Pharmaceutical composition containing antiepileptic drug and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition containing an anti-epileptic drug and a preparation method thereof, the pharmaceutical composition contains lactose with a certain particle size, and the obtained composition is non-sticky and / or good in stability.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to a pharmaceutical composition containing an anti-epileptic drug and a preparation method thereof. Background Art

[0002] Epilepsy is a common neurological disease characterized by sudden abnormal discharges of brain neurons, leading to transient brain dysfunction. According to statistics, the incidence of epilepsy in my country is currently 7%, making it the second largest neurological disease after headaches.

[0003] At present, the commonly used drugs for treating epilepsy-related diseases include levetiracetam, brivaracetam, carbamazepine, etc. Among them, brivaracetam is a racetam derivative with a wide range of anti-epileptic activity and high safety. The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) approved it on January 14, 2016 and February 18, 2016, respectively, for the treatment of partial-onset epilepsy patients aged 16 years and above, with or without secondary generalized seizures. The trade name is

[0004] A lot of research has been done on brivaracetam immediate-release preparations in the prior art, such as the original patent CN102292071A, which discloses the use of cyclodextrin to reduce the sticking problem during the compression of brivaracetam immediate-release preparations. However, due to the large specific surface area of ​​low-melting-point brivaracetam in contact with the die during tableting, continuous industrial production makes low-melting-point brivaracetam easy to soften and cause sticking, resulting in poor stability of the active ingredient. Summary of the invention

[0005] The object of the present invention is to provide a brivaracetam preparation which is non-adhesive and / or has good stability and can release completely within 30 minutes.

[0006] The inventors of the present application unexpectedly discovered that a specific lactose selection can increase the stability of the composition of the present application, and therefore the first aspect of the present invention provides a pharmaceutical composition comprising brivaracetam or its salt and lactose, wherein the lactose D85 is ≤ 300 microns. Wherein, D85 represents the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 85%.

[0007] Further, the lactose is anhydrous lactose and lactose monohydrate, wherein the lactose monohydrate has a D85 of ≤200 microns. Further, the anhydrous lactose has a D85 of ≤300 microns.

[0008] Furthermore, the present invention provides a pharmaceutical composition comprising an internal part and an external part, wherein the internal part comprises brivaracetam or its salt and internal lactose, wherein the internal lactose D85≦200 microns; and the external part comprises external lactose, wherein the external lactose D85≦300 microns.

[0009] Furthermore, the internally added lactose of the present invention is selected from one or more of lactose monohydrate and anhydrous lactose, preferably lactose monohydrate.

[0010] Furthermore, the added lactose of the present invention is selected from one or more of lactose monohydrate and anhydrous lactose, preferably anhydrous lactose.

[0011] Furthermore, the content of brivaracetam or its salt is 10-30% by weight, preferably 18.5%-30%, preferably 18.5%.

[0012] Furthermore, the content of the internally added lactose is 20-60% by weight, preferably 30-50%, preferably 35-45%, preferably 36.5%; the content of the externally added lactose is 20-60% by weight, preferably 20-50%, preferably 24-36%, preferably 32-36%, preferably 35.8%.

[0013] The pharmaceutical composition of the present invention further comprises other excipients, which include binders, disintegrants, lubricants, etc. Furthermore, the internally added part comprises brivaracetam or its salt, internally added lactose, internally added disintegrants and / or binders, and the externally added part comprises externally added lactose, externally added disintegrants, and lubricants.

[0014] Furthermore, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene glycol, povidone, etc., preferably cross-linked povidone, cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose.

[0015] Furthermore, the binder is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, and starch, preferably low-substituted hydroxypropyl cellulose, starch, and cross-linked polyvinyl pyrrolidone, preferably low-substituted hydroxypropyl cellulose and starch, and preferably low-substituted hydroxypropyl cellulose.

[0016] The lubricant is selected from one or more of Tween, magnesium stearate, and sodium stearyl alcohol sulfonate.

