Alogliptin and metformin double-release tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to alogliptin and metformin double-release tablets and a preparation method thereof. The invention aims to solve the problems of poor API uniformity and poor preparation stability. The first purpose of the invention is to provide the alogliptin and metformin double-release tablet, the alogliptin and metformin double-release tablet comprises an alogliptin quick-release part and a metformin slow-release part, and the alogliptin quick-release part and the metformin slow-release part are both prepared by wet granulation; the weight ratio of the alogliptin quick release part to the metformin slow release part is 1: (1.5-4.8). The second purpose of the invention is to provide a method for preparing the alogliptin and metformin double-release tablet.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more specifically, to an alogliptin metformin dual-release tablet and a preparation method thereof. Background Art

[0002] DPP-4 inhibitors, or dipeptidyl peptidase 4 inhibitors, are a class of drugs for the treatment of type 2 diabetes. This class of drugs can inhibit the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), increase the levels of endogenous GLP-1 and GIP, promote the release of insulin from pancreatic β cells, and inhibit the secretion of glucagon from pancreatic α cells, thereby increasing insulin levels and lowering blood sugar, and are less likely to induce hypoglycemia and weight gain. Alogliptin is an orally effective DPP-4 inhibitor with good market prospects. Metformin hydrochloride belongs to the biguanide hypoglycemic drug class, which can increase the liver's sensitivity to insulin, reduce the production of glycogen, and have a direct or indirect effect on insulin resistance. Alogliptin can be used alone or in combination with metformin hydrochloride for the treatment of type 2 diabetes.

[0003] The prior art has proposed a variety of solutions for alogliptin-metformin combination preparations, such as:

[0004] (1) CN101801351B provides a drug combination of alogliptin and metformin rapid-release tablets. Since only rapid-release alogliptin and metformin are provided, the blood concentration of metformin in the body fluctuates greatly and has serious side effects.

[0005] (2) CN105287581A provides a method for preparing alogliptin by spraying it on metformin sustained-release tablets. The preparation process is complicated, the content of alogliptin is difficult to control during spraying, the reproducibility is poor, and the loss of the raw material drug is large.

[0006] (3) CN114010612B provides a method for preparing a sitagliptin metformin bilayer sustained-release tablet. The preparation process of this patented technology is complicated. The premixed excipients need to be spray-dried first and then wet granulated. The granulation process also uses an organic solvent, which poses a high safety risk. The weight difference between the two layers of the bilayer tablet is too large during tableting, which can lead to unsatisfactory uniformity of the dosage unit during production and is difficult to control.

[0007] It can be seen that there are still many deficiencies when alogliptin and metformin are used in combination in the prior art. Summary of the invention

[0008] The present invention aims to overcome at least one defect of the above-mentioned prior art and provide an alogliptin metformin dual-release tablet and a preparation method thereof, so as to solve the problems of poor API uniformity and poor preparation stability.

[0009] The first aspect of the present invention is to provide an alogliptin metformin dual-release tablet, comprising an alogliptin immediate-release portion and a metformin sustained-release portion, wherein the alogliptin immediate-release portion and the metformin sustained-release portion are both prepared by wet granulation;

[0010] The weight ratio of the alogliptin immediate-release portion to the metformin sustained-release portion is 1:(1.5-4.8).

[0011] The test of the present invention shows that when the weight ratio of the immediate-release portion of alogliptin to the sustained-release portion of metformin is not within the set range of the present invention, the friability of the dual-release tablets obtained will increase, and unstable phenomena such as cracking and lid lifting will occur. In addition, the API content is unstable and the content uniformity is poor, and it cannot meet the qualified standards.

[0012] Furthermore, the weight ratio of the alogliptin immediate-release portion to the metformin sustained-release portion is 1:(2.5-4.5).

[0013] In some embodiments, the immediate-release portion of alogliptin is prepared from immediate-release mixed particles, and the particle size distribution of the immediate-release mixed particles is as follows: the immediate-release mixed particles with a particle size greater than 40 mesh account for ≤40wt%, preferably 5-40wt%.

[0014] The test of the present invention shows that when the proportion of immediate-release mixed granules with a particle size greater than 40 mesh exceeds 40wt%, the content uniformity of alogliptin API decreases significantly, the friability of dual-release tablets increases significantly, and unstable phenomena such as tablet splitting and lid lifting occur.

