Trazodone hydrochloride sustained release tablet and preparation method thereof

Abstract

The invention relates to the field of medicines, and provides a trazodone hydrochloride sustained release tablet and a preparation method thereof. The method comprises the following steps: performing first mixing treatment and second mixing treatment on trazodone hydrochloride, a filling agent, a sustained-release framework material and an adhesive to obtain a second mixed material; the second mixed material is put into a hot melt extruder to be subjected to hot melt extrusion, particles are obtained, the feeding speed is 10-60 rpm, the rotating speed of a screw is 100-600 rpm, the temperature of a feeding area is 30-50 DEG C, the temperature of a compression area is 60-80 DEG C, the temperature of a melting area is 70-90 DEG C, and the temperature of a metering area is 80-110 DEG C; and mixing the particles with a lubricant, and tabletting to obtain the trazodone hydrochloride sustained-release tablet. According to the preparation method, the preparation process is simple, conditions are easy to control, continuous and large-scale industrial production can be achieved, special equipment is not needed, the preparation cost is low, and the prepared product is good in stability.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a tianeptine hydrochloride sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] Tianeptine hydrochloride is a tetracyclic atypical antidepressant, which mainly plays an antidepressant effect by selectively antagonizing the reuptake of 5-hydroxytryptamine (5-HT) and weakly inhibiting the reuptake of norepinephrine (NA).

[0003] The conventional tianeptine hydrochloride sustained-release tablet is composed of a tablet core, a semi-permeable membrane coating and a drug release hole, and has a complex preparation process, high requirements for equipment, high preparation cost, difficulty in realizing industrialized production, and poor stability of the product. SUMMARY

[0004] In view of the above problems in the prior art, the present application aims to provide a tianeptine hydrochloride sustained-release tablet and a preparation method thereof, so as to solve the problems of the prior art, i.e., a complex preparation process of the tianeptine hydrochloride sustained-release tablet, high requirements for equipment, high preparation cost, difficulty in realizing industrialized production, and poor stability of the product.

[0005] To achieve the above-mentioned purposes, the technical solutions adopted by the present application are as follows:

[0006] In a first aspect, the present application provides a preparation method of a tianeptine hydrochloride sustained-release tablet, which comprises the following components by mass percentage: tianeptine hydrochloride 40-60%, a filler 20-35%, a sustained-release matrix material 5-20%, a binding agent 5-10%, and a lubricant 0.5-3%; wherein the sustained-release matrix material comprises at least one of carnauba wax, hydrogenated oil, stearic acid, insect wax, beeswax, lanolin, glyceryl stearate, propylene glycol stearate, and octadecanol.

[0007] The preparation method of the tianeptine hydrochloride sustained-release tablet comprises the following steps:

[0008] S1, first mixing tianeptine hydrochloride, a filler, a sustained-release matrix material and a binding agent to obtain a first mixture, and then sieving the first mixture and second mixing to obtain a second mixture;

[0009] S2, the second mixture is put into a hot melt extruder to perform hot melt extrusion, to obtain granules, wherein the hot melt extruder comprises a feeding zone, a compression zone, a melting zone and a metering zone, the feeding speed of the feeding zone is 10-60 rpm, the screw rotation speed is 100-600 rpm, and the temperature of the feeding zone is 30-50℃, the temperature of the compression zone is 60-80℃, the temperature of the melting zone is 70-90℃, and the temperature of the metering zone is 80-110℃;

[0010] S3, the granules are mixed with a lubricant and tableted, to obtain the trazodone hydrochloride sustained-release tablets.

[0011] In a second aspect, the embodiments of the present application provide a trazodone hydrochloride sustained-release tablet, which is prepared by the preparation method of the trazodone hydrochloride sustained-release tablet of the first aspect.

[0012] Compared with the prior art, the technical scheme provided by the embodiments of the present application has at least the following beneficial effects:

[0013] The preparation method of the trazodone hydrochloride sustained-release tablet provided by the embodiments of the present application adopts a specific hot melt extrusion process, the temperature of each section of the hot melt extruder is controlled in a step-by-step manner during the hot melt granulation process, and the temperature of the entire granulation process is relatively low (not more than 110℃), which can avoid the degradation of the raw drug due to excessively high temperature during the granulation process, and is conducive to improving the stability of the drug. Secondly, during the granulation process, the temperature of each section of the hot melt extruder is controlled in a step-by-step manner, which can better melt the sustained-release matrix material and effectively wrap the raw drug, form a sustained-release matrix structure, and prevent the raw drug from migrating in the formed sustained-release matrix structure, thereby improving the stability of the product. In addition, the preparation method provided by the embodiments of the present application has simple preparation process and easy-to-control conditions, can realize continuous and large-batch industrial production, does not require special equipment, has low preparation cost, and has good market promotion and application value. DETAILED DESCRIPTION

[0014] In order to make the technical problems, technical schemes and beneficial effects of the present application clearer, the following embodiments will be further described in detail. It should be understood that the specific embodiments described herein are only used to explain the present application, but the embodiments of the present application are not limited thereto.

[0015] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as generally understood by those skilled in the art to which the present application belongs. The experimental reagents used in the following embodiments, unless otherwise specified, are conventional biochemical reagents; the amounts of the experimental reagents, unless otherwise specified, are the amounts of reagents in conventional experimental operations; and the experimental methods, unless otherwise specified, are conventional methods.

