Trazodone hydrochloride sustained release tablet and preparation method thereof

Abstract

According to the trazodone hydrochloride sustained release tablet and the preparation method thereof, high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose are combined to serve as a sustained release material, the sustained release tablet can play a synergistic role to form a double-skeleton structure, so that medicine is stably released at a constant speed within 12-24 hours, and the sustained release effect is good. The sustained-release tablet can accurately regulate and control the drug release speed and reduce the fluctuation of blood concentration, so that the drug taking frequency is reduced to once a day, the risk of adverse reactions such as dizziness and drowsiness is reduced, the curative effect, compliance and safety of a patient are improved, and meanwhile, the sustained-release tablet is consistent in release behavior in different pH media, good in in-vivo absorption predictability and suitable for clinical application. Related substances grow slowly, the tablet stability is good, and the preparation method is simple, low in cost and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a trazodone hydrochloride sustained-release tablet and its preparation method. Background Technology

[0002] Trazodone hydrochloride is a triazolylpyridine antidepressant primarily used to treat various types of depression and anxiety disorders accompanied by depressive symptoms. Its mechanism of action mainly involves selectively inhibiting the reuptake of serotonin (5-HT) and antagonizing 5-HT2 receptors.

[0003] Currently, most commercially available trazodone hydrochloride preparations are immediate-release tablets. Patients need to take the medication 2-3 times daily, which can easily lead to large fluctuations in blood drug concentration, resulting in peak and trough phenomena. High blood drug concentrations (Cmax) may increase the incidence of adverse reactions such as dizziness, drowsiness, and orthostatic hypotension; low blood drug concentrations (trough concentrations) may affect efficacy and lead to poor symptom control.

[0004] Sustained-release formulation technology can solve the above problems. It enables the drug to be released slowly and evenly in the body, maintaining a stable blood drug concentration, thereby reducing the frequency of dosing (usually once a day), improving patient compliance, reducing the incidence of adverse reactions, and maintaining a continuous therapeutic effect. However, developing trazodone hydrochloride into a sustained-release formulation faces many technical challenges: (1) Solubility problem: Trazodone hydrochloride has high solubility in water, making it difficult to design a formulation process that allows for slow release. (2) Stability problem: Trazodone is relatively sensitive to light, heat, and humidity, and its stability needs to be considered during the formulation process. (3) Release behavior control: It is necessary to accurately control the drug release curve so that it can be continuously released in the gastrointestinal tract for about 12-24 hours to avoid dose dumping. (4) Individual differences: It is necessary to ensure that the release behavior of sustained-release tablets is consistent in gastrointestinal environments with different pH values, and to reduce the influence of food and individual physiological differences.

[0005] Patent CN 105748421A discloses a sustained-release tablet containing trazodone hydrochloride and its preparation method, which uses high-viscosity HPMC as a matrix material in combination with a water-soluble filler to control drug release. With the passage of time, the gel layer thickens in the monolayer matrix structure, the drug diffusion path lengthens, and the release rate naturally slows down (the slope of the dose-time curve decreases), leading to insufficient blood drug concentration in the later stages, indicating room for improvement.

[0006] Patent CN 105748421A discloses a sustained-release formulation of trazodone hydrochloride oral solution and its preparation method, which uses a resin polymer sustained-release material to control drug release. Resin polymer sustained-release materials mostly employ diffusion or first-order release, with the release rate decreasing over time, leading to insufficient blood drug concentration in the later stages. Furthermore, the manufacturing process is relatively complex, leaving room for improvement. Summary of the Invention

[0007] The purpose of this invention is to provide a trazodone hydrochloride sustained-release tablet based on existing technology. This sustained-release tablet uses a combination of high-viscosity and low-viscosity hydroxypropyl methylcellulose as sustained-release materials, which can work synergistically to form a dual-framework structure, enabling stable and uniform drug release within 12-24 hours. This allows for precise control of the drug release rate, reduces fluctuations in blood drug concentration, thereby reducing the frequency of dosing to once a day, and lowering the risk of adverse reactions such as dizziness and drowsiness. It also improves patient efficacy, compliance, and safety. Furthermore, this sustained-release tablet exhibits consistent release behavior in different pH media, good predictability of in vivo absorption, slow growth of related substances, good tablet stability, simple preparation method, low cost, and suitability for industrial production.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned trazodone hydrochloride sustained-release tablets.

