Brivaracetam dual release trilayer tablets and method of preparation thereof

Abstract

The present invention relates to a dual-release tri-layer tablet for brivaracetam, which is composed of three layers: an immediate-release layer, a barrier layer, and a sustained-release layer, wherein the barrier layer is drug-free and located in the center, and at least 75% of the area of ​​each of the immediate-release layer and sustained-release layer is covered by the barrier layer, and the sustained-release material in the barrier layer comprises a wax-like sustained-release material. The tablet has the following properties: after administration of the tablet, the drug substance dissolves at a rate of 25% or more within 30 minutes, 30-65% within 2 hours, 65% or more within 6 hours, and 80% or more but less than 100% within 14 hours, when measured by the paddle method at a rotation speed of 50 rpm in test solutions of pH 1.2, pH 4.5, pH 6.8, or water; and the tablet also shows zero-order release 30 minutes after administration, thereby significantly improving the release profile of the drug brivaracetam, enhancing compliance and safety, and optimizing the therapeutic effect of the drug. The present invention also relates to a dual-release tri-layer tablet for brivaracetam, and a method for preparing the same, which belong to the pharmaceutical technology.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical technology, particularly to a dual release trilayer tablet of brivaracetam and its manufacturing method [Background technology]

[0002] The chemical name of brivaracetam is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide, and its molecular formula is C 11 H 20 N2O2. Brivaracetam is an effective drug for treating epilepsy and is clinically used as monotherapy for partial seizures in epileptic patients aged 4 years and older. Brivaracetam is readily soluble in water and weakly acidic liquids, and effective blood concentrations in the body are maintained for a short period of time. Currently available brivaracetam tablets and oral liquid formulations must be administered twice daily.

[0003] Previous reports on the release behavior of brivaracetam, such as CN106692095A, CN201510202995, and CN114028343A, disclose brivaracetam immediate-release formulations, which have the same drawbacks as the commercially available formulations, namely, too fast drug release rate, large fluctuations in blood concentration that are difficult to control, obvious side effects, significant toxic side effects, frequent administration, poor compliance, etc. On the other hand, CN113908153A and CN102046153B disclose sustained-release brivaracetam formulations, which have a long-lasting effect but a slow onset of effect and limited therapeutic efficacy. Summary of the Invention

[0004] The present invention provides a brivaracetam tablet and a method for manufacturing the same in order to improve the release profile of the brivaracetam drug, increase compliance and safety, and optimize the therapeutic effect of the drug.

[0005] In a first aspect, the present invention provides a pharmaceutical composition comprising three layers: an immediate-release layer, a barrier layer, and a sustained-release layer, wherein the barrier layer does not contain a drug and is located in the center, and at least 60% of the area of ​​each of the immediate-release layer and the sustained-release layer that is in contact with the barrier layer is covered by the barrier layer; and the sustained-release material in the barrier layer comprises a waxy sustained-release material, and the active pharmaceutical ingredient is selected from one or more of brivaracetam, a pharmaceutically acceptable coordination compound of brivaracetam, a pharmaceutically acceptable salt of brivaracetam, a pharmaceutically acceptable solvate of brivaracetam, a pharmaceutically acceptable hydrate of brivaracetam, and other structurally related derivatives of levetiracetam; The tablet has the properties of dissolving 25% or more of the active ingredient in the paddle method at a rotation speed of 50 rpm in test solutions of pH 1.2, pH 4.5, pH 6.8 or water within 30 minutes after administration, 30 to 65% within 2 hours, 65% or more within 6 hours, and 80% or more but less than 100% within 14 hours, and exhibits zero-order release within 30 minutes after administration.

[0006] The brivaracetam double-release tri-layer tablet is characterized in that the content of the active ingredient in the immediate-release layer is 20-35%, preferably 25-30%, of the total amount of the active ingredient, and the content of the active ingredient in the sustained-release layer is 65-80%, preferably 70-75%, of the total amount of the active ingredient.

[0007] Preferably, the formulation of the immediate release layer comprises: The weight ratio of the disintegrant in the immediate-release layer is 2% to 7.5%, preferably 5%, and the disintegrant is one or more of cross-carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose, which ensures that the immediate-release portion is released quickly and effectively in the gastrointestinal environment.

