A ticoraxen solid dispersion, its preparation method and its application

Abstract

This invention discloses a ticoraxen solid dispersion, its preparation method, and its applications. Specifically, this invention provides a ticoraxen solid dispersion comprising the active ingredient ticoraxen and a carrier; the carrier is one or more selected from copovidone, povidone, and hydroxypropyl methylcellulose; the weight ratio of ticoraxen to the carrier is 1:(1~6). The ticoraxen solid dispersion of this invention exhibits good release efficiency, and the ticoraxen tablets prepared from it dissolve rapidly and have good stability, making it suitable for industrial-scale production.

Description

[0001] This application claims priority to Chinese patent application 2025112538899, filed on September 3, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical preparations, and more specifically, to a ticoraxen solid dispersion, its preparation method, and its application. Background Technology

[0003] Tegoprazan, chemically named (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazolium-6-carboxamide, has the following chemical structural formula: .

[0004] As a competitive potassium acid blocker (P-CAB), it has a unique mechanism of action, with rapid onset of action, relieving symptoms quickly within 30 minutes; it also inhibits both resting and activated proton pumps, has a long half-life, and provides strong and long-lasting acid suppression; it does not require acid activation, and clinical trials have shown that the mucosal healing rate is as high as 98.9% after 8 weeks, which has a significant impact on improving patients' quality of life and provides a brand-new medication option.

[0005] Tiggorasen is a weakly basic drug, readily soluble in gastric acid (pH 1–3) (rapid release to exert its acid-suppressing effect), but its solubility is significantly reduced at the neutral pH of the intestine (e.g., 6.8). Tiggorasen exhibits high hydrophobicity and high permeability, classifying it as a BCS class II drug. Its solubility in water at 25°C is extremely low (potentially <0.1 mg / mL without pH adjustment). After oral administration, its slow dissolution rate in gastrointestinal fluids results in low oral bioavailability, severely impacting its efficacy and greatly limiting its clinical application. Therefore, improving the dissolution rate of tiggorasen in the gastrointestinal tract is the primary challenge to overcome in the research and development of its oral formulations.

[0006] Typically, when a drug exists in amorphous form or one or more crystalline forms, pharmaceutically important factors (such as solubility, dissolution characteristics, and bioavailability) can be altered by the drug form. If multiple types of crystalline forms are mixed at the end of the formulation process, the final drug properties may change. Therefore, it is very important to ensure the stability of the compound's crystal form throughout the entire formulation cycle.

[0007] Patent JP4481344B2 discloses an amorphous form of tigorasen. Amorphous solid dispersions are a typical supersaturated drug delivery system, which generates supersaturated concentrations by increasing drug solubility or dissolution rate to increase drug absorption. However, such supersaturated solutions are in a thermodynamically metastable state, and the drug is easily converted into a stable crystalline state in the gastrointestinal tract. When stability is given the highest priority, it is necessary to sacrifice solubility, while when solubility is considered first, stability may be sacrificed. Therefore, it is difficult to make a decision on how to simultaneously satisfy stability and solubility.

[0008] Current formulation technologies lack applications that can simultaneously satisfy the requirements of tigorasan stability and solubility, necessitating further research into tigorasan formulations. Summary of the Invention

[0009] In view of the lack of ticoraxan formulations in the prior art that simultaneously possess good stability and solubility, this invention provides a ticoraxan solid dispersion, a preparation method, and its applications. The ticoraxan solid dispersion of this invention exhibits good release efficiency, and the ticoraxan tablets prepared from it dissolve rapidly and have good stability, making it suitable for industrial-scale production.

[0010] The present invention provides a ticoraxan solid dispersion comprising the active ingredient ticoraxan and a carrier; the carrier is one or more selected from copovidone, povidone, hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, and poloxamer; the weight ratio of ticoraxan to the carrier is 1:(1~6).

[0011] In one embodiment, the weight ratio of ticoraxan to the carrier is 1:(1~4); preferably 1:(1~3); more preferably 1:(1.5~2.34).

[0012] In one embodiment, the ticoraxen is in an amorphous form or in crystal form B.

[0013] In one embodiment, when the carrier is a combination of copovidone and povidone, the weight ratio of the copovidone to povidone is 1:4 to 4:1; preferably 1:1 to 3:1; more preferably 2:1 to 2.5:1.

[0014] In one embodiment, when the carrier is a combination of copovidone and hydroxypropyl methylcellulose, the weight ratio of copovidone to hydroxypropyl methylcellulose is 1:4 to 2:1; preferably 1:1.

[0015] In one embodiment, when the carrier is a combination of povidone and hydroxypropyl methylcellulose, the weight ratio of povidone to hydroxypropyl methylcellulose is 1:4 to 2:1; preferably 1:1.