[0009] The technical solution of the present invention is as follows: A trazodone hydrochloride sustained-release tablet, which is made of the following components in parts by weight: 140-160 parts of trazodone hydrochloride, 100-140 parts of sustained-release material, 50-70 parts of filler, 3-8 parts of binder, 1-5 parts of lubricant, and 1-5 parts of flow aid.

[0010] In this invention, the filler is one or more of microcrystalline cellulose, lactose, or pregelatinized starch, preferably microcrystalline cellulose; the slow-release material is high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose, with a mass ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose of 0.25-4:1; the binder is povidone K30 or hydroxypropyl cellulose, preferably povidone K30; the lubricant is magnesium stearate; and the flow aid is colloidal silica.

[0011] For the purposes of this invention, the viscosity range of high-viscosity hydroxypropyl methylcellulose is 10,000-100,000 mPa·s, specifically including but not limited to HPMC K100M, HPMC K15M, or HPMC K10M. The viscosity range of low-viscosity hydroxypropyl methylcellulose is 3-15 mPa·s, specifically including but not limited to E3 LV, E5 LV, or E15LV.

[0012] In a preferred embodiment, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 145-155 parts of trazodone hydrochloride, 110-130 parts of sustained-release material, 55-65 parts of microcrystalline cellulose, 4-6 parts of povidone K30, 2-4 parts of magnesium stearate, and 1.5-2.5 parts of colloidal silica.

[0013] In a more preferred embodiment, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 115-125 parts sustained-release material, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica.

[0014] The sustained-release materials are high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose. For example, the high-viscosity hydroxypropyl methylcellulose is HPMC K100M or HPMC K10M; the low-viscosity hydroxypropyl methylcellulose is E3 LV or E5. LV; The mass ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose is 0.25-4:1. The mass ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose can be, but is not limited to, 0.25:1, 0.28:1, 0.3:1, 0.32:1, 0.33:1, 0.34:1, 0.35:1, 0.5:1, 0.8:1, 1:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.5:1, 3.8:1, or 4:1. Preferably, the mass ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose in the sustained-release material is 0.3-3:1.

[0015] In a particularly preferred embodiment, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 120 parts sustained-release material, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica; wherein the sustained-release material is HPMC K100M and E5 LV, and the mass ratio of HPMC K100M to E5 LV is 0.3-3:1.

[0016] For example, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 30 parts HPMC K100M, 90 parts E5 LV, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica.

[0017] For example, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 80 parts HPMC K100M, 40 parts E5 LV, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica.

[0018] For example, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 90 parts HPMC K100M, 30 parts E5 LV, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica.

[0019] In another particularly preferred embodiment, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 120 parts sustained-release material, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica; wherein the sustained-release material is HPMC K10M and E3 LV, and the mass ratio of HPMC K10M to E3 LV is 0.3-3:1.

[0020] For example, the trazodone hydrochloride sustained-release tablet mentioned in this invention is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 80 parts HPMC K10M, 40 parts E3 LV, 40 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica.

[0021] The sustained-release tablets provided by this invention, in the in vitro release rate test, release no more than 20% at 1 hour, 30-50% at 4 hours, 60-80% at 8 hours, and no less than 85% at 24 hours.

[0022] The sustained-release tablets provided by this invention exhibit consistent release behavior in release media with different pH values, demonstrating pH-independent release characteristics and good predictability of in vivo absorption.

[0023] The present invention also provides a method for preparing the above-mentioned trazodone hydrochloride sustained-release tablets, comprising the following steps: (1) Pretreatment: Sift trazodone hydrochloride, low viscosity hydroxypropyl methylcellulose and filler for later use; (2) Preparation of adhesive solution: Dissolve the adhesive in an aqueous ethanol solution to prepare an adhesive solution; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, low viscosity hydroxypropyl methylcellulose and filler in step (1) are mixed evenly, and the binder solution in step (2) is added for wet granulation, drying and granulation. The resulting granules are then mixed with magnesium stearate, high viscosity hydroxypropyl methylcellulose and colloidal silica, and tableted to make sustained-release tablets.

[0024] For the purposes of this invention, the viscosity range of high-viscosity hydroxypropyl methylcellulose is 10,000-100,000 mPa·s, specifically including but not limited to HPMC K100M, HPMC K15M, or HPMC K10M. The viscosity range of low-viscosity hydroxypropyl methylcellulose is 3-15 mPa·s, specifically including but not limited to E3 LV, E5 LV, or E15LV.

