A pharmaceutical composition comprising bupropion, a method of preparing the same, and use thereof

Abstract

The present application relates to a kind of pharmaceutical composition comprising bupropion and its preparation method and its application, including bupropion or its salt and cysteine or its salt in the pharmaceutical composition, the particle size of cysteine or its salt is controlled to D90≥0.25mm in the preparation process of pharmaceutical composition.In the preparation process, the problem of sticking is improved by controlling the particle size of or its salt in the tabletting process, the tabletting yield of the obtained bupropion dextromethorphan double-layer tablet is significantly improved, and the dissolution of the obtained bupropion dextromethorphan compound preparation is better, more stable, further improves the bioavailability and curative effect of drug.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a pharmaceutical composition containing bupropion, its preparation method, and its application. Background Technology

[0002] Depression is a group of mood disorders or affective disorders caused by various factors, with depression as the main symptom. Clinically, it is characterized by depressed mood, slowed thinking, reduced willpower, cognitive impairment, and physical symptoms. Studies show that the lifetime prevalence of depression is 5.2%–16.2%. Major depressive disorder (MDD) is a debilitating, chronic, biologically based illness characterized by depressed mood, inability to feel pleasure, guilt and worthlessness, lack of energy, and other emotional and physical symptoms, which impair social, occupational, educational, or other important functioning. Currently, drug therapy is an effective means of relieving symptoms and improving the quality of life of patients with depression. However, eight classes of monoamine neurotransmitter receptor modulators, including monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective 5-HT reuptake inhibitors (SSRIs), 5-HT2A receptor antagonists and 5-HT reuptake inhibitors (SARIs), NE / DA reuptake inhibitors (NDRIs), NE and specific 5-HT antidepressants (NaSSAs), NE reuptake inhibitors (NaRIs), and 5-HT and NE reuptake inhibitors (SNRIs), all have drawbacks such as slow onset of action and significant side effects.

[0003] Dextromethorphan is the dextrorotatory isomer of levomycin and a low-affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It interacts with NMDA receptor signaling and exerts its effects through serotonin transporters and Sigma-1 receptors, making it widely applicable in the treatment of cough, acute and chronic pain, neuroprotection, and related diseases. Bupropion belongs to the aminoketone class of antidepressants. It is a type of aminoketone antidepressant with a chemical structure different from tricyclic, tetracyclic, or other known antidepressants. It has no significant effect on the uptake of serotonin (5-HT) or norepinephrine, nor on monoamine oxidase activity. However, this class of products can block dopamine (DA) reuptake, thereby producing an antidepressant effect.

[0004] In the currently marketed bupropion-dextromethorphan combination extended-release tablets (brand name Auvelity), dextromethorphan is an antagonist of NMDA (N-methyl-D-aspartate) receptors and also a sigma-1 receptor agonist. It acts on NMDA receptors and sigma-1 receptors in the brain, regulating glutamatergic neurotransmission. Bupropion prevents the degradation of dextromethorphan, improving its bioavailability, and also acts as an inhibitor of norepinephrine and dopamine reuptake. This mechanism of action provides a new option for patients with depression. However, the existing manufacturing process of bupropion-dextromethorphan combination formulations suffers from technical problems such as low tablet yield and low dissolution rates.

[0005] Therefore, improving the dissolution rate, bioavailability, and efficacy of bupropion-dextromethorphan combination preparations, and further increasing the tableting yield in the preparation process, are urgent problems to be solved in this field. Summary of the Invention

[0006] Stability tests on bupropion hydrochloride showed that it readily degrades to m-chlorobenzoic acid under alkaline conditions. Therefore, when compressing bupropion hydrochloride sustained-release tablets or bilayer tablets containing bupropion hydrochloride, a stabilizer to maintain an acidic microenvironment is necessary. Current research indicates that cysteine ​​hydrochloride (pH 1.5-2.0) as a stabilizer can significantly improve the microenvironment within bupropion hydrochloride tablets. The inventors have discovered that, on the one hand, cysteine ​​hydrochloride has strong hygroscopic properties; when compressing tablets stabilized with cysteine ​​hydrochloride, the material easily absorbs moisture, leading to sticking and punching during compression, resulting in a low tableting yield. On the other hand, cysteine ​​hydrochloride is highly corrosive to metals; metal punches in prolonged contact with cysteine ​​hydrochloride are easily corroded and become rough, further exacerbating sticking and punching.

