Tandospirone citrate film-coated tablet and preparation method thereof

Abstract

The invention provides a tandospirone citrate film-coated tablet and a preparation method thereof.The film-coated tablet comprises a tablet core and a coating, and the tablet core is prepared from tandospirone citrate, pregelatinized starch, corn starch, calcium carboxymethyl cellulose, polyvinyl alcohol EG-05P and magnesium stearate; according to the present invention, the coating powder comprising hydroxypropyl methylcellulose, concentrated glycerol, titanium dioxide and carnauba wax is adopted to coat the obtained tablet core, the use amount of each component and the coating weight gain ratio are controlled, the hygroscopicity of the tandospirone citrate is covered, and the fluidized bed granulation mode is adopted to substantially reduce the batch-to-batch difference, and simultaneously control the particle size of the bulk drug, according to the present invention, the dissolution rate of the sample can be always maintained within a certain range, and the dissolution RSD in the phosphate medium with the pH value of 6.8 for 5 min is far less than the dissolution RSD in the original development agent, such that the intra-batch uniformity is ensured, and the problems of non-uniform granulation, large inter-batch difference, and lactose intolerance due to the long-term use of lactose during the preparation process are solved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tandospirone citrate film-coated tablet and a preparation method thereof. Background Art

[0002] Tandospirone is a 5-HT1A receptor agonist and an anti-anxiety drug. This product was developed by Sumitomo Pharma Co., Ltd. of Japan and first launched in Japan in 1996 under the trade name "Sediel" in the form of film-coated tablets. In 2003, this product entered the Chinese market with a market specification of 10 mg / tablet, which is suitable for anxiety caused by various neuroses, such as generalized anxiety disorder, and anxiety associated with physical diseases such as primary hypertension and peptic ulcer.

[0003] Tandospirone can selectively act on the 5-HT1A receptor, one of the subtypes of 5-hydroxytryptamine receptors in the brain, thereby exerting an anti-anxiety effect and improving the symptoms of the psychosomatic disease model. The main mechanism is related to the downregulation of the density of 5-HT2 receptors in the postsynaptic membrane of 5-hydroxytryptamine nerves. Long-term use can also play an antidepressant role. Compared with traditional antianxiety drugs, its antianxiety effect is more effective and safer. After long-term clinical application verification, tandospirone has a significant antianxiety effect and is worthy of clinical promotion and use.

[0004] So far, the only marketed preparations of tandospirone are film-coated tablets and capsules. At the same time, patent CN116283926A provides a method for preparing tandospirone citrate film-coated tablets, which uses a common wet granulation method. At the same time, the prescription contains a large amount of lactose. About 90% of adults in China have symptoms of lactose intolerance, so it is necessary to reduce the amount of lactose in the prescription or find excipients that can replace lactose. The same granulation method also has the risk of uneven content.

[0005] In addition, the original preparation (tandospirone citrate tablets (specification: 10 mg, trade name "Sediel")) also contains a large amount of lactose in its formula, and the RSD of the original preparation in 5 min dissolution in pH 6.8 phosphate medium is relatively large at 18.17%.

[0006] The above prior art uses lactose and common granulation methods, which fails to solve the risks of lactose intolerance and uneven content. Summary of the invention

[0007] The purpose of the present invention is to provide a tandospirone citrate film-coated tablet on the basis of the prior art, comprising a tablet core and a coating, wherein the tablet core is made of tandospirone citrate, pregelatinized starch, corn starch, carboxymethylcellulose calcium, polyvinyl alcohol EG-05P and magnesium stearate, lactose is avoided in the formula, the dosage of each component and the weight gain ratio of the coating are controlled, the hygroscopicity of the tandospirone citrate itself is covered, and a fluidized bed granulation method is adopted, so that the batch difference is greatly reduced, and the particle size of the raw material is controlled, so that the dissolution rate of the sample can always be kept within a certain range, and the RSD of the 5min dissolution in a pH 6.8 phosphate medium is much smaller than that of the original preparation, so that the batch uniformity is ensured, and the problems of uneven granulation, large batch difference and lactose intolerance caused by long-term use of lactose in the preparation process are solved.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned tandospirone citrate film-coated tablets.

[0009] The technical solution of the present invention is as follows:

[0010] A tandospirone citrate film-coated tablet comprises a tablet core and a coating, wherein the tablet core is made of tandospirone citrate, pregelatinized starch, corn starch, carboxymethylcellulose calcium, polyvinyl alcohol EG-05P and magnesium stearate; and a coating powder composed of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax is used to coat the obtained tablet core.

[0011] In the present invention, in the process of preparing the film-coated tablet, tandospirone citrate, pregelatinized starch, corn starch and carboxymethylcellulose calcium are firstly mixed uniformly, polyvinyl alcohol EG-05P aqueous solution is added as a binder solution for fluidized bed granulation, and the granules are granulated after drying, and the obtained granules are collected and mixed with magnesium stearate and then tableted to prepare tablet cores; and the obtained tablet cores are coated with a coating solution made of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax to obtain the tablet cores.

[0012] Due to the hygroscopicity of the active ingredient tandospirone citrate itself, the prepared tablet core inevitably has high hygroscopicity. In the present invention, hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax are used as coating powders to coat the tablet core, and the coating weight gain ratio is controlled, which can basically prevent the prepared tablet core from absorbing moisture.

