Hot-melt extrudate of tigorasan and preparation method of hot-melt extrudate

Abstract

The invention discloses a tigorasan hot-melt extrudate as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The tigorasan hot-melt extrudate comprises the following raw materials: tigorasan and a carrier material in a mass ratio of 1: 11-2: 3. The solid preparation prepared from the hot-melt extrudate has the characteristics of good stability and high dissolution rate.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a ticagrelor hot-melt extrudate, a preparation method thereof, and an application thereof. Background Art

[0002] Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) acid-suppressing drug. It is nearly insoluble in water and slightly soluble in organic solvents such as ethanol and dimethyl sulfoxide (DMSO). This poor water solubility significantly limits its bioavailability. Generally, reducing the particle size of the raw material is a common approach to increasing the dissolution rate and bioavailability of solid dosage forms. However, in practice, it has been found that after pulverization to a smaller particle size, this drug exhibits increased adsorption and severe agglomeration, posing significant challenges to the production process.

[0003] Therefore, developing a solid preparation of ticagrelor that can achieve a smooth process and improve bioavailability has become a difficult problem that needs to be solved urgently.

[0004] Researchers have conducted various studies and attempts to address this issue. For example, CN120131557A discloses a method for preparing a solid dispersion using amorphous ticlopidine and copovidone. However, this method requires the use of a large amount of organic solvents during the preparation process and is complex. It may also result in problems such as solvent residue and high solvent recovery costs. Furthermore, the resulting solid dispersion is usually only a powder and requires secondary granulation, resulting in a complex processing procedure. Summary of the Invention

[0005] The invention provides a tiglasan hot-melt extrudate. A solid preparation is prepared by using the hot-melt extrudate, which has the characteristics of good stability and high solubility.

[0006] To achieve the above object, the present invention is implemented through the following technical solutions:

[0007] A ticloplast hot-melt extrudate comprises the following raw materials in a mass ratio: ticloplast: carrier material of 1:11-2:3.

[0008] To address the low dissolution rate of ticagrelor, the inventors investigated various pharmaceutical approaches to improve the solubility and bioavailability of poorly soluble drugs. However, these approaches all presented challenges such as complex processes, difficult operations, and instability. For example, amorphous ticagrelor can be used as a raw material to prepare solid preparations, which offer the advantages of high solubility and rapid efficacy, but are unstable and have a short shelf life.

[0009] Finally, the present invention discovered through experiments that after the ticagrelor raw material and the carrier material are prepared into an amorphous hot-melt extrudate by hot-melt extrusion, each crystal form of ticagrelor can be converted into an amorphous state by hot-melt extrusion and uniformly dispersed in the carrier. This not only maintains the advantages of high solubility and rapid effect of the amorphous drug, but also inhibits recrystallization and maintains stability, thereby significantly improving the stability of the drug.

[0010] The aforementioned carrier materials are materials that exhibit good chemical inertness, thermal stability, good processing fluidity, and good thermoplasticity, and are suitable for hot-melt extrusion processes. Common polymeric carrier materials include povidones, copovidones, cellulose derivatives, and acrylic resins. Common non-polymeric carrier materials include waxes and lipids.

[0011] In some embodiments, the weight ratio of ticlopidine to the carrier material is 3:16 to 2:3, for example, 3:16, 1:2, or 2:3. The above raw materials ensure that the resulting hot-melt extrudate has good physical and chemical properties, facilitating the tableting process, and that the subsequently obtained tablets have good solubility.

[0012] In some embodiments, the raw material of the ticaglassen hot-melt extrudate further includes a plasticizer, and the mass ratio of the plasticizer to the carrier material is 1:22-5:27, preferably 5:88-5:27, and more preferably 1:16-5:27.

[0013] In some embodiments, the raw materials for the ticagrelor hot-melt extrudate further include a plasticizer, wherein the plasticizer is selected from one or more of a citrate plasticizer, a poloxamer, glycerol, a glyceryl monoacetate plasticizer, propylene glycol, sorbitol, a phthalate plasticizer, and polyethylene glycol. The polyethylene glycol has a number average molecular weight of 200-4000 Da, preferably 1000 Da. The phthalate plasticizer may be dioctyl phthalate, and the glyceryl monoacetate plasticizer may be glyceryl monoacetate.