[0007] To address the aforementioned problems, the present invention aims to provide a pharmaceutical composition containing bupropion and its preparation method. During the preparation process, the particle size of cysteine ​​hydrochloride is controlled to improve the problem of adhesion during tableting, resulting in a significantly increased tableting yield of bupropion-dextromethorphan bilayer tablets. Simultaneously, the obtained bupropion-dextromethorphan compound preparation exhibits better and more stable dissolution, further enhancing the bioavailability and efficacy of the drug.

[0008] This invention provides a pharmaceutical composition comprising bupropion or a salt thereof and cysteine ​​or a salt thereof, wherein the particle size of the cysteine ​​or salt thereof is controlled to be D during the preparation of the pharmaceutical composition. 90 ≥0.25mm.

[0009] In a further preferred embodiment of the present invention, the content of bupropion or its salt in the bupropion pharmaceutical composition is 10-40 wt%, preferably 15-35 wt%, and more preferably 20-30 wt%.

[0010] In a further preferred embodiment of the present invention, the content of cysteine ​​or its salt in the bupropion pharmaceutical composition is 5-35 wt%, preferably 10-30 wt%, and more preferably 12-25 wt%.

[0011] In a further preferred embodiment of the present invention, the bupropion pharmaceutical composition further comprises one or more of a sustained-release agent, a filler, a flow aid, and a lubricant.

[0012] In a further preferred embodiment of the present invention, the sustained-release agent of the bupropion pharmaceutical composition is selected from one or more of hydroxypropyl methylcellulose, carbomer, carbomer homopolymer, carbomer interpolymer, polyoxyethylene, sodium alginate, and methylcellulose, preferably carbomer homopolymer.

[0013] In a further preferred embodiment of the present invention, the content of the sustained-release agent in the bupropion pharmaceutical composition is 3-25 wt%, preferably 5-20 wt%, and more preferably 10-15 wt%.

[0014] In a further preferred embodiment of the present invention, the filler of the bupropion pharmaceutical composition is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, microcrystalline cellulose colloidal silica co-treated material, anhydrous calcium hydrogen phosphate, and sorbitol, preferably one or more of microcrystalline cellulose and microcrystalline cellulose colloidal silica co-treated material.

[0015] In a further preferred embodiment of the present invention, the filler content of the bupropion pharmaceutical composition is 10-70 wt%, preferably 20-60 wt%, and more preferably 30-50 wt%.

[0016] In a further preferred embodiment of the present invention, the lubricant of the bupropion pharmaceutical composition is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, preferably magnesium stearate.

[0017] In a further preferred embodiment of the present invention, the lubricant content of the bupropion pharmaceutical composition is 0.1-5 wt%, preferably 0.5-3 wt%, and more preferably 0.7-2 wt%.

[0018] In a further preferred embodiment of the present invention, the gliding agent of the bupropion pharmaceutical composition is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide, preferably silicon dioxide.

[0019] In a further preferred embodiment of the present invention, the content of the bupropion drug composition as a gliding agent is 0.1-5 wt%, preferably 0.2-3 wt%, and more preferably 0.5-1.5 wt%.

[0020] In a further preferred embodiment of the present invention, the bupropion salt is bupropion hydrochloride and the cysteine ​​salt is cysteine ​​hydrochloride.

