Briracetam orally disintegrating tablet and preparation method thereof

Abstract

The invention discloses a briracetam orally disintegrating tablet and a preparation method thereof, and belongs to the technical field of biological medicines. The briracetam orally disintegrating tablet is prepared from the following components in parts by mass: 10 to 50 parts of a briracetam cyclodextrin inclusion compound, 10 to 87 parts of a filling agent, 1 to 20 parts of a disintegrating agent, 1 to 10 parts of a lubricating agent and 1 to 10 parts of a flavoring agent. According to the preparation method disclosed by the invention, the defect of poor flowability of the briracetam is effectively improved by a process of firstly preparing the cyclodextrin inclusion compound of the briracetam and then pressing the inclusion compound into the tablet; performance inspection on the tablets shows that the tablets have the characteristic of rapid disintegration accidentally, and the stability is remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a brivaracetam oral disintegrating tablet and a preparation method thereof. BACKGROUND

[0002] Brivaracetam is an antiepileptic drug developed by UCB, which is mainly used for the treatment of partial seizures. The drug can selectively bind to synaptic vesicle protein 2A (SV2A) in the brain with high affinity. Synaptic vesicle protein 2A is a transmembrane glycoprotein present in the presynaptic region of neurons and endocrine cells. Although the specific function of this protein still needs to be further studied, studies have shown that it can regulate the exocytosis of neurotransmitters. The binding of brivaracetam to SV2A may be the main mechanism of its anticonvulsant activity.

[0003] As an adjunctive therapy for partial seizures, the listing of brivaracetam provides a new choice for clinical treatment, especially for patients whose seizures are not fully controlled after using one or more other adjunctive therapies.

[0004] At present, there are two dosage forms of brivaracetam on the market worldwide, namely tablets and oral solutions, which are both suitable for the treatment of partial seizures in patients 1 month and older. Although the oral solution alleviates the difficulty of taking medicine for patients with epilepsy to some extent, it still has obvious limitations in actual clinical use: first, although the oral solution can improve the swallowing problem, it is easy to cause coughing risk due to its large volume, and the bitter taste of the drug itself greatly reduces the patient's medication compliance, making the medication compliance of special groups such as children not good, and thus adversely affecting the treatment effect; second, when the patient is in a state of seizure, it is often difficult to complete the swallowing action. Therefore, the existing dosage forms still have room for improvement in terms of clinical medication convenience.

[0005] Oral disintegrating tablets can quickly disintegrate in the oral cavity (usually within a few seconds to tens of seconds) after contacting saliva, without the need for swallowing action or water for administration. This feature is particularly important for people with difficulty swallowing (such as children, the elderly, postoperative patients, stroke patients) or patients who cannot cooperate with normal swallowing during a seizure period or a state of confusion, and can significantly reduce the difficulty of administration and the risk of aspiration. In addition, the dose control of oral disintegrating tablets is precise, avoiding the risk of medication due to dose errors that may occur with oral liquid preparations.

[0006] EP4559454A1 and CN104800176A disclose a preparation method of a brivaracetam oral disintegrating tablet, which includes disintegrating agents, diluents, lubricants, glidants, sweeteners, and flavorings. However, the bitter taste of the drug has not been effectively masked.

[0007] Studies have found that during the preparation and storage of the preparation, brivaracetam is prone to color change, and impurities increase, which is not conducive to product quality control and clinical use safety. CN102292071A discloses a fast-release pharmaceutical composition containing brivaracetam as an active ingredient, which comprises cyclodextrin, disintegrating agent and diluent, and the flowability and compression molding property of the material can be improved by adding cyclodextrin in the pharmaceutical composition; however, the patent does not make relevant research on the taste and impurity change of brivaracetam.

[0008] Cyclodextrin is a kind of cyclic oligosaccharide connected by glucose units through glycosidic bond, and common ones are α-, β- and γ-cyclodextrin, and the molecular structure presents a hollow cylindrical shape of "inner hydrophobic and outer hydrophilic". The components producing bad smell in drugs are mostly hydrophobic substances or hydrophobic parts, when they are included by the hydrophobic cavity of cyclodextrin, their chemical structure is "hidden" and cannot directly contact the olfactory or gustatory receptors of the human body, thereby blocking the transmission of odor signals, achieving the effect of masking odor. At the same time, the inclusion compound formed has good stability and can maintain stable structure during storage and taking.

