Linagliptin tablet and preparation method thereof

Abstract

The invention belongs to the technical field of medicine oral solid preparations, and particularly relates to a linagliptin tablet and a preparation method thereof. The linagliptin tablet adopts a preparation process of a powder direct compression method, and raw materials and auxiliary materials comprise linagliptin, a filling agent, a disintegrating agent, a flow aid, a lubricating agent and a film coating premix. The filler is composed of one or two of microcrystalline cellulose, spray-dried lactose and pregelatinized starch; the disintegrating agent is prepared from one or two of polyvinylpolypyrrolidone, sodium carboxymethyl starch and low-substituted hydroxy propyl cellulose; the flow aid is prepared from one of silicon dioxide or superfine silica powder; the lubricant is magnesium stearate; and the film coating agent is a gastric-soluble film coating premix. The preparation method adopts a powder direct compression process, is simple and easy to implement, saves energy, reduces consumption, optimizes the composition and dosage of auxiliary materials, is high in yield, solves the problem of low content in a granulation process, optimizes the disintegration and dissolution behaviors of the preparation, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of oral solid pharmaceutical preparations, and relates to a linagliptin tablet and a preparation method thereof. Background Art

[0002]

[0003] The chemical structural formula of linagliptin compound is shown as above, and its chemical name is 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione; clinically, the drug synthesized from this compound belongs to a new and effective selective dipeptidyl peptidase-4 (DPP-4) inhibitor and can be used for the treatment of type 2 diabetes.

[0004] Linagliptin is a very unique non-peptide DPP-4 (dipeptidyl peptidase 4) inhibitor. This unique structure enables linagliptin to bind tightly to DPP-4. Due to the unique structure of linagliptin, the half-life of this drug is particularly long (>100 h), and the plasma protein binding rate is very high (>80%). Different from other DPP-4 inhibitors that are metabolized by the kidneys, it is excreted through bile and intestines without liver metabolism, and 90% is excreted in the original form. Therefore, linagliptin can be administered as a single dose to all adult patients without adjustment according to their kidney damage. DPP-4 can degrade the incretin hormone-like polypeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Linagliptin can increase the concentration of active incretin hormones, stimulate insulin release in a glucose-dependent manner, and reduce the level of glucagon in circulation. These two incretin hormones are both involved in the physiological regulation of glucose homeostasis. The incretin secretion maintains a relatively low basal level throughout the day and rises immediately after a meal. Under normal or elevated glucose levels, GLP-1 and GIP can increase the biosynthesis and secretion of insulin by pancreatic β-cells. In addition, GLP-1 can also reduce the glucagon secretion of pancreatic α-cells and decrease the hepatic glucose output.

[0005] Linagliptin drugs are mainly used for the treatment of type 2 diabetes. Compared with traditional hypoglycemic drugs, the advantages of DPP-4 inhibitors are that they do not increase the risk of hypoglycemia, have a neutral effect on body weight, and have good cardiovascular safety.

[0006] Linagliptin tablets were developed by Boehringer Ingelheim and were first approved by the FDA for marketing in the United States in May 2011. Subsequently, Boehringer Ingelheim's linagliptin tablets were approved for marketing in many countries / regions such as the European Union and Japan, and were approved for import into China in 2013. Patent CN115227661A discloses a linagliptin tablet and its preparation method, which adopts a dry granulation and double-layer granule process. The linagliptin tablet includes linagliptin and microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate, and has good dissolution and stability. However, due to its relatively complex process flow, the content of the preparation may be low during the preparation process. Linagliptin is a highly soluble drug, and the adjustment of excipients and processes will affect the product and its quality. Therefore, it is necessary to provide a linagliptin and its preparation method with high preparation content, excellent dissolution behavior, and simple process flow to make up for the deficiencies of the existing technology. Summary of the Invention

[0007] Aiming at the deficiencies of the existing technology, the present invention optimizes the composition and dosage of excipients, provides a simple and feasible direct powder compression preparation process. After the raw materials are mixed with fillers, disintegrants, and glidants, they are sieved and then mixed with the lubricant magnesium stearate and pressed into tablets, which solves the problem of loss of raw materials during granulation. At the same time, the direct powder compression process also optimizes the disintegration and dissolution behavior of the preparation. Through strict and comprehensive internal control of raw and auxiliary materials, intermediate control during the production process, and finished product release quality standards, the product has excellent dissolution behavior, improves batch-to-batch uniformity, and enhances long-term stability.

