Lacosamide particles and preparation method thereof
By controlling the ratio of diluent, disintegrant and binder, the lacosamide particles are prepared, which solves the compression and hardness problems caused by their poor fluidity, and achieves good dissolution and fluidity, avoids additional additive costs. , significantly improve the quality and clinical advantages of the product.
Patent Information
- Application Number
- CN202411527583.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-30
- Publication Date
- 2025-01-03
AI Technical Summary
The poor fluidity of lacosamide leads to poor compression, low hardness, easy to break when preparing granules with other auxiliary materials. It requires additional microcrystalline cellulose and colloidal silica to improve fluidity, which increases the cost. .
By preparing lacosamide particles, combining specific proportions of diluents, disintegrants and binders, the loose density and tap density are controlled within the range of 0.45-0.65g/ml, and wet particles are prepared by drying to avoid additional additions Microcrystalline cellulose and colloidal silica improve fluidity and dissolution.
The good hardness and compression of the lacosamide particles are achieved, the production of powder is reduced, the production cost is reduced, and the dissolution is reached within 5 minutes, which improves the flowability and dissolution, and solves the poor flowability in the prior art. The problem.
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Abstract
Description
Technical Field
[0001] The present application relates to lacosamide granules and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. Background Art
[0002] Lacosamide is a drug used to treat epilepsy, especially as an adjunctive treatment for partial-onset epilepsy in patients aged 4 years and above. It works by regulating sodium ion channels in nerve cells to reduce abnormal electrical activity, thereby achieving the purpose of controlling epileptic seizures. Lacosamide is available in a variety of dosage forms, including oral solution, tablets, etc.
[0003] Chinese patent CN112022804A provides a lacosamide oral solution, which improves the taste by adding a flavoring agent, but the oral solution is not convenient to carry. Lacosamide granules are a dosage form that is convenient for specific groups of people (such as children or adults with dysphagia). This granular drug can be dissolved in water to form a solution, which is easy to take and carry.
[0004] Lacosamide has poor fluidity, and generally requires the additional addition of microcrystalline cellulose and colloidal silicon dioxide to improve the fluidity of the mixture, which undoubtedly increases the cost; in addition, the poor fluidity of lacosamide leads to poor compressibility and low hardness when it is used to prepare granules with other excipients, and the granules are easy to break, thereby producing more powder. Summary of the invention
[0005] According to one aspect of the present application, a lacosamide granule is provided, which can maintain good hardness and good compressibility, prevent the granules from breaking and producing more powder, and solve the problem in the prior art that when preparing granules with other excipients due to the poor fluidity of lacosamide, the granules have poor compressibility, low hardness, and are easy to break, thereby producing more powder. In addition, the lacosamide granule has good solubility.
[0006] The lacosamide particles comprise 8-12 wt % of lacosamide, and the lacosamide particles have a bulk density of 0.45-0.55 g / ml and a tap density of 0.55-0.65 g / ml.
[0007] Optionally, the bulk density of the lacosamide particles is independently selected from any value of 0.45 g / ml, 0.48 g / ml, 0.49 g / ml, 0.50 g / ml, 0.53 g / ml, 0.55 g / ml, or a range between the above two values.
[0008] Optionally, the tap density of the lacosamide particles is independently selected from any value of 0.55 g / ml, 0.57 g / ml, 0.59 g / ml, 0.60 g / ml, 0.63 g / ml, 0.65 g / ml, or a range between any two of the above values.
[0009] Optionally, the lacosamide granules include the following components:
[0010]
[0011] Optionally, the diluent is selected from any one or more of mannitol, sorbitol, lactose, microcrystalline cellulose, and sucrose; preferably, the diluent is sorbitol and mannitol.
[0012] Optionally, the weight ratio of sorbitol to mannitol is (4-6):1; preferably, the weight ratio of sorbitol to mannitol is 5:1.
[0013] Optionally, the binder is selected from any one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, and carboxymethyl cellulose.
[0014] Optionally, the binder is hypromellose.
[0015] Optionally, the disintegrant is selected from any one or more of cross-linked polyvinylpyrrolidone, starch, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and sodium carboxymethyl starch.
[0016] Optionally, the disintegrant is sodium carboxymethyl cellulose and sodium carboxymethyl starch in a weight ratio of 1:(0.4-0.8); preferably, the weight ratio of sodium carboxymethyl cellulose and sodium carboxymethyl starch is 1:0.6.
[0017] Optionally, the weight average molecular weight of the sodium carboxymethyl cellulose is 200,000-500,000; preferably, the weight average molecular weight of the sodium carboxymethyl cellulose is 395,000.
[0018] Optionally, the source of starch in the sodium carboxymethyl starch is potato starch.
[0019] Optionally, the sodium carboxymethyl starch has a model of ZW-SSG-C, purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.
[0020] Optionally, the co-solvent is sodium lauryl sulfate and / or polysorbate 80.
[0021] Optionally, the co-solvent is sodium lauryl sulfate.
[0022] The flavoring agents described in this application are not particularly limited, and those skilled in the art can make routine selections.