[0009] Therefore, the present application designs to first prepare brivaracetam into a cyclodextrin inclusion compound and then press it into a tablet, so as to improve its bad smell and flowability, shorten its in-mouth disintegration time, and further improve the stability of brivaracetam. SUMMARY

[0010] The purpose of the present application is to provide an oral disintegrating tablet containing brivaracetam cyclodextrin inclusion compound, which is composed of brivaracetam cyclodextrin inclusion compound, filler, disintegrating agent and other pharmaceutically acceptable excipients, so as to mask the bad smell of brivaracetam, improve the compliance of pediatric patients, improve the stability, and solve the problem of poor flowability of brivaracetam.

[0011] In order to achieve the above purpose, the present application adopts the following technical means:

[0012] An oral disintegrating tablet of brivaracetam comprises, by mass fraction: 10-50 parts of brivaracetam cyclodextrin inclusion compound, 10-87 parts of filler, 1-20 parts of disintegrating agent, 1-10 parts of lubricant and 1-10 parts of flavoring agent.

[0013] The brivaracetam cyclodextrin inclusion compound is prepared from brivaracetam and cyclodextrin, and the molar ratio of the cyclodextrin to brivaracetam is 1:1-1:0.1.

[0014] Further, the cyclodextrin is selected from a-cyclodextrin, b-cyclodextrin, g-cyclodextrin, hydroxypropyl-b-cyclodextrin, dimethyl-b-cyclodextrin, dihydroxypropyl-b-cyclodextrin, maltodextrin cyclodextrin, maltotriodextrin cyclodextrin, b-cyclodextrin sulfobutyl ether, hydroxyethyl-b-cyclodextrin, methyl-b-cyclodextrin, glucosyl-b-cyclodextrin. Preferably a-cyclodextrin, b-cyclodextrin, g-cyclodextrin.

[0015] In the present application, the brivaracetam cyclodextrin inclusion compound is prepared by saturated solubility method. Specifically: the cyclodextrin is placed in a container, dissolved with solvent (aqueous solution or aqueous ethanol solution), heated to 40-70℃, brivaracetam or brivaracetam solution is added, stirred, filtered, refrigerated, dried to obtain brivaracetam cyclodextrin inclusion compound. After heating and dissolving the cyclodextrin, the brivaracetam is completely and uniformly dispersed in the solution of the cyclodextrin by stirring or ultrasonic mixing. The minimum temperature of the heated brivaracetam cyclodextrin solution should be lower than the melting point of brivaracetam to prevent degradation of brivaracetam caused by high temperature. Therefore, the temperature of the cyclodextrin solution in the present application is controlled between 40-70℃. The above mixture is cooled to 0-10℃, cooled for 12-48 hours, filtered, fluidized bed dried or oven dried, and the obtained brivaracetam cyclodextrin inclusion compound is collected.

[0016] Further, the filler is selected from anhydrous lactose, lactose monohydrate, starch, microcrystalline cellulose, mannitol, sugar powder, dextrin. Preferably a mixture of microcrystalline cellulose and mannitol, the mass ratio of the two is 1:1-10. The inventors found in experiments that after mixing the two, the grit feeling of the tablet in the oral cavity is significantly reduced.

[0017] Further, the disintegrant is selected from sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, dry starch, cross-linked sodium carboxymethyl cellulose. Preferably sodium carboxymethyl starch. The inventors found in experiments that when different disintegrants are added, there is a large difference in the wetting time of the tablets, and the effect is best when sodium carboxymethyl starch is used.

[0018] Further, the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, talc, micronized silica gel, gaseous silicon dioxide. Preferably micronized silica gel.

[0019] Further, the flavoring agent is selected from steviol glycoside, erythritol, trehalose, sorbitol, sodium saccharin, aspartame, sucralose, essence. Preferably sucralose and essence, the mass ratio of the two is 10-30:1. The inventors found in experiments that the taste masking effect of brivaracetam is more obvious when the two are used together.

[0020] The preparation method of the above-mentioned brivaracetam oral disintegrating tablet comprises the following steps:

[0021] Step 1, preparation of brivaracetam cyclodextrin inclusion compound;

[0022] Step 2, mix the brivaracetam cyclodextrin inclusion compound, filler, disintegrant, glidant, and flavoring agent, and press into tablets to obtain the brivaracetam orally disintegrating tablet.

