Abesili tablet and preparation method thereof

Abstract

The invention discloses an abelsilib tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The abesilib tablet comprises abesilib, a filling agent, a disintegrating agent, an adhesive, a flow aid, a lubricating agent and stabilizing agents sabolixa sodium and glycine. The preparation method of the abelsiil tablet comprises the steps of pretreatment, stabilizer treatment, granulation, drying, size stabilization, total mixing, tabletting, coating and the like. According to the present invention, through the synergistic stabilization effect of the sabolixabate sodium and the glycine and the optimized preparation process, the stability of the abesillitic tablet is improved, the process is simple and controllable, the cost is low, the product quality uniformity is good, the abesillitic tablet is suitable for large-scale production, and the reliable oral preparation selection is provided for breast cancer treatment.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an abexicillin tablet and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Breast cancer is one of the most common malignant tumors among women worldwide, and its clinical treatment has always been a hot topic in the field of oncology. Currently, the main treatment methods for breast cancer include surgery, radiotherapy, chemotherapy, endocrine therapy, and targeted therapy.

[0004] Cyclin-dependent kinase 4 / 6 (CDK4 / 6) are key molecules in cell cycle regulation. Upon binding to cyclin D, they phosphorylate retinoblastoma protein (Rb), propelling cells from G1 phase to S phase and thus promoting cell proliferation. In HR+ breast cancer, Cyclin D1 is often overexpressed, leading to CDK4 / 6 overactivation and subsequently driving abnormal tumor cell proliferation. Based on this mechanism, CDK4 / 6 inhibitors have become novel targets for breast cancer treatment. Abecib, an orally administered selective CDK4 / 6 inhibitor, specifically inhibits CDK4 / 6 activity, blocking cell cycle progression in tumor cells and thereby suppressing tumor cell proliferation.

[0005] Chinese patent CN116251066A discloses an abecitabine tablet and its preparation method, comprising 30%–40% abecitabine, 53%–63% filler, 1%–5% disintegrant, 0.5%–5% glidant, and 0.5%–2% lubricant. The abecitabine tablet is prepared by direct compression of powder, and the in vitro dissolution rate can reach more than 85% within 15 minutes.

[0006] Currently, existing abexicillin formulations still face several challenges in their preparation. For example, some preparation processes are complex and costly; others exhibit poor stability during storage, impacting the drug's efficacy and safety. Therefore, developing a simple, low-cost, and highly stable abexicillin tablet and its preparation method is of significant clinical importance and market value. Summary of the Invention

[0007] To overcome the problems of poor stability and complex processes in existing abexicillin formulations, this invention provides an abexicillin tablet with high stability, simple preparation process, and controllable cost, as well as its preparation method.

[0008] The abecitabine tablets of the present invention are composed of the following components in parts by weight: Active ingredient: Abecitabine 50-150 parts by weight; Filler: Selected from any combination of the following: Combination 1: 60-120 parts by weight of microcrystalline cellulose, 30-80 parts by weight of lactose; Combination 2: 50-100 parts by weight of mannitol, 40-80 parts by weight of pregelatinized starch; Combination 3: 45-100 parts by weight of dicalcium phosphate, 35-75 parts by weight of corn starch; Disintegrant: selected from 5-10 parts by weight of croscarmellose sodium, 6-12 parts by weight of carboxymethyl starch sodium, or 4-9 parts by weight of croscarmellose. Adhesive: Selected from 2-5 parts by weight of hydroxypropyl methylcellulose, 3-6 parts by weight of povidone, or 5-8 parts by weight of starch paste with a mass fraction of 10%; Glide aid: selected from 1-3 parts by weight of micronized silica gel, 2-4 parts by weight of talc, or 1.5-3.5 parts by weight of sodium fumarate stearate; Lubricant: Selected from 0.5-2 parts by weight of magnesium stearate, 1-3 parts by weight of zinc stearate, or 1.5-4 parts by weight of polyethylene glycol 6000; Stabilizer: A combination of 1-3 parts by weight of sodium sapoxetine and 2-5 parts by weight of glycine.

