Briracetam oral solution and preparation method thereof
By adjusting the formulation and preparation process of bricetramine oral solution and using ingredients such as leucine and maltitol, the stability and taste issues of bricetramine have been resolved, achieving safe medication and a good taste for pediatric patients.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
- Filing Date
- 2026-03-06
- Publication Date
- 2026-05-19
AI Technical Summary
Briracetam oral solution is prone to hydrolysis and degradation during preparation, generating related impurities and having a distinctly bitter taste, which affects medication adherence in pediatric patients. Traditional solutions require the addition of preservatives, which may be unsafe for children.
The combination of leucine, maltitol, sodium carboxymethyl cellulose, anhydrous citric acid, and sodium citrate enhances stability through multi-point hydrogen bonds and a microscopic protective layer. The high solubility and hydrophilicity of maltitol reduce water activity, leucine competitively binds to bitter taste receptors, and maltitol provides sweetness, thus avoiding the use of preservatives.
It improves the stability of briracetam oral solution and the compliance of pediatric patients, ensuring safety and good taste, and is suitable for children and the elderly.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically to a briceceran oral solution and its preparation method. Background Technology
[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
[0003] Brivaracetam, a third-generation antiepileptic drug, is a structural derivative of levetiracetam, a second-generation antiepileptic drug. It exerts its antiepileptic effect by selectively binding to synaptic vesicle protein 2a (SV2A) in the brain. Its affinity for SV2A is 15 to 30 times higher than that of levetiracetam, and its synaptic inhibition ability under high-frequency excitation is 100 times stronger. It also has a faster onset of action and can quickly cross the blood-brain barrier. It is suitable for the treatment of partial seizures, especially for patients who are intolerant to levetiracetam (such as those with irritability, depression, or other psychiatric side effects).
[0004] Epilepsy commonly occurs in childhood, with the highest incidence rate in children under one year old. The severity and prognosis of childhood epilepsy vary, and it can have a profound impact on development and personality. Bricetan can be used to treat partial-onset epilepsy in patients one month and older, and it is the only drug approved by the U.S. Food and Drug Administration (FDA) in recent years for the treatment of partial-onset epilepsy in pediatric patients one month and older.
[0005] Compared to solid dosage forms such as tablets and capsules, bricetratan oral solution has the advantages of flexible dosage adjustment and convenient administration, making it more suitable for special populations such as children, the elderly, and patients with swallowing difficulties, and its clinical application value is significant.
[0006] However, briracetam is chemically unstable, containing amide bonds in its molecular structure, making it prone to hydrolysis and degradation in solution, generating related impurities. Furthermore, briracetam has a distinctly bitter taste, resulting in a poor palatability for directly prepared oral solutions, which can lead to decreased patient compliance, particularly affecting medication adherence in children. Moreover, traditional oral solutions require the addition of preservatives such as antibacterial agents and are processed using injection-grade filling and sealing techniques, followed by final sterilization. However, the amount of preservatives safe for adults in oral solutions cannot guarantee complete safety for children.
[0007] Therefore, it is of great significance to prepare a bricetratan oral solution that is stable, free of preservatives and flavorings, highly safe for use by infants and children, has a good taste, is easy to operate, and is suitable for industrial production. Summary of the Invention
[0008] To overcome the above problems, the present invention provides a briracetam oral solution and a method for preparing the same.
[0009] To achieve the above technical objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a briracetam oral solution, the raw materials comprising, by weight: 1 part briracetam, 3-6 parts leucine, 20-30 parts maltitol, 1-3 parts sodium carboxymethyl cellulose, 0.1-0.5 parts anhydrous citric acid, 0.3-1.5 parts sodium citrate, and 15-20 parts glycerol.
[0010] A second aspect of the present invention provides a method for preparing the briracetam oral solution described in the first aspect, comprising the following steps: (1) Bricetan and leucine were sieved and mixed to obtain a raw material mixture; (2) Dissolve sodium carboxymethyl cellulose in the first purified water, and mix thoroughly for the first time to obtain solution A; (3) Dissolve anhydrous citric acid, sodium citrate and glycerol in the second purified water, mix well the second time, then add the raw material mixture and maltitol in sequence, mix well the third time to obtain solution B; (4) Mix solution A and solution B for the fourth time, then make up to a certain volume, filter and fill to obtain bricetrast oral solution.