[0023] In another aspect, the present application provides a method for preparing the lacosamide granules, comprising: mixing a mixture comprising lacosamide, a diluent, a disintegrant, and a binder with a mixed solution to prepare a soft material, extruding to obtain wet granules, and drying to obtain;
[0024] The mixed solution comprises a co-solvent, a flavoring agent and purified water.
[0025] Optionally, the weight ratio of the purified water to the co-solvent is (60-65):1, preferably, the weight ratio of the purified water to the co-solvent is 63:1.
[0026] The beneficial effects of this application include:
[0027] 1. The present application controls the bulk density of lacosamide granules to be 0.45-0.55 g / ml and the tap density to be 0.55-0.65 g / ml. The lacosamide granules can maintain good hardness and good compressibility, prevent the granules from breaking and producing more powder, and solve the problem in the prior art that the granules have poor compressibility, low hardness, and are easy to break when preparing granules with other excipients due to the poor fluidity of lacosamide, thereby producing more powder. In addition, within the range of the bulk density and tap density control, the lacosamide granules have good solubility.
[0028] 2. The present application uses sodium carboxymethyl cellulose with a weight average molecular weight of 200,000-500,000 and sodium carboxymethyl starch derived from potato starch to control the disintegration rate of lacosamide within a controllable range, thereby preventing the disintegration from being too fast and producing too much lacosamide in a short period of time, resulting in poor fluidity, thereby causing adhesion of lacosamide molecules and reducing the dissolution effect, while also preventing the disintegration from being too slow and affecting the solubility.
[0029] 3. The inventors found that the types of diluents and binders also affect the solubility of lacosamide granules. When the binder is hydroxypropyl methylcellulose and the diluents are sorbitol and mannitol, in combination with the disintegrant of the present application, the lacosamide granules can achieve 100% dissolution within 5 minutes.
[0030] 4. The present application uses sodium carboxymethyl cellulose with a weight average molecular weight of 200,000-500,000 and sodium carboxymethyl starch derived from potato starch, and is combined with hydroxypropyl methylcellulose, sorbitol and mannitol. During the preparation process, the quality problem caused by the poor fluidity of lacosamide is improved. The process does not require the additional addition of microcrystalline cellulose and colloidal silicon dioxide, which solves the high cost problem caused by the need for microcrystalline cellulose and colloidal silicon dioxide in the prior art. At the same time, the components of the present application can control the density of lacosamide particles within a certain range, which not only solves the problems of poor compressibility, low hardness and easy breakage of the particles, but also has good solubility and obvious clinical advantages.
[0031] 5. After testing, the application controls the types of diluents, disintegrants, binders, and solubilizers. In the process of extruding wet granules, the extrusion is smooth, there is no problem of clogging the sieve holes, the material loss is small, and the material is not easy to stick after extrusion. If the solubilizer, diluent or disintegrant is changed alone, the material is easy to stick after extrusion. If the binder is changed alone, the extrusion process is smoother in the early stage, but more material is lost in the later stage, and the sieve holes are easily blocked.
[0032] 6. Through research, the inventors found that the Carr index of the prepared lacosamide granules is between 16 and 18. The granules have good fluidity, which is conducive to subsequent filling. DETAILED DESCRIPTION
[0033] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.
[0034] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.
[0035] Example 1
[0036] Lacosamide granules, mass composition is as follows:
[0037]
[0038] The cosolvent is sodium dodecyl sulfate; the disintegrant is sodium carboxymethyl cellulose and sodium carboxymethyl starch, with a weight ratio of 1:0.4; the weight average molecular weight of the sodium carboxymethyl cellulose is 395,000, and the source of starch in the sodium carboxymethyl starch is potato starch, model ZW-SSG-C, purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd. The diluent is sorbitol and mannitol, with a weight ratio of 4:1, and the binder is hypromellose. The flavoring agent is sucralose.
[0039] The preparation method of the lacosamide granules is as follows: lacosamide, a diluent, a disintegrant, and a binder are mixed, and then mixed with a mixed solution to prepare a soft material, which is extruded to obtain wet granules, and dried to obtain the obtained granules;
[0040] The mixed solution is a mixed solution of a co-solvent, a flavoring agent and purified water.
[0041] The weight ratio of the purified water to the co-solvent is 63:1.
[0042] Example 2
[0043] Lacosamide granules, mass composition is as follows:
[0044]
[0045] The cosolvent is sodium dodecyl sulfate; the disintegrant is sodium carboxymethyl cellulose and sodium carboxymethyl starch, with a weight ratio of 1:0.8; the weight average molecular weight of the sodium carboxymethyl cellulose is 395,000, and the source of starch in the sodium carboxymethyl starch is potato starch, model ZW-SSG-C, purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd. The diluent is sorbitol and mannitol, with a weight ratio of 6:1, and the binder is hypromellose. The flavoring agent is sucralose.
[0046] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0047] Example 3
[0048] Lacosamide granules, mass composition is as follows:
[0049]
[0050] The cosolvent is sodium dodecyl sulfate; the disintegrant is sodium carboxymethyl cellulose and sodium carboxymethyl starch, with a weight ratio of 1:0.6; the weight average molecular weight of the sodium carboxymethyl cellulose is 395,000, and the source of starch in the sodium carboxymethyl starch is potato starch, model ZW-SSG-C, purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd. The diluent is sorbitol and mannitol, with a weight ratio of 5:1, and the binder is hypromellose. The flavoring agent is sucralose.