[0017] Further, the content of the binder is 1.85-10% by weight, in some embodiments, the content of the binder is 1.85-6.85% by weight, in some embodiments, the content of the binder is 1.85-5% by weight, in some embodiments, the content of the binder is 5-6.85% by weight, preferably 5% or 6.85%; the content of the disintegrant is 1-10% by weight, 3.7-8.7%, preferably 3.7-6.85%, preferably 6.85-8.7%, preferably 1.85-6.85%, 1.85-5%, 5-6.85%, preferably 1.85%, 3.7% or 6.85%, 8.7%, further, the content of the internal disintegrant is 1.85%-6.85% by weight, 1.85-5%, 5-6.85%, preferably 1.85%, 5% or 6.85%, and the content of the external disintegrant is 1.85% by weight. The content of the lubricant is 0-1% by weight, preferably 0.5% by weight.

[0018] Furthermore, the pharmaceutical composition of the present invention comprises by weight:

[0019] Brivaracetam 10-30%

[0020] Add lactose 20-60%

[0021] Added lactose 20-60%

[0022] The D85 of the internally added lactose is ≤200 microns, and the D85 of the externally added lactose is ≤300 microns. Preferably, the internally added lactose is lactose monohydrate, and the externally added lactose is anhydrous lactose.

[0023] Furthermore, the pharmaceutical composition of the present invention comprises, by weight:

[0024]

[0025] wherein the internally added lactose is lactose monohydrate, D85≦200 microns; the externally added lactose is anhydrous lactose, D85≦300 microns; the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene glycol, povidone, etc., preferably cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose; the binder is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, starch, Low-substituted hydroxypropyl cellulose, starch, and cross-linked polyvinyl pyrrolidone are preferred, starch and low-substituted hydroxypropyl cellulose are preferred, and low-substituted hydroxypropyl cellulose is preferred; the lubricant is selected from one or more of Tween, magnesium stearate, and sodium stearyl alcohol sulfonate. Further, the disintegrant comprises an internal disintegrant and an external disintegrant, and the ratio of the internal disintegrant to the external disintegrant is 1:0.27-1:1. In certain embodiments, the ratio of the internal disintegrant to the external disintegrant is 1:0.27-1:0.37. In certain embodiments, the ratio of the internal disintegrant to the external disintegrant is 1:1-1:0.37.

[0026] Furthermore, the pharmaceutical composition of the present invention comprises, by weight:

[0027]

[0028] Furthermore, the pharmaceutical composition of the present invention comprises, by weight:

[0029]

[0030]

[0031] The second aspect of the present invention provides a preparation, which is a pharmaceutically acceptable oral dosage form such as tablets, granules, orodisintegrating tablets, pills, etc., preferably tablets.

[0032] The third aspect of the present invention provides a method for preparing the above-mentioned composition, which comprises weighing raw materials and auxiliary materials, sieving, mixing the internal raw materials and auxiliary materials brivaracetam, internal lactose, disintegrants and / or binders to obtain a mixed powder, granulating the mixed powder with a dry granulator, mixing the external auxiliary materials, lactose, and disintegrants, adding a lubricant, mixing, tableting, and coating. DETAILED DESCRIPTION

[0033] The present invention is further described in detail by the following examples, which are not intended to limit the scope of protection of the present invention. The drugs, reagents and instruments used in the present invention can all be obtained by conventional means.

[0034] The in vitro dissolution test investigation method in the following examples is as follows:

[0035] 900 ml of pH 6.4 phosphate buffer was used as the dissolution medium, the rotation speed was 50 rpm, and the operation was carried out according to the law. Samples were taken after 5, 10, 15, and 30 minutes, and conventional HPLC was used for detection.

[0036] Example 1 Prescriptions 1-3 are shown in Table 1:

[0037] Table 1

[0038]

[0039] Preparation process: weigh the raw and auxiliary materials according to the prescription amount, sieve them, mix them in a mixer for 5-30 minutes to obtain a mixed powder, granulate the mixed powder with a dry granulator, take the external auxiliary materials and add them to the mixer to mix, then add magnesium stearate and mix for 5-15 minutes, tablet press and coat.

