Lacosamide injection and preparation method thereof

Abstract

The invention relates to a lacosamide injection and a preparation method thereof. The injection contains lacosamide, a stabilizer, an antioxidant, a complexing agent and a buffer solution. The injection is characterized in that the stabilizer is sodium gluconate, the antioxidant is sodium pyrosulfite, alpha tocopherol and glutathione, the complexing agent is edetate disodium, and the buffer solution is an acetic acid-sodium acetate buffer solution. Meanwhile, the invention discloses a corresponding preparation method. Compared with the prior art, the preparation method has the advantages that the stability of lacosamide is obviously improved, particularly, the generation of two main impurities, namely an impurity D (N-deacetylated lacosamide hydrochloride) and an impurity F (demethylated lacosamide), can be obviously reduced, the quality of a preparation product is improved, the toxic and side effects are reduced, and the preparation method is simple, low in cost and suitable for industrial production. The method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a lacosamide injection and a preparation method thereof. Background Art

[0002] Lacosamide

[0003] Chemical name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide

[0004] CAS: 175481-36-4

[0005] Molecular formula: C 13 H 18 N2O3

[0006] Molecular weight: 250.29

[0007] Structural formula:

[0008]

[0009] Lacosamide is the first third-generation new anti-epileptic drug launched in the EU that selectively enhances the slow inactivation of sodium ion channels. It was first developed by UCB and has been approved for marketing in many countries for the treatment of partial epileptic seizures. Compared with other anti-epileptic drugs, lacosamide can control the activity of nerve cells by regulating the overactivity of sodium ion channels, thereby treating epilepsy.

[0010] There are generally two impurities in lacosamide, one is N-deacetyl lacosamide hydrochloride (impurity D), and the other is demethyl lacosamide (impurity F). Both impurities are inferior to lacosamide in efficacy and safety.

[0011] Lacosamide is suitable for monotherapy and combination therapy of partial seizures in patients with epilepsy aged 4 years and above. The currently marketed lacosamide dosage forms include tablets, injections, oral solutions, etc. However, for epileptic patients, oral medication often causes difficulty in swallowing, and it can irritate the gastrointestinal tract and has a slow onset of action, making it unsuitable for emergency use. The injection is administered by intravenous injection, and can still be administered in time in status epilepticus. It has a fast onset of action and can effectively control epileptic seizures.

[0012] The chemical properties of lacosamide injection prepared by the conventional process are poor, and the quality of the drug will decline after long-term storage, and some impurities will be generated, which will bring toxic side effects and leave hidden dangers for clinical use. Moreover, among the various existing technical solutions disclosed, there are few prescriptions and preparation processes for lacosamide injection. Therefore, it is necessary to develop a new prescription and preparation process for lacosamide injection so that the prepared product has better quality stability to meet the needs of the market. Summary of the invention

[0013] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a lacosamide injection with significantly improved quality stability and a preparation method thereof, so as to solve the problem of poor long-term storage stability of lacosamide injection, effectively inhibit the formation of lacosamide impurities, reduce adverse drug reactions, and improve the safety of medication.

[0014] To achieve the purpose of the present invention, the technical solution is implemented in the following way:

[0015] A lacosamide injection contains lacosamide as an active ingredient, a stabilizer, an antioxidant, a chelating agent, and a buffer; characterized in that the stabilizer is sodium gluconate; the antioxidant is sodium pyrosulfite, α-tocopherol and glutathione; the chelating agent is disodium edetate; and the buffer is acetic acid-sodium acetate buffer.

[0016] Preferably, in the above lacosamide injection, every 1000 injections are made of the following components:

[0017] Lacosamide 200g; sodium gluconate 5-10g; sodium metabisulfite 0.1-0.4g; alpha-tocopherol 0.1-0.4g; glutathione 0.1-0.4g; disodium edetate 0.1-0.6g; acetic acid-sodium acetate buffer 2000ml; solution pH value is 4.0-5.0.

[0018] More preferably, in the above lacosamide injection, every 1000 injections are made of the following components:

[0019] Lacosamide 200 g; sodium gluconate 8 g; sodium metabisulfite 0.2 g; α-tocopherol 0.2 g; glutathione 0.2 g; disodium edetate 0.3 g; acetic acid-sodium acetate buffer 2000 ml; solution pH value is 4.5-5.0.