[0013] For the present invention, the mass ratio of the active component tandospirone citrate to the hypromellose in the coating powder is 1:0.08-0.12, which can be but not limited to 1:0.08, 1:0.082, 1:0.084, 1:0.086, 1:0.09, 1:0.092, 1:0.094, 1:0.096, 1:0.098, 1:0.102, 1:0.104, 1:0.106, 1:0.108, 1:0.11 or :0.12. In order to obtain better effects, the mass ratio of tandospirone citrate to hypromellose is 1:0.09-0.10, and more preferably, the mass ratio of tandospirone citrate to hypromellose is 1:0.10.

[0014] For the present invention, the mass ratio of the active ingredient tandospirone citrate to the concentrated glycerol in the coating powder is 1:0.2-0.5, and can be but not limited to 1:0.20, 1:0.25, 1:0.30, 1:0.35, 1:0.40, 1:0.45 or 1:0.50. In order to obtain better effects, the mass ratio of tandospirone citrate to concentrated glycerol is 1:0.35-0.45, and more preferably, the mass ratio of tandospirone citrate to concentrated glycerol is 1:0.40.

[0015] For the present invention, the mass ratio of the active ingredient tandospirone citrate to titanium dioxide in the coating powder is 1:0.35-0.40, which can be but not limited to 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.385, 1:0.39 or 1:0.40. In order to obtain better effects, the mass ratio of tandospirone citrate to titanium dioxide is 1:0.38-0.39, and more preferably, the mass ratio of tandospirone citrate to titanium dioxide is 1:0.385.

[0016] For the present invention, the mass ratio of the active ingredient tandospirone citrate to the carnauba wax in the coating powder is 1:0.1-0.6, and can be but not limited to 1:0.10, 1:0.15, 1:0.20, 1:0.25, 1:0.30, 1:0.35, 1:0.40, 1:0.45, 1:0.50, 1:0.55 or 1:0.60. In order to obtain better effects, the mass ratio of tandospirone citrate to carnauba wax is 1:0.4-0.5, and more preferably, the mass ratio of tandospirone citrate to carnauba wax is 1:0.45.

[0017] In one embodiment, the film-coated tablet provided by the present invention includes a tablet core and a coating, and the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 60-70 parts of pregelatinized starch, 1.5-3.0 parts of corn starch, 2.0-3.5 parts of carboxymethylcellulose calcium, 0.3-1.2 parts of polyvinyl alcohol EG-05P, and 0.8-2.8 parts of magnesium stearate; the mass ratio of tandospirone citrate to hydroxypropyl methylcellulose in the coating powder is 1:0.08-0.12; the mass ratio of tandospirone citrate to concentrated glycerol in the coating powder is 1:0.2-0.5; the mass ratio of tandospirone citrate to titanium dioxide in the coating powder is 1:0.35-0.40; the mass ratio of tandospirone citrate to carnauba wax in the coating powder is 1:0.1-0.6.

[0018] In a preferred embodiment, the film-coated tablet provided by the present invention includes a core and a coating, and the core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 64-68 parts of pregelatinized starch, 2.0-2.5 parts of corn starch, 2.5-3.0 parts of carboxymethylcellulose calcium, 0.5-1.0 parts of polyvinyl alcohol EG-05P, and 1.0-1.5 parts of magnesium stearate; wherein the mass ratio of tandospirone citrate to hydroxypropyl methylcellulose in the coating powder is 1:0.09-0.10; the mass ratio of tandospirone citrate to concentrated glycerol in the coating powder is 1:0.35-0.45; the mass ratio of tandospirone citrate to titanium dioxide in the coating powder is 1:0.38-0.39; the mass ratio of tandospirone citrate to carnauba wax in the coating powder is 1:0.4-0.5.

[0019] In a more preferred embodiment, the film-coated tablet provided by the present invention includes a core and a coating, and the core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 65-67 parts of pregelatinized starch, 2.1-2.3 parts of corn starch, 2.7-2.9 parts of carboxymethylcellulose calcium, 0.8 parts of polyvinyl alcohol EG-05P, and 1.2 parts of magnesium stearate; wherein the mass ratio of tandospirone citrate to hydroxypropyl methylcellulose in the coating powder is 1:0.10; the mass ratio of tandospirone citrate to concentrated glycerol in the coating powder is 1:0.4; the mass ratio of tandospirone citrate to titanium dioxide in the coating powder is 1:0.385; the mass ratio of tandospirone citrate to carnauba wax in the coating powder is 1:0.45.

[0020] In a particularly preferred embodiment, the film-coated tablet provided by the present invention comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 65 parts of pregelatinized starch, 2.1 parts of corn starch, 2.7 parts of carboxymethylcellulose calcium, and polyvinyl alcohol EG-05P. 0.8 parts, magnesium stearate 1.2 parts; wherein, the mass ratio of tandospirone citrate to hydroxypropyl methylcellulose in the coating powder is 1:0.10; the mass ratio of tandospirone citrate to concentrated glycerol in the coating powder is 1:0.4; the mass ratio of tandospirone citrate to titanium dioxide in the coating powder is 1:0.385; the mass ratio of tandospirone citrate to carnauba wax in the coating powder is 1:0.45; that is: 1 part of hypromellose in the coating powder; 4 parts of concentrated glycerol in the coating powder; 3.85 parts of titanium dioxide in the coating powder; 4.5 parts of carnauba wax in the coating powder.

