Trelagliptin succinate solid preparation and preparation method thereof

Abstract

The present invention discloses a solid preparation of trelagliptin succinate and a preparation method thereof, wherein the method comprises the following steps: preparing materials according to the following components in mass parts: trelagliptin succinate, 50-80 parts; filler, 5-20 parts; binder, 1-10 parts; disintegrant, 3-15 parts; lubricant, 0-5 parts; trelagliptin succinate, filler, and binder are mixed in proportion to obtain a premixed powder; then water is added to the premixed powder to granulate to obtain drug-containing particles; the drug-containing particles are dried in a fluidized bed to obtain dried drug-containing particles; disintegrants and lubricants are added to the dried drug-containing particles, and mixed uniformly to obtain total mixed particles; and then pressed into tablets to obtain trelagliptin tablet cores. The method is simple and feasible, and the dissolution of the obtained solid preparation meets the requirements of the rapid-release agent, and the tablet weight variability is small and the stability is good.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a solid preparation of trelagliptin succinate and a preparation method thereof. Background Art

[0002] Trelagliptin is a long-acting dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Pharmaceutical Company Limited of Japan. It is one of the only two long-acting hypoglycemic drugs for type 2 diabetes. Trelagliptin selectively and continuously inhibits the inactivation of glucagon-like peptide-1 (GLP-1) and diabetes-dependent insulinotropic polypeptide (GIP) by DPP-IV, increases the concentration of GLP-1 and GIP in the blood, and increases insulin secretion dependent on blood sugar levels, thereby controlling blood sugar levels in diabetic patients.

[0003] Takeda Pharmaceutical Co., Ltd. submitted a new drug application for trelagliptin tablets to the Ministry of Health, Labor and Welfare (MHLW) of Japan on March 7, 2014, and was approved for marketing by MHLW on March 26, 2015 for the treatment of type 2 diabetes. The product name is The specifications are 100mg and 50mg. This product has a long half-life and can be administered once a week.

[0004] Patent CN201380041306.5 mainly protects the formulation composition technology of tablets containing trelagliptin or its salts. Because the content of trelagliptin in the unit preparation is relatively large (content>50%), the tablet preparation process is greatly affected by the raw material drug. After research, it was found that the raw material drug of this product (stable crystal form A crystal form) is needle-shaped crystal with poor fluidity, and it is easy to have the risk of astringency during the tableting process. When preparing tablets according to the patent prescription, sticking or astringency is very likely to occur during the tableting process, affecting the product production process. In severe cases, the tablets cannot be compressed into shape. In addition, mannitol itself has a certain risk of astringency, which will increase the risk of astringency during the tableting process of trelagliptin tablets. Therefore, the formulation composition technology of this patent has poor applicability.

[0005] Patent CN201610596858.8 adopts a dry direct tableting method, which is relatively simple and easy to operate. However, due to the high content of trelagliptin or its succinate in the unit preparation for clinical application (content>50%), the raw material is needle-shaped crystals with a relatively loose density (loose density <0.2g / cm 3), poor fluidity, and the raw materials tend to spontaneously aggregate into large particles or large agglomerates. Using the ordinary dry direct tableting method, the fluidity of the mixed materials is poor, the raw and auxiliary materials are prone to uneven mixing, the compressibility and formability of the materials during the tableting process are poor, and problems such as astringency and stickiness are prone to occur, resulting in an unsightly tablet appearance and a large difference in tablet weight.

[0006] Patent CN201610143310.8 A solid preparation of trelagliptin succinate and a preparation method thereof, wherein trelagliptin succinate, a diluent, and a disintegrant are mixed evenly, purified water is added for wet granulation, a lubricant is added, the mixture is mixed, and tableting is performed. Trelagliptin succinate is unstable under hot and humid conditions, and will produce impurities under high temperature conditions after granulation with microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose. Therefore, in this method, mannitol, pregelatinized starch, cross-linked polyvinylpyrrolidone, and magnesium stearate are selected as excipients that will not produce impurities with the raw materials at high temperatures.

