A stable ticoraxan amorphous solid dosage form and its preparation method

Abstract

This invention relates to a solid dosage form of ticoraxen in amorphous form and a method for preparing the above-mentioned solid dosage form by direct powder compression or dry granulation. Addressing the technical challenge of crystal transformation induced by hygrothermal stress in wet granulation / coating processes of ticoraxen in amorphous form, this invention innovatively employs a non-aqueous preparation process, significantly shortening the process cycle, reducing production costs, and facilitating commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to a solid dosage form composition of ticoraxone amorphous crystals and a method for preparing the above solid dosage form by direct powder pressing or dry granulation. Background Technology

[0002] Tegoprazan, 4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, has the following chemical structural formula: Formula (I)

[0003] Tigorasine is a competitive potassium acid blocker (P-CAB), and its solid dosage form is currently approved for marketing in China and South Korea. This drug has a unique mechanism of action, with rapid onset of action, providing symptom relief within 30 minutes; it simultaneously inhibits both resting and activated proton pumps, has a long half-life, and provides strong and sustained acid suppression; it does not require acid activation, and clinical trials have demonstrated a 98.9% mucosal healing rate after 8 weeks, offering significant advantages such as effective control of nocturnal acid breakthrough. This groundbreaking innovation will have a significant impact on improving patients' quality of life and provide new medication options.

[0004] Patent JP4481344B2 discloses ticoraxan and its preparation method, which uses gradient elution column chromatography with a mixed solution of ethyl acetate and methanol to purify the residue and obtain a white solid in a non-crystalline form.

[0005] Patent CN107207478B discloses a crystalline form A of tigorafenib, whose X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1±0.2°, 10.0±0.2°, 12.6±0.2°, 14.9±0.2°, 15.6±0.2°, 16.5±0.2°, 17.2±0.2°, 19.6±0.2°, 23.1±0.2°, 24.2±0.2°, 28.1±0.2°, 30.2±0.2°, and 31.6±0.2°.

[0006] Patent CN117222643A discloses a crystalline form B of tigorafenib, whose X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.5±0.2° and 14.1±0.2°, and has one or more of the following characteristic peaks: 15.4±0.2°, 16.2±0.2°, 19.1±0.2°, 20.6±0.2°, 21.8±0.2°, 22.8±0.2°, 25.1±0.2°, 28.4±0.2°, and 32.2±0.2°.

[0007] Patent CN107207478B discloses the difference in the stability process between amorphous and crystalline form A of ticoraxan. Although amorphous form has superior solubility, which is beneficial to improving bioavailability, its disadvantage in stability causes drawbacks in its application. This invention effectively solves the problem of stability of amorphous formulations. Summary of the Invention

[0008] Technical Problem: The purpose of this invention is to provide a new tigorazine formulation composition and its preparation technology, which avoids stability problems in crystal form, dissolution, and related aspects caused by the damp heat effect, and provides a more efficient and low-cost approach for product commercialization.

[0009] Technical solution: The first aspect of the present invention provides a ticoraxen formulation composition.

[0010] Specifically, a tigorazine formulation composition includes an active ingredient and an inactive ingredient, the inactive ingredient including fillers, disintegrants, binders and lubricants.

[0011] In some embodiments, the filler is selected from at least one of the following excipients: starch, microcrystalline cellulose, mannitol, lactose, calcium phosphate, preferably microcrystalline cellulose and mannitol.

[0012] In some embodiments, the disintegrant is selected from natural starch, pregelatinized starch, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, preferably crospovidone sodium carboxymethyl cellulose.

[0013] In some embodiments, the adhesive is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, methylcellulose, ethylcellulose, with hydroxypropyl cellulose being preferred.

[0014] In some embodiments, the lubricant is selected from magnesium stearate, calcium stearate, sodium stearate fumarate, talc, stearic acid, with magnesium stearate being preferred.

[0015] In some embodiments, this document provides an oral pharmaceutical formulation comprising: (a) Tigrazine: 25% (b) Microcrystalline cellulose: 0-65% (c) Mannitol: 0-65% (d) Cross-linked sodium carboxymethyl cellulose: 1-5% (e) Hydroxypropyl cellulose: 2-10% (f) Magnesium stearate: 0.5-1.5%.

[0016] In some embodiments, the fillers disclosed herein contain microcrystalline cellulose and cross-linked polyvinylpyrrolidone in a weight ratio of 1:1 to 4:1, preferably 1:1 to 3:1, and more preferably 1:1 to 2:1.

[0017] On the other hand, this invention provides two methods for preparing ticoraxine tablets. The preparation process of this invention is simple and controllable, and easy to commercialize.

