Preparation method of upatinib sustained release tablet

Abstract

The invention discloses a preparation method of an upatinib sustained-release tablet. The preparation method comprises the following steps: 1) wet granulation: mixing an upatinib bulk drug with a filler, and granulating to obtain dry granules; 2) total mixing: mixing the dry granules with other auxiliary materials, finishing the granules, adding a lubricant, and mixing; (3) tabletting; and 4) coating, wherein the dry particles account for 24-99% of the weight of the tablet. By expanding the particle proportion range, the risk of uneven mixing is remarkably reduced, the content uniformity is improved, the similar factors (f2) of the obtained sustained release tablet in a dissolution medium at the pH value of 1.0-6.8 are all larger than or equal to 50, related substances are not detected after 6 months of acceleration, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a method for preparing utpatinib extended-release tablets. Background Technology

[0002] Upatinib, a new-generation JAK1 (Janus kinase 1) inhibitor, has shown significant efficacy in treating various inflammatory diseases, and its extended-release tablet form plays an important role in treating diseases such as psoriatic arthritis. However, during the preparation of utpatinib extended-release tablets, the low proportion of the main component makes mixing difficult, easily leading to uneven mixing, which affects product quality and efficacy.

[0003] Patent CN118370734A discloses an utpatinib sustained-release tablet with a core formulation of: 2.59% amorphous utpatinib, 15.24% microcrystalline cellulose (pH 101), 1.64% hydroxypropyl methylcellulose (K4M CR), 12.83% microcrystalline cellulose (pH 102), 17.34% mannitol, 33.79% ascorbic acid, 14.91% hydroxypropyl methylcellulose (K4M CR), 0.41% colloidal silica, and 1.24% magnesium stearate. By using specific acids such as malic acid as pH adjusters, the utpatinib sustained-release tablet achieves a relatively good dissolution rate. This patent allows for a particle content range of up to 25%, but when the particle content reaches 26%, the f2 value is less than 50, indicating that the dissolution effect is significantly unsatisfactory. Furthermore, it fails to address the problems of uneven mixing and large batch-to-batch variations due to equipment variability.

[0004] Patent CN117357492A discloses an utpatinib sustained-release tablet and its preparation method. This patent comprises the following components by mass percentage: 1-10% utpatinib, 5-50% release inhibitor, 20-70% filler, 10-50% pore-forming agent, and 0.1-5% lubricant. It employs a fluidized bed process and reduces the risk of hydrophilic polymers forming granules and hardening during granulation by adding a hydrophobic polymer, thus lowering the tablet's hygroscopicity and reducing the requirements for packaging sealing. Although this patent allows for a particle content of 53% or 78%, the addition of a hydrophobic polymer is necessary, and the hydrophilic polymer content must be within a predetermined range. Otherwise, a large proportion of hydroxypropyl methylcellulose can cause bed collapse during granulation, and the patent does not solve the problems of uneven mixing and large batch-to-batch variations.

[0005] Existing preparation methods are insufficient to meet the requirements of industrial production, and the stability and consistency of product quality are difficult to guarantee. Furthermore, different crystalline and amorphous forms of utpatinib raw materials exhibit differences in physicochemical properties, posing numerous challenges to their application in sustained-release tablet preparation. Therefore, developing preparation methods applicable to various raw material forms, reducing the risk of mixing, and effectively improving product quality is urgently needed. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing utpatinib sustained-release tablets, which solves the problems of high mixing risk, limited process design, and large batch-to-batch differences in equipment faced during the preparation of utpatinib sustained-release tablets, while improving the matching degree between the process and the production line to meet the needs of large-scale industrial production.

[0007] To achieve the objectives of this invention, the following technical solution is adopted:

[0008] A method for preparing utpatinib extended-release tablets includes the following steps:

[0009] 1) Wet granulation: After the utpatinib active pharmaceutical ingredient is mixed evenly with the filler and matrix material, it is wet granulated to obtain dry granules;

[0010] 2) Total mixing: The dry granules obtained in step 1) are mixed evenly with any pharmaceutically acceptable excipients other than the lubricant, then granulated, and then the lubricant is added and mixing is continued to obtain a uniformly mixed powder.

[0011] 3) Compress the total powder mixture obtained in step 2) into tablets to obtain plain tablets;

[0012] 4) Coat the uncoated tablets obtained in step 3) with a coating material to obtain finished tablets;

[0013] The dry granules comprise 24% to 99% of the weight of the tablets.

