A kind of brivaracetam rapid-release tablet and preparation method thereof

Abstract

The present application discloses a brivaracetam rapid-release tablet and a preparation method thereof, belonging to the field of medical technology. The brivaracetam rapid-release tablets described in the present application include: 15-20wt% brivaracetam, 3-10wt% disintegrant, 60-70wt% diluent, 5-10wt% binder, 1-5wt% lubricant, using a polyvidone binder, can be granulated normally in the process of preparing the rapid-release tablet, without the problem of top-carriage, using sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose as disintegrants, not only disintegrating quickly, but also brivaracetam can be dissolved in a short time, using lactose monohydrate and anhydrous lactose as diluents, solving the problem of astringency caused by lactose monohydrate, the prepared brivaracetam tablets dissolve quickly, and the process is simple, solving the problems of top-carriage and astringency in the preparation process, low production cost, suitable for large-scale production.

Description

Technical Field

[0001] The present application relates to a brivaracetam rapid-release tablet and a preparation method thereof, belonging to the field of medical technology. Background Art

[0002] Epilepsy is a common neurological disease characterized by sudden abnormal discharges of brain neurons, leading to transient brain dysfunction. Brivaracetam is a new type of anti-epileptic drug belonging to the pyrrolidone class of compounds. It acts on specific receptors in the brain to reduce the occurrence of abnormal electrical activity, thereby exerting its anticonvulsant effect. Brivaracetam tablets are mainly used to treat partial seizures in adults and children over 4 years old, especially when other anti-epileptic drugs cannot effectively control the condition or the patient cannot tolerate other drugs.

[0003] Patent 202111284451.9 provides a brivaracetam tablet, including: brivaracetam, anhydrous lactose, lactose monohydrate, carboxycellulose salt, stearate lubricant, stearyl fumarate lubricant, good powder mixing effect during granulation, high production efficiency, small content uniformity deviation, low dissolution variability, however, according to its records, the dissolution in 5 minutes is less than 40%. Patent 202110319785.9 provides a dry granulation process for brivaracetam tablets, brivaracetam, lactose, anhydrous lactose, cyclodextrin, cross-linked sodium carboxymethyl cellulose, and magnesium stearate are obtained by dry granulation, and 63% is dissolved in a medium with a pH of 6.4 in 5 minutes. In addition, in the preparation process of brivaracetam tablets, there are still problems such as over-carriage and astringency that affect the production of brivaracetam tablets. Summary of the invention

[0004] According to one aspect of the present application, a brivaracetam rapid-release tablet is provided, which uses a povidone-type adhesive, can be granulated normally during the preparation of the rapid-release tablet without the problem of topping, uses sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose as disintegrants, which not only disintegrates quickly but also allows brivaracetam to be dissolved in a short time, and uses lactose monohydrate and anhydrous lactose together as diluents to solve the astringency problem caused by lactose monohydrate.

[0005] The brivaracetam rapid-release tablets described in the present application include brivaracetam and a binder;

[0006] The brivaracetam accounts for 15-20wt% of the total mass of the brivaracetam immediate-release tablet, and the binder accounts for 5-10wt% of the total mass of the brivaracetam immediate-release tablet;

[0007] The adhesive is a polyvidone adhesive.

[0008] Optionally, the povidone-based adhesive is copovidone; preferably, the povidone-based adhesive is copovidone VA64.

[0009] Optionally, the brivaracetam immediate-release tablet comprises 15-20wt% brivaracetam, 3-10wt% disintegrant, 60-70wt% diluent, 5-10wt% binder, and 1-5wt% lubricant.

[0010] Optionally, the brivaracetam rapid-release tablet comprises: 18wt% brivaracetam, 6wt% disintegrant, 67wt% diluent, 7wt% binder, and 2wt% lubricant.

[0011] Optionally, the disintegrant is selected from any one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone.

[0012] Preferably, the disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose in a mass ratio of (2.5-3.5):1.

[0013] Specifically, the disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose in a mass ratio of 3:1.

[0014] Optionally, the degree of polymerization of the low-substituted hydroxypropyl cellulose is 650-730; preferably, the degree of polymerization of the low-substituted hydroxypropyl cellulose is 680.

[0015] Optionally, the diluent is selected from any one or more of anhydrous lactose, lactose monohydrate, starch, and microcrystalline cellulose.

[0016] Preferably, the diluent is anhydrous lactose and lactose monohydrate, and the mass ratio of the anhydrous lactose to the lactose monohydrate is (2.5-3.5):1.

[0017] Specifically, the mass ratio of anhydrous lactose to lactose monohydrate is 3:1.

[0018] Optionally, the lubricant is selected from any one or more of stearic acid, magnesium stearate, calcium stearate and talc.