[0020] During the development of the product, the inventors found that the prescription had a great influence on the quality stability of lacosamide injection. After a large number of comparative tests, we surprisingly found that by adding sodium gluconate, sodium pyrosulfite, α-tocopherol, glutathione, disodium edetate to the prescription, and using acetic acid-sodium acetate buffer, the stability of lacosamide injection can be improved. At the same time, if the product is obtained by activated carbon adsorption, secondary filtration and nitrogen filling throughout the preparation process, the quality stability of lacosamide injection can be further improved.

[0021] In the experiment, the inventors found that by adding the stabilizer sodium gluconate to the prescription, the quality stability of lacosamide injection can be significantly improved. Sodium gluconate is a buffer that can effectively adjust the pH value of the solution, making it less likely to undergo acid-base reactions, and it also has good antioxidant properties and metal ion chelating properties, thereby effectively preventing drug decomposition, precipitation and discoloration, and significantly improving the stability of the drug.

[0022] During the experiment, the inventors also found that by adding antioxidants sodium metabisulfite, α-tocopherol and glutathione to the prescription, since all three have strong reducing properties, they can effectively prevent the drug from being oxidized, and sodium metabisulfite has antibacterial properties, which can reduce the risk of microbial contamination of the product. The combination of the three can produce a synergistic effect, which can significantly improve the quality stability of lacosamide injection and greatly reduce the generation of impurities.

[0023] In the experiment, the inventors also found that by adding the chelating agent edetate disodium to the prescription, the quality stability of lacosamide injection was also improved. Since the injection production equipment and packaging materials contain metal ions, the precipitation of metal ions during long-term storage poses a great quality risk to the drug. Edetate disodium is a commonly used metal ion chelating agent in injection, which can form a stable water-soluble chelate with metal ions, remove free metal ions in the entire preparation environment, avoid lacosamide from being oxidized and degraded by metal ions, and is conducive to improving the stability of the drug during preparation, storage and clinical preparation.

[0024] In the experiment, the present invention used an acetic acid-sodium acetate buffer. According to research, lacosamide has high requirements for pH and is easily degraded in an overly acidic or alkaline environment, while lacosamide has the highest solubility and the best stability in a solution of pH 4.0-5.0. Therefore, an acetic acid-sodium acetate buffer system is selected to keep the pH value of the solution at 4.0-5.0, with a very small fluctuation range and will not change with the storage time, thereby ensuring the stability of the drug.

[0025] In the experiment, the present invention added activated carbon during the product preparation process, and the activated carbon was fully contacted with the solution by stirring. Because activated carbon is a porous adsorbent with a large number of tiny pores and active sites on its surface, it can adsorb and remove organic matter, pigments, heavy metals and impurities in the solution, which can effectively improve product quality.

[0026] In the experiment, the present invention used a secondary sterilization filtration process with a sterilization filter membrane. Because the conventional high-temperature sterilization method has a high temperature and a long time, it will lead to the degradation of raw materials and the increase of impurities, which will affect the safety of medication. The filling volume of the present invention is 20.5-21 ml, and a 0.22 μm sterilization filter membrane is used for filtration before filling. After two sterilization filtrations, the test results prove that the product is sterile and meets the regulations.

[0027] In the experiment, the present invention filled the whole process of product preparation and filling with nitrogen, because the excellent inertness of nitrogen can protect the drug from oxidative degradation caused by contact with oxygen in the air during production and storage, improve the stability of the drug, and prevent it from deteriorating.

[0028] The present invention further discloses a method for preparing the lacosamide injection, comprising the following steps:

[0029] (1) Preparation of CO2-saturated water for injection: Add CO2 to the water for injection until it is saturated, while controlling the temperature of the CO2-saturated water for injection to be below 40°C and the pH of the CO2-saturated water for injection to be 5.0-6.5;

[0030] (2) Preparation of pH buffer: Using the CO2-saturated water for injection prepared above, add 18 g of sodium acetate and 9.8 ml of acetic acid per liter to prepare an acetic acid-sodium acetate buffer;

[0031] (3) Preparation of lacosamide solution: sodium gluconate, sodium pyrosulfite, α-tocopherol, glutathione, disodium edetate, and lacosamide in the prescribed amount are sequentially added to the pH buffer solution prepared above and mixed and dissolved;

[0032] (4) Add needle-grade activated carbon to the above mixed solution, stir for 10-30 minutes, filter and decarbonize, and filter the filtrate for secondary sterilization with a sterilization filter membrane with a pore size of 0.22 μm before filling.