[0021] For example, the film-coated tablet provided by the present invention includes a core and a coating, and the core is made of the following components in parts by weight: 10.0 g of tandospirone citrate, 65.0 g of pregelatinized starch, 2.1 g of corn starch, 2.7 g of carboxymethylcellulose calcium, 0.8 g of polyvinyl alcohol EG-05P, and 1.2 g of magnesium stearate; wherein the coating powder contains 1.0 g of hydroxypropyl methylcellulose; the coating powder contains 4.0 g of concentrated glycerin; the coating powder contains 3.85 g of titanium dioxide; and the coating powder contains 4.5 g of carnauba wax.

[0022] In a particularly preferred embodiment, the film-coated tablet provided by the present invention comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 66 parts of pregelatinized starch, 2.2 parts of corn starch, 2.8 parts of carboxymethylcellulose calcium, and polyvinyl alcohol EG-05P. 0.8 parts, magnesium stearate 1.2 parts; wherein, the mass ratio of tandospirone citrate to hydroxypropyl methylcellulose in the coating powder is 1:0.10; the mass ratio of tandospirone citrate to concentrated glycerol in the coating powder is 1:0.4; the mass ratio of tandospirone citrate to titanium dioxide in the coating powder is 1:0.385; the mass ratio of tandospirone citrate to carnauba wax in the coating powder is 1:0.45; that is: 1 part of hypromellose in the coating powder; 4 parts of concentrated glycerol in the coating powder; 3.85 parts of titanium dioxide in the coating powder; 4.5 parts of carnauba wax in the coating powder.

[0023] For example, the film-coated tablet provided by the present invention includes a core and a coating, and the core is made of the following components in parts by weight: 10.0 g of tandospirone citrate, 66.0 g of pregelatinized starch, 2.2 g of corn starch, 2.8 g of carboxymethylcellulose calcium, 0.8 g of polyvinyl alcohol EG-05P, and 1.2 g of magnesium stearate; wherein, the coating powder contains 1.0 g of hydroxypropyl methylcellulose; the coating powder contains 4.0 g of concentrated glycerin; the coating powder contains 3.85 g of titanium dioxide; and the coating powder contains 4.5 g of carnauba wax.

[0024] In a particularly preferred embodiment, the film-coated tablet provided by the present invention comprises a core and a coating, wherein the core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 67 parts of pregelatinized starch, 2.3 parts of corn starch, 2.9 parts of carboxymethylcellulose calcium, and polyvinyl alcohol EG-05P. 0.8 parts, magnesium stearate 1.2 parts; wherein, the mass ratio of tandospirone citrate to hydroxypropyl methylcellulose in the coating powder is 1:0.10; the mass ratio of tandospirone citrate to concentrated glycerol in the coating powder is 1:0.4; the mass ratio of tandospirone citrate to titanium dioxide in the coating powder is 1:0.385; the mass ratio of tandospirone citrate to carnauba wax in the coating powder is 1:0.45; that is: 1 part of hypromellose in the coating powder; 4 parts of concentrated glycerol in the coating powder; 3.85 parts of titanium dioxide in the coating powder; 4.5 parts of carnauba wax in the coating powder.

[0025] For example, the film-coated tablet provided by the present invention includes a tablet core and a coating, and the tablet core is made of the following components in parts by weight: 10.0 g of tandospirone citrate, 67.0 g of pregelatinized starch, 2.3 g of corn starch, 2.9 g of carboxymethylcellulose calcium, 0.8 g of polyvinyl alcohol EG-05P, and 1.2 g of magnesium stearate; wherein, the amount of hydroxypropyl methylcellulose in the coating powder is 1.0 g; the amount of concentrated glycerin in the coating powder is 4.0 g; the amount of titanium dioxide in the coating powder is 3.85 g; and the amount of carnauba wax in the coating powder is 4.5 g.

[0026] The present invention also provides a method for preparing the above-mentioned tandospirone citrate film-coated tablets, comprising the following steps:

[0027] (1) Pretreatment: pulverizing tandospirone citrate; sieving auxiliary materials for later use;

[0028] (2) Preparation of adhesive solution: polyvinyl alcohol EG-05P and water are mixed evenly to prepare an adhesive solution;

[0029] (3) Granulation: Add tandospirone citrate, pregelatinized starch, corn starch, and carboxymethylcellulose calcium into a fluidized bed, mix well, add the binder solution obtained in step (2) by top spraying, perform fluidized bed granulation, and granulate after drying;

[0030] (4) Total mixing and tableting: collecting the granules obtained in step (3) and mixing with magnesium stearate for tableting;

[0031] (5) Preparation of coating solution: Hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax are used as coating powders and mixed with water to prepare a coating solution;

[0032] (6) Coating: Add the coating solution obtained in step (5) to the tablet core obtained in step (4) for coating.

[0033] In the present invention, in step (1), tandospirone citrate is pulverized to control the particle size D90 to be 70 μm-160 μm. The auxiliary materials are sieved through a 40-80 mesh sieve.