[0014] Furthermore, step 1) also includes a flow aid and / or a pH adjuster.

[0015] Furthermore, the excipients in step 2) are selected from one or more of fillers, skeleton materials, pH adjusters and flow aids.

[0016] Furthermore, the utpatinib raw material is in the form of hemihydrate crystal form C, anhydrous form, or amorphous form;

[0017] The filler is selected from one or more of microcrystalline cellulose and mannitol;

[0018] The skeleton material is selected from hydroxypropyl methylcellulose;

[0019] The pH adjuster is selected from one or more of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and maleic acid.

[0020] The flow aid is colloidal silica;

[0021] The lubricant is selected from magnesium stearate or calcium stearate;

[0022] The coating material is a film coating premix.

[0023] Furthermore, step 1) wet granulation specifically includes:

[0024] S11) The utpatinib active pharmaceutical ingredient, filler, and matrix material are put into a wet granulator and mixed. The stirring speed is set to 150-300 rpm and the cutting speed is set to 1700-2400 rpm. After dry mixing for 3-5 minutes, purified water is pumped in to form a soft mass. The stirring speed is set to 150-300 rpm and the cutting speed is set to 1700-2400 r / min. The mixing time is 3-7 minutes.

[0025] S12) The soft material is prepared into wet granules by a granulator, and the rotation speed of the granulator is set to 500-800 r / min;

[0026] S13) The wet particles are dried using a fluidized bed to obtain dry particles, and the rapid moisture content of the wet particles does not exceed 4%.

[0027] Furthermore, step 2) the total mixing step specifically includes:

[0028] S21) Premix the dry granules obtained in step 1) with the auxiliary materials other than the lubricant, set the rotation speed to 15-20 r / min, and mix for 3-7 min;

[0029] S22) After granulation, continue mixing, setting the mixing speed to 15 rpm and the mixing time to 10-20 min;

[0030] Add lubricant to S23 and mix for 3-7 minutes.

[0031] Furthermore, in step 3), a rotary tablet press is used for tableting, and the hardness of the raw tablet is controlled between 140 and 220 N.

[0032] On the other hand, the present invention provides an utpatinib sustained-release tablet prepared according to the above method.

[0033] Further, the tablet comprises the following components, by weight percentage: 3.13% utpatinib active pharmaceutical ingredient, 18.5%–54.88% filler, 2.29%–20% matrix material, 0–20% pH adjuster, and 0–0.5% flow aid; 0–36.38% filler, 0–17.71% matrix material, 0–20% pH adjuster, 0–0.5% flow aid, and 1.5% lubricant.

[0034] Compared with the prior art, the present invention has the following beneficial technical effects:

[0035] (1) Effectively reduce mixing risk: By innovatively designing formulations with different particle ratios and processes applicable to various raw material forms, the particle ratio range is expanded to 99%, further optimizing the dispersion of materials in the total mixing stage and reducing mixing risk. This makes the physical properties of different forms of utpatinib raw materials and excipients more compatible, improves the content uniformity of the formulation, and ensures product quality and efficacy.

[0036] (2) Optimized in vitro dissolution performance: In vitro dissolution curves of formulations with different particle sizes and using different raw material forms were studied. The cumulative dissolution rates at 1h, 4h, and 16h compared to the commercially available reference formulation all met the relevant quality standards, and the f2 similarity factor was not lower than 80. This indicates that the utpatinib sustained-release tablets prepared in this invention can achieve stable and continuous drug release in vitro, ensuring effective absorption and utilization of the drug in vivo, and achieving good therapeutic effects regardless of the raw material form used.

[0037] (3) Improved production line compatibility: The preparation process of this invention has good flexibility, and can select appropriate particle ratio formulations and raw material forms according to the characteristics of different production lines. The high adaptability improves the matching degree of granulation and mixing equipment in the workshop production line, which is conducive to the smooth progress of large-scale industrial production and facilitates comprehensive and effective control of drug quality.

[0038] (4) Ensuring process stability: Through innovative wet granulation technology combined with an extremely high particle ratio design, the uniformity of materials is fundamentally improved, the total mixing time is effectively shortened, and the high stability of batch-to-batch quality is ensured. Long-term accelerated testing showed no detected degradation impurities, proving that the active ingredients remain highly stable after long-term storage, verifying long-term stability. This breakthrough overcomes the bottleneck of high mixing difficulty in low-specification solid dosage forms. Detailed Implementation

[0039] The following examples illustrate specific implementation methods, providing a further detailed description of the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples.