[0014] In some embodiments, the raw materials of the ticaglassen hot-melt extrudate further include a plasticizer, and the mass percentage of the plasticizer in the hot-melt extrudate is 4-10%, preferably 5-10%.

[0015] In some embodiments, the tigolaxant is one or more of crystalline form A, crystalline form B, and amorphous form.

[0016] In some embodiments, the carrier material is selected from one or more of povidone and copovidone.

[0017] On the other hand, the present invention also discloses a method for preparing a ticaglassen hot melt extrudate, comprising the following steps:

[0018] (1) taking the raw materials of the above-mentioned tiglasan hot melt extrudate and mixing them uniformly to obtain a physical mixture;

[0019] (2) The physical mixture is subjected to hot melt extrusion to obtain a product.

[0020] The above-mentioned method for preparing the ticaglassen hot-melt extrudate does not require the use of organic solvents in the process flow, has the characteristics of continuous production and high production capacity, and the ticaglassen hot-melt extrudate prepared by this method has high stability and can be used in subsequent production without the need for secondary granulation processing.

[0021] In some embodiments of the above preparation method, in step (1), the raw material is first sieved, preferably, through a 40-100 mesh sieve.

[0022] In some embodiments of the above preparation method, in step (2), the physical mixture is hot-melt extruded using a twin-screw hot-melt extruder.

[0023] In some embodiments of the above preparation method, in step (2), the temperature of the hot melt extrusion is 120-220°C, preferably 150-190°C, and more preferably 150-170°C.

[0024] In some embodiments of the above preparation method, after step (2), a crushing step is further included. Preferably, the crushing step is to crush the strip-shaped hot-melt extrudate to a preset particle size, for example, 40-100 mesh or 60-100 mesh.

[0025] On the other hand, the present invention also discloses a ticagrelor preparation comprising the above-mentioned ticagrelor hot-melt extrudate and pharmaceutically acceptable excipients.

[0026] In some embodiments, the pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant, a glidant, and a lubricant.

[0027] In some embodiments, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, and calcium hydrogen phosphate.

[0028] In some embodiments, the content of the filler in the ticlopidine formulation is 15-35 wt %.For example, the ticlopidine formulation is a coated tablet, and the content of the filler in the ticlopidine coated tablet is 15-35 wt %.

[0029] In some embodiments, the filler is selected from a mixture of microcrystalline cellulose and mannitol. For example, the mass ratio of microcrystalline cellulose to mannitol can be 48-78:33-63 or 53-63:40-48.

[0030] In some embodiments, the disintegrant is selected from one or more of: cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and dry starch.

[0031] In some embodiments, the content of the disintegrant in the ticaglasan preparation is 2-6 wt %.For example, the ticaglasan preparation is a coated tablet, and the content of the disintegrant in the ticaglasan coated tablet is 2-6 wt %.

[0032] In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, and sodium stearyl fumarate.

[0033] In some embodiments, the glidant is selected from one or more of colloidal silicon dioxide and talc.

[0034] In some embodiments, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, and sodium stearyl fumarate.

[0035] In some embodiments, the ticaglan in the ticaglan formulation is amorphous.

[0036] In some embodiments, the ticagrelor preparation is a solid oral preparation, preferably a solid oral immediate-release preparation, and more preferably a gastric-soluble film-coated tablet.

[0037] On the other hand, the present invention also discloses a method for preparing the above-mentioned ticlopidine preparation, comprising the following steps: mixing the ticlopidine hot-melt extrudate with the pharmaceutically acceptable excipients and then tableting to obtain the ticlopidine preparation.

[0038] In some embodiments, the tableted preparation is further coated with a gastric-soluble film.

[0039] The above-mentioned “crystalline form A” refers to the crystalline form A of ticlopidine disclosed in CN 107207478 A.

[0040] The above-mentioned “crystalline form B” refers to the crystalline form B of ticlopidine disclosed in CN 117222643 A.

[0041] The above-mentioned “amorphous form” refers to the amorphous form of ticlopidine disclosed in CN 116715660 A.

[0042] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0043] The reagents and raw materials used in the present invention are commercially available.