[0008] The filler may be one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and corn starch, with a weight ratio of 40 to 85% in the immediate-release layer. Preferably, the filler is a combination of anhydrous calcium hydrogen phosphate and corn starch, or a combination of microcrystalline cellulose and lactose. Preferably, the weight ratio of the combination of microcrystalline cellulose and lactose is 1:1 to 1:3, optimally 1:1. This selection ensures that the particles in the immediate-release layer have good compressibility and flowability, resulting in tablets with good consistency.

[0009] The binder has a weight percentage of 3 to 8% in the immediate-release layer, and is selected from hydroxypropyl cellulose or povidone K30 aqueous solution.

[0010] Preferably, the waxy sustained release material is selected from one or more of glyceryl behenate, carnauba wax and cetyl alcohol; Preferably, the sustained-release material in the barrier layer is composed of a waxy sustained-release material and a swellable sustained-release material, wherein the weight ratio of the waxy sustained-release material to the swellable sustained-release material is 0.4-0.8, preferably 0.5-0.7, and the total mass ratio of both materials in the barrier layer formulation is 60% or more; The swellable sustained release material is selected from one or more of guar gum, vegetable gum, seaweed gum, hydroxypropyl methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose.

[0011] Preferably, the thickness of the barrier layer is 1 mm or more, preferably 1 to 3 mm; Preferably, the filler is 15-30%, preferably 20-27%, of the barrier layer, and lactose, crystalline cellulose, anhydrous calcium hydrogen phosphate, or mannitol is selected, and preferably crystalline cellulose and lactose are selected. Hydroxypropyl cellulose or povidone K30 aqueous solution is selected as the binder, accounting for 6-15% of the formulation amount of the barrier layer, ensuring appropriate fluidity during manufacturing.

[0012] Preferably, the formulation of the sustained-release layer comprises an active ingredient, a sustained-release material, a filler, a flow aid and a lubricant; The sustained-release material accounts for 20% to 60%, preferably 25 to 40%, of the formulation, and the sustained-release material is one or two of HPMC K15M, HPMC K4M, HPMC K750, HPMC K100M, HPMC K100LV, EUDRAGIT® L100-55, glyceryl behenate, and xanthan gum, and more preferably a combination of HPMC K100M and EUDRAGIT® L100-55, a combination of HPMC K4M and EUDRAGIT® L100-55, or HPMC K100M.

[0013] The filler accounts for 35-65% of the sustained-release layer weight and is one or more of microcrystalline cellulose, lactose, anhydrous calcium hydrogen phosphate, and corn starch. Through testing, the present invention has confirmed that this selection of parameters ensures the compressibility and flowability of the formulation, as well as sufficient porosity after tableting.

[0014] Any of the above Brivaracetam dual release tri-layer tablets also has a film coating, and the coating material is selected from gastric soluble coating powder, and the coating weight gain is 2%-5%, preferably 3%.

[0015] In any of the above-mentioned Brivaracetam dual-release tri-layer tablets, the content of the active ingredient in the formulation of the immediate-release layer or the sustained-release layer is 20% or less. Through testing, it has been confirmed that the adoption of this parameter can ensure that the active ingredient is sufficiently dispersed by the excipients, and can effectively prevent dissolution and sticking due to the low melting point of the active ingredient under pressure during tableting.