[0016] In one embodiment, the ticoraxan solid dispersion, by weight parts, comprises components from any of the following embodiments: Option 1: 10 parts amorphous ticoraxan and 40 parts copovidone; Option 2: 10 parts amorphous ticoraxan and 40 parts povidone; Option 3: 10 parts amorphous ticoraxan and 40 parts hydroxypropyl methylcellulose; Option 4: 10 parts amorphous ticoraxan, 20 parts copovidone, and 20 parts povidone; Option 5: 10 parts amorphous ticoraxan, 20 parts copovidone, and 20 parts hydroxypropyl methylcellulose; Option 6: 10 parts amorphous ticoraxan, 20 parts povidone, and 20 parts hydroxypropyl methylcellulose; Option 7: 10 parts amorphous ticoraxan, 20 parts copovidone, and 10 parts povidone; Option 8: 10 parts amorphous ticoraxan, 12 parts copovidone, and 3 parts povidone; Option 9: 10 parts amorphous ticoraxan, 30 parts copovidone, and 10 parts povidone; Option 10: 10 parts amorphous ticoraxan, 20 parts copovidone, and 10 parts povidone; Option 11: 15 parts amorphous ticoraxan, 25 parts copovidone, and 10 parts povidone; Option 12: 10 parts of tegorasen (crystal form B), 20 parts of copovidone, and 10 parts of povidone; Option 13: 10 parts of tegorasen (crystal form B), 12 parts of copovidone, and 3 parts of povidone; Option 14: 10 parts of tegorasen of crystal form B, 8 parts of copovidone, and 2 parts of povidone.

[0017] The present invention provides a method for preparing ticoraxen solid dispersion, which includes the following steps: mixing ticoraxen and the carrier in a solvent, and then drying, pulverizing and sieving to obtain the ticoraxen solid dispersion.

[0018] In one embodiment, the solvent is anhydrous ethanol, acetone, an aqueous solution of ethanol, or a mixture of ethanol and acetone.

[0019] Preferably, in the ethanol-water solution, the volume ratio of ethanol to water is (2~6):1; for example, the volume ratio of ethanol to water is 4:1.

[0020] Preferably, in the mixed solvent of ethanol and acetone, the volume ratio of ethanol to acetone is (2~6):1; for example, the volume ratio of ethanol to acetone is 4:1.

[0021] In one embodiment, the weight ratio of ticoraxan to the solvent is 1:(6~20); preferably 1:8~1:15, more preferably 1:10~1:12.

[0022] In one embodiment, the drying method is rotary evaporation or spray drying, preferably spray drying.

[0023] Preferably, when the solvent is an aqueous ethanol solution, the drying method is spray drying.

[0024] In one embodiment, the drying temperature is 30~100℃; for example, 50~80℃; preferably, when the drying method is rotary evaporation, the rotary evaporation temperature is 30~80℃; for example, 50~60℃.

[0025] The drying time is a conventional drying time in the art. In one embodiment, the drying time is 5 to 30 minutes, for example, 10 to 20 minutes.

[0026] In one embodiment, the pulverization method is mechanical pulverization.

[0027] In one embodiment, the sieve used for sieving has a mesh size of 80-120, for example, 100 mesh.

[0028] The present invention provides a ticoraxen solid dispersion, which is prepared by the preparation method described above.

[0029] The present invention provides a ticoraxen tablet comprising the ticoraxen solid dispersion, a filler, a disintegrant, and a lubricant.

[0030] In one embodiment, the filler is one or more of lactose, mannitol, and microcrystalline cellulose; preferably, it is a combination of lactose, microcrystalline cellulose, lactose, and microcrystalline cellulose, or a combination of mannitol and microcrystalline cellulose.

[0031] In one embodiment, the disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose, and calcium carboxymethyl cellulose; for example, the disintegrant is croscarmellose sodium, low-substituted hydroxypropyl cellulose, or croscarmellose.

[0032] In one embodiment, the lubricant is one or more of magnesium stearate, stearic fumaric acid, and calcium stearate; preferably magnesium stearate, stearic fumaric acid, or calcium stearate.

[0033] In one embodiment, the ticoraxan solid dispersion accounts for 15% to 50% of the weight of the ticoraxan tablets; preferably 20% to 40%; for example, 30%.

[0034] In one embodiment, the filler constitutes 49% to 77% of the weight of the ticorax tablets; preferably 64% to 75%; for example, 66%.

[0035] In one embodiment, the disintegrant accounts for 2% to 10% of the weight of the ticoraxate tablets; preferably 3% to 8%; for example, 5%.

[0036] In one embodiment, the lubricant accounts for 0.05% to 5% of the weight of the ticoraxate tablets; preferably 0.08% to 3%; for example, 1% to 2%.

[0037] In a given scheme, by weight, it consists of any of the following schemes: Option A: 160 parts of the ticoraxan solid dispersion of Option 4, 80 parts of mannitol, 116 parts of microcrystalline cellulose, 40 parts of croscarmellose sodium and 4 parts of magnesium stearate; Option B: 100 parts of the ticoraxan solid dispersion of Option 12, 264 parts of lactose, 32 parts of croscarmellose sodium and 4 parts of magnesium stearate; Option C: 80 parts of the ticoraxan solid dispersion of Option 4, 130 parts of lactose, 178 parts of microcrystalline cellulose, 8 parts of low-substituted hydroxypropyl cellulose and 4 parts of stearic fumaric acid; Scheme D: 80 parts of the tigoraxan solid dispersion of Scheme 12, 180 parts of mannitol, 120 parts of microcrystalline cellulose, 12 parts of crospovidone and 8 parts of calcium stearate; Scheme E: 120 parts of the ticoraxan solid dispersion of Scheme 4, 256 parts of microcrystalline cellulose, 20 parts of croscarmellose sodium, and 4 parts of magnesium stearate.