[0040] In this invention, unless otherwise stated, the proportions and substitution schemes of the components in utpatinib extended-release tablets can be combined to form new formulations. The operation methods for utpatinib extended-release tablets are all conventional methods in the art, such as fluidized bed granulation, material mixing, tableting, and coating.

[0041] Unless otherwise specified, all raw and auxiliary materials used in the following examples are commercially available.

[0042] Raw material names model manufacturing enterprises Upatinib Hemihydrate crystal form C Zhejiang Huahai Pharmaceutical Co., Ltd. Upatinib Anhydrous Tiandi Hengyi Pharmaceutical Co., Ltd.

[0043] Upatinib amorphous was prepared according to method A in Example 5 (Preparation of amorphous free base) of patent WO2017066775A1.

[0044] In the following examples, the trade name of the reference formulation is... Chinese name is The product is 15mg / tablet and is manufactured by AbbVie Ireland NL BV.

[0045] Example 1 (24% of particles)

[0046] The prescription consists of the following components:

[0047]

[0048]

[0049] Preparation method:

[0050] (1) Wet granulation:

[0051] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0052] b) According to the formula, add the raw and auxiliary materials added to the granulation into a wet granulator and mix. Set the stirring speed to 150 rpm and the cutting speed to 2400 rpm. After dry mixing for 3 to 5 minutes, pump in purified water to make soft material. Set the stirring speed to 150 rpm and the cutting speed to 2400 r / min. Mix for 3 to 7 minutes.

[0053] c) The soft material is granulated by a granulator at a speed of 500 r / min and a 5×5 mm sieve to form wet granules.

[0054] d) Transfer the wet granules to a fluidized bed dryer with an inlet air temperature of 80°C to ensure the moisture content of the wet granules does not exceed 4%. The dried granules are then passed through a φ1.5mm sieve to obtain dry granules.

[0055] (2) Total Mixing:

[0056] a) Premixing: According to the formulation, add the dry granules obtained in step (1) and other additives except magnesium stearate into the mixing hopper and mix at a speed of 20 r / min for 3 to 7 minutes to make the materials initially mixed evenly.

[0057] b) After granulation through a φ1.5mm sieve, add the granules into a mixing hopper, set the mixing speed to 15 rpm, and the mixing time to 10-20 min.

[0058] c) Then add magnesium stearate and mix for 3-7 minutes to obtain the total powder mixture.

[0059] (3) Tableting: A rotary tablet press is used, and a φ8mm punch die is used to press the raw tablets, controlling the hardness of the raw tablets to be 140-220N.

[0060] (4) Coating: Put the uncoated tablets into a coating machine and coat them with 15% (w / w) coating solution. Control the weight gain of the coating to 3%-5% to obtain coated tablets.

[0061] Example 2 (32% of particles)

[0062] The prescription consists of the following components:

[0063]

[0064]

[0065] Preparation method:

[0066] Preparation method:

[0067] (1) Wet granulation:

[0068] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0069] b) According to the formula, add the raw and auxiliary materials added to the granulation into a wet granulator and mix. Set the stirring speed to 300 rpm and the cutting speed to 2000 rpm. After dry mixing for 3 to 5 minutes, pump in purified water to make soft material. Set the stirring speed to 300 rpm and the cutting speed to 2000 r / min. Mix for 3 to 7 minutes.

[0070] c) The soft material is granulated by a granulator at a speed of 700 r / min and a 5×5 mm sieve to form wet granules.

[0071] d) Transfer the wet granules to a fluidized bed dryer with an inlet air temperature of 80°C to ensure the moisture content of the wet granules does not exceed 4%. The dried granules are then passed through a φ1.5mm sieve to obtain dry granules.

[0072] (2) Total Mixing:

[0073] a) Premixing: According to the formulation, add the dry granules obtained in step (1) and other additives except magnesium stearate into the mixing hopper and mix at a speed of 15-20 r / min for 3-7 min to make the materials initially mixed evenly.

[0074] b) After granulation through a φ1.5mm sieve, add the granules into a mixing hopper, set the mixing speed to 15 rpm, and the mixing time to 10-20 min.

[0075] c) Then add magnesium stearate and mix for 3-7 minutes to obtain the total powder mixture.