[0016] In another aspect, the present invention provides a method for producing a fully mixed granule for the fast-release layer, comprising: weighing and mixing raw materials required for preparing a fast-release layer, a disintegrant, and a filler in a formulation amount, adding a binder and wet-granulating the mixture; drying the mixture after wet-granulation; and, when the moisture content becomes less than 4.0%, dry-granulating the mixture and completely mixing the mixture to obtain a fully mixed granule for the fast-release layer; Step b: weighing and mixing the required amounts of sustained-release materials and fillers for the sustained-release layer, adding the sprayed liquid and an appropriate amount of purified water to wet-granulate the mixture, drying the mixture after wet-granulation, and when the moisture content becomes less than 4.0%, dry-granulating the mixture and completely mixing to obtain a completely mixed granule for the sustained-release layer; and (c) weighing and mixing the sustained-release material and filler in the prescribed amounts required for producing the barrier layer, adding a binder and wet-granulating the mixture, drying the mixture after wet-granulation, and when the moisture content becomes less than 4.0%, dry-granulating the mixture and completely mixing the mixture to obtain a completely mixed granule for the barrier layer. Furthermore, in the total blending in step a, a portion of the dry granules for the rapid-release layer is blended with a prescribed amount of a flow aid, sieved, and then pre-blended with the remaining dry granules for the rapid-release layer. A portion of the pre-blended mixture is blended with a prescribed amount of a lubricant, sieved, and then thoroughly blended with the remaining pre-blended mixture to obtain a completely blended granule for the rapid-release layer. Furthermore, in the total blending in step b, a portion of the dry granules for the sustained-release layer is blended with a prescribed amount of a flow aid, sieved, and then pre-blended with the remaining dry granules for the sustained-release layer. A portion of the pre-blended mixture is blended with a prescribed amount of a lubricant, sieved, and then thoroughly blended with the remaining pre-blended mixture to obtain a completely blended granule for the sustained-release layer. Furthermore, in the total blending in step c, a portion of the dry granules for the barrier layer is blended with a prescribed amount of a flow aid, sieved, and then pre-blended with the remaining dry granules for the barrier layer. A portion of the pre-blended mixture is blended with a prescribed amount of a lubricant, sieved, and then thoroughly blended with the remaining pre-blended mixture to obtain a completely blended granule for the barrier layer. Preferably, the present invention provides any of the above methods for producing a dual-release trilayer tablet of brivaracetam, further comprising a tableting step, characterized in that the sustained-release layer, the barrier layer and the immediate-release layer are tableted in this order.

[0017] Compared with the prior art, the technical solution of the present invention has the following advantages: 1. The structure contains both an immediate-release part and a sustained-release part, which can achieve the rapid onset of action of existing Brivaracetam immediate-release preparations and the long-lasting sustained-release effect of ordinary sustained-release preparations, thereby reducing the number of administrations, improving patient compliance, and reducing the incidence of side effects caused by large fluctuations in blood concentration. Compared with the existing technology of Brivaracetam sustained-release formulations, the present invention develops a special barrier layer formulation interposed between the immediate-release layer and the sustained-release layer, so that the sustained-release layer in the present invention has one less release surface than ordinary sustained-release formulations, and this barrier layer can ensure the release of the sustained-release layer slower and achieve the effect of zero-order release.

[0018] 2. The distribution of API in the present invention is 20%-35%:65%-80% for immediate-release API:sustained-release API, which avoids the side effects caused by the excessively high maximum blood drug concentration after oral administration of existing Brivaracetam immediate-release formulations and the drawback of the existing Brivaracetam sustained-release tablet technology of slow onset of effect.

[0019] 3. It was confirmed that the content of API in the immediate-release and sustained-release layers was 20% or less, which ensured that the API was sufficiently dispersed by the excipients and effectively avoided the deterioration of tablet weight consistency or dissolution consistency caused by the API's low melting point melting and sticking under pressure during tableting.

[0020] From the above test results, the tablets provided by the present invention dissolve 25% or more of the active ingredient in 30 minutes, 30-60% in 2 hours, 60% or more in 6 hours, and 80% or more but less than 100% in 14 hours, show zero-order release 30 minutes after tablet administration, have good dissolution consistency and tablet weight consistency, and take into account both rapid onset of action and long-lasting slow release, and are thought to be able to achieve the effectiveness of pharmaceutical therapy even with once-daily administration. [Brief explanation of the drawings]

[0021] [Figure 1]The structures of the tablets of Examples 1 to 7 and Comparative Examples 1 to 8 are shown below. [Figure 2] FIG. 1 shows the dissolution of brivaracetam in Example 1 and Comparative Example 1. [Figure 3] FIG. 1 shows the dissolution of brivaracetam in Example 2 and Comparative Example 2. [Figure 4] FIG. 1 shows the deviation of brivaracetam dissolution in Example 3 and Comparative Example 3. [Figure 5] FIG. 1 shows the dissolution of brivaracetam in Example 4 and Comparative Example 5. [Figure 6] FIG. 1 shows the dissolution of brivaracetam in Example 4 and Comparative Example 6. [Figure 7] FIG. 1 shows the dissolution of brivaracetam in Example 5 and Comparative Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0022] The technical solutions of the present invention will be described in detail below in conjunction with exemplary embodiments, which should not be understood as limitations on the scope of the claims filed by the present invention.