[0034] For the present invention, in step (2), the mass content of polyvinyl alcohol EG-05P in the aqueous binder solution is 5 to 8%, which may be but is not limited to 5%, 5.5%, 6%, 6.5%, 7.0%, 7.5% or 8%. Preferably, the mass content of polyvinyl alcohol EG-05P in the aqueous binder solution is 6%.

[0035] In the present invention, in step (3), the parameters of the fluidized bed granulation are as follows: air inlet temperature 50-60°C, air volume 100-120m 3 / h, material temperature 30-40℃, peristaltic pump speed 5-15rpm. Drying parameters are as follows: material temperature 60℃, drying for 30min, until the moisture content is no more than 2%.

[0036] For the present invention, in step (5), the mass content of coating powder in the coating solution is 10-15%, which can be but not limited to 10%, 10.5%, 11%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14%, 14.5% or 15%. Preferably, the mass content of coating powder in the coating solution is 12%.

[0037] For the present invention, in step (6), the parameter conditions during coating are as follows: wind temperature 70-80°C, air outlet temperature 35-45°C, coating machine speed 3-8rpm, peristaltic pump speed 1-10rpm, atomization pressure 0.1-0.4Mp, gun pressure 0.1-0.4Mpa, tablet bed temperature 40-55°C, when the coating weight gain reaches 2.0%-4.0%, stop spraying and drying for 15 minutes.

[0038] Adopt the technical scheme of the present invention, the advantages are as follows:

[0039] The invention provides a tandospirone citrate film-coated tablet, comprising a tablet core and a coating, wherein the tablet core is prepared from tandospirone citrate, pregelatinized starch, corn starch, carboxymethylcellulose calcium, polyvinyl alcohol EG-05P and magnesium stearate, and a coating powder composed of hydroxypropyl methylcellulose, concentrated glycerol, titanium dioxide and carnauba wax is used for coating the obtained tablet core, lactose is avoided from being used in the formula, the dosage of each component and the coating weight gain ratio are controlled, the hygroscopicity of the tandospirone citrate itself is covered, a fluidized bed granulation method is adopted, batch differences are greatly reduced, the particle size of the raw material drug is controlled, the dissolution rate of the sample can be kept within a certain range, and the RSD of the 5-minute dissolution in a pH 6.8 phosphate medium is much smaller than that of the original preparation, thereby ensuring the intra-batch uniformity and solving the problems of uneven granulation and large batch differences in the preparation process, and lactose intolerance caused by long-term use of lactose. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the dissolution curve of the film-coated tablet in the embodiment when 0.1 mol / L hydrochloric acid solution is used as the dissolution medium;

[0041] Figure 2 is the dissolution curve of the film-coated tablet in the embodiment when pH 6.8 phosphate solution is used as the dissolution medium;

[0042] Figure 3 This is the dissolution curve of the film-coated tablet in the comparative example when 0.1 mol / L hydrochloric acid solution is used as the dissolution medium;

[0043] Figure 4 This is the dissolution curve of the film-coated tablet in the comparative example when pH 6.8 phosphate solution is used as the dissolution medium. DETAILED DESCRIPTION

[0044] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0045] Example 1

[0046] A tandospirone citrate film-coated tablet, the formula of the film-coated tablet (100 preparation units) is as follows:

[0047]

[0048] The preparation method of the above-mentioned tandospirone citrate film-coated tablets comprises the following steps:

[0049] (1) Pretreatment: pulverize tandospirone citrate to control the particle size D90 to be 70 μm-160 μm; auxiliary materials: pregelatinized starch and corn starch are sieved through a 40-mesh sieve, and carboxymethylcellulose calcium is sieved through an 80-mesh sieve for later use.

[0050] (2) Preparation of adhesive solution: Weigh 12.53 g of purified water, add polyvinyl alcohol EG-05P while stirring, and stir until dissolved to prepare an adhesive solution. The mass content of polyvinyl alcohol EG-05P in the adhesive solution is 6%, and set aside.

[0051] (3) Granulation: Tandospirone citrate, pregelatinized starch, corn starch, and carboxymethylcellulose calcium are added to a fluidized bed, mixed evenly, and the binder solution obtained in step (2) is added by top spraying for fluidized bed granulation. After drying, the particles are sized using a 30-mesh screen. The parameters of the fluidized bed granulation are as follows: air inlet temperature 50-60° C., air volume 100-120 m 3 / h, material temperature 30-40°C, peristaltic pump speed 5-15rpm; drying parameters are as follows: material temperature 60°C, drying time 30min, until the moisture content is no more than 2%.

[0052] (4) Total mixing and tableting: The collected granules obtained in step (3) were mixed with magnesium stearate for 10 minutes, and tableting was performed. The intermediate was tested, and the tablet weight was determined based on the test results of the intermediate. The hardness was 40N to 60N, and the tablet weight difference was ±7.5%.

[0053] (5) Preparation of coating solution: Weigh 97.90 g of purified water, add 13.35 g of coating powder (the total amount of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax) while stirring, and stir until dissolved to prepare a coating solution. The mass content of the coating powder in the coating solution is 12%, and set aside.

