A sustained-release bupropion hydrochloride preparation and a method for preparing the same

Abstract

The application provides a bupropion hydrochloride sustained-release tablet and a preparation method, and belongs to the technical field of pharmacy. The pharmaceutical composition contains 150 parts of bupropion hydrochloride, 122.5-157.5 parts of glycerin monostearate, 17.5-22.5 parts of triethyl citrate, 68-104 parts of microcrystalline cellulose and 2-6 parts of magnesium stearate, wherein the bupropion hydrochloride raw material and the glycerin monostearate and the triethyl citrate are prepared into a solid dispersion through a hot melt extrusion process. The application provides a bupropion hydrochloride sustained-release tablet which is stable in drug release, slow in growth of related substances, does not need to be coated and can be taken and eaten, and a preparation method.

Description

Technical Field

[0001] This invention relates to a bupropion hydrochloride sustained-release tablet and its preparation method, belonging to the field of pharmaceutical technology. Background Technology

[0002] Bupropion hydrochloride, chemically named (±)-2-tert-butylamino-3′-chlorophenylacetone hydrochloride, has the molecular formula C0. 13 H 18 ClNO·HCl, structural formula is

[0003]

[0004] Bupropion hydrochloride is an aminoketone antibiotic with a weak inhibitory effect on the uptake of norepinephrine, serotonin (5-HT), and dopamine. Its marketed immediate-release tablets are used to treat depression, while the 0.15g extended-release tablets are also used as a smoking cessation medication. However, overdose of the immediate-release tablets may lead to seizures (incidence approximately 0.4%). Using the extended-release formulation of bupropion hydrochloride allows for a slow release of the drug, avoiding peak and trough fluctuations in blood drug concentration, thereby reducing the incidence of seizures and the frequency of dosing. This can improve patient compliance.

[0005] The existing bupropion hydrochloride extended-release tablet, WELLBUTRIN SR, contains bupropion hydrochloride, hydroxypropyl methylcellulose, microcrystalline cellulose, cysteine ​​hydrochloride, magnesium stearate, and a film-coating premix (gastric-soluble). Because bupropion hydrochloride is unstable under alkaline conditions, an acidic environment regulator is often added. The original patent used cysteine ​​hydrochloride as the acidic environment regulator. However, the addition of the acidic environment regulator brings environmental pollution and corrosion to equipment and molds. Chinese patent CN101869553A replaced the cysteine ​​hydrochloride acidic regulator in the formulation with micronized silica gel, thus overcoming the above defects. However, micronized silica gel is prone to generating dust during commercial production, which is detrimental to GMP production, and it is also prone to moisture absorption, affecting product stability.

[0006] Chinese patent CN 111643472A describes: "The bupropion hydrochloride sustained-release tablets prepared by US patent 6153223 exhibit a problem of accelerated release during stable storage, affecting the safety of clinical use. Analysis suggests this may be related to the instability of the sustained-release material hydroxypropyl methylcellulose under acidic conditions. This could potentially increase the incidence of epilepsy in clinical practice." Therefore, this patent formulation does not include an acid protectant. Instead, it improves drug stability by preparing carnauba wax and bupropion hydrochloride solid dispersions. Furthermore, because the waxy skeleton affects drug release, polyethylene glycol 4000 is introduced into the formulation to regulate release. However, it is well known that polyethylene glycol 4000 has strong hygroscopicity and a melting point of 48-53°C, which can easily cause sticking to the die during high-speed tableting, hindering commercial production. In the formulation, HPMC is prone to gel destruction due to competition between ions and water of crystallization in high-ionic-strength media. Furthermore, the second edition of the original *Encyclopedia of Pharmaceutical Technology* mentions that "waxy materials often experience an increase in melting point and hardening during storage, leading to an increased drug release rate," raising concerns about product stability. In addition, the large tablet size makes oral swallowing difficult; the instructions clearly state that the tablet should not be broken, as this could easily cause a sudden drug release, reducing patient compliance.