[0025] In this invention, in step (1), trazodone hydrochloride, low-viscosity hydroxypropyl methylcellulose and filler are passed through a 60-100 mesh sieve, preferably through an 80 mesh sieve.

[0026] For the purposes of this invention, in step (2), the volume ratio of ethanol in the ethanol aqueous solution is 40-60%, which may be but is not limited to 40%, 45%, 50%, 55% or 60%, and preferably, the volume ratio of ethanol in the ethanol aqueous solution is 50%.

[0027] In step (2), the concentration of polyvinyl ketone K30 in the adhesive solution is 3-8%, which may be, but is not limited to, 3%, 4%, 5%, 6%, 7% or 8%, and preferably, the concentration of polyvinyl ketone K30 in the adhesive solution is 5%.

[0028] In this invention, in step (3), the drying temperature is 50-60°C, and the product is dried until the moisture content is less than 2.0%; preferably, the drying temperature is 55°C, and the product is dried until the moisture content is less than 1.5%.

[0029] The advantages of using the technical solution of this invention are as follows: This invention provides a trazodone hydrochloride sustained-release tablet, which uses a combination of high-viscosity and low-viscosity hydroxypropyl methylcellulose as sustained-release materials. These materials work synergistically to form a dual-framework structure, enabling stable and uniform drug release over 12-24 hours. This allows for precise control of the drug release rate, reducing fluctuations in blood drug concentration and thus reducing the frequency of dosing to once daily. It also reduces the risk of adverse reactions such as dizziness and drowsiness, improving patient efficacy, compliance, and safety. Furthermore, this sustained-release tablet exhibits consistent release behavior in different pH media, good predictability of in vivo absorption, slow growth of related substances, good tablet stability, and a simple, low-cost preparation method, making it suitable for industrial production. Detailed Implementation

[0030] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims. Example

[0031] A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0032] The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K100M and colloidal silica are added. After mixing evenly again, the tablets are compressed using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0033] Example 2 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0034] The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E3 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E3 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, magnesium stearate, HPMC K10M and colloidal silica are added, and after mixing evenly again, tablets are made using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0035] Example 3 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0036] The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K100M and colloidal silica are added. After mixing evenly again, the tablets are compressed using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0037] Example 4 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0038] The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K100M and colloidal silica are added. After mixing evenly again, the tablets are compressed using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0039] Comparative Example 1 Tablets prepared according to Example 1 in patent CN 105748421A.

[0040] Comparative Example 2 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0041] The viscosity of HPMC K200M is 100,000 mPa·s. The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K200M and colloidal silica are added. After mixing evenly again, the tablets are compressed using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0042] Comparative Example 3 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0043] The viscosity of HPMC K4M is 4,000 mPa·s. The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, magnesium stearate, HPMC K4M and colloidal silica are added, and after mixing evenly again, tablets are made using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0044] Comparative Example 4 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0045] The viscosity of HPMC E100 LV is 100 mPa·s; The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E100 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E100 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K100M and colloidal silica are added. After mixing evenly again, the tablets are tableted using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0046] Comparative Example 5 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0047] The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K100M and colloidal silica are added. After mixing evenly again, the tablets are compressed using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0048] Comparative Example 6 A trazodone hydrochloride sustained-release tablet is made from the following components in parts by weight:

[0049] The method for preparing the above tablets includes the following steps: (1) Pretreatment: Trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose were passed through an 80-mesh sieve and set aside for later use; (2) Preparation of adhesive solution: Dissolve povidone K30 in 50% (v / v) ethanol aqueous solution to prepare an adhesive solution with a concentration of 5%; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, HPMC E5 LV and microcrystalline cellulose in step (1) are put into a high-efficiency wet granulator and mixed evenly. Then, the binder solution in step (2) is added for wet granulation. During the granulation process, the speed of the shredder is set to 1500 rpm. The resulting wet granules are put into a fluidized bed dryer and dried at 55°C until the moisture content is less than 1.5%. Then, the granules are sized with a 24-mesh sieve. The resulting granules are transferred to a three-dimensional mixer, and magnesium stearate, HPMC K100M and colloidal silica are added. After mixing evenly again, the tablets are compressed using a high-speed rotary tablet press. The tablet hardness is controlled at 10±2 kp to make sustained-release tablets.