[0044] The positive progress effect of the present invention is:

[0045] The present invention discloses a hot-melt extrudate of ticlopidine, which converts various crystalline forms of ticlopidine into an amorphous state through hot-melt extrusion and uniformly disperses the crystalline form in a carrier. This not only maintains the high solubility and rapid efficacy of the amorphous drug, but also inhibits recrystallization and maintains stability, significantly improving drug stability. Solid preparations prepared using this hot-melt extrudate exhibit excellent stability and high solubility.

[0046] Furthermore, the method for preparing the ticaglassen hot-melt extrudate does not require the use of organic solvents in its preparation process, and has the characteristics of continuous production and high production capacity. At the same time, the ticaglassen hot-melt extrudate prepared by the method has high stability and can be used in subsequent production without the need for secondary granulation processing. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 Dissolution curves of the hot-melt extruded rapid-release tablets of tigolaxan prepared in the Examples and Comparative Examples in an acetate buffer solution medium with a pH of 4.0.

[0048] Figure 2 The differential scanning calorimetry (DSC) spectra of the amorphous raw material, the biophysical mixture of ticagrelor prepared in Example 1, the hot melt extrudate, the tablet 0-month sample, and the tablet accelerated 6-month sample.

[0049] Figure 3 The differential scanning calorimetry (DSC) patterns of the Form B bulk drug substance, the biophysical mixture of Tegolacrila prepared in Example 2, the hot-melt extrudate, the tablet sample after 0 months, and the tablet sample after 6 months of accelerated storage.

[0050] Figure 4 The differential scanning calorimetry (DSC) spectra of the crystal form A bulk drug, the biophysical mixture of ticagrelor prepared in Example 5, the hot melt extrudate, the tablet 0-month sample, and the tablet accelerated 6-month sample.

[0051] Figure 5 The X-ray powder diffraction patterns of the amorphous bulk drug, the biophysical mixture of ticagrelor prepared in Example 1, the hot-melt extrudate, the tablet 0-month sample, and the tablet accelerated 6-month sample.

[0052] Figure 6The X-ray powder diffraction patterns of the Form B bulk drug, the biophysical mixture of Tegolacrilin prepared in Example 2, the hot-melt extrudate, the tablet sample at 0 months, and the tablet sample accelerated for 6 months.

[0053] Figure 7 The X-ray powder diffraction patterns of the crystal form A bulk drug, the biophysical mixture of ticagrelor prepared in Example 5, the hot melt extrudate, the tablet 0-month sample, and the tablet accelerated 6-month sample. DETAILED DESCRIPTION

[0054] The present invention is further illustrated by way of examples below, but the invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications. Methods and conditions where specific reagents or amounts are not specified in each example were performed using the same processes and conditions.

[0055] Example 1

[0056] A ticloplast tablet is prepared by the following method:

[0057] 1. Preparation of hot melt extrudate

[0058] (1) The amorphous active ingredient tigolaxane 15% (15 g), copovidone 80% (80 g), and polyethylene glycol 1000 5% (5 g) were sieved through a 40-mesh sieve, mixed evenly, and prepared into a physical mixture.

[0059] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 160°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0060] (3) The obtained strip-shaped extrudate is cooled and then crushed into 80 meshes using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 15%.

[0061] 2. Tablet Preparation

[0062] The prepared ticlopidine solid dispersion and various excipients were mixed according to the prescription in the following table and then tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0063] Table 1. Tablet prescription of Example 1

[0064]

[0065] Example 2

[0066] A ticloplast tablet is prepared by the following method:

[0067] 1. Preparation of hot melt extrudate

[0068] (1) The active ingredient of crystal form B, 15% (15 g) of tigolaxane, 80% (80 g) of copovidone, and 5% (5 g) of polyethylene glycol 1000 were sieved through a 40-mesh sieve respectively, mixed evenly, and prepared into a physical mixture.

[0069] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 160°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0070] (3) The obtained strip-shaped extrudate is cooled and then crushed into 80 meshes using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 15%.