[0007] Through the compatibility test of raw materials and excipients of the original patented formulation of this product, it was found that under light conditions, the light-induced impurities M1-15 in the composition increased significantly. The "API+HPMC (hydrophilic gel skeleton material)" showed a significant increase in moisture absorption and weight gain and related substances under high humidity 75%RH conditions. Therefore, this product had to be coated to achieve the purpose of light protection and moisture prevention, which inadvertently increased the production cost. Summary of the Invention

[0008] Objective of the Invention: To address the deficiencies of existing technologies, this invention provides a sustained-release formulation of bupropion hydrochloride and its preparation method, overcoming the aforementioned shortcomings. The inventors used glyceryl monostearate, an erosion-type matrix material, to replace hydroxypropyl methylcellulose as the sustained-release material and employed a hot-melt extrusion process to prepare sustained-release granules, resulting in stable bupropion hydrochloride sustained-release tablets. However, testing revealed that the tablet release rate increased, posing a risk of burst release, and the uncoated tablets were unstable under light exposure. Further research revealed that introducing a certain amount of triethyl citrate into the formulation, followed by tableting using a hot-melt extrusion process to prepare sustained-release granules, yielded even more stable bupropion hydrochloride sustained-release tablets. Furthermore, no increase in impurity M1-15 was observed in the tablets even without coating or light protection, and the tablets could be broken open for consumption without affecting drug release. Thus, without the need for acid regulators or coating, a stable bupropion hydrochloride sustained-release formulation suitable for commercial production can be obtained, successfully overcoming the deficiencies of existing technologies.

[0009] The technical solution of this invention is:

[0010] A bupropion hydrochloride sustained-release tablet is composed of 150 parts of bupropion hydrochloride, 122.5-157.5 parts of glyceryl monostearate, 17.5-22.5 parts of triethyl citrate, 68-104 parts of microcrystalline cellulose, and 2-6 parts of magnesium stearate, all of which are parts by weight.

[0011] Furthermore, the bupropion hydrochloride sustained-release tablets are composed of 150 parts of bupropion hydrochloride, 140 parts of glyceryl monostearate, 20 parts of triethyl citrate, 86 parts of microcrystalline cellulose, and 4 parts of magnesium stearate.

[0012] The proportions of glyceryl monostearate and triethyl citrate in the formulation of this invention are 35% to 45%;

[0013] The formulation ratio of glyceryl monostearate to triethyl citrate described in this invention is 7:1;

[0014] The preparation method for bupropion hydrochloride sustained-release tablets according to the present invention includes the following steps:

[0015] Step 1: Pretreatment: Add the prescribed amount of bupropion hydrochloride and glyceryl monostearate into a ball mill and set the speed to 80 r / min;

[0016] Step 2: Granulation: Set the extrusion temperature of the twin-screw hot melt extruder to 100-150°C. After reaching the preset temperature, start the screw and add the uniformly ground and mixed material (S1) into the twin-screw hot melt extruder. At the same time, use a high-precision gear pump from Germany (Huino) to precisely deliver the plasticizer triethyl citrate into the twin-screw extruder. The screw speed is 80 r / min, and the gear pump speed is 5 r / min. The mixture is extruded in strip form through the screw. Cool the hot melt extruded strips, pulverize them, and pass them through a 20-80 mesh sieve to obtain drug solid dispersion granules or powder.

[0017] Step 3: Premixing: Add the solid granules obtained from S2, along with the prescribed amount of microcrystalline cellulose and pregelatinized starch, into a wet granulator and set the stirring / chopping speed to 200 / 450 rpm for 5 minutes.

[0018] Step 4: Total mixing: Add the premixed material from S3 to the hopper mixer, then add the prescribed amount of magnesium stearate, set the total mixing speed to 12 r / min, and mix for 10 min;

[0019] Step 5: Tableting: After mixing S4, the material is tableted using a rotary tablet press with an 11mm shallow concave die.

