045 and a method for preparing the same. By using a fixed ratio of mannitol and corn starch as fillers, the present invention addresses product quality issues such as instability and susceptibility to degradation of the active ingredient and difficulty in uniformly mixing raw and excipient materials in wet processes, resulting in poor content uniformity in the preparation. While achieving effective dissolution of the active ingredient, it also effectively reduces the generation of impurities, thereby effectively ensuring the effectiveness and safety of the drug. Furthermore, the preparation product has high content uniformity. This combination achieves the goal of meeting content uniformity requirements through a simple mixing method, simplifying the preparation process.

Description

Technical Field

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

[0002] Pulmonary hypertension is a malignant disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure due to pulmonary artery disease. Severe cases can lead to right heart failure and even death. Recent data indicate that the incidence and prevalence of pulmonary hypertension in adults range from 0 to 6 cases per million and 48 to 55 cases per million, respectively. Due to its rapid progression, high mortality and disability rates, it is considered a "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 novel structure. SYN045 is a prostacyclin receptor (PGI2)-targeted drug. Preclinical studies have demonstrated a significant antihypertensive effect, significantly improving pulmonary hypertension-related symptoms in rats with pulmonary arterial hypertension. It also increases the rats' tolerated dose and survival rate, demonstrating a high safety profile.

[0004] The SYN045 compound has poor solubility and strong hydrophobicity, making it insoluble in water. This could affect dissolution, absorption, and bioavailability of the drug after administration, thereby limiting its efficacy. Furthermore, due to SYN045's high potency, the small formulation size required for clinical development presents issues with poor content uniformity. Furthermore, during formulation research for the new compound SYN045, it was discovered that its formulation exhibited poor stability and was prone to the formation of impurities, resulting in reduced drug content and posing a certain safety risk to the drug.

[0005] Given the excellent activity of SYN045, there is an urgent need to develop a SYN045 pharmaceutical composition with good in vitro dissolution, high content uniformity, and few impurities to ensure the safety and efficacy of clinical use. Summary of the Invention

[0006] The present invention addresses the shortcomings of the prior art by providing a pharmaceutical composition of the compound SYN045, characterized by excellent dissolution, high content uniformity, and low impurity content, and a method for its preparation. By utilizing a fixed-ratio composition of mannitol and corn starch as a filler, the present invention addresses the product quality issues inherent in wet-processing processes. This allows for efficient dissolution of the active ingredient while minimizing impurity generation, ensuring drug efficacy and safety. Furthermore, the formulation achieves high content uniformity. This combination eliminates the need for complex mixing methods to meet content uniformity requirements, simplifying the preparation process.

[0007] In order to achieve the purpose of the present invention, the following technical solutions are adopted:

[0008] An object of the present invention is to provide a pharmaceutical composition comprising the compound SYN045, the composition comprising the following components in percentage by weight: 0.06%-0.8% of the compound SYN045, 83%-88% of a filler, 2.7%-3.4% of a binder, 9.0%-11.2% of a disintegrant, and 0.9%-1.2% of a lubricant; wherein the filler is a mixture of mannitol and corn starch; and the mass ratio of mannitol to corn starch is 14:90-121.

[0009] Furthermore, the binder is hydroxypropyl cellulose.

[0010] Furthermore, the disintegrant is low-substituted hydroxypropyl cellulose.

[0011] Furthermore, the lubricant is one or both of magnesium stearate and talc.

[0012] Furthermore, the pharmaceutical composition comprising the compound SYN045 can be prepared as an oral solid preparation.

[0013] The second object of the present invention is to provide a pharmaceutical preparation comprising the above-mentioned pharmaceutical composition comprising the compound SYN045.

[0014] Furthermore, the dosage form of the pharmaceutical preparation is tablets, capsules, granules or dry suspensions.

[0015] Furthermore, the tablet can be a common tablet or a coated tablet.

[0016] Furthermore, the pharmaceutical preparation may further comprise other excipients.

[0017] Furthermore, the coated tablet may further comprise a coating agent.

[0018] Furthermore, the coated tablet comprises the following components in percentage by mass: compound SYN045 0.08%-0.7%, filler 81%-85%, binder 2.6%-3.3%, disintegrant 8.8%-10.9%, lubricant 0.88%-1.09% and coating agent 2.6%-3.3%.