[0021] In another aspect of the invention, a method for preparing a pharmaceutical composition is provided, the pharmaceutical composition comprising bupropion or a salt thereof and cysteine ​​or a salt thereof, wherein the particle size of the cysteine ​​or salt thereof is controlled to be D during the preparation of the pharmaceutical composition. 90 ≥0.25mm.

[0022] In a further preferred embodiment of the present invention, the bupropion pharmaceutical composition further comprises one or more of a sustained-release agent, a filler, a flow aid, and a lubricant.

[0023] In a further preferred embodiment of the present invention, cysteine ​​or its salt is mixed with a filler and optionally a flow aid and then granulated. The granulation is performed using a ≥1.0 mm sieve, preferably using a 1.0 mm sieve.

[0024] In a further preferred embodiment of the present invention, the preparation method of the pharmaceutical composition includes the following steps: 1) granulating bupropion or its salt with a sustained-release agent and a filler; 2) granulating the prepared granules with cysteine ​​or its salt and a filler and optional flow aid, wherein the granulation is performed using a ≥1.0 mm sieve, mixing evenly, and then adding a lubricant to mix.

[0025] In a further preferred embodiment of the present invention, the granulation is fluidized bed granulation, the material temperature is controlled at 33-43°C, and the moisture content of the granules is controlled at ≤3%.

[0026] In a further preferred embodiment of the present invention, the granulation is divided into three stages: premixing, sieving, and granulation.

[0027] In a further preferred embodiment of the present invention, the mass ratio of the filler in step 1) to the filler in step 2) is 0.2-10:1, preferably 0.5-8:1, and more preferably 1-6:1.

[0028] In a further preferred embodiment of the present invention, the filler in step 1) is preferably microcrystalline cellulose, and the filler in step 2) is preferably microcrystalline cellulose colloidal silica co-treated material.

[0029] In another aspect of the invention, a method for improving the viscosity of cysteine ​​hydrochloride during the preparation of a pharmaceutical composition containing bupropion is provided, wherein the particle size of cysteine ​​hydrochloride is controlled to be D during the preparation of the pharmaceutical composition. 90 ≥0.25mm.

[0030] In another aspect of the invention, a dextromethorphan-bupropion pharmaceutical composition is provided, the pharmaceutical composition comprising bupropion or a salt thereof and cysteine ​​or a salt thereof, dextromethorphan or a salt thereof, wherein the particle size of cysteine ​​or its salt is controlled to be D during the preparation of the pharmaceutical composition. 90 ≥0.25mm.

[0031] In a further preferred embodiment of the present invention, the mass ratio of bupropion or its salt to dextromethorphan or its salt in the pharmaceutical composition is 0.1-10:1, preferably 0.5-5:1, and more preferably 2-3:1.

[0032] In a further preferred embodiment of the invention, the pharmaceutical composition is a bilayer tablet, with bupropion or its salt and dextromethorphan or its salt in different layers.

[0033] In a further preferred embodiment of the present invention, the bupropion layer comprises bupropion or a salt thereof and cysteine ​​or a salt thereof.

[0034] In a further preferred embodiment of the present invention, the content of bupropion or its salt in the bupropion drug layer is 10-40 wt%, preferably 15-35 wt%, and more preferably 20-30 wt%.

[0035] In a further preferred embodiment of the present invention, the content of cysteine ​​or its salt in the bupropion drug layer is 5-35 wt%, preferably 10-30 wt%, and more preferably 12-25 wt%.

[0036] In a further preferred embodiment of the present invention, the bupropion drug layer further comprises one or more of a sustained-release agent, a filler, a flow aid, and a lubricant.

[0037] In a further preferred embodiment of the present invention, the sustained-release agent in the bupropion drug layer is selected from one or more of hydroxypropyl methylcellulose, carbomer, carbomer homopolymer, carbomer interpolymer, polyoxyethylene, sodium alginate, and methylcellulose, preferably carbomer homopolymer.