[0033] Wherein, in the lacosamide injection of the present invention, the amount of activated carbon for injection added in the step (4) is 0.1-2.0 g per liter of the mixed solution.

[0034] Wherein, in the lacosamide injection of the present invention, nitrogen filling is maintained throughout the steps (3) and (4).

[0035] Wherein, the pH value of the lacosamide injection of the present invention is 4.0-5.0.

[0036] Advantages and positive effects of the injection of the present invention:

[0037] 1. Sodium gluconate is used as a stabilizer in the injection formulation of the present invention, which can effectively prevent drug decomposition, precipitation and discoloration, and can significantly improve the quality stability of the drug.

[0038] 2. Sodium metabisulfite, α-tocopherol and glutathione are used as antioxidants in the injection prescription of the present invention. Since all three have strong reducing properties, they can effectively prevent the drug from being oxidized, and sodium metabisulfite has antibacterial properties, which can reduce the risk of microbial contamination of the product. The combination of the three can produce a synergistic effect, which can significantly improve the quality stability of lacosamide injection and greatly reduce the generation of impurities.

[0039] 3. Disodium edetate is used as a chelating agent in the injection formulation of the present invention, which can form a stable water-soluble chelate with metal ions, remove free metal ions in the entire preparation environment, avoid oxidative degradation of lacosamide by metal ions, and help improve the stability of the drug during preparation, storage and clinical preparation.

[0040] 4. The injection formulation of the present invention uses acetic acid-sodium acetate solution as a buffered salt solution to maintain the pH value of the prepared solution at 4.0-5.0. The pH fluctuation range of the buffer system is extremely small during storage. Lacosamide has the highest solubility and the best stability within this pH range, so the product can be guaranteed to be of stable and qualified quality within the validity period.

[0041] 5. Activated carbon is added during the preparation process of the product of the present invention, which can adsorb and remove organic matter, pigments, heavy metals and impurities in the solution, thereby effectively improving product quality.

[0042] 6. The present invention uses a secondary sterilization filtration process with a sterilization filter membrane during the production process, avoiding the degradation of raw materials and auxiliary materials caused by long-term high temperature in conventional high-temperature sterilization methods, reducing the production of related substances, and the test results prove that the product is sterile and meets the regulations. At the same time, the sterilization method can reduce energy consumption and simplify the production process in industrial production.

[0043] 7. The product of the present invention is filled with nitrogen throughout the preparation and filling process. The inert nitrogen can prevent the drug from contacting with oxygen in the air and causing oxidative degradation, thereby improving the stability of the drug and preventing it from deteriorating.

[0044] 8. The lacosamide injection produced by the present invention significantly improves the quality stability of the drug and greatly reduces the generation of impurities by adopting a specific prescription process, especially can significantly reduce the generation of two major impurities, impurity D (N-deacetyl lacosamide hydrochloride) and impurity F (desmethyl lacosamide), improves the quality of the preparation product, reduces toxic and side effects, thereby reducing adverse reactions of the drug and improving the safety of medication.

[0045] 9. The product obtained by the present invention has a simple preparation process, low production cost, no need for special equipment, easy control of the process, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0046] The following examples are used to illustrate and understand the essence of the present invention, but are not intended to limit the scope of the present invention in any way.

[0047] The dosage specification used in the following examples is 200 mg / 20 ml / bottle, and is filled in 20 ml medium borosilicate glass tube injection bottles, and the prescription quantity is the formula quantity for 1000 bottles.

[0048] Embodiment 1:

[0049] Prescription: Lacosamide 200g, sodium gluconate 5g, sodium metabisulfite 0.1g, α-tocopherol 0.1g, glutathione 0.1g, disodium edetate 0.1g, acetic acid-sodium acetate buffer 1000ml, made into 1000 bottles.