[0023] Examples 1-7. Exemplary Formulations of the Present Invention The formulations corresponding to Examples 1 to 7 are shown in Tables 1 to 7, and the steps of the manufacturing method are as follows.

[0024] 1. Manufacturing: All-mixed granules for the immediate-release layer, all-mixed granules for the sustained-release layer, and all-mixed granules for the barrier layer a. The raw materials required for producing the immediate-release layer, Brivalaseta, disintegrant, and filler, are weighed and mixed in the required amounts, a binder is added, and wet granulation is carried out. After wet granulation, the mixture is dried, and when the moisture content is less than 4.0%, dry granulation is carried out and the mixture is thoroughly mixed to obtain fully mixed granules for the immediate-release layer. Here, for the total blending, a portion of the dry granules for the rapid-release layer is mixed with the prescribed amount of flow aid, sieved, and then pre-blended with the remaining dry granules for the rapid-release layer. A portion of the pre-blended mixture is mixed with the prescribed amount of lubricant, sieved, and then thoroughly blended with the remaining pre-blended mixture to obtain the fully blended granules for the rapid-release layer.

[0025] b. The required amount of sustained-release material and filler for the sustained-release layer are weighed and mixed, and an appropriate amount of purified water is added to the sprayed liquid to perform wet granulation. After wet granulation, the mixture is dried. When the moisture content is less than 4.0%, dry granulation is performed and the mixture is thoroughly mixed to obtain fully mixed granules for the sustained-release layer. Here, for the fully mixed process, a portion of the dry granules for the sustained-release layer is mixed with the prescribed amount of flow aid, sieved, and then premixed with the remaining dry granules for the sustained-release layer. A portion of the premix is ​​mixed with the prescribed amount of lubricant, sieved, and then thoroughly mixed with the remaining premix to obtain fully mixed granules for the sustained-release layer.

[0026] c. The sustained-release material and filler required for producing the barrier layer are weighed and mixed in the prescribed amounts, a binder is added, and wet granulation is performed. After wet granulation, the mixture is dried. When the moisture content is less than 4.0%, dry granulation is performed and the mixture is thoroughly mixed to obtain fully mixed granules for the barrier layer. Here, the fully mixed step involves mixing a portion of the dry granules for the barrier layer with the prescribed amount of flow aid, sieving the mixture, and then premixing it with the remaining dry granules for the barrier layer. A portion of the premix is ​​mixed with the prescribed amount of lubricant, sieving the mixture, and then thoroughly mixing it with the remaining premix to obtain fully mixed granules for the barrier layer.

[0027] 2.Tablet compression The tableting order for three-layer tablets is sustained-release layer > barrier layer > immediate-release layer, immediate-release layer > barrier layer > sustained-release layer, and barrier layer > sustained-release layer > immediate-release layer. As a result of the test, it was confirmed that the three-layer tablets obtained by tableting in the order of sustained-release layer > barrier layer > immediate-release layer had a consistent hardness and good dissolution consistency in the in vitro dissolution curve.

[0028] Table 1. Formulation for Example 1 [Table 1]

[0029] Table 2. Formulation for Example 2 [Table 2]

[0030] Table 3. Formulation for Example 3 [Table 3]

[0031] Table 4. Formulation for Example 4 [Table 4]

[0032] Table 5. Formulation for Example 5 [Table 5]

[0033] Table 6. Formulation for Example 6 [Table 6]

[0034] Table 7. Formulation for Example 7 [Table 7]

[0035] 2. Exam Performance test: Dissolution at each stage: Dissolution at 0.5 hours, 2 hours, 6 hours, 14 hours, and 18 hours after tablet administration in vitro Dissolution Consistency Tablet weight consistency In vitro dissolution, paddle method, sedimentation basket, 50 rpm, pH 6.4 phosphate buffer. The factors and test results that were found to have a significant impact on the physical and chemical properties of tablets during research and development are as follows: Tables 8 to 11 show comparative example recipes for verifying these influencing factors.