[0020] Beneficial effects: (1) The technical solution of this invention adopts hot melt extrusion process, and solid dispersion is prepared by adding glyceryl monostearate and triethyl citrate. The combination of the two significantly improves the drug release stability of bupropion hydrochloride sustained-release tablets; (2) Under light conditions, the related substances of the bare tablets of this product grow slowly, so there is no need for coating process; (3) The sustained-release tablets prepared by this invention can be broken in proportion for oral administration, and the drug release curve is similar to that of the whole tablet, which improves the medication compliance. Detailed Implementation

[0021] To better understand the technical solution of the present invention, further explanation is provided below with reference to specific embodiments.

[0022] Example 1 prescription:

[0023]

[0024] The preparation method is as follows:

[0025] Step 1: Pretreatment: Weigh 150g of bupropion hydrochloride and 140g of glyceryl monostearate and add them to a ball mill. Set the speed to 80r / min and grind and mix for 20min. Then set aside for later use.

[0026] Step 2: Granulation: An 11mm co-rotating twin-screw hot melt extruder is used. The extrusion temperature of the hot melt extruder is set to 100-150°C. After reaching the preset temperature, the screw is started at a speed of 80 r / min and a feed rate of approximately 8 g / min. The material that was ground and mixed evenly in Step 1 is added to the twin-screw hot melt extruder. At the same time, 20g of the plasticizer triethyl citrate is precisely fed into the twin-screw extruder using a high-precision gear pump from Germany. The gear pump speed is 5 r / min. The mixture is extruded in strip form through the screw. The hot melt extruded strip is cooled and pulverized through a 1.5mm sieve to obtain drug solid dispersion granules or powder.

[0027] Step 3: Premixing: Weigh 86g of microcrystalline cellulose and the solid particles obtained in step 2 and add them to a wet granulator. Set the stirring speed to 200rpm and the chopping speed to 450rpm and mix for 5min.

[0028] Step 4: Total mixing: Weigh 4g of magnesium stearate and add it alternately to the premixed material from Step 3 into the hopper mixer. Set the total mixing speed to 15r / min and mix for 10min.

[0029] Step 5: Tableting: The mixed material from step 4 is tableted using a 5-punch rotary tablet press with an 11mm shallow concave die. Theoretically, the tablet contains 400mg of protein and the average hardness is not less than 100N.

[0030] Example 2 prescription:

[0031]

[0032] Preparation method: 1000 bupropion hydrochloride sustained-release tablets were prepared according to the preparation method in Example 1. The difference is that 22.5g of triethyl citrate was added during the hot melt extrusion preparation process, and the proportion of glyceryl monostearate + triethyl citrate in the prescription was 45%. The dosage of the prescription is the same as that in Example 2.

[0033] Example 3 prescription:

[0034]

[0035] Preparation method: 1000 bupropion hydrochloride sustained-release tablets were prepared according to the preparation method in Example 1. The difference is that 17.5g of triethyl citrate was added during the hot melt extrusion preparation process, and the proportion of glyceryl monostearate + triethyl citrate in the prescription was 35%. The dosage of the prescription was the same as that in Example 3.

[0036] Comparison Example 1: Refer to the formulation and process in the original patent "United States Patent 5427798" (without performing the subsequent coating process).

[0037]

[0038] The preparation method is as follows:

[0039] Step 1: Wetting agent preparation: Add the prescribed amount of cysteine ​​hydrochloride to purified water and stir until completely dissolved. This is wetting agent 1. Weigh out a certain amount of purified water. This is wetting agent 2, for later use.

[0040] Step 2: Premixing: Add the prescribed amounts of microcrystalline cellulose, bupropion hydrochloride, and hydroxypropyl methylcellulose to a wet granulator, set the stirring paddle speed to 200 rpm and the chopping blade speed to 450 rpm, and mix for 5 minutes;

[0041] Step 3: Granulation: Add the premixed material to the fluidized bed granulator. Preheat the air inlet temperature to 55℃. When the material temperature is higher than 30℃, start spraying wetting agent 1. After spraying wetting agent 1, continue spraying wetting agent 2 until it is finished. The fan frequency is 25-45Hz, the atomization pressure is 0.2-0.3Mpa, and the peristaltic pump speed is 15-25rpm.