[0019] Furthermore, the coating agent is one or more of cellulose derivatives, polyvinyl compounds or sodium acrylate resins, and is preferably an Opadry gastric-soluble coating agent.

[0020] Furthermore, the dry suspension may further comprise a suspending agent and a flavoring agent.

[0021] Furthermore, the dry suspension comprises the following components in percentage by mass: compound SYN045 0.08%-0.7%, filler 83%-87%, binder 2.7%-3.4%, disintegrant 9.0%-11.2%, lubricant 0.9%-1.2%, suspending agent 0.39%-0.48% and flavoring agent 0.04%-0.06%.

[0022] Furthermore, the flavoring agent is one or more of citric acid, malic acid, aspartame or orange flavor, preferably orange flavor.

[0023] Furthermore, the suspending agent is one or more of xanthan gum, gum arabic, sodium alginate or chitosan, preferably xanthan gum.

[0024] A third object of the present invention is to provide a method for preparing the pharmaceutical composition comprising the compound SYN045, comprising the following steps: 1. crushing and sieving the raw material SYN045, and sieving mannitol and hydroxypropyl cellulose separately for later use; 2. mixing the prescribed amount of SYN045 with half the prescribed amount of mannitol, adding the prescribed amounts of corn starch, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose, and then adding the remaining prescribed amount of mannitol and mixing to obtain a mixed powder; 3. adding the mixed powder to a wet granulator, adding purified water, wet granulating, drying, and sieving to obtain granules; 4. adding magnesium stearate to the granules obtained by the wet granulation, and mixing to obtain the total mixed granules, which are the pharmaceutical composition comprising the compound SYN045.

[0025] Furthermore, in step 1, the raw material SYN045 is crushed and passed through an 80-mesh sieve, mannitol is passed through a 60-mesh sieve, and hydroxypropyl cellulose is passed through a 40-mesh sieve.

[0026] Furthermore, in step 3, after drying, the granules are sieved through a 14-mesh sieve.

[0027] Furthermore, in step 4, the mixing time is 3-15 minutes, preferably 10 minutes.

[0028] A fourth object of the present invention is to provide a second method for preparing the pharmaceutical composition comprising the compound SYN045, comprising the following steps: 1. Mixing the prescribed amount of SYN045 and mannitol in equal amounts in a stepwise manner, adding corn starch, low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose, mixing, and sieving to obtain a mixed powder; 2. Adding the mixed powder to a wet granulator and adding purified water for wet granulation, drying, and sieving to obtain granules; 3. Adding magnesium stearate to the granules obtained by wet granulation, mixing, and obtaining a total mixed granule, which is the pharmaceutical composition comprising the compound SYN045.

[0029] Furthermore, in step 1, corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose are added and mixed, and then passed through a 60-mesh sieve.

[0030] Furthermore, in the step 2, the granules are sieved through a 14-mesh sieve after drying.

[0031] Furthermore, in step 3, the mixing time is 3-15 minutes, preferably 10 minutes.

[0032] A fifth object of the present invention is to provide a method for preparing ordinary tablets, coated tablets, capsules, granules and dry suspensions from the pharmaceutical composition comprising the compound SYN045, comprising the following steps: compressing the pharmaceutical composition comprising the compound SYN045 and packaging the resulting tablets to obtain SYN045 tablets; compressing the pharmaceutical composition comprising the compound SYN045, coating the resulting tablet cores, and packaging the resulting SYN045 coated tablets; filling the pharmaceutical composition comprising the compound SYN045 into capsules and packaging the resulting SYN045 capsules; filling the pharmaceutical composition comprising the compound SYN045 into granules and packaging the resulting SYN045 granules; and adding a suspending agent and a flavoring agent to the pharmaceutical composition comprising the compound SYN045 according to the prescribed amount, mixing the mixture, and then filling and packaging the dry suspension to obtain a SYN045 dry suspension.

[0033] The new compound SYN045 is a poorly soluble drug. During the formulation screening study, it was found that mannitol is a very beneficial excipient for the dissolution of SYN045. However, in the formulation research, especially when the wet granulation process is used, there are obvious formulation stability issues, which easily lead to the generation of impurities.