[0036] Comparative Example 1 Table 8. Formulation of Comparative Example 1 [Table 8]

[0037] However, in comparison with the tablet of Example 1, the sustained-release material used in the sustained-release layer of Comparative Example 1 was sodium carboxymethylcellulose. Comparative Example 2 Table 9. Formulation of Comparative Example 2 [Table 9]

[0038] In comparison with the tablets of Example 2, the proportion of the active ingredient in the immediate-release layer to the total amount of active ingredient in the tablet in Comparative Example 2 was 12%, and the proportion of the active ingredient in the sustained-release layer to the total amount of active ingredient in the tablet was 88%.

[0039] Comparative Examples 3 and 4 Table 10. Formulations for Comparative Examples 3 and 4 [Table 10]

[0040] However, in Comparative Example 3, the ratio of the active ingredient in the sustained-release layer to the total amount of the formulation of the sustained-release layer is greater than 20% compared to the tablets of Example 3. In Comparative Example 4, the ratio of the active ingredient in the immediate-release layer to the total amount of the formulation of the immediate-release layer is greater than 20% compared to the tablets of Example 3.

[0041] Comparative Examples 5-6 Table 11. Formulations for Comparative Examples 5 and 6 [Table 11]

[0042] However, in Comparative Example 5, the weight ratio of wax (carnauba wax) to HPMC in the barrier layer was 0.18 compared to the tablet in Example 4. In Comparative Example 6, the ratio of the total amount of wax (carnauba wax) and HPMC in the barrier layer was 47.06% compared to the tablet in Example 5.

[0043] Comparative Example 7 The difference between Comparative Example 7 and Example 5 is that in Comparative Example 7, all the particles for the barrier layer obtained in Example 5 were used to compression mold a barrier layer having a thickness of 0.8 mm, and the other formulations were the same as those in Example 5.

[0044] Comparative Example 8 The difference between Comparative Example 8 and Examples 5, 6 and 7 is that the ratio of crystalline cellulose to lactose in the immediate-release layer of Comparative Example 8 is 1:4, and the rest is the same as Examples 5, 6 and 7.

[0045] 2.1 Effects of sustained-release materials The only difference between Comparative Example 1 and Example 1 is that the sustained-release material is different. The dissolution curves of brivaracetam in Example 1 and Comparative Example 1 are shown in FIG. Dissolution characteristics: As shown in Figure 2, after changing to sodium carboxymethylcellulose, the dissolution rate decreased at each stage, and especially after 6 hours, the dissolution rate in Comparative Example 1 was significantly lower than that in Example 1, which resulted in a low blood concentration in the sustained release stage, making it difficult to achieve the desired effect. After administration of the tablet of Example 1, 25% or more of the active ingredient was dissolved within 30 minutes, 30 to 65% within 2 hours, 65% or more within 6 hours, and 80% or more but less than 100% within 14 hours, and the tablet showed zero-order release 30 minutes after administration.

[0046] 2.2 Effect of API partition ratio between sustained-release and immediate-release layers The only difference between Comparative Example 2 and Example 2 is the ratio of API in the immediate-release layer and the sustained-release layer, while the other additives are exactly the same. In Comparative Example 2, the ratio of the drug substance in the immediate-release layer to the total amount of drug substance in the tablet was 12% (less than 20%), and the ratio of the drug substance in the sustained-release layer to the total amount of drug substance in the tablet was 88% (more than 80%). The dissolution curves of brivaracetam in Example 2 and Comparative Example 2 are shown in FIG. Dissolution profile: As shown in Figure 3, after the API in the immediate-release layer decreased, it only reached 25% or more 2 hours after administration of the tablet, and no immediate effect was obtained. On the other hand, after administration of Tablet 2 in Example 2, 30% of the active ingredient was dissolved within 30 minutes, 30 to 60% within 2 hours, 65% or more within 6 hours, and 80% or more but less than 100% within 14 hours, and the tablet showed zero-order release 30 minutes after administration.