[0007] The existing preparation method of trelagliptin solid preparation adopts dry direct tableting, dry granulation and wet granulation process. Since the raw material is in the form of needle-shaped crystals, the density is relatively loose (loose density <0.2g / cm3), the fluidity is poor, and it is easy to spontaneously aggregate into large particles or large agglomerates. If the direct tableting process is adopted, the problem of uneven mixing of raw and auxiliary materials is easy to occur, resulting in the uniformity and content of the product not meeting the quality standards; since the content of trelagliptin in the unit preparation is relatively large (content>50%), and the raw material is in the form of needle-shaped crystals, the self-adhesion is poor, if the dry granulation method is adopted, the rolling and forming properties of the raw and auxiliary materials are poor, resulting in the instability of the dry granulation process, large batch differences, and cumbersome production process operations. If wet granulation is adopted, the problems of uneven material mixing, poor fluidity and poor material forming properties in the dry granulation process can be solved, but since succinic acid trelagliptin is unstable under hot and humid conditions, it is easy to react with the auxiliary materials in the wet granulation to produce impurities, and the stability of the solid preparation is poor. Summary of the invention

[0008] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing a solid preparation of trelagliptin succinate to solve the problem of stability of raw materials and auxiliary materials after granulation in wet granulation.

[0009] In order to solve the above technical problems, the technical solution of the present invention is as follows:

[0010] The present invention provides a method for preparing a solid preparation of trelagliptin succinate, comprising the following steps:

[0011] Step A: Prepare the materials according to the following components in parts by weight: 50-80 parts of trelagliptin succinate; 5-20 parts of filler; 1-10 parts of binder; 3-15 parts of disintegrant; 0-5 parts of lubricant;

[0012] Step B: mixing trelagliptin succinate, a filler and a binder in proportion to obtain a premixed powder; then adding water to the premixed powder to granulate to obtain drug-containing granules;

[0013] Step C: drying the drug-containing particles in a fluidized bed to obtain dried drug-containing particles;

[0014] Step D: adding a disintegrant and a lubricant to the dried drug-containing granules, mixing them evenly to obtain a total mixed granule; and then pressing them into tablets to obtain trelagliptin tablet cores.

[0015] Furthermore, the method further comprises coating the trelagliptin tablet core to obtain trelagliptin coated tablets.

[0016] Furthermore, the components of the solid preparation do not contain sugar alcohol.

[0017] Furthermore, the drying temperature of the fluidized bed is 40-45°C.

[0018] Furthermore, the trelagliptin succinate is in crystal form A, and the particle size D90 is less than 200 μm.

[0019] Furthermore, the filler is selected from one of microcrystalline cellulose, pregelatinized starch, corn starch and lactose, preferably microcrystalline cellulose, lactose or pregelatinized starch, and more preferably microcrystalline cellulose.

[0020] Furthermore, the binder is one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, sodium carboxymethyl cellulose, povidone, sucrose, and starch slurry, preferably hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, and more preferably hydroxypropyl cellulose.

[0021] The hydroxypropyl cellulose mentioned above complies with the provisions of Part IV of the Chinese Pharmacopoeia (2015 Edition) for pharmaceutical excipients, i.e., the hydroxypropyl cellulose is a partially substituted 2-hydroxypropyl ether cellulose. Calculated on a dry basis, the content of hydroxypropoxy (-OCH2CHOHCH3) should be

[0022] Furthermore, the disintegrant is one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone, preferably cross-linked sodium carboxymethyl cellulose.

[0023] The low-substituted hydroxypropyl cellulose mentioned above complies with the provisions of Part IV of the Chinese Pharmacopoeia (2015 Edition) for pharmaceutical excipients, i.e., the low-substituted hydroxypropyl cellulose is low-substituted 2-hydroxypropyl ether cellulose.

[0024] Furthermore, the lubricant is one of stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, talc, and silicon dioxide, preferably sodium stearyl fumarate.

[0025] The present invention also provides a solid preparation of trelagliptin succinate obtained by the preparation method of the solid preparation of trelagliptin succinate.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1) In this method, after the trelagliptin succinate, the filler and the binder are wet-granulated, a disintegrant and a lubricant are added, thereby avoiding the generation of impurities between the disintegrant and the trelagliptin succinate during the wet granulation and ensuring the stability of the product during long-term storage.