[0019] Preferably, the lubricant comprises magnesium stearate.

[0020] On the other hand, the present application provides a method for preparing the brivaracetam tablets, comprising: mixing brivaracetam, a binder, 45-55 wt% of a disintegrant, and a diluent, dry granulating, then adding the remaining disintegrant and lubricant, and tableting.

[0021] The preparation method of the present application is a conventional method for tablets, and those skilled in the art can also make conventional selections according to actual needs.

[0022] The beneficial effects of this application include:

[0023] 1. The inventor encountered a problem of lifting the car during the preparation process of the tablets of the present application, resulting in the inability to granulate normally. After a series of studies, the inventor found that adding a polyvidone binder, especially copolyvidone, can solve the problem of the inability to granulate normally due to lifting the car. The possible reason is that the addition of copolyvidone increases the interaction between the particles, enhances the fluidity, avoids the accumulation of a large number of particles, and thus solves the problem of lifting the car.

[0024] 2. The inventor solved the problem of the car hitting the granulation process by adding copolyvidone, but the inventor found that the dissolution effect was significantly reduced compared to not adding copolyvidone. In addition, the inventor found in the process of adjusting the excipients that the disintegration of the product was improved, but the dissolution effect has not been improved. When adjusting the disintegrant, the inventor unexpectedly found that when the disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and the mass ratio of the two is controlled to (2.5-3.5): 1, at this time, not only the good disintegration is maintained, but also the problem of poor dissolution caused by copolyvidone is solved. The inventor speculates that the possible reason is that the combination of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose can quickly destroy the connection and cohesion between the particles caused by copolyvidone during the dry granulation process, so that brivaracetam can be dissolved in a short time.

[0025] 3. The inventors found that when lactose monohydrate was used as a diluent, a problem of astringency was found during the granulation process. Based on this, the inventors conducted a lot of research and thought and found that when anhydrous lactose was added again on the basis of lactose monohydrate, and the mass ratio of anhydrous lactose to lactose monohydrate was controlled to (2.5-3.5):1, the astringency problem caused by the addition of lactose monohydrate could be solved without affecting the disintegration time.

[0026] 4. The brivaracetam tablets prepared in the present application have fast dissolution and simple process, solve the problems of bumping and astringency in the preparation process, have low production cost, and are suitable for large-scale production. DETAILED DESCRIPTION

[0027] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0028] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0029] Example 1

[0030] The raw materials of Brivaracetam tablets (3000 tablets) are as follows:

[0031] Brivaracetam 150g

[0032] Disintegrant 41.67g

[0033] Thinner 541.67g

[0034] Adhesive 41.67g

[0035] Lubricant 8.33g

[0036] The disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, with a mass ratio of 2.5:1; the polymerization degree of the low-substituted hydroxypropyl cellulose is 680.

[0037] The diluents are anhydrous lactose and lactose monohydrate, with a mass ratio of 2.5:1.

[0038] The adhesive is copolyvidone VA64.

[0039] The lubricant is magnesium stearate.

[0040] The preparation method is as follows:

[0041] Brivaracetam, a binder, 50 wt% of a disintegrant, and a diluent are mixed and dry granulated, and then the remaining disintegrant and a lubricant are added and tableted.

[0042] Example 2

[0043] The raw materials of Brivaracetam tablets (3000 tablets) are as follows:

[0044] Brivaracetam 150g

[0045] Disintegrant 66.67g

[0046] Diluent 583.33g

[0047] Adhesive 66.67g

[0048] Lubricant 25g

[0049] The disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, with a mass ratio of 3.5:1; the polymerization degree of the low-substituted hydroxypropyl cellulose is 680.

[0050] The diluents are anhydrous lactose and lactose monohydrate, with a mass ratio of 3.5:1.

[0051] The adhesive is copolyvidone VA64.

[0052] The lubricant is magnesium stearate.

[0053] The preparation method is the same as Example 1.

[0054] Example 3

[0055] The raw materials of Brivaracetam tablets (3000 tablets) are as follows:

[0056] Brivaracetam 150g

[0057] Disintegrant 50g

[0058] Diluent 558.33g

[0059] Adhesive 58.33g

[0060] Lubricant 16.67g

[0061] The disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose in a mass ratio of 3:1; the polymerization degree of the low-substituted hydroxypropyl cellulose is 680.

[0062] The diluents are anhydrous lactose and lactose monohydrate, with a mass ratio of 3:1.

[0063] The adhesive is copolyvidone VA64.

[0064] The lubricant is magnesium stearate.

[0065] The preparation method is the same as Example 1.

[0066] The test results of Examples 1-3 are shown in Table 1 below.