[0050] Dissolution curves were performed on the tablets in the examples and comparative examples to investigate the in vitro release rate. The method was: basket method, 100 rpm, 37℃±0.5℃, pH 6.8 phosphate buffer. The results are shown in Table 1.

[0051] Table 1. Dissolution results of pH 6.8 phosphate buffer.

[0052] As shown in Table 1, in Example 1, the selected high-viscosity and low-viscosity hydroxypropyl methylcellulose (HPMC) types were HPMC K100M and HPMC E5 LV, respectively. In Example 2, the selected high-viscosity and low-viscosity hydroxypropyl methylcellulose (HPMC) types were HPMC K10M and HPMC E3 LV, respectively. The viscosity ranges of the high-viscosity and low-viscosity hydroxypropyl methylcellulose were 10,000-100,000 mPa·s and 3-15 mPa·s, respectively. The tablets prepared in Examples 1 and 2 achieved stable and uniform release within 12-24 hours, with good dissolution effect, meeting the acceptance criteria. In Examples 1, 2, and 4, the selected high-viscosity and low-viscosity hydroxypropyl methylcellulose types were HPMC K100M and HPMC E5 LV, but the mass ratio of high-viscosity to low-viscosity hydroxypropyl methylcellulose was controlled at 0.3-3:1. The prepared tablets also achieved stable and uniform release within 12-24 hours, with good dissolution effect, meeting the acceptance criteria.

[0053] In Comparative Example 1, using a single high-viscosity hydroxypropyl methylcellulose (HPMC K100M), the resulting tablets exhibited slow and incomplete dissolution, failing to meet acceptable standards. In Comparative Example 2, using high-viscosity hydroxypropyl methylcellulose (HPMC K200M) with a viscosity exceeding 100,000 mPa·s, the resulting tablets also showed slow and incomplete dissolution, failing to meet acceptable standards. In Comparative Example 3, using high-viscosity hydroxypropyl methylcellulose (HPMC K4M) with a viscosity below 10,000 mPa·s, the resulting tablets dissolved quickly, failing to meet acceptable standards. In Comparative Example 4, using low-viscosity hydroxypropyl methylcellulose (HPMC E100 LV) with a viscosity exceeding 15 mPa·s, the resulting tablets also showed slow and incomplete dissolution, failing to meet acceptable standards. In Comparative Examples 5 and 6, the mass ratio of high-viscosity to low-viscosity hydroxypropyl methylcellulose was either too low or too high, resulting in tablets with either slow or fast dissolution, similarly failing to meet acceptable standards.

[0054] Dissolution curves were performed on the tablets in the examples and comparative examples to investigate the in vitro release rate. The method was: basket method, 100 rpm, 37℃±0.5℃, 0.1M hydrochloric acid solution. The results are shown in Table 2.

[0055] Table 2 Dissolution results of 0.1M hydrochloric acid solution

[0056] As shown in Table 2, and as demonstrated in Examples 1-4, the high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose selected in this invention have viscosity ranges of 10,000-100,000 mPa·s and 3-15 mPa·s, respectively, with a mass ratio controlled at 0.25-4:1. They achieve stable and uniform release within 12-24 hours, exhibiting good dissolution effects, enabling precise control of drug release rate, and demonstrating good stability.

[0057] In Comparative Example 2, the high-viscosity hydroxypropyl methylcellulose (HPMC K200M) had a viscosity of 100,000 mPa·s. Since its viscosity was higher than 100,000 mPa·s, its dissolution rate was slow and did not meet the acceptable standard. In Comparative Example 3, the high-viscosity hydroxypropyl methylcellulose (HPMC K4M) had a viscosity of 4,000 mPa·s. Since its viscosity was lower than 10,000 mPa·s, its dissolution rate was fast and did not meet the acceptable standard. In Comparative Example 4, the low-viscosity hydroxypropyl methylcellulose (HPMC E100 LV) had a viscosity of 100 mPa·s. Since its viscosity was higher than 15 mPa·s, its dissolution rate was slow and did not meet the acceptable standard. In Comparative Examples 5 and 6, the mass ratio of high-viscosity to low-viscosity hydroxypropyl methylcellulose was too low or too high, resulting in dissolution rates that were either too slow or too fast, which also did not meet the acceptable standard.

