Method for preparing tigorazan tablets through fluidized bed granulation method

Abstract

The invention discloses a method for preparing a tigorazan tablet by a fluidized bed granulation method. The method comprises the following steps: 1) preparing a pharmaceutical active component tigorazan and an adhesive into a granulation solution, and granulating the granulation solution and a filler in a fluidized bed to obtain granules; the invention relates to a preparation method of a tigorazan tablet, which comprises the following steps: 1) preparing granules, 2) carrying out dry granulation on the granules, and 3) tabletting the granules obtained after dry granulation in the step 2) and optional pharmaceutically acceptable auxiliary materials so as to obtain the tigorazan tablet. The tablet prepared by a fluidized bed preparation method can solve the problem of easy crystal transformation of amorphous raw materials, and is simple and convenient in process, good in stability and more suitable for commercialized mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing tigolacine tablets by fluidized bed granulation method. Background Art

[0002] Tigolacine tablets are drugs used to treat reflux esophagitis, belonging to drugs that inhibit gastric acid secretion, and can prevent excessive gastric acid from refluxing into the esophagus and causing damage to the esophagus. Tigolacine reversibly inhibits the activity of H⁺,K⁺-ATPase in a potassium ion competitive manner, can stay in the gastric parietal cells to inhibit gastric acid production, and can effectively inhibit the formation of upper gastrointestinal mucosal damage. In April 2022, the first-class chemical new drug tigolacine tablets (trade name: Taixinzan®) of Shandong Luoxin Pharmaceutical Co., Ltd. was approved for marketing. Currently, this drug has been approved for three indications, namely reflux esophagitis, duodenal ulcer, and in combination with appropriate antibiotics to eradicate Helicobacter pylori. The research results show that in Chinese patients infected with Helicobacter pylori, the Hp eradication rate of the bismuth quadruple therapy containing tigolacine (93.5%) is superior to that of the bismuth quadruple therapy containing esomeprazole (86.4%), and it has good efficacy in different sensitive and drug-resistant populations, and at the same time has good safety and tolerance. At the same time, tigolacine is more convenient to take, not affected by eating time and metabolic genotype, bringing a more convenient choice for patients with a busy work and fast-paced life.

[0003] The original patent CN110121333A discloses the composition and preparation process of tigolacine tablets, but the preparation process of this tablet is a wet preparation process. If amorphous tigolacine is used as the raw material, it will be unstable and there will be a phenomenon of crystal transformation. After crystal transformation, it will further affect the dissolution rate of the tablets, and qualified tigolacine tablets cannot be made. However, due to the advantages of high solubility and good bioavailability of amorphous tigolacine, it is necessary to develop a preparation process suitable for amorphous tigolacine tablets.

[0004] Patent CN116715660A discloses an amorphous form of tigolacine. It is mentioned in the text that this amorphous form has good solubility, high bioavailability, and excellent stability under light protection conditions, but has a certain hygroscopicity; Patent CN116621821A discloses an amorphous form of tigolacine and its solid dispersion, but neither of these two amorphous form patents discloses the formulation and process for preparing tablets using amorphous tigolacine. Summary of the Invention

[0005] Object of the Invention: The object of the present invention is to provide a method for preparing tigolacine tablets by fluidized bed granulation method and the prepared tigolacine tablets. The tablets prepared by the fluidized bed preparation method can solve the problem of easy crystal transformation of amorphous raw materials, and the process is simple and convenient, with good stability, and is more suitable for large-scale commercial production. Technical Solution

[0006] The present invention provides a method for preparing tigolaciclib tablets by fluidized bed granulation method, which comprises the following steps: 1) Preparing a granulation solution from the drug active ingredient tigolaciclib and a binder, and granulating the granulation solution with a filler in a fluidized bed to obtain granules; 2) Dry screening the granules; 3) Tableting the granules obtained after dry screening in step 2) and optionally present pharmaceutically acceptable excipients to obtain tigolaciclib tablets.

