Fluvoxamine maleate tablet and preparation method thereof

Abstract

The invention discloses a fluvoxamine maleate tablet and a preparation method thereof, the fluvoxamine maleate tablet is prepared from the following raw materials in parts by mass: 45 to 55 parts of fluvoxamine maleate, 145 to 155 parts of mannitol, 38 to 42 parts of corn starch, 3 to 8 parts of pregelatinized starch, 0.5 to 1 part of colloidal silicon dioxide and 1.5 to 2 parts of sodium stearyl fumarate, and corn starch accounting for 4.4-5.6% of the total mass is used as a starch slurry raw material. By adopting a wet granulation process, the granules are good in flowability and compressibility, qualified in quality, stable in property, high in release speed and high in solubility, and the dissolution rate of the granules in different pH environments and water media for 15 minutes is greater than 85%. Compared with the traditional antidepressant drug, the fluvoxamine maleate and the pseudoadrenaline have low efficacy and are not easy to cause excitement, hidrosis and other symptoms; the anti-choline and anti-histamine efficacy is low, and the phenomena of weight gain, drowsiness and the like are rarely caused; the interaction among the medicines is small, and the drug combination is facilitated.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a fluvoxamine maleate tablet and a preparation method thereof. Background Art

[0002] Fluvoxamine maleate, chemical name: (E)-5-methoxy-4'-trifluoromethylphenylvalerone-oxime-(2-aminoacetyl oxime) maleate, molecular formula C 19 H 25 F3N2O6, molecular weight 434.407, chemical structural formula:

[0003] Fluvoxamine maleate is a drug for treating depression and obsessive-compulsive disorder, belonging to the type of selective serotonin reuptake inhibitor (SSRIs) antidepressants and also monocyclic SSRIs. It regulates the concentration of serotonin through 5HT4-receptor antagonism and selective serotonin reuptake inhibition, thus effectively treating depression and major depressive disorders. Compared with traditional antidepressants, fluvoxamine maleate has the advantages of low pseudoepinephrine potency, not easily causing symptoms such as excitement and sweating; low anticholinergic and antihistamine potency, rarely causing phenomena such as weight gain and drowsiness; and small drug interactions, which is beneficial for combined medication.

[0004] The dosage form of fluvoxamine maleate is mostly tablets, and the existing fluvoxamine maleate tablets still have certain defects, such as slow dissolution rate. Therefore, it is necessary to provide a fluvoxamine maleate tablet with a fast dissolution rate.

[0005] The information disclosed in this background art section is only intended to increase the understanding of the overall background of the present invention, and should not be regarded as an admission or any form of implication that this information constitutes the prior art already known to those of ordinary skill in the art. Summary of the Invention

[0006] The purpose of the present invention is to provide a fluvoxamine maleate tablet and a preparation method thereof, and the fluvoxamine maleate tablet has stable properties and a fast release rate.

[0007] In order to achieve the above purpose, the technical solution provided by a specific embodiment of the present invention is as follows:

[0008] A fluvoxamine maleate tablet, comprising the following raw materials in parts by mass: 45-55 parts of fluvoxamine maleate, 145-155 parts of mannitol, 38-42 parts of corn starch, 3-8 parts of pregelatinized starch, 0.5-1 part of colloidal silicon dioxide, 1.5-2 parts of sodium stearyl fumarate; wherein, 4.4%-5.6% of the total mass of the corn starch is used as the raw material of the starch paste.

[0009] In one or more embodiments of the present invention, the raw materials include the following parts by mass: 50 parts of fluvoxamine maleate, 151.5 parts of mannitol, 40 parts of corn starch, 6 parts of pregelatinized starch, 0.75 part of colloidal silicon dioxide, and 1.75 parts of sodium stearyl fumarate.

[0010] In one or more embodiments of the present invention, D90 of the fluvoxamine maleate is ≤ 20 μm.

[0011] In one or more embodiments of the present invention, the particle size of the colloidal silicon dioxide is 10 - 15 nm.