[0050] Preparation process:

[0051] (1) Preparation of CO2-saturated water for injection: Add CO2 to the water for injection until it is saturated, while controlling the temperature of the CO2-saturated water for injection to be below 40°C and the pH of the CO2-saturated water for injection to be 5.0-6.5;

[0052] (2) Preparation of pH buffer solution: Use the CO2-saturated water for injection prepared above, add 18 g of sodium acetate and 9.8 ml of acetic acid per liter, stir and dissolve;

[0053] (3) Preparation of lacosamide solution: sodium gluconate, sodium pyrosulfite, α-tocopherol, glutathione, disodium edetate and lacosamide in the prescribed amount were sequentially added to the pH buffer prepared above and mixed and dissolved, and nitrogen was filled throughout the process;

[0054] (4) Add 0.5 g of needle-grade activated carbon to the above mixed solution, stir for 10-30 min, filter and decarbonize, filter the filtrate for a second time with a sterilizing filter membrane with a pore size of 0.22 μm, and then fill it with nitrogen throughout the process.

[0055] Embodiment 2:

[0056] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0057] Preparation process: Prepared according to the preparation method of Example 1.

[0058] Embodiment 3:

[0059] Prescription: Lacosamide 200g, sodium gluconate 10, sodium metabisulfite 0.4g, α-tocopherol 0.4g, glutathione 0.4g, disodium edetate 0.6g, acetic acid-sodium acetate buffer 1000ml, made into 1000 bottles.

[0060] Preparation process: Prepared according to the preparation method of Example 1.

[0061] Comparative Example 1:

[0062] Prescription: 200g of lacosamide, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0063] Preparation process: Prepared according to the preparation method of Example 1.

[0064] Comparative Example 2:

[0065] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0066] Preparation process: Prepared according to the preparation method of Example 1.

[0067] Comparative Example 3:

[0068] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0069] Preparation process: Prepared according to the preparation method of Example 1.

[0070] Comparative Example 4:

[0071] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of α-tocopherol, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0072] Preparation process: Prepared according to the preparation method of Example 1.

[0073] Comparative Example 5:

[0074] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0075] Preparation process: Prepared according to the preparation method of Example 1.

[0076] Comparative Example 6:

[0077] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0078] Preparation process: Prepared according to the preparation method of Example 1.

[0079] Comparative Example 7:

[0080] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0081] Preparation process: Prepared according to the preparation method of Example 1.

[0082] Comparative Example 8:

[0083] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of α-tocopherol, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0084] Preparation process: Prepared according to the preparation method of Example 1.

[0085] Comparative Example 9:

[0086] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.25g of glutathione, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0087] Preparation process: Prepared according to the preparation method of Example 1.

[0088] Comparative Example 10:

[0089] Prescription: Lacosamide 200g, sodium gluconate 8g, sodium metabisulfite 0.25g, alpha-tocopherol 0.25g, glutathione 0.25g, disodium edetate 0.4g, water for injection 1000ml, made into 1000 bottles.

[0090] Preparation process: Prepared with reference to the preparation method of Example 1, the solvent was replaced by water for injection from acetic acid-sodium acetate buffer.

[0091] Comparative Example 11:

[0092] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0093] Preparation process: Prepared with reference to the preparation method of Example 1. The main difference is that in step (4), no activated carbon is added for mixed adsorption.

[0094] Comparative Example 12:

[0095] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0096] Preparation process: Prepared with reference to the preparation method of Example 1. The main difference is that the secondary filtration sterilization in step (4) is changed to high temperature sterilization.

[0097] Comparative Example 13:

[0098] Prescription: 200g of lacosamide, 8g of sodium gluconate, 0.25g of sodium metabisulfite, 0.25g of α-tocopherol, 0.25g of glutathione, 0.4g of disodium edetate, 1000ml of acetic acid-sodium acetate buffer, made into 1000 bottles.

[0099] Preparation process: Prepared with reference to the preparation method of Example 1. The main difference is that nitrogen is not charged during the preparation and filling process.

[0100] Test Example 1: Stability Test of Lacosamide Injection

[0101] The lacosamide injection prepared in each example and comparative example and a commercially available product (trade name: Vipat) were subjected to accelerated stability studies.

[0102] 1. Sample acceleration conditions: Place the samples at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. Take samples six months after the accelerated test to test the relevant substances and contents.