[0009] The preparation method of abexicillin tablets of the present invention includes the following steps: (1) Pretreatment: The abecitabine raw material was crushed and passed through a 100-mesh sieve, and the filler, disintegrant, binder, flow aid and lubricant were passed through an 80-mesh sieve respectively for later use; (2) Stabilizer treatment: Weigh the prescribed amount of sodium sapoxetine and glycine, add purified water and mix, then wet grind until the particle size is ≤5μm, vacuum dry (50-55℃, water content ≤1%), and pass through a 100-mesh sieve for later use; (3) Granulation: Mix abexicillin, filler, 70% of total disintegrant and treated stabilizer evenly, add 4%-10% by mass of binder solution (4%-6% hydroxypropyl methylcellulose solution, 5%-7% povidone solution or 10% starch paste), stir to form soft material, and granulate through an 18-mesh sieve to obtain wet granules. (4) Drying: The wet granules are dried at 60-65℃ until the moisture content is 2%-3% to obtain dry granules; (5) Granulation: Dry granules are granulated by passing them through a 16-mesh sieve; (6) Final mixing: Add the remaining 30% disintegrant, glidant and lubricant, and mix for 15-20 minutes; (7) Tableting and coating: After tableting, the tablets are coated with a gastric-soluble film coating premix, and the coating weight gain is 2%.

[0010] It should be noted that the dissolution rate, hardness and friability, and microbial limit of the abecilibi tablets in Examples 1-9 were all tested accordingly. The tablets showed stable physical properties such as hardness and friability, and the dissolution uniformity met the requirements (dissolution ≥85% in 15 minutes). All indicators met the requirements of the Chinese Pharmacopoeia.

[0011] Compared with the prior art, the technical advantages of the present invention are as follows: (1) Significantly improved stability: Through the synergistic stabilizing effect of sodium sapoxetine and glycine, combined with wet grinding to control the particle size to ≤5μm, the content retention rate of the formulation is ≥99.05% after 6 months under accelerated conditions at 40℃.

[0012] (2) Simple and controllable process: The wet granulation process avoids the need for complex equipment and the production cost is lower than that of powder direct tableting and other processes, making it suitable for large-scale production. Attached Figure Description

[0013] Figure 1 Examples 1-9, Comparative Examples 1-6, and the stability of commercially available formulation abexilide tablets. Detailed Implementation

[0014] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0015] Examples 1-3 Abecitabine Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0016] (2) Stabilizer treatment: Weigh the prescribed amount of sodium sapoxetine and glycine, add 4 ml of purified water, mix evenly and then perform wet grinding until the particle size is ≤5 μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the moisture content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0017] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add 4%-6% of hydroxypropyl methylcellulose solution (5% in Example 1, 4% in Example 2, and 6% in Example 3), stir to make a suitable soft material, granulate with an 18-mesh sieve to obtain wet granules.

[0018] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0019] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0020] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0021] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0022] Examples 4-6 Abecitabine Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0023] (2) Stabilizer treatment: Weigh out the prescribed amount of sodium sapoxetine and glycine, add 3-5 ml of purified water, mix evenly and then perform wet grinding until the particle size is ≤5 μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the moisture content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0024] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add a 5%-7% povidone solution (6% in Example 4, 5% in Example 5, and 7% in Example 6), stir to make a suitable soft material, granulate it with an 18-mesh sieve to obtain wet granules.

[0025] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0026] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0027] (6) Total mixing: Add the remaining disintegrant, glidant and lubricant to the granulated granules and mix for 15-20 minutes to make the mixture uniform. Coat with gastric-soluble film coating premix, and the coating weight gain is 2%.

[0028] Examples 7-9: Abecitabine Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0029] (2) Stabilizer treatment: Weigh out the prescribed amount of sodium sapoxetine and glycine, add 3-5 ml of purified water, mix evenly and then perform wet grinding until the particle size is ≤5 μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the moisture content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0030] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant, and the treated stabilizer and mix them evenly to obtain a mixed powder; add 10% starch slurry solution by mass, stir to make a suitable soft material, and granulate it with an 18-mesh sieve to obtain wet granules.

[0031] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0032] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0033] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0034] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0035] Comparative Example 1: Abeciliary Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0036] (2) Granulation: Weigh the prescribed amount of abexilic acid, filler, and 70% of the total amount of disintegrant and mix them evenly to obtain a mixed powder; add 5% hydroxypropyl methylcellulose solution by mass, stir to make a suitable soft material, and granulate it through an 18-mesh sieve to obtain wet granules.

