A preparation method of fluvoxamine maleate film-coated tablets

Abstract

The invention discloses a method for preparing a fluvoxamine maleate film-coated tablet, wherein dry granulation is adopted to prepare drug-containing particles and blank particles respectively, the blank particles are coated, and then the blank particles are mixed with drug-containing particles and external excipients, tabletted, and coated to obtain the drug-containing particles; the drug-containing particles are prepared by mixing fluvoxamine maleate with one or more excipients; and the blank particles are prepared by mixing one or more excipients. The invention granulates hygroscopic excipients and raw materials separately, and coats the blank particles containing hygroscopic excipients. After the coated blank particles are mixed with the drug-containing particles and tabletted, the coating layer of the blank particles forms a grid structure, which is equivalent to coating the drug-containing particles, and can effectively block the entry of moisture, thereby improving the wet and hot stability of the fluvoxamine maleate film-coated tablets during storage and use, and effectively solving the problem of the instability of fluvoxamine maleate to wet and hot during the preparation process.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, in particular to a method for preparing a fluvoxamine maleate film-coated tablet. Background Art

[0002] Fluvoxamine maleate is a serotonin reuptake inhibitor (SSRI). SSRI is an antidepressant widely used in clinical practice. Its mechanism of action is to selectively inhibit the reuptake of 5-HT by the presynaptic membrane of the central nervous system, increase the concentration of 5-HT in the synaptic cleft, and achieve the purpose of antidepressant. Fluvoxamine maleate was launched in Europe in 1994, in Japan in 1999, and in the United States in 2001. Currently, only ordinary fluvoxamine maleate tablets are sold in the domestic market in China, such as "Lanshi" produced by Solvay Pharmaceuticals of the Netherlands and "Rebil" produced by Livzon Pharmaceuticals.

[0003] Due to the special structure of fluvoxamine maleate, it is very sensitive to water and temperature. In a humid or high temperature environment, fluvoxamine maleate is prone to produce impurities such as Z isomers and adducts. In addition, since hygroscopic excipients are inevitably used in the production of fluvoxamine maleate tablets, it is required that the temperature and humidity of the environment be strictly controlled during the production of fluvoxamine maleate tablets, and the intermediate products, plain tablets and coated tablets, cannot be stored in an exposed state for a long time. The instructions for fluvoxamine maleate tablets indicate that the recommended starting dose for children and adolescents over 8 years old is 25 mg, while the specifications of fluvoxamine maleate tablets are only 50 mg and 100 mg, so it is often necessary to take the fluvoxamine maleate tablets out of the aluminum-plastic plate and split them for consumption, which will cause 1 / 2 of the fluvoxamine maleate tablets to be exposed to the environment, especially in the high temperature and high humidity environment in summer, which is very unstable. Therefore, it is necessary not only to consider the effects of temperature and humidity on the stability of fluvoxamine maleate tablets during the preparation process, but also to consider the effects of temperature and humidity on the stability of fluvoxamine maleate tablets during storage and use, especially the problem of moisture and heat stability of split tablets during exposed placement.

[0004] CN202111381394.6 discloses a solid pharmaceutical composition for treating mental illness. The patent adopts a wet granulation process to prepare samples. During the wet granulation, a large amount of purified water is added to make a soft material, and a high temperature of 50-60°C is used for drying, which makes the particles in a high temperature and high humidity state, which will cause the rapid growth of impurities in the particles during the soft material making and drying process.

[0005] CN200710069781 discloses a method for preparing a fluvoxamine maleate pharmaceutical composition. In this patent, a mixed powder of fluvoxamine maleate, a filler and a disintegrant is dry-pressed by a dry granulator, and then the obtained blocks are granulated by a swing granulator, and then mixed with an external auxiliary material, and then tableted and coated. This method can solve the problem of the fluvoxamine maleate being unstable to moisture and heat in the sample during the preparation process to a certain extent, but the raw material and the hygroscopic auxiliary material are mixed and granulated, and there is still a problem of moisture and heat stability during storage and use.