[0067] Table 1

[0068]

[0069]

[0070] Comparative Example 1

[0071] The raw materials of brivaracetam tablets are the same as those in Example 3, except that there is no binder; the disintegrant is sodium carboxymethyl starch.

[0072] The preparation method of brivaracetam tablets is the same as that of Example 3.

[0073] During the dry granulation process, the comparative example had a vehicle-lifting phenomenon, and could not be granulated normally.

[0074] The dissolution test results of the comparative example are shown in Table 2. The accelerated conditions are: 40±2°C, RH 75%±5%.

[0075] Table 2

[0076]

[0077] Comparative Example 2

[0078] The raw materials of brivaracetam tablets are the same as those in Example 3, except that the binder is povidone K30 and the disintegrant is sodium carboxymethyl starch.

[0079] The preparation method of brivaracetam tablets is the same as that of Example 3.

[0080] During the dry granulation process, the comparative example had a vehicle-lifting phenomenon, and could not be granulated normally.

[0081] Comparative Example 3

[0082] The raw materials of brivaracetam tablets are the same as those in Example 3, except that the binder is povidone K60 and the disintegrant is sodium carboxymethyl starch.

[0083] The preparation method of brivaracetam tablets is the same as that of Example 3.

[0084] In the dry granulation process, no lifting phenomenon occurred in this comparative example, and granulation could be performed normally.

[0085] The dissolution test results of the comparative example are shown in Table 3. The accelerated conditions are: 40±2°C, RH 75%±5%.

[0086] Table 3

[0087]

[0088] The comparative example dissolves slowly in the early stage.

[0089] Comparative Example 4

[0090] The raw materials of brivaracetam tablets are the same as those in Example 3, except that the disintegrant is sodium carboxymethyl starch.

[0091] The preparation method of brivaracetam tablets is the same as that of Example 3.

[0092] The dissolution test results of the comparative example are shown in Table 4. The accelerated conditions are: 40±2°C, RH 75%±5%.

[0093] Table 4

[0094]

[0095] Compared with Comparative Example 3, the dissolution of this comparative example is improved.

[0096] Comparative Example 5

[0097] The raw materials of brivaracetam tablets are the same as those in Example 3, except that the diluents are anhydrous lactose and lactose monohydrate in a mass ratio of 1:1.

[0098] The preparation method of brivaracetam tablets is the same as that of Example 3.

[0099] This comparative example showed astringency during the preparation process.

[0100] Comparative Example 6

[0101] The raw materials of brivaracetam tablets are the same as those in Example 3, except that the diluents are microcrystalline cellulose and lactose monohydrate in a mass ratio of 3:1.

[0102] The preparation method of brivaracetam tablets is the same as that of Example 3.

[0103] This comparative example showed astringency during the preparation process.

[0104] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A brivaracetam immediate-release tablet, characterized in that: Includes brivaracetam and adhesives; The brivaracetam accounts for 15-20wt% of the total mass of the brivaracetam immediate-release tablet, and the binder accounts for 5-10wt% of the total mass of the brivaracetam immediate-release tablet; The adhesive is a polyvidone adhesive.

2. The brivaracetam rapid-release tablet according to claim 1, characterized in that The polyvidone adhesive is copolyvidone.

3. The brivaracetam rapid-release tablet according to claim 1, characterized in that include: 15-20wt% brivaracetam, 3-10wt% disintegrant, 60-70wt% diluent, 5-10wt% binder, 1-5wt% lubricant.

4. The brivaracetam rapid-release tablet according to claim 3, characterized in that: The disintegrant is selected from any one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl pyrrolidone.

5. The brivaracetam rapid-release tablet according to claim 4, characterized in that: The disintegrants are sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, with a mass ratio of (2.5-3.5):

1.

6. The brivaracetam rapid-release tablet according to claim 3, characterized in that: The diluent is selected from any one or more of anhydrous lactose, lactose monohydrate, starch, and microcrystalline cellulose.

7. The brivaracetam rapid-release tablet according to claim 6, characterized in that: The diluent is anhydrous lactose and monohydrate lactose, and the mass ratio is (2.5-3.5):

1.

8. The brivaracetam rapid-release tablet according to claim 7, characterized in that: The mass ratio of the anhydrous lactose to the monohydrate lactose is 3:

1.

9. The brivaracetam rapid-release tablet according to claim 3, characterized in that: The lubricant is selected from any one or more of stearic acid, magnesium stearate, calcium stearate and talc.

10. A method for preparing the brivaracetam immediate-release tablet according to any one of claims 3 to 9, characterized in that: Brivaracetam, a binder, 45-55 wt% of a disintegrant, and a diluent are mixed and dry granulated, and then the remaining disintegrant and a lubricant are added and tableted.

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