[0011] In one or more embodiments, in step (1), bricetam and leucine are mixed by passing them through a 30-50 mesh sieve.
[0012] Preferably, in step (1), bricetam and leucine are sieved and mixed 2 to 4 times.
[0013] In one or more embodiments, in step (2), the ratio of the volume of the first purified water to the volume of the bricetan oral solution is 25% to 35%.
[0014] In one or more embodiments, in step (2), the first method for uniform mixing is stirring, and the stirring conditions are: stirring temperature of 45~55℃, stirring speed of 2000~2500 rpm, and stirring time of 18~22 min.
[0015] In one or more embodiments, in step (3), the ratio of the volume of the second purified water to the volume of the bricetramine oral solution is 20% to 30%.
[0016] In one or more embodiments, in step (3), the second method of uniform mixing is stirring, and the stirring conditions are: stirring temperature of 45~55℃, stirring speed of 60~70 rpm, and stirring time of 8~12 min.
[0017] In one or more embodiments, in step (3), the third method of uniform mixing is stirring, and the stirring conditions are: stirring temperature of 35~40℃, stirring speed of 60~70 rpm, and stirring time of 28~32 min.
[0018] In one or more embodiments, in step (4), the fourth method of uniform mixing is stirring, and the stirring conditions are: stirring temperature of 20~25℃, stirring speed of 60~70 rpm, and stirring time of 28~32 min.
[0019] In one or more embodiments, in step (4), the filter element used for filtration is made of polypropylene with a pore size of 1~3μm.
[0020] The beneficial effects of this invention are as follows: In this invention, by adjusting the formulation and preparation process of briceceran oral solution, the stability of briceceran is effectively improved, the antibacterial effect is effectively enhanced without the addition of preservatives, and the taste of the oral solution is adjusted, thereby improving the compliance of pediatric patients. Among them, (1) Regarding the improvement of stability: the amino and carboxyl groups in leucine can form multi-point hydrogen bonds with the amide carbonyl group, heterocyclic N, and polar hydroxyl group of briceceran, reducing the contact between briceceran and water molecules and oxygen; leucine has weak surface activity, and under the condition of uniform mixing with briceceran through sieving, it can form a microscopic protective layer around the briceceran molecule, thereby improving the stability of briceceran. Maltitol has high solubility and strong hydrophilicity, and can bind a large number of free water molecules through hydrogen bonds; the degradation of briceceran involves hydrolysis reaction, and by reducing the water activity of the system, the probability of collision between drug molecules and free water molecules can be effectively reduced, thereby inhibiting hydrolysis. (2) Regarding the antibacterial effect: Maltitol has a strong ability to bind free water molecules, which greatly reduces the water activity in the system. The reduction in water activity directly inhibits the growth of microorganisms. Secondly, maltitol is a non-fermentable polyol and is hardly utilized by common bacteria, molds, and yeasts. Leucine has weak surface activity and not only accumulates around briracetam molecules but also accumulates at the air-liquid interface of the solution, forming a molecular film that prevents oxygen from entering the solution and inhibits the growth of aerobic bacteria. (3) Regarding the regulation of the taste of oral solutions: The bitterness of briracetam originates from its molecules binding to bitter taste receptors (TAS2Rs) on the tongue. The molecular structure of leucine allows it to preferentially bind to these bitter taste receptors, competitively binding to the oral TAS2R bitter taste receptor binding sites, thus blocking the activation of bitter taste receptors by briracetam. Furthermore, maltitol has a pure sweetness, close to natural sugar, and a refreshing aftertaste, making it an ideal sugar-free sweetener. Detailed Implementation
[0021] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
[0022] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.
[0023] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0024] Example 1 The formulation of bricetan oral solution is shown in Table 1.
