Levetiracetam oral solution and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and discloses a levetiracetam oral solution and a preparation method thereof, the levetiracetam oral solution comprises the following raw material components by mass concentration: 80-120 mg / ml of an active component levetiracetam, a pH value regulator, 2.50-2.90 mg / ml of a bacteriostatic agent, 180-220 mg / ml of a cosolvent and 280-350 mg / ml of a flavoring agent, and the pH value of the levetiracetam oral solution is 5.0-5.6. The preparation method is carried out according to the following charging sequence: purified water and glycerol, methylparaben, propylparaben, mono-ammonium glycyrrhizinate S, acesulfame potassium, sodium acetate, liquid maltitol, levetiracetam, 1% acetic acid solution and essence. Compared with the prior art, the levetiracetam oral solution prepared by the preparation method disclosed by the invention is better in mouth feel and higher in stability; the adjustment of the preparation process greatly shortens the time required for preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a levetiracetam oral solution and a preparation method thereof. Background Art

[0002] Epilepsy, as a chronic brain disease, affects people in all countries of the world. During an epileptic seizure, a part of the body or the whole body experiences brief involuntary convulsions (i.e., partial or generalized seizures), sometimes accompanied by loss of consciousness and urinary and fecal incontinence. Levetiracetam, as one of the first-choice drugs for partial epileptic seizures, has been widely used. A variety of preparations have been approved in China, including tablets, sustained-release tablets, suspensions, injections, oral solutions and other dosage forms.

[0003] Levetiracetam has good stability under high temperature, light and oxidation conditions, but poor stability under acid and alkaline conditions; and the oral solution of levetiracetam tastes bitter and has a very poor taste, which greatly affects the patient's compliance with the medication. The added antibacterial agents and flavor enhancers contain insoluble excipients, and the dissolution waiting time is too long, which prolongs the preparation cycle and reduces production efficiency. Summary of the invention

[0004] The purpose of the present invention is to provide a levetiracetam oral solution and a preparation method thereof to solve the problem of poor stability of the current levetiracetam drug under acid and alkaline conditions, thereby solving the stability problem of the levetiracetam oral solution.

[0005] The technical solution of the present invention is as follows:

[0006] The present invention provides a levetiracetam oral solution, comprising the following raw material components in mass concentrations: 80-120 mg / ml of active ingredient levetiracetam, a pH regulator, 2.50-2.90 mg / ml of an antibacterial agent, 180-220 mg / ml of a cosolvent, and 280-350 mg / ml of a flavoring agent.

[0007] The dosage of the pH regulator is set to make the pH value of the levetiracetam oral solution be 5.0-5.6.

[0008] Preferably, the composition comprises: 100 mg / ml levetiracetam, 3 mg / ml antibacterial agent, 210 mg / ml cosolvent and 308 mg / ml flavoring agent; the dosage of the pH regulator is set so that the pH value of the levetiracetam oral solution is 5.6.

[0009] According to a preferred embodiment, the pH adjuster is sodium acetate and 1% acetic acid.

[0010] According to a preferred embodiment, the antibacterial agent is methylparaben and propylparaben.

[0011] According to a preferred embodiment, the co-solvent is glycerol.

[0012] According to a preferred embodiment, the flavoring agent includes acesulfame potassium (acesulfame potassium), glycyrrhizic acid monoammonium salt S, liquid maltitol, and flavor.

[0013] According to a preferred embodiment, the concentration of the flavor is 2.0 mg / ml to 4.0 mg / ml, and the concentration of the monoammonium glycyrrhizinate S is 1.2 mg / ml to 2.0 mg / ml. Through the above-mentioned formula improvement and concentration setting, the bitterness and taste of the levetiracetam oral solution are improved, and the patient's medication compliance is improved.

[0014] According to a preferred embodiment, the flavor is grape flavor.

[0015] Another aspect of the present invention provides a method for preparing a levetiracetam oral solution, comprising the following steps:

[0016] (1) Add 15%-25% of the prescribed amount of purified water and the prescribed amount of glycerol, continue stirring, and heat the solution to 50°C ± 10°C;

[0017] (2) Maintaining the solution temperature, add the prescribed amount of methylparaben, propylparaben, monoammonium glycyrrhizinate S, and acesulfame potassium (acesulfame potassium) in sequence and stir evenly; adding the prescribed amount of methylparaben, propylparaben, monoammonium glycyrrhizinate S, and acesulfame potassium (acesulfame potassium) in sequence can avoid large fluctuations in pH, which may lead to a decrease in the stability of the raw materials.