[0054] (6) The tablet cores obtained in step (4) are placed in a coating pan, and the coating liquid is added by a spray gun for coating. The parameters during coating are as follows: air temperature 70-80°C, air outlet temperature 35-45°C, coating machine speed 3-8rpm, peristaltic pump speed 1-10rpm, atomization pressure 0.1-0.4Mp, gun pressure 0.1-0.4Mpa, tablet bed temperature 40-55°C, when the coating weight gain reaches 2.0%-4.0%, stop spraying and dry for 15 minutes.

[0055] Example 2

[0056] A tandospirone citrate film-coated tablet, the formula of the film-coated tablet (100 preparation units) is as follows:

[0057]

[0058] The preparation method of the above-mentioned tandospirone citrate film-coated tablets comprises the following steps:

[0059] (1) Pretreatment: pulverize tandospirone citrate to control the particle size D90 to be 70 μm-160 μm; auxiliary materials: pregelatinized starch and corn starch are sieved through a 40-mesh sieve, and carboxymethylcellulose calcium is sieved through an 80-mesh sieve for later use.

[0060] (2) Preparation of adhesive solution: Weigh 12.53 g of purified water, add polyvinyl alcohol EG-05P while stirring, and stir until dissolved to prepare an adhesive solution. The mass content of polyvinyl alcohol EG-05P in the adhesive solution is 6%, and set aside.

[0061] (3) Granulation: Tandospirone citrate, pregelatinized starch, corn starch, and carboxymethylcellulose calcium are added to a fluidized bed, mixed evenly, and the binder solution obtained in step (2) is added by top spraying for fluidized bed granulation. After drying, the particles are sized using a 30-mesh screen. The parameters of the fluidized bed granulation are as follows: air inlet temperature 50-60° C., air volume 100-120 m 3 / h, material temperature 30-40°C, peristaltic pump speed 5-15rpm; drying parameters are as follows: material temperature 60°C, drying time 30min, until the moisture content is no more than 2%.

[0062] (4) Total mixing and tableting: The collected granules obtained in step (3) were mixed with magnesium stearate for 10 minutes, and tableting was performed. The intermediate was tested, and the tablet weight was determined based on the test results of the intermediate. The hardness was 40N to 60N, and the tablet weight difference was ±7.5%.

[0063] (5) Preparation of coating solution: Weigh 97.90 g of purified water, add 13.35 g of coating powder (the total amount of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax) while stirring, and stir until dissolved to prepare a coating solution. The mass content of the coating powder in the coating solution is 12%, and set aside.

[0064] (6) The tablet cores obtained in step (4) are placed in a coating pan, and the coating liquid is added by a spray gun for coating. The parameters during coating are as follows: air temperature 70-80°C, air outlet temperature 35-45°C, coating machine speed 3-8rpm, peristaltic pump speed 1-10rpm, atomization pressure 0.1-0.4Mp, gun pressure 0.1-0.4Mpa, tablet bed temperature 40-55°C, when the coating weight gain reaches 2.0%-4.0%, stop spraying and dry for 15 minutes.

[0065] Example 3

[0066] A tandospirone citrate film-coated tablet, the formula of the film-coated tablet (100 preparation units) is as follows:

[0067]

[0068] The preparation method of the above-mentioned tandospirone citrate film-coated tablets comprises the following steps:

[0069] (1) Pretreatment: pulverize tandospirone citrate to control the particle size D90 to be 70 μm-160 μm; auxiliary materials: pregelatinized starch and corn starch are sieved through a 40-mesh sieve, and carboxymethylcellulose calcium is sieved through an 80-mesh sieve for later use.

[0070] (2) Preparation of adhesive solution: Weigh 12.53 g of purified water, add polyvinyl alcohol EG-05P while stirring, and stir until dissolved to prepare an adhesive solution. The mass content of polyvinyl alcohol EG-05P in the adhesive solution is 6%, and set aside.

[0071] (3) Granulation: Tandospirone citrate, pregelatinized starch, corn starch, and carboxymethylcellulose calcium are added to a fluidized bed, mixed evenly, and the binder solution obtained in step (2) is added by top spraying for fluidized bed granulation. After drying, the particles are sized using a 30-mesh screen. The parameters of the fluidized bed granulation are as follows: air inlet temperature 50-60° C., air volume 100-120 m 3 / h, material temperature 30-40°C, peristaltic pump speed 5-15rpm; drying parameters are as follows: material temperature 60°C, drying time 30min, until the moisture content is no more than 2%.

[0072] (4) Total mixing and tableting: The collected granules obtained in step (3) were mixed with magnesium stearate for 10 minutes, and tableting was performed. The intermediate was tested, and the tablet weight was determined based on the test results of the intermediate. The hardness was 40N to 60N, and the tablet weight difference was ±7.5%.

[0073] (5) Preparation of coating solution: Weigh 97.90 g of purified water, add 13.35 g of coating powder (the total amount of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax) while stirring, and stir until dissolved to prepare a coating solution. The mass content of the coating powder in the coating solution is 12%, and set aside.

[0074] (6) The tablet cores obtained in step (4) are placed in a coating pan, and the coating liquid is added by a spray gun for coating. The parameters during coating are as follows: air temperature 70-80°C, air outlet temperature 35-45°C, coating machine speed 3-8rpm, peristaltic pump speed 1-10rpm, atomization pressure 0.1-0.4Mp, gun pressure 0.1-0.4Mpa, tablet bed temperature 40-55°C, when the coating weight gain reaches 2.0%-4.0%, stop spraying and dry for 15 minutes.