[0023] Further, the step of preparing the brivaracetam cyclodextrin inclusion compound in step 1 is as follows: place the cyclodextrin in a container, dissolve with a solvent, heat to 40-70°C, add the brivaracetam or brivaracetam solution, stir, filter, cool, and dry to obtain the brivaracetam cyclodextrin inclusion compound.

[0024] The present application effectively improves the poor flowability of brivaracetam by first preparing the cyclodextrin inclusion compound of brivaracetam and then pressing the inclusion compound into tablets; and unexpectedly finds that the prepared tablets have the characteristics of rapid disintegration and significantly improved stability.

[0025] The technical effect of the present application is that:

[0026] (1) The brivaracetam cyclodextrin orally disintegrating tablet of the present application can effectively mask the bitter taste of brivaracetam, and the cyclodextrin avoids the bitter components from contacting the taste receptors, improves the taste, and improves the patient's medication compliance.

[0027] (2) The brivaracetam cyclodextrin orally disintegrating tablet of the present application significantly improves the stability of brivaracetam, inhibits impurity generation, and improves the flowability of the material, which is beneficial to industrialized production and quality control. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The dissolution curves of the brivaracetam tablets of Examples 5-9. DETAILED DESCRIPTION

[0029] The preferred embodiments of the present application will be described in detail below with reference to the examples. It should be understood that the following examples are given only for the purpose of illustration and are not intended to limit the scope of the present application. Those skilled in the art can make various modifications and substitutions to the present application without departing from the spirit and principles of the present application.

[0030] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0031] The materials and reagents used in the following examples are commercially available unless otherwise specified.

[0032] Example 1

[0033] The molar ratio of brivaracetam to α-cyclodextrin is 1:1.

[0034] Prescription composition:

[0035] Brivaracetam 5.3 g (0.025 mol)

[0036] α-cyclodextrin 24.3 g (0.025 mol)

[0037] 50% ethanol solution 1500 mL.

[0038] Preparation method: take α-cyclodextrin 24.3 g in a beaker, add 50% ethanol solution to dissolve, put on a magnetic heating stirrer, stir at 60°C, add brivaracetam 5.3 g, continue to stir for 3 h after adding all, filter, 4°C refrigeration for 12 h, precipitate solid, filter, dry to get loose powder, brivaracetam-α cyclodextrin inclusion compound is obtained.

[0039] Example 2

[0040] The molar ratio of brivaracetam and β-cyclodextrin is 1:1.

[0041] Prescription composition:

[0042] Brivaracetam 5.3 g (0.025 mol)

[0043] β-cyclodextrin 28.3 g (0.025 mol)

[0044] Water 1000 mL.

[0045] Preparation method: take β-cyclodextrin 28.3 g in a beaker, add water to dissolve, put on a magnetic heating stirrer, stir at 60°C, add brivaracetam aqueous solution (containing brivaracetam 5.3 g), continue to stir for 1 h after adding all, filter, 4°C refrigeration for 24 h, precipitate solid, filter, dry to get loose powder, brivaracetam-β cyclodextrin inclusion compound is obtained.

[0046] Example 3

[0047] The molar ratio of brivaracetam and γ-cyclodextrin is 1:10.

[0048] Prescription composition:

[0049] Brivaracetam 5.3 g (0.025 mol)

[0050] γ-cyclodextrin 324.25 g (0.25 mol)

[0051] Water 2000 mL.

[0052] Preparation method: take γ-cyclodextrin 324.25 g in a beaker, add water to dissolve, put on a magnetic heating stirrer, stir at 60°C, add brivaracetam 5.3 g, continue to stir for 3 h after adding all, filter, 4°C refrigeration for 36 h, precipitate solid, filter, dry to get loose powder, brivaracetam-γ cyclodextrin inclusion compound is obtained.

[0053] Example 4

[0054] Comparison of the angle of repose of brivaracetam bulk drug substance and brivaracetam cyclodextrin inclusion complex.

[0055] A clean and dry glass funnel with an internal diameter of typically 75 mm and a neck diameter of 3 mm is placed with its lower end outlet at a vertical distance of 25 mm from a glass receiving tray placed horizontally. About 50 g of the test product is slowly poured into the funnel and the powder is allowed to flow naturally to form a cone on the receiving tray. After the powder has completely flowed out, the angle between the slope of the cone and the horizontal plane is measured using a protractor. The measurement is repeated three times and the average value is taken. The result is reported to one decimal place.