[0012] The technical solution provided by another specific embodiment of the present invention is as follows:

[0013] A preparation method of a fluvoxamine maleate tablet, comprising the following steps:

[0014] Prepare fluvoxamine maleate, mannitol, corn starch, pregelatinized starch, colloidal silicon dioxide, and sodium stearyl fumarate;

[0015] Take a part of the corn starch, mix it with water to make a starch paste;

[0016] Mix fluvoxamine maleate, mannitol, and the remaining corn starch, then add a binder and mix, granulate by wet method, and then dry to make dry granules;

[0017] Mix pregelatinized starch, colloidal silicon dioxide, sodium stearyl fumarate, and the dry granules, size the granules, and press tablets to obtain fluvoxamine maleate tablets.

[0018] In one or more embodiments of the present invention, the mass of the corn starch used in the starch paste is 4.4% - 5.6% of the total mass of the raw material corn starch.

[0019] In one or more embodiments of the present invention, when mixing fluvoxamine maleate, mannitol, and the remaining corn starch, the rotation speed is 18 - 22 Hz, and the time is 5 - 15 min.

[0020] In one or more embodiments of the present invention, during wet granulation, the stirring rotation speed is 100 - 150 rpm, the cutting rotation speed is 1500 - 2000 rpm, and the time is 5 - 15 min.

[0021] In one or more embodiments of the present invention, the drying operation is: drying at 50°C - 70°C until the moisture content is less than 1.5%.

[0022] In one or more embodiments of the present invention, the sizing operation is sizing with a 16 - mesh to 20 - mesh sieve.

[0023] Compared with the prior art, the present invention prepares fluvoxamine maleate tablets by a wet granulation method. The granules have good fluidity and compressibility, qualified quality, and stable properties. The fluvoxamine maleate tablets have a fast release rate, a relatively high solubility in different pH environments, and a dissolution rate of more than 85% in 15 minutes in pH 1.0 hydrochloric acid, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution, and water medium, showing significant efficacy in the treatment of depression and obsessive-compulsive disorder. Description of the Drawings

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments recorded in the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0025] Figure 1 It is the dissolution curve of 12 samples in water medium in Example 2 of the present invention;

[0026] Figure 2 It is the dissolution curve of the tablets in water medium in Example 2 of the present invention. Detailed Embodiments

[0027] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0028] A specific embodiment of the present invention provides a fluvoxamine maleate tablet, which comprises the following raw materials in parts by mass: 45-55 parts of fluvoxamine maleate, 145-155 parts of mannitol, 38-42 parts of corn starch, 3-8 parts of pregelatinized starch, 0.5-1 part of colloidal silica, and 1.5-2 parts of sodium stearyl fumarate.

[0029] Specifically, mannitol, as a filler, can improve the compressibility of tablets. Its shape is relatively regular, and it can also improve the fluidity during the mixing of raw materials, enhancing the mixing uniformity. Corn starch, as a binder and disintegrant, can improve the adhesion between raw materials and the compressibility. It has good water absorption, which helps to accelerate the disintegration of tablets and improve the dissolution rate. Part of the pre-gelatinized starch has been gelatinized and has a certain viscosity. Adding it to the tablets can further improve the adhesion between raw materials and enhance the structural stability of the tablets. Colloidal silicon dioxide, as a glidant, helps to improve the mixing uniformity of raw materials and reduce the pores inside the tablets, enhancing the structural stability of the tablets. Sodium stearyl fumarate, as a lubricant, has good lubricity, improves the fluidity during the mixing of raw materials, and improves the compressibility of the tablets.

[0030] Furthermore, the preferred amounts of raw materials are 50 parts of fluvoxamine maleate, 151.5 parts of mannitol, 40 parts of corn starch, 6 parts of pre-gelatinized starch, 0.75 part of colloidal silicon dioxide, and 1.75 parts of sodium stearyl fumarate.