[0047] 2.3 Effect of API content in sustained-release layer The only difference between Comparative Example 3 and Example 3 is the ratio of API to additives in the sustained-release layer. In Comparative Example 3, the filler content was reduced, so the API content was increased from 19.7% to 21.31%, which was slightly higher than 20%. Dissolution experiments were carried out on six tablets randomly selected from each of Example 3 and Comparative Example 3. The dissolution data for Example 3 is shown in Table 12, and the dissolution data for Comparative Example 3 is shown in Table 13.

[0048] Table 12. Example 3, paddle method 50 rpm, pH 6.4, 900 ml, n=6 tablets, dissolution and dissolution deviation [Table 12]

[0049] [Table 13]

[0050] The dissolution deviation curves comparing the two tablets are shown in Figure 4. As shown in Table 13, the tablet of Comparative Example 3 did not meet the requirements of the present invention, namely, that the drug substance dissolved 25% or more in 30 minutes after administration, 30 to 65% in 2 hours, 65% or more in 6 hours, and 80% or more but less than 100% in 14 hours, and that the tablet showed zero-order release 30 minutes after administration. As shown in FIG. 4, it was found that Comparative Example 3 had a large elution deviation RSD. It can be determined that the absolute content of API in the sustained-release layer remains unchanged, but when the content of filler decreases, it significantly affects the dissolution characteristics of the tablet, and accordingly affects the blood concentration, and therefore the efficacy, stability, and safety of the drug.

[0051] 2.4 Effect of API content in the fast release layer The only difference between Comparative Example 4 and Example 3 is that the API in the immediate-release layer formulation in Comparative Example 4 is higher than 20%. Testing showed that the tablet weight consistency was significantly lower than that of Example 3.

[0052] Table 14. [Table 14]

[0053] In accordance with the present invention, it was observed that higher API content in the immediate-release layer resulted in lower layer weight and less consistent tablet weight, as shown in the formulations of Comparative Example 4 and Example 3 and in Table 14.

[0054] 2.5 Effect of the composition ratio of sustained-release materials in the barrier layer The only difference between Comparative Example 5 and Example 4 is that the ratio of the waxy sustained-release material to the swellable sustained-release material in the barrier layer is less than 0.5. Dissolution data is shown in FIG. As shown in Figure 5, when the ratio of waxy sustained-release material to swelling sustained-release material in the barrier layer is reduced, the most significant effect is that the dissolution rate at each stage is significantly higher than that of the tablets of Example 4, resulting in a higher initial blood concentration and a shorter drug action time.

[0055] 2.6 Effect of sustained-release material content in the barrier layer The only difference between the tablets of Comparative Example 6 and Example 4 is that the proportion of sustained-release material in the barrier layer is less than 60% (64.12% in Example 4), i.e., the proportion of filler and other additives is increased. Dissolution data is shown in FIG. As shown in Figure 6, by reducing the total proportion of sustained-release material in the barrier layer, the dissolution rate at each stage was significantly higher than that of the tablets of Example 4, and the dissolution curve tended to flatten after 3 hours, which resulted in high blood concentrations in the early stage of drug release and subsequent inability to reach the effective value. This prevented the real consideration of both rapid onset and long-term efficacy, and actually shortened the effective time.

[0056] 2.7 Effect of barrier layer thickness The difference between Comparative Example 7 and Example 5 is that the thickness of the barrier layer in Comparative Example 7 is 0.08 mm, while the thickness of the barrier layer in Example 5 is 2 mm. The test results are shown in Figure 7. As shown in Figure 7, the effect of reducing the mass ratio of the barrier layer on the dissolution characteristics of the tablet was mainly due to excessively fast dissolution, resulting in an excessively high initial blood concentration and a shortened effective time.

[0057] 2.8 Effect of the ratio of crystalline cellulose to lactose in the fast-release layer The difference between Comparative Example 8 and Examples 5, 6, and 7 is the ratio of crystalline cellulose to lactose in the immediate-release layer, but the total amount of crystalline cellulose and lactose in the immediate-release layer remains the same. The ratio of crystalline cellulose to lactose in Comparative Example 8 was 1:4, the ratio of crystalline cellulose to lactose in Example 5 was 1:2, the ratio of crystalline cellulose to lactose in Example 6 was 1:1, and the ratio of crystalline cellulose to lactose in Example 7 was 1:3. The flowability of the rapid-release layer granules is shown in Table 15.