[0058] The examples and comparative examples were placed under accelerated conditions (40°C, 75%RH) to investigate dissolution after 6 months of acceleration (method: basket method, 100 rpm, 1000 ml, 37°C ± 0.5°C, 0.1 M hydrochloric acid solution).

[0059] Table 3. Stability Dissolution Results

[0060] As shown in Table 3, and as demonstrated in Examples 1-4, the viscosity ranges of the high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose selected in this invention are 10,000-100,000 mPa·s and 3-15 mPa·s, respectively, with a mass ratio controlled at 0.25-4:1. The resulting tablets, after accelerated release for 6 months, achieve stable and uniform release within 12-24 hours, exhibiting good dissolution effects, enabling precise control of drug release rate, and demonstrating good stability.

[0061] In Comparative Example 1, a single high-viscosity hydroxypropyl methylcellulose (HPMC K100M) was used. The resulting tablets showed a slow dissolution rate after 6 months of accelerated dissolution, failing to meet acceptable standards. In Comparative Example 2, a high-viscosity hydroxypropyl methylcellulose (HPMC K200M) with a viscosity exceeding 100,000 mPa·s was used. The resulting tablets also showed a slow dissolution rate after 6 months of accelerated dissolution, failing to meet acceptable standards. In Comparative Example 3, a high-viscosity hydroxypropyl methylcellulose (HPMC K4M) with a viscosity below 10,000 mPa·s was used. The resulting tablets showed a fast dissolution rate after 6 months of accelerated dissolution, failing to meet acceptable standards. In Comparative Example 4, a low-viscosity hydroxypropyl methylcellulose (HPMC E100 LV) with a viscosity exceeding 15... The tablets prepared with mPa·s showed a slow dissolution rate after 6 months of accelerated dissolution, which did not meet the acceptable standard. In Comparative Examples 5 and 6, the mass ratio of high-viscosity and low-viscosity hydroxypropyl methylcellulose was too low or too high, and the tablets prepared with these ratios showed a slow or fast dissolution rate after 6 months of accelerated dissolution, which also did not meet the acceptable standard.

[0062] In summary, the viscosity and mass ratio of the high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose selected in this invention need to be controlled within a suitable range. The resulting tablets achieve stable and uniform release within 12-24 hours, enabling precise control of the drug release rate, reducing fluctuations in blood drug concentration, thereby reducing the frequency of dosing to once a day, and reducing the risk of adverse reactions such as dizziness and drowsiness. This improves patient efficacy, compliance, and safety. Furthermore, the sustained-release tablet exhibits consistent release behavior in different pH media, good predictability of in vivo absorption, slow growth of related substances, good tablet stability, and a simple and low-cost preparation method, making it suitable for industrial production.

[0063] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions 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 trazodone hydrochloride sustained-release tablet, characterized in that, The sustained-release tablet is made from the following components in parts by weight: 140-160 parts trazodone hydrochloride, 100-140 parts sustained-release material, 50-70 parts filler, 3-8 parts binder, 1-5 parts lubricant, and 1-5 parts flow aid; wherein the filler is one or more of microcrystalline cellulose, lactose, or pregelatinized starch; the sustained-release material is high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose, with a mass ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose of 0.25-4:1; the binder is povidone K30 or hydroxypropyl cellulose; the lubricant is magnesium stearate; and the flow aid is colloidal silica.

2. The trazodone hydrochloride sustained-release tablet according to claim 1, characterized in that, The filler is microcrystalline cellulose; the binder is povidone K30; the viscosity range of the high-viscosity hydroxypropyl methylcellulose is 10,000-100,000 mPa·s; preferably, the high-viscosity hydroxypropyl methylcellulose is HPMC K100M, HPMC K15M or HPMC K10M; the viscosity range of the low-viscosity hydroxypropyl methylcellulose is 3-15 mPa·s; preferably, the low-viscosity hydroxypropyl methylcellulose is E3 LV, E5 LV or E15 LV.

3. The trazodone hydrochloride sustained-release tablet according to claim 2, characterized in that, The sustained-release tablet is made of the following components in parts by weight: 145-155 parts of trazodone hydrochloride, 110-130 parts of sustained-release material, 55-65 parts of microcrystalline cellulose, 4-6 parts of povidone K304, 2-4 parts of magnesium stearate, and 1.5-2.5 parts of colloidal silica.