[0056] Table 1 Comparison of the angle of repose of brivaracetam, examples 1-3

[0057]

[0058] From the comparison of the angle of repose, it can be seen that the cyclodextrin inclusion complex improves the flowability of the original brivaracetam bulk drug substance.

[0059] Example 5

[0060] Brivaracetam tablet

[0061]

[0062] Preparation process:

[0063] (1) The prescribed amount of sucralose, microfine silica gel and sodium carboxymethyl starch are mixed together and the prescribed amount of brivaracetam is added and mixed well.

[0064] (2) The prescribed amount of filler is mixed well with the powder from step (1) and compressed into tablets.

[0065] Example 6

[0066] Brivaracetam orally disintegrating tablet (using the brivaracetam-α-cyclodextrin inclusion complex of example 1 as the active ingredient)

[0067]

[0068]

[0069] Preparation process:

[0070] (1) The prescribed amount of sucralose, microfine silica gel and sodium carboxymethyl starch are mixed together and the prescribed amount of filler is added and mixed well.

[0071] (2) The prescribed amount of brivaracetam-α-cyclodextrin inclusion complex is mixed well with the powder from step (1) and compressed into tablets.

[0072] Example 7

[0073] Brivaracetam orally disintegrating tablets (using the brivaracetam-β-cyclodextrin inclusion complex of Example 2 as the active ingredient)

[0074]

[0075] Preparation process:

[0076] (1) Weigh the prescribed amount of sucralose, microfine silica gel, sodium carboxymethyl starch, and mix them evenly, then add the prescribed amount of filler and mix them evenly;

[0077] (2) Weigh the prescribed amount of brivaracetam-β-cyclodextrin inclusion complex and mix it evenly with the powder of step (1), then press it into tablets.

[0078] Example 8

[0079] Brivaracetam orally disintegrating tablets (using the brivaracetam-γ-cyclodextrin inclusion complex of Example 3 as the active ingredient)

[0080]

[0081] Preparation process:

[0082] (1) Weigh the prescribed amount of sucralose, microfine silica gel, sodium carboxymethyl starch, and mix them evenly, then add the prescribed amount of filler and mix them evenly;

[0083] (2) Weigh the prescribed amount of brivaracetam-γ-cyclodextrin inclusion complex and mix it evenly with the powder of step (1), then press it into tablets.

[0084] Example 9

[0085] Brivaracetam orally disintegrating tablets (using the brivaracetam-β-cyclodextrin inclusion complex of Example 2 as the active ingredient)

[0086]

[0087] Preparation process:

[0088] (1) Weigh the prescribed amount of sucralose, lemon flavor, microfine silica gel, and sodium carboxymethyl cellulose, and mix them evenly, then add the prescribed amount of filler and mix them evenly;

[0089] (2) Weigh the prescribed amount of brivaracetam-β-cyclodextrin inclusion complex and mix it evenly with the powder of step (1), then press it into tablets.

[0090] Example 10

[0091] Investigation of disintegration time

[0092] The burette is filled with 37°C water to the 0 mark, and the water drop speed is controlled (2 mL / min), and the distance between the water drop and the tablet is not more than 2 cm. The tablet is placed on a 30-mesh screen, and the water in the burette is just dropped onto the tablet. The time when the tablet starts to dissolve and all of it leaks from the screen is recorded as the disintegration time. The disintegration time within 60 s is qualified. The determination is repeated three times, and the average value is taken, and the result is rounded to one decimal place.

[0093] Table 2 Investigation of disintegration time of Examples 5-9

[0094]

[0095] From the disintegration time, it can be seen that the cyclodextrin inclusion compound can significantly improve the disintegration time of the tablet.

[0096] Example 11

[0097] Investigation of taste of Examples 5-9

[0098] First, 10 healthy volunteers (half male and half female) are selected to form an evaluation team. During the evaluation process, the volunteers need to hold the self-made oral disintegrating tablets in the mouth for 30 seconds and then spit them out, and then rinse their mouths three times. A single-blind test design and a five-level scoring system (indicated by ★, 0-5 stars) are used, in which five stars represent the best taste (completely no odor), and one star represents an unbearable strong odor. All evaluation results are recorded in a standardized questionnaire, and the final average score is calculated to objectively reflect the taste quality of the tablets.

[0099] Table 3 Taste evaluation star index

[0100]

[0101] Table 4 Determination results of taste evaluation of Examples 5-9

[0102]

[0103] From the taste evaluation, it can be seen that the cyclodextrin inclusion compound can mask the bad odor of the tablet. The taste-masking effect is better after adding sucralose and flavor in the prescription.