[0103] 2. Determination method:

[0104] 1) The content determination method is determined according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia): octylsilane bonded silica gel is used as the filler; water-acetonitrile-methanesulfonic acid (870:130:0.75) is used as the mobile phase; the flow rate is 2.0 ml / min; the column temperature is 35°C; the detection wavelength is 215 nm. System suitability requirements: In the chromatogram of the reference solution, the tailing factor of the lacosamide peak shall not be greater than 2.0. Prepare a reference solution containing approximately 250 mg of lacosamide per 1 ml, inject 20 μl of the test sample and the reference sample into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

[0105] 2) The determination method of related substances is determined according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia): octadecylsilane bonded silica gel is used as the filler (chromatographic column 4.6*150mm, filler 5μm); 0.01% phosphoric acid aqueous solution (containing 0.01mol / L sodium octane sulfonate)-acetonitrile (88:12) is used as the mobile phase A, 0.01% phosphoric acid aqueous solution (containing 0.01mol / L sodium octane sulfonate)-acetonitrile (20:80) is used as the mobile phase B, and the gradient in Table 1 is used for elution; the flow rate is 1.5ml / min; the column temperature is 35℃; the detection wavelength is 215nm. Take this product as the test solution, accurately measure 1ml of the test solution into a 100ml volumetric flask, add water (adjust the pH to 4.2 with 0.1mol / L hydrochloric acid) to dilute to the scale, shake well, and use it as the control solution. Inject 10 μl of the test sample and reference sample into the liquid chromatograph, record the chromatogram, and perform calculations according to the 1% reference method.

[0106] Table 1 High performance liquid chromatography elution gradient table:

[0107] Time (min) Mobile phase A (%) Mobile phase B (%) 0.01 100 0 50.00 100 0 70.00 85 15 100.00 85 15 100.01 100 0 130.00 100 0

[0108] 3. Comparison of stability data: See Table 2.

[0109] Table 2 Stability data comparison table:

[0110]

[0111] As can be seen from the results in Table 2, the quality stability of the lacosamide injection prepared in Examples 1 to 3 of the present invention is better, and the amount of impurities generated during the accelerated investigation is less, especially the generation of the two main impurities, impurity D and impurity F, is significantly reduced. From the results of Comparative Example 1, it can be seen that the stability of the main drug lacosamide can be significantly improved by adding sodium gluconate, so that the amount of impurities generated is less; from the results of Comparative Examples 2 to 8, it can be seen that the quality stability of the product can be significantly improved by adding antioxidants sodium pyrosulfite, α-tocopherol and glutathione, so that the amount of impurities generated is less, and the three of them will have a synergistic effect after combined use, and the effect is better; from the results of Comparative Example 9, it can be seen that the stability of the product can be improved to a certain extent by adding the complexing agent disodium edetate; from the results of Comparative Example 10, it can be seen that by using acetic acid-sodium acetate solution as the buffer salt solution, the product quality can be guaranteed to be more stable, and the amount of impurities generated during the storage process is less; From the results of Comparative Example 11, it can be seen that by adding activated carbon for mixed adsorption, the quality of the product can be made better and more stable; from the results of Comparative Example 12, it can be seen that the product sterilized at high temperature is unstable during the storage process, so the sterilization method of aseptic filtration is more effective; from the results of Comparative Example 13, it can be seen that nitrogen filling throughout the preparation and filling process can effectively prevent the injection from being oxidized, so that less impurities are generated; from the results of commercially available products, it can be seen that the product of the present invention has better long-term stability than commercially available products. The present invention can significantly reduce the generation of these two main impurities, impurity D (N-deacetyl lacosamide hydrochloride) and impurity F (desmethyl lacosamide) through a specific prescription and preparation process.

[0112] Test Example 2: pH Stability Test of Lacosamide Injection

[0113] Accelerated stability studies were performed on the lacosamide injections prepared in each example, comparative example 10, and commercially available products.

[0114] Sample acceleration conditions: Place the samples at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. Take samples for solution pH testing 1, 2, 3, and 6 months after the accelerated test.