[0031] Furthermore, D90 of fluvoxamine maleate ≤ 20 μm, the particle size of colloidal silicon dioxide is 10 - 15 nm, and mannitol is 40 mesh. By reducing the particle size of fluvoxamine maleate, the dissolution rate of the tablets can be accelerated. By controlling the particle size of colloidal silicon dioxide, the fluidity of the raw materials can be further improved, and it can better fill in the tablets, improving the compressibility of the tablets. Mannitol may form lumps during storage. Therefore, to ensure the mixing uniformity of the raw materials, it is solved by controlling the particle size of mannitol.

[0032] Another specific embodiment of the present invention provides a method for preparing fluvoxamine maleate tablets, which includes steps 1 - 4.

[0033] Step 1, prepare fluvoxamine maleate, mannitol, corn starch, pre-gelatinized starch, colloidal silicon dioxide, and sodium stearyl fumarate.

[0034] Specifically, prepare the above raw materials according to the raw material ratio. Among them, mannitol is sieved through a 40 - mesh sieve, and D90 of fluvoxamine maleate ≤ 20 μm.

[0035] Step 2, take a part of corn starch and mix it with water to make a starch paste.

[0036] Specifically, take 4.4% - 5.6% of the total mass of the raw material corn starch, heat and mix it with water or mix it with boiling water, and prepare a 5% starch paste for use as a binder. Cool it to below 45 °C for standby.

[0037] Step 3, mix fluvoxamine maleate, mannitol, and the remaining corn starch, then add the binder and mix, perform wet granulation, and then dry to make dry granules.

[0038] Specifically, when fluvoxamine maleate, mannitol and the remaining corn starch are mixed, the rotation speed is 18 - 22 Hz and the time is 5 - 15 min. After adding the binder, wet granulation is carried out. During wet granulation, the stirring rotation speed is 100 - 150 rpm, the cutting rotation speed is 1500 - 2000 rpm, and the time is 5 - 15 min. Then it is dried at 50°C - 70°C until the moisture content is less than 1.5% to form dry granules. By controlling the rotation speed, the raw materials can be mixed evenly, and at the same time, the moisture content after drying is controlled to improve the compressibility and storage stability of the tablets.

[0039] Step 4: Mix pregelatinized starch, colloidal silicon dioxide, sodium stearyl fumarate and dry granules, perform granulation and tabletting to obtain fluvoxamine maleate tablets.

[0040] Specifically, granulation is carried out using a 16 - mesh to 20 - mesh sieve to ensure uniform particle size, so as to improve compressibility and quality.

[0041] The present invention will be further described in detail below in conjunction with specific embodiments.

[0042] The raw materials used in the present invention are sourced as follows: corn starch, Anhui Shanhe Pharmaceutical Excipients Co., Ltd., model SH - M; pregelatinized starch, Anhui Shanhe Pharmaceutical Excipients Co., Ltd., model SH - YJ - H; colloidal silicon dioxide, Evonik Operations GmbH, model Aerosil 200 Pharma; reference preparation, licensee Abbott Laboratories (Singapore) Private Limited, trade name: Luvox, specification: 50 mg.

[0043] Example 1

[0044] The fluvoxamine maleate tablets in this example are scored tablets and are made from the following raw and auxiliary materials by mass, and the amount of the binder corn starch paste is investigated: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 35 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, 1.75 mg of sodium stearyl fumarate.

[0045] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and successively place mannitol (passed through a 40 - mesh sieve), fluvoxamine maleate (after pulverization), and corn starch into a wet - type mixing granulator for premixing for 10 min at a rotation speed of 20 Hz.

[0046] Then, the binder with a concentration of 5% was atomized and added into the wet granulator, with a stirring speed of 100 rpm, a cutting speed of 1500 rpm, and granulation for 3 minutes. After adding the binder, stirring was carried out for 5 minutes to make soft materials, and fluidized bed drying was performed at 70 °C until the moisture content was less than 1.5%. The colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules were mixed and then added into the hopper of a swing granulator equipped with an 18-mesh stainless steel sieve for granulation. After dry granulation, the materials were mixed in a mixing barrel for 5 minutes and then tabletted.