[0038] In a further preferred embodiment of the present invention, the content of the sustained-release agent in the bupropion layer is 3-25 wt%, preferably 5-20 wt%, and more preferably 10-15 wt%.

[0039] In a further preferred embodiment of the present invention, the filler in the bupropion layer is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, microcrystalline cellulose colloidal silica co-treated material, anhydrous calcium hydrogen phosphate, and sorbitol, preferably one or more of microcrystalline cellulose and microcrystalline cellulose colloidal silica co-treated material.

[0040] In a further preferred embodiment of the present invention, the content of the filler in the bupropion drug layer is 10-70 wt%, preferably 20-60 wt%, and more preferably 30-50 wt%.

[0041] In a further preferred embodiment of the present invention, the lubricant in the bupropion layer is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, with magnesium stearate being preferred.

[0042] In a further preferred embodiment of the present invention, the content of lubricant in the bupropion layer is 0.1-5 wt%, preferably 0.5-3 wt%, and more preferably 0.7-2 wt%.

[0043] In a further preferred embodiment of the present invention, the flow aid in the bupropion layer is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide, preferably silicon dioxide.

[0044] In a further preferred embodiment of the present invention, the content of the bupropion layer in the glidant is 0.1-5 wt%, preferably 0.2-3 wt%, and more preferably 0.5-1.5 wt%.

[0045] In a further preferred embodiment of the present invention, the dextromethorphan layer includes dextromethorphan or its salt, as well as one or more fillers, disintegrants, flow aids and lubricants.

[0046] In a further preferred embodiment of the present invention, the content of dextromethorphan or its salt in the dextromethorphan layer is 10-40 wt%, preferably 15-35 wt%, and more preferably 20-30 wt%.

[0047] In a further preferred embodiment of the present invention, the filler in the dextromethorphan layer is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and sorbitol, with microcrystalline cellulose being preferred.

[0048] In a further preferred embodiment of the present invention, the content of the filler in the dextromethorphan layer is 45-85 wt%, preferably 50-75 wt%, and more preferably 55-70 wt%.

[0049] In a further preferred embodiment of the present invention, the disintegrant in the dextromethorphan layer is selected from one or more of crospovidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose, preferably crospovidone.

[0050] In a further preferred embodiment of the present invention, the content of the disintegrant in the dextromethorphan layer is 1-10 wt%, preferably 2-8 wt%, and more preferably 3-7 wt%.

[0051] In a further preferred embodiment of the present invention, the flow aid in the dextromethorphan layer is selected from one or more of aluminum magnesium metasilicate, magnesium aluminum silicate, and silicon dioxide, preferably silicon dioxide.

[0052] In a further preferred embodiment of the present invention, the content of the flow aid in the dextromethorphan layer is 0.5-10 wt%, preferably 1-8 wt%, and more preferably 2-7 wt%.

[0053] In a further preferred embodiment of the present invention, the lubricant in the dextromethorphan layer is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, with magnesium stearate being preferred.

[0054] In a further preferred embodiment of the present invention, the content of the lubricant in the dextromethorphan layer is 0.1-6 wt%, preferably 0.5-5 wt%, and more preferably 1-4 wt%.

[0055] In a further preferred embodiment of the present invention, the dextromethorphan salt is dextromethorphan hydrobromide, the bupropion salt is bupropion hydrochloride, and the cysteine ​​salt is cysteine ​​hydrochloride.

[0056] In another aspect of the present invention, a method for preparing a dextromethorphan-bupropion pharmaceutical composition is provided, wherein the particle size of cysteine ​​or its salt is controlled to be D90≥0.25mm during the preparation of the pharmaceutical composition.

[0057] In a further preferred embodiment of the invention, cysteine ​​or its salt is mixed with a filler and optionally a flow aid and then granulated, wherein the granulation is performed using a sieve with a diameter of ≥1.0 mm.