[0115] Table 3 Product pH stability test results: pH 0:00 Accelerate January Accelerate February Accelerate March Accelerate June Example 1 4.56 4.53 4.58 4.56 4.57 Example 2 4.50 4.51 4.53 4.55 4.54 Example 3 4.48 4.45 4.53 4.58 4.58 Comparative Example 10 6.65 6.77 6.86 7.11 7.25 Commercially available products 4.68 4.88 5.13 5.36 5.71

[0117] As shown in Table 3, the pH value of the lacosamide injection prepared in Examples 1 to 3 of the present invention is maintained at 4.0-5.0, and the pH fluctuation range is extremely small during the storage process, which can ensure that the pH value of the sample is qualified within the validity period, thereby ensuring that the product quality is more stable. As shown in the results of Comparative Example 10, if no buffer solution is used in the prescription, the pH of the solution will change with the storage time, which is not conducive to the stability of the product; as shown in the results of the commercial product, the product of the present invention has better pH stability than the commercial product, and has better control over the quality of the product.

[0118] Test Example 3: Heavy Metal Detection Test of Lacosamide Injection

[0119] Three batches of samples were prepared according to the recipe of Example 2, and the heavy metal content was tested simultaneously with the commercially available products.

[0120] Table 4 Product heavy metal content test results:

[0122] As can be seen from the results in Table 4, the heavy metal impurity contents of the three batches of lacosamide injection prepared according to the prescription process of Example 2 of the present invention are significantly better than those of Comparative Example 9, indicating that the addition of the complexing agent disodium edetate can better control the heavy metal level, and the heavy metal impurity content of Example 2 is less than that of the products already on the market, the quality is better, and the clinical medication risk is smaller.

[0123] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and evolutions of the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A lacosamide injection, comprising lacosamide as an active ingredient, a stabilizer, an antioxidant, a chelating agent, and a buffer. The stabilizer is sodium gluconate; the antioxidants are sodium pyrosulfite, alpha tocopherol and glutathione; the complexing agent is disodium edetate; and the buffer is acetic acid-sodium acetate buffer.

2. The lacosamide injection as claimed in claim 1, characterized in that Each 1000 injections are prepared from the following components: 200 g of lacosamide; 5-10 g of sodium gluconate; 0.3-1.2 g of antioxidant; 0.1-0.6 g of chelating agent; 2000 ml of acetic acid-sodium acetate buffer; and the pH value of the solution is 4.0-5.

0.

3. The lacosamide injection according to any one of claims 1 to 2, characterized in that: Each 1000 injections are made of the following components: 200 g of lacosamide; 5-10 g of sodium gluconate; 0.1-0.4 g of sodium metabisulfite; 0.1-0.4 g of α-tocopherol; 0.1-0.4 g of glutathione; 0.1-0.6 g of disodium edetate; 2000 ml of acetic acid-sodium acetate buffer; and the pH value of the solution is 4.0-5.

0.

4. The lacosamide injection according to any one of claims 1 to 3, characterized in that: Each 1000 injections are made of the following components: 200 g of lacosamide; 8 g of sodium gluconate; 0.2 g of sodium metabisulfite; 0.2 g of α-tocopherol; 0.2 g of glutathione; 0.3 g of disodium edetate; 2000 ml of acetic acid-sodium acetate buffer; the pH value of the solution is 4.5-5.

0.

5. The method for preparing the lacosamide injection according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Preparation of CO2-saturated water for injection: Add CO2 to the water for injection until it is saturated, while controlling the temperature of the CO2-saturated water for injection to be below 40°C and the pH of the CO2-saturated water for injection to be 5.0-6.5; (2) Preparation of pH buffer: Using the CO2-saturated water for injection prepared above, add 18 g of sodium acetate and 9.8 ml of acetic acid per liter to prepare an acetic acid-sodium acetate buffer; (3) Preparation of lacosamide solution: sodium gluconate, sodium pyrosulfite, α-tocopherol, glutathione, disodium edetate, and lacosamide in the prescribed amount are sequentially added to the pH buffer solution prepared above and mixed and dissolved; (4) Add needle-grade activated carbon to the above mixed solution, stir for 10-30 minutes, filter and decarbonize, and filter the filtrate for secondary sterilization with a sterilization filter membrane with a pore size of 0.22 μm before filling.

6. The method for preparing lacosamide injection according to claim 5, characterized in that: In the step (4), the amount of activated carbon added is 0.1-2.0 g per liter of mixed solution.

7. The method for preparing lacosamide injection according to claim 5, characterized in that: Nitrogen is filled throughout the preparation and filling process.

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