[0047] Example 2

[0048] The fluvoxamine maleate tablets in this example were scored tablets, which were made from the following raw and auxiliary materials by mass, and the amount of the binder corn starch paste was investigated: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0049] Manufacturing method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet mixing granulator for premixing for 10 minutes at a speed of 20 Hz.

[0050] Then, the binder with a concentration of 5% was atomized and added into the wet granulator, with a stirring speed of 125 rpm, a cutting speed of 1800 rpm, and granulation for 3 minutes. After adding the binder, stirring was carried out for 5 minutes to make soft materials, and fluidized bed drying was performed at 70 °C until the moisture content was less than 1.5%. The colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules were mixed and then added into the hopper of a swing granulator equipped with an 18-mesh stainless steel sieve for granulation. After dry granulation, the materials were mixed in a mixing barrel for 5 minutes and then tabletted.

[0051] Example 3

[0052] The fluvoxamine maleate tablets in this example were scored tablets, which were made from the following raw and auxiliary materials by mass, and the amount of the binder corn starch paste was investigated: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 45 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0053] Manufacturing method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet mixing granulator for premixing for 10 minutes at a speed of 20 Hz.

[0054] Then, atomize the binder with a concentration of 5% and add it to the wet granulator. Stir at a speed of 150 rpm and cut at a speed of 2000 rpm for 3 minutes of granulation. After adding the binder, stir for 5 minutes to make the soft material, and dry it by fluidized bed drying at 70°C until the moisture content is less than 1.5%. Mix the colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate and dry granules, and then add them to the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried material, mix it in a mixing barrel for 5 minutes and then press tablets.

[0055] Example 4

[0056] The fluvoxamine maleate tablets in this example are scored tablets and are made from the following raw and auxiliary materials by mass, investigating the dosage of the filler corn starch: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 36 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0057] Manufacturing method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (passed through a 40-mesh sieve), fluvoxamine maleate (after pulverization), and corn starch in a wet mixing granulator for premixing for 10 minutes at a speed of 20 Hz.

[0058] Then, atomize the binder with a concentration of 5% and add it to the wet granulator. Stir at a speed of 125 rpm and cut at a speed of 1800 rpm for 3 minutes of granulation. After adding the slurry, stir for 5 minutes to make the soft material, and dry it by fluidized bed drying at 70°C until the moisture content is less than 1.5%. Mix the converted colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate and dry granules, and then add them to the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried material, mix it in a mixing barrel for 5 minutes and then press tablets.

[0059] Example 5

[0060] The fluvoxamine maleate tablets in this example are scored tablets and are made from the following raw and auxiliary materials by mass, investigating the dosage of the filler corn starch: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 40 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0061] Manufacturing method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (passed through a 40-mesh sieve), fluvoxamine maleate (after pulverization), and corn starch in a wet mixing granulator for premixing for 10 minutes at a speed of 20 Hz.

[0062] Then, the binder with a concentration of 5% was atomized and added into the wet granulator. The stirring speed was 125 rpm, the cutting speed was 1800 rpm, and granulation was carried out for 3 minutes. After the addition of the slurry was completed, stirring was carried out for 5 minutes to prepare the soft material. Drying was carried out by fluidized bed drying at 70°C until the moisture content was less than 1.5%. The calculated colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate and dry granules were mixed and then added into the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for granulation. After the materials were granulated and dried, they were mixed in a mixing barrel for 5 minutes and then tabletted.

[0063] Example 6

[0064] The fluvoxamine maleate tablets in this example were scored tablets and were prepared from the following raw and auxiliary materials by mass to investigate the dosage of the binder corn starch paste: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.5 mg of sodium stearyl fumarate.

[0065] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass fraction, and successively place mannitol (passed through a 40-mesh sieve), fluvoxamine maleate (after pulverization), and corn starch into a wet mixing granulator for premixing for 10 minutes at a speed of 20 Hz.