[0015] In some embodiments, the rapid-release mixed granules with a particle size of 40-100 mesh account for 15-50 wt %, and the rapid-release mixed granules with a particle size less than 100 mesh account for 10-60 wt %.

[0016] The test of the present invention shows that when the particle size distribution of the rapid-release mixed granules is not within the above-set range, the content uniformity of the alogliptin API is significantly reduced, and the friability of the dual-release tablets is significantly increased, and unstable phenomena such as tablet splitting and lid lifting occur.

[0017] In some embodiments, the metformin sustained-release portion is prepared from sustained-release mixed particles, and the particle size distribution of the sustained-release mixed particles is as follows: the sustained-release mixed particles with a particle size greater than 40 mesh account for ≤40wt%, preferably 5-40wt%.

[0018] The test of the present invention shows that when the proportion of immediate-release mixed granules with a particle size greater than 40 mesh exceeds 40wt%, the content uniformity of alogliptin API decreases significantly, the friability of dual-release tablets increases significantly, and unstable phenomena such as tablet splitting and lid lifting occur.

[0019] In some embodiments, the sustained-release mixed particles with a particle size of 40-100 mesh account for 15-50 wt %, and the sustained-release mixed particles with a particle size less than 100 mesh account for 10-60 wt %.

[0020] The test of the present invention shows that when the particle size distribution of the sustained-release mixed granules is not within the above-set range, the content uniformity of the metformin API is significantly reduced, and the friability of the dual-release tablets is significantly increased, and unstable phenomena such as tablet splitting and lid lifting occur.

[0021] In some embodiments, the alogliptin immediate-release portion comprises the following components: alogliptin or a pharmaceutically acceptable salt thereof, a first filler, a first binder, a disintegrant, a first glidant, and a first lubricant.

[0022] Optionally, the alogliptin or pharmaceutically acceptable salt thereof is specifically alogliptin benzoate.

[0023] In some embodiments, the alogliptin immediate-release portion includes the following components in parts by weight: 15-20 parts of alogliptin benzoate, 220-400 parts of a first filler, 10-30 parts of a first binder, 10-50 parts of a disintegrant, 2-10 parts of a first glidant, and 2-5 parts of a first lubricant.

[0024] Optionally, the first binder is any one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, starch or hydroxypropyl cellulose.

[0025] Optionally, the first filler is any one or more of lactose, starch, pregelatinized starch, microcrystalline cellulose, corn starch, dextrin, glucose, mannitol, sorbitol, calcium sulfate, calcium carbonate, and calcium bicarbonate, preferably a combination of mannitol and microcrystalline cellulose.

[0026] The test of the present invention shows that when mannitol and microcrystalline cellulose are used together as the first filler, the friability and stability of the preparation are significantly better than the case where either mannitol or microcrystalline cellulose is used alone.

[0027] Optionally, the disintegrant is any one or more of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, cross-linked polyvidone and partially pregelatinized starch.

[0028] Optionally, the first glidant is any one or more of talc, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol, stearic acid or glyceryl behenate.

[0029] Optionally, the first lubricant is any one or more of talc, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol, stearic acid or glyceryl behenate.

[0030] In some embodiments, the metformin sustained-release portion comprises the following components: metformin hydrochloride, a sustained-release polymer, a second filler, a second binder, a second glidant, and a second lubricant.

[0031] In some embodiments, the metformin sustained-release portion includes the following components in parts by weight: 400-600 parts of metformin hydrochloride, 100-500 parts of sustained-release polymer, 50-150 parts of a second filler, 20-40 parts of a second binder, 5-15 parts of a second glidant, and 10-30 parts of a second lubricant.

[0032] Preferably, the weight percentage of the sustained-release polymer in the metformin sustained-release portion is 10-45%.

[0033] Optionally, the sustained-release polymer is any one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, alginate, polyethylene oxide, methyl cellulose, carboxymethyl cellulose, povidone, and chitosan.