[0016] In a first aspect, the embodiments of the present application provide a preparation method of trazodone hydrochloride sustained-release tablets, the trazodone hydrochloride sustained-release tablets comprising the following components in percentage by mass: 40-60% of trazodone hydrochloride, 20-35% of a filler, 5-20% of a sustained-release matrix material, 5-10% of a binder, and 0.5-3% of a lubricant; wherein the sustained-release matrix material comprises at least one of carnauba wax, hydrogenated oil, stearic acid, insect wax, beeswax, lanolin, glyceryl stearate, propylene glycol stearate, and octadecanol.

[0017] The preparation method of the trazodone hydrochloride sustained-release tablets comprises the following steps:

[0018] S1, performing first mixing treatment on trazodone hydrochloride, the filler, the sustained-release matrix material, and the binder to obtain a first mixture, and performing second mixing treatment on the first mixture after sieving to obtain a second mixture;

[0019] S2, performing hot melt extrusion on the second mixture in a hot melt extruder to obtain granules, wherein the hot melt extruder comprises a feeding zone, a compression zone, a melting zone, and a metering zone, the feeding speed of the feeding zone is 10-60 rpm, the screw rotation speed is 100-600 rpm, and the temperature of the feeding zone is 30-50℃, the temperature of the compression zone is 60-80℃, the temperature of the melting zone is 70-90℃, and the temperature of the metering zone is 80-110℃;

[0020] S3, mixing the granules with the lubricant and tabletting to obtain the trazodone hydrochloride sustained-release tablets.

[0021] The preparation method of the trazodone hydrochloride sustained-release tablets provided by the embodiments of the present application adopts a specific hot melt extrusion process, controls the temperature of each section of the hot melt extruder in a step-by-step manner during hot melt granulation, and the temperature of the entire granulation process is relatively low (not more than 110℃), which can avoid the degradation of the raw drug due to excessively high temperature during the granulation process, and is conducive to improving the stability of the drug. Secondly, by controlling the temperature of each section of the hot melt extruder in a step-by-step manner during the granulation process, the sustained-release matrix material can be better melted, and the raw drug can be effectively wrapped to form a sustained-release matrix structure, which can prevent the migration of the raw drug in the formed sustained-release matrix structure, thereby improving the stability of the product. In addition, the preparation method provided by the embodiments of the present application has simple preparation process and easy-to-control conditions, can realize continuous and large-batch industrial production, does not require special equipment, has low preparation cost, and has good market promotion and application value.

[0022] In some embodiments, in step S1, the first mixing speed of the first mixing treatment is 24-26 Hz (for example, it can be 24 Hz, 25 Hz or 26 Hz, etc.), and the first mixing time is 3-8 min (for example, it can be 3 min, 4 min, 5 min, 6 min, 7 min or 8 min, etc.); the second mixing speed of the second mixing treatment is 24-26 Hz (for example, it can be 24 Hz, 25 Hz or 26 Hz, etc.), and the second mixing time is 15-25 min (for example, it can be 15 min, 18 min, 20 min, 22 min or 25 min, etc.).

[0023] By sequentially performing the first mixing treatment and the second mixing treatment on the trazodone hydrochloride, the filler, the sustained-release matrix material and the binder, the sustained-release matrix material can be effectively dispersed before granulation, which is beneficial to improve the wrapping effect of the sustained-release matrix material on the raw drug in the subsequent granulation process, thereby improving the stability of the drug.

[0024] In some embodiments, the sustained-release matrix material comprises Brazilian palm wax, hydrogenated oil, stearic acid, beeswax and propylene glycol stearate; and the mass ratio of the Brazilian palm wax, the hydrogenated oil, the stearic acid, the beeswax and the propylene glycol stearate is 30-80:6-15:3-10:10-17:8-12.

[0025] The preparation method of the trazodone hydrochloride sustained-release tablet according to the embodiments of the present application comprises the following steps:

[0026] S1, performing third mixing treatment on the trazodone hydrochloride, the filler, the Brazilian palm wax, the hydrogenated oil and the binder to obtain a third mixture, and performing third mixing treatment on the third mixture after sieving to obtain a third mixture;

[0027] S2, mixing the third mixture and propylene glycol stearate in the feeding area of a hot melt extruder to obtain a fourth mixture, conveying the fourth mixture to the compression area for mixing to obtain a fifth mixture, adding the fifth mixture, stearic acid, beeswax and propylene glycol stearate to the melting area for mixing to obtain a sixth mixture, and conveying the sixth mixture to the metering area for mixing and extrusion to obtain granules; wherein the hot melt extruder comprises a feeding area, a compression area, a melting area and a metering area, the feeding speed of the feeding area is 10-60 rpm, the screw rotation speed is 100-600 rpm, and the feeding area temperature is 30-50℃, the compression area temperature of the compression area is 60-80℃, the melting area temperature of the melting area is 70-90℃, and the metering area temperature of the metering area is 80-110℃;

[0028] S3, mixing the granules with a lubricant and tabletting to obtain the trazodone hydrochloride sustained-release tablet.