[0040] Dissolution results: Prescriptions 1-3 were subjected to in vitro dissolution tests, and the results are shown in Table 2:

[0041] Table 2

[0042]

[0043] Stability test:

[0044] The prepared prescriptions 1-3 were placed at a high temperature of 60°C for 5 days, 10 days and 30 days, and samples were taken and tested for related substances using the HPLC method. The results are shown in Table 3 below.

[0045] Table 3

[0046]

[0047] Adhesion results: Prescription 2-3 effectively avoided the problem of excessive adhesion during the preparation of brivaracetam.

[0048] Example 2 Prescriptions 4-8 are shown in Table 4:

[0049] Table 4

[0050]

[0051] Preparation process: weigh the raw and auxiliary materials according to the prescription amount, sieve them, mix them in a mixer for 5-30 minutes to obtain a mixed powder, granulate the mixed powder with a dry granulator, take the external auxiliary materials and add them to the mixer to mix, then add magnesium stearate and mix for 5-15 minutes, tablet press and coat.

[0052] Dissolution results: Prescriptions 4-8 were subjected to in vitro dissolution tests. The results are shown in Table 5:

[0053] Table 5

[0054]

[0055] Stability study: The prepared prescriptions 4-8 were placed at a high temperature of 60°C for 5 days, 10 days and 30 days, and the HPLC method was used to sample and detect related substances. The results are shown in Table 6 below.

[0056] Table 6

[0057]

[0058] Example 3 Prescription 9 See Table 7:

[0059] Table 7

[0060]

[0061]

[0062] Preparation process: weigh the raw and auxiliary materials according to the prescription amount, sieve them, mix them in a mixer for 5-30 minutes to obtain a mixed powder, granulate the mixed powder with a dry granulator, take the external auxiliary materials and add them to the mixer to mix, then add magnesium stearate and mix for 5-15 minutes, tablet press and coat.

[0063] Dissolution results: Prescription 9 was subjected to an in vitro dissolution test, and the results are shown in Table 8:

[0064] Table 8

[0065]

[0066] Stability study: The prepared prescription was placed at a high temperature of 60°C for 5 days, 10 days and 30 days, and the HPLC method was used to sample and detect related substances. The results are shown in Table 9 below.

[0067] Table 9

[0068]

[0069] Example 4 Prescription 10 See Table 10:

[0070] Table 10

[0071]

[0072] Preparation process: weigh the raw and auxiliary materials according to the prescription amount, sieve them, mix them in a mixer for 5-30 minutes to obtain a mixed powder, granulate the mixed powder with a dry granulator, take the external auxiliary materials and add them to the mixer to mix, then add magnesium stearate and mix for 5-15 minutes, tablet press and coat.

[0073] Dissolution results: Prescription 10 was subjected to an in vitro dissolution test, and the results are shown in Table 11:

[0074] Table 11

[0075]

[0076] Stability study: The prepared prescription was placed at a high temperature of 60°C for 5 days, 10 days and 30 days, and the HPLC method was used to sample and detect related substances. The results are shown in Table 12 below.

[0077] Table 12

[0078]

[0079]

[0080] Example 5 Dissolution and stability study of commercially available brivaracetam tablets (original USB batch number 300231)

[0081] The dissolution results are shown in Table 13:

[0082] Table 13

[0083] Sampling point (min) Dissolution % 5 58 10 98 15 100 30 100 45 101

[0084] Stability study: The original tablets were placed at a high temperature of 60°C for 10 days, and samples were taken using the HPLC method to detect related substances. The results are shown in Table 14 below.

[0085] Table 14

[0086]

Claims

1. A pharmaceutical composition comprising brivaracetam or its salt and lactose, characterized in that The lactose D85≦300 μm.

