A sustained-release tablet containing trazodone hydrochloride and a preparation method thereof

Abstract

The present application belongs to the field of medicine processing, and relates to a sustained-release tablet containing trazodone hydrochloride and a preparation method thereof. The sustained-release tablet is prepared from the following raw materials in parts by mass: 75-150 parts of active ingredient, 42-84 parts of filling agent, 12-24 parts of binding agent, 12-24 parts of release retardant, 3-6 parts of lubricant and wetting agent; the active ingredient is trazodone hydrochloride; the filling agent is one or more of sucrose, corn starch, lactose and microcrystalline cellulose; the binding agent is one or more of povidone K30, povidone K90 and hypromellose; the release retardant is one of Brazil palm wax, insect wax and lanolin; the lubricant is one or more of magnesium stearate, talc and silicon dioxide; and the wetting agent is one of purified water, 10% ethanol solution and propylene glycol solution. The method can solve the problem of particle caking and improve the dissolution behavior of the preparation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical processing and relates to a sustained-release tablet containing trazodone hydrochloride and its preparation method. Background Technology

[0002] Trazodone hydrochloride is a tetracyclic atypical antidepressant that selectively antagonizes the reuptake of serotonin (5-HT) and has a weak inhibitory effect on norepinephrine (NA) reuptake. It has no effect on dopamine (DA), histamine, or acetylcholine, nor does it inhibit the activity of monoamine oxidase inhibitors (MAO) in the brain. Furthermore, it also antagonizes 5-HT2A or 5-HT2C receptors. The 5-HT2 receptor, located on the presynaptic membrane, is an autoreceptor that plays a negative feedback regulatory role in 5-HT release; this drug also increases 5-HT release by inhibiting negative feedback regulation, thus achieving an antidepressant effect. It also has central sedative effects and mild muscle relaxants, but no anticonvulsant or central nervous system excitatory effects. It can improve sleep, significantly shorten the sleep latency in patients with depression, prolong overall sleep time, and improve sleep quality.

[0003] Studies have found that trazodone hydrochloride tablets are typically prescribed for immediate release, administered twice or three times daily. This dosage often results in the drug not maintaining its therapeutic window in the bloodstream. Consequently, high blood concentrations may lead to a higher risk of dose-related side effects, while low blood concentrations result in lower efficacy. Furthermore, multiple daily doses can cause multiple blood drug peaks within a day, leading to several sleep cycles. Therefore, there is a need for sustained-release tablets containing trazodone hydrochloride that provide a stable and continuous release of the active ingredient over a certain period, maintaining a stable and effective blood concentration, along with their preparation methods. Most existing methods for preparing sustained-release trazodone hydrochloride tablets utilize sustained-release matrix or excipients to achieve a stable and continuous release of the active ingredient. However, these methods suffer from expensive excipients, complex formulation processes, and demanding equipment requirements, increasing the difficulty of industrial-scale production. Therefore, there is a need to develop a method with controllable production costs and a simple formulation process, making sustained-release trazodone hydrochloride tablets more suitable for industrial application. Summary of the Invention

[0004] This invention provides a sustained-release tablet containing trazodone hydrochloride and its preparation method, which can greatly improve the flowability and compressibility of the material, enhance the anti-adhesion of the particles, solve the problem of tablet sticking during compression, and effectively improve the dissolution behavior of the formulation.

[0005] The technical solution provided by this invention is as follows:

[0006] A sustained-release tablet containing trazodone hydrochloride is prepared from the following raw materials in parts by weight: 75-150 parts of active ingredient, 42-84 parts of filler, 12-24 parts of binder, 12-24 parts of release inhibitor, 3-6 parts of lubricant, and 15-19 parts of wetting agent; wherein the active ingredient is trazodone hydrochloride; the filler is one or more of sucrose, corn starch, lactose, and microcrystalline cellulose; the binder is one or more of povidone K30, povidone K90, and hydroxypropyl methylcellulose; the release inhibitor is one of carnauba wax, insect wax, and lanolin; the lubricant is one or more of magnesium stearate, talc, and silica; and the wetting agent is one of purified water, 10% ethanol solution, and propylene glycol solution.