[0029] Compared with using a single material as the sustained-release matrix material, the composition of the specific ratio of carnauba wax, hydrogenated oil, stearic acid, beeswax and propylene glycol stearate is used as the sustained-release matrix material in the embodiment of the application, the rigidity barrier is provided by the carnauba wax, the overall disintegration of the matrix structure can be delayed, the impact resistance of the matrix structure is improved by the hydrogenated oil and the beeswax, the breakage in the process of tabletting or storage can be reduced, the phase separation of the matrix structure can be reduced by the compatibility of the stearic acid and the propylene glycol stearate, and the change of the release behavior caused by the migration of the components in the storage process can be avoided. The physicochemical properties of the components of the above sustained-release matrix material are complementary and synergistic, the limitations of a single material are overcome, the release rate is more precisely controllable, the risk of burst release is reduced, the matrix structure is more stable, the drug compatibility is wide, the process adaptability is strong, which is beneficial to reduce the production difficulty, improve the production efficiency, reduce the production cost, realize industrialized mass production and the like, and the performance and safety are taken into account.

[0030] The technical scheme provided by the embodiment of the application fully considers the physicochemical properties of the components in the sustained-release matrix material and the preparation process characteristics, the feeding time of the components of the sustained-release matrix material is scientifically and reasonably controlled, the matrix structure with a stable structure and a more precisely controllable release rate can be formed, the migration of the raw drug in the formed matrix structure can be effectively prevented, and thus the stability and safety of the drug are improved.

[0031] In some other embodiments, the sustained-release matrix material comprises carnauba wax, insect wax, glyceryl stearate and octadecanol; and the mass ratio of the carnauba wax, the insect wax, the glyceryl stearate and the octadecanol is 25-60: 12-20: 5-10: 8-11.

[0032] The preparation method of the sustained-release tablet of the trazodone hydrochloride provided in the embodiment of the application comprises the following steps:

[0033] S1, the trazodone hydrochloride, the filler, the carnauba wax, the insect wax and the binder are subjected to seventh mixing treatment to obtain a seventh mixed material, and the seventh mixed material is sieved and subjected to eighth mixing treatment to obtain an eighth mixed material;

[0034] S2, the eighth mixture and glycerin stearate are put into a feeding zone of a hot melt extruder for mixing to obtain a ninth mixture, the ninth mixture is transported to a compression zone for mixing to obtain a tenth mixture, the tenth mixture is added into a melting zone for mixing to obtain an eleventh mixture, the eleventh mixture and octadecanol are transported to a metering zone for mixing and extrusion to obtain granular materials; wherein the hot melt extruder comprises a feeding zone, a compression zone, a melting zone and a metering zone, the feeding speed of the feeding zone is 10-60 rpm, the screw rotation speed is 100-600 rpm, and the temperature of the feeding zone is 30-50 ℃, the temperature of the compression zone is 60-80 ℃, the temperature of the melting zone is 70-90 ℃, and the temperature of the metering zone is 80-110 ℃;

[0035] S3, the granular materials are mixed with lubricants and tableted to obtain the sustained-release tizoxactin hydrochloride tablets.

[0036] Compared with using a single material as the sustained-release matrix material, the embodiment of the application uses a composition of Brazilian palm wax, insect wax, glycerin stearate and octadecanol in a specific ratio as the sustained-release matrix material, the Brazilian palm wax and insect wax provide a rigid barrier to delay the overall disintegration of the matrix structure, the glycerin stearate acts as a "compatibility regulator" to improve the interface bonding of the waxy (Brazilian palm wax, insect wax) and fatty alcohol (octadecanol), reduce phase separation during storage, ensure long-term stability, and the linear molecular structure of octadecanol can enhance the mechanical strength of the matrix structure, reducing the risk of breakage or cracking during tableting. The physicochemical properties of the components of the above-mentioned sustained-release matrix material are complementary and synergistic, overcoming the limitations of single materials, having the advantages of more precise controllable release rate, reducing the risk of burst release, more stable matrix structure, wide drug compatibility, strong process adaptability, being conducive to reducing production difficulty, improving production efficiency, reducing production cost, and realizing industrial mass production, etc., balancing performance and safety.

[0037] The technical scheme provided by the embodiment of the application fully considers the physicochemical properties of the components in the sustained-release matrix material and the preparation process characteristics, by scientifically and reasonably controlling the feeding time of the components in the sustained-release matrix material, a matrix structure with stable structure and more precise controllable release rate can be formed, and the migration of the drug substance in the formed matrix structure can be effectively prevented, thereby improving the stability and safety of the drug.

[0038] In some embodiments, the filler comprises at least one of sucrose, corn starch, lactose, microcrystalline cellulose, sorbitol or mannitol. Preferably, the filler is D 90 sucrose with a particle size of 50-500 μm.

[0039] In some embodiments, the binder comprises at least one of povidone, hydroxypropyl cellulose or hydroxypropyl methyl cellulose. Preferably, the binder is povidone.

[0040] In some embodiments, the lubricant comprises at least one of magnesium stearate, talc, silicon dioxide, sodium stearyl fumarate or calcium stearate. Preferably, the lubricant is magnesium stearate.

[0041] In the second aspect, the embodiments of the present application further provide a tianeptine hydrochloride sustained-release tablet, which is prepared by the preparation method of the tianeptine hydrochloride sustained-release tablet.

[0042] In some embodiments, the tianeptine hydrochloride sustained-release tablet can have a specification of 150 mg or 75 mg.

[0043] In practical applications, the 150 mg specification sustained-release tablet can be prepared by using a 14 mm x 6 mm capsule type punch die, and the tablet weight is controlled to be 272-300 mg and the hardness is controlled to be 40-120 N. The 75 mg specification sustained-release tablet can be prepared by using a 12 mm x 4 mm capsule type punch die, and the tablet weight is controlled to be 136-150 mg and the hardness is controlled to be 30-80 N.