[0042] Step 4: Drying: Set the fan frequency to 30Hz and the inlet air temperature to 65℃, and dry until the particle moisture content is 0.4%~1.5%, then collect the material;

[0043] Step 5: Granulation: Add magnesium stearate to the material from step 4 and granulate it. The screen mesh size is 1.2 mm and the granulator speed is 500 rpm.

[0044] Step 6: General mixing: Add the materials from step 5 into the hopper mixer, set the speed to 15 rpm, and mix for 10 minutes;

[0045] Step 7: Tableting: The mixed material from step 6 is compressed into tablets using a rotary tablet press with an 11mm shallow concave die. The theoretical tablet weight is 400mg.

[0046] Comparative Example 2: The amount of triethyl citrate is lower than that of the present invention, and the ratio of glyceryl monostearate to triethyl citrate is 10:1; the proportion of the formulation is 41.25%.

[0047]

[0048] Preparation method: 1000 bupropion hydrochloride sustained-release tablets were prepared according to the preparation method of Example 1, except that 15g of triethyl citrate was added to the prescription, and the prescription amount was the same as that of Control Example 2.

[0049] The formulation of Comparative Example 3: The amount of triethyl citrate is higher than that of the present invention, and the ratio of glyceryl monostearate to triethyl citrate is 5:1; the formulation accounts for 37.5%.

[0050]

[0051] Preparation method: 1000 bupropion hydrochloride sustained-release tablets were prepared according to the preparation method of Example 1, except that 25g of triethyl citrate was added to the prescription, and the prescription amount was the same as that of Control Example 3.

[0052] Comparative Example 4 prescription: Glyceryl monostearate was introduced alone, accounting for 40% of the prescription.

[0053]

[0054] The preparation method is as follows:

[0055] Step 1: Pretreatment: Weigh 150g of bupropion hydrochloride and 160g of glyceryl monostearate and add them to a ball mill. Set the speed to 80r / min and grind and mix for 20min. Then set aside for later use.

[0056] Step 2: Granulation: Using an 11mm co-rotating twin-screw hot melt extruder, set the extrusion temperature of the hot melt extruder to 100-150°C. After reaching the preset temperature, start the screw at a speed of 80 r / min and a feed rate of approximately 5 g / min. Add the material that has been ground and mixed evenly in Step 1 to the twin-screw hot melt extruder. The mixture is extruded in strip form through the screw. Cool the hot melt extruded strips and pulverize them through a 1.5mm sieve to obtain drug solid dispersion granules or powder.

[0057] Step 3: Premixing: Weigh 86g of microcrystalline cellulose and the solid particles obtained in step 2 and add them to a wet granulator. Set the stirring speed to 200rpm and the chopping speed to 450rpm and mix for 5min.

[0058] Step 4: Total mixing: Weigh 4g of magnesium stearate and add it alternately to the premixed material from Step 3 into the hopper mixer. Set the total mixing speed to 15r / min and mix for 10min.

[0059] Step 5: Tableting: The mixed material from step 4 is tableted using a 5-punch rotary tablet press with an 11mm shallow concave die. Theoretically, the tablet contains 400mg of protein and the average hardness is not less than 100N.

[0060] Comparative Example 5 prescription: Glyceryl monostearate: Triethyl citrate = 7:1; prescription ratio 30%.

[0061]

[0062] Preparation method: 1000 bupropion hydrochloride sustained-release tablets were prepared according to the preparation method of Example 1, except that the proportion of glyceryl monostearate + triethyl citrate in the prescription was 30%, and the prescription amount was the same as that of control example 6.

[0063] The prescription in Comparative Example 6 was: glyceryl monostearate: triethyl citrate = 7:1; the prescription ratio was 50%.

[0064]

[0065] Preparation method: 1000 bupropion hydrochloride sustained-release tablets were prepared according to the preparation method of Example 1, except that the proportion of glyceryl monostearate + triethyl citrate in the prescription was 50%, and the prescription amount was the same as that of control example 5.