[0034] Optionally, the second filler is any one or more of lactose, starch, pregelatinized starch, microcrystalline cellulose, corn starch, dextrin, glucose, mannitol, sorbitol, calcium sulfate, calcium carbonate, and calcium bicarbonate; and / or the disintegrant is any one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and partially pregelatinized starch.

[0035] Optionally, the second binder is any one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, starch or hydroxypropyl cellulose.

[0036] Optionally, the second glidant is any one or more of talc, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol, stearic acid or glyceryl behenate.

[0037] Optionally, the second lubricant is any one or more of talc, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol, stearic acid or glyceryl behenate.

[0038] In some embodiments, the weight percentage of the sustained-release polymer in the metformin sustained-release portion is 10-45%.

[0039] The second aspect of the present invention is to provide a method for preparing the alogliptin metformin dual-release tablets, comprising the following steps:

[0040] 1) mixing alogliptin and a first filler, dissolving a first binder in purified water to prepare a granulation liquid, spraying the mixture with the alogliptin and the first filler to prepare granules, drying and granulating, adding a disintegrant and a first glidant to mix, and finally adding a first lubricant to mix to prepare immediate-release mixed granules;

[0041] The crushed metformin hydrochloride is mixed with the second filler and the second binder, and purified water is sprayed into the granules for granulation. After drying, the granules are granulated, and a sustained-release polymer and a second glidant are added and mixed, and finally a second lubricant is added and mixed to obtain sustained-release mixed granules.

[0042] 2) using the sustained-release mixed granules as the first layer material and the immediate-release mixed granules as the second layer material, and pressing them into plain tablets using a tablet press;

[0043] 3) Coating: Use gastric soluble film coating premix to coat the plain tablets, and the coating weight gain is 2%-5%.

[0044] Compared with the prior art, the beneficial effects of the present invention are as follows: alogliptin immediate-release layer and metformin sustained-release layer are prepared by wet granulation, and the layer weight ratio of the immediate-release layer and the sustained-release layer is set to 1:(1.5-4.8), thereby improving the uniformity of API content and the stability of the preparation of the dual-release tablet; by making specific settings for the particle size distribution of the immediate-release granules and the sustained-release granules, the friability of the preparation is reduced and the stability of the preparation is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is the dissolution curve of alogliptin and metformin in Example 1.

[0046] Figure 2 This is the dissolution curve of alogliptin and metformin in Example 2.

[0047] Figure 3 This is the dissolution curve of alogliptin and metformin in Example 3.

[0048] Figure 4 This is the dissolution curve of alogliptin and metformin in Example 4.

[0049] Figure 5 This is the dissolution curve of alogliptin and metformin in Comparative Example 1.

[0050] Figure 6 This is the dissolution curve of alogliptin and metformin in Comparative Example 2.

[0051] Figure 7 This is the dissolution curve of alogliptin and metformin in Comparative Example 3.

[0052] Figure 8 This is the dissolution curve of alogliptin and metformin in Comparative Example 4. DETAILED DESCRIPTION

[0053] Example 1

[0054] This embodiment provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 1;

[0055] Table 1. Prescription table of Example 1

[0056]

[0057] The preparation method of Example 1 is as follows:

[0058] S1. Alogliptin benzoate and an immediate-release layer filler are mixed, an immediate-release layer binder is dissolved in purified water to prepare a granulation solution, and then the solution is sprayed into the mixture of alogliptin and the immediate-release layer filler for granulation, the granules are granulated after drying, a disintegrant and an immediate-release layer glidant are added and mixed, and finally an immediate-release layer lubricant is added and mixed to prepare immediate-release mixed granules;

[0059] The crushed metformin hydrochloride is mixed with a sustained-release layer filler and a sustained-release layer binder, and purified water is sprayed into the granules. After drying, the granules are sized, and a sustained-release polymer and a sustained-release layer glidant are added and mixed. Finally, a sustained-release layer lubricant is added and mixed to obtain sustained-release mixed granules.

[0060] 2) using the sustained-release mixed granules as the first layer material and the immediate-release mixed granules as the second layer material, and pressing them into plain tablets using a tablet press;

[0061] 3) Coating: Use gastric soluble film coating premix to coat the plain tablets, and the coating weight gain is 2%-5%.