[0037] (3) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0038] (4) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0039] (5) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0040] (6) Tableting, coating with gastric-soluble film coating premix, with a coating weight gain of 2%.

[0041] Comparative Example 2: Abecitabine tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0042] (2) Stabilizer treatment: Weigh the prescribed amount of sodium sapoxetine and DL-alanine, add 4 ml of purified water, mix evenly and then perform wet grinding until the particle size is ≤5 μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the water content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0043] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add 5% hydroxypropyl methylcellulose solution by mass, stir to make a suitable soft material, granulate with an 18-mesh sieve to obtain wet granules.

[0044] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0045] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0046] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0047] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0048] Comparative Example 3: Abecitabine Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0049] (2) Stabilizer treatment: Weigh the prescribed amount of glycine, add 2ml of purified water, mix evenly and then perform wet grinding until the particle size is ≤5μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the water content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0050] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add 5% hydroxypropyl methylcellulose solution by mass, stir to make a suitable soft material, granulate with an 18-mesh sieve to obtain wet granules.

[0051] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0052] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0053] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0054] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0055] Comparative Example 4: Abecitabine tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0056] (2) Stabilizer treatment: Weigh the prescribed amount of sodium sapoxetine, add 2 ml of purified water, mix evenly and then perform wet grinding until the particle size is ≤5 μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the moisture content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0057] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add 5% hydroxypropyl methylcellulose solution by mass, stir to make a suitable soft material, granulate with an 18-mesh sieve to obtain wet granules.

[0058] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0059] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0060] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0061] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0062] Comparative Example 5: Abecitabine Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0063] (2) Stabilizer treatment: Weigh out the prescribed amount of sodium sapoxetine and glycine, mix them evenly, and set aside.

[0064] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add 5% hydroxypropyl methylcellulose solution by mass, stir to make a suitable soft material, granulate with an 18-mesh sieve to obtain wet granules.

[0065] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0066] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0067] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0068] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0069] Comparative Example 6: Abecitabine Tablets formula: Preparation method: (1) Pretreatment: Crush the abecili raw material and pass it through a 100-mesh sieve for later use; pass the selected filler, disintegrant, binder, flow aid and lubricant through an 80-mesh sieve for later use.

[0070] (2) Stabilizer treatment: Weigh out the prescribed amount of sodium sapoxetine and glycine, mix them evenly and then dry grind them until the particle size is ≤5μm. Place the ground mixture in a vacuum drying oven and dry it at 50-55℃ until the moisture content is ≤1%. After drying, pass it through a 100-mesh sieve for later use.

[0071] (3) Granulation: Weigh the prescribed amount of abexilic acid, filler, 70% of the total amount of disintegrant and treated stabilizer and mix them evenly to obtain a mixed powder; add 5% hydroxypropyl methylcellulose solution by mass, stir to make a suitable soft material, granulate with an 18-mesh sieve to obtain wet granules.

[0072] (4) Drying: Place the wet granules in a forced-air drying oven and dry them at 60-65℃ until the moisture content of the granules is 2%-3% to obtain dry granules.

[0073] (5) Granulation: The dry granules are granulated using a 16-mesh sieve.

[0074] (6) Mixing: Add the remaining disintegrant, flow aid and lubricant to the granulated particles and mix for 15-20 minutes to make the mixture uniform.

[0075] (7) Tableting, coating with gastric-soluble film coating premix, coating weight gain 2%.