[0066] Experimental Example 1:

[0067] One hundred tablets each of Examples 1-3 and Control Examples 1-6 were laid flat in a petri dish and placed in a light irradiation chamber for a light irradiation test. The test samples were placed in a light chamber equipped with fluorescent lamps or other suitable light irradiation devices at an illuminance of 4500 lx ± 500 lx for 30 days. Samples were taken on day 5, day 10, and day 30 to detect related substances in the samples.

[0068] The relevant substances shall be determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The relative humidity of the grinding and weighing environment should be controlled below 45%.

[0069] A mixed solution of methanol and 0.001 mol / L hydrochloric acid (20:80).

[0070] For the test solution, accurately weigh 20 tablets of this product, grind them into a fine powder, accurately weigh an appropriate amount (approximately equivalent to 60 mg of bupropion hydrochloride), place it in a 100 ml dry volumetric flask, add approximately 70 ml of solvent, sonicate for about 10 minutes, cool, dilute to the mark with solvent, shake well, let stand for 30 minutes, take the supernatant, filter, discard approximately 3 ml of the initial filtrate, and take the subsequent filtrate.

[0071] Bupropion hydrochloride reference standard stock solution: Take an appropriate amount of bupropion hydrochloride reference standard, accurately weigh it, dissolve it in solvent and quantitatively dilute it to prepare a solution containing approximately 0.12 mg per ml.

[0072] For the sensitivity solution, accurately measure an appropriate amount of bupropion hydrochloride reference stock solution, dilute with solvent to prepare a solution containing approximately 0.6 μg of bupropion hydrochloride per 1 ml.

[0073] To prepare a stock solution of m-chlorobenzoic acid reference standard, take an appropriate amount of m-chlorobenzoic acid reference standard, accurately weigh it, dissolve it in methanol, and quantitatively dilute it to prepare a solution containing approximately 0.12 mg per ml.

[0074] Accurately measure appropriate amounts of bupropion hydrochloride reference stock solution and m-chlorobenzoic acid reference stock solution, respectively, and quantitatively dilute with solvent to prepare a solution containing approximately 1.2 μg each of bupropion hydrochloride and m-chlorobenzoic acid per 1 ml.

[0075] For the system suitability solution, take 1 ml of bupropion hydrochloride extended-release tablet system suitability control standard, place it in a 100 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0076] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Waters Symmetry 4.6 mm × 100 mm, 3.5 μm, or a column with equivalent performance); acetonitrile-trifluoroacetic acid-water (10:0.04:90) was used as mobile phase A, and acetonitrile-trifluoroacetic acid-water (95:0.03:5) was used as mobile phase B; the flow rate was 1.5 ml / min, and gradient elution was performed according to the table below; the detection wavelengths were 226 nm (adjustable ±2 nm to meet the relative response factor requirements) and 259 nm (used for calculating the content of bupropion diketone derivatives); the column temperature was 40 °C; and the injection volume was 5 μl.

[0077] The system suitability requirements stipulate that the chromatogram of the system suitability solution recorded at a wavelength (226nm±2nm) meeting the relative response factor requirement should be substantially consistent with the reference chromatogram of the system suitability solution. Bupropion hydrochloride impurity F, bupropion hydrochloride impurity C, and m-chlorobenzoic acid should elute sequentially, with a resolution of not less than 1.3 between each component peak. At a wavelength (226nm±2nm) meeting the relative response factor requirement, the signal-to-noise ratio of the bupropion peak in the sensitivity solution should be not less than 10. The RSD of the bupropion peak area in the mixed reference solution should not exceed 10%. The response factor of the m-chlorobenzoic acid peak in the mixed reference solution should be 3.8 to 4.5 times that of the bupropion peak.

[0078] The test solution and the mixed reference solution are precisely measured and injected into the liquid chromatograph separately, and the chromatograms are recorded.

[0079] If a peak of bupropion dione derivative is present in the chromatogram of the test solution at a wavelength of 259 nm, the content shall be calculated according to Formula 2. If other impurity peaks besides bupropion dione derivative are present in the chromatogram of the test solution at a wavelength (226 nm ± 2 nm) where the relative response factor meets the requirements, the content shall be calculated according to Formula 1 or Formula 2.