[0044] The tianeptine hydrochloride sustained-release tablet provided by the embodiments of the present application has good safety and stability.

[0045] The present application has undergone multiple tests, and now some test results are taken as reference to further describe the invention in detail, which is described in detail below in combination with specific embodiments.

[0046] Example 1

[0047] The prescription of the tianeptine hydrochloride sustained-release tablet of the present embodiment is shown in Table 1:

[0048] Table 1 Prescription of tianeptine hydrochloride sustained-release tablet

[0049]

[0050] The preparation method of the tianeptine hydrochloride sustained-release tablet of the present embodiment is as follows:

[0051] (1) Put tianeptine hydrochloride, sucrose, carnauba wax, hydrogenated oil, stearic acid, beeswax, propylene glycol stearate and povidone into a mixer for first mixing treatment to obtain a first mixed material, the first mixing speed is 25 Hz, and the first mixing time is 3 min; screen the first mixed material through a 1.5 mm sieve, and then put the screened material into the mixer for second mixing treatment to obtain a second mixed material, the second mixing speed is 25 Hz, and the second mixing time is 15 min.

[0052] (2) The second mixture prepared in step (1) is put into a hot melt extruder to perform hot melt extrusion, so as to obtain granules; wherein the feeding speed of the feeding zone of the hot melt extruder is 30 rpm, the screw rotation speed is 100 rpm, the feeding zone temperature is 30°C, the compression zone temperature of the compression zone is 60°C, the melting zone temperature of the melting zone is 80°C, and the metering zone temperature of the metering zone is 110°C.

[0053] (3) The granules prepared in step (2) are put into a mixer, and then magnesium stearate is put into the mixer to perform mixing and tabletting, so as to obtain the trazodone hydrochloride sustained-release tablets; wherein the mixing rotation speed is 25 Hz, and the mixing time is 2 min.

[0054] Example 2

[0055] The prescription of the trazodone hydrochloride sustained-release tablets of the present example is the same as that of Example 1.

[0056] The preparation method of the trazodone hydrochloride sustained-release tablets of the present example is as follows:

[0057] (1) Trazodone hydrochloride, sucrose, carnauba wax, hydrogenated oil and povidone are put into a mixer to perform third mixing treatment, so as to obtain a third mixture; the third mixing rotation speed is 25 Hz, and the third mixing time is 3 min; the third mixture is sieved through a 1.5 mm sieve, and then the sieved mixture is put into a mixer to perform fourth mixing treatment, so as to obtain a fourth mixture; the fourth mixing rotation speed is 25 Hz, and the fourth mixing time is 15 min.

[0058] (2) The fourth mixture prepared in step (1) and propylene glycol stearate are put into the feeding zone of a hot melt extruder to perform mixing, so as to obtain a fourth mixture; the fourth mixture is conveyed to the compression zone to perform mixing, so as to obtain a fifth mixture; the fifth mixture, stearic acid, beeswax and propylene glycol stearate are added to the melting zone to perform mixing, so as to obtain a sixth mixture; the sixth mixture is conveyed to the metering zone to perform mixing and extrusion, so as to obtain granules; wherein the feeding speed of the feeding zone of the hot melt extruder is 30 rpm, the screw rotation speed is 100 rpm, the feeding zone temperature is 30°C, the compression zone temperature of the compression zone is 60°C, the melting zone temperature of the melting zone is 80°C, and the metering zone temperature of the metering zone is 110°C.

[0059] (3) The granules prepared in step (2) are put into a mixer, and then magnesium stearate is put into the mixer to perform mixing and tabletting, so as to obtain the trazodone hydrochloride sustained-release tablets; wherein the mixing rotation speed is 25 Hz, and the mixing time is 2 min.

[0060] Example 3

[0061] The prescription of the trazodone hydrochloride sustained-release tablets of the present example is shown in Table 2.

[0062] Table 2 Formulation of Trazodone Hydrochloride Sustained Release Tablet

[0063]

[0064] The preparation method of the Trazodone Hydrochloride Sustained Release Tablet of this example is the same as that of Example 2.

[0065] Example 4

[0066] The formulation of the Trazodone Hydrochloride Sustained Release Tablet of this example is shown in Table 3.

[0067] Table 3 Formulation of Trazodone Hydrochloride Sustained Release Tablet

[0068]

[0069] The preparation method of the Trazodone Hydrochloride Sustained Release Tablet of this example is the same as that of Example 2.

[0070] Example 5

[0071] The formulation of the Trazodone Hydrochloride Sustained Release Tablet of this example is shown in Table 4.

[0072] Table 4 Formulation of Trazodone Hydrochloride Sustained Release Tablet

[0073]

[0074]

[0075] The preparation method of the Trazodone Hydrochloride Sustained Release Tablet of this example is the same as that of Example 2.

[0076] Example 6

[0077] The formulation of the Trazodone Hydrochloride Sustained Release Tablet of this example is shown in Table 5.

[0078] Table 5 Formulation of Trazodone Hydrochloride Sustained Release Tablet

[0079]

[0080] The preparation method of the Trazodone Hydrochloride Sustained Release Tablet of this example is the same as that of Example 2.

[0081] Example 7

[0082] The formulation of the Trazodone Hydrochloride Sustained Release Tablet of this example is shown in Table 6.

[0083] Table 6 Formulation of Trazodone Hydrochloride Sustained Release Tablet

[0084]

[0085] The preparation method of the Trazodone Hydrochloride Sustained Release Tablet of this example is the same as that of Example 2.