[0071] 2. Tablet Preparation

[0072] The prepared ticlopidine solid dispersion and various excipients were mixed according to the prescription in the following table and then tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0073] Table 2. Tablet prescription of Example 2

[0074]

[0075] Example 3

[0076] A ticloplast tablet is prepared by the following method:

[0077] 1. Preparation of hot melt extrudate

[0078] (1) The active ingredient of crystal form B, 30% (30 g) of tigolaxane, 60% (60 g) of povidone, and 10% (10 g) of dioctyl phthalate were sieved through a 60-mesh sieve respectively, mixed evenly, and prepared into a physical mixture.

[0079] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 150°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0080] (3) The obtained strip-shaped extrudate is cooled and then crushed into 60 meshes using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 30%.

[0081] 2. Tablet Preparation

[0082] The prepared ticlopidine solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0083] Table 3. Tablet prescription of Example 3

[0084]

[0085] Example 4

[0086] A ticloplast tablet is prepared by the following method:

[0087] 1. Preparation of hot melt extrudate

[0088] (1) The active ingredient of crystal form B, 30% (30 g) of tigolaxane, 60% (60 g) of copovidone, and 10% (10 g) of glycerol monoacetate were sieved through an 80-mesh sieve respectively, mixed evenly, and prepared into a physical mixture.

[0089] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 170°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0090] (3) The prepared strip-shaped extrudate is cooled and then crushed into 80 mesh using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 30%.

[0091] 2. Tablet Preparation

[0092] The prepared ticlopidine solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0093] Table 4. Tablet prescription of Example 4

[0094]

[0095] Example 5

[0096] 1. Preparation of hot melt extrudate

[0097] A ticloplast tablet is prepared by the following method:

[0098] (1) The active ingredient of crystal form A, 15% (15 g) of tigolaxane, 80% (80 g) of copovidone, and 5% (5 g) of polyethylene glycol 1000 were sieved through a 100-mesh sieve, mixed evenly, and prepared into a physical mixture.

[0099] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 160°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0100] (3) The prepared strip-shaped extrudate is cooled and then crushed into 100 mesh using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 15%.

[0101] 2. Tablet Preparation

[0102] The prepared ticlopidine solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0103] Table 5. Tablet prescription of Example 5

[0104]

[0105] Example 6

[0106] A ticloplast tablet is prepared by the following method:

[0107] 1. Preparation of hot melt extrudate

[0108] (1) The amorphous active ingredient tigolaxan 36% (36 g), copovidone 54% (54 g), and polyethylene glycol 1000 10% (10 g) were sieved through a 40-mesh sieve and mixed evenly to prepare a physical mixture.

[0109] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 150°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0110] (3) The prepared strip-shaped extrudate is cooled and then crushed into 80 meshes using a crusher to obtain tigolasan hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasan in the hot-melt extruded granules (or powder) is 36%.

[0111] 2. Tablet Preparation

[0112] The prepared ticlopidine solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0113] Table 6. Tablet prescription of Example 6

[0114]

[0115] Example 7

[0116] A ticloplast tablet is prepared by the following method:

[0117] 1. Preparation of hot melt extrudate

[0118] (1) The amorphous active ingredient tigolaxan 25% (25 g) and copolyvidone 75% (75 g) were sieved through a 40-mesh sieve respectively, and mixed evenly to prepare a physical mixture.

[0119] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 190°C, and is transported to the feed port and then melt-mixed and extruded to obtain a strip-shaped extrudate.

[0120] (3) The prepared strip-shaped extrudate is cooled and then crushed into 80 meshes using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 25%.

[0121] 2. Tablet Preparation

[0122] The prepared tigolaxan solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0123] Table 7. Tablet prescription of Example 7

[0124]

[0125] Example 8

[0126] A ticloplast tablet is prepared by the following method:

[0127] 1. Preparation of hot melt extrudate

[0128] (1) The amorphous active ingredient tigolaxane 8% (8 g), copovidone 88% (88 g), and polyethylene glycol 1000 4% (4 g) were passed through a 40-mesh sieve and mixed evenly to prepare a physical mixture.

[0129] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 160°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0130] (3) The obtained strip-shaped extrudate is cooled and then crushed into 80 meshes using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 8%.