[0076] Commercially available preparation: National Drug Approval Number HJ20200068 Stability verification of abexili tablets Examples 1-9, Comparative Examples 1-6, and the commercially available abexicillin tablets were placed at 40℃±2℃ and relative humidity 25%±5% for 6 months. Samples were taken on day 0, at the end of month 1, at the end of month 3, and at the end of month 6. The abexicillin content was determined by high performance liquid chromatography (HPLC). A gradient elution mobile phase consisting of 0.1% phosphoric acid aqueous solution and acetonitrile was prepared, filtered through a filter membrane, and degassed by ultrasonication before use. Abexicillin reference standard was accurately weighed, dissolved and diluted with a suitable solvent to prepare a series of concentration solutions. The samples were processed simultaneously. A C18 column (250mm×4.6mm, 5μm) was used. Under the conditions of column temperature 30℃, flow rate 1.0mL / min, and specific detection wavelength, the reference standard and sample solutions were injected separately, and the chromatograms were recorded. The abexicillin content in the sample was calculated based on the peak area of ​​the two solutions using the external standard method, and the system suitability test requirements (resolution ≥1.5, peak area RSD ≤2.0%) had to be met.

[0077] Table 1. Abeciline content Table 1 shows that after 6 months of accelerated storage at 40℃±2℃ and 25%±5% relative humidity, the abexicillin content in Examples 1-9 remained above 99.05%. This indicates that the combination of saprazan sodium and glycine as synergistic stabilizers, along with the wet milling process to ≤5μm, effectively inhibits abexicillin degradation and significantly improves formulation stability. This invention, through the synergistic stabilization system of saprazan sodium and glycine and the particle size control process of wet milling, significantly improves the stability of abexicillin tablets, solving the problems of easy degradation and short shelf life in existing technologies. The data from the examples confirm that this formulation and process can maintain a high content retention rate for a long period under accelerated conditions, providing a better solution for the quality control of breast cancer treatment drugs.

Claims

1. An abexicillin tablet, characterized in that, The abecitabine tablets comprise the following components: 50-150 parts by weight of abecitabine, fillers, disintegrants, binders, flow aids, lubricants, and stabilizers; the stabilizer is a combination of 1-3 parts by weight of sodium sapoxetine and 2-5 parts by weight of glycine.

2. The abecitabine tablets according to claim 1, characterized in that, The filler is any combination of the following: Combination 1: 60-120 parts by weight of microcrystalline cellulose, 30-80 parts by weight of lactose; Combination 2: 50-100 parts by weight of mannitol, 40-80 parts by weight of pregelatinized starch; Combination 3: 45-100 parts by weight of dicalcium phosphate and 35-75 parts by weight of corn starch.

3. The abecitabine tablets according to claim 1, characterized in that, The disintegrant is any one of the following: 5-10 parts by weight of croscarmellose sodium, 6-12 parts by weight of carboxymethyl starch sodium, or 4-9 parts by weight of croscarmellose.

4. The abecitabine tablets according to claim 1, characterized in that, The adhesive is any one of the following: 2-5 parts by weight of hydroxypropyl methylcellulose, 3-6 parts by weight of povidone, and 5-8 parts by weight of starch paste with a mass fraction of 10%.

5. The abecitabine tablets according to claim 1, characterized in that, The flow aid is any one of the following: 1-3 parts by weight of micronized silica gel, 2-4 parts by weight of talc, and 1.5-3.5 parts by weight of sodium fumarate stearate.

6. The abecitabine tablets according to claim 1, characterized in that, The lubricant is any one of the following: 0.5-2 parts by weight of magnesium stearate, 1-3 parts by weight of zinc stearate, and 1.5-4 parts by weight of polyethylene glycol 6000.

7. A method for preparing the abecitabine tablets of claim 1, characterized in that, The preparation method includes the following steps: (1) Pretreatment; (2) Stabilizer treatment: weigh sodium sapoxetine and glycine, add purified water, mix and wet grind until the particle size is ≤5μm, vacuum dry, sieve and set aside; (3) Granulation; (4) Drying; (5) Granulation; (6) Total mixture; (7) Tableting.

8. The preparation method according to claim 7, characterized in that, The granulation step is as follows: take abexicillin, filler, 70% of the total amount of disintegrant, and the treated stabilizer, mix them evenly, add 4%-10% of the mass fraction of binder solution, stir, soften the material, granulate, and obtain wet granules.

9. The preparation method according to claim 8, characterized in that, The adhesive solution is: a hydroxypropyl methylcellulose solution with a mass fraction of 4%-6%, a povidone solution with a mass fraction of 5%-7%, or a starch paste solution with a mass fraction of 10%.

10. The preparation method according to claim 7, characterized in that, The abecicilline tablets obtained by compression are then coated with a film.

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