[0018] The present invention provides a method for preparing ticorapone tablets using a direct powder compression process. The specific preparation method includes the following steps: (a) Micronization reduces the particle size (D90) of amorphous ticorlan raw material to within the range of 50-200 μm, and it passes through a 40-100 mesh sieve; (b) Mix the active pharmaceutical ingredient obtained in step (a) with the filler, binder and disintegrant for 5-15 minutes; (c) Add lubricant and continue mixing for 2-5 minutes; (d) The mixed powder is directly compressed into tablets containing ticoraxen without going through wet granulation or fluidized bed granulation steps.

[0019] Another method for preparing ticorapone tablets according to the present invention employs a dry granulation process, and the specific preparation method includes the following steps: (a) Micronization reduces the particle size (D90) of amorphous ticorlan raw material to within the range of 50-200 μm, and it passes through a 40-100 mesh sieve; (b) Dry mix the active pharmaceutical ingredient obtained in step (a) with the filler, binder, partial disintegrant and partial lubricant for 5-15 minutes; (c) The mixture obtained in step (b) is granulated into particles of suitable size using a dry granulation machine; (d) Add the remaining disintegrant and mix for 5-10 minutes, then add the remaining lubricant and continue mixing for 2-5 minutes; (e) The mixed granules are directly compressed into tablets without going through wet granulation or fluidized bed granulation steps.

[0020] In some implementations, the preparation process controls the ambient humidity to below 60%RH.

[0021] In some implementation schemes, the prepared core has a hardness of 70~150N and a brittleness of no more than 1.0%.

[0022] Beneficial effects of the present invention The ticoraxen tablets of the present invention are prepared into stable tablets from amorphous ticoraxen through a simple formulation and preparation process, enabling commercial production, transportation and storage. Detailed Implementation

[0023] This disclosure is further described in detail through the following embodiments and experimental examples. These embodiments and experimental examples are for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0024] Example 1

[0025] Preparation process of Example 1: (a) Pretreatment: Amorphous ticorazine, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, and croscarmellose sodium were passed through a 40-mesh sieve; (b) Premixing: Mix the sieved raw and auxiliary materials at a speed of 17.5 rpm for 10 min; (c) Total mixing: Mix the premixed material with magnesium stearate for 5 minutes; (d) Tableting: 8.5mm round die is used to control the hardness of tablets to 70~150N.

[0026] Example 2

[0027] Preparation process of Example 2: (a) Pretreatment: Amorphous ticorazine, microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, and sodium carboxymethyl starch were passed through a 40-mesh sieve; (b) Premixing: Mix the sieved raw and auxiliary materials at a speed of 17.5 rpm for 10 min; (c) Blending: Mix the premixed material with stearic acid for 5 minutes; (d) Tableting: 8.5mm round die is used to control the hardness of tablets to 70~150N.

[0028] Example 3

[0029] (a) Pretreatment: Amorphous ticorazine, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, and 1 / 2 of the prescribed amount of croscarmellose sodium are passed through a 40-mesh sieve; (b) Premixing: Mix the sieved raw and auxiliary materials at a speed of 17.5 rpm for 10 min; (c) Dry granulation: The premixed material is pressed into thin sheets using a dry granulator and then crushed into suitable granules. (d) Total mixing: Mix the premixed material with the remaining cross-linked sodium carboxymethyl cellulose for 5 min, then add magnesium stearate and mix for 5 min; (e) Tableting: Tableting is performed using an 8.5mm round die to control the hardness of tablets to 70~150N.

[0030] Comparative Example 1 Formula and process for tigoraxanthin tablets using wet granulation

[0031] Preparation process of Comparative Example 1: (a) Mixing: Amorphous ticorazine, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, and croscarmellose sodium are mixed in a wet granulator; (b) Granulation: The mixed material is sprayed with purified water to form granules, and then dried and granulated. (c) Mixing: Mix the granulated material with magnesium stearate for 5 minutes; (d) Tableting: 8.5mm round die is used to control the hardness of tablets to 70~150N.

[0032] Comparative Example 2 Formula and manufacturing process of tegoragen tablets with coating

[0033] Comparative Example 2 Preparation Process: (a) Mixing: Amorphous ticorazine, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, and croscarmellose sodium are mixed in a wet granulator; (b) Granulation: The mixed material is sprayed with purified water to form granules, and then dried and granulated. (c) Mixing: Mix the granulated material with magnesium stearate for 5 minutes; (d) Tableting: Using an 8.5mm circular die, tablets with a hardness of 70~150N are controlled; (e) Coating: The above tablets are coated with a gastrointestinal coating premix, resulting in a 3% increase in weight.

[0034] Comparative Example 3 Formulation and process of fluidized bed granulation of tegorapa tablets

[0035] Preparation process of Comparative Example 3: (a) Mixing: Amorphous ticorazine, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, and croscarmellose sodium are mixed in a fluidized bed; (b) Granulation: The mixed material is spray-granulated with purified water, dried, and sized. (c) Mixing: Mix the granulated material with magnesium stearate for 5 minutes; (d) Tableting: 8.5mm round die is used to control the hardness of tablets to 70~150N.