[0066] Then, the binder with a concentration of 5% was atomized and added into the wet granulator. The stirring speed was 125 rpm, the cutting speed was 1800 rpm, and granulation was carried out for 3 minutes. After the addition of the binder was completed, stirring was carried out for 5 minutes to prepare the soft material. Drying was carried out by fluidized bed drying at 70°C until the moisture content was less than 1.5%. The colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate and dry granules were mixed and then added into the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for granulation. After the materials were granulated and dried, they were mixed in a mixing barrel for 5 minutes and then tabletted.

[0067] Example 7

[0068] The fluvoxamine maleate tablets in this example were scored tablets and were prepared from the following raw and auxiliary materials by mass to investigate the dosage of the binder corn starch paste: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 2.0 mg of sodium stearyl fumarate.

[0069] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 minutes at a rotation speed of 20 Hz.

[0070] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm, granulate for 3 minutes. After adding the binder, stir for 5 minutes to make soft materials, and dry them by fluidized bed drying at 70°C until the moisture content is less than 1.5%. Mix colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate and dry granules, and add them into the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried materials, mix them in a mixing barrel for 5 minutes and then press tablets.

[0071] Example 8

[0072] The fluvoxamine maleate tablets in this example are scored tablets, and are made from the following raw and auxiliary materials by mass, to investigate the dosage of the binder corn starch paste: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0073] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 5 minutes at a rotation speed of 20 Hz.

[0074] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm, granulate for 3 minutes. After adding the binder, stir for 5 minutes to make soft materials, and dry them by fluidized bed drying at 70°C until the moisture content is less than 1.5%. Mix colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate and dry granules, and add them into the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried materials, mix them in a mixing barrel for 5 minutes and then press tablets.

[0075] Example 9

[0076] The fluvoxamine maleate tablets in this example are scored tablets, and are made from the following raw and auxiliary materials by mass, to investigate the dosage of the binder corn starch paste: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0077] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass fraction, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 15 minutes at a rotation speed of 20 Hz.

[0078] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm. Granulate for 3 minutes. After adding the binder, stir for 5 minutes to prepare soft materials, and dry them by fluidized bed drying at 70°C until the moisture content is less than 1.5%. Mix colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and add them to the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried materials, mix them in a mixing barrel for 5 minutes and then press tablets.

[0079] Comparative Example 1

[0080] The fluvoxamine maleate tablets in this comparative example are scored tablets and are made from the following raw and auxiliary materials in terms of mass, to investigate the dosage of the binder corn starch paste: fluvoxamine maleate 50 mg, mannitol 151.5 mg, corn starch 38 mg, 5% starch paste 20 mg, pregelatinized starch 6 mg, colloidal silicon dioxide 0.75 mg, sodium stearyl fumarate 1.75 mg.

[0081] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45°C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass fraction, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 minutes at a rotation speed of 20 Hz.

[0082] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm. Granulate for 3 minutes. After adding the binder, stir for 5 minutes to prepare soft materials, and dry them by fluidized bed drying at 70°C until the moisture content is less than 1.5%. Mix colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and add them to the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried materials, mix them in a mixing barrel for 5 minutes and then press tablets.

[0083] Comparative Example 2

[0084] The fluvoxamine maleate tablets in this comparative example are scored tablets and are made from the following raw and auxiliary materials in terms of mass, to investigate the dosage of the binder corn starch paste: fluvoxamine maleate 50 mg, mannitol 151.5 mg, corn starch 38 mg, 5% starch paste 60 mg, pregelatinized starch 6 mg, colloidal silicon dioxide 0.75 mg, sodium stearyl fumarate 1.75 mg.

[0085] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, cool it below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (sieved through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 min at a rotation speed of 20 Hz.

[0086] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm, granulate for 3 min. After adding the binder, stir for 5 minutes to prepare soft materials, and dry them by fluidized bed drying at 70 °C until the moisture content is less than 1.5%. Mix colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and then add them into the hopper of a swing granulator equipped with an 18-mesh stainless steel sieve for granulation. After dry granulation, mix the materials in a mixing barrel for 5 minutes and then press tablets.