[0038] The present invention provides a method for preparing ticoraxen tablets, comprising the following steps: mixing the ticoraxen solid dispersion, the filler, the disintegrant, and the lubricant as described above, and compressing them into tablets to obtain the ticoraxen tablets.

[0039] In one embodiment, the mixing method is mechanical stirring; the mixing equipment is preferably a three-dimensional motion mixer.

[0040] In one embodiment, when the filler is a combination of microcrystalline cellulose and mannitol, a combination of lactose and microcrystalline cellulose, or microcrystalline cellulose, the preparation method includes the following steps: Step 1: Mix the ticoraxan solid dispersion and the filler to obtain a first mixture; Step 2: Mix the first mixture with the disintegrant to obtain a second mixture; Step 3: Mix the second mixture with the lubricant and compress it into tablets to obtain the ticoraxan tablets.

[0041] Preferably, the mixing time in step 1 is 5 to 15 minutes; for example, 10 minutes.

[0042] Preferably, the mixing time in step 2 is 5 to 15 minutes; for example, 10 minutes.

[0043] Preferably, the mixing time in step 3 is 1 to 6 minutes; for example, 3 minutes.

[0044] In one embodiment, when the filler is lactose, the preparation method includes the following steps: after the ticoraxan solid dispersion, the filler and the disintegrant are mixed for the first time, the lubricant is added for the second mixing and tableting, thereby obtaining the ticoraxan tablet.

[0045] Preferably, the first mixing time is 5 to 15 minutes; for example, 10 minutes.

[0046] Preferably, the second mixing time is 1 to 6 minutes; for example, 3 minutes.

[0047] In this invention, "tigorasen of crystal form B" refers to crystal form B of tigorasen as described in patent CN117222643A. Specifically, it exhibits characteristic peaks at 2θ values ​​of 9.5±0.2° and 14.1±0.2° in its X-ray powder diffraction pattern, and possesses 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°.

[0048] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0049] The reagents and raw materials used in this invention are all commercially available.

[0050] This invention has one or more of the following beneficial effects: (1) The tigorasen solid dispersion of the present invention exhibits good dissolution performance, with a release rate of >89% in 15 minutes. It can avoid the transformation of the crystal form of the drug during storage, maintain the high energy state of the drug, and avoid the decrease in solubility. Furthermore, the carrier interacts with the drug molecules through hydrogen bonds, reducing drug degradation (such as hydrolysis or oxidation).

[0051] (2) The tablets prepared by the solid dispersion of ticoraxen of the present invention have a fast dissolution rate, maintain the supersaturated state of the drug in the gastrointestinal tract, and prolong the absorption time. At the same time, the ticoraxen tablets of the present invention have good stability.

[0052] (3) The tigorasin solid dispersion of the present invention does not contain surfactants or other materials that may cause safety issues, and the solid dispersion can reduce the dosage, thereby reducing potential side effects (such as headache, gastrointestinal discomfort, etc.) caused by high doses and improving the safety of medication.

[0053] (4) Tigorafenib has a bitter taste, and existing formulations require coating to mask the bitter taste. The tigorafenib solid dispersion provided by the present invention can encapsulate drug molecules through a carrier, thereby improving oral compliance without the need for coating.

[0054] (5) The solid dispersion formulation of the present invention has a simple preparation method, is easy to operate, and has mature technology. It can be produced on a large scale and is of great significance to industrial production. Attached Figure Description

[0055] Figure 1 Examples 1 show the in vitro release curves of formulations 1-8 in different carrier materials for solid dispersions. Figure 2 The in vitro release curves of solid dispersions with different proportions of formulations 9-15 in Example 2 are shown. Figure 3 The in vitro release curves of solid dispersions of formulations 16-20 in Examples 3 with different solvents and their removal methods are shown. Figure 4 The in vitro release curves of tigoraxane tablets in Examples 4-8 and Comparative Examples 1-3 are shown. Figure 5 The in vitro release curves of formulation 9 in Example 2, Comparative Example 4, and Comparative Example 5 are shown. Figure 6 The in vitro release curves under accelerated and long-term conditions are shown in Example 4; Figure 7 The in vitro release curves under accelerated and long-term conditions are shown in Example 5; Figure 8 The powder diffraction pattern of the solid dispersion of Formula 5; Figure 9 The accelerated, long-term powder diffraction pattern for Example 4; Figure 10 DSC spectrum of solid dispersion of Formulation 5; Figure 11 This is the accelerated, long-term DSC spectrum of Example 4; Figure 12 The powder diffraction pattern of the solid dispersion of formulation 16; Figure 13The accelerated, long-term powder diffraction pattern for Example 5; Figure 14 DSC spectrum of Formulation 16 solid dispersion; Figure 15 This is the accelerated, long-term DSC spectrum of Example 5. Detailed Implementation

[0056] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0057] Among them, ticoraxen (amorphous) is prepared with reference to the amorphous form of ticoraxen disclosed in patent CN116715660A.