[0008] The first object of the present invention is to provide a linagliptin tablet and its preparation method, which is characterized in that: the linagliptin tablet contains linagliptin, filler, disintegrant, glidant, lubricant, and film coating premix;

[0009] In some embodiments, the filler is composed of one or two of microcrystalline cellulose, spray-dried lactose, and pregelatinized starch; the disintegrant is composed of one or two of crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; the glidant is composed of one of silicon dioxide or colloidal silica; the lubricant is magnesium stearate; the film coating agent is a gastric-soluble film coating premix.

[0010] In a preferred embodiment, the filler is composed of spray-dried lactose and microcrystalline cellulose. Through a suitable proportion formula, under the action of colloidal silica, the material has good compressibility and fluidity. At the same time, crospovidone is used to optimize the disintegration time limit and improve the dissolution and release of the drug.

[0011] The second object of the present invention is to provide a

[0012] In some embodiments, for the linagliptin tablet of the present invention, calculated by weight parts, the prescription composition of the raw and auxiliary materials is as follows:

[0013]

[0014] In a preferred embodiment, the raw and auxiliary material prescription composition is as follows by weight parts:

[0015]

[0016] The third object of the present invention is to provide a preparation method of the linagliptin tablets, comprising the following steps;

[0017] (1) Premixing process: Premix linagliptin with spray-dried lactose, microcrystalline cellulose, and colloidal silicon dioxide to obtain a premixed material;

[0018] (2) Sieving and mixing process; Sieve the obtained premixed material through a 30-mesh sieve to obtain a sieved and mixed powder, and mix it again;

[0019] (3) Total mixing process: Mix the mixed powder obtained in (2) with magnesium stearate;

[0020] (4) Tableting process; Use a tableting machine to tablet;

[0021] (5) Coating process; Prepare a coating solution with a solid content of 10% by mixing a film coating premix with purified water, and coat the linagliptin tablets prepared in (4) to obtain the product.

[0022] In some embodiments, the preparation method comprises the following steps:

[0023] Step (1) is: Premixing process: Add linagliptin, filler, disintegrant, and glidant to a three-dimensional mixer and premix for 5 minutes;

[0024] Step (2) is: Sieving and mixing process: Pass the premixed material through a 30-mesh sieve using a rocking granulator; then re-add it to the three-dimensional mixer and mix for 10 minutes;

[0025] Step (3) is: Total mixing process: Add the lubricant magnesium stearate, and the mixing time is 5 minutes;

[0026] Step (4) is: Tableting process: Use a high-speed rotary tableting machine with a die specification of a Φ9.0mm round shallow concave punch die; Calculate the theoretical tablet weight according to the linagliptin content in the mixed powder, the tableting speed is 150,000 - 300,000 tablets per hour, the tablet weight range: theoretical tablet weight ±6%, the average hardness is 50 - 70N, and the tablet weight variation, friability, and disintegration time limit of the tablets all meet the requirements.

[0027] Step (5) is: Coating process: Add the film coating premix into purified water and stir for 30 minutes to prepare a suspension coating solution with a solid content of 10%; Add the linagliptin tablets into the BGB-150 high-efficiency coating machine, set the main machine rotation speed of the coating machine at 4 - 8 revolutions per minute, set the inlet air temperature at 55 - 70 °C, adjust the position of the coating spray gun to a distance of 30 cm from the tablet bed, and the atomization pressure at 0.5 MPa - 0.9 Mpa. During the process, control the tablet bed temperature at 45 °C - 50 °C; Stop coating when the coating weight gain reaches 2% - 5%, and continue drying for 15 - 20 minutes to obtain the linagliptin tablets.