[0036] Comparison of dissolution curves of tegora tablets Experimental materials: 50mg tigoraxane tablets reference formulation (Tasinza), and self-developed tigoraxane tablets prepared in Examples 1 and 2; Dissolution conditions: pH 4.5 acetate buffer, paddle motion at 50 rpm, medium volume 900 ml, temperature: 37.0 ± 0.5℃ The dissolution results are shown in Table 1 below.

[0037] As can be seen from the table above, Examples 1, 2 and 3 have good similarity to the reference formulation in the distinguishing medium.

[0038] Stability comparison of tegora tablets Determination of related substances and their contents Table 2 shows the comparison of related substances in the packaged samples of Example 1, Comparative Example 1, and Reference Preparation under accelerated conditions (40℃ / 75%RH) for 6 months. The results above show that, under accelerated conditions (40°C / 75%RH) for 6 months, the growth trends of related substances and their contents in Examples 1, 3, and the reference formulation are similar. Comparative Example 1 is slightly worse than Examples 1, 3, and the reference formulation in terms of related substances. This indicates that the direct powder compression process of Example 1 and the dry granulation process of Example 3 are superior to the wet granulation process of Comparative Example 1 in terms of product stability. Crystal stability study Example 1 and Comparative Example 1 were placed under influencing conditions (high temperature 60℃, high humidity 92.5%RH, 40℃ & 75%RH) for one month, and their crystal stability was examined by XRPD. Example 1 showed no new characteristic peaks after one month under the influencing conditions, maintaining good crystal stability. Comparative Example 1 showed a change in characteristic angles under high temperature conditions after one month under the influencing conditions, indicating crystal instability. Comparative Examples 2 and 3 showed new characteristic angles during the preparation process, indicating crystal transformation. This demonstrates that humidity and heat during the process significantly alter the crystal stability of the products.

[0039] Figure 1 XRPD crystal structure diagram of the sample prepared in Example 1 on day 0. Figure 2 XRPD crystal structure diagram of the sample prepared in Example 1 after 30 days, which is affected by factors. Figure 3 XRPD crystal form of sample prepared for Comparative Example 1 on day 0 Figure 4 XRPD crystal structure diagram of the sample prepared for Comparative Example 1 after 30 days, showing the influencing factors. Figure 5XRPD crystal structure diagram of the 0-day sample prepared for Comparative Example 2 Figure 6 The image shows the XRPD crystal form of the 0-day sample prepared for Comparative Example 3.

Claims

1. A process for the preparation of a solid formulation of tegoprazan characterized in that The process comprises the following steps: (a) mixing the raw material with the filler, the binder, the disintegrant; (b) adding the lubricant and continuing mixing; (c) compressing the mixture obtained in step b into tablets containing tegoprazan without going through the steps of wet granulation, fluidized bed granulation.

2. A process for the preparation of a solid formulation of tegoprazan characterized in that The process comprises the following steps: (a) dry granulating the raw material alone or dry granulating the raw material together with one or more excipients selected from the group consisting of the filler, the binder, the disintegrant, the lubricant; (b) mixing the granules obtained in step a with the remaining excipients; (c) compressing the mixture obtained in step b into tablets containing tegoprazan without going through the steps of wet granulation, fluidized bed granulation.

3. The method of claim 1 or claim 2, wherein: The filler consists of any one or two of microcrystalline cellulose, mannitol, lactose, starch, and when two excipients are selected together as the filler, the weight ratio of the two is (1:10) to (10:1).

4. The method of claim 3, wherein: The amount of each filler is 10-65% of the total weight of the preparation.

5. The method of claim 1 or claim 2, wherein: The disintegrant consists of any one or two of croscarmellose sodium, sodium starch glycolate, crospovidone, and the amount is 1-5% of the total weight of the preparation.

6. The method of claim 1 or claim 2, wherein: The binder consists of any one or two of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, and the amount is 2-10% of the total weight of the preparation.

7. The method of claim 1 or claim 2, wherein: The lubricant consists of any one or two of magnesium stearate, sodium stearyl fumarate, talc, and the amount is 2-10% of the total weight of the preparation.

8. The method of claim 1 and claim 2, wherein: The hardness of the compressed tablets is 70-150 N.

9. The method of claim 1 and claim 2, wherein: The control of the environment during the preparation process is that the humidity is below 60% RH.

10. The tablet containing tegoprazan according to claim 1 and claim 2, wherein: The tablets contain the following components (by weight percentage): (a) tegoprazan: 25% (b) microcrystalline cellulose: 10-65% (c) mannitol: 10-65% (d) croscarmellose sodium: 1-5% (e) hydroxypropyl cellulose: 2-10% (f) magnesium stearate: 0.5-1.5%.

Images