4. The trazodone hydrochloride sustained-release tablet according to claim 3, characterized in that, The sustained-release tablet is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 115-125 parts sustained-release material, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica; wherein, the mass ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose in the sustained-release material is 0.3-3:1; the high-viscosity hydroxypropyl methylcellulose is HPMC K100M or HPMC K10M; and the low-viscosity hydroxypropyl methylcellulose is E3 LV or E5 LV.

5. The trazodone hydrochloride sustained-release tablet according to claim 4, characterized in that, The sustained-release tablet is made of the following components in parts by weight: 150 parts trazodone hydrochloride, 120 parts sustained-release material, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica; wherein the sustained-release material is HPMC K100M and E5 LV, and the mass ratio of HPMC K100M to E5 LV is 0.3-3:

1.

6. The trazodone hydrochloride sustained-release tablet according to claim 5, characterized in that, This sustained-release tablet is made from the following components in parts by weight: 150 parts of trazodone hydrochloride, 30 parts of HPMC K100M, 90 parts of E5 LV, 60 parts of microcrystalline cellulose, 5 parts of povidone K30, 3 parts of magnesium stearate, and 2 parts of colloidal silica. 150 parts of trazodone hydrochloride, 80 parts of HPMC K100M, 40 parts of E5 LV, 60 parts of microcrystalline cellulose, 5 parts of povidone K30, 3 parts of magnesium stearate, and 2 parts of colloidal silica. 150 parts of trazodone hydrochloride, 90 parts of HPMC K100M, 30 parts of E5 LV, 60 parts of microcrystalline cellulose, 5 parts of povidone K30, 3 parts of magnesium stearate, and 2 parts of colloidal silica.

7. The trazodone hydrochloride sustained-release tablet according to claim 4, characterized in that, The sustained-release tablet is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 120 parts sustained-release material, 60 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica; wherein the sustained-release material is HPMC K10M and E3 LV, and the mass ratio of HPMC K10M to E3 LV is 0.3-3:1; preferably, the sustained-release tablet is made from the following components in parts by weight: 150 parts trazodone hydrochloride, 80 parts HPMC K10M, 40 parts E3 LV, 40 parts microcrystalline cellulose, 5 parts povidone K30, 3 parts magnesium stearate, and 2 parts colloidal silica.

8. The method for preparing trazodone hydrochloride sustained-release tablets according to claim 1, characterized in that, Includes the following steps: (1) Pretreatment: Sieve trazodone hydrochloride, low viscosity hydroxypropyl methylcellulose and filler for later use; (2) Preparation of adhesive solution: Dissolve the adhesive in an aqueous ethanol solution to prepare an adhesive solution; (3) Granulation, mixing and tableting: The sieved trazodone hydrochloride, low viscosity hydroxypropyl methylcellulose and filler in step (1) are mixed evenly, and the binder solution in step (2) is added for wet granulation, drying and granulation. The resulting granules are then mixed with magnesium stearate, high viscosity hydroxypropyl methylcellulose and colloidal silica, and tableted to make sustained-release tablets.

9. The method for preparing trazodone hydrochloride sustained-release tablets according to claim 8, characterized in that, The filler is microcrystalline cellulose; the binder is povidone K30; the viscosity range of the high-viscosity hydroxypropyl methylcellulose is 10,000-100,000 mPa·s; preferably, the high-viscosity hydroxypropyl methylcellulose is HPMC K100M, HPMC K15M or HPMC K10M; the viscosity range of the low-viscosity hydroxypropyl methylcellulose is 3-15 mPa·s; preferably, the low-viscosity hydroxypropyl methylcellulose is E3 LV, E5 LV or E15 LV.

10. The method for preparing trazodone hydrochloride sustained-release tablets according to claim 9, characterized in that, In step (1), the sample is passed through a 60-100 mesh sieve, preferably 80 mesh; In step (2), the volume ratio of ethanol in the aqueous ethanol solution is 40-60%, preferably 50%; the concentration of polyvinyl ketone K30 in the adhesive solution is 3-8%, preferably 5%. In step (3), the drying temperature is 50-60℃, and the product is dried until the moisture content is less than 2.0%; preferably, the drying temperature is 55℃, and the product is dried until the moisture content is less than 1.5%.

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