[0034] Combined with preclinical rat efficacy dose confirmation experiments, SYN045 demonstrated strong efficacy. The clinical trial design, translating to a once-daily oral dose of 0.1 mg in humans, suggests that the SYN045 formulation size is very small. The low dosage of the active ingredient in the formulation makes it extremely difficult to mix uniformly with the excipients in the formulation, resulting in low content uniformity in the formulation.

[0035] The inventors surprisingly discovered that by uniformly dispersing SYN045 using a mixture of mannitol and corn starch fillers, the material can achieve good fluidity, uniform content, rapid drug dissolution, and few impurities.

[0036] Experimental investigations have shown that the use of a fixed-ratio combination of mannitol and corn starch as a filler overcomes the product quality issues inherent in wet processing, resulting in a pharmaceutical composition containing SYN045 with excellent processing properties. This pharmaceutical composition, formulated into an oral solid dosage form, demonstrates rapid and complete dissolution of SYN045, with a 20-minute dissolution rate exceeding 90%, demonstrating good bioavailability. Furthermore, the composition exhibits excellent compatibility between the drug and excipients, a high drug content, and low impurity levels, with total impurities below 1.0% and other individual impurities below 0.1%. This ensures high product quality and ensures clinical safety and efficacy. Furthermore, the formulation exhibits high content uniformity, eliminating the need for complex mixing methods to meet content uniformity requirements and simplifying the preparation process.

[0037] The preparation process of the present invention can adopt a method of mixing in equal amounts in a stepwise manner, which makes the mixing more uniform. Alternatively, the raw material drug and half of the mannitol can be first mixed and then mixed with the remaining excipients. The latter method can also meet the content uniformity requirements in the quality standard by optimizing the process, and the operation is simpler and faster, which is suitable for industrial production. DETAILED DESCRIPTION

[0038] The present invention is further described in detail below through specific implementation methods, but it is only used to help understand the present invention so that professionals in the field can implement or use the present invention, and does not constitute any limitation to the present invention.

[0039] Example 1

[0040] Preparation of SYN045 tablets (1000 tablets)

[0041] A SYN045 tablet comprising the following components in percentage by mass:

[0042]

[0043]

[0044] Preparation method:

[0045] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0046] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0047] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0048] 4. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0049] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0050] Example 2

[0051] Preparation of SYN045 tablets (1000 tablets)

[0052] A SYN045 tablet comprising the following components in percentage by mass:

[0053]

[0054] Preparation method:

[0055] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0056] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0057] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0058] 4. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0059] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0060] Example 3

[0061] Preparation of SYN045 tablets (1000 tablets)

[0062] A SYN045 tablet comprising the following components in percentage by mass:

[0063]

[0064] Preparation method:

[0065] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0066] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0067] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0068] 4. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0069] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0070] Example 4

[0071] Preparation of SYN045 tablets (1000 tablets)

[0072] A SYN045 tablet comprising the following components in percentage by mass:

[0073]

[0074] Preparation method:

[0075] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0076] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0077] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0078] 4. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0079] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0080] Example 5

[0081] Preparation of SYN045 tablets (1000 tablets)

[0082] A SYN045 tablet comprising the following components in percentage by mass:

[0083]

[0084] Preparation method:

[0085] 1. Take the prescribed amount of SYN045 and mannitol in equal amounts and mix them evenly. Add corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, mix evenly, and pass through a 60-mesh sieve to obtain a mixed powder.

[0086] 2. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0087] 3. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0088] 4. The mixed granules are tableted and packaged to obtain SYN045 tablets.

[0089] Example 6

[0090] Preparation of SYN045 tablets (1000 tablets)

[0091] A SYN045 tablet comprising the following components in percentage by mass:

[0092]

[0093]

[0094] Preparation method:

[0095] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0096] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0097] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0098] 4. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0099] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0100] Example 7

[0101] Preparation of SYN045 tablets (1000 tablets)

[0102] A SYN045 tablet comprising the following components in percentage by mass:

[0103]

[0104] Preparation method:

[0105] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0106] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0107] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0108] 4. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0109] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0110] Example 8

[0111] Preparation of SYN045 tablets (1000 tablets)

[0112] A SYN045 tablet comprising the following components in percentage by mass:

[0113]

[0114] Preparation method:

[0115] 1. Take the prescribed amount of SYN045 and mannitol in equal amounts and mix them evenly. Add corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, mix evenly, and pass through a 60-mesh sieve to obtain a mixed powder.