[0062] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 1 is shown in Table 2:

[0063] Table 2. Particle size distribution of Example 1

[0064]

[0065]

[0066] Example 2

[0067] This embodiment provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 2;

[0068] Table 3. Prescription table of Example 2

[0069]

[0070] The preparation method of Example 2 is the same as that of Example 1.

[0071] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 2 is shown in Table 4:

[0072] Table 4. Particle size distribution table of Example 2

[0073]

[0074] Example 3

[0075] This embodiment provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 5;

[0076] Table 5. Prescription table of Example 3

[0077]

[0078] The preparation method of Example 3 is the same as that of Example 1.

[0079] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 3 is shown in Table 6:

[0080] Table 6. Particle size distribution table of Example 3

[0081]

[0082] Example 4

[0083] This embodiment provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 7;

[0084] Table 7. Prescription table of Example 4

[0085]

[0086]

[0087] The preparation method of Example 4 is the same as that of Example 1.

[0088] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 4 is shown in Table 8:

[0089] Table 8. Particle size distribution table of Example 4

[0090]

[0091] Example 5

[0092] The prescription and preparation method of this example are exactly the same as those of Example 2, except that the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules is different.

[0093] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 5 is shown in Table 9:

[0094] Table 9. Particle size distribution of Example 5

[0095]

[0096] Example 6

[0097] The prescription and preparation method of this example are exactly the same as those of Example 2, except that the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules is different.

[0098] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 6 is shown in Table 10:

[0099] Table 10. Particle size distribution of Example 6

[0100]

[0101] Example 7

[0102] The prescription and preparation method of this example are exactly the same as those of Example 2, except that the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules is different.

[0103] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Example 7 is shown in Table 11:

[0104] Table 11. Particle size distribution of Example 7

[0105]

[0106] Comparative Example 1

[0107] This comparative example provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 12:

[0108] Table 12. Prescription table of comparative example 1

[0109]

[0110]

[0111] The preparation method of Comparative Example 1 is the same as that of Example 1.

[0112] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Comparative Example 1 is shown in Table 8:

[0113] Table 13. Particle size distribution table of comparative example 1

[0114]

[0115] Comparative Example 2

[0116] This comparative example provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 14:

[0117] Table 14. Comparative Example 2 Prescription Table

[0118]

[0119] The preparation method of Comparative Example 2 is the same as that of Example 1.

[0120] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Comparative Example 2 is shown in Table 15:

[0121] Table 15. Particle size distribution table of comparative example 2

[0122]

[0123] Comparative Example 3

[0124] This comparative example provides an alogliptin metformin dual-release tablet, the prescription of which is shown in Table 16:

[0125] Table 16. Comparative Example 3 Prescription Table

[0126]

[0127] The preparation method of Comparative Example 3 is the same as that of Example 1.

[0128] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Comparative Example 3 is shown in Table 17:

[0129] Table 17. Particle size distribution table of comparative example 3

[0130]

[0131] Comparative Example 4

[0132] This comparative example provides a logliptin metformin dual-release tablet, the prescription is shown in Table 18

[0133] Table 18. Comparative Example 4 Prescription Table

[0134]

[0135] The preparation method of Comparative Example 4 is the same as that of Example 1.

[0136] The particle size distribution of the quick-release mixed granules and the sustained-release mixed granules of Comparative Example 4 is shown in Table 19:

[0137] Table 19. Particle size distribution table of comparative example 4

[0138]

[0139] Comparative Example 5

[0140] The prescription and preparation method of this comparative example are exactly the same as those of Example 2, except that the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules is different.

[0141] The particle size distribution of the quick-release mixed granules and the sustained-release mixed granules of Comparative Example 5 is shown in Table 20:

[0142] Table 20. Particle size distribution table of comparative example 5

[0143]

[0144]

[0145] Comparative Example 6

[0146] The prescription and preparation method of this comparative example are exactly the same as those of Example 2, except that the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules is different.

[0147] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Comparative Example 6 is shown in Table 21:

[0148] Table 21. Particle size distribution table of comparative example 6

[0149]

[0150] Comparative Example 7

[0151] The prescription and preparation method of this comparative example are exactly the same as those of Example 2, except that the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules is different.