[0058] In a further preferred embodiment of the present invention, a method for preparing a dextromethorphan-bupropion pharmaceutical composition includes the following steps:

[0059] 1) Preparation of immediate-release layer: Mix dextromethorphan or its salt with one or more of fillers, disintegrants, and gliding agents until homogeneous, then add lubricant and mix until homogeneous for later use;

[0060] 2) Preparation of sustained-release layer: ① Mix bupropion or its salt with sustained-release agent and filler evenly and then granulate; ② Mix the prepared granules with cysteine ​​or its salt and filler and optional flow aid and then granulate. The granulation is carried out using a ≥1.0mm sieve, mixing evenly, and then adding lubricant and mixing evenly for later use.

[0061] 3) Preparation of double-layer tablets: First, gently press the sustained-release layer, then fill it with the immediate-release layer material, and press it into shape in one step.

[0062] In a further preferred embodiment of the present invention, the hardness of the tablets made from the double-layer sheet is controlled within the range of 80N~170N.

[0063] In a further preferred embodiment of the present invention, a coating step is further included after the preparation of the bilayer sheet.

[0064] In another aspect of the invention, a pharmaceutical composition comprising bupropion is provided for use in the preparation of an NMDA receptor antagonist drug.

[0065] In another aspect of the invention, a pharmaceutical composition comprising bupropion is provided for use in the preparation of 5-HT and / or NE reuptake inhibitor medicaments.

[0066] In another aspect of the invention, a pharmaceutical composition comprising bupropion is provided for use as a medicament in the preparation of depression, Alzheimer's-related agitation, dementia-related agitation and anxiety, neuropathic pain, or diabetic peripheral neuropathy.

[0067] In a further preferred embodiment of the present invention, the depression is moderate to severe depression, including treatment-resistant depression.

[0068] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0069] 1. In the process of preparing bupropion granules, this invention improves the problem of cysteine ​​hydrochloride sticking during tableting by controlling the particle size of cysteine ​​hydrochloride, thereby increasing the tablet yield to >80%; and improves the dissolution of the drug composition by adding fillers in steps.

[0070] 2. The dextromethorphan-bupropion bilayer tablets prepared by this invention met the requirements in dissolution experiments using water, 0.1 mol / L hydrochloric acid solution, pH 4.5 acetate buffer solution, and pH 6.8 phosphate buffer solution as dissolution media, employing the basket method at 75 rpm / min. Specifically, the immediate-release layer showed a dextromethorphan dissolution rate ≥90% at 15 min; the sustained-release layer showed dissolution rates of 25%–50%, 60%–90%, and over 80% of bupropion at 60 min, 240 min, and 480 min, respectively. The dextromethorphan-bupropion bilayer tablets prepared by this invention exhibit better stability.

[0071] 3. The preparation process of this invention is simple and easy to implement, which is conducive to industrial production and widespread use. Attached Figure Description

[0072] Figure 1 : In vitro dissolution curve of bupropion hydrochloride;

[0073] Figure 2 In vitro dissolution curve of dextromethorphan hydrobromide. Detailed Implementation

[0074] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0075] Examples

[0076] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, proportions or percentages used herein are by weight.

[0077] Example 1: Preparation of immediate-release layer material

[0078] The prescription is as follows:

[0079] Dextromethorphan hydrobromide 45g

[0080] Microcrystalline cellulose 88g

[0081] 5g of crospovidone

[0082] 10g of colloidal silica

[0083] 5g magnesium stearate

[0084] Preparation method: (1) Sieving: The prescribed amounts of colloidal silica, cross-linked polyvinylpyrrolidone, dextromethorphan hydrobromide and microcrystalline cellulose are added to a granulator equipped with a 1.0 mm sieve in sequence. The sieving frequency is set to 15 Hz. The fixed hopper is turned on to lift the granulator for sieving. After sieving, the material is placed in a mixing tank.