[0006] In order to solve the stability problem of fluvoxamine maleate pharmaceutical preparations, CN201610132971.0 discloses a pharmaceutical composition containing fluvoxamine maleate and a preparation method thereof. The patent mixes fluvoxamine maleate with pharmaceutically acceptable excipients and crushes them into a mixture, and then mixes the mixture with pre-prepared blank particles and compresses and coats them. The drug-containing particles contain hygroscopic excipients such as starch and pregelatinized starch, which are easy to absorb moisture during storage and use, causing impurity growth. Therefore, the problem of wet and hot stability of tablets or split tablets during naked placement cannot be solved. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing fluvoxamine maleate film-coated tablets, so as to solve the problem of impurity growth caused by a hot and humid environment during the preparation, storage and use of fluvoxamine maleate film-coated tablets.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A method for preparing fluvoxamine maleate film-coated tablets, comprising preparing drug-containing granules and blank granules respectively by dry granulation, coating the blank granules, and then mixing the blank granules with the drug-containing granules and external excipients, tabletting, and coating the tablets;

[0010] The drug-containing particles are prepared by mixing fluvoxamine maleate with one or more auxiliary materials; and the blank particles are prepared by mixing one or more auxiliary materials.

[0011] Preferably, it comprises the following steps:

[0012] (1) mixing fluvoxamine maleate and filler A and performing dry granulation to obtain drug-containing granules;

[0013] (2) mixing filler B, disintegrant, and binder and performing dry granulation to obtain blank granules;

[0014] (3) preparing a water-soluble coating solution and spray coating the blank particles in a fluidized bed;

[0015] (4) mixing the coated blank granules with the drug-containing granules, lubricant, and glidant, and tableting to obtain plain tablets;

[0016] (5) preparing a film coating premix and film coating the plain tablets to obtain fluvoxamine maleate film-coated tablets; the filler A is mannitol; the filler B is one or more of mannitol, microcrystalline cellulose, lactose or pregelatinized starch; and the mass ratio of the filler A to the filler B is 1:2-2.5.

[0017] Further preferably, it is composed of the following raw materials in the following weight ratio: 10-30 parts of fluvoxamine maleate, 5-15 parts of water-soluble coating material, 30-60 parts of filler, 0-8 parts of disintegrant, 0-30 parts of binder, 1-5 parts of lubricant, 1-5 parts of glidant, and 1-6 parts of film coating premix.

[0018] The water-soluble coating material is one or more of polyethylene glycol (PEG), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP), or a mixture of one or more of the above and mannitol.

[0019] The disintegrant is one or more of starch, sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl methylcellulose (L-HPC) or cross-linked sodium carboxymethyl cellulose (CCNa).

[0020] The lubricant is one or more of magnesium stearate, calcium stearate, glyceryl monostearate, sodium stearyl fumarate and talc.

[0021] The glidant is one or more of talc and colloidal silicon dioxide.

[0022] The binder is polyvinyl pyrrolidone K30.

[0023] The present invention adopts a dry granulation process to prepare drug-containing granules and blank granules, and coats the blank granules, which can effectively improve the problem of impurity growth caused during the production process of the product and under hot and humid conditions:

[0024] (1) The drug-containing granules were prepared by dry granulation process, which prevented fluvoxamine maleate from being exposed to high temperature and high humidity environment and improved the stability of the drug during the preparation process; the blank granules were prepared by dry granulation process to prevent moisture absorption of hygroscopic materials during the granulation process.

[0025] (2) Blank particles are used instead of drug-containing particles for coating, which avoids the generation of impurities in the drug-containing particles due to high humidity and high temperature during the coating process, and is beneficial to the stability of the drug-containing particles.

[0026] (3) Pregelatinized starch, corn starch and other hygroscopic excipients are dry granulated and then coated. The coating material blocks the entry of moisture, increases the moisture barrier, and effectively separates the drug-containing particles from the hygroscopic excipients. This can effectively prevent the influence of moisture on the drug-containing particles. After the film-coated tablets are divided, they can still achieve a good moisture-proof effect, thereby increasing the stability of the drug.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention adopts dry granulation to prepare drug-containing particles and blank particles, which effectively solves the problem that fluvoxamine maleate is unstable to moisture and heat during the preparation process.

[0029] The present invention granulates hygroscopic auxiliary materials and raw materials separately, and coats blank particles containing hygroscopic auxiliary materials. After the coated blank particles are mixed with drug-containing particles for tableting, the coating layer of the blank particles forms a grid structure, which is equivalent to coating the drug-containing particles, and can effectively block the entry of moisture, thereby improving the wet and hot stability of the fluvoxamine maleate film-coated tablets during storage and use.

[0030] The method of the invention can effectively solve the problem of impurity growth caused by the hot and humid environment during the preparation, storage and use of the fluvoxamine maleate film-coated tablets. DETAILED DESCRIPTION

[0031] The technical solution of this patent is further described in detail below in conjunction with specific implementation methods.