[0007] Furthermore, the tigolaciclib is amorphous.

[0008] Furthermore, the granulation solution in step 1) is a solution in which tigolaciclib and copovidone are dissolved in absolute ethanol at a ratio of 1:0.5. The function of copovidone is to ensure the stability of the crystal form of the active pharmaceutical ingredient in the preparation.

[0009] Furthermore, step 1) further includes a disintegrant.

[0010] Furthermore, the excipients in step 3) include a filler, a disintegrant, a diluent, a glidant and a lubricant.

[0011] Furthermore, the filler is selected from at least one of the group consisting of lactose, microcrystalline cellulose, mannitol and colloidal silicon dioxide. The filler in step 1) can dilute the proportion of copovidone in the formulation and improve the disintegration of the self-developed preparation.

[0012] Furthermore, the disintegrant is one or more selected from sodium croscarmellose, crospovidone or sodium carboxymethyl starch.

[0013] Furthermore, the lubricant is selected from at least one of the group consisting of: stearic acid, magnesium stearate, calcium stearate, sodium benzoate and sodium stearyl fumarate.

[0014] Furthermore, the diluent is sodium chloride or potassium chloride.

[0015] Furthermore, during the granulation process in step 1), the material temperature is controlled to be maintained at 30-45 °C. When the temperature is lower than 30 °C, adhesion will occur; when it is higher than 45 °C, more fines will be generated, affecting the particle state.

[0016] Furthermore, the dry screening in step 2) is to pass the dry granules after granulation in step 1) through a sieve with a mesh size of 0.8-2.1 mm.

[0017] Further, the dry granules obtained in step 2) are mixed with a filler, a disintegrant, a diluent, and a glidant, and then a lubricant is added and mixed again, followed by tabletting. The tabletting hardness is 6 - 12 kg. The tabletting hardness affects the dissolution curve of the drug. Controlling the tabletting hardness within the range of 6 - 12 kg can ensure that the cumulative dissolution rate within 15 min is greater than 85% in the pH 4.0 acetate buffer medium, which is similar to that of the reference preparation. Beneficial effects

[0018] Using amorphous tigolacic as the raw material and through the fluidized bed preparation process, copovidone in the granulating liquid can be evenly distributed on the surface of tigolacic, avoiding the crystal transformation of the amorphous form, obtaining tablets with qualified hardness, and maintaining consistent dissolution with the reference preparation; by adjusting the addition method of the disintegrant and the dosage of the diluent, the dissolution rate of the tablets can be increased.

[0019] If the wet granulation method is used with amorphous tigolacic as the raw material, it will lead to too fast dissolution, inconsistent with the reference preparation, and at the same time, it will also cause crystal transformation of the amorphous form; if the direct powder compression process is used, special treatment of the API is required (such as preparing solid dispersions through spray drying, hot melt extrusion process, etc.), the process is more complex, the yield will be reduced, and it cannot meet the commercialization requirements.

[0020] In addition, fluidized bed granulation is carried out by spraying liquid, and the API in the solution can be evenly distributed on the surface of microcrystalline cellulose and other excipients. For APIs with different properties (such as differences in particle size, etc.) provided by different suppliers, granules with similar good compressibility can still be obtained, which is a more robust process technology. And the process is simple and convenient, with good stability, and is more suitable for large-scale commercial production. Description of the drawings

[0021] Figure 1 It is the XRD pattern of amorphous tigolacic in Example 1 of the present invention.

[0022] Figure 2 It is the dissolution trend chart of Example 2 in the pH 4.0 acetate buffer medium.

[0023] Figure 3 It is the crystal form stability chart of Example 2.

[0024] Figure 4 It is the dissolution trend chart of Example 3 in the pH 4.0 acetate buffer medium.

[0025] Figure 5 It is the crystal form stability chart of Example 3.

[0026] Figure 6 It is the dissolution trend chart of Example 4 in the pH 4.0 acetate buffer medium.