[0086] Example 8

[0087] The prescription of the trazodone hydrochloride sustained-release tablet of this example is shown in Table 7.

[0088] Table 7 Prescription of trazodone hydrochloride sustained-release tablet

[0089]

[0090] The preparation method of the trazodone hydrochloride sustained-release tablet of this example is as follows:

[0091] (1) Put trazodone hydrochloride, sucrose, carnauba wax, insect wax and a binder into a mixer for seventh mixing treatment to obtain a seventh mixed material, the seventh mixing speed is 25 Hz, and the seventh mixing time is 3 min; screen the seventh mixed material through a 1.5 mm sieve, and then put the screened material into the mixer for eighth mixing treatment to obtain an eighth mixed material, the eighth mixing speed is 25 Hz, and the eighth mixing time is 20 min.

[0092] (2) Put the eighth mixed material prepared in step (2) and glyceryl stearate into the feeding area of the hot melt extruder for mixing to obtain a ninth mixed material, convey the ninth mixed material to the compression area for mixing to obtain a tenth mixed material, add the tenth mixed material to the melting area for mixing to obtain an eleventh mixed material, and convey the eleventh mixed material and octadecanol to the metering area for mixing and extrusion to obtain granular material; wherein the feeding speed of the feeding area of the hot melt extruder is 60 rpm, the screw rotation speed is 200 rpm, and the feeding area temperature is 40°C, the compression area temperature of the compression area is 70°C, the melting area temperature of the melting area is 90°C, and the metering area temperature of the metering area is 100°C.

[0093] (3) Put the granular material prepared in step (2) into the mixer, and then put magnesium stearate into the mixer for mixing and tabletting to obtain the trazodone hydrochloride sustained-release tablet, wherein the mixing speed is 25 Hz, and the mixing time is 3 min.

[0094] Comparative Example 1

[0095] The prescription of the trazodone hydrochloride sustained-release tablet of this comparative example is the same as that of Example 1.

[0096] The preparation method of the trazodone hydrochloride sustained-release tablet of this comparative example is basically the same as that of Example 2, except that the feeding speed of the feeding area of the hot melt extruder in step (2) is 90 rpm.

[0097] Comparative Example 2

[0098] The prescription of the trazodone hydrochloride sustained-release tablet of this comparative example is the same as that of Example 1.

[0099] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is basically the same as that of Example 2, except that the temperature of the feeding zone in step (2) is 60°C, the compression zone temperature of the compression zone is 90°C, the melting zone temperature of the melting zone is 120°C, and the metering zone temperature of the metering zone is 130°C.

[0100] Comparative Example 3

[0101] The prescription of the trazodone hydrochloride sustained-release tablets of the present comparative example is the same as that of Example 1.

[0102] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is as follows:

[0103] (1) The trazodone hydrochloride, sucrose, carnauba wax, hydrogenated oil, stearic acid, beeswax, propylene glycol stearate and povidone were put into a mixer for first mixing treatment to obtain a first mixed material, the first mixing speed was 25 Hz, and the first mixing time was 3 min. The first mixed material was sieved through a 1.5 mm sieve, and then the sieved material was put into the mixer for second mixing treatment to obtain a second mixed material, the second mixing speed was 25 Hz, and the second mixing time was 15 min.

[0104] (2) The second mixed material prepared in step (1) was put into the mixer, and magnesium stearate was further put into the mixer for mixing and tabletting to obtain the trazodone hydrochloride sustained-release tablets, wherein the mixing speed was 25 Hz, and the mixing time was 2 min.

[0105] Comparative Example 4

[0106] The prescription of the trazodone hydrochloride sustained-release tablets of the present comparative example is the same as that of Example 1.

[0107] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is as follows:

[0108] (1) The trazodone hydrochloride, sucrose, carnauba wax, hydrogenated oil, stearic acid, beeswax, propylene glycol stearate and povidone were put into a mixer for first mixing treatment to obtain a first mixed material, the first mixing speed was 25 Hz, and the first mixing time was 3 min. The first mixed material was sieved through a 1.5 mm sieve, and then the sieved material was put into the mixer for second mixing treatment to obtain a second mixed material, the second mixing speed was 25 Hz, and the second mixing time was 15 min.

[0109] (2) The second mixture prepared in step (1) is put into a fluidized bed, the inlet air temperature is set to 110°C, and the material temperature is about 86°C, and hot melt granulation is performed. After 30 minutes of granulation, the inlet air temperature is set to 10°C, and the granular mixture suspended in the fluidized bed granulator is cooled to an outlet air temperature of 65°C, and then the wetting agent is prepared for granulation. Then, a predetermined amount of misty wetting agent is sprayed on the granular mixture in the fluidized bed, and the granulation parameters are set: inlet air temperature 60°C, material temperature 50°C, peristaltic pump speed 15 rpm, atomization pressure 1.0 bar, and the air flow is controlled to ensure that the material is not caked during the process. After the wetting agent granulation is completed, drying is performed for 3 minutes, and the material is discharged. A 1.5 mm sieve is used to size the granules, and the granular material is obtained.

[0110] (3) The granular material prepared in step (2) is put into a mixer, and magnesium stearate is added for mixing and tabletting, and the trazodone hydrochloride sustained-release tablets are obtained. The mixing speed is 25 Hz, and the mixing time is 2 minutes.

[0111] Comparative Example 5

[0112] The trazodone hydrochloride sustained-release tablets of the present comparative example have the same prescription as Example 1.