[0007] The present invention also provides a method for preparing sustained-release tablets containing trazodone hydrochloride, comprising the following steps:

[0008] The active ingredient, filler, binder, and release inhibitor are mixed evenly in a powder mixer and then fed into a preheated fluidized bed granulator for hot melt granulation. After granulation, the suspended granular mixture in the fluidized bed granulator is cooled, and a predetermined amount of mist wetting agent is sprayed onto the mixture in the fluidized bed granulator for granulation. After granulation with wetting agent, the mixture is dried and discharged. The resulting dry granules and lubricant are added to a two-dimensional mixer and stirred to obtain an intermediate, which is then compressed into tablets.

[0009] Furthermore, the active ingredients, fillers, binders, and release inhibitors are mixed in a powder mixer at 44 Hz for 25 min.

[0010] Furthermore, the granulation time for hot melt granulation is 5–7 minutes, the inlet air temperature is 80–120°C, and the material temperature is 80–86°C.

[0011] Furthermore, after granulation for 5-7 minutes, the inlet air temperature is set to 10°C, and the suspended granular mixture of components in the fluidized bed granulator is cooled to an outlet air temperature of 64-68°C before the wetting agent is added.

[0012] Furthermore, after adding the wetting agent, the inlet air temperature is 55-70℃, the material temperature is 50-60℃, the peristaltic pump speed is 10-12 rpm, and the atomization pressure is 2.0-2.3 bar.

[0013] Furthermore, the drying time is 15 minutes, and the air inlet temperature during drying is 60-65°C.

[0014] Furthermore, the dry particles are granulated by passing them through a 1000-1500µm sieve.

[0015] Furthermore, the dry granules and lubricant were added to a two-dimensional mixer and stirred at a frequency of 44 Hz for 10 minutes.

[0016] Furthermore, tableting was performed with a weight difference controlled within ±3%.

[0017] Beneficial effects

[0018] This invention employs fluidized bed granulation, which simplifies the formulation and process, and can be readily met by conventional fluidized bed equipment. By controlling the fluidized bed granulation parameters and setting a higher heater temperature, the material is added only after the fluidized bed granulation vessel reaches the target temperature. This allows for rapid granulation, preventing raw material loss, ensuring material flowability, and maintaining stable tablet weight during compression. The melted sustained-release excipients are evenly distributed on the component granules, solving the granule agglomeration problem and maintaining a stable and slow release of trazodone hydrochloride for a certain period. The invention also improves the formulation's dissolution behavior, making it more similar to the original formulation. By controlling the proportion of sustained-release materials in the formulation, burst release can be prevented, maintaining effective blood drug concentrations for a long time while ensuring complete release of the active ingredient. Attached Figure Description

[0019] Figure 1 The main structure of the fluidized bed multi-functional dryer and granulator;

[0020] Figure 2 To study the dissolution profiles of the reference formulation and the self-made formulation in a pH 6.0 medium. Detailed Implementation

[0021] A method for preparing sustained-release tablets containing trazodone hydrochloride.

[0022] Components Single-dose prescription / mg Prescription percentage / % Active ingredients 75～150 43～60 filler 42～84 25～30 adhesives 12～24 6～12 Release inhibitors 12～33 8～12 lubricant 3～6 1～3 wetting agent 15～19 /

[0023] The active ingredient is trazodone hydrochloride; the filler can be one or more of sucrose, corn starch, lactose, and microcrystalline cellulose; the binder can be one or more of povidone K30, povidone K90, and hydroxypropyl methylcellulose; the release inhibitor can be one of carnauba wax, insect wax, and lanolin; the lubricant can be one or more of magnesium stearate, talc, and silica; and the wetting agent can be one of purified water, 10% ethanol solution, and propylene glycol solution.