[0076] (3) Tableting: A rotary tablet press is used, and a φ8mm punch die is used to press the raw tablets, controlling the hardness of the raw tablets to be 140-220N.

[0077] (4) Coating: Put the uncoated tablets into a coating machine and coat them with 15% (w / w) coating solution. Control the weight gain of the coating to 3%-5% to obtain coated tablets.

[0078] Example 3 (39% of particles)

[0079] The prescription consists of the following components:

[0080]

[0081] Preparation method:

[0082] (1) Wet granulation:

[0083] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0084] b) According to the prescription composition, add the raw and auxiliary materials added to the granulation into a wet granulator and mix. Set the stirring speed to 180 rpm and the cutting speed to 1900 rpm. After dry mixing for 3 to 5 minutes, pump in purified water to make soft material. Set the stirring speed to 180 rpm and the cutting speed to 1900 r / min. Mix for 3 to 7 minutes.

[0085] c) The soft material is granulated by a granulator at a speed of 600 r / min and a 5×5 mm sieve to form wet granules.

[0086] d) Transfer the wet granules to a fluidized bed dryer with an inlet air temperature of 80°C to ensure the moisture content of the wet granules does not exceed 4%. The dried granules are then passed through a φ1.5mm sieve to obtain dry granules.

[0087] (2) Total Mixing:

[0088] a) Premixing: According to the formulation, add the dry granules obtained in step (1) and other additives except magnesium stearate into the mixing hopper and mix at a speed of 15-20 r / min for 3-7 min to make the materials initially mixed evenly.

[0089] b) After granulation through a φ1.5mm sieve, add the granules into a mixing hopper, set the mixing speed to 15 rpm, and the mixing time to 10-20 min.

[0090] c) Then add magnesium stearate and mix for 3-7 minutes to obtain the total powder mixture.

[0091] (3) Tableting: A rotary tablet press is used, and a φ8mm punch die is used to press the raw tablets, controlling the hardness of the raw tablets to be 140-220N.

[0092] (4) Coating: Put the uncoated tablets into a coating machine and coat them with 15% (w / w) coating solution. Control the weight gain of the coating to 3%-5% to obtain coated tablets.

[0093] Example 4 (39% of particles)

[0094] The prescription consists of the following components:

[0095]

[0096] Preparation method:

[0097] (1) Wet granulation:

[0098] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0099] b) According to the prescription composition, add the raw and auxiliary materials added to the granulation into a wet granulator and mix. Set the stirring speed to 180 rpm and the cutting speed to 1900 rpm. After dry mixing for 3 to 5 minutes, pump in purified water to make soft material. Set the stirring speed to 180 rpm and the cutting speed to 1900 r / min. Mix for 3 to 7 minutes.

[0100] c) The soft material is granulated by a granulator at a speed of 600 r / min and a 5×5 mm sieve to form wet granules.

[0101] d) Transfer the wet granules to a fluidized bed dryer with an inlet air temperature of 80°C to ensure the moisture content of the wet granules does not exceed 4%. The dried granules are then passed through a φ1.5mm sieve to obtain dry granules.

[0102] (2) Total Mixing:

[0103] a) Premixing: According to the formulation, add the dry granules obtained in step (1) and other additives except magnesium stearate into the mixing hopper and mix at a speed of 15-20 r / min for 3-7 min to make the materials initially mixed evenly.

[0104] b) After granulation through a φ1.5mm sieve, add the granules into a mixing hopper, set the mixing speed to 15 rpm, and the mixing time to 10-20 min.

[0105] c) Then add magnesium stearate and mix for 3-7 minutes to obtain the total powder mixture.

[0106] (3) Tableting: A rotary tablet press is used, and a φ8mm punch die is used to press the raw tablets, controlling the hardness of the raw tablets to be 140-220N.

[0107] (4) Coating: Put the uncoated tablets into a coating machine and coat them with 15% (w / w) coating solution. Control the weight gain of the coating to 3%-5% to obtain coated tablets.

[0108] Example 5 (39% of particles)

[0109] The prescription consists of the following components:

[0110]

[0111] Preparation method:

[0112] (1) Wet granulation:

[0113] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0114] b) According to the prescription composition, add the raw and auxiliary materials added to the granulation into a wet granulator and mix. Set the stirring speed to 180 rpm and the cutting speed to 1900 rpm. After dry mixing for 3 to 5 minutes, pump in purified water to make soft material. Set the stirring speed to 180 rpm and the cutting speed to 1900 r / min. Mix for 3 to 7 minutes.