[0058] Example 1

[0059] Tigoraxan solid dispersions with different carriers were prepared according to the formulations in Table 1.

[0060] Table 1

[0061] Preparation process of prescriptions 1-8: The prescribed amount of ticoraxan and the carrier were dissolved in an ethanol-water solution (8:2) at a preset ratio and stirred until completely dissolved. The solvent was removed by spray drying, and the dried product was pulverized through an 80-mesh sieve to obtain a ticoraxan solid dispersion.

[0062] Example 2

[0063] Prepare tigoraxan solid dispersions in different proportions according to the formulations in Table 2.

[0064] Table 2

[0065] Preparation process of prescriptions 9-15: The prescribed amount of ticoraxan and the carrier were dissolved in an ethanol-water solution (8:2) at a preset ratio and stirred until completely dissolved. The solvent was removed by spray drying, and the dried product was pulverized through a 120-mesh sieve to obtain a ticoraxan solid dispersion.

[0066] Example 3

[0067] Tiegoxagen solid dispersions prepared according to different solvents and removal methods in Table 3

[0068] Table 3

[0069] Preparation process of prescriptions 16-19: Tigorafenib in crystal form B was prepared according to patent CN 117222643A.

[0070] The prescribed amount of ticoraxan and the carrier are dissolved in a solvent in a preset ratio and stirred until completely dissolved. The solvent is removed by spray drying, and after drying, the mixture is pulverized through a 100-sieve to obtain a ticoraxan solid dispersion.

[0071] Preparation process of prescription 20: The prescribed amount of ticoraxan and the carrier were dissolved in an ethanol-water solution (8:2) at a predetermined ratio and stirred until completely dissolved. The solvent was removed by rotary evaporation (50~60℃), dried, and then pulverized through a 100-sieve to obtain a ticoraxan solid dispersion.

[0072] Example 4

[0073] The raw materials and excipients for the preparation of ticoraxone tablets are shown in Table 4: Table 4

[0074] Preparation process: Weigh out the prescribed amounts of ticoraxan solid dispersion, microcrystalline cellulose, and mannitol and add them to a three-dimensional motion mixer. Mix for 10 minutes. Add the prescribed amount of croscarmellose sodium to the three-dimensional motion mixer and mix for 10 minutes. Add the prescribed amount of magnesium stearate and mix for 3 minutes. Compress into tablets to obtain the final product.

[0075] Example 5

[0076] The raw materials and excipients for the preparation of ticorazine tablets are as follows: Table 5

[0077] Preparation process: Weigh out the prescribed amounts of ticoraxan solid dispersion, lactose, and croscarmellose sodium and add them to a three-dimensional motion mixer. Mix for 10 minutes. Add the prescribed amount of magnesium stearate and mix for 3 minutes. Compress into tablets to obtain the final product.

[0078] Example 6

[0079] The raw materials and excipients for the preparation of ticorazine tablets are as follows: Table 6

[0080] Preparation process: Weigh out the prescribed amounts of ticoraxan solid dispersion, lactose, and microcrystalline cellulose and add them to a three-dimensional motion mixer. Mix for 10 minutes. Add the prescribed amount of low-substituted hydroxypropyl cellulose and mix for 10 minutes. Add the prescribed amount of stearic fumaric acid and mix for 3 minutes. Compress into tablets to obtain the final product.

[0081] Example 7

[0082] The raw materials and excipients for the preparation of ticorazine tablets are as follows: Table 7

[0083] Preparation process: Weigh out the prescribed amounts of ticoraxan solid dispersion, mannitol, and microcrystalline cellulose and add them to a three-dimensional motion mixer. Mix for 10 minutes. Add the prescribed amount of crospovidone and mix for 10 minutes. Add the prescribed amount of calcium stearate and mix for 3 minutes. Compress into tablets to obtain the final product.

[0084] Example 8

[0085] The raw materials and excipients for the preparation of ticorazine tablets are as follows: Table 8

[0086] Preparation process: Weigh out the prescribed amounts of ticoraxan solid dispersion and microcrystalline cellulose and add them to a three-dimensional motion mixer, mix for 10 min; add the prescribed amount of croscarmellose sodium and mix for 10 min; add the prescribed amount of magnesium stearate and mix for 3 min, then compress into tablets to obtain the final product.

[0087] Comparative Example 1

[0088] The raw materials and excipients for the preparation of ticorazine tablets are as follows: Table 9

[0089] Preparation process: Weigh out the prescribed amounts of ticoraxan solid dispersion, microcrystalline cellulose, and mannitol and add them to a three-dimensional motion mixer. Mix for 10 minutes. Add the prescribed amount of croscarmellose sodium and mix for 10 minutes. Add the prescribed amount of magnesium stearate and mix for 3 minutes. Compress into tablets to obtain the final product.