[0152] The particle size distribution of the rapid-release mixed granules and the sustained-release mixed granules of Comparative Example 7 is shown in Table 22:

[0153] Table 22. Particle size distribution of comparative example 7

[0154]

[0155] Test Case

[0156] 1. Friability and stability test

[0157] 1.1 Friability test method

[0158] For tablets weighing 0.65g or less, take a number of tablets so that the total weight is about 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a hair dryer to blow away the powder that falls off the tablets, weigh them accurately, place them in a friability tester, and rotate them 100 times. Take them out, remove the powder in the same way, weigh them accurately, and the weight loss should not exceed 1%, and no broken, cracked, or crushed tablets should be detected. This test is generally performed only once. If the weight loss exceeds 1%, it should be repeated twice, and the average weight loss of the three times should not exceed 1%, and no broken, cracked, or crushed tablets should be detected.

[0159] 1.2 API content uniformity determination method

[0160] The content uniformity test was carried out according to the content uniformity test method 0941 of the fourth volume of the Chinese Pharmacopoeia.

[0161] 1.3 Acceptable standards for friability, API content and uniformity

[0162] Friability<1.0%

[0163] API content: 90-110%

[0164] API content uniformity: A+2.2S≤15.0

[0165] 1.5 Summary of friability and stability

[0166] Table 23. Summary of friability and stability of Examples 1-7 and Comparative Examples 1-7

[0167]

[0168] With reference to Table 23 and the prescriptions of the embodiments and comparative examples, it can be seen that:

[0169] Compared with Example 1, in Comparative Example 1, only the weight ratio of the alogliptin immediate-release layer to the metformin sustained-release layer was increased to 1:1, which caused a significant increase in the A+2.2S value of alogliptin, an increase in friability, and the occurrence of unstable phenomena such as flakes and lid lifting; in Comparative Example 2, only the weight ratio of the alogliptin immediate-release layer to the metformin sustained-release layer was lowered to 1:5, which also caused a significant increase in the A+2.2S value of alogliptin, an increase in friability, and the occurrence of unstable phenomena such as flakes and lid lifting.

[0170] Compared with Example 1, Comparative Example 3 only replaced the filler of the immediate-release layer from the combination of mannitol + MCC PH101 to mannitol alone, and Comparative Example 4 replaced it with MCC PH101 alone. The results both caused a significant increase in the A+2.2S value of alogliptin, an increase in friability, and unstable phenomena such as fragmentation and lid lifting.

[0171] Compared with Example 2, Comparative Examples 5-7 only changed the particle size distribution of the immediate-release mixed granules and the sustained-release mixed granules, so that at least one of the particle sizes of the immediate-release mixed granules and the sustained-release mixed granules failed to meet the requirements (particles with a particle size greater than 40 mesh accounted for 5-40wt%, particles with a particle size of 40-100 mesh accounted for 15-50wt%, and particles with a particle size less than 100 mesh accounted for 10-60wt%). As a result, the A+2.2S values ​​of the two APIs, alogliptin and metformin, increased significantly, and the friability increased, resulting in unstable preparations.

[0172] 2. Dissolution Test

[0173] 2.1 Dissolution method

[0174] Medium pH 1.2, basket method, rotation speed 100 rpm, medium volume 1000 ml, medium temperature 37°C.

[0175] 2.2 Dissolution Acceptance Criteria

[0176] Alogliptin passed the test: 1h, dissolution>80%.

[0177] Metformin passed the test: dissolution <50% in 1 hour, dissolution >80% in 8 hours.

[0178] 2.3 Dissolution Summary

[0179] Table 24. Summary of the dissolution of alogliptin in Examples 1-4 and Comparative Examples 1-4

[0180]

[0181] Table 25. Summary of Metformin Dissolution in Examples 1-4 and Comparative Examples 1-4

[0182]

[0183]

[0184] Reference Table 24, Figure 1-8 And the prescriptions of each embodiment and comparative example show that:

[0185] Compared with Example 1, in Comparative Example 1, the weight proportion of the sustained-release skeleton material is lowered to 5%, resulting in the dissolution rate of metformin in 1 hour being higher than 50% of the upper limit of the qualified standard; while in Comparative Example 2, the weight proportion of the sustained-release skeleton material is increased to 50%, resulting in the dissolution rate of metformin in 8 hours being lower than 80% of the lower limit of the qualified standard.