[0027] Figure 7 It is the dissolution trend graph of Example 5 in the pH 4.0 acetate buffer medium. Detailed implementation manners

[0028] To deepen the understanding of the present invention, the present invention will be further described in detail below in combination with examples and drawings. The examples are only used to explain the present invention and do not constitute a limitation on the protection scope of the present invention.

[0029] The reference preparation, drug raw materials and excipients used herein are all commercially available, except that the amorphous tigolacic raw material is self-made.

[0030] Evaluation methods for physicochemical properties Hardness: It is tested using a hardness tester. During the test, the tablet stands between two pressing plates, and pressure is applied along the diameter direction of the tablet. The pressure required to break it is its hardness.

[0031] Friability: Using a friability tester, weigh 10 tablets or 6.5 g (if the weight of 10 tablets does not reach 6.5 g) and put them into the rotating drum. The rotating drum rotates at a speed of 25 rpm for 4 min. The tablets are driven by the baffle to scrape up and fall, etc., and are subjected to friction, impact, etc. as the rotating drum rotates. After rotation is completed, take out the tablets and weigh them. Calculate the friability according to the following formula: Friability = (initial tablet weight - final tablet weight) * 100% / initial tablet weight Disintegration time: Refer to the "Disintegration Time Limit Inspection Method" <0921> in the fourth part of the Chinese Pharmacopoeia 2015 edition, and use a disintegration tester for determination.

[0032] Dissolution: It is determined by referring to the second method (paddle method) in the fourth part of the Chinese Pharmacopoeia 2020 edition. The rotation speed of the dissolution apparatus is 50 rpm. The dissolution medium is pH 4.0 acetate buffer. Samples are taken at the set time points and detected by HPLC method.

[0033] Among them, the HPLC analysis parameters are as follows:

[0034] Example 1 Preparation of amorphous tigolacic The preparation of the amorphous raw material of tigolacic described in the present invention refers to the preparation method disclosed in Patent CN116715660A.

[0035] The specific preparation method is as follows: Add 50 g of tigecalson sample (the preparation method refers to patent CN101341149A) and 150 mL of methanol into a 250 mL single-necked flask, and externally heat to dissolve clearly at 65 °C. Add 1.5 L of purified water into a 2 L three-necked flask with a dropping funnel hollow plug, start stirring, and cool down to 0 - 10 °C. Then transfer the above methanol solution dissolved with tigecalson sample to the dropping funnel while it is still hot, and rinse with a small amount of methanol; slowly drip it into the water, keeping the internal temperature not exceeding 10 °C. After dripping, continue to stir and crystallize at this temperature for 1 - 2 h, filter, and wash with a small amount of purified water. The wet filter cake is vacuum dried at 30 - 35 °C until the water content is not more than 10%, and then heated to 40 - 45 °C for vacuum drying until the water content is not more than 3.0% to obtain 45 g of amorphous tigecalson, with a yield of 90%. Test XRD as Figure 1 shown.

[0036] Example 2 Preparation of tigecalson tablets by conventional process - wet granulation preparation process Prepare tigecalson tablets according to the wet granulation preparation process and the original research prescription of the original research patent CN110121333A, respectively select crystalline form A and the amorphous tigecalson prepared in Example 1 as raw materials for preparation, and investigate the dissolution curve and crystal form stability of tigecalson tablets in pH 4.0 acetate buffer medium.

[0037] The preparation process is as follows: 1) Premixing: Put the prescribed amount of tigecalson, mannitol, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium into a wet mixing granulator, and mix at a stirring speed of 3 r / s and a cutter speed of 15 r / s for 5 min; 2) Wet granulation: Prepare a binder of 6% hydroxypropyl cellulose in the prescribed amount, add it to the premix, and perform wet granulation at a stirring speed of 3 r / s, a cutter speed of 15 r / s, and a granulation time of 3 min; 3) Drying: Place the wet granules in a fluidized bed and dry at an inlet air temperature of 60 - 80 °C until the water content < 2.0%; 4) Total mixing: Put the dry granules, colloidal silica, and magnesium stearate into a square conical hopper mixer and mix at 12 rpm for 15 min; 5) Tableting: Use a Φ8.0 mm round shallow concave punch, and control the hardness at 6 - 12 kg; 6) Coating: The coating weight gain is 3.0%.