[0087] Comparative Example 3

[0088] The fluvoxamine maleate tablets in this comparative example are scored tablets, which are made from the following raw and auxiliary materials by mass, and the dosage of the filler corn starch is investigated: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 33 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0089] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, cool it below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (sieved through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 min at a rotation speed of 20 Hz.

[0090] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm, granulate for 3 min. After adding the slurry, stir for 5 minutes to prepare soft materials, and dry them by fluidized bed drying at 70 °C until the moisture content is less than 1.5%. Mix the converted colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and then add them into the hopper of a swing granulator equipped with an 18-mesh stainless steel sieve for granulation. After dry granulation, mix the materials in a mixing barrel for 5 minutes and then press tablets.

[0091] Comparative Example 4

[0092] The fluvoxamine maleate tablets in this comparative example are scored tablets and are made from the following raw and auxiliary materials in the following amounts. The amount of the filler corn starch is investigated: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 43 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.75 mg of sodium stearyl fumarate.

[0093] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 min at a rotation speed of 20 Hz.

[0094] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm. Granulate for 3 min. After the addition of the paste is completed, stir for 5 min to make soft materials, and dry by fluidized bed drying at 70 °C until the moisture content is less than 1.5%. Mix the converted colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and add them into the hopper of a swing granulator equipped with an 18-mesh stainless steel sieve for granulation. After dry granulation, mix the materials in a mixing barrel for 5 min and then press tablets.

[0095] Comparative Example 5

[0096] The fluvoxamine maleate tablets in this comparative example are scored tablets and are made from the following raw and auxiliary materials in the following amounts. The amount of the binder corn starch paste is investigated: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 1.2 mg of sodium stearyl fumarate.

[0097] Preparation method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, and cool it to below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the mass parts, and sequentially place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 min at a rotation speed of 20 Hz.

[0098] Then, atomize the 5% binder and add it into the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm. Granulate for 3 min. After the addition of the binder is completed, stir for 5 min to make soft materials, and dry by fluidized bed drying at 70 °C until the moisture content is less than 1.5%. Mix the colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and add them into the hopper of a swing granulator equipped with an 18-mesh stainless steel sieve for granulation. After dry granulation, mix the materials in a mixing barrel for 5 min and then press tablets.

[0099] Comparative Example 6

[0100] The fluvoxamine maleate tablets in this comparative example are scored tablets and are made from the following raw and auxiliary materials in the following amounts to investigate the amount of the binder corn starch paste: 50 mg of fluvoxamine maleate, 151.5 mg of mannitol, 38 mg of corn starch, 40 mg of 5% starch paste, 6 mg of pregelatinized starch, 0.75 mg of colloidal silicon dioxide, and 2.3 mg of sodium stearyl fumarate.

[0101] Manufacturing method: Weigh an appropriate amount of corn starch, add purified water to prepare a 5% binder, cool it to below 45 °C for standby (corn starch paste); accurately weigh each raw and auxiliary material according to the parts by mass, and successively place mannitol (screened through 40 meshes), fluvoxamine maleate (after pulverization), and corn starch into a wet granulator for premixing for 10 min at a rotation speed of 20 Hz.

[0102] Then, atomize the 5% binder and add it to the wet granulator, with a stirring speed of 125 rpm and a cutting speed of 1800 rpm, granulate for 3 min. After adding the binder, stir for 5 minutes to make soft materials, and dry them by fluidized bed drying at 70 °C until the moisture content is less than 1.5%. Mix colloidal silicon dioxide, pregelatinized starch, sodium stearyl fumarate, and dry granules, and add them to the hopper of a swing granulator equipped with an 18-mesh stainless steel screen for sizing. After sizing the dried materials, mix them in a mixing barrel for 5 minutes and then press tablets.