[0186] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the technical solution of the present invention, and are not intended to limit the specific implementation methods of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the claims of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. An alogliptin metformin dual-release tablet, characterized in that: It comprises an alogliptin immediate-release part and a metformin sustained-release part, and both the alogliptin immediate-release part and the metformin sustained-release part are prepared by wet granulation; The weight ratio of the alogliptin immediate-release portion to the metformin sustained-release portion is 1:(1.5-4.8).

2. The alogliptin metformin dual-release tablet according to claim 1, characterized in that: The weight ratio of the alogliptin immediate-release portion to the metformin sustained-release portion is 1:(2.5-4.5).

3. The alogliptin metformin dual-release tablet according to claim 1, characterized in that: The immediate-release portion of alogliptin is prepared from immediate-release mixed particles, and the particle size distribution of the immediate-release mixed particles is as follows: the immediate-release mixed particles with a particle size greater than 40 mesh account for ≤40wt%, and / or the immediate-release mixed particles with a particle size greater than 40 mesh account for 5-40wt%.

4. The alogliptin metformin dual-release tablet according to claim 1, characterized in that: The rapid-release portion of alogliptin is prepared from rapid-release mixed particles, and the particle size distribution of the rapid-release mixed particles is as follows: rapid-release mixed particles with a particle size of 40-100 mesh account for 15-50wt%, and rapid-release mixed particles with a particle size less than 100 mesh account for 10-60wt%.

5. The alogliptin metformin dual-release tablet according to claim 1, characterized in that: The metformin sustained-release part is prepared from sustained-release mixed particles, and the particle size distribution of the sustained-release mixed particles is as follows: the sustained-release mixed particles with a particle size greater than 40 mesh account for ≤40wt%, and / or the sustained-release mixed particles with a particle size greater than 40 mesh account for 5-40wt%.

6. The alogliptin metformin dual-release tablet according to claim 1, characterized in that: The metformin sustained-release part is prepared from sustained-release mixed particles, and the particle size distribution of the sustained-release mixed particles is as follows: the sustained-release mixed particles with a particle size of 40-100 mesh account for 15-50wt%, and the sustained-release mixed particles with a particle size less than 100 mesh account for 10-60wt%.

7. The alogliptin metformin dual-release tablet according to any one of claims 1 to 6, characterized in that: The alogliptin immediate-release portion comprises the following components: alogliptin or a pharmaceutically acceptable salt thereof, a first filler, a first binder, a disintegrant, a first glidant, and a first lubricant. Preferably, the first filler is a combination of mannitol and microcrystalline cellulose.

8. The alogliptin metformin dual-release tablet according to any one of claims 1 to 6, characterized in that: The metformin sustained-release portion comprises the following components: metformin hydrochloride, a sustained-release polymer, a second filler, a second binder, a second glidant, and a second lubricant; and / or, The sustained-release polymer is any one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, alginate, polyethylene oxide, methyl cellulose, carboxymethyl cellulose, povidone, and chitosan.

9. The alogliptin metformin dual-release tablet according to claim 8, characterized in that: The weight percentage of the sustained-release polymer in the metformin sustained-release portion is 10-45%.

10. A method for preparing the alogliptin metformin dual-release tablets according to any one of claims 1 to 9, characterized in that: The following steps are involved: 1) mixing alogliptin and a first filler, dissolving a first binder in purified water to prepare a granulation liquid, spraying the mixture with the alogliptin and the first filler to prepare granules, drying and granulating, adding a disintegrant and a first glidant to mix, and finally adding a first lubricant to mix to prepare immediate-release mixed granules; The crushed metformin hydrochloride is mixed with the second filler and the second binder, and purified water is sprayed into the granules for granulation. After drying, the granules are granulated, and a sustained-release polymer and a second glidant are added and mixed, and finally a second lubricant is added and mixed to obtain sustained-release mixed granules. 2) using the sustained-release mixed granules as the first layer material and the immediate-release mixed granules as the second layer material, and pressing them into plain tablets using a tablet press; 3) Coating: Use gastric soluble film coating premix to coat the plain tablets, and the coating weight gain is 2%-5%.

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