[0115] c) The soft material is granulated by a granulator at a speed of 600 r / min and a 5×5 mm sieve to form wet granules.

[0116] d) Transfer the wet granules to a fluidized bed dryer with an inlet air temperature of 80°C to ensure the moisture content of the wet granules does not exceed 4%. The dried granules are then passed through a φ1.5mm sieve to obtain dry granules.

[0117] (2) Total Mixing:

[0118] a) Premixing: According to the formulation, add the dry granules obtained in step (1) and other additives except magnesium stearate into the mixing hopper and mix at a speed of 15-20 r / min for 3-7 min to make the materials initially mixed evenly.

[0119] b) After granulation through a φ1.5mm sieve, add the granules into a mixing hopper, set the mixing speed to 15 rpm, and the mixing time to 10-20 min.

[0120] c) Then add magnesium stearate and mix for 3-7 minutes to obtain the total powder mixture.

[0121] (3) Tableting: A rotary tablet press is used, and a φ8mm punch die is used to press the raw tablets, controlling the hardness of the raw tablets to be 140-220N.

[0122] (4) Coating: Put the uncoated tablets into a coating machine and coat them with 15% (w / w) coating solution. Control the weight gain of the coating to 3%-5% to obtain coated tablets.

[0123] Example 6 (99% of particles)

[0124] The prescription consists of the following components:

[0125]

[0126] Preparation method:

[0127] (1) Wet granulation:

[0128] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0129] b) According to the formula, add the raw and auxiliary materials added to the granulation into a wet granulator and mix. Set the stirring speed to 160 rpm and the cutting speed to 1800 rpm. After dry mixing for 3 to 5 minutes, pump in purified water to make soft material. Set the stirring speed to 160 rpm and the cutting speed to 1800 r / min. Mix for 3 to 7 minutes.

[0130] c) The soft material is granulated by a granulator at a speed of 500 r / min and a 5×5 mm sieve to form wet granules.

[0131] d) Transfer the wet granules to a fluidized bed dryer with an inlet air temperature of 80°C to ensure the moisture content of the wet granules does not exceed 4%. The dried granules are then passed through a φ1.5mm sieve to obtain dry granules.

[0132] (2) Total Mixing:

[0133] a) Premixing: According to the formulation, add the dry granules obtained in step (1) and other additives except magnesium stearate into the mixing hopper and mix at a speed of 15-20 r / min for 3-7 min to make the materials initially mixed evenly.

[0134] b) After granulation through a φ1.5mm sieve, add the granules into a mixing hopper, set the mixing speed to 15 rpm, and the mixing time to 10-20 min.

[0135] c) Then add magnesium stearate and mix for 3-7 minutes to obtain the total powder mixture.

[0136] (3) Tableting: A rotary tablet press is used, and a φ8mm punch die is used to press the raw tablets, controlling the hardness of the raw tablets to be 140-220N.

[0137] (4) Coating: Put the uncoated tablets into a coating machine and coat them with 15% (w / w) coating solution. Control the weight gain of the coating to 3%-5% to obtain coated tablets.

[0138] Comparative Example 1 (20% of particles)

[0139] The prescription consists of the following components:

[0140]

[0141] The preparation method is the same as in Example 1.

[0142] Comparative Example 2 (15% of particles)

[0143] The prescription consists of the following components:

[0144]

[0145] The preparation method is the same as in Example 1.

[0146] Comparative Example 3 (13% of particles)

[0147] The prescription consists of the following components:

[0148]

[0149] The preparation method is the same as in Example 1.

[0150] Comparative Example 4 (39% of particles)

[0151] The prescription composition is the same as in Example 3, and the preparation method is as follows:

[0152] The difference from Example 3 is that in step (1) of wet granulation, the moisture content of the wet granules is rapidly reduced to 5%. All other preparation methods are the same as in Example 3.

[0153] Comparative Example 5 (39% of particles)

[0154] The prescription composition is the same as in Example 3, and the preparation method is as follows:

[0155] The difference from Example 3 is that step (1) uses fluidized bed granulation.

[0156] a) Crush, sieve, and set aside the raw and auxiliary materials.

[0157] b) Set the fan frequency to 20-50Hz, and according to the formula, preheat the raw and auxiliary materials added in the granulation process in the fluidized bed to a material temperature of 40±2℃; pump in purified water to contact the material and then granulate to form wet granules.