2. The pharmaceutical composition according to claim 1, characterized in that The lactose is lactose monohydrate and lactose anhydrous, the lactose monohydrate D85≦200 microns, and preferably the anhydrous lactose D85≦300 microns.

3. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises an internal part and an external part, wherein the internal part comprises brivaracetam or its salt and internal lactose, wherein the internal lactose D85 is ≤200 microns; and the external part comprises external lactose, wherein the external lactose D85 is ≤300 microns.

4. The pharmaceutical composition according to claim 3, characterized in that The internally added lactose is selected from one or more of lactose monohydrate and anhydrous lactose, preferably lactose monohydrate; the externally added lactose is selected from one or more of lactose monohydrate and anhydrous lactose, preferably anhydrous lactose; the content of the internally added lactose is preferably 20-60% by weight, preferably 30-50%, preferably 35-45%, preferably 36.5%; the content of the externally added lactose is preferably 20-60% by weight, preferably 20-50%, preferably 24-36%, preferably 32-36%, preferably 35.8%.

5. The pharmaceutical composition according to claim 1, characterized in that The content of brivaracetam or its salt is 10-30% by weight, preferably 18.5%-30% by weight, preferably 18.5%.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The internal part of the pharmaceutical composition comprises brivaracetam or its salt, internal lactose, internal disintegrant and / or binder; the external part comprises external lactose, external disintegrant and lubricant; wherein the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene glycol, povidone, etc., preferably cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose; the binder is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and starch, preferably low-substituted hydroxypropyl cellulose, starch and cross-linked polyvinylpyrrolidone, preferably starch and low-substituted hydroxypropyl cellulose, preferably low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of Tween, magnesium stearate and sodium stearyl alcohol sulfonate.

7. The pharmaceutical composition according to claim 6, characterized in that The content of the binder is 1.85-10% by weight, preferably 1.85-6.85%, preferably 1.85-5%, preferably 5-6.85%, preferably 5% or 6.85%; the content of the disintegrant is 1-10% by weight, preferably 3.7-8.7%, preferably 3.7-6.85%, preferably 6.85-8.7%, preferably 1.85-6.85%, 1.85-5%, preferably 5-6.85%, preferably 1.85%, 3.7% or 6.85%, 8.7%; preferably the content of the internal disintegrant is 1.85%-6.85% by weight, preferably 1.85-5%, preferably 5-6.85%, preferably 1.85%, 5% or 6.85%; preferably the external disintegrant is 1.85% by weight; the content of the lubricant is 0-1% by weight, preferably 0.5%.

8. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The pharmaceutical composition comprises the following components by weight: Preferably, the pharmaceutical composition comprises by weight: The internally added lactose is lactose monohydrate, with D85≦200 microns; the externally added lactose is anhydrous lactose, with D85≦300 microns; the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene glycol, povidone, etc., preferably cross-linked povidone, cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose, povidone, preferably cross-linked sodium carboxymethyl cellulose; the binder is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, starch, preferably low-substituted hydroxypropyl cellulose, starch, cross-linked polyvinyl pyrrolidone, preferably starch, low-substituted hydroxypropyl cellulose, preferably low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of Tween, magnesium stearate, and sodium stearyl alcohol sulfonate. Further, the disintegrant comprises an internally added disintegrant and an externally added disintegrant.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition comprises the following components by weight: The D85 of the lactose monohydrate is ≤200 microns, and the D85 of the lactose anhydrous is ≤300 microns.

10. A preparation comprising the pharmaceutical composition according to any one of claims 1 to 9, characterized in that The preparation is a tablet.

11. A method for preparing the pharmaceutical composition according to claim 10, characterized in that The preparation method comprises weighing raw materials and auxiliary materials, sieving, mixing internal raw materials and auxiliary materials including brivaracetam, internal lactose, internal disintegrant and / or binder to obtain mixed powder, granulating the mixed powder by using a dry granulator, mixing external auxiliary materials, external lactose and external disintegrant, adding a lubricant, mixing, tableting, and coating.

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