[0075] Comparative Example 1

[0076] A tandospirone citrate film-coated tablet, the formula of the film-coated tablet (100 preparation units) is as follows:

[0077]

[0078] In Comparative Example 1, the difference is that polyvinyl alcohol 17-88 is used instead of polyvinyl alcohol EG-05P as the binder during granulation, and other components and preparation methods are the same as those in Example 1.

[0079] A plurality of comparative examples are provided in the present application, wherein the specific formulas of comparative examples 2-5 are as follows:

[0080]

[0081] Comparative Example 2

[0082] The formula of the film-coated tablets is the same as that of Example 1, except that in Example 1, polyvinyl alcohol and water are mixed as a binder for granulation in the granulation step; whereas in Comparative Example 2, polyvinyl alcohol EG-05P is directly mixed with tandospirone citrate, pregelatinized starch, corn starch, and carboxymethylcellulose calcium, and water is used as a binder for granulation. The other steps are the same as those of Example 1, as follows:

[0083] (1) Pretreatment: pulverize tandospirone citrate to control the particle size D90 to be 70 μm-160 μm; auxiliary materials: pregelatinized starch and corn starch are sieved through a 40-mesh sieve, and carboxymethylcellulose calcium is sieved through an 80-mesh sieve for later use.

[0084] (2) Granulation: Tandospirone citrate, pregelatinized starch, corn starch, polyvinyl alcohol EG-05P, and calcium carboxymethyl cellulose were added to a fluidized bed and mixed evenly. 12.53 g of purified water was added as a binder by top spraying for fluidized bed granulation. After drying, granulation was performed using a 30-mesh screen. The parameters of the fluidized bed granulation were as follows: inlet air temperature 50-60°C, air volume 100-120, material temperature 30-40°C, and peristaltic pump speed 5-15 rpm. The drying parameters were as follows: material temperature 60°C, drying time 30 min, until the moisture content was no more than 2%.

[0085] (3) Total mixing and tableting: The collected granules obtained in step (3) were mixed with magnesium stearate for 10 minutes, and tableted. The intermediate was tested and the tablet weight was determined based on the test results of the intermediate. The hardness was 40N to 60N and the tablet weight difference was ±7.5%.

[0086] (4) Preparation of coating solution: Weigh 97.90 g of purified water, add 13.35 g of coating powder (the total amount of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax) while stirring, and stir until dissolved to prepare a coating solution. The mass content of the coating powder in the coating solution is 12%, and set aside.

[0087] (5) The tablet cores obtained in step (3) are placed in a coating pan, and the coating liquid is added by a spray gun for coating. The parameters during coating are as follows: air temperature 70-80°C, air outlet temperature 35-45°C, coating machine speed 3-8rpm, peristaltic pump speed 1-10rpm, atomization pressure 0.1-0.4Mp, gun pressure 0.1-0.4Mpa, tablet bed temperature 40-55°C, when the coating weight gain reaches 2.0%-4.0%, stop spraying and dry for 15 minutes.

[0088] Comparative Example 3

[0089] Compared with Example 1, the difference is that the amount of magnesium stearate is reduced, and tableting is performed after mixing. Other components and preparation methods are the same as those in Example 1.

[0090] Comparative Example 4

[0091] Compared with Example 1, the difference is that the hardness of the film-coated tablet is controlled at 30N-40N, and the other components and preparation method are the same as those of Example 1.

[0092] Comparative Example 5

[0093] Compared with Example 1, the difference is that the amount of carboxymethylcellulose calcium is increased, and the other components and preparation method are the same as those of Example 1.

[0094] Effect verification

[0095] 1. The content uniformity of the film-coated tablets in the examples and comparative examples is as follows:

[0096] Table 1 Content uniformity data of examples and comparative examples

[0097]

[0098] It can be seen from the content uniformity data in Table 1 that the content uniformity of Examples 1 to 3 all meet the requirements. Except for Comparative Example 1, the other comparative examples all meet the requirements. The reason may be that the viscosity of polyvinyl alcohol 17-88 in Comparative Example 1 is relatively high, and the granulation is uneven, which leads to unqualified content uniformity of the film-coated tablets.

[0099] 2. Comparative study on the dissolution curves of film-coated tablets in the examples and comparative examples in in vitro dissolution media

[0100] Test method: According to the dissolution test method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), use 0.1mol / L hydrochloric acid solution and pH6.8 phosphate solution as the dissolution medium, the volume is 900ml, the speed is 50 revolutions per minute, operate according to the law, in 0.1mol / L hydrochloric acid solution, at 5min, 10min, 15min, 20min, 30min, sample detection, in pH6.8 phosphate solution, at 5min, 10min, 15min, 20min, 30min, sample detection, the results are shown in Table 2-3 and Figure 1-2 shown.

[0101] The dissolution curves of the film-coated tablets in Example 1, Comparative Examples 3 and Comparative Examples 5 under accelerated conditions (40° C., 75% RH) were compared and studied. The specific results are shown in Tables 4 and 5.

[0102] Table 2 Dissolution curves of Examples 1 to 3 Dissolution data

[0103]

[0104] Table 3 Comparative Examples 2-5 Dissolution Curve Experimental Data

[0105]

[0106] Note: The content uniformity of the film-coated tablets in Comparative Example 1 was unqualified and no dissolution test was performed.