[0116] 2. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0117] 3. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0118] 4. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0119] Example 9

[0120] Preparation of SYN045 tablets (1000 tablets)

[0121] A SYN045 tablet comprising the following components in percentage by mass:

[0122]

[0123] Preparation method:

[0124] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0125] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0126] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0127] 4. Add talcum powder to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0128] 5. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0129] Example 10

[0130] Preparation of SYN045 capsules (1000 capsules)

[0131] A SYN045 capsule comprising the following components in percentage by mass:

[0132]

[0133]

[0134] Preparation method:

[0135] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0136] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0137] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0138] 4. Add talcum powder to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0139] 5. Fill the total mixed granules into capsules and package to obtain SYN045 capsules.

[0140] Example 11

[0141] Preparation of SYN045 granules (1000 bags)

[0142] A SYN045 granule comprises the following components in percentage by mass:

[0143]

[0144] Preparation method:

[0145] 1. Take the prescribed amount of SYN045 and mannitol in equal amounts and mix them evenly. Add corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, mix evenly, and pass through a 60-mesh sieve to obtain a mixed powder.

[0146] 2. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0147] 3. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0148] 4. Fill and package the total mixed granules to obtain SYN045 granules.

[0149] Example 12

[0150] Preparation of SYN045 tablets (1000 tablets)

[0151] A SYN045 tablet comprising the following components in percentage by mass:

[0152]

[0153] Preparation method:

[0154] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0155] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0156] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0157] 4. Add talcum powder to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0158] 5. The mixed granules are compressed into tablets, and the obtained tablet cores are coated with Opadry gastric-soluble coating powder and packaged to obtain SYN045 coated tablets.

[0159] Example 13

[0160] Preparation of SYN045 tablets (1000 tablets)

[0161] A SYN045 tablet comprising the following components in percentage by mass:

[0162]

[0163] Preparation method:

[0164] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0165] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0166] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0167] 4. Add talcum powder to the granules obtained by wet granulation and mix for 3 minutes to obtain the total mixed granules;

[0168] 5. The mixed granules are compressed into tablets, and the obtained tablet cores are coated with Opadry gastric-soluble coating powder and packaged to obtain SYN045 coated tablets.

[0169] Example 14

[0170] Preparation of SYN045 tablets (1000 tablets)

[0171] A SYN045 tablet comprising the following components in percentage by mass:

[0172]

[0173] Preparation method:

[0174] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0175] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0176] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0177] 4. Add talcum powder to the granules obtained by wet granulation and mix for 15 minutes to obtain the total mixed granules;

[0178] 5. The mixed granules are compressed into tablets, and the obtained tablet cores are coated with Opadry gastric-soluble coating powder and packaged to obtain SYN045 coated tablets.

[0179] Example 15

[0180] Preparation of SYN045 dry suspension (1000 bags)

[0181] A SYN045 dry suspension comprises the following components in percentage by weight:

[0182]

[0183]

[0184] Preparation method:

[0185] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0186] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0187] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0188] 4. Add magnesium stearate, xanthan gum, and orange flavor to the granules obtained by wet granulation and mix for 10 minutes to obtain the final mixed granules;

[0189] 5. Fill and package the total mixed granules into a dry suspension to obtain SYN045 dry suspension.

[0190] Example 16

[0191] Preparation of SYN045 dry suspension (1000 bags)

[0192] A SYN045 dry suspension comprises the following components in percentage by weight:

[0193]

[0194]

[0195] Preparation method:

[0196] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0197] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0198] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0199] 4. Add magnesium stearate, xanthan gum, and orange flavor to the granules obtained by wet granulation and mix for 10 minutes to obtain the final mixed granules;

[0200] 5. Fill and package the total mixed granules into a dry suspension to obtain SYN045 dry suspension.

[0201] Example 17

[0202] Preparation of SYN045 dry suspension (1000 bags)

[0203] A SYN045 dry suspension comprises the following components in percentage by weight:

[0204]

[0205]

[0206] Preparation method:

[0207] 1. Grind the raw material SYN045 and pass it through an 80-mesh sieve, pass mannitol through a 60-mesh sieve, and pass hydroxypropyl cellulose through a 40-mesh sieve for later use;

[0208] 2. Take the prescribed amount of SYN045 and mix it with half of the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix well to obtain a mixed powder;

[0209] 3. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0210] 4. Add magnesium stearate, xanthan gum, and orange flavor to the granules obtained by wet granulation and mix for 10 minutes to obtain the final mixed granules;

[0211] 5. Fill and package the total mixed granules into a dry suspension to obtain SYN045 dry suspension.