[0038] The formulation of the preparation is shown in Table 1, Table 1 Formulation of tigecalson tablets involved in Example 2

[0039] The results show that: (1) Dissolution behavior: Select the preparation method consistent with that of the reference preparation. ① For the amorphous preparation 2-2 and the A-crystal preparation 2-1 in the pH 4.0 acetate buffer medium, under the conditions of paddle method at 50 rpm and 900 ml / cup, the dissolution rate at 15 min is greater than 85% for both, and both are rapidly dissolved, as Figure 2 shown.

[0040] (2) Crystal form stability of the active pharmaceutical ingredient in the preparation: For the tigolacine tablets prepared with amorphous active pharmaceutical ingredient and wet granulation preparation process, after being placed in an aluminum-plastic packaging device under accelerated conditions (40 °C, 75% RH) for 2 months, the crystal form of the active pharmaceutical ingredient in the self-developed preparation undergoes crystal transformation (the characteristic peak with the highest intensity of crystal form A at 17.2 appears), and the crystal form is unstable, as Figure 3 shown.

[0041] Example 3 Preparation of tigolacine tablets by fluidized bed preparation process 1) Weighing of raw and auxiliary materials: Weigh the internally added prescription amount of tigolacine, anhydrous ethanol, copovidone, microcrystalline cellulose, and croscarmellose sodium for standby; 2) Pretreatment of auxiliary materials: Mechanically crush sodium chloride through a 40-mesh sieve, and pass colloidal silicon dioxide through a 40-mesh sieve for standby; 3) Fluidized bed granulation: ① Preparation of granulation liquid: Add an appropriate amount of anhydrous ethanol, and while stirring, add the prescription amount of tigolacine, stir until the active pharmaceutical ingredient dissolves and becomes clear, and then add the prescription amount of copovidone until completely dissolved; ② Granulation: After preheating the empty pot, mix microcrystalline cellulose and croscarmellose sodium and put them into the DPL-II fluidized bed for granulation. Set the fan frequency to 200 - 250 m3 / h. When the material temperature reaches above 40 °C, start spraying the liquid for granulation, and control the material temperature to remain at 30 - 45 °C. After spraying the liquid, dry for more than 45 min, and control the weight loss not to exceed 3.5%; Generally, the liquid supply speed is proportional to the particle size. Under a certain spray pressure, as the speed increases, the particle size of the atomized droplets of the binder also increases. If the flow rate is too high, it is easy to cause the wet particles to aggregate into clusters and cause bed collapse; on the contrary, when the speed is too low, there will be more fine powder, nozzle blockage, and the granulation time will be prolonged. Therefore, when the liquid supply speed is 5 - 17 pm, the prepared particles will basically not form clusters and will not block the nozzle, and the dissolution curves in the pH 4.0 acetate buffer are similar to those of the reference preparation.

[0042] 4) Screening: Screen the dried granules after granulation through a 1-mm sieve; 5) Total mixing: Place the dried granules from step 4), mannitol, croscarmellose sodium, sodium chloride, colloidal silicon dioxide, and magnesium stearate in a three-dimensional mixer and mix for 10 min; 5) Tabletting: Oval punch of Φ14.0*7.5mm, hardness range: 6 - 12 kg.

[0043] 6) Coating: Weight gain of 2% - 4%.