[0107] Table 4 Experimental data of dissolution curve of 0.1 mol / L hydrochloric acid solution under accelerated conditions

[0108]

[0109] Table 5 Experimental data of dissolution curve of phosphate solution at pH 6.8 under accelerated conditions

[0110]

[0111]

[0112] The film-coated tablets in Examples 1 to 3 of the present invention are substantially completely dissolved in 0.1 mol / L hydrochloric acid solution in 15 minutes, and about 60% is dissolved in 5 minutes; substantially completely dissolved in pH 6.8 phosphate solution in 15 minutes, and about 65% is dissolved in 5 minutes; and the dissolution in 5 minutes can still be maintained without significant fluctuations under accelerated conditions for 6 months.

[0113] The film-coated tablets of Comparative Example 2 dissolved too quickly in 5 minutes, indicating that the adhesive using water was not viscous enough and directly promoted the release of the drug.

[0114] The film-coated tablets of Comparative Example 3 dissolved too quickly in 5 minutes and increased significantly after 6 months of acceleration, indicating that when the magnesium stearate content is low, the tableting is not smooth and the release of the tablet core cannot be effectively prevented, resulting in accelerated release.

[0115] The film-coated tablets of Comparative Example 4 were dissolved too quickly in 5 minutes because the hardness of the film-coated tablets was reduced to 30N-40N, indicating that the degree of compression between particles in the tablet core was low, and thus the release was faster.

[0116] In Comparative Example 5, the amount of carboxymethylcellulose calcium increased, which accelerated the disintegration rate, thereby promoting the disintegration of the tablet core and accelerating the release. Therefore, the 5-minute dissolution was too fast and the accelerated release increased significantly after 6 months.

[0117] The film-coated tablets in the comparative example could not ensure stable release during the 6-month storage process under accelerated conditions, and the quality was unstable.

[0118] 3. Stability test of the film-coated tablets of the embodiments and comparative examples. Specific experimental results are shown in Tables 6 and 7.

[0119] Table 6 Stability test results in the examples

[0120]

[0121] Table 7 Comparative Examples Stability Test Results

[0122]

[0123]

[0124] The film-coated tablets in Examples 1-3, Comparative Examples 3 and 5 were subjected to a 12-month stability test. The results showed that there was no significant change in the sample content and related substances in Examples 1-3, and the sample quality was stable. The impurities in the film-coated tablets in Comparative Examples 3 and 5 gradually increased during the storage process and exceeded the limit after 12 months.

[0125] The RSDs of the samples of Examples 1-3 dissolved in a pH 6.8 phosphate medium for 5 min were 2.1%, 2.5%, and 2.0%, respectively, which were much lower than 18.17% of the original preparation (tandospirone citrate tablets (specification: 10 mg, trade name "Sediel", batch number: 2239C)), indicating that the product of the present invention is more stable within the batch than the original preparation. The specific values ​​are shown in Table 8.

[0126] Table 8 Experimental data of dissolution curves of samples of Examples 1-3 and the original preparation in pH 6.8 phosphate solution

[0127]

[0128] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A tandospirone citrate film-coated tablet, It is characterized in that The film-coated tablet comprises a tablet core and a coating, wherein the tablet core is made of tandospirone citrate, pregelatinized starch, corn starch, carboxymethylcellulose calcium, polyvinyl alcohol EG-05P and magnesium stearate; and the coating powder composed of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax is used to coat the obtained tablet core.

2. The tandospirone citrate film-coated tablet according to claim 1, It is characterized in that In the preparation process, tandospirone citrate, pregelatinized starch, corn starch and carboxymethylcellulose calcium are firstly mixed evenly, polyvinyl alcohol EG-05P aqueous solution is added as a binder solution for fluidized bed granulation, and the particles are granulated after drying, and the obtained particles are collected and mixed with magnesium stearate and then tableted to form tablet cores; and the obtained tablet cores are coated with a coating solution made of hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax to obtain the tablet cores.

3. The tandospirone citrate film-coated tablet according to claim 2, It is characterized in that The film-coated tablet comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 60-70 parts of pregelatinized starch, 1.5-3.0 parts of corn starch, 2.0-3.5 parts of carboxymethylcellulose calcium, 0.3-1.2 parts of polyvinyl alcohol EG-05P, and 0.8-2.8 parts of magnesium stearate; wherein the mass ratio of the tandospirone citrate to the hydroxypropyl methylcellulose in the coating powder is 1:0.08-0.12; the mass ratio of the tandospirone citrate to the concentrated glycerol in the coating powder is 1:0.2-0.5; the mass ratio of the tandospirone citrate to the titanium dioxide in the coating powder is 1:0.35-0.40; and the mass ratio of the tandospirone citrate to the carnauba wax in the coating powder is 1:0.1-0.

6.

4. The tandospirone citrate film-coated tablet according to claim 3, It is characterized in that The film-coated tablet comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 64-68 parts of pregelatinized starch, 2.0-2.5 parts of corn starch, 2.5-3.0 parts of carboxymethylcellulose calcium, 0.5-1.0 parts of polyvinyl alcohol EG-05P, and 1.0-1.5 parts of magnesium stearate; wherein the mass ratio of the tandospirone citrate to the hydroxypropyl methylcellulose in the coating powder is 1:0.09-0.10; the mass ratio of the tandospirone citrate to the concentrated glycerol in the coating powder is 1:0.35-0.45; the mass ratio of the tandospirone citrate to the titanium dioxide in the coating powder is 1:0.38-0.39; The mass ratio of the tandospirone citrate to the carnauba wax in the coating powder is 1:0.4-0.