[0028] In a preferred embodiment, the coating weight gain is preferably 4.5%.

[0029] Compared with the prior art, the technical effect of the present invention is that:

[0030] Through the preparation process of direct powder compression method, optimize the addition and processing of excipients, reduce the loss of raw materials in the granulation process of the existing preparation method, the process is simple and easy to operate, energy-saving and consumption-reducing, with a high yield rate, solve the problems such as unqualified friability, optimize the disintegration and dissolution behavior of the preparation. In addition, by optimizing the composition and dosage of excipients, the dissolution of linagliptin tablets is more stable, with high batch-to-batch and within-batch uniformity, improve the stability of linagliptin tablets, and is suitable for industrial production. Description of the Drawings

[0031] Figure 1 : Batch-to-batch dissolution curves of Examples 1 - 3

[0032] Figure 2 : Batch-to-batch dissolution curves of Examples 1 - 3 and Comparative Examples 1 - 3 (medium pH 6.8)

[0033] Figure 3 : Within-batch dissolution uniformity of Example 2 (medium pH 6.8)

[0034] Figure 4 : Within-batch dissolution uniformity of Example 3 (medium pH 6.8)

[0035] Figure 5 : Within-batch dissolution uniformity of Example 4 (medium pH 6.8)

[0036] Figure 6 : Within-batch dissolution uniformity of Comparative Example 1 (medium pH 6.8)

[0037] Figure 7 : Comparison of dissolution curves of Examples 1 - 3, Comparative Examples 1 - 3 and reference preparation after 6 months of accelerated test (medium pH 6.8) Specific Embodiments

[0038] The present invention will be further described in detail below in conjunction with specific embodiments. However, the embodiments of the present invention are not limited by the following embodiments. Any further changes, modifications, substitutions, combinations, and simplifications made on the basis of the essence of the present invention shall be regarded as equivalent substitutions and included within the scope of protection of the present invention.

[0039] Example 1: Linagliptin Tablets

[0040] Prescription composition for 1000 tablets

[0041] Ingredient Weight (g) Linagliptin 5 Spray-dried lactose 60 Microcrystalline cellulose 45 Crospovidone 10 Aerosil 1 Magnesium stearate 1 Film coating premix 10

[0042] Preparation process:

[0043] Premix the prescribed amount of linagliptin with spray-dried lactose, microcrystalline cellulose, and colloidal silicon dioxide to obtain a premixed material; pass the obtained premixed material through a 30-mesh sieve to obtain a sieved mixed powder, and mix again; mix the mixed powder with magnesium stearate; press the tablets using a tableting machine, with a coating weight gain of 4.5%, and then obtain the product.

[0044] Example 2: Linagliptin Tablets

[0045] Prescription composition for 1000 tablets

[0046] Ingredient Weight (g) Linagliptin 5 Spray-dried lactose 65 Microcrystalline cellulose 40 Crospovidone 10 Aerosil 1 Magnesium stearate 1 Film coating premix 10

[0047] Preparation process: Use the preparation method of Example 1.

[0048] Example 3: Linagliptin Tablets

[0049] Prescription composition for 1000 tablets

[0050] Ingredient Weight (g) Linagliptin 5 Spray-dried lactose 70 Microcrystalline cellulose 35 Crospovidone 10 Aerosil 1 Magnesium stearate 1 Film coating premix 10

[0051] Preparation process: Use the preparation method of Example 1.

[0052] Example 4: Linagliptin Tablets

[0053] Prescription composition for 1000 tablets

[0054]

[0055]

[0056] Premix the prescribed amount of linagliptin with spray-dried lactose, microcrystalline cellulose, and colloidal silicon dioxide to obtain a premixed material; pass the obtained premixed material through a 30-mesh sieve to obtain a sieved mixed powder, and mix again; mix the mixed powder with magnesium stearate; press the tablets using a tableting machine, with a coating weight gain of 5%, and then dry to obtain the product.