[0103] Comparative Example 7

[0104] The difference between this comparative example and Example 2 is that the D90 of fluvoxamine maleate is 30 μm. After testing, the dissolution rate of the tablets in the aqueous medium is less than 85% in 15 minutes.

[0105] Comparative Example 8

[0106] The difference between this comparative example and Example 2 is that during wet granulation, the stirring speed is 70 rpm and the cutting speed is 1000 rpm. After testing, the dissolution rate of the tablets in the aqueous medium is less than 85% in 15 minutes.

[0107] After testing, the friability of the tablets using 20 mg of starch paste in Comparative Example 1 does not meet the requirements, and there is a considerable proportion of lamination phenomenon, which is due to insufficient binder dosage resulting in insufficient binding strength of the tablet core, so this formulation dosage is excluded. The 15-minute dissolution of the tablets using 60 mg of starch paste in Comparative Example 2 is less than 85%, and the slow disintegration due to the large amount of binder leads to slow dissolution. For the determination of the dissolution curves of the tablets in Examples 1-3 in the aqueous medium, the dissolution in 15 minutes is greater than 85%, which is rapid dissolution and is similar to the reference preparation. Therefore, it is proposed that the amount of starch paste is 40 mg / tablet, and when the dosage is 35 mg - 45 mg / tablet, it can be regarded as having no difference.

[0108] In Comparative Example 3, the 15-minute dissolution of 33 mg corn starch was less than 85%, which was due to the slow dissolution caused by the small amount of disintegrant. In Comparative Example 4, the prescription using 43 mg corn starch had loose tablets and cracked pieces, which was due to the high amount of disintegrant, resulting in loose bonding inside the tablet core. The tablets in Examples 2, 4 and 5 were tested for aqueous medium dissolution curves, and the 15-minute dissolution was greater than 85%, which was a rapid dissolution, similar to the reference preparation.

[0109] In Comparative Example 5, 1.2 mg of sodium stearyl fumarate was used in the tableting process, and the process was not smooth. In Comparative Example 6, 2.3 mg of sodium stearyl fumarate was used, and the dissolution was less than 85% in 15 minutes. The reason for the slow dissolution was that sodium stearyl fumarate was a hydrophobic lubricant, and excessive use would hinder water penetration and delay tablet disintegration. The tablets in Examples 2, 6, and 7 were subjected to aqueous medium dissolution curve determination, and the dissolution in 15 minutes was greater than 85%, which was a rapid dissolution, similar to the reference preparation. Therefore, the proposed sodium stearyl fumarate dosage is 1.75 mg / tablet, and it can be regarded as no difference when the dosage is 1.5 mg to 2.0 mg / tablet.

[0110] For Example 2, Example 8 and Example 9, mannitol, fluvoxamine maleate and corn starch were premixed in a wet mixing granulator, and 10 samples were randomly taken from different positions to detect the content of fluvoxamine maleate. The search results are shown in Table 1.

[0111] Table 1 Test results of fluvoxamine maleate content in tablets

[0112]

[0113] It can be seen from Table 1 that when mixing for 5, 10 and 15 minutes, the contents at different positions are all within the required range, and the RSD is ≤5.0% (refer to the Technical Guidelines for Research on Mixing Uniformity and Central Control Dose Unit Uniformity of Chemical Oral Solid Preparations (Trial) , all single values ​​are within ±10.0% (absolute) of the mean, RSD≤5.0%), which all meet the requirements, proving that the raw and excipients are mixed uniformly. Therefore, the optimal premixing parameters under pilot scale are determined: the mixing speed is 20Hz, and the premixing time is 10min.

[0114] The 12 samples in Example 2 were randomly selected and their dissolution rates were measured in aqueous media at different times. The results are shown in Table 2. Figure 1 and Figure 2 shown.

[0115] Table 2 Dissolution at different times

[0116]

[0117] From Table 2, Figure 1 and Figure 2It can be seen that in the aqueous medium, the dissolution of the samples is rapid dissolution, which meets the expectations.