[0158] c) Stop the pumping, and adjust the inlet air temperature to 60-80℃ to ensure the material's moisture content does not exceed 4%. The dried granules are then passed through a φ1.0mm sieve to obtain dry granules.

[0159] The remaining steps (2)(3)(4) are the same as in Example 3.

[0160] Performance testing

[0161] 1. Stability test

[0162] In accordance with the 2020 edition of the Chinese Pharmacopoeia (Volume IV: 9001 Guidelines for Stability Testing of Raw Materials and Preparations), accelerated stability tests and long-term stability tests were conducted on the tablets prepared in Examples 1-6 and Comparative Examples 1-5 of this invention. Accelerated stability test conditions: temperature 40℃±2℃, humidity 75%±5%RH, with samples taken on day 0, month 3, and month 6. Long-term stability test conditions: temperature 30±2℃, relative humidity 65±5%, with samples taken on day 0 and month 6. Appearance, active ingredient content, related substances, and dissolution were examined; the results are shown in Table 1-11 below.

[0163] Table 1: Stability test results of Example 1

[0164]

[0165]

[0166] Table 2: Stability test results of Example 2

[0167]

[0168] Table 3: Stability test results of Example 3

[0169]

[0170] Table 4: Stability test results of Example 4

[0171]

[0172]

[0173] Table 5: Stability test results of Example 5

[0174]

[0175] Table 6: Stability test results of Example 6

[0176]

[0177]

[0178] Table 7: Stability test results of Comparative Example 1

[0179]

[0180] Table 8: Stability test results of Comparative Example 2

[0181]

[0182] Table 9: Stability test results of Comparative Example 3

[0183]

[0184]

[0185] Table 10: Stability test results of Comparative Example 4

[0186]

[0187] Table 11: Results of stability test for Comparative Example 5

[0188]

[0189]

[0190] Impurity A structural formula:

[0191]

[0192] Impurity D structural formula:

[0193]

[0194] The results show that the impurity content of Comparative Example 4 gradually increased during the accelerated test, and the increase was significant. The initial impurity content of Comparative Example 5 was higher than that of wet granulation, and the content of impurity A exceeded the limit after 3 months of accelerated testing. Therefore, Comparative Examples 4 and 5 had poor stability and did not meet the requirements.

[0195] 2. Mixing uniformity

[0196] According to the test methods in the "Technical Guidelines for the Study of Mixing Uniformity and Controlled Dosage Unit Uniformity of Oral Solid Dosage Forms (Draft for Comments)" published on the CDE website, samples were taken at 10 min, 15 min and 20 min during the total mixing step b of the examples and comparative examples to test the mixing uniformity. The mixing uniformity was expressed as RSD (Relative Standard Deviation). The test results are shown in Table 12-18 below.

[0197] Table 12: Results of Mixing Uniformity Test in Example 1

[0198]

[0199]

[0200] Table 13: Results of Mixing Uniformity Test in Example 2

[0201]

[0202] Table 14: Mixing Uniformity Test Results of Examples 3 and 5

[0203]

[0204]

[0205] Table 15: Results of Mixing Uniformity Test in Example 6

[0206]

[0207] Table 16: Results of Mixing Uniformity Test in Comparative Example 1

[0208]

[0209] Table 17: Results of Mixing Uniformity Test in Comparative Example 2

[0210]

[0211]

[0212] Table 18: Results of Mixing Uniformity Test in Comparative Example 3

[0213]

[0214] The results show that the RSD of Examples 1-6 was less than 2.5% after mixing for 10 minutes, while Comparative Examples 1-3 required mixing for 15 minutes or even 20 minutes to achieve an RSD of less than 5%. In other words, the higher the particle content, the shorter the time to achieve uniform mixing, thus improving the mixing uniformity.

[0215] 3. Dissolution test

[0216] The in vitro release rate was determined using a drug dissolution apparatus. The utpatinib tablets prepared in Examples 1-6 and the reference formulation were used as dissolution media in hydrochloric acid solution with pH 1.0, acetate buffer solution with pH 4.5, and phosphate buffer solution with pH 6.8, respectively. The dissolution method was performed using a rotating basket method at 100 rpm. Samples were taken at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, and 24 h to determine the dissolution results. The f2 value (similarity factor) was taken at 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h. The results are shown in Tables 19-21.