[0024] 1. Preparation of formulations using a fluidized bed granulator and a process of first hot-melting and then adding a wetting agent;

[0025] 2. Fluidized bed thermal granulation: Control the fluidized bed thermal granulation parameters as follows:

[0026] Inlet air temperature 80~120℃,

[0027] The outlet air temperature is 82-90℃.

[0028] Material temperature 80~86℃;

[0029] Set a higher heater temperature so that the inlet air temperature in the fluidized bed granulation pot reaches the target temperature of 100-120℃ before adding the material, to achieve the following:

[0030] ① Granules can be formed quickly, avoiding loss of raw materials;

[0031] ②After melting, the slow-release excipients can be evenly distributed on the component particles, thus solving the problem of particle agglomeration;

[0032] ③ Improves the dissolution behavior of the formulation, making it more similar to the dissolution behavior of the original formulation.

[0033] 3. Fluidized bed granulation with wetting agent: After cooling the hot melt granulation, control the parameters of fluidized bed granulation with wetting agent as follows:

[0034] The peristaltic pump dispenses liquid at a rate of 10–12 rpm.

[0035] Atomization pressure: 2.0–2.3 bar.

[0036] Inlet air temperature: 60–64℃;

[0037] Brief introduction to fluidized bed granulation process:

[0038] The fluidized bed multi-functional dryer and granulator is a new type of pharmaceutical equipment developed based on fluidized bed drying technology. It integrates granulation and drying functions and is widely used in the pharmaceutical industry. The fluidized bed multi-functional dryer and granulator mainly consists of a main unit, an air handling system, a spray system, a main air duct system, an exhaust system, and an electrical control cabinet.

[0039] The main structure of the fluidized bed multi-functional dryer and granulator is as follows: Figure 1 As shown, its working principle is as follows: Under the negative pressure suction of the induced draft fan, the airflow passes through the air filter, heat exchanger, and air supply duct, and enters the fluidized bed granulation chamber through the airflow distribution plate, agitating and boiling the powder into a fluidized state. Atomized liquid material and compressed air enter the nozzle through their respective pipes, atomizing into fine droplets, which are sprayed into the fluidized bed granulation chamber and mixed with the powder, adhering to form granules. Simultaneously, the granules are dried by hot air, and some fine powder rises to the filter bag and is captured. After a certain time, the left exhaust valve closes, and the left chamber filter bag shakes up and down under the action of a cylinder, causing the shaken-off powder to fall back into the fluidized bed for further granulation. After shaking the bag, the left exhaust valve opens again, and after a certain time, the right exhaust valve closes, causing the right chamber filter bag to shake. The left and right chambers alternate shaking in this cycle, cleaning the captured powder, keeping the filter bag unobstructed, and ultimately completing the drying and granulation process.

[0040] Example 1: (Fluidized Bed Granulation Process 1)

[0041]

[0042]

[0043] Example 1 Operation:

[0044] ① Weighing: Accurately weigh the prescribed amounts of each raw and auxiliary material, and set aside for later use;

[0045] ② Premixing: Place the active ingredients, binder, filler, and release inhibitor in a suitable stainless steel powder mixer and mix at 44 Hz for 25 minutes to obtain a completely uniform powder;

[0046] ③ Hot melt granulation: Add the homogeneous mixture obtained in step ② to the preheated fluidized bed granulator, set the inlet air temperature to 80-120℃ and the material temperature to 80-86℃, and carry out hot melt granulation. After granulation for 20-50 minutes, set the inlet air temperature to 10℃ and cool the suspended granulated mixture in the fluidized bed granulator until the outlet air temperature reaches 64-68℃. Then prepare the wetting agent for granulation.

[0047] ④ Granulation with wetting agent: Spray a predetermined amount of mist wetting agent into the mixture in the fluidized bed granulator for granulation. Set the granulation parameters: air inlet temperature 55-70℃, material temperature 50-60℃, peristaltic pump speed 8-15rpm, atomization pressure 0.5-1.0bar. Control the air volume during the process to ensure that the material does not clump.