5.

5. The tandospirone citrate film-coated tablet according to claim 4, It is characterized in that The film-coated tablet comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 65-67 parts of pregelatinized starch, 2.1-2.3 parts of corn starch, 2.7-2.9 parts of carboxymethylcellulose calcium, 0.8 part of polyvinyl alcohol EG-05P, and 1.2 parts of magnesium stearate; wherein the mass ratio of the tandospirone citrate to the hydroxypropyl methylcellulose in the coating powder is 1:0.10; the mass ratio of the tandospirone citrate to the concentrated glycerol in the coating powder is 1:0.4; the mass ratio of the tandospirone citrate to the titanium dioxide in the coating powder is 1:0.385; and the mass ratio of the tandospirone citrate to the carnauba wax in the coating powder is 1:0.

45.

6. The tandospirone citrate film-coated tablet according to claim 5, It is characterized in that The film-coated tablet comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 10 parts of tandospirone citrate, 65 parts of pregelatinized starch, 2.1 parts of corn starch, 2.7 parts of carboxymethylcellulose calcium, 0.8 parts of polyvinyl alcohol EG-05P, and 1.2 parts of magnesium stearate; wherein, the coating powder contains 1 part of hydroxypropyl methylcellulose; the coating powder contains 4 parts of concentrated glycerin; the coating powder contains 3.85 parts of titanium dioxide; and the coating powder contains 4.5 parts of carnauba wax; 10 parts of tandospirone citrate, 66 parts of pregelatinized starch, 2.2 parts of corn starch, 2.8 parts of carboxymethylcellulose calcium, 0.8 parts of polyvinyl alcohol EG-05P, and 1.2 parts of magnesium stearate; wherein, the coating powder contains 1 part of hydroxypropyl methylcellulose; the coating powder contains 4 parts of concentrated glycerin; the coating powder contains 3.85 parts of titanium dioxide; and the coating powder contains 4.5 parts of carnauba wax; 10 parts of tandospirone citrate, 67 parts of pregelatinized starch, 2.3 parts of corn starch, 2.9 parts of carboxymethylcellulose calcium, 0.8 parts of polyvinyl alcohol EG-05P, and 1.2 parts of magnesium stearate; wherein, the coating powder contains 1 part of hydroxypropyl methylcellulose; the coating powder contains 4 parts of concentrated glycerin; the coating powder contains 3.85 parts of titanium dioxide; and the coating powder contains 4.5 parts of carnauba wax.

7. The method for preparing the tandospirone citrate film-coated tablets according to claim 1, It is characterized in that The steps include: (1) Pretreatment: pulverizing tandospirone citrate; sieving auxiliary materials for later use; (2) Preparation of adhesive solution: polyvinyl alcohol EG-05P and water are mixed evenly to prepare an adhesive solution; (3) Granulation: Add tandospirone citrate, pregelatinized starch, corn starch, and carboxymethylcellulose calcium into a fluidized bed, mix well, add the binder solution obtained in step (2) by top spraying, perform fluidized bed granulation, and granulate after drying; (4) Total mixing and tableting: collecting the granules obtained in step (3) and mixing with magnesium stearate and then tableting; (5) Preparation of coating solution: Hydroxypropyl methylcellulose, concentrated glycerin, titanium dioxide and carnauba wax are used as coating powders and mixed with water to prepare a coating solution; (6) Coating: Add the coating solution obtained in step (5) to the tablet core obtained in step (4) for coating.

8. The method for preparing the tandospirone citrate film-coated tablets according to claim 8, It is characterized in that In step (1), tandospirone citrate is crushed to control the particle size D90 to be 70 μm-160 μm; the auxiliary materials are sieved through a 40-80 mesh sieve; in step (2), the mass content of polyvinyl alcohol EG-05P in the adhesive aqueous solution is 5-8%, preferably 6%; in step (5), the mass content of the coating powder in the coating solution is 10-15%, preferably 12%.

9. The method for preparing the tandospirone citrate film-coated tablets according to claim 8, It is characterized in that In step (3), the parameters of the fluidized bed granulation are as follows: air inlet temperature 50-60°C, air volume 100-120m 3 / h, material temperature 30-40°C, peristaltic pump speed 5-15rpm; drying parameters are as follows: material temperature 60°C, drying 30min, until the moisture content is not higher than 2%; in step (5), when tableting, the hardness is 40N-60N.

10. The method for preparing the tandospirone citrate film-coated tablets according to claim 8, It is characterized in that In step (6), the parameter conditions during coating are as follows: wind temperature 70-80°C, air outlet temperature 35-45°C, coating machine speed 3-8rpm, peristaltic pump speed 1-10rpm, atomization pressure 0.1-0.4Mp, gun pressure 0.1-0.4Mpa, tablet bed temperature 40-55°C, when the coating weight gain reaches 2.0%-4.0%, stop spraying and drying for 15 minutes.

Images