[0118] In addition, the dissolution rates of the tablets in the examples and comparative examples of the present invention were tested in hydrochloric acid at pH 1.0, acetate buffer at pH 4.5, and phosphate buffer at pH 6.8, respectively. The results showed that the dissolution rates of the tablets in the examples were greater than 85% at 15 minutes, while the dissolution rates of the tablets in the comparative examples were less than 85% at 15 minutes.

[0119] In summary, the present invention uses a wet granulation process to prepare fluvoxamine maleate tablets. The tablets are scored tablets and are composed of the active ingredient fluvoxamine maleate, mannitol, corn starch, pregelatinized starch, colloidal silicon dioxide, and sodium stearyl fumarate. Among them, mannitol is a filler, corn starch is a binder and disintegrant, sodium stearyl fumarate is a lubricant, pregelatinized starch is a binder, and colloidal silicon dioxide is a retention aid. The granules prepared by this process have good fluidity and compressibility, meet the quality requirements, are stable in nature, have a fast release rate, and the dissolution rate is greater than 85% at 15 minutes in four dissolution media.

[0120] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, in any aspect, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present invention. Any reference signs in the claims should not be construed as limiting the claims involved.

[0121] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A fluvoxamine maleate tablet, characterized in that, It comprises the following raw materials in parts by mass: 45 - 55 parts of fluvoxamine maleate, 145 - 155 parts of mannitol, 38 - 42 parts of corn starch, 3 - 8 parts of pregelatinized starch, 0.5 - 1 part of colloidal silicon dioxide, and 1.5 - 2 parts of sodium stearyl fumarate; Among them, 4.4% - 5.6% of the total mass of the corn starch is used as the raw material for the starch paste.

2. The fluvoxamine maleate tablet according to claim 1, wherein It comprises the following raw materials in parts by mass: 50 parts of fluvoxamine maleate, 151.5 parts of mannitol, 40 parts of corn starch, 6 parts of pregelatinized starch, 0.75 part of colloidal silicon dioxide, and 1.75 parts of sodium stearyl fumarate.

3. The fluvoxamine maleate tablet according to claim 1, wherein The D90 of the fluvoxamine maleate ≤ 20 μm.

4. The fluvoxamine maleate tablet according to claim 1, characterized in that, The particle size of the colloidal silicon dioxide is 10 - 15 nm.

5. The preparation method of the fluvoxamine maleate tablet according to any one of claims 1-4, characterized in that, It comprises the following steps: Prepare fluvoxamine maleate, mannitol, corn starch, pregelatinized starch, colloidal silicon dioxide, and sodium stearyl fumarate; Take a part of the corn starch and mix it with water to make a starch paste; Mix the fluvoxamine maleate, mannitol, and the remaining corn starch, then add a binder and mix, perform wet granulation, and then dry to make dry granules; Mix the pregelatinized starch, colloidal silicon dioxide, sodium stearyl fumarate, and the dry granules, perform sizing and tabletting to obtain fluvoxamine maleate tablets.

6. The preparation method of fluvoxamine maleate tablets according to claim 5, characterized in that, The mass of the corn starch used in the starch paste is 4.4% - 5.6% of the total mass of the raw material corn starch.

7. The preparation method of the fluvoxamine maleate tablets according to claim 5, characterized in that, When mixing the fluvoxamine maleate, mannitol, and the remaining corn starch, the rotation speed is 18 - 22 Hz and the time is 5 - 15 min.

8. The preparation method of the fluvoxamine maleate tablet according to claim 5, characterized in that, When performing wet granulation, the stirring rotation speed is 100 - 150 rpm, the cutting rotation speed is 1500 - 2000 rpm, and the time is 5 - 15 min.

9. The preparation method of fluvoxamine maleate tablets according to claim 5, characterized in that, The drying operation is: drying at 50°C - 70°C until the moisture content is less than 1.5%.

10. The preparation method of the fluvoxamine maleate tablets according to claim 5, characterized in that, The sizing operation is sizing using a 16 - mesh to 20 - mesh sieve.

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