[0113] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is basically the same as that of Example 1, except that:

[0114] (1) Trazodone hydrochloride, sucrose, carnauba wax, hydrogenated oil, stearic acid, beeswax, propylene glycol stearate, and povidone are put into a mixer for mixing treatment, and the mixture is obtained. The mixing speed is 25 Hz, and the mixing time is 15 minutes.

[0115] (2) The mixture prepared in step (1) is put into a hot melt extruder for hot melt extrusion, and the granular material is obtained. The feeding speed of the feeding zone of the hot melt extruder is 30 rpm, the screw speed is 100 rpm, the feeding zone temperature is 30°C, the compression zone temperature of the compression zone is 60°C, the melting zone temperature of the melting zone is 80°C, and the metering zone temperature of the metering zone is 110°C.

[0116] Comparative Example 6

[0117] The prescription of the trazodone hydrochloride sustained-release tablets of the present comparative example is shown in Table 8.

[0118] Table 8 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0119]

[0120]

[0121] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is the same as that of Example 1.

[0122] Comparative Example 7

[0123] The prescription of the trazodone hydrochloride sustained-release tablets of this comparative example is shown in Table 9.

[0124] Table 9 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0125]

[0126] The preparation method of the trazodone hydrochloride sustained-release tablets in this comparative example is the same as that in Example 1.

[0127] Comparative Example 8

[0128] The prescription of the trazodone hydrochloride sustained-release tablets of this comparative example is shown in Table 10.

[0129] Table 10 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0130]

[0131] The preparation method of the trazodone hydrochloride sustained-release tablets in this comparative example is the same as that in Example 1.

[0132] Comparative Example 9

[0133] The prescription of the trazodone hydrochloride sustained-release tablets of this comparative example is shown in Table 11.

[0134] Table 11 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0135]

[0136]

[0137] The preparation method of the trazodone hydrochloride sustained-release tablets in this comparative example is the same as that in Example 1.

[0138] Comparative Example 10

[0139] The prescription of the trazodone hydrochloride sustained-release tablets of this comparative example is shown in Table 12.

[0140] Table 12 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0141]

[0142] The preparation method of the trazodone hydrochloride sustained-release tablets in this comparative example is the same as that in Example 1.

[0143] Comparative Example 11

[0144] The prescription of the trazodone hydrochloride sustained-release tablets of this comparative example is shown in Table 13.

[0145] Table 13 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0146]

[0147] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is as follows:

[0148] (1) The trazodone hydrochloride, sucrose, insect wax and the binder were put into a mixer for seventh mixing treatment to obtain a seventh mixed material, the seventh mixing speed was 25 Hz, and the seventh mixing time was 3 min; the seventh mixed material was sieved through a 1.5 mm sieve, and then the sieved material was put into a mixer for eighth mixing treatment to obtain an eighth mixed material, the eighth mixing speed was 25 Hz, and the eighth mixing time was 20 min.

[0149] (2) The eighth mixed material prepared in step (2) was put into the feeding area of the hot melt extruder for mixing to obtain a ninth mixed material, the ninth mixed material was transported to the compression area for mixing to obtain a tenth mixed material, the tenth mixed material was added to the melting area for mixing to obtain an eleventh mixed material, and the eleventh mixed material was transported to the metering area for mixing and extrusion to obtain granular material; wherein the feeding speed of the feeding area of the hot melt extruder was 60 rpm, the screw rotation speed was 200 rpm, the feeding area temperature was 40℃, the compression area temperature of the compression area was 70℃, the melting area temperature of the melting area was 90℃, and the metering area temperature of the metering area was 100℃.

[0150] (3) The granular material prepared in step (2) was put into a mixer, and then magnesium stearate was put into the mixer for mixing and tabletting to obtain trazodone hydrochloride sustained-release tablets, wherein the mixing speed was 25 Hz, and the mixing time was 3 min.

[0151] Comparative Example 12

[0152] The prescription of the trazodone hydrochloride sustained-release tablets of the present comparative example is shown in Table 14.

[0153] Table 14 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0154]

[0155] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example was the same as that of Comparative Example 11.

[0156] Comparative Example 13

[0157] The prescription of the trazodone hydrochloride sustained-release tablets of the present comparative example is shown in Table 15.

[0158] Table 15 Prescription of Trazodone Hydrochloride Sustained-Release Tablets

[0159]

[0160]

[0161] The preparation method of the trazodone hydrochloride sustained-release tablets of the present comparative example is the same as that of Comparative Example 11.

[0162] The in-vitro dissolution test was performed on the corresponding test samples of the trazodone hydrochloride sustained-release tablets with a specification of 75 mg prepared according to Examples 1-8 and Comparative Examples 1-5 of the present application and the reference preparation at 0 day and after the accelerated test at 40°C for 3 months.

[0163] Test method: According to the second method of General Rule 0931 in the 2020 edition of Chinese Pharmacopoeia, the slurry method was adopted, 1000 mL of pH 6.0 phosphate buffer was used as the dissolution medium, the rotation speed was 100 revolutions per minute, the temperature was 37°C, and the samples were taken for detection at 0.5, 1, 2, 4, 6, 8, 10 and 12 hours, respectively.

[0164] Test results: See Table 16.