[0048] ⑤ Granulation drying and sizing: After granulation with wetting agent, set drying parameters, inlet air temperature 60-65℃, dry for 3 minutes, discharge, sizing the dry granules through a 1000-1500um sieve and weighing;

[0049] ⑥ Total Mixing: Calculate the amount of lubricant added, add it to the dry granules obtained above into a two-dimensional mixer, turn on the stirring frequency of 44Hz, mix for 10 minutes to obtain the intermediate;

[0050] ⑦ Calculate the standard tablet weight based on the intermediate content, and compress the tablets while controlling the tablet weight difference to ±3%.

[0051] Example 2: (Fluidized bed granulation process two, preferred technical solution of the present invention)

[0052] Components Single-dose prescription / mg Prescription percentage / % effect Trazodone Hydrochloride 150 52.1 Active ingredients sucrose 75.46 26.2 filler Povidone 24 8.3 adhesives Brazilian carnauba wax 32.54 11.3 Release inhibitors magnesium stearate 6 2.1 lubricant Purified water 17-18 / wetting agent

[0053] Example 2 Operation:

[0054] ① Weighing: Same as in Example 1;

[0055] ② Premixing: Same as in Example 1;

[0056] ③ Hot melt granulation: The granulation time is 5-7 minutes, and other operations are the same as in Example 1;

[0057] ④ Granulation with wetting agent: peristaltic pump speed 10-12 rpm, atomization pressure 2.0-2.3 bar, other operations are the same as in Example 1;

[0058] ⑤ Particle drying and sizing: Drying time 15 min, other operations are the same as in Example 1;

[0059] ⑥ Total mixture: Same as in Example 1;

[0060] ⑦ Calculate the standard tablet weight based on the intermediate content, and compress the tablets while controlling the tablet weight difference to ±3%.

[0061] Example 3: (Granulation process using an electrically heated forced-air drying oven)

[0062] Components Single-dose prescription / mg Prescription percentage / % effect Trazodone Hydrochloride 150 52.1 Active ingredients sucrose 75.46 26.2 filler Povidone 24 8.3 adhesives Brazilian carnauba wax 32.54 11.3 Release inhibitors magnesium stearate 6 2.1 lubricant Purified water 17-18 / wetting agent

[0063] Example 3 Operation:

[0064] ① Weighing: Same as in Example 1;

[0065] ② Premixing: Same as in Example 1;

[0066] ③ Granulation in an electric heating drying oven: Spread the uniform mixture obtained in step ② on a tray, set the temperature of the electric heating drying oven to 90℃, and place the tray into the oven after the actual temperature is reached. Stir the mixture in the tray with a spatula every 5 minutes to ensure that it is heated evenly. After heating for 10 to 30 minutes, remove the tray and let it cool.

[0067] ④ Granulation with wetting agent: Add the mixture obtained in step ③ to the wet granulator, start stirring at 100-300 rpm, shear at 800-1200 rpm, gradually add wetting agent to make soft material, control the wetting agent to be added in 3-7 minutes, stop the machine and discharge the material;

[0068] ⑤ Particle boiling drying: Set the inlet air temperature to 60-65℃ and the material temperature to 40-60℃, and dry the material. After drying for 3 minutes, take a sample to control the moisture content. Stop drying when the moisture content is 1.8-2.3% and discharge the material.

[0069] ⑥ Dry granulation: Dry granules are granulated by passing them through a 1000-1500µm sieve and then weighed;

[0070] ⑦ Total mixture: Same as in Example 1;

[0071] ⑧ Calculate the standard tablet weight based on the intermediate content, and compress the tablets while controlling the tablet weight difference to ±3%.

[0072]

[0073] Results Discussion and Analysis

[0074] Comparing Examples 1 and 2, it can be seen that the formulation composition ratios and hot-melt granulation times are different. The formulation of Example 2 has a higher proportion of sustained-release materials, which greatly shortens the granulation time. The resulting granules are uniform, have good flowability, and have less fine powder than those in Example 1, resulting in better compressibility. Comparing Examples 2 and 3, it can be seen that the granulation processes are different. The granulation process in Example 3 is complex, and the hot-melt granulation process is difficult to control. The granules are agglomerated, have more fine powder, and have poor material flowability and compressibility. Comparing the above three examples, Example 2 has more advantages in terms of the resulting granules and the granulation process.