[0090] Comparative Example 2

[0091] The formulation of ticorapone tablets is prepared using a wet granulation process, and the raw and excipient composition is as follows: Table 10

[0092] Preparation process: Tigorafenib was pulverized to a particle size D90 (μm) ≤10. Lactose monohydrate and croscarmellose sodium were passed through an 80-mesh sieve. Tigorafenib, lactose monohydrate, croscarmellose sodium, and microcrystalline cellulose were weighed according to the prescription and added to a wet granulation mixer. The stirring speed was set to 200 rpm and the shearing speed to 600 rpm, and the mixture was mixed for 10 min. The stirring speed was set to 400 rpm and the shearing speed to 1000 rpm. A 5% hydroxypropyl methylcellulose aqueous solution was slowly sprayed in via atomization. The mixture was then fluidized bed dried (50-60℃), granulated through a 20-mesh sieve, mixed with magnesium stearate for 5 min, compressed into tablets, and coated with a 10% solids content film coating premix aqueous solution at a 3% weight gain.

[0093] Comparative Example 3

[0094] The formulation of ticorapone tablets is prepared using a direct compression process from powder. The raw and excipient composition is as follows: Table 11

[0095] Tigorafenib was pulverized with gas to a particle size D90 (μm) ≤10. Anhydrous lactose and sodium carboxymethyl starch were passed through an 80-mesh sieve, and microcrystalline cellulose was passed through a 40-mesh sieve. Tigorafenib, anhydrous lactose, and microcrystalline cellulose were weighed according to the prescription and added to a three-dimensional motion mixer and mixed for 10 min. Sodium carboxymethyl starch was added according to the prescription and mixed for another 10 min. Colloidal silica and magnesium stearate were added according to the prescription and mixed for 3 min. The mixture was then compressed into tablets and coated with a 10% solids content film coating premix aqueous solution at a 3% weight gain.

[0096] Comparative Example 4

[0097] Tiegoxagen solid dispersion was prepared according to patent CN 120131557A, with the following raw and auxiliary material composition: Table 12

[0098] Amorphous ticoraxan and copovidone were dissolved in anhydrous ethanol at a ratio of 1:0.5 and stirred until completely dissolved. The completely dissolved drug solution was added to a rotary evaporator (60°C) for rotary evaporation. The evaporated material was placed in a petri dish, weighed, and then placed in a vacuum drying oven at 45°C for drying to obtain the final product.

[0099] Comparative Example 5

[0100] The raw materials and auxiliary materials for the preparation of the solid dispersion are as follows: Table 13

[0101] The prescribed amount of amorphous ticoraxan and the carrier were dissolved in an ethanol-water solution (8:2) at a predetermined ratio and stirred until completely dissolved. The solvent was removed by spray drying, and the dried product was pulverized through a 120-mesh sieve to obtain a solid dispersion of ticoraxan.

[0102] Verification of Examples

[0103] Verification Experiment Example 1: Effect of different carriers on the release rate of ticorazine solid dispersion in Example 1

[0104] 0.200 g of ticoraxen solid dispersions obtained from formulations 1-8 in Examples 1 were weighed for powder dissolution tests to evaluate their release behavior. Following the method of General Chapter 0931, Section II, Part IV of the 2020 Chinese Pharmacopoeia, 900 mL of pH 4.0 solution was used as the dissolution medium at a rotation speed of 50 r / min. 10 mL of solution was taken at different time points, filtered through a microporous membrane, and the filtrate was used as the test solution, with the same volume of dissolution medium added simultaneously. The test solution and reference solution were injected separately into the liquid chromatograph under the chromatographic conditions described in the Assay section, and the chromatograms were recorded. The release rate per tablet was calculated based on peak area using the external standard method. The liquid chromatographic data and chromatograms are shown in Table 14 and... Figure 1 .

[0105] Table 14 Results of Tigraxen Solid Dispersion Release Rate Measurement (%)

[0106] The results show that formulations 1 to 8 of the present invention all exhibit good dissolution performance. Formulation 5, which uses a combination of copovidone and povidone, is slightly better than other carrier materials.

[0107] Verification Experiment Example 2: Effect of different proportions of components in Example 2 on the release rate of ticorazine solid dispersion.

[0108] 0.200 g of ticoraxen solid dispersions obtained from formulations 9-14 in Examples 2 were weighed for powder dissolution tests to evaluate their release behavior. The release rate determination method was the same as that in Verification Experiment Example 1 above. Liquid chromatography data and chromatograms are shown in Table 15 and... Figure 2 .

[0109] Table 15 Results of Tigrasen Solid Dispersion Release Rate Determination (%)

[0110] The results showed that formulations 9-14 of this invention all exhibited good dissolution performance, with a release rate of >85% at 15 minutes. Formulation 15 had a drug loading of up to 62.5%, but a slightly slower release rate. This was because the excessive drug loading prevented the carrier from completely encapsulating the drug, leaving it exposed on the surface and thus reducing the dissolution rate. Furthermore, the excess drug could potentially disrupt the continuous phase structure of the carrier, leading to a decrease in the carrier's dissolution rate. Formulations 11 and 12 had a drug loading of 20%, and their dissolution rates were essentially the same as those of formulations 9 and 13. The carrier material exhibited strong encapsulation of the drug, allowing for rapid dissolution and the formation of a supersaturated solution, significantly improving the drug's dissolution rate and extent. The ethanol-water (8:2) ratio used in formulations 9-13 ensured complete dissolution of the carrier and ticoraxan without recrystallization.