[0165] Table 16 In-vitro dissolution of the test samples with a specification of 75 mg in pH 6.0 dissolution medium

[0166]

[0167]

[0168]

[0169] As can be seen from Table 16, the product quality stability of the trazodone hydrochloride sustained-release tablets prepared according to Examples 1-8 of the present application is good, and the dissolution behaviors at 0 day and after the acceleration at 40°C for 3 months are similar to those of the reference preparation.

[0170] The dissolution behaviors of the trazodone hydrochloride sustained-release tablets prepared according to Comparative Example 1 at 0 day and after the acceleration at 40°C for 3 months are not similar to those of the reference preparation, which indicates that the feeding speed and the screw rotation speed of the hot melt granulation are too fast, resulting in that the granulation time of the material particles is too short, and the sustained-release matrix material cannot completely wrap the raw material, and the granulation is incomplete.

[0171] Although the dissolution behaviors of the trazodone hydrochloride sustained-release tablets prepared according to Comparative Example 2 at 0 day and after the acceleration at 40°C for 3 months are similar to those of the reference preparation, the RSD value is obviously too large, which indicates that the temperature range of each section of the hot melt extruder during the hot melt granulation process has a significant influence on the product quality stability. Therefore, by controlling the temperature of the feeding zone to be 30-50°C, the compression zone temperature of the compression zone to be 60-80°C, the melting zone temperature of the melting zone to be 70-90°C, and the metering zone temperature of the metering zone to be 80-110°C, it is beneficial to reduce the cumulative dissolution RSD value of the product and improve the quality stability of the product.

[0172] The dissolution behavior of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 3 is obviously faster than that of the reference preparation at 0 day, indicating that the sustained-release matrix material not subjected to hot melt granulation cannot effectively wrap the drug substance, and cannot achieve good sustained-release behavior.

[0173] The dissolution behavior of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 4 is similar to that of the reference preparation at 0 day and after 3 months of acceleration, but the dissolution behavior after 3 months of acceleration is obviously faster than that at 0 day, and the cumulative dissolution at each time point after 3 months of acceleration is more than 10% than that at 0 day, indicating that the fluidized bed process has a stability risk, and the fluidized bed process is relatively complex and has a large difficulty in scale-up production.

[0174] The dissolution behavior of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 5 is similar to that of the reference preparation at 0 day and after 3 months of acceleration, but the RSD value is obviously large, which indicates that the sustained-release matrix material is not completely dispersed in the premixing process before hot melt granulation, resulting in too much or too little of the sustained-release matrix material in the local part during subsequent hot melt granulation, and the drug substance is wrapped by the sustained-release matrix material with different effects, thereby causing the large RSD of dissolution.

[0175] The related substance of the trazodone hydrochloride sustained-release tablets prepared in Examples 1 to 8 and Comparative Examples 1 to 13 with a specification of 150 mg and the reference preparation at 0 day and after the naked tablets are placed at 60°C and 75% humidity for 10 days is detected. The test results are shown in Table 17, wherein "ND" represents not detected.

[0176] Table 17: Related substance detection results of each test sample with a specification of 150 mg

[0177]

[0178]

[0179] As can be seen from Table 17, the related substance content of the trazodone hydrochloride sustained-release tablets prepared in Examples 1 to 8 at 0 day is equivalent to that of the reference preparation, and the related substance content after being placed at a temperature of 60°C and a humidity of 75% RH for 10 days is better than that of the reference preparation.

[0180] As can be seen from the comparison results of Examples 5 to 7, the related substance content after being placed at a temperature of 60°C and a humidity of 75% RH for 10 days increases with the increase of the sucrose particle size, which may be due to the fact that the sucrose particle size increases and is more prone to moisture absorption.

[0181] The related substance content of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 1 after being placed at a temperature of 60°C and a humidity of 75% RH for 10 days is worse than that of Example 1, which indicates that the feeding speed and screw rotation speed are too fast, which easily leads to incomplete granulation, thereby causing the finished product to be more prone to degradation.

[0182] The related substances of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 2 at 0 day were worse than those of the reference preparation and Example 1, indicating that the high temperature of the hot melt granulation directly led to the degradation of trazodone hydrochloride; the related substances after being placed at 60°C and 75% RH for 10 days were better than those of the reference preparation but worse than those of Example 1, indicating that the high temperature of the hot melt led to the degradation of trazodone hydrochloride during the stability period of the finished product.

[0183] The related substances of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 3 after being placed at 60°C and 75% RH for 10 days were significantly worse than those of the reference preparation and Example 1, indicating that the sustained-release matrix material could not wrap and protect trazodone hydrochloride without the granulation process.

[0184] The related substances of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 4 after being placed at 60°C and 75% RH for 10 days were equivalent to those of the reference preparation but worse than those of Example 1, indicating that the finished product obtained by the hot melt extruder was safer and more stable than that obtained by the fluidized bed hot melt granulation.

[0185] The related substances of the trazodone hydrochloride sustained-release tablets prepared in Comparative Example 5 after being placed at 60°C and 75% RH for 10 days were significantly worse than those of Example 1, indicating that the sustained-release matrix material was not completely dispersed in the premixing process before the hot melt granulation, resulting in too much or too little of the sustained-release matrix material in the subsequent hot melt granulation, which could not effectively wrap and protect the trazodone hydrochloride sustained-release tablets.

[0186] The related substances of the trazodone hydrochloride sustained-release tablets prepared in Comparative Examples 6-10 after being placed at 60°C and 75% RH for 10 days were significantly worse than those of Example 1, indicating that the combination of the specific proportions of carnauba wax, hydrogenated oil, stearic acid, beeswax and propylene glycol stearate as the sustained-release matrix material could more effectively wrap and protect the raw material drug trazodone hydrochloride and delay the degradation of trazodone hydrochloride than the single sustained-release matrix material, which was conducive to improving the quality stability of the product.