[0025] Table 1. Formulation of Biriracetam Oral Solution
[0026] Preparation method: (1) Bricetan and leucine were mixed three times through a 40-mesh sieve to obtain a raw material mixture; (2) Dissolve sodium carboxymethyl cellulose in 750 mL of purified water and mix by stirring (55℃, 2000 rpm, 20 min) to obtain solution A; (3) Dissolve anhydrous citric acid, sodium citrate and glycerol in 900 mL of purified water and stir (45℃, 70 rpm, 10 min) to dissolve. Then add the raw material mixture and maltitol in sequence and stir (40℃, 70 rpm, 30 min) to mix and obtain solution B. (4) Mix solution A and solution B (room temperature (25℃), 60 rpm, 30 min), add purified water to make up to 3000 mL, filter (filter material is polypropylene, filter pore size is 1.0 μm), and fill to obtain bricetan oral solution.
[0027] Example 2 The formulation of bricetan oral solution is shown in Table 2.
[0028] Table 2. Formulation of Biriracetam Oral Solution
[0029] Preparation method: (1) Bricetan and leucine were mixed three times through a 40-mesh sieve to obtain a raw material mixture; (2) Dissolve sodium carboxymethyl cellulose in 1050 mL of purified water and mix by stirring (45℃, 2500 rpm, 20 min) to obtain solution A; (3) Dissolve anhydrous citric acid, sodium citrate and glycerol in 900 mL of purified water and stir (45℃, 60 rpm, 10 min) to dissolve. Then add the raw material mixture and maltitol in sequence and stir (35℃, 60 rpm, 30 min) to mix and obtain solution B. (4) Mix solution A and solution B (room temperature (25℃), 70 rpm, 30 min). After the solution temperature stabilizes at room temperature, add purified water to make up to 3000 mL, filter (the filter material is polypropylene and the filter pore size is 1.0 μm), and fill to obtain bricetan oral solution.
[0030] Example 3 The formulation of bricetan oral solution is shown in Table 3.
[0031] Table 3. Formulation of Biriracetam Oral Solution
[0032] Preparation method: (1) Bricetan and leucine were mixed three times through a 40-mesh sieve to obtain a raw material mixture; (2) Dissolve sodium carboxymethyl cellulose in 840 mL of purified water and mix by stirring (50℃, 2200 rpm, 20 min) to obtain solution A; (3) Dissolve anhydrous citric acid, sodium citrate and glycerol in 750 mL of purified water and stir (42℃, 65 rpm, 10 min) to dissolve. Then add the raw material mixture and maltitol in sequence and stir (37℃, 65 rpm, 30 min) to mix and obtain solution B. (4) Mix solution A and solution B (room temperature (25℃), 65 rpm, 30 min). After the solution temperature stabilizes at room temperature, add purified water to make up to 3000 mL, filter (the filter material is polypropylene and the filter pore size is 1.0 μm), and fill to obtain bricetan oral solution.
[0033] Example 4 The formulation of bricetan oral solution is shown in Table 4.
[0034] Table 4. Formulation of Biriracetam Oral Solution
[0035] Preparation method: (1) Bricetan and leucine were mixed three times through a 40-mesh sieve to obtain a raw material mixture; (2) Dissolve sodium carboxymethyl cellulose in 960 mL of purified water and mix by stirring (52℃, 2000 rpm, 20 min) to obtain solution A; (3) Dissolve anhydrous citric acid, sodium citrate and glycerol in 690 mL of purified water and stir (48℃, 68 rpm, 10 min) to dissolve. Then add the raw material mixture and maltitol in sequence and stir (36℃, 68 rpm, 30 min) to mix and obtain solution B. (4) Mix solution A and solution B (room temperature (25℃), 68 rpm, 30 min). After the solution temperature stabilizes at room temperature, add purified water to make up to 3000 mL, filter (the filter material is polypropylene and the filter pore size is 1.0 μm), and fill to obtain bricetan oral solution.
[0036] Comparative Example 1 The formulation of bricetan oral solution is shown in Table 5.
[0037] Table 5. Formulation of Biriracetam Oral Solution
[0038] The preparation method is the same as in Example 1.
[0039] Comparative Example 2 The formulation of bricetan oral solution is shown in Table 6.
[0040] Table 6. Formulation of Biriracetam Oral Solution
[0041] The preparation method is the same as in Example 1.