[0018] (3) adding a pH adjuster and liquid maltitol in sequence and stirring evenly;

[0019] (4) When the temperature of the drug solution drops to less than 50°C, add levetiracetam, keep the temperature of the drug solution less than 50°C, and stir evenly;

[0020] (5) Add purified water to about 90% ± 5% of the prescribed amount and adjust the pH value of the solution to 5.0 ± 0.3-5.6 ± 0.3;

[0021] (6) When the temperature of the liquid medicine drops to less than 30°C, add the prescribed amount of flavor and stir evenly;

[0022] (7) Add purified water to the liquid preparation tank to make up to 450 L and stir evenly;

[0023] (8) filtering to obtain a levetiracetam oral solution.

[0024] According to a preferred embodiment, the time limit from the start of step (1) to the start of step (8) is ≤ 24 hours.

[0025] According to a preferred embodiment, step (8) uses a group of polypropylene filter elements for filtration, the filter element pore size is 5.0 μm, the filtrate temperature during filtration should be less than 30° C., and the filtration pressure is ≤0.2 MPa.

[0026] According to the above-mentioned levetiracetam oral solution, in its preparation process, 1% acetic acid solution is first prepared.

[0027] Another aspect of the present invention provides a levetiracetam oral solution prepared by the above-mentioned preparation method.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. A levetiracetam oral solution, which controls the pH value of the liquid to 5.0-5.6 by optimizing the pH regulator or buffer system, thereby overcoming the problem of instability of the levetiracetam oral solution under acidic and alkaline conditions; through long-term illumination and high temperature conditions, it is found that the levetiracetam oral solution prepared in this application has good stability; this application study found that when the pH value of the sample is 4.0 or below and above 8.0, the increase of related impurities is obvious; and through compatibility studies, it is shown that the excipients of this application are compatible with the raw materials;

[0030] 2. A levetiracetam oral solution, which greatly improves the taste of the product by improving the concentration of flavor and glycyrrhizic acid monoammonium salt S. Experiments have found that the design of this application improves the taste score, the taste of the homemade preparation is better than the reference preparation, and the patient's medication compliance is improved;

[0031] 3. A method for preparing levetiracetam oral solution, by adjusting and controlling the order of adding antibacterial agents and flavor correctives, sequentially adding methylparaben, propylparaben, glycyrrhizic acid monoammonium salt S, and acesulfame potassium, shortening the dissolution time of poorly soluble excipients, so that the dissolution time is shortened to less than 1 / 2 of the original time, significantly reducing the drug preparation time; at the same time, reducing the significant change in the pH value of the drug solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Schematic diagram of the structure of levetiracetam oral solution. DETAILED DESCRIPTION

[0033] The specific embodiments listed in the present invention are only examples of the present invention, and the present invention is not limited to the specific embodiments described below. For those skilled in the art, any equivalent modifications and substitutions to the embodiments described below are also within the scope of the present invention. Therefore, the equal transformations and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturers are not specified for all reagents or instruments, they are all conventional products that can be purchased commercially. In order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. It should be understood by those skilled in the art that the present invention can also be implemented without certain specific details. In other embodiments, the methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the purport of the present invention.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. Unless otherwise specified, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0035] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0036] Example 1 A levetiracetam oral solution and a preparation method thereof

[0037] The formula of the levetiracetam oral solution prepared in this example is as shown in Table 1:

[0038] Table 1 Formula of levetiracetam oral solution

[0039] Element Prescription dosage (kg) effect levetiracetam 45 Active ingredients Sodium acetate 0.414 pH Adjusters acetic acid 0.016～0.023 pH Adjusters Methylparaben 1.215 Antibacterial Agents Propylparaben 0.135 Antibacterial Agents glycerin 94.5 Solvent Acesulfame Potassium (Acesulfame K) 2.07 Flavoring agents <![CDATA[Monoammonium glycyrrhizinate S [2] > 0.54 Flavoring agents Liquid Maltitol 135 Flavoring agents Grape flavor 0.9 Flavoring agents Add purified water to 450L Solvents

[0040] Levetiracetam oral solution was prepared according to the following preparation process:

[0041] 1. Liquid preparation

[0042] (1) Weighing: Weigh the raw and excipient materials according to the prescribed amount and set aside, including the raw material drug and glycyrrhizic acid monoammonium salt S, on a dry and pure basis.

[0043] (2) Preparation of 1% acetic acid: Weigh acetic acid, add 2.97 kg of purified water and stir until completely dissolved, and set aside.