[0187] The related substances of the trazodone hydrochloride sustained-release tablets prepared in Comparative Examples 11-13 after being placed at 60°C and 75% RH for 10 days were significantly worse than those of Example 8, indicating that the combination of the specific proportions of carnauba wax, insect wax, glyceryl stearate and octadecanol as the sustained-release matrix material could more effectively wrap and protect the raw material drug trazodone hydrochloride and delay the degradation of trazodone hydrochloride than the single sustained-release matrix material, which was conducive to improving the quality stability of the product.

[0188] The above examples are only used to illustrate the technical solutions of the present application, but not limit the same; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can be modified, or some technical features can be replaced by equivalent ones; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application, and should be included in the protection scope of the present application.

Claims

1. A method for preparing trazodone hydrochloride sustained-release tablets, characterized in that: The trazodone hydrochloride sustained-release tablet comprises the following components, calculated by mass percentage: 40% to 60% trazodone hydrochloride, 20% to 35% filler, 5% to 20% sustained-release matrix material, 5% to 10% binder, and 0.5% to 3% lubricant; wherein the sustained-release matrix material comprises at least one of carnauba wax, hydrogenated oil, stearic acid, insect wax, beeswax, lanolin, glyceryl stearate, propylene glycol stearate, and stearyl alcohol; The preparation method of the trazodone hydrochloride sustained-release tablets comprises the following steps: S1, performing a first mixing process on trazodone hydrochloride, a filler, a sustained-release matrix material, and a binder to obtain a first mixed material, and performing a second mixing process on the first mixed material after screening to obtain a second mixed material; S2. Putting the second mixed material into a hot melt extruder for hot melt extrusion to obtain granules, wherein the hot melt extruder includes a feeding zone, a compression zone, a melting zone and a metering zone, the feeding speed of the feeding zone is 10-60 rpm, the screw speed is 100-600 rpm, the feeding zone temperature is 30-50° C., the compression zone temperature of the compression zone is 60-80° C., the melting zone temperature of the melting zone is 70-90° C., and the metering zone temperature of the metering zone is 80-110° C.; S3. Mixing the granules with a lubricant and tableting to obtain the trazodone hydrochloride sustained-release tablets.

2. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 1, wherein In step S1 , the first mixing speed of the first mixing process is 24-26 Hz, and the first mixing time is 3-8 min; the second mixing speed of the second mixing process is 24-26 Hz, and the second mixing time is 15-25 min.

3. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 1, wherein The sustained-release matrix material includes carnauba wax, hydrogenated oil, stearic acid, beeswax and propylene glycol stearate; The mass ratio of the carnauba wax, hydrogenated oil, stearic acid, beeswax and propylene glycol stearate is 30-80:6-15:3-10:10-17:8-12.

4. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 3, wherein: In step S1, trazodone hydrochloride, a filler, carnauba wax, hydrogenated oil, and a binder are subjected to a third mixing process to obtain a third mixed material, and the third mixed material is sieved and then subjected to a third mixing process to obtain a third mixed material; In step S2, the third mixture and propylene glycol stearate are put into the feed zone of the hot melt extruder for mixing to obtain a fourth mixed material, the fourth mixed material is conveyed to the compression zone for mixing to obtain a fifth mixed material, the fifth mixed material, stearic acid, beeswax and propylene glycol stearate are added to the melting zone for mixing to obtain a sixth mixed material, the sixth mixed material is conveyed to the metering zone for mixing and extrusion to obtain granules.

5. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 1, wherein The sustained-release matrix material comprises carnauba wax, insect wax, glyceryl stearate and stearyl alcohol; The mass ratio of the carnauba wax, insect wax, glyceryl stearate and stearyl alcohol is 25-60:12-20:5-10:8-11.

6. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 5, characterized in that: In step S1, trazodone hydrochloride, a filler, carnauba wax, insect wax, and a binder are subjected to a seventh mixing process to obtain a seventh mixed material, and the seventh mixed material is sieved and then subjected to an eighth mixing process to obtain an eighth mixed material; In step S2, the eighth mixture and glyceryl stearate are put into the feed zone of the hot melt extruder for mixing to obtain a ninth mixed material, the ninth mixed material is conveyed to the compression zone for mixing to obtain a tenth mixed material, the tenth mixed material is added to the melting zone for mixing to obtain an eleventh mixed material, the eleventh mixture and the octadecanol material are conveyed to the metering zone for mixing and extrusion to obtain granules.

7. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 1, wherein: The filler comprises at least one of sucrose, corn starch, lactose, microcrystalline cellulose, sorbitol or mannitol.

8. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 7, characterized in that: The filler is D 90 It is sucrose of 50 to 500 μm.

9. The method for preparing the trazodone hydrochloride sustained-release tablets according to claim 1, wherein: The binder comprises at least one of povidone, hydroxypropyl cellulose or hypromellose; The lubricant includes at least one of magnesium stearate, talc, silicon dioxide, sodium stearyl fumarate or calcium stearate.

10. A trazodone hydrochloride sustained-release tablet, characterized in that: The trazodone hydrochloride sustained-release tablet is prepared by the preparation method of the trazodone hydrochloride sustained-release tablet according to any one of claims 1 to 9.

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