[0032] Embodiment 1:

[0033] The prescription is as follows:

[0034] Preparation process:

[0035] (1) Place polyethylene glycol and mannitol in purified water to prepare a solution for later use.

[0036] (2) Place Opadry in purified water to prepare a solution for later use.

[0037] (3) Fluvoxamine maleate and mannitol were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0038] (4) Mannitol, pregelatinized starch and starch were initially mixed in a mixer for 5 minutes, passed through a 40-mesh sieve and continued to mix in the mixer for 10 minutes.

[0039] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0040] (6) The material obtained in step (4) is placed in a dry granulator and granulated into 40 mesh pieces.

[0041] (7) Place the granules obtained in step (6) in a fluidized bed, turn on the fan, heat, and put the granules in a good fluidized state. Spray the coating material in step (1) into the fluidized bed, coat at 40-50°C, and sieve through a 30-mesh sieve to size the granules.

[0042] (8) The granules obtained in step (5) are mixed evenly with the coated granules obtained in step (7), sodium stearyl fumarate and colloidal silicon dioxide, and then tabletted.

[0043] (9) placing the plain tablet obtained in step (8) in a high-efficiency coating machine and coating the tablet with the coating solution obtained in step (2).

[0044] Embodiment 2:

[0045] The prescription is as follows:

[0046]

[0047] Preparation process:

[0048] (1) Place polyvinyl alcohol and mannitol in purified water to prepare a solution for later use.

[0049] (2) Place Opadry in purified water to prepare a solution for later use.

[0050] (3) Fluvoxamine maleate and mannitol were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0051] (4) Mannitol, pregelatinized starch and polyvinylpyrrolidone K30 were initially mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0052] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0053] (6) The material obtained in step (4) is placed in a dry granulator and granulated into 40 mesh size particles.

[0054] (7) Place the granules obtained in step (6) in a fluidized bed, turn on the fan, heat, and put the granules in a good fluidized state. Spray the coating material in step (1) into the fluidized bed, coat at 40-50°C, and sieve through a 30-mesh screen to size the granules.

[0055] (8) The granules obtained in step (5) are mixed evenly with the coated granules obtained in step (7), magnesium stearate and colloidal silicon dioxide, and then tabletted.

[0056] (9) placing the plain tablet obtained in step (8) in a high-efficiency coating machine and coating the tablet with the coating solution obtained in step (2).

[0057] Embodiment 3:

[0058] The prescription is as follows:

[0059] Preparation process:

[0060] (1) Place polyvinyl alcohol, polyethylene glycol and mannitol in purified water to prepare a solution for later use.

[0061] (2) Place Opadry in purified water to prepare a solution for later use.

[0062] (3) Fluvoxamine maleate and mannitol were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0063] (4) Mannitol, microcrystalline cellulose and starch were initially mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0064] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0065] (6) The material obtained in step (4) is placed in a dry granulator and granulated into 40 mesh size particles.

[0066] (7) Place the granules obtained in step (6) in a fluidized bed, turn on the fan, heat, and put the granules in a good fluidized state. Spray the coating material in step (1) into the fluidized bed, coat at 40-50°C, and sieve through a 30-mesh screen to size the granules.

[0067] (8) The granules obtained in step (5) are mixed evenly with the coated granules obtained in step (7), sodium stearyl fumarate and colloidal silicon dioxide, and then tabletted.

[0068] (9) placing the plain tablet obtained in step (8) in a high-efficiency coating machine and coating the tablet with the coating solution obtained in step (2).

[0069] Embodiment 4:

[0070] The prescription is as follows:

[0071] Preparation process:

[0072] (1) Place hydroxypropyl methylcellulose, polyethylene glycol and mannitol in purified water to prepare a solution for later use.

[0073] (2) Place Opadry in purified water to prepare a solution for later use.

[0074] (3) Fluvoxamine maleate and mannitol were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0075] (4) Mannitol, lactose, sodium carboxymethyl starch and polyvinylpyrrolidone K30 were initially mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0076] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0077] (6) The material obtained in step (4) is placed in a dry granulator and granulated into 40 mesh pieces.

[0078] (7) Place the granules obtained in step (6) in a fluidized bed, turn on the fan, heat, and put the granules in a good fluidized state. Spray the coating material in step (1) into the fluidized bed, coat at 40-50°C, and sieve through a 30-mesh sieve to size the granules.

[0079] (8) The granules obtained in step (5) are mixed evenly with the coated granules obtained in step (7), glyceryl monostearate, and colloidal silicon dioxide, and then tabletted.