[0051] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0052] The test results of Examples 1-3 are as follows:
[0053]
[0054]
[0055] The test methods of this application are all carried out in accordance with CHP2020. In the particle size distribution, >10 mesh refers to particles that cannot pass through the 10 mesh sieve, 10 mesh to 35 mesh refers to particles between the 10 mesh sieve and the 35 mesh sieve, 35 mesh to 50 mesh refers to particles between the 35 mesh sieve and the 50 mesh sieve, 50 mesh to 80 mesh refers to particles between 50 mesh and 80 mesh, and <80 mesh refers to particles that pass through the 80 mesh sieve.
[0056] Comparative Example 1
[0057] The composition of the lacosamide granules is the same as that of Example 1, except that the weight average molecular weight of the sodium carboxymethyl cellulose is 725,000.
[0058] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0059] Comparative Example 2
[0060] The composition of the lacosamide granules is the same as that of Example 1, except that the weight average molecular weight of the sodium carboxymethyl cellulose is 90,500.
[0061] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0062] The particle size distribution is as follows:
[0063]
[0064] More than 15% of the particles are above 10 mesh and below 80 mesh, and there is a lot of powder loss.
[0065] Comparative Example 3
[0066] The composition of the lacosamide granules is the same as that of Example 1, except that the source of the starch in the sodium carboxymethyl starch is corn starch, and the weight ratio of the sodium carboxymethyl cellulose to the sodium carboxymethyl starch is 0.6:1.
[0067] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0068] The particle size distribution is as follows:
[0069]
[0070] More than 15% of the particles are above 10 mesh and below 80 mesh, and there is a lot of powder loss.
[0071] Comparative Example 4
[0072] The composition of the lacosamide granules is the same as that of Example 1, except that the disintegrant is cross-linked polyvinylpyrrolidone.
[0073] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0074] Comparative Example 5
[0075] Lacosamide granules, composed as follows:
[0076]
[0077] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0078] The bulk density and tap density of the lacosamide granules are significantly higher than those in Example 1.
[0079] Comparative Example 6
[0080] Lacosamide granules, composed as follows:
[0081]
[0082] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0083] The bulk density and tap density of the lacosamide granules are relatively small, and the granules have a small amount of powder loss problem. The particle size distribution is as follows:
[0084]
[0085]
[0086] Comparative Example 7
[0087] The composition of lacosamide granules is the same as that of Example 1, except that the diluent is mannitol.
[0088] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0089] Comparative Example 8
[0090] The composition of the lacosamide granules is the same as that of Example 1, except that the binder is hydroxypropyl cellulose and the diluent is sorbitol.
[0091] The specific implementation method of the lacosamide granules is the same as that of Example 1.
[0092] The particles have a slight powdering problem, and the particle size distribution is as follows:
[0093]
[0094] The dissolution properties of the embodiments and comparative examples were tested, and the test results are as follows:
[0095]
[0096]
[0097] The particles of the embodiment and the comparative example were subjected to accelerated testing at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 6 months. The test results are as follows:
[0098]
[0099]
[0100] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.
Claims
1. A lacosamide granule, characterized in that: The lacosamide particles comprise 8-12 wt % of lacosamide, and the lacosamide particles have a bulk density of 0.45-0.55 g / ml and a tap density of 0.55-0.65 g / ml.
2. The lacosamide granules according to claim 1, characterized in that: The lacosamide granules include the following components:
3. The lacosamide granules according to claim 2, characterized in that: The diluent is selected from any one or more of mannitol, sorbitol, lactose, microcrystalline cellulose, and sucrose.
4. The lacosamide granules according to claim 3, characterized in that: The diluents are sorbitol and mannitol in a weight ratio of (4-6):
1.
5. The lacosamide granules according to any one of claims 2 to 4, characterized in that: The binder is selected from any one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin and carboxymethyl cellulose.
6. The lacosamide granules according to any one of claims 2 to 4, characterized in that: The disintegrant is selected from any one or more of cross-linked polyvinylpyrrolidone, starch, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and sodium carboxymethyl starch.
7. The lacosamide granules according to claim 6, characterized in that: The disintegrants are sodium carboxymethyl cellulose and sodium carboxymethyl starch, and the weight ratio is 1:(0.4-0.8).
8. The lacosamide granules according to any one of claims 2 to 4, characterized in that: The cosolvent is sodium lauryl sulfate and / or polysorbate 80.
9. A method for preparing the lacosamide granules according to any one of claims 2 to 8, characterized in that: include: A mixture including lacosamide, a diluent, a disintegrant, and a binder is mixed with the mixed solution to prepare a soft material, which is extruded to obtain wet granules, and dried to obtain; The mixed solution comprises a co-solvent, a flavoring agent and purified water.
10. The method for preparing lacosamide granules according to claim 9, characterized in that: The weight ratio of the purified water to the co-solvent is (60-65):1.