[0111] Verification Experiment Example 3: Effect of Different Solvents and Removal Methods on the Release Rate of Solid Dispersions (Example 3)

[0112] 0.200 g of ticoraxan solid dispersions obtained from formulations 16-20 in Examples 3 were weighed for powder dissolution tests to evaluate their release behavior. The release rate determination method was the same as that in Validation Experiment Example 1 above. Liquid chromatography data and chromatograms are shown in Table 16 and... Figure 3 .

[0113] Table 16 Results of Tigrasen Solid Dispersion Release Rate Determination (%)

[0114] The results show that formulations 16-20 of the present invention all exhibit good dissolution performance, and the solvents used in the formulations can completely dissolve ticoraxen. No drug recrystallization or carrier precipitation occurs during the preparation process. Formulation 20 uses a different solvent removal method than formulation 16. The spray drying method used in formulation 16 can quickly dry and form particles, with a shorter solvent removal time, making it easier to pulverize and sieve, and more suitable for industrial production. Considering the residual solvent in the solid dispersion and the solvent removal rate, the use of ethanol-water (8:2) in formulation 16 is more effective than other carrier materials, and spray drying may be more conducive to the formation of amorphous dispersions than rotary evaporation.

[0115] Verification Experiment Example 4: Tigris Acid Release Determination

[0116] The ticoraxan tablets obtained in Examples 4-8 and Comparative Examples 1-3 were subjected to tablet release assays according to the release assay method described in Validation Experiment Example 1 above. Liquid chromatography data and chromatograms are shown in Table 17 and... Figure 4 .

[0117] Table 17 Results of Tegoragen Tablet Release Rate Measurement (%)

[0118] The results showed that Examples 4-8 all exhibited good dissolution performance in pH 4.0 medium. Comparative Examples 1-3 released slowly in pH 4.0 medium. The slow release of Comparative Example 1 was due to the excessive drug loading, which prevented the carrier from completely encapsulating the drug, leaving the drug exposed on the surface. The release rate decreased due to aggregation. The slow release of Comparative Examples 2-3 was related to the solubility properties of the raw materials themselves. Tigrasen has high solubility in acidic media but low solubility in pH 4.0 and alkaline environments. Therefore, the solid dispersion showed better release rate than wet granulation and direct powder compression.

[0119] Verification Experiment Example 5: Determination of Tiegorasen Solid Dispersion Release Rate

[0120] 0.200 g of ticoraxan solid dispersions obtained from Formulation 9 in Example 2 and Comparative Examples 4 and 5 were weighed for powder dissolution tests to evaluate their release behavior. The release rate determination method was the same as that in Validation Example 1 above. Liquid chromatography data and chromatograms are shown in Table 18 and... Figure 5 .

[0121] Table 18 Results of Tigrasen Solid Dispersion Release Rate Measurement (%)

[0122] The results show that, compared with the ticorazine solid dispersion prepared by patent CN 120131557A (Comparative Example 4), formulation 9 of the present invention exhibits better dissolution performance. Furthermore, even within the proportions of the carrier materials (copovidone and povidone) used in the present invention, a decrease in the proportion of ticorazine significantly reduces the dissolution rate of the prepared solid dispersion.

[0123] Verification Experiment Example 6: Stability Study of Tigraxone Tablet Release Rate

[0124] The ticoraxan tablets obtained in Examples 4 and 5 were placed at 40℃ / 75%RH for 6 months and at 30℃ / 65%RH for 12 months, respectively, to investigate their release rates. Liquid chromatography data and chromatograms are shown in Table 19. Figure 6 , Figure 7 The release rate was determined using the same method as in the verification experiment example 1 described above.

[0125] Table 19 Results of stability release assay for ticoraxan tablets (%)

[0126] The above results indicate that the ticoraxan tablets prepared in this invention are relatively stable under conditions of 40℃ / 75%RH for 6 months and 30℃ / 65%RH for 12 months, with no significant change in release rate.

[0127] Verification Experiment Example 7: Stability Study of Related Substances and Enantiomers of Tigraxan Tablets.

[0128] The tegopraxin tablets obtained in Examples 4 and 5 were placed under strong light at 4500±500 lux for 14 days, under high temperature conditions of 60℃ and high humidity conditions of 90%RH for 1 month, under conditions of 40℃ / 75%RH for 6 months, and under conditions of 30℃ / 65%RH for 12 months, respectively, to investigate their related substances.

[0129] The high-performance liquid chromatography (HPLC) method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) was used. Octadecylsilane-bonded silica gel was used as the stationary phase (Ultimate XB-C18, 4.6 mm x 250 mm, 5 μm or equivalent column). The mobile phase was 0.05 mol / L ammonium dihydrogen phosphate solution (adjusted to pH 7.0 with ammonia). The detection wavelength was 220 nm; the column temperature was 30 °C; and the injection volume was 10 μL. Chromatograms were recorded. The HPLC data are shown in Table 20.

[0130] Table 20 Results of stability determination of related substances in ticoraxan tablets (%)

[0131] The results above show that the tegogastric tablets prepared by this invention have good stability. After 6 months at 40℃ / 75%RH, 12 months at 30℃ / 65%RH, 1 month at 60℃, 1 month at 90%RH, and 14 days under strong light at 4500±500 lux, the increase in related substances and enantiomers is not significant.