[0044] (3) Add 20% of the prescribed amount of purified water to the liquid preparation tank, turn on the heating, add the prescribed amount of glycerin, turn on the stirring, the stirring speed is 80rpm, and heat to 50℃±10℃. Add the prescribed amount of methylparaben, propylparaben, monoammonium glycyrrhizinate S, and acesulfame potassium (acesulfame potassium) in the order of addition. After the addition is completed, continue to maintain the temperature of the liquid at 50.0℃±10.0℃, stir at 80rpm, and stir for 10 minutes. Using this order of addition avoids large changes in pH, ensures the stability of the liquid, and shortens the dissolution time of poorly soluble excipients.

[0045] (4) Sodium acetate and liquid maltitol were added in sequence, with a stirring speed of 80 rpm and stirring for 5 min.

[0046] (5) When the temperature of the drug solution drops to less than 50°C, add levetiracetam (structural formula: Figure 1 As shown), keep the liquid temperature <50°C, stir at 80 rpm, and stir for 15 minutes.

[0047] (6) Add purified water to about 90% of the prescribed amount, stir at 80 rpm, and stir for 5 minutes.

[0048] (7) Take samples to test the pH value of the drug solution and use a pH adjuster (sodium acetate or 1% acetic acid) to adjust the pH of the solution to 5.3±0.3.

[0049] (8) Cool the liquid to less than 30°C, add the prescribed amount of grape flavor essence, stir at a speed of 80 rpm, and stir for 10 minutes.

[0050] (9) Add purified water to the liquid preparation tank to make the volume 450L, stir at 80rpm, and continue stirring for 15min to obtain the pre-filtration preparation liquid (intermediate product). The time limit from the start of liquid preparation to the start of filtration is ≤24 hours.

[0051] 2. Filter

[0052] Filter the liquid medicine through a set of polypropylene filter elements with a pore size of 5.0μm. During filtration, the filtrate temperature should be less than 30℃ and the filtration pressure should be ≤0.2MPa.

[0053] Example 2

[0054] The same formula and preparation process as in Example 1 are used, and the only difference from Example 1 is that in step (7), a pH adjuster is used to adjust the pH of the solution to 5.0±0.3.

[0055] Example 3

[0056] The same formula and preparation process as in Example 1 are used, and the only difference from Example 1 is that in step (7), a pH adjuster is used to adjust the pH of the solution to 5.6±0.3.

[0057] Stability test of the drug solution prepared in Example 1-3 under illumination (4500lx±500lx):

[0058] The drug solutions prepared in Examples 1-3 were placed under illumination (4500 lx ± 500 lx) for 30 days, and samples were taken on the 0th, 14th and 30th days to test the properties, pH value and content of related substances (parahydroxybenzoic acid, methylparaben and propylparaben). It was used as a reference preparation for comparison.

[0059] The results of the investigation of each group under light treatment are shown in Table 2 and Table 3 below:

[0060] Table 2 Results of 30-day observation of light intensity (4500lx±500lx)

[0061]

[0062]

[0063] The key change data in Table 2 are summarized as shown in Table 3 below:

[0064] Table 3 Light intensity (4500lx±500lx) 30-day increase

[0065]

[0066] As can be seen from Table 2 and Table 3 above, the levetiracetam oral solutions prepared in Example 1, Example 2, and Example 3 and the reference preparation were observed under illumination (4500 lx±500 lx) for 30 days, compared with 0 day:

[0067] ① Properties: The properties of the self-made product did not change, while the reference product changed from a colorless clear solution to an almost colorless clear solution;

[0068] ③ pH value and related substances: There is no significant change in pH value and related substances between the self-made product and the reference preparation;

[0069] ④ Para-hydroxybenzoic acid: the reference preparation had a 0.012% increase in para-hydroxybenzoic acid, while no para-hydroxybenzoic acid was detected in the samples of Example 1 and Example 2, indicating better stability;

[0070] ⑤ Content: There was no significant change in the contents of methylparaben, propylparaben and levetiracetam in the levetiracetam oral solution prepared in Examples 1-3 and the reference preparation, indicating that the drug had good stability.

[0071] From the above results, it can be seen that the drug solutions with pH values ​​of 5.0 to 5.6 prepared in Examples 1-3 have no significant difference in stability under illumination (4500 lx±500 lx) for 30 days.

[0072] Stability test of the levetiracetam oral solution prepared in Example 1-3 under high temperature (60°C ± 2°C):

[0073] The levetiracetam oral solution prepared in Example 1-3 was placed under high temperature (60°C ± 2°C) for 30 days, and samples were taken on the 0th, 14th and 30th days to detect the properties, pH value, and content of related substances (parahydroxybenzoic acid, methylparaben, propylparaben). It was used as a reference preparation for comparison.