[0028] 2) After trelagliptin succinate, filler, binder and water are mixed, fluidized bed drying is adopted, and the temperature of the fluidized bed is controlled at 40-45° C. This can effectively control the drying at a lower temperature, reduce the impurities generated by the reaction of filler, binder and trelagliptin succinate, and ensure the stability of the product.

[0029] 3) Controlling the particle size of trelagliptin succinate to less than 200 μm can ensure mixing uniformity, finished product content uniformity and dissolution.

[0030] 4) The solid preparation of the present invention does not contain sugar alcohol, which effectively improves the stickiness and astringency problems caused by the large content of the main drug and the physicochemical properties of the raw material drug. The prepared tablets have a smooth appearance, uniform color, small tablet weight difference, and good tablet formability.

[0031] 5) The process of this method is simple and feasible, the scale-up production is durable, the process parameters are stable and controllable, the production process has good reproducibility, the dissolution of the obtained solid preparation meets the requirements of the immediate release agent, and the tablet weight variability is small. DETAILED DESCRIPTION

[0032] The present invention will be further explained and illustrated below in conjunction with specific embodiments of the present invention.

[0033] Embodiment 1:

[0034] Investigation of API particle size: API particle size (D 90 ) were 294μm, 178μm, 154μm, 146μm, 97μm, and 49μm, respectively. The APIs with different particle sizes were taken to investigate the effect of particle size on the tablet preparation process and tablet quality.

[0035] D 90 (Also known as D(0.9)) represents the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that 90% of the particles have a particle size smaller than it.

[0036] Table 1: Example 1 prescription composition

[0037]

[0038] Preparation process:

[0039] ① API pretreatment: Take an appropriate amount of trelagliptin succinate API and perform the following pretreatments: untreated, sieved through a 40-mesh sieve, sieved through a 60-mesh sieve, sieved through an 80-mesh sieve, sieved through a 200-mesh sieve, and mechanically crushed for later use. The actual particle size of the API (D 90 ) are 294μm, 178μm, 154μm, 146μm, 97μm and 49μm respectively.

[0040] ② Weigh the API, microcrystalline cellulose and hydroxypropyl cellulose according to the prescribed amount and mix them evenly to obtain the premixed powder.

[0041] ③Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0042] ④Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0043] ⑤ Take the prescribed amount of cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0044] ⑥ Use tablet pressing equipment and molds to prepare trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain trelagliptin coated tablets.

[0045] Example 1 Trelagliptin tablets were prepared using APIs with different particle sizes, and the properties such as premixed powder content uniformity, total mixed granule content uniformity and granule flowability, tablet content uniformity and dissolution were investigated. The specific data are shown in Table 2.

[0046] Table 2: Performance data of trelagliptin prepared from raw materials with different particle sizes in Example 1

[0047]

[0048] The raw material drug is Trelagliptin succinate A crystal form, which is needle-shaped crystals with poor fluidity and tends to spontaneously aggregate into large particles or large agglomerates during storage. The raw material particle size has a great influence on the mixing uniformity of the intermediates in the tablet preparation process. It is preferred to control the raw material particle size to less than 200 μm, which can ensure that the content uniformity after mixing, the content uniformity of the finished product, the dissolution rate, etc. meet the requirements.

[0049] Comparative Example 1:

[0050] Table 3: Comparative Example 1 Prescription Composition

[0051]

[0052] Preparation process:

[0053] ① Weigh the API, mannitol, microcrystalline cellulose and hydroxypropyl cellulose according to the prescribed amount and mix them evenly to obtain the premixed powder.

[0054] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0055] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0056] ④ Take the prescribed amount of cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0057] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0058] Comparative Example 2:

[0059] Preparation process:

[0060] ① Weigh the API and microcrystalline cellulose according to the prescription amount of Example 1, mix them evenly, and obtain a premixed powder.

[0061] ② Weigh the prescribed amount of hydroxypropyl cellulose, add appropriate amount of water, prepare an adhesive solution, and set aside.

[0062] ③ Add the binder solution to the premixed powder and use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0063] ④Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0064] ⑤ Take the prescribed amount of cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0065] ⑥ Use tablet pressing equipment and molds to prepare trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain trelagliptin coated tablets.