[0132] Verification Experiment Example 8: Investigation of the crystal form stability of ticorla green slices.

[0133] The ticoraxan tablets obtained in Examples 4 and 5 were placed at 40°C / 75%RH for 6 months and at 30°C / 65%RH for 12 months, respectively. Their crystal form was investigated using X-ray powder diffraction and differential scanning calorimetry. For X-ray powder diffraction, the starting and ending angles were set to 0–50°, the step size was set to 0.02, and the testing speed was 5° / min. The powder diffraction pattern of the solid dispersion of Formulation 5 is shown below. Figure 8 The accelerated and long-term powder diffraction patterns of Example 4 are shown below. Figure 9 The DSC chromatogram of the solid dispersion of Formulation 5 is shown below. Figure 10 Example 4, accelerated and long-term DSC spectra are shown below. Figure 11 The powder diffraction pattern of the solid dispersion of Formula 16 is shown in [reference needed]. Figure 12 The accelerated and long-term powder diffraction patterns of Example 5 are shown below. Figure 13 The DSC spectrum of the solid dispersion of Formulation 16 is shown below. Figure 14 Example 5 accelerated and long-term DSC spectra are shown below. Figure 15 .

[0134] As shown in the figure, under different stability test conditions, the tegoragen tablets prepared by this invention have good stability and can maintain their physicochemical properties without any change in crystallization characteristics, thus having the advantage of being able to be stored for a long time.

[0135] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A ticoraxen solid dispersion, characterized in that, It includes the active ingredient ticoraxen and a carrier; The carrier is one or more of copovidone, povidone and hydroxypropyl methylcellulose; The weight ratio of tegoragen to the carrier is 1:(1~6).

2. The ticoraxen solid dispersion as described in claim 1, characterized in that, It satisfies one or two of the following conditions: (1) The weight ratio of tegorasen to the carrier is 1:(1~4); preferably 1:(1~3); more preferably 1:(1.5~2.34). (2) The ticoraxen is in an amorphous form or crystal form B; The ticoraxen B crystal form has characteristic peaks at 2θ values ​​of 9.5±0.2° and 14.1±0.2° in its X-ray powder diffraction pattern, 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°.

3. The ticoraxen solid dispersion as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) When the carrier is a combination of copovidone and povidone, the weight ratio of copovidone to povidone is 1:4 to 4:1; preferably 1:1 to 3:1; more preferably 2:1 to 2.5:1; (2) When the carrier is a combination of copovidone and hydroxypropyl methylcellulose, the weight ratio of copovidone to hydroxypropyl methylcellulose is 1:4 to 2:1; preferably 1:

1. (3) When the carrier is a combination of povidone and hydroxypropyl methylcellulose, the weight ratio of povidone and hydroxypropyl methylcellulose is 1:4 to 2:1; preferably 1:

1.

4. The ticoraxen solid dispersion according to any one of claims 1 to 3, characterized in that, The ticoraxan solid dispersion, by weight, comprises components from any of the following schemes: Option 1: 10 parts amorphous ticoraxan and 40 parts copovidone; Option 2: 10 parts amorphous ticoraxan and 40 parts povidone; Option 3: 10 parts amorphous ticoraxan and 40 parts hydroxypropyl methylcellulose; Option 4: 10 parts amorphous ticoraxan, 20 parts copovidone, and 20 parts povidone; Option 5: 10 parts amorphous ticoraxan, 20 parts copovidone, and 20 parts hydroxypropyl methylcellulose; Option 6: 10 parts amorphous ticoraxan, 20 parts povidone, and 20 parts hydroxypropyl methylcellulose; Option 7: 10 parts amorphous ticoraxan, 20 parts copovidone, and 10 parts povidone; Option 8: 10 parts amorphous ticoraxan, 12 parts copovidone, and 3 parts povidone; Option 9: 10 parts amorphous ticoraxan, 30 parts copovidone, and 10 parts povidone; Option 10: 10 parts amorphous ticoraxan, 20 parts copovidone, and 10 parts povidone; Option 11: 15 parts amorphous ticoraxan, 25 parts copovidone, and 10 parts povidone; Option 12: 10 parts of tegorasen (crystal form B), 20 parts of copovidone, and 10 parts of povidone; Option 13: 10 parts of tegorasen (crystal form B), 12 parts of copovidone, and 3 parts of povidone; Option 14: 10 parts of tegorasen of crystal form B, 8 parts of copovidone, and 2 parts of povidone.

5. A method for preparing the ticoraxan solid dispersion as described in any one of claims 1 to 4, characterized in that, It includes the following steps: mixing the ticoraxan and the carrier in a solvent, drying, pulverizing and sieving to obtain the ticoraxan solid dispersion.