[0042] Comparative Example 3 The formulation of bricetan oral solution is shown in Table 7.
[0043] Table 7 Formulation of Biriracetam Oral Solution
[0044] The preparation method is the same as in Example 1, except that sorbitol is added instead of maltitol.
[0045] Comparative Example 4 The formulation of the briceracetam oral solution is the same as in Example 1, except that the preparation method was adjusted: briceracetam and leucine were not premixed.
[0046] Preparation method: (1) Dissolve sodium carboxymethyl cellulose in 750 mL of purified water and mix by stirring (55℃, 2000 rpm, 20 min) to obtain solution A; (2) Dissolve anhydrous citric acid, sodium citrate and glycerol in 900 mL of purified water and stir (45℃, 70 rpm, 40 min) to dissolve. Then add briracetam, leucine and maltitol in sequence and stir (40℃, 70 rpm, 30 min) to mix and obtain solution B. (4) Mix solution A and solution B (room temperature (25℃), 60 rpm, 30 min). After the solution temperature stabilizes at room temperature, add purified water to make up to 3000 mL, filter (the filter material is polypropylene and the filter pore size is 1.0 μm), and fill to obtain bricetan oral solution.
[0047] Example 5 The stability of the brisaectam oral solutions prepared in Examples 1-4 was investigated under conditions following the guidelines of the 2025 edition of the Chinese Pharmacopoeia 9001 and ICH Q1. The solutions were stored in their commercially available packaging at 40℃±2℃ and 75%±5% relative humidity for 6 months. Samples were taken at the end of the 3rd and 6th months of the test period to examine changes in sample mass. The results are shown in Table 8.
[0048] Table 8 Stability Test Results
[0049] Analysis of Table 8 shows that impurities were not detected in the samples from Example 1 to Example 4 on day 0. No increase in impurities was observed from day 0 to 3 and 6 months of accelerated processing, and all impurities were not detected. Furthermore, there was no obvious trend in the content of impurities, indicating that the sample quality was stable.
[0050] In Comparative Example 1, an increasing trend was observed from day 0 to 3 and 6 months of accelerated reaction, while the content showed a decreasing trend. This indicates that the ratio of raw material to leucine was not within the range of 1:3 to 1:6, resulting in poor sample stability. In Comparative Example 2, a significant increasing trend was observed from day 0 to 3 and 6 months of accelerated reaction, while the content showed a significant decreasing trend. This indicates that without the addition of leucine, the sample stability was the worst. In Comparative Example 3, a significant increasing trend was observed from day 0 to 3 and 6 months of accelerated reaction, while the content showed a significant decreasing trend. This indicates that replacing maltitol with sorbitol resulted in poor sample stability. In Comparative Example 4, an increasing trend was observed from day 0 to 3 and 6 months of accelerated reaction, while the content showed a decreasing trend. This indicates that brimacin and leucine were not premixed, resulting in poor sample stability.
[0051] Example 6 The bricetratan oral solutions prepared in Examples 1 to 4 were subjected to microbial testing according to the biological limit test method (General Chapters 1105 and 1106 of Chinese Pharmacopoeia 2020). The total aerobic bacteria count in 1 mL of the test sample should not exceed 10. 2 The total CFU, mold, and yeast count must not exceed 10. 1 CFU should be negative for Escherichia coli and Burkholderia cepacia. Test results are shown in Table 9.
[0052] Table 9 Microbial Detection Results
[0053] Analysis of Table 9 shows that all microbiological tests of the samples in Examples 1 to 4 met the requirements. In Comparative Example 1, the total aerobic bacteria count was unqualified, indicating that the ratio of raw material to leucine was not within the range of 1:3 to 1:6, resulting in poor antibacterial activity. In Comparative Example 2, the total aerobic bacteria count, total mold and yeast count, and Escherichia coli count were unqualified, indicating that the lack of leucine resulted in the worst antibacterial activity. In Comparative Example 3, the total aerobic bacteria count, total mold and yeast count, and Burkholderia cepacia count were unqualified, indicating that replacing maltitol with sorbitol resulted in poor antibacterial activity. In Comparative Example 4, the total aerobic bacteria count and Escherichia coli count were unqualified, indicating that bricetam and leucine were not premixed, resulting in poor antibacterial activity.