[0085] (2) Initial mixing and final mixing: Initial mixing: Set the mixing speed to 10 rpm and the mixing time to 10 min; Final mixing: Add magnesium stearate through a 40-mesh standard sieve into the mixing tank, set the mixing speed to 10 rpm and the mixing time to 5 min.

[0086] Example 2: Fluidized Bed Granulation of Slow-Release Layer Materials

[0087] The prescription is as follows:

[0088] 105g of bupropion hydrochloride

[0089] 163g of microcrystalline cellulose

[0090] 54g of carbomer homopolymer

[0091] Preparation method: (1) Premixing: Carbomer homopolymer, bupropion hydrochloride and microcrystalline cellulose are added to the mixing tank, the mixing speed is set to 10 rpm and the mixing time is 5 min. After premixing, the mixture is transferred to the granulator.

[0092] (2) Sieving: After premixing, the material is added to a granulator equipped with a sieve with a 1.0 mm aperture. The sieving frequency is set to 15 Hz. The material is discharged after sieving.

[0093] (3) Granulation: Preheat the fluidized bed and transfer the material into the fluidized bed; preheat the material, and when the material temperature reaches 38℃, set the outer layer atomization pressure to 150KPa, the inner layer atomization pressure to 120KPa, the purified water flow rate to 40±10g / min; the air volume setting range is 400-1000m3 / h, the air inlet temperature setting range is 60±10℃, and the purified water flow rate range is 40±10g / min to ensure that the material does not collapse on the bed and to keep the material temperature within the range of 38℃±5℃ during the granulation stable stage. When all the purified water is sprayed, turn off the peristaltic pump, stop spraying, and the granulation stage ends.

[0094] Example 3: Sieving and mixing of the sustained-release layer and pressing of bilayer tablets

[0095] The prescription is as follows:

[0096] 322g of granules were obtained by fluidized bed preparation

[0097] 50g of cysteine ​​hydrochloride

[0098] 31.5g of colloidal silica microcrystalline cellulose co-treated product

[0099] Magnesium stearate 3.5g

[0100] Preparation method: (1) Sieving and mixing: Cysteine ​​hydrochloride and colloidal silica microcrystalline cellulose co-treatment material were added to the fluidized bed granulation material, premixed and then added to a granulator equipped with a 1.0 mm sieve for granulation (the particle size D90 of cysteine ​​hydrochloride was measured to be ≥0.25 mm). After granulation, the material was added to a mixer, and the mixing speed was set to 10 rpm and the mixing time was 15 min. After mixing, magnesium stearate was added to the mixing tank through a 40 mesh standard sieve, and the speed was set to 10 rpm and the mixing time was 5 min.

[0101] (2) Tableting: A Fitt P3030 tablet press was used, with the following die specifications: 11.0mm round shallow concave punch, theoretical tablet weight: 0.560g (0.407g of sustained-release layer and 0.153g of immediate-release layer). After normal operation during the test run, transfer the sustained-release layer intermediate to the first material hopper of the tablet press. Sustained-release layer (layer I) tablet weight adjustment: Using the lowest speed of 10rpm, adjust the filling amount and pressure of the first layer of the tablet press. Adjust the pressure of the sustained-release layer (layer I) to shape the tablet appearance and meet the tablet weight inspection requirements. Immediate-release layer (layer II) tablet weight adjustment: After the sustained-release layer filling amount stabilizes, transfer the immediate-release layer intermediate to the second material hopper of the tablet press. Adjust the pressure of the first layer and the filling amount and pressure of the second layer of the tablet press to ensure that the appearance and weight of the two-layer tablets meet the requirements. Tablet appearance: intact and smooth. Hardness 80-170N. Tableting yield 84.79%.