[0057] Comparative Example 1: Linagliptin Tablets

[0058] Prescription composition: 1000 tablets

[0059] Ingredient Weight (g) Linagliptin 5 Spray-dried lactose 55 Microcrystalline cellulose 50 Crospovidone 7 Povidone K30 3 Aerosil 1 Magnesium stearate 1 Film coating premix 10

[0060] Preparation process:

[0061] Mix the prescribed amount of linagliptin with spray-dried lactose, microcrystalline cellulose, and colloidal silicon dioxide in a wet granulator, and prepare a 7% binder solution of povidone K30 with purified water; after wet granulation, dry the wet granules in a fluidized bed granulator; screen and size the dry granules, then mix them with crospovidone and magnesium stearate to obtain the total mixed material, and then press tablets and coat them to obtain the product.

[0062] Comparative Example 2: Linagliptin tablets

[0063] Prescription composition: 1000 tablets

[0064]

[0065]

[0066] Preparation process:

[0067] Mix the prescribed amount of linagliptin with spray-dried lactose, microcrystalline cellulose, and colloidal silicon dioxide in a wet granulator, and prepare a 7% binder solution of povidone K30 with purified water; after wet granulation, dry the wet granules in a fluidized bed granulator; screen and size the dry granules, then mix them with sodium carboxymethyl starch and magnesium stearate to obtain the total mixed material, and then press tablets and coat them to obtain the product.

[0068] Comparative Example 3: Linagliptin tablets

[0069] Prescription composition: 1000 tablets

[0070] Ingredient Weight (g) Linagliptin 5 Spray-dried lactose 60 Microcrystalline cellulose 45 Crospovidone 10 Aerosil 1 Magnesium stearate 1 Film coating premix 10

[0071] Preparation process:

[0072] Take the prescribed amount of linagliptin and mix it evenly with spray-dried lactose, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide in a mixer, perform dry granulation, then mix it with magnesium stearate, press tablets, and coat them to obtain the product.

[0073] Comparative Example 4: Linagliptin tablets

[0074] Prescription composition: 1000 tablets

[0075]

[0076]

[0077] Preparation process: Take linagliptin, microcrystalline cellulose and mannitol and mix them, and granulate by dry granulation to obtain inner granules; mix the inner granules with sodium carboxymethyl starch and colloidal silica, and granulate by dry granulation to obtain drug granules. Mix the above drug granules with magnesium stearate, and then press tablets and coat them to obtain the product.

[0078] Comparative Example 5: Linagliptin tablets

[0079] Prescription composition for 1000 tablets

[0080] Ingredient Weight (g) Linagliptin 5 Spray-dried lactose 50 Microcrystalline cellulose 55 Crospovidone 15 Aerosil 1 Magnesium stearate 1 Film coating premix 10

[0081] Preparation process: The same as that of Example 1.

[0082] Verification examples

[0083] 1. Comparison of basic parameter test effects

[0084] For the linagliptin tablets of Examples 1-4 and the linagliptin tablets of Comparative Examples 1-5, hardness, weight difference, friability, disintegration time limit and content were tested.

[0085] Table 1 Basic parameter analysis of tablets in examples and comparative examples

[0086]

[0087]

[0088] It can be obtained from Table 1 that in Examples 1-4, the hardness, friability, disintegration time limit and content are similar to those of the reference preparation, and the hardness and content of Comparative Examples 1-5 are slightly lower than those of the groups of Examples 1-3.

[0089] 2. Dissolution comparison of examples, comparative examples and original research reference preparation

[0090] Batch-to-batch uniformity and in-batch dissolution effects of Examples 1-4 and Comparative Examples 1-3 were tested. It can be seen from Figure 1-2 that the batch-to-batch dissolution uniformity of Examples 1-3 of the present invention is better than that of Comparative Examples 1-3.