[0080] Formula 1: m-chlorobenzoic acid content (%) = (ru / rs) × (Cs / Cu) × 100%

[0081] In the formula, ru represents the peak area of ​​intermediate chlorobenzoic acid in the test solution.

[0082] rs represents the peak area of ​​intermediate chlorobenzoic acid in the mixed reference solution.

[0083] Cu is the concentration of bupropion hydrochloride in the test solution.

[0084] Cs represents the concentration of intermediate chlorobenzoic acid in the mixed reference solution.

[0085] Formula 2: Other impurity content (%) = (ru / rs) × (Cs / Cu) × (1 / F) × 100%

[0086] In the formula, ru represents the peak area of ​​each impurity in the test solution.

[0087] rs represents the peak area of ​​bupropion in the mixed reference solution.

[0088] Cu is the concentration of bupropion hydrochloride in the test solution.

[0089] Cs represents the concentration of bupropion hydrochloride in the mixed reference solution.

[0090] F is the relative response factor of each impurity.

[0091]

[0092] Note: / indicates not detected.

[0093] Experimental Example 2:

[0094] Release rate was tested for tablets in Examples 1-3 and Control Examples 1-6; refer to the method for determination of dissolution and release rate (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0095] The dissolution conditions were as follows: 900 ml of water was used as the dissolution medium, the rotation speed was 50 revolutions per minute, and the operation was carried out according to the procedure. After 1 hour, 4 hours and 8 hours, 10 ml of the dissolution solution was taken, and the same volume of dissolution medium at the same temperature was added to the dissolution vessel immediately.

[0096] Take the dissolution of the test solution at 1 hour, 4 hours and 8 hours respectively, filter it, accurately measure 5 ml of the filtrate, put it in a 50 ml volumetric flask, dilute with water to the mark, and shake well.

[0097] For the reference solution, accurately weigh an appropriate amount of bupropion hydrochloride reference standard, dissolve it in water, and quantitatively dilute it to prepare a solution containing approximately 10 µg per ml.

[0098] The test solution and the reference solution were taken and the absorbance was measured at a wavelength of 252 nm by ultraviolet-visible spectrophotometry (General Rule 0401). The dissolution amount of each tablet at different times was calculated.

[0099] The dissolution limits for each tablet at 1 hour, 4 hours, and 8 hours should be 20%–40%, 45%–70%, and above 75% of the labeled amount, respectively, and all should comply with the regulations. The results are recorded in Table 2.

[0100] Examples 1-3 and Control Example 1 were placed under accelerated conditions (40℃ / 75%RH), and tablet release was measured at 3 and 6 months, respectively. The similarity factor (f2) method in the non-model-dependent method was used to compare the similarity with the release rate at day 0. The results are recorded in Table 3.

[0101]

[0102]

[0103] Note: Dissolution similarity is determined when the dissolution similarity factor f2 ≥ 50.

[0104] The results in Table 1-3 show that:

[0105] (1) The tablets prepared in Examples 1-3 of this invention have a slow release and no significant difference compared with the release curve of the original formulation process control example after 10 days;

[0106] (2) The amount of triethyl citrate in the formulation of Comparative Example 2 is lower than that in the present invention, and the product release meets the requirements. However, according to the data of related substances in Table 1, the increase of light-induced impurities is obvious.

[0107] (3) The amount of triethyl citrate in the formulation of Comparative Example 3 is higher than that in the present invention and the proportion of glyceryl monostearate and triethyl citrate in the formulation of Comparative Example 6 is higher than that in the present invention. The strength of the sustained-release skeleton is significantly improved, but the release is incomplete.

[0108] (4) The formulation of Comparative Example 4 did not contain triethyl citrate and the formulation of Comparative Example 5 contained glyceryl monostearate and triethyl citrate in lower proportions than those of the present invention, resulting in excessively rapid product release and significant increase in light-induced impurities.