[0104] Example 12

[0105] In vitro dissolution evaluation

[0106] The dissolution medium was pH 1.2 hydrochloric acid solution with a volume of 900 mL, the rotation speed was 50 rpm, the temperature was 37 ± 0.5 °C, and the dissolution test was carried out. The sample was taken at 5, 10, 15, 30, 45 and 60 min, the sampling volume was 5 mL, the sample was filtered through a 0.45 μm filter membrane, and the initial filtrate 2 mL was discarded as the sample solution. The dissolution curve determination results are shown in the following table and Figure 1

[0107] Table 5 In-vitro dissolution of Examples 5-9

[0108]

[0109] From the dissolution results, the cumulative release of brivaracetam within 5 minutes was significantly improved after the preparation of the cyclodextrin inclusion compound.

[0110] Example 13

[0111] Influencing factor test

[0112] After removing the outer packaging of the self-prepared preparations of Examples 5, 8 and 9, they were placed in open weighing bottles and placed in a constant temperature environment of 60 °C ± 2 °C. The self-prepared preparations were sampled at 10 days and 30 days after placement, and the changes in the properties and related substances of the self-prepared preparations were investigated.

[0113] Table 6 Quality evaluation results of Example 5 under high temperature 60 °C conditions

[0114]

[0115] Table 7 Quality evaluation results of Example 8 under high temperature 60 °C conditions

[0116]

[0117] Table 8 Quality evaluation results of Example 9 under high temperature 60 °C conditions

[0118]

[0119] From the influencing factor test, it can be seen that the tablet surface of the cyclodextrin inclusion compound is smooth, the related substances do not increase basically, the content and dissolution do not decrease, and the taste is good; while the mixture tablet is yellow, the related substances increase significantly, and the content and dissolution decrease more.​

Claims

1. A bricetam orally disintegrating tablet, characterized in that, The product comprises, by weight, 10-50 parts of bricetan cyclodextrin inclusion complex, 10-87 parts of filler, 1-20 parts of disintegrant, 1-10 parts of lubricant, and 1-10 parts of flavoring agent. The bricetaram cyclodextrin inclusion complex is made from bricetaram and cyclodextrin, wherein the molar ratio of cyclodextrin to bricetaram is 1:1 to 1:0.

1.

2. The bricetam orally disintegrating tablet according to claim 1, characterized in that, The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, maltodextrin, maltotriose cyclodextrin, β-cyclodextrin sulfonyl ether, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin, and glucosyl-β-cyclodextrin.

3. The bricetam orally disintegrating tablet according to claim 2, characterized in that, The cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

4. The bricetam orally disintegrating tablet according to claim 1, characterized in that, The filler is selected from anhydrous lactose, lactose monohydrate, starch, microcrystalline cellulose, mannitol, powdered sugar, and dextrin.

5. The briceceran orally disintegrating tablet according to claim 4, characterized in that, The filler is a mixture of microcrystalline cellulose and mannitol.

6. The briceceran orally disintegrating tablet according to claim 1, characterized in that, The disintegrant is selected from sodium carboxymethyl starch, crospovidone, dry starch, and crospovidone carboxymethyl cellulose.

7. The bricetam orally disintegrating tablet according to claim 1, characterized in that, The lubricant is selected from stearic acid, magnesium stearate, calcium stearate, talc, micronized silica, and gaseous silica.

8. The bricetam orally disintegrating tablet according to claim 1, characterized in that, The flavoring agent is selected from steviol glycosides, erythritol, trehalose, sorbitol, sodium saccharin, aspartame, sucralose, and flavorings.

9. The method for preparing bricetam orally disintegrating tablets according to any one of claims 1-8, characterized in that, Includes the following steps: Step 1: Prepare bricetan cyclodextrin inclusion complex; Step 2: Mix the bricetramine cyclodextrin inclusion complex, filler, disintegrant, glidant, and flavoring agent, compress the mixture into tablets, and obtain bricetramine orally disintegrating tablets.

10. The preparation method according to claim 9, characterized in that, The steps for preparing the briceracetam cyclodextrin inclusion complex in step 1 are as follows: place the cyclodextrin in a container, add a solvent to dissolve it, heat to 40℃-70℃, add briceracetam or briceracetam solution, stir, filter, cool, and dry to obtain the briceracetam cyclodextrin inclusion complex.

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