[0212] Comparative Example 1

[0213] Preparation of SYN045 tablets (1000 tablets)

[0214] A SYN045 tablet comprising the following components in percentage by mass:

[0215]

[0216] The preparation method is the same as that of Example 1, except that the amount of corn starch in Example 1 is increased, and the types and amounts of other raw materials and auxiliary materials are the same.

[0217] Comparative Example 2

[0218] Preparation of SYN045 tablets (1000 tablets)

[0219] A SYN045 tablet comprising the following components in percentage by mass:

[0220]

[0221] The preparation method is the same as that of Example 1, except that the amount of corn starch in Example 1 is reduced, and the types and amounts of other raw materials and auxiliary materials are the same.

[0222] Comparative Example 3

[0223] Preparation of SYN045 tablets (1000 tablets)

[0224] A SYN045 tablet comprising the following components in percentage by mass:

[0225]

[0226] The preparation method is the same as that of Example 1, except that the mannitol in Example 1 is replaced by lactose, and the types and amounts of other raw materials and auxiliary materials are the same.

[0227] Comparative Example 4

[0228] Preparation of SYN045 tablets (1000 tablets)

[0229] A SYN045 tablet comprising the following components in percentage by mass:

[0230]

[0231] The preparation method is the same as that of Example 1, except that the corn starch in Example 1 is replaced by potato starch, and the types and amounts of other raw materials are the same.

[0232] Comparative Example 5

[0233] Preparation of SYN045 tablets (1000 tablets)

[0234] A SYN045 tablet comprising the following components in percentage by mass:

[0235]

[0236] Preparation method:

[0237] 1. Take the prescribed amount of SYN045 and mix it with mannitol, corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose for 20 minutes to obtain a mixed powder;

[0238] 2. Add the mixed powder into the wet granulator and add purified water for wet granulation. After drying, pass through a 14-mesh sieve to granulate.

[0239] 3. Add magnesium stearate to the granules obtained by wet granulation and mix for 10 minutes to obtain the total mixed granules;

[0240] 4. Compress the mixed granules into tablets and package them to obtain SYN045 tablets.

[0241] Test Example 1 Quality Study

[0242] In order to investigate the quality of the products, the quality of the samples prepared in Examples 1-17 and Comparative Examples 1-5 was compared. Samples were taken from each of the above products at month 0 to test the content, related substances, content uniformity and dissolution rate. The results are shown in Table 1.

[0243] Content detection method:

[0244] Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512).

[0245] Solvent methanol-water (80:20)

[0246] Take 10 tablets of this product, place them in a 100ml volumetric flask, add an appropriate amount of solvent, dissolve them by ultrasonication, then add solvent to dilute to the scale, shake well, and filter.

[0247] Reference Solution: Accurately weigh an appropriate amount of SYN045 reference substance, dissolve it in a solvent by ultrasonication, and quantitatively dilute it to a solution containing approximately 60 μg per 1 ml. Shake well. The preparation of the SYN045 reference substance is described in patent CN202410701022.4.

[0248] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler; 0.2% (v / v) formic acid aqueous solution-methanol (20:80) was used as the mobile phase; the flow rate was 1 ml per minute; the column temperature was 30°C; the detection wavelength was 280 nm; and the injection volume was 20 μl.

[0249] Determination Method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

[0250] Content uniformity test method:

[0251] Determined according to the content uniformity test method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0941).

[0252] Take 1 tablet / granule / bag of this product, place it in a 10ml volumetric flask, add an appropriate amount of solvent (methanol-water 80:20), sonicate to dissolve, then add solvent to dilute to the scale, shake well, filter, and use as the test solution.

[0253] Determine the content according to the method under Assay and calculate the content uniformity of 10 tablets / capsules / bags. This should comply with the regulations (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0941). Content uniformity requirements are A+2.2S≤15.0 and RSD<5%.

[0254] Related substance detection methods:

[0255] Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512).