[0091] It can be seen from Figure 3-6 that the in-batch dissolution uniformity of the examples of the present invention is good and is better than that of Comparative Example 1.

[0092] It can be seen from Figure 7 that the dissolution curves of the examples, comparative examples and reference preparation in the accelerated test for 6 months are all greater than 85% at 15 minutes, and the in vitro dissolution is similar. The dissolution uniformity of other examples of the present invention is also high. The dissolution uniformity experiments were also carried out on other comparative examples. Due to space limitations, they will not be elaborated one by one. If needed later, they can all be provided.

Claims

1. A linagliptin tablet, characterized in that, The described linagliptin tablets mainly contain: linagliptin, fillers, disintegrants, glidants, lubricants and film coating premixes.

2. The linagliptin tablet according to claim 1, characterized in that, The described fillers are composed of one or two of microcrystalline cellulose, spray-dried lactose, and pregelatinized starch; the disintegrants are composed of one or two of cross-linked povidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; the glidant is one of colloidal silica or microcrystalline silica; the lubricant is magnesium stearate; and the film coating agent is a gastric-soluble film coating premix.

3. The linagliptin tablet according to claim 1, characterized in that, Calculated by weight parts, the composition of the raw and auxiliary materials prescription is as follows:

4. The linagliptin tablet according to claim 3, characterized in that, Calculated by weight parts, the preferred composition of the raw and auxiliary materials prescription is:

5. The linagliptin tablet according to claim 1, characterized in that, The described linagliptin tablets include the following steps; (1) Premixing process: Premix linagliptin with fillers, disintegrants, and glidants to obtain premixed materials. (2) Sieving and mixing process; Pass the obtained premixed materials through a 30-mesh sieve to obtain sieved and mixed powder, and mix again. (3) Total mixing process: Mix the mixed powder obtained in (2) with the lubricant. (4) Tableting process; Use a tableting machine to tablet. (5) Coating process; Prepare a coating solution with a solid content of 10% by mixing the film coating premix with purified water, and coat the linagliptin plain tablets prepared in (4) to obtain the product.

6. The linagliptin tablet according to claim 5, characterized in that: Step (1) is: Premixing process: Add linagliptin, fillers, disintegrants, and glidants to a three-dimensional mixer and premix for 5 minutes.

7. The linagliptin tablet according to claim 5, characterized in that: Step (2) is: Sieving and mixing process: Pass the premixed materials through a 30-mesh sieve using a rocking granulator; then re-add them to a three-dimensional mixer and mix for 10 minutes.

8. The linagliptin tablet according to claim 5, characterized in that: Step (3) is: Total mixing process: Add the lubricant magnesium stearate, and the mixing time is 5 minutes.

9. The linagliptin tablet according to claim 5, characterized in that: Step (4) is: Tableting process: Use a high-speed rotary tableting machine with a die specification of a Φ9.0mm circular shallow concave punch die; calculate the theoretical tablet weight based on the linagliptin content in the mixed powder, the tableting speed is 150,000 - 300,000 tablets per hour, the tablet weight range: theoretical tablet weight ±6%, the average hardness is 50 - 70N, and the tablet weight variation, friability, and disintegration time limit of the tablets all meet the regulations.

10. The linagliptin tablet according to claim 5, characterized in that: Step (5) is: Coating process: Add the film coating premix to purified water, stir for 30 minutes to prepare a suspension coating solution with a solid content of 10%; add the linagliptin plain tablets to a BGB-150 high-efficiency coating machine, set the main machine rotation speed of the coating machine at 4 - 8 revolutions per minute, set the inlet air temperature at 55 - 70°C, adjust the distance between the coating spray gun and the tablet bed to 30 cm, the atomization pressure is 0.5 MPa - 0.9 Mpa, and control the tablet bed temperature at 45°C - 50°C during the process; stop coating when the coating weight gain reaches 2% - 5%, and continue drying for 15 - 20 minutes to obtain the linagliptin tablets. Preferably, the coating weight gain is 4.5%.

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