6. The method for preparing the ticoraxan solid dispersion as described in claim 5, characterized in that, It satisfies one or more of the following conditions: (1) The solvent is anhydrous ethanol, acetone, aqueous ethanol solution, or a mixed solution of ethanol and acetone; Preferably, in the ethanol-water solution, the volume ratio of ethanol to water is (2~6):1; for example, the volume ratio of ethanol to water is 4:

1. Preferably, in the mixed solvent of ethanol and acetone, the volume ratio of ethanol to acetone is (2~6):1; for example, the volume ratio of ethanol to acetone is 4:

1. (2) The weight ratio of ticoraxan to the solvent is 1:(6~20); preferably 1:8~1:15, more preferably 1:10~1:12; (3) The drying method is rotary evaporation or spray drying, preferably spray drying; for example, when the solvent is an aqueous ethanol solution, the drying method is spray drying; (4) The drying temperature is 30~100℃; for example, 50~80℃; preferably, when the drying method is rotary evaporation, the rotary evaporation temperature is 30~80℃; for example, 50~60℃; (5) The drying time is 5~30 min, for example 10~20 min; (6) The pulverization method is mechanical pulverization; (7) The sieve used for sieving is 80~120 mesh, for example 100 mesh.

7. A ticoraxen tablet comprising the ticoraxen solid dispersion as described in any one of claims 1 to 4, a filler, a disintegrant, and a lubricant; Preferably, it satisfies one or more of the following conditions: (1) The filler is one or more of lactose, mannitol and microcrystalline cellulose, preferably a combination of lactose, microcrystalline cellulose, lactose and microcrystalline cellulose, or a combination of mannitol and microcrystalline cellulose; (2) The disintegrant is one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose and calcium carboxymethyl cellulose; (3) The lubricant is one or more of magnesium stearate, stearic fumaric acid and calcium stearate; (4) The tigorazine solid dispersion accounts for 15% to 50% of the weight of the tigorazine tablets; preferably 20% to 40%; for example, 30%; (5) The filler accounts for 49% to 77% of the weight of the ticorapone tablets; preferably 64% to 75%; for example, 66%; (6) The disintegrant accounts for 2% to 10% of the weight of the ticoraxate tablets; preferably 3% to 8%; for example, 5%; (7) The lubricant accounts for 0.05% to 5% of the weight of ticorax tablets; preferably 0.08% to 3%; for example 1% to 2%.

8. The tigorapa tablets as described in claim 7, characterized in that, It consists of any of the following schemes: Scheme A: 160 parts of ticoraxan solid dispersion as described in Scheme 4 of claim 4, 80 parts of mannitol, 116 parts of microcrystalline cellulose, 40 parts of croscarmellose sodium and 4 parts of magnesium stearate; Option B: 100 parts of ticoraxan solid dispersion as described in Option 12 of claim 4, 264 parts of lactose, 32 parts of croscarmellose sodium and 4 parts of magnesium stearate; Scheme C: 80 parts of ticoraxan solid dispersion as described in Scheme 4 of claim 4, 130 parts of lactose, 178 parts of microcrystalline cellulose, 8 parts of low-substituted hydroxypropyl cellulose and 4 parts of stearic fumaric acid; Scheme D: 80 parts of ticoraxan solid dispersion as described in Scheme 12 of claim 4, 180 parts of mannitol, 120 parts of microcrystalline cellulose, 12 parts of crospovidone and 8 parts of calcium stearate; Scheme E: 120 parts of ticoraxan solid dispersion as described in Scheme 4 of claim 4, 256 parts of microcrystalline cellulose, 20 parts of croscarmellose sodium, and 4 parts of magnesium stearate.

9. A method for preparing ticoraxen tablets as described in claim 7 or 8, characterized in that, The process includes the following steps: mixing the ticoraxen solid dispersion, the filler, the disintegrant, and the lubricant, and compressing them into tablets to obtain the ticoraxen tablets.

10. The method for preparing ticoraxant tablets as described in claim 9, characterized in that, It satisfies one or more of the following conditions: (1) The mixing method is mechanical stirring; (2) When the filler is a combination of microcrystalline cellulose and mannitol, a combination of lactose and microcrystalline cellulose, or microcrystalline cellulose, the preparation method includes the following steps: Step 1: Mix the ticoraxan solid dispersion and the filler to obtain a first mixture; Step 2: Mix the first mixture with the disintegrant to obtain a second mixture; Step 3: Mix the second mixture with the lubricant and compress it into tablets to obtain the ticoraxan tablets; Preferably, the mixing time in step 1 is 5 to 15 minutes; for example, 10 minutes. Preferably, the mixing time in step 2 is 5 to 15 minutes; for example, 10 minutes. Preferably, the mixing time in step 3 is 1 to 6 minutes; for example, 3 minutes. (3) When the filler is lactose, the preparation method includes the following steps: after mixing the ticoraxan solid dispersion, the filler and the disintegrant for the first time, the lubricant is added for the second mixing and tableting to obtain the ticoraxan tablet; Preferably, the first mixing time is 5 to 15 minutes; for example, 10 minutes. Preferably, the second mixing time is 1 to 6 minutes; for example, 3 minutes.

11. The ticoraxen solid dispersion as described in claim 1, characterized in that, The carrier further includes one or more of copovidone, polyethylene glycol, hydroxypropyl methylcellulose acetate succinate, and poloxamer; the weight ratio of ticoraxan to the carrier is 1:(1~6).

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