[0058] Table 15. [Table 15]

[0059] The angle of repose is the angle formed by the inclined surface formed by piling powder and the horizontal plane at the bottom. The larger the angle of repose, the higher the coefficient of friction, and the worse the powder's fluidity. Generally, a powder with an angle of repose of less than 40° is considered to have good fluidity, and the Hausner ratio refers to the ratio of the powder's tap density to its bulk density. The higher the Hausner ratio, the worse the powder's fluidity. A Hausner ratio greater than 1.35 means that the powder's fluidity is poor. As shown in Table 15, the powder test showed that the angle of repose of the rapid-release layer granules in Comparative Example 8 was 44.7°, greater than 40°, and the Hausner ratio was 1.41, greater than 1.35, indicating poor powder fluidity, while Examples 5, 6, and 7 passed.

Claims

1. It consists of three layers: an immediate-release layer, a barrier layer, and a sustained-release layer, where: the barrier layer does not contain a drug and is located at the center, and at least 60% of the area of ​​each of the immediate-release layer and the sustained-release layer that contacts the barrier layer is covered by the barrier layer; and the sustained-release material in the barrier layer comprises a waxy sustained-release material; the drug substance is selected from one or more of brivaracetam, pharmaceutically acceptable coordination compounds of brivaracetam, pharmaceutically acceptable salts of brivaracetam, pharmaceutically acceptable solvates of brivaracetam and pharmaceutically acceptable hydrates of brivaracetam, and other structurally related derivatives of levetiracetam; The tablet has the properties of dissolving 25% or more of the active ingredient in 30 minutes, 30-65% in 2 hours, 65% or more in 6 hours, and 80% or more but less than 100% in 14 hours after administration of the tablet, when measured by the paddle method at a rotation speed of 50 rpm in test solutions of pH 1.2, pH 4.5, pH 6.8 or water, and also shows zero-order release in vitro 30 minutes after administration of the tablet.

2. The brivaracetam dual-release tri-layer tablet according to claim 1, wherein the content of the active ingredient in the immediate-release layer is 20-35% or 25-30% of the total amount of the active ingredient, and the content of the active ingredient in the sustained-release layer is 65-80% or 70-75% of the total amount of the active ingredient.

3. In the formulation of the immediate-release layer, The weight ratio of the disintegrant in the immediate-release layer is 2% to 7.5% or 5%, and the disintegrant is one or more of crosscarboxymethyl starch sodium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose; The weight ratio of the filler in the immediate-release layer is 40-85%, and the filler is one or more of lactose, crystalline cellulose, anhydrous calcium hydrogen phosphate, and corn starch. The brivaracetam dual-release trilayer tablet according to claim 1, characterized in that the weight percentage of binder in the immediate-release layer is 3-8%, and the binder is selected from hydroxypropyl cellulose or povidone K30 aqueous solution.

4. The brivaracetam dual release trilayer tablet according to claim 3, characterized in that the filler is a combination of anhydrous calcium hydrogen phosphate and corn starch or a combination of microcrystalline cellulose and lactose.

5. The brivaracetam dual release trilayer tablet according to claim 3, characterized in that the weight ratio of the combination of microcrystalline cellulose and lactose is 1:1 to 1:

3.

6. The Brivaracetam dual release trilayer tablet according to claim 1, characterized in that the waxy sustained release material is selected from one or more of glyceryl behenate, carnauba wax and cetyl alcohol.

7. The sustained-release material in the barrier layer is composed of a waxy sustained-release material and a swellable sustained-release material, wherein the weight ratio of the waxy sustained-release material to the swellable sustained-release material is 0.4-0.8 or 0.5-0.7, and the total mass proportion of the two materials in the barrier layer formulation is 60% or more; The brivaracetam dual-release trilayer tablet according to claim 1, wherein the swellable sustained-release material is selected from one or more of guar gum, vegetable gum, seaweed gum, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxyethylcellulose.

8. The brivaracetam dual release trilayer tablet according to claim 7, characterized in that the thickness of the barrier layer is 1 mm or more or 1-3 mm.