[0080] (9) placing the plain tablet obtained in step (8) in a high-efficiency coating machine and coating the tablet with the coating solution obtained in step (2).

[0081] Embodiment 5:

[0082] The prescription is as follows:

[0083] Preparation process:

[0084] (1) Place polyvinyl alcohol, polyvinyl pyrrolidone and mannitol in purified water to prepare a solution for later use.

[0085] (2) Place Opadry in purified water to prepare a solution for later use.

[0086] (3) Fluvoxamine maleate and mannitol were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0087] (4) Mannitol, pregelatinized starch, cross-linked sodium carboxymethyl cellulose and polyvinyl pyrrolidone K30 were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0088] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0089] (6) The material obtained in step (4) is placed in a dry granulator and granulated into 40 mesh pieces.

[0090] (7) Place the granules obtained in step (6) in a fluidized bed, turn on the fan, heat, and put the granules in a good fluidized state. Spray the coating material in step (1) into the fluidized bed, coat at 40-50°C, and sieve through a 30-mesh screen to size the granules.

[0091] (8) The granules obtained in step (5) are mixed evenly with the coated granules obtained in step (7), talcum powder and colloidal silicon dioxide, and then tabletted.

[0092] (9) Place the plain tablet obtained in step (8) in a high-efficiency coating machine and coat it with the coating solution obtained in step (2).

[0093] The prescription is as follows:

[0094] Preparation process:

[0095] (1) Place Opadry in purified water to prepare a solution for later use.

[0096] (2) Fluvoxamine maleate and mannitol were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0097] (3) Mannitol, pregelatinized starch and starch were initially mixed in a mixer for 5 minutes, passed through a 40-mesh sieve and continued to mix in the mixer for 10 minutes.

[0098] (4) The material obtained in step (2) is placed in a dry granulator and granulated into 40 mesh size particles.

[0099] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0100] (6) The granules obtained in step (4) are mixed evenly with the granules obtained in step (5), sodium stearyl fumarate and colloidal silicon dioxide, and then tabletted.

[0101] (7) Place the plain tablet obtained in step (6) in a high-efficiency coating machine and coat it with the coating solution obtained in step (1).

[0102] The prescription is as follows:

[0103]

[0104]

[0105] Preparation process:

[0106] (3) Place polyvinyl alcohol, polyethylene glycol and mannitol in purified water to prepare a solution for later use.

[0107] (4) Place Opadry in purified water to prepare a solution for later use.

[0108] (3) Fluvoxamine maleate and lactose were preliminarily mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0109] (4) Mannitol, microcrystalline cellulose and starch were initially mixed in a mixer for 5 minutes, passed through a 40-mesh sieve, and continued to be mixed in the mixer for 10 minutes.

[0110] (5) The material obtained in step (3) is placed in a dry granulator and granulated into 40 mesh size particles.

[0111] (6) The material obtained in step (4) is placed in a dry granulator and granulated into 40 mesh pieces.

[0112] (7) Place the granules obtained in step (5) in a fluidized bed, turn on the fan, heat, and put the granules in a good fluidized state. Spray the coating material in step (1) into the fluidized bed, coat at 40-50°C, and sieve through a 30-mesh sieve to size the granules.

[0113] (8) The granules obtained in step (5) are mixed evenly with the coated granules obtained in step (7), sodium stearyl fumarate and colloidal silicon dioxide, and then tabletted.

[0114] (9) placing the plain tablet obtained in step (8) in a high-efficiency coating machine and coating the tablet with the coating solution obtained in step (2).

[0115] Prescription process evaluation:

[0116] After the preparation, the coated tablets obtained in Examples 1-3 and Comparative Examples 1-2 were selected for inner packaging (aluminum-plastic packaging) and manual segmentation. The inner packaging samples, bare tablets, and segmented tablets (1 / 2 tablets) were placed in a long-term stability test box (temperature: 25°C, relative humidity: 60%), an intermediate condition stability test box (temperature: 30°C, relative humidity: 65%), and an accelerated condition stability test box (temperature: 40°C, relative humidity: 75%), respectively. After 30 days, the related substances were measured and compared with those on day 0. The results of the related substances in each experimental group are as follows:

[0117] Table 1 Stability data of samples under long-term conditions

[0118]

[0119] Under the conditions of the long-term stability test, the impurity content of Examples 1, 2, and 3, whether aluminum-plastic packaging or bare chips and 1 / 2 split chips, did not change significantly compared with that at 0 day, and all met the limit requirements; while the impurity content of Comparative Examples 1 and 2 was compared with that at 30 days, and the addition products and unknown impurities increased significantly.