[0256] Test solution: Take an appropriate amount of this product or its contents, accurately weigh it, add mobile phase to dissolve it and quantitatively dilute it to make a solution containing approximately 0.5 mg of compound SYN045 per 1 mL. Filter and take the filtrate.

[0257] Chromatographic conditions: Column: Welchrom-C 18 Chromatographic column (4.6 mm x 200 mm, 5 μm); mobile phase: 0.1 mol / L sodium dihydrogen phosphate solution (pH adjusted to 4.0 with phosphoric acid)-acetonitrile (55:45); flow rate: 1.0 mL / min; detection wavelength: 280 nm; injection volume: 20 μL.

[0258] Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0259] If there are impurity peaks in the chromatogram of the limit test solution, the total amount of impurities calculated by the area normalization method shall not exceed 1.5%, the single largest impurity shall not exceed 0.5%, and the single other impurity shall not exceed 0.2%.

[0260] Dissolution test method:

[0261] The dissolution and release rate was determined according to the dissolution and release rate determination method (General Chapter 0931 Method 2 of Part IV of the Chinese Pharmacopoeia 2020 Edition) and the high performance liquid chromatography method (General Chapter 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0262] Use 900 ml of pH 1.0 hydrochloric acid solution containing 0.3% SDS as the dissolution medium at 50 rpm. Take samples after 5, 10, 15, 20, and 30 minutes. Assay the test and reference solutions at a wavelength of 280 nm. Calculate the dissolution rate for each tablet at different times. The dissolution rate should be >80% at 20 minutes.

[0263] Table 1 Drug quality research test data

[0264]

[0265]

[0266] Test conclusion:

[0267] Experimental studies have shown that the samples prepared in Examples 1-17 have high drug content and low impurity content, with total impurities less than 1.0% and other single impurities not exceeding 0.1%. The solubility is high, and the solubility in 20 minutes is above 90%, meeting the requirement of "dissolution in 20 minutes is greater than 80%". The content uniformity is high, meeting the requirements of "RSD% <5%, A+2.2S≤15.0", and the content difference is small.

[0268] Among them, Examples 5, 8, and 11 used an equal amount incremental mixing method, which resulted in relatively higher content uniformity and more uniform mixing; while the remaining Examples used a method of first mixing the API with half of the mannitol and then continuing to mix with the remaining excipients. Their overall content uniformity was slightly lower than that of Examples 5, 8, and 11, but they still met the quality standards and achieved greater improvements in operational convenience. Examples 13 and 14 achieved comparable results to Example 12; and Examples 16 and 17 achieved comparable results to Example 15.

[0269] The amount of corn starch used in Comparative Example 1 was too high, resulting in a significant decrease in the solubility of the preparation product. The 20-min solubility was 79.6%, which was lower than the lower limit of 80% required by the dissolution quality standard, and the product quality was difficult to guarantee.

[0270] The amount of corn starch used in Comparative Example 2 is too low, resulting in a decrease in the content of the preparation product, which is 97.7%. The impurities are significantly increased, with total impurities being 1.61%, exceeding 1.5%, and other single impurities being 0.17%. The product quality cannot be guaranteed.

[0271] In comparative example 3, the filler mannitol was replaced with lactose, and the content was reduced to 92.5%. The impurities increased, the total impurities were 1.88%, which exceeded 1.5%, and the other single impurities were 0.19%. The product quality could not be guaranteed. At the same time, the solubility was significantly reduced, and the 20-min solubility was only 78.8%, which was lower than the lower limit of 80% required by the quality standard, and the quality was difficult to guarantee.

[0272] In Comparative Example 4, the filler corn starch was replaced with potato starch. The content of the preparation was significantly reduced to only 90.1%, and the impurities increased significantly. The total impurities were 1.99%, which exceeded 1.5%, and the other single impurities were 0.20%. Serious problems occurred in the quality of the drug.

[0273] Comparative Example 5 is a preparation process in which the raw and auxiliary materials are directly mixed without equal addition or screening operations. The content uniformity is significantly reduced, with A+2.2S being 19.7 and RSD being 7.2%, which does not meet the quality standard requirements of "RSD% < 5%, A+2.2S ≤ 15.0", and the product quality cannot be guaranteed.