[0066] Comparative Example 3:

[0067] Preparation process of comparative example 3a:

[0068] ① According to the prescription amount of Example 1, weigh the API, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and hydroxypropyl cellulose, mix them evenly to obtain a premixed powder.

[0069] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0070] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0071] ④Take the prescribed amount of sodium stearyl fumarate, add it to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0072] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0073] Preparation process of comparative example 3b:

[0074] ① According to the prescription amount of Example 1, weigh the API, microcrystalline cellulose, half the amount of cross-linked sodium carboxymethyl cellulose and hydroxypropyl cellulose, mix them evenly to obtain a premixed powder.

[0075] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0076] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0077] ④ Take the prescribed amount of sodium stearyl fumarate and the remaining half amount of cross-linked sodium carboxymethyl cellulose, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0078] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0079] Embodiment 2:

[0080] Table 4: Prescription composition of Examples 2a and 2b

[0081]

[0082] Preparation process:

[0083] ① Weigh the API, microcrystalline cellulose and hydroxypropyl cellulose according to the prescribed amount and mix them evenly to obtain the premixed powder.

[0084] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0085] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0086] ④ Take the prescribed amount of cross-linked sodium carboxymethyl cellulose and magnesium stearate or stearic acid, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0087] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0088] Embodiment 3:

[0089] Table 5: Prescription composition of Examples 3a and 3b

[0090]

[0091] Preparation process:

[0092] ① Weigh the API, lactose or pregelatinized starch, and hydroxypropyl cellulose according to the prescribed amount and mix them evenly to obtain the premixed powder.

[0093] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0094] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0095] ④ Take the prescribed amount of cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0096] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0097] Embodiment 4:

[0098] Table 6: Prescription composition of Examples 4a and 4b

[0099]

[0100]

[0101] Preparation process:

[0102] ① Weigh the API, microcrystalline cellulose, hypromellose or povidone according to the prescribed amount and mix them evenly to obtain the premixed powder.

[0103] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0104] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0105] ④ Take the prescribed amount of cross-linked sodium carboxymethyl cellulose and sodium stearyl fumarate, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0106] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0107] Embodiment 5:

[0108] Table 7: Prescription composition of Examples 5a and 5b

[0109]

[0110] Preparation process:

[0111] ① Weigh the API, microcrystalline cellulose and hydroxypropyl cellulose according to the prescribed amount and mix them evenly to obtain the premixed powder.

[0112] ②Take an appropriate amount of purified water, add it to the premixed powder, use a high-efficiency wet granulator to prepare a soft material, and use a granulator to perform wet granulation to obtain drug-containing granules.

[0113] ③Put the drug-containing granules in a fluidized bed for drying, and use a granulator to dry granulate them to obtain dried drug-containing granules.

[0114] ④ Take the prescribed amount of low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone and sodium stearyl fumarate, add them to the dried drug-containing granules and mix evenly to obtain the total mixed granules.

[0115] ⑤ Use tablet pressing equipment and molds to prepare Trelagliptin tablet cores, and use coating equipment to coat the tablet cores to obtain Trelagliptin coated tablets.

[0116] The weight difference of the Trelagliptin tablets prepared in Example 1 and Comparative Example 1 was investigated. The comparative data of Example 1 and Comparative Example 1 are as follows:

[0117] Table 8: Comparative data of Example 1 and Comparative Example 1

[0118]

[0119] The Chinese Pharmacopoeia stipulates that for tablets with an average tablet weight of less than 300 mg, the tablet weight difference should be controlled to be less than 7.5%. Experimental studies have found that the prescription containing mannitol (Comparative Example 1) has a serious astringent phenomenon at the beginning of tablet compression, resulting in a large tablet weight difference, which is far greater than the limit requirement of the Chinese Pharmacopoeia for tablet weight difference; Example 1 without mannitol has no sticking or astringent phenomenon during the tablet compression process, and the prepared tablets have a smooth appearance, uniform color, small tablet weight difference, and good tablet formability.