[0217] Table 19: Dissolution results under hydrochloric acid solution at pH 1.0

[0218]

[0219]

[0220] Table 20: Dissolution results under acetate buffer solution conditions at pH 4.5

[0221]

[0222] Table 21: Dissolution results under phosphate buffer solution conditions at pH 6.8

[0223]

[0224]

[0225] To compare solubility properties using a similarity factor f2, two solutions should be considered similar and bioequivalent; f2 should be between 50 and 100. Therefore, the in vitro release behavior of Examples 1-6 is consistent with the reference formulation.

[0226] 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, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing utpatinib sustained-release tablets, characterized in that, Includes the following steps: 1) Wet granulation: After the utpatinib active pharmaceutical ingredient is mixed evenly with the filler and matrix material, it is wet granulated to obtain dry granules; 2) Total mixing: The dry granules obtained in step 1) are mixed evenly with any pharmaceutically acceptable excipients other than the lubricant, then granulated, and then the lubricant is added and mixing is continued to obtain a uniformly mixed powder. 3) Compress the total powder mixture obtained in step 2) into tablets to obtain plain tablets; 4) Coat the uncoated tablets obtained in step 3) with a coating material to obtain finished tablets; The dry granules comprise 24% to 99% of the weight of the tablets.

2. The preparation method according to claim 1, characterized in that, Step 1) also includes a flow aid and / or a pH adjuster.

3. The preparation method according to claim 1, characterized in that, The excipients in step 2) are selected from one or more of fillers, skeleton materials, pH adjusters and flow aids.

4. The preparation method according to claim 3, characterized in that, Any one or more of the following ag items: a. The utpatinib raw material is in the form of hemihydrate crystal form C, anhydrous or amorphous; b. The filler is selected from one or more of microcrystalline cellulose and mannitol; c. The skeleton material is selected from hydroxypropyl methylcellulose; d. The pH adjuster is selected from one or more of tartaric acid, fumaric acid, citric acid, succinic acid and maleic acid; e. The flow aid is colloidal silica; f. The lubricant is selected from magnesium stearate or calcium stearate; g. The coating material is a film coating premix.

5. The preparation method according to claim 1, characterized in that, Step 1) wet granulation specifically includes: S11) The utpatinib active pharmaceutical ingredient, filler, and matrix material are put into a wet granulator and mixed. The stirring speed is set to 150-300 rpm and the cutting speed is set to 1700-2400 rpm. After dry mixing for 3-5 minutes, purified water is pumped in to form a soft mass. The stirring speed is set to 150-300 rpm and the cutting speed is set to 1700-2400 r / min. The mixing time is 3-7 minutes. S12) The soft material is prepared into wet granules by a granulator, and the rotation speed of the granulator is set to 500-800 r / min; S13) The wet particles are dried using a fluidized bed to obtain dry particles, and the rapid moisture content of the wet particles does not exceed 4%.

6. The preparation method according to claim 1, characterized in that Step 2) of the total mixing step specifically includes: S21) Premix the dry granules obtained in step 1) with the auxiliary materials other than the lubricant, set the rotation speed to 15-20 r / min, and mix for 3-7 min; S22) After granulation, continue mixing, setting the mixing speed to 15 rpm and the mixing time to 10-20 min; Add lubricant to S23 and mix for 3-7 minutes.

7. The preparation method according to claim 1, characterized in that, In step 3), a rotary tablet press is used to compress the tablets, and the hardness of the raw tablets is controlled between 140 and 220 N.

8. Upatinib extended-release tablets prepared by the method according to any one of claims 1-7.

9. The utpatinib extended-release tablet according to claim 8, characterized in that, The tablets comprise the following components, by weight percentage: 3.13%–9.38% utpatinib active pharmaceutical ingredient, 18.5%–54.88% filler, 2.29%–20% matrix material, 0–20% pH adjuster, and 0–0.5% gliding agent; 0–36.38% filler, 0–17.71% matrix material, 0–20% pH adjuster, 0–0.5% gliding agent, and 1.5% lubricant.

10. The utpatinib extended-release tablet according to claim 9, characterized in that, The tablets comprise the following components, by weight percentage: 3.13% utpatinib active pharmaceutical ingredient, 18.5%–54.88% filler, 2.29%–20% matrix material, 0–20% pH adjuster, and 0–0.5% gliding agent; 0–36.38% filler, 0–17.71% matrix material, 0–20% pH adjuster, 0–0.5% gliding agent, and 1.5% lubricant.

Images