[0074] The results of the investigation of each group under high temperature treatment are shown in Table 4 and Table 5 below:

[0075] Table 4 Results of 30-day investigation under high temperature (60°C ± 2°C) conditions

[0076]

[0077]

[0078] The key change data in Table 4 are summarized as shown in Table 5 below:

[0079] Table 5: Increase in high temperature (60℃±2℃) for 30 days

[0080]

[0081] As can be seen from Table 4 and Table 5 above, the levetiracetam oral solution prepared in Example 1-3 and the reference preparation were investigated under high temperature (60°C ± 2°C) for 30 days, compared with 0 day:

[0082] ① Properties: Both the self-made product and the reference product changed from a colorless clear solution to an almost colorless clear solution;

[0083] ② Solution clarity and color: The color of the self-made product and the reference preparation is darker than the yellow-green No. 1 standard colorimetric solution and is clear;

[0084] ③ pH value: There is no significant change in pH value between the self-made product and the reference product;

[0085] ④Related substances and p-hydroxybenzoic acid: The related substances of self-made products increased by 0.14%, 0.11%, and 0.14%, respectively, and p-hydroxybenzoic acid increased by 0.32%, 0.59%, and 1.1%, respectively. With the increase of pH value, the increase was greater. The related substances of reference preparations increased by 0.096%, and p-hydroxybenzoic acid increased by 0.643%, and the increase trend was consistent with that of reference preparations.

[0086] ⑤Content: There was no significant change in the contents of methylparaben, propylparaben and levetiracetam between the self-made preparation and the reference preparation.

[0087] In summary, the pH value of the drug solution prepared in Examples 1-3 of the present application is controlled at 5.0 to 5.6, and the sample stability is good, preferably 5.3.

[0088] Comparative Example 1

[0089] The same formula and preparation process as in Example 1 are used, and the only difference from Example 1 is that in step (7), a pH adjuster is used to adjust the pH of the solution to 5.9±0.3.

[0090] The stability of the levetiracetam oral solution prepared in Comparative Example 1 and Example 1 is shown in the following table:

[0091] Table 6 Results of investigation under high temperature (60℃±2℃) for 30 days at different pH values

[0092]

[0093] As can be seen from the above table, the levetiracetam oral solution with a pH of 5.9 produced more levetiracetam acid, other individual impurities and p-hydroxybenzoic acid; especially after being placed for 30 days, the content of p-hydroxybenzoic acid was twice that of the levetiracetam oral solution of Example 1.

[0094] Example 4 Taste Evaluation of a Levetiracetam Oral Solution

[0095] Also use As a reference preparation. In this example, the dosage of liquid maltitol and acesulfame potassium is kept consistent with the reference preparation, which are 300 mg / ml and 4.6 mg / ml respectively. The dosage and proportion of grape flavor essence and glycyrrhizic acid monoammonium salt S are investigated to make the taste better and more convenient for patients to use.

[0096] The taste evaluation method is as follows: 10 volunteers are selected, with a gender ratio close to 1:1. 5 ml of the sample to be tested is held in the mouth, and the time is 15 seconds. After rinsing the mouth, the next sample is re-evaluated. Samples are randomly selected for testing.

[0097] The taste scoring criteria are as follows in Table 7:

[0098] Table 7 Taste Rating Criteria

[0099]

[0100]

[0101] The dosage, proportion and taste score of grape flavor essence and monoammonium glycyrrhizinate S are shown in Table 8 below:

[0102] Table 8 Oral sensory scoring groups and results

[0103]

[0104] It can be seen from Tables 7 and 8 above that flavors have a masking effect on the bitterness of the raw materials. When the flavor concentration is in the range of 2.0 mg / ml to 4.0 mg / ml, the bitterness and odor increase with the increase of flavor concentration, and the overall taste decreases. The amount of flavor should not be too much, and the flavor concentration is selected to be 2 mg / ml.

[0105] As the concentration of monoammonium glycyrrhizinate S increases, the bitterness decreases. The concentration of monoammonium glycyrrhizinate S between 1.2 mg / ml and 2 mg / ml can meet the taste requirements. According to the reference reverse analysis results and the previous solubility research on the substance, the preferred concentration is 1.2 mg / ml.