[0131] 2. Tablet Preparation

[0132] The prepared tigolaxan solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0133] Table 8. Tablet prescription of Example 8

[0134]

[0135] Comparative Example 1

[0136] A ticloplast tablet is prepared by the following method:

[0137] 1. Prescription

[0138] Table 9. Tablet prescription of Comparative Example 1

[0139]

[0140] 2. Tablet Preparation

[0141] According to the above prescription, the raw materials were mixed and tableted. After tableting, gastric-soluble film coating was performed according to Example 1 to prepare film-coated tablets with a specification of 50 mg.

[0142] Comparative Example 2

[0143] A ticloplast tablet is prepared by the following method:

[0144] 1. Preparation of hot melt extrudate

[0145] (1) Pass the amorphous active ingredient tigolaxan 50% (50 g), copovidone 40% (40 g), and polyethylene glycol 1000 10% (10 g) through a 40-mesh sieve and mix well to prepare a physical mixture.

[0146] (2) The physical mixture is added into the feeder of a twin-screw hot melt extruder, each section of which has been heated to 160°C, and transported to the feed port, where it is melt-mixed and extruded to obtain a strip-shaped extrudate.

[0147] (3) The obtained strip-shaped extrudate is cooled and then crushed into 80 meshes using a crusher to obtain tigolasen hot-melt extruded granules (or powder), wherein the content of the active ingredient tigolasen in the hot-melt extruded granules (or powder) is 50%.

[0148] 2. Tablet Preparation

[0149] The prepared tigolaxan solid dispersion and various excipients were mixed according to the prescription in the following table and tableted. After tableting, gastric-soluble film coating was applied to prepare film-coated tablets with a specification of 50 mg.

[0150] Table 10. Tablet prescription of comparative example 2

[0151]

[0152] Effect embodiment

[0153] 1. Appearance evaluation and preparation process evaluation

[0154] The appearance evaluation and tableting process of the hot-melt extrudates obtained in the above examples and comparative examples are described, and the results are shown in the table below.

[0155] Table 11. Extrudate appearance evaluation and preparation process description

[0156]

[0157] The above results show that the hot-melt extrudates prepared in Examples 1-6 and 8 have a good appearance, and the subsequent tableting process goes smoothly. The hot-melt extrudate in Example 7 is slightly fragile because no plasticizer is added; the extrudate prepared in Comparative Example 2 is easy to break due to the small amount of carrier added, and top cracking occurs during the tableting process.

[0158] 2. Dissolution test

[0159] According to the second method of the general rules of the fourth part of the Chinese Pharmacopoeia 2020, each embodiment and comparative example was subjected to an in vitro dissolution test, with 900ml of acetate buffer solution with a pH of 4.0 as the dissolution medium, a rotation speed of 50rpm, sampling points of 5min, 10min, 15min, 20min, 30min, 45min, 60min, 5ml was sampled, 3.5ml was filtered off, and the subsequent filtrate was taken as the test solution. It was determined by high performance liquid chromatography (general rules of the fourth part of the Chinese Pharmacopoeia 2020). The dissolution results are shown in the table below.

[0160] Table 12. Dissolution curve results

[0161]

[0162] The results show that the dissolution curves of the tablets of Examples 1-8 are compared with those of Comparative Example 1 ( Figure 1 ) As can be seen, the dissolution rate of various crystalline forms of tigrasen prepared into amorphous immediate-release formulations via hot-melt extrusion improved, particularly in Examples 1-6, where the improvement in dissolution rate was significant. Comparing Examples 1-6 with Example 7 demonstrates that the addition of a plasticizer significantly increases the dissolution rate. However, the results of Example 8 and Comparative Example 2 demonstrate that excessive or insufficient amounts of a carrier can adversely affect the dissolution rate.

[0163] 3. Stability study

[0164] Tigorapen tablets prepared in Examples 1, 2, and 5 were subjected to accelerated testing at 40°C and 75% CO2, packaged in PVDC aluminum-plastic packaging. Samples were tested at 3 and 6 months after the accelerated test, and related substances were detected according to high-performance liquid chromatography (HPLC) (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Differential scanning calorimetry and X-ray powder diffraction analysis were also performed on the raw materials and formulations. The differential scanning calorimetry method involved weighing 1-5 mg of sample into an aluminum pan, heating the sample under a nitrogen stream with a switching temperature of 220°C to 226°C and a scanning rate of 5°C / min. X-ray powder diffraction analysis employed a copper target, a tube voltage of 45 kV, a tube current of 40 mA, and a 2θ scanning angle of 0-55°.