[0120] According to the process of Example 1 and Comparative Example 2, different batches (1000 tablets, 5000 tablets and 10000 tablets) of Trelagliptin tablets were prepared respectively. The comparative data of Example 1 and Comparative Example 2 are as follows:

[0121] Table 9: Comparative data of Example 1 and Comparative Example 2

[0122]

[0123] Note: “ / ” in the table means that it is not necessary to prepare an adhesive solution.

[0124] It was found through experimental studies that when different batches (1000 tablets, 5000 tablets and 10000 tablets) of Trelagliptin tablets were prepared according to Comparative Example 2, in order to achieve the same granulation effect, the binder concentration needed to be adjusted accordingly when the binder dosage was fixed during the wet granulation process of different batches. When the batches were 1000 tablets, 5000 tablets and 10000 tablets, the determined binder concentrations were 5%, 7.5% and 10%, respectively. Therefore, in the process of different batch amplification studies, the binder concentration in the granulation process needed to be adjusted and optimized. The operation process was cumbersome and time-consuming. The amplification production feasibility and durability of the wet granulation process of Comparative Example 2 were poor. However, the wet granulation process in Prescription Example 1 was adopted, and the binder dosage was dry added according to the prescription. Compared with the wet addition of the binder, the wet granulation production process can be effectively simplified, which is conducive to the amplification of the product process, and the production efficiency can be significantly improved. The quality of the intermediate particles and the finished product obtained is better.

[0125] The stability of the Trelagliptin tablets prepared in Example 1 and Comparative Example 3 was investigated at a temperature of 60° C. for 10 days and 30 days, and at a temperature of 30° C. and a humidity of 65% RH for 18 months. The comparative data of Example 1 and Comparative Example 3 are as follows:

[0126] Table 10: Comparative data of the relevant substances of Example 1 and Comparative Example 3 placed at 60°C for 10 days and 30 days

[0127]

[0128]

[0129] Table 11: Comparative data of long-term stability of relevant substances of Example 1 and Comparative Example 3 (30°C, 65%RH)

[0130]

[0131] Table 12: Comparative data of long-term stability dissolution curves of Example 1 and Comparative Example 3 (30°C, 65% RH)

[0132]

[0133] From the above research results, it can be seen that the Trelagliptin Tablets prepared in Comparative Examples 3a and 3b are unstable when stored at a high temperature of 60°C, and the related substances increase significantly; when placed at 30°C for 18 months, the impurity D and total impurities increase significantly, the stability is poor, and the dissolution rate also slows down significantly. Therefore, when Trelagliptin Tablets are prepared using Example 1, the increase of related substances is not obvious, and the dissolution rate has almost no change after being placed for 18 months, indicating that the method for preparing Trelagliptin Tablets in Example 1 can ensure the stability of the product during long-term storage.

[0134] The dissolution stability of the Trelagliptin tablets prepared in Examples 1 and 2 was investigated after being placed at a temperature of 60° C. The comparative data between Example 1 and Example 2 are as follows:

[0135] Table 13: Comparative data of Example 1 and Example 2

[0136]

[0137] From the experimental results of the above examples, it can be seen that after the trelagliptin tablets containing sodium stearyl fumarate, magnesium stearate and stearic acid were placed at a high temperature of 60°C for 10 days, the dissolution rate in 15 minutes was ≥85%, and the dissolution rate did not change significantly, indicating that the trelagliptin tablets have good stability.

[0138] The stability and dissolution stability of the Trelagliptin tablets prepared in Example 3 after being placed at a temperature of 60° C. The data of Example 3 are as follows:

[0139] Table 14: Data of Example 3

[0140]

[0141] From the research results of Examples 3a and 3b, it can be seen that the trelagliptin tablets containing lactose or pre-modified starch have good stability at a high temperature of 60°C, and the related substances and dissolution properties do not change significantly.

[0142] The stability and dissolution stability of the Trelagliptin tablets prepared in Example 4 after being placed at a temperature of 60° C. are investigated. The data of Example 4 are as follows:

[0143] Table 15: Data of Example 4

[0144]

[0145] From the research results of Examples 4a and 4b, it can be seen that the trelagliptin tablets containing HPMC or PVP have good stability at a high temperature of 60°C, and the related substances and dissolution properties have not changed significantly.