[0106] Example 5 Screening of solvents

[0107] Methylparaben, propylparaben, and glycyrrhizic acid monoammonium salt S have low solubility in water, while methylparaben and propylparaben have high solubility in glycerol. Different solvents have a great influence on the dissolution time of insoluble substances, which needs to be investigated in detail. Different solvents are used to dissolve insoluble excipients such as methylparaben, propylparaben, and glycyrrhizic acid monoammonium salt S in turn, and the dissolution time is shown in Table 9:

[0108] Table 9 Dissolution time of poorly soluble excipients in different solvents

[0109]

[0110]

[0111] It can be seen from Table 9 above that when purified water + glycerol is used as the solvent, the dissolution time of the insoluble excipient is greatly shortened, so purified water + glycerol is selected as the solvent for the insoluble excipient.

[0112] Example 6 Investigation of the Addition Order of Acesulfame Potassium

[0113] In the previous experiments, it was found that the dissolution time of acesulfame potassium was relatively long, so the dissolution time of acesulfame potassium was investigated;

[0114] The test plan and results are shown in Table 10 below:

[0115] Table 10 Results of total dissolution time of poorly soluble excipients and acesulfame potassium

[0116]

[0117] Insoluble excipients in the table include methylparaben, propylparaben, and monoammonium glycyrrhizinate S. As can be seen from Table 9 above, the dissolution time is long when the insoluble excipients and acesulfame potassium are added separately. When acesulfame potassium and the insoluble excipients are added together, the total dissolution time is shortened to 17 minutes, and the production efficiency is also improved. Therefore, acesulfame potassium is added together with the insoluble excipients, and then the remaining raw excipients are added.

[0118] In summary, in order to simplify the production process, the final order of adding materials is: 20% of the prescribed amount of purified water + glycerin → methylparaben, propylparaben, glycyrrhizic acid monoammonium salt S, acesulfame potassium → sodium acetate → liquid maltitol → levetiracetam → 1% acetic acid solution → flavor.

[0119] The above-mentioned embodiments only express the specific implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the protection scope of the present application. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the technical solution concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A levetiracetam oral solution, characterized in that: The raw material components include the following mass concentrations: active ingredient levetiracetam 80-120 mg / ml, pH regulator, antibacterial agent 2.50-2.90 mg / ml, cosolvent 180-220 mg / ml and flavoring agent 280-350 mg / ml, The dosage of the pH adjuster is set to make the pH value of the levetiracetam oral solution be 5.0-5.

6.

2. A levetiracetam oral solution according to claim 1, characterized in that, The pH value regulator is sodium acetate and 1% acetic acid.

3. A levetiracetam oral solution according to claim 1, characterized in that, The antibacterial agents are methylparaben and propylparaben.

4. A levetiracetam oral solution according to claim 1, characterized in that, The cosolvent is glycerol.

5. A levetiracetam oral solution according to claim 1, characterized in that, The flavoring agent includes acesulfame potassium, glycyrrhizic acid monoammonium salt S, liquid maltitol and essence.

6. A levetiracetam oral solution according to claim 5, characterized in that: The concentration of the essence is 2.0 mg / ml to 4.0 mg / ml, and the concentration of the glycyrrhizic acid monoammonium salt S is 1.2 mg / ml to 2.0 mg / ml.

7. A levetiracetam oral solution according to claim 6, characterized in that: The flavor is grape flavor.

8. A method for preparing a levetiracetam oral solution, characterized in that: The steps include: (1) Add 15%-25% of the prescribed amount of purified water and the prescribed amount of glycerol, continue stirring, and heat the solution to 50°C ± 10°C; (2) maintaining the solution temperature, adding the prescribed amount of methylparaben, propylparaben, monoammonium glycyrrhizinate S, and acesulfame potassium in sequence, and stirring evenly; (3) adding a pH adjuster and liquid maltitol in sequence and stirring evenly; (4) When the temperature of the drug solution drops to less than 50°C, add levetiracetam, keep the temperature of the drug solution less than 50°C, and stir evenly; (5) Add purified water to 90% ± 5% of the prescribed amount and adjust the pH value of the solution to 5.0 ± 0.3-5.6 ± 0.3; (6) When the temperature of the liquid medicine drops to less than 30°C, add the prescribed amount of flavor and stir evenly; (7) Add purified water to the liquid preparation tank to make up to 450 L and stir evenly; (8) filtering to obtain a levetiracetam oral solution.

9. The method for preparing a levetiracetam oral solution according to claim 8, characterized in that: The time limit from the start of step (1) to the start of step (8) is ≤ 24 hours.

10. The method for preparing a levetiracetam oral solution according to claim 8, characterized in that: Step (8) uses a group of polypropylene filter elements for filtration, the filter element pore size is 5.0 μm, the filtrate temperature during filtration should be less than 30° C., and the filtration pressure should be ≤0.2 MPa.

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