[0054] Example 7 Taste tests were performed on the bricetam oral solutions prepared in Examples 1 to 4. Using the SA402B taste analysis system with its accompanying sensors: hydrochloride bitterness (BT0); basic bitterness (AN0); acidic bitterness (CO0); and astringency (AE1), taste evaluations were performed on Examples 1 to 4. The results of the electronic tongue taste measurement are shown in Table 10.
[0055] Table 10 Results of Electronic Tongue Palatability Test
[0056] Analysis of Table 10 shows that the samples in Examples 1-4 had lower taste values for BTO, COO, AE1, and BTO, with less bitterness and astringency, resulting in a better taste. Comparative Example 1 had higher taste values for all four samples than Examples 1-4, with more bitterness and astringency, indicating that the ratio of the active pharmaceutical ingredient to leucine was not within the range of 1:3 to 1:6, resulting in a poor taste. Comparative Example 2 had higher taste values for all four samples than Examples 1-4 and Comparative Example 1, with more bitterness and astringency, indicating that the sample without added leucine had the worst taste. Comparative Example 3 had higher taste values for all four samples than Examples 1-4, with more bitterness and astringency, indicating that replacing maltitol with sorbitol resulted in a poor taste. Comparative Example 4 had higher taste values for all four samples than Examples 1-4, with more bitterness and astringency, indicating that bricetam and leucine were not premixed, resulting in a poor taste.
[0057] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A bricetrast oral solution, characterized in that, The raw materials, by weight, include: 1 part briracetam, 3-6 parts leucine, 20-30 parts maltitol, 1-3 parts sodium carboxymethyl cellulose, 0.1-0.5 parts anhydrous citric acid, 0.3-1.5 parts sodium citrate, and 15-20 parts glycerol.
2. The method for preparing the briceceran oral solution according to claim 1, characterized in that, Includes the following steps: (1) Bricetan and leucine were sieved and mixed to obtain a raw material mixture; (2) Dissolve sodium carboxymethyl cellulose in the first purified water, and mix thoroughly for the first time to obtain solution A; (3) Dissolve anhydrous citric acid, sodium citrate and glycerol in the second purified water, mix well the second time, then add the raw material mixture and maltitol in sequence, mix well the third time to obtain solution B; (4) Mix solution A and solution B for the fourth time, then make up to a certain volume, filter and fill to obtain bricetrast oral solution.
3. The preparation method according to claim 2, characterized in that, In step (1), bricetam and leucine are mixed and passed through a 30-50 mesh sieve; Preferably, bricetam and leucine are sieved and mixed 2 to 4 times.
4. The preparation method according to claim 2, characterized in that, In step (2), the ratio of the volume of the first purified water to the volume of the bricetan oral solution is 25% to 35%.
5. The preparation method according to claim 2, characterized in that, In step (2), the first method for uniform mixing is stirring. The stirring conditions are: stirring temperature of 45~55℃, stirring speed of 2000~2500 rpm, and stirring time of 18~22min.
6. The preparation method according to claim 2, characterized in that, In step (3), the ratio of the volume of the second purified water to the volume of the bricetrast oral solution is 20% to 30%.
7. The preparation method according to claim 2, characterized in that, In step (3), the second method for uniform mixing is stirring. The stirring conditions are: stirring temperature of 45~55℃, stirring speed of 60~70 rpm, and stirring time of 8~12 min.
8. The preparation method according to claim 2, characterized in that, In step (3), the third method for uniform mixing is stirring. The stirring conditions are: stirring temperature of 35~40℃, stirring speed of 60~70 rpm, and stirring time of 28~32 min.
9. The preparation method according to claim 2, characterized in that, In step (4), the fourth method for uniform mixing is stirring. The stirring conditions are: stirring temperature of 20~25℃, stirring speed of 60~70 rpm, and stirring time of 28~32 min.
10. The preparation method according to claim 2, characterized in that, In step (4), the filter element used for filtration is made of polypropylene with a pore size of 1~3 μm.