[0146] The stability and dissolution stability of the Trelagliptin tablets prepared in Example 5 after being placed at a temperature of 60° C. The data of Example 5 are as follows:

[0147] Table 16: Data of Example 5

[0148]

[0149] From the research results of Examples 5a and 5b, it can be seen that the trelagliptin tablets containing cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose have good stability at a high temperature of 60°C, and the related substances and dissolution properties do not change significantly.

Claims

1. A method for preparing a solid preparation of trelagliptin succinate, characterized in that The following steps are involved: Step A: Prepare the materials according to the following components in parts by weight: 50-80 parts of trelagliptin succinate; 5-20 parts of filler; 1-10 parts of binder; 3-15 parts of disintegrant; 0-5 parts of lubricant; The filler is selected from one of microcrystalline cellulose, pregelatinized starch and lactose; The binder is one of hypromellose, povidone and hydroxypropyl cellulose; The disintegrant is one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose; The lubricant is one of stearic acid, magnesium stearate, and sodium stearyl fumarate; Step B: mixing trelagliptin succinate, a filler and a binder according to a certain proportion to obtain a premixed powder; then adding water to the premixed powder to granulate to obtain drug-containing granules; Step C: drying the drug-containing particles in a fluidized bed to obtain dried drug-containing particles; the drying temperature of the fluidized bed is 40-45° C.; Step D: adding a disintegrant and a lubricant to the dried drug-containing granules, mixing them evenly to obtain a total mixed granule; and then pressing them into tablets to obtain trelagliptin tablet cores.

2. The method for preparing the solid preparation of trelagliptin succinate according to claim 1, characterized in that The method also includes coating the trelagliptin tablet core to obtain the trelagliptin coated tablet.

3. The method for preparing the solid preparation of trelagliptin succinate according to claim 1 or 2, characterized in that The components of the solid preparation do not contain sugar alcohol.

4. The method for preparing the solid preparation of trelagliptin succinate according to claim 1 or 2, characterized in that The filler is microcrystalline cellulose.

5. The method for preparing the solid preparation of trelagliptin succinate according to claim 3, characterized in that The filler is microcrystalline cellulose.

6. The method for preparing the solid preparation of trelagliptin succinate according to any one of claims 1 to 2 or 5, characterized in that The adhesive is hydroxypropyl cellulose.

7. The method for preparing the solid preparation of trelagliptin succinate according to claim 3, characterized in that The adhesive is hydroxypropyl cellulose.

8. The method for preparing the solid preparation of trelagliptin succinate according to claim 4, characterized in that The adhesive is hydroxypropyl cellulose.

9. The method for preparing the solid preparation of trelagliptin succinate according to any one of claims 1-2, 5 or 7-8, characterized in that The disintegrant is cross-linked carboxymethyl cellulose sodium.

10. The method for preparing the solid preparation of trelagliptin succinate according to claim 3, characterized in that The disintegrant is cross-linked carboxymethyl cellulose sodium.

11. The method for preparing the solid preparation of trelagliptin succinate according to claim 4, characterized in that The disintegrant is cross-linked carboxymethyl cellulose sodium.

12. The method for preparing the solid preparation of trelagliptin succinate according to claim 6, characterized in that The disintegrant is cross-linked carboxymethyl cellulose sodium.

13. The method for preparing the solid preparation of trelagliptin succinate according to any one of claims 1-2, 5, 7-8 or 10-12, characterized in that The lubricant is sodium stearyl fumarate.

14. The method for preparing the solid preparation of trelagliptin succinate according to claim 3, characterized in that The lubricant is sodium stearyl fumarate.

15. The method for preparing the solid preparation of trelagliptin succinate according to claim 4, characterized in that The lubricant is sodium stearyl fumarate.

16. The method for preparing the solid preparation of trelagliptin succinate according to claim 6, characterized in that The lubricant is sodium stearyl fumarate.

17. The method for preparing the solid preparation of trelagliptin succinate according to claim 9, characterized in that The lubricant is sodium stearyl fumarate.

18. The solid preparation of trelagliptin obtained according to the method for preparing the solid preparation of trelagliptin succinate according to any one of claims 1 to 17.

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