[0120] Table 2 Stability data of samples under intermediate conditions

[0121]

[0122] Under the conditions of the intermediate stability test, the impurity content of Examples 1, 2, and 3, whether aluminum-plastic packaging or bare chips and 1 / 2 split tablets, was compared with that of Day 0. Although the Z-isomer and addition product increased slightly, the increase was much smaller than that of Comparative Examples 1 and 2. The bare chips and 1 / 2 split tablet addition products of Comparative Examples 1 and 2 did not meet the limit requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0123] Table 3 Stability data of samples under accelerated conditions

[0124]

[0125]

[0126] Under the conditions of the accelerated stability test, the impurity content of Examples 1, 2, and 3, whether aluminum-plastic packaging or bare chips and 1 / 2 split tablets, increased compared with that on day 0, and the Z-isomer and addition product increased, but the increase was much smaller than that of Comparative Examples 1 and 2. The bare chips and 1 / 2 split tablet addition products of Comparative Examples 1 and 2 did not meet the limit requirements of the 2020 edition of the Chinese Pharmacopoeia.

[0127] Compared with Comparative Example 1, in Examples 1, 2, and 3, the blank auxiliary material particles were coated, and the coating material blocked the entry of moisture, making the samples of Examples 1, 2, and 3 more stable than the sample of Comparative Example 1. Compared with Comparative Example 2, the particles of Examples 1, 2, and 3 were all coated. Although there was no significant change in the impurity growth level during the stability placement process, the blank auxiliary material particles were coated in Examples 1, 2, and 3, avoiding the influence of moisture and heat on the product quality, so that they had a better impurity control level at 0 days.

[0128] In summary, the use of this preparation process can effectively reduce the problem of impurity growth caused by the humid and hot environment during the preparation, storage and use of this product.

Claims

1. A method for preparing fluvoxamine maleate film-coated tablets, characterized in that: The drug-containing granules and blank granules are prepared by dry granulation, the blank granules are coated, and then the blank granules are mixed with the drug-containing granules and external excipients, tableted, and coated. The drug-containing particles are prepared by mixing fluvoxamine maleate with one or more excipients; the blank particles are prepared by mixing one or more excipients; It includes the following steps: (1) mixing fluvoxamine maleate and filler A and performing dry granulation to obtain drug-containing granules; (2) Mixing filler B, disintegrant, and binder and performing dry granulation to obtain blank granules; (3) preparing a water-soluble coating solution and spray coating the blank particles in a fluidized bed; (4) Mixing the coated blank granules with the drug-containing granules, lubricant, and glidant, and tableting to obtain plain tablets; (5) preparing a film coating premix, and film coating the plain tablets to obtain fluvoxamine maleate film-coated tablets; the filler A is mannitol; the filler B is one or more of mannitol, microcrystalline cellulose, lactose or pregelatinized starch; the mass ratio of the filler A to the filler B is 1:2-2.

5.

2. The method for preparing a fluvoxamine maleate film-coated tablet according to claim 1, characterized in that The invention is composed of the following raw materials in weight proportion: 10-30 parts of fluvoxamine maleate, 5-15 parts of water-soluble coating material, 30-60 parts of filler, 0-8 parts of disintegrant, 0-30 parts of binder, 1-5 parts of lubricant, 1-5 parts of glidant and 1-6 parts of film coating premix.

3. The method for preparing a fluvoxamine maleate film-coated tablet according to claim 2, characterized in that: The water-soluble coating material is one or more of polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose or polyvinyl pyrrolidone, or a mixture of one or more of them and mannitol.

4. The method for preparing a fluvoxamine maleate film-coated tablet according to claim 1, characterized in that: The disintegrant is one or more of starch, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose or cross-linked sodium carboxymethyl cellulose.

5. The method for preparing a fluvoxamine maleate film-coated tablet according to claim 1, characterized in that: The lubricant is one or more of magnesium stearate, calcium stearate, glyceryl monostearate, sodium stearyl fumarate and talc.

6. The method for preparing a fluvoxamine maleate film-coated tablet according to claim 1, characterized in that: The glidant is one or more of talc and colloidal silicon dioxide.

7. The method for preparing a fluvoxamine maleate film-coated tablet according to claim 1, characterized in that: The adhesive is polyvinyl pyrrolidone K30.

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