[0075] Evaluation of similarity between melt-down and mellowing processes:

[0076] The similarity factor (f2) is a parameter that measures the similarity between two dissolution curves. The calculation formula is as follows:

[0077] f2=50·log{[1+(1 / n)∑ t＝l n (R t -T t ) 2 ] -0.5 ·100}

[0078] Where n is the number of sampling time points, Rt is the dissolution value of the reference sample (or the sample before the change) at time t, and Tt is the dissolution value of the test batch (the sample after the change) at time t.

[0079] The specific steps for determining the similarity factor are as follows:

[0080] (1) Take 12 tablets (capsules) of the test sample (after modification) and 12 tablets (capsules) of the reference sample (before modification) respectively, and determine their dissolution curves.

[0081] (2) Take the average dissolution value at each time point on the two curves and calculate the similarity factor (f2) according to the above formula.

[0082] (3) The closer the f2 value is to 100, the more similar the two curves are considered. Generally, if the f2 value is higher than 50, the two curves are considered to be similar, and the test (after modification) and the reference product (before modification) are equivalent.

[0083] In vitro dissolution data of the self-made formulations prepared in Examples 2 and 3 showed that the self-made formulations prepared in the above two examples had good similarity to the reference formulation, and the in vivo bioequivalence results of the above two cases can be preliminarily assessed as good. However, the in vitro dissolution data of the self-made formulation prepared in Example 1 showed that it was not similar to the reference formulation, and the in vivo bioequivalence of this example was assessed as poor.

[0084]

[0085]

Claims

1. A method for preparing a sustained-release tablet containing trazodone hydrochloride, characterized in that, The sustained-release tablets containing trazodone hydrochloride are prepared from the following raw materials by weight: 150 mg of active ingredient, 75.46 mg of filler, 24 mg of binder, 32.54 mg of release inhibitor, 6 mg of lubricant, and 17-18 mg of wetting agent; wherein the active ingredient is trazodone hydrochloride; the filler is sucrose; the binder is povidone; the release inhibitor is carnauba wax; the lubricant is magnesium stearate; and the wetting agent is purified water. The method includes the following steps: The active ingredient, binder, filler, and release inhibitor are placed in a mixer and mixed at 44 Hz for 25 minutes to obtain a completely uniform powder. The powder is then fed into a preheated fluidized bed granulator for hot melt granulation. The inlet air temperature is set to 80-120℃ and the material temperature to 80-86℃. The hot melt granulation time is 5-7 minutes. After granulation, the inlet air temperature is set to 10℃, and the suspended granulated mixture in the fluidized bed granulator is cooled until the outlet air temperature reaches 64-68℃. Spray a predetermined amount of mist wetting agent into the mixture in the fluidized bed granulator for granulation. Set the granulation parameters: inlet air temperature 55~70℃, material temperature 50~60℃, peristaltic pump speed 10~12rpm, atomization pressure 2.0~2.3bar. Control the air volume during the process to ensure that the material does not clump. After granulation with wetting agent, set drying parameters: air inlet temperature 60~65℃, dry for 15 minutes, discharge, and granulate the dry particles through a 1000~1500 μm sieve for granulation. The dry granules and lubricant are added to a mixer and stirred to obtain an intermediate, which is then compressed into tablets.

2. The method for preparing sustained-release tablets containing trazodone hydrochloride according to claim 1, characterized in that, The dry granules and lubricant were added to a two-dimensional mixer and stirred at a frequency of 44 Hz for 10 minutes.

3. The method for preparing sustained-release tablets containing trazodone hydrochloride according to claim 1, characterized in that, Tableting was performed with a weight difference controlled within ±3%.

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