[0274] In summary, the formulations prepared from the compositions of the present invention exhibit high content, low impurities, high dissolution, and high content uniformity, with total impurities below 1.0% and other individual impurities no greater than 0.1%. The formulations also exhibit high dissolution rates, with dissolution rates exceeding 90% in 20 minutes, meeting the quality standard requirement of "dissolution rates greater than 80% in 20 minutes." This improves bioavailability, ensures clinical safety and efficacy, and significantly enhances product quality. Furthermore, the optimized preparation process is simple to operate, also ensuring product quality and facilitating industrial production and application.

[0275] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition comprising compound SYN045, characterized in that: The invention comprises the following components in percentage by weight: SYN045 compound 0.06%-0.8%, filler 83%-88%, binder 2.7%-3.4%, disintegrant 9.0%-11.2% and lubricant 0.9%-1.2%; Wherein, the filler is a mixture of mannitol and corn starch; The mass ratio of mannitol to corn starch is 105.4:14, 106.3:14, 90.4:14, 120.4:14, 91.3:14, 121.3:14, 105.8:14, 90.8:14, and 120.8:14; The chemical name of the compound SYN045 is 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide.

2. The pharmaceutical composition comprising compound SYN045 according to claim 1, wherein The binder is hydroxypropyl cellulose; and / or The disintegrant is low-substituted hydroxypropyl cellulose; and / or The lubricant is one or both of magnesium stearate and talc.

3. A pharmaceutical preparation, characterized in that A pharmaceutical composition comprising the compound SYN045 according to claim 1 or 2.

4. The pharmaceutical preparation according to claim 3, characterized in that The dosage form of the pharmaceutical preparation is tablet, capsule, granule or dry suspension.

5. The pharmaceutical preparation according to claim 4, characterized in that The tablet comprises the following components in percentage by mass: 0.08%-0.7% of compound SYN045, 81%-85% of filler, 2.6%-3.3% of binder, 8.8%-10.9% of disintegrant, 0.88%-1.09% of lubricant and 2.6%-3.3% of coating agent.

6. The pharmaceutical preparation according to claim 5, characterized in that The coating agent is Opadry gastric soluble coating agent; and / or The binder is hydroxypropyl cellulose; and / or The disintegrant is low-substituted hydroxypropyl cellulose; and / or The lubricant is one or both of magnesium stearate and talc.

7. The pharmaceutical preparation according to claim 4, characterized in that The dry suspension comprises the following components in percentage by weight: 0.08%-0.7% of compound SYN045, 83%-87% of filler, 2.7%-3.4% of binder, 9.0%-11.2% of disintegrant, 0.9%-1.2% of lubricant, 0.39%-0.48% of suspending agent and 0.04%-0.06% of flavoring agent.

8. The pharmaceutical preparation according to claim 7, wherein The suspending agent is one or more of xanthan gum, gum arabic, sodium alginate or chitosan; and / or The binder is hydroxypropyl cellulose; and / or The disintegrant is low-substituted hydroxypropyl cellulose; and / or The lubricant is one or both of magnesium stearate and talc.

9. A method for preparing the pharmaceutical composition comprising the compound SYN045 according to claim 2, characterized in that: The following steps are involved: S1. Grind and sieve the raw material SYN045, and sieve mannitol and hydroxypropyl cellulose separately for later use; S2. Take the prescribed amount of SYN045 and mix it with half the prescribed amount of mannitol, add the prescribed amount of corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, and then add the remaining prescribed amount of mannitol and mix to obtain a mixed powder; S3, adding the prescribed amount of purified water to the mixed powder, performing wet granulation, drying, and sieving the granules to obtain prefabricated granules; S4. Add magnesium stearate to the prefabricated granules and mix well to obtain a pharmaceutical composition comprising the compound SYN045.

10. A method for preparing the pharmaceutical composition comprising the compound SYN045 according to claim 2, characterized in that: The following steps are involved: S1. Take the prescribed amount of SYN045 and mannitol in equal amounts and mix them evenly. Add corn starch, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose and continue mixing. Sieve to obtain a mixed powder. S2. Add the prescribed amount of purified water to the mixed powder for wet granulation, dry, and sieve to obtain preformed granules; S3. Add magnesium stearate to the prefabricated granules and mix well to obtain a pharmaceutical composition comprising the compound SYN045.

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