[0109] (5) Comparison of data of Examples 1-3 and Control Example 1 under accelerated conditions. When accelerated for 3 months, Control Example 1 showed a significant trend of faster release compared with its own 0-day release. Examples 1-3 showed basically no change compared with its own 0-day release, and were more stable.

[0110] In summary, this invention does not add acidic protective agents. Instead, it uses a combination of glyceryl monostearate and triethyl citrate to replace unstable hydroxypropyl methylcellulose. Only within the specified dosage range and formulation ratio can it achieve the effects of slow release and stability under light.

[0111] Experimental Example 3:

[0112] Examples 1-3 and Control Examples 1, 4, and 5 were sliced ​​into two or more halves using a slicer and then immersed in the dissolution medium for release determination. The release rate was compared with the release rate at day 0 using the similarity factor (f2) method, a non-model-dependent method. The results are recorded in Table 4.

[0113]

[0114] The results showed that the samples prepared in Examples 1-3 could still maintain a stable release after being broken into tablets. The product release stability was significantly better than that of Control Example 1, Control Example 4 (no triethyl citrate was added to the formula) and Control Example 5 (the formula had a low proportion of glyceryl monostearate and triethyl citrate). This effectively avoided the risk of unstable release and sudden release after breaking the sustained-release tablets, and the products were safe and reliable.

[0115] Experimental Example 4:

[0116] The tablets from Examples 1-3 and Control Example 1 were placed in a medium containing a 50% ethanol solution. Dissolution conditions: 900 ml of 50% ethanol solution, rotation speed of 100 rpm, operated according to the procedure. After 1 hour, 4 hours and 8 hours, 10 ml of the dissolution solution was collected, and the same volume and temperature of dissolution medium were immediately added to the dissolution vessel.

[0117]

[0118] The results showed that the formulations of Examples 1-3, which introduced glyceryl monostearate and triethyl citrate and were prepared using a hot-melt extrusion process to create a sustained-release dispersion matrix, showed more stable tablet release compared to Control Example 1, which used hydroxypropyl methylcellulose as the gel matrix. The release amounts at 1h, 4h, and 8h were all above 20%~40%, 45%~70%, and 75% of the labeled amounts, respectively, meeting the requirements. This significantly reduced the risk of drug burst release and effectively ensured medication safety.

Claims

1. A sustained release bupropion hydrochloride tablet, characterized in that, It contains 150 parts of bupropion hydrochloride, 122.5-157.5 parts of glyceryl monostearate, 17.5-22.5 parts of triethyl citrate, 68-104 parts of microcrystalline cellulose, and 2-6 parts of magnesium stearate. The proportions of glyceryl monostearate and triethyl citrate in the formulation are 35%-45%, and the ratio of glyceryl monostearate to triethyl citrate is 7:

1. The parts mentioned are by weight.

2. The bupropion hydrochloride sustained release tablet according to claim 1, wherein It contains 150 parts of bupropion hydrochloride, 140 parts of glyceryl monostearate, 20 parts of triethyl citrate, 86 parts of microcrystalline cellulose, and 4 parts of magnesium stearate.

3. The method for preparing bupropion hydrochloride sustained-release tablets as described in claim 1, characterized in that, Includes the following steps: Step 1: Pretreatment: Add the prescribed amounts of bupropion hydrochloride and glyceryl monostearate to a ball mill and grind them; Step 2: Granulation: The material that has been ground and mixed evenly in step 1 and triethyl citrate are added to a twin-screw hot melt extruder. After the hot melt extrusion is cooled, the material is pulverized and then sieved to obtain drug solid dispersion granules or powder. Step 3: Premixing: Add the solid granules or powder obtained in Step 2, along with the prescribed amount of microcrystalline cellulose and pregelatinized starch, into a wet granulator and stir / crush. Step 4: Final mixing: Add the premixed material from Step 3 to the hopper mixer, and then add the prescribed amount of magnesium stearate and mix. Step 5: Tableting: The mixed material from step 4 is pressed into tablets using a rotary tablet press.

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