[0044] Table 2 Prescription of Tegoprazan Tablets in Example 3

[0045] The results showed that: (1) The dissolution behavior was as Figure 4 shown: When the amount of cross-linked carboxymethylcellulose sodium added internally was 15 mg / tablet, the amount of cross-linked carboxymethylcellulose sodium added externally increased to 21 mg / tablet, and the amount of sodium chloride was 15 mg / tablet, the cumulative dissolution of Example 3 in pH 4.0 medium at 15 min was greater than 85%, and the dissolution curve was similar to that of the reference preparation. Disintegration time limit: Completely disintegrated in about 1 min.

[0046] (2) Crystal form stability of the active pharmaceutical ingredient in the preparation: For the tegoprazan tablets prepared by using amorphous active pharmaceutical ingredient and fluidized bed granulation preparation process, after being placed in an aluminum-plastic package under accelerated conditions (40 °C, 75% RH) for 2 months, the crystal form of the active pharmaceutical ingredient in the self-developed preparation did not undergo crystal transformation (the characteristic peak of crystal form A did not appear), and the crystal form was stable, see Figure 5 .

[0047] Example 4 Preparation of Tegoprazan Tablets by Fluidized Bed Preparation Process It was the same as the preparation process of Example 3, except that the addition method of the disintegrant cross-linked carboxymethylcellulose sodium was changed from internal and external addition in Example 3 to all external addition. The specific prescription amounts added are shown in Table 3, and the results were as Figure 6 shown. In the pH 4.0 dissolution medium, compared with the reference preparation (Tegocare), the dissolution rate was slower at 5 - 15 min.

[0048] Table 3 Prescription of Tegoprazan Tablets in Example 4

[0049] Example 5 Preparation of Tegoprazan Tablets by Fluidized Bed Preparation Process Compared with Example 3, the content of sodium chloride was changed to 10 mg / tablet, and the contents of other components were the same, and the process conditions were the same. Taking the dissolution curve and related substances of the prepared tablets in pH 4.0 acetate buffer solution as indexes, the specific results were as Figure 7 shown: When the amount of sodium chloride in the self-developed preparation was 10 mg / tablet, the cumulative dissolution at 15 min in pH 4.0 medium did not exceed 85%; when the amount of sodium chloride was 15 mg / tablet, the cumulative dissolution of the self-developed preparation in pH 4.0 medium at 15 min was greater than 85%, and the dissolution curve was similar to that of the reference preparation (Tegocare).

[0050] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing tegras tablets by fluidized bed granulation, characterized in that: The steps include: 1) preparing a granulation solution of the active pharmaceutical ingredient tegrasin and a binder and granulating the solution with a filler in a fluidized bed to obtain granules; 2) dry granulating the granules; 3) tabletting the granules obtained after dry granulation in step 2) and any pharmaceutically acceptable excipients, thereby obtaining tegrasin tablets.

2. The method according to claim 1, characterized in that The teigolan is in an amorphous form.

3. The method according to claim 1, characterized in that The granulation solution in step 1) is a solution in which tigolasan and copovidone are dissolved in anhydrous ethanol at a ratio of 1:0.

5.

4. The method according to claim 1, characterized in that: The step 1) further comprises a disintegrant.

5. The method according to claim 1, characterized in that The auxiliary materials in step 3) include fillers, disintegrants, diluents, glidants and lubricants.

6. The method according to claim 4 or 5, characterized in that: The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or sodium starch glycolate.

7. The method according to claim 5, characterized in that The diluent is sodium chloride or potassium chloride.

8. The method according to any one of claims 1 to 7, characterized in that: During the granulation process in step 1), the material temperature is controlled to be maintained at 30-45°C.

9. The method according to claim 1, characterized in that: The dry granulation in step 2) is to pass the dry granules granulated in step 1) through a 0.8-2.1 mm sieve.

10. The method according to claim 1, characterized in that The dry granules obtained in step 2) are mixed with a filler, a disintegrant, a diluent, and a glidant, and then a lubricant is added and mixed again, and tableting is performed. The tableting hardness is 6-12 kg.

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