9. The proportion of filler in the barrier layer is 15 to 30% or 20 to 27%, and the filler is selected from one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and mannitol; The brivaracetam dual release trilayer tablet according to claim 8, characterized in that the binder accounts for 6-15% of the formulation weight of the barrier layer, and is selected from hydroxypropyl cellulose or povidone K30 aqueous solution.

10. The formulation of the sustained-release layer comprises an active ingredient, a sustained-release material, a filler, a flow aid, and a lubricant; wherein the sustained-release material accounts for 20% to 60% or 25 to 40% of the prescribed amount; The brivaracetam dual-release trilayer tablet according to claim 1, wherein the sustained-release material is one or two of HPMC K15M, HPMC K4M, HPMC K750, HPMC K100M, HPMC K100LV, EUDRAGIT® L100-55, glyceryl behenate, and xanthan gum.

11. The sustained release material is HPMC K100M and EUDRAGIT® a combination of HPMC K4M and EUDRAGIT® L100-55, or a combination of HPMC K4M and EUDRAGIT® L100-55, or HPMC K100M; The brivaracetam dual-release trilayer tablet according to claim 10, characterized in that the filler accounts for 35-65% of the weight of the sustained-release layer, and the filler is one or more of microcrystalline cellulose, lactose, anhydrous calcium hydrogen phosphate, and corn starch.

12. The brivaracetam dual-release trilayer tablet according to any one of claims 1 to 11, characterized in that the content of active pharmaceutical ingredients in the formulation of the immediate-release layer or the sustained-release layer is 20% or less.

13. The brivaracetam dual release trilayer tablet according to any of claims 1 to 11, characterized in that it also has a film coating, the coating material is selected from gastric soluble coating powder, and the weight gain of the coating is 2% to 5% or 3%.

14. Step a) of weighing and mixing raw materials necessary for producing the rapid-release layer, such as Brivalaseta, a disintegrant, and a filler, and then adding a binder to wet-granulate the mixture, followed by drying and, when the moisture content is less than 4.0%, dry-granulating the mixture and completely mixing to obtain a completely mixed granule for the rapid-release layer; Step b: weighing and mixing the sustained-release material and filler in the prescribed amounts required for producing the sustained-release layer, adding the sprayed liquid and an appropriate amount of purified water to wet-granulate, drying the wet-granulated material, and when the moisture content becomes less than 4.0%, dry-granulating the granules and completely mixing them to obtain a completely mixed granule for the sustained-release layer; and c) step (c) of weighing and mixing the sustained-release material and filler in the prescribed amounts required for preparing the barrier layer, adding a binder and wet-granulating the resulting mixture, drying the resulting mixture after wet-granulation, and then dry-granulating the resulting mixture when the moisture content is less than 4.0%, and then completely mixing the resulting mixture to obtain a completely mixed granule for the barrier layer.

15. where: For the total mixing in step a, a portion of the dry granules for the rapid-release layer is mixed with a prescribed amount of a flow aid, sieved, and then premixed with the remaining dry granules for the rapid-release layer. A portion of the pre-mixture is mixed with the prescribed amount of lubricant, sieved, and then thoroughly mixed with the remaining pre-mixture to obtain fully mixed granules for the immediate-release layer. For the total mixing in step b, a portion of the dry granules for the sustained-release layer is mixed with a prescribed amount of a flow aid, sieved, and then premixed with the remaining dry granules for the sustained-release layer. A portion of the pre-mixture is mixed with the prescribed amount of lubricant, sieved, and then thoroughly mixed with the remaining pre-mixture to obtain thoroughly mixed granules for the sustained-release layer. As for the total mixing in step c, a part of the dry granules for the barrier layer is mixed with a prescribed amount of a flow aid, sieved, and then premixed with the remaining dry granules for the barrier layer. The manufacturing process according to claim 14, characterized in that a part of the premix is ​​mixed with a prescribed amount of lubricant, sieved, and then thoroughly mixed with the remaining premix to obtain thoroughly mixed granules for the barrier layer.

16. The manufacturing process according to claim 14, further comprising a tableting step, wherein the sustained-release layer, the barrier layer and the immediate-release layer are tableted in this order.

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