[0165] The test results are shown in Table 13 below. The differential scanning calorimetry analysis and X-ray powder diffraction analysis are shown in Table 13 below. Figure 2-7 shown.

[0166] Table 13 Test results of related substances in stability samples

[0167]

[0168] From the above accelerated results, it can be seen that the tegrasen tablets prepared by the present invention have little change in related substances from 0 months to 6 months of accelerated storage, and have good stability. Figure 2-Figure 7 From the DSC and X-ray powder diffraction patterns of the medium tablets and the accelerated 6-month samples, it can be seen that no crystal transformation occurred in the 0-month and 6-month samples, indicating that the prepared ticagrelor tablets have good crystal stability.

Claims

1. A ticloplast hot melt extrudate, characterized in that: The method comprises the following raw materials in a mass ratio: tiglasan: carrier material of 1:11-2:

3.

2. The tegrasin hot melt extrudate according to claim 1, wherein The mass ratio of the tegrassen to the carrier material is 3:16 to 2:3, for example, 3:16, 1:2, or 2:

3.

3. The tiglasan hot melt extrudate according to claim 1, wherein The raw materials also include a plasticizer and meet one or more of the following conditions: (1) The mass ratio of the plasticizer to the carrier material is 1:22-5:27, preferably 5:88-5:27, and more preferably 1:16-5:27; (2) The plasticizer is selected from one or more of: citrate plasticizers, poloxamer, glycerol, glycerol monoacetate plasticizers, propylene glycol, sorbitol, phthalate plasticizers and polyethylene glycol; the number average molecular weight of the polyethylene glycol is 200-4000 Da, for example, 1000 Da; the phthalate plasticizer can be dioctyl phthalate; the glycerol monoacetate plasticizer can be glycerol monoacetate; (3) The mass percentage of the plasticizer in the hot melt extrudate is 4-10%, preferably 5-10%.

4. The tiglasan hot melt extrudate according to any one of claims 1 to 3, characterized in that Meet one or more of the following conditions: (1) The tigolaxant is one or more of crystalline form A, crystalline form B, and amorphous form; (2) The carrier material is selected from one or more of povidone and copovidone.

5. A method for preparing a ticloplast hot melt extrudate, characterized in that: The following steps are involved: (1) taking the raw materials of the tegrasin hot melt extrudate according to any one of claims 1 to 4, mixing them uniformly to obtain a physical mixture; (2) The physical mixture is subjected to hot melt extrusion to obtain a product.

6. The method for preparing the tiglasan hot melt extrudate according to claim 5, wherein: Meet one or more of the following conditions: 1) In step (1), the raw material is first sieved, preferably through a 40-100 mesh sieve; 2) In step (2), the physical mixture is hot-melt extruded using a twin-screw hot-melt extruder; 3) In step (2), the temperature of the hot melt extrusion is 120-220°C, preferably 150-190°C, more preferably 150-170°C; 4) After step (2), a crushing step is further included. Preferably, the crushing step is to crush the hot-melt extrudate into a preset particle size, for example, 40-100 mesh or 60-100 mesh.

7. A ticlopidine preparation, characterized in that: The invention comprises the ticaglasan hot-melt extrudate according to any one of claims 1 to 4 and pharmaceutically acceptable excipients.

8. The tigolaxant preparation according to claim 7, wherein: The pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant, a glidant and a lubricant; Preferably, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, and calcium hydrogen phosphate; and / or, the disintegrant is selected from: one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and dry starch; And / or, the glidant is selected from: one or more of colloidal silicon dioxide and talc; And / or, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, and sodium stearyl fumarate.

9. The ticagrelor preparation according to claim 7, wherein The tigolaxan in the tigolaxan preparation is amorphous.

10. The method for preparing the ticlopidine preparation according to any one of claims 7 to 9, characterized in that: The method comprises the following steps: mixing the tigolaxan hot melt extrudate with the pharmaceutically acceptable excipients and then tableting to obtain the product.

Images