[0102] Example 4: Double-layer sheet coating

[0103] The prescription for the coating powder is as follows: (1000 tablets)

[0104] Film-coated premix (gastric-soluble type) (88A170009-CN) 45g

[0105] 225g of purified water

[0106] Preparation method: (1) Weigh 45g of film coating premix (gastric-soluble type) (88A170009-CN) and 225g of purified water, place them in a stainless steel bucket, add the film coating premix (gastric-soluble type) (88A170009-CN) while stirring, and stir for more than 45min. After stirring, pass the coating solution through a 60-mesh sieve, keep the coating solution in a state of continuous stirring, and set aside for later use.

[0107] (2) After preheating the core, the tablets are coated. During the coating process, the temperature of the tablet bed is monitored by an infrared temperature detector (control range: 35-50℃) until the coating weight gain meets the requirements.

[0108] (3) Drying: After coating, the product is dried.

[0109] Comparative Example 1: Strained-release layer sieved and mixed

[0110] Using the formulation of Example 3, cysteine ​​hydrochloride and colloidal silica microcrystalline cellulose were added to the fluidized bed granulation material for premixing. The mixture was then added to a granulator equipped with a 0.8mm sieve for granulation. After granulation, the mixture was added to a mixer, with a mixing speed of 10 rpm and a mixing time of 15 minutes. After mixing, magnesium stearate was added to the mixing tank through a 40-mesh standard sieve, with a mixing speed of 10 rpm and a mixing time of 5 minutes. During subsequent tableting, severe sticking and punching problems occurred, resulting in a significant decrease in the tablet yield.

Claims

1. A pharmaceutical composition comprising bupropion or a salt thereof and cysteine ​​or a salt thereof, wherein the particle size of the cysteine ​​or salt thereof is controlled to be D during the preparation of the pharmaceutical composition. 90 ≥0.25mm.

2. The pharmaceutical composition of claim 1, further satisfying one or more of the following conditions: The content of bupropion or its salt in the bupropion pharmaceutical composition is 10-40 wt%, preferably 15-35 wt%, more preferably 20-30 wt%; The cysteine ​​or its salt content in the bupropion pharmaceutical composition is 5-35 wt%, preferably 10-30 wt%, more preferably 12-25 wt%; The bupropion pharmaceutical composition further comprises one or more of a sustained-release agent, a filler, a flow aid, and a lubricant; The sustained-release agent of the bupropion drug composition is selected from one or more of hydroxypropyl methylcellulose, carbomer, carbomer homopolymer, carbomer interpolymer, polyoxyethylene, sodium alginate, and methylcellulose. The sustained-release agent in the bupropion drug composition contains 3-25 wt%, preferably 5-20 wt%, and more preferably 10-15 wt%. The filler in the bupropion pharmaceutical composition is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, microcrystalline cellulose colloidal silica co-treated material, anhydrous calcium hydrogen phosphate, and sorbitol; The filler content of the bupropion pharmaceutical composition is 10-70 wt%, preferably 20-60 wt%, more preferably 30-50 wt%; The lubricant in the bupropion pharmaceutical composition is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc. The lubricant content of the bupropion pharmaceutical composition is 0.1-5 wt%, preferably 0.5-3 wt%, more preferably 0.7-2 wt%; The bupropion drug composition uses a flow aid selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide. The content of the bupropion drug composition in terms of the glidant is 0.1-5 wt%, preferably 0.2-3 wt%, and more preferably 0.5-1.5 wt%.

3. The method for preparing the pharmaceutical composition according to any one of claims 1-2, wherein the pharmaceutical composition comprises bupropion or a salt thereof and cysteine ​​or a salt thereof, and the particle size of cysteine ​​or its salt thereof is controlled to be D90≥0.25mm during the preparation of the pharmaceutical composition.

4. The method for preparing the pharmaceutical composition according to claim 3, further satisfying one or more of the following conditions: The cysteine ​​or its salt is mixed with a filler and optional flow aid and then granulated, wherein the granulation is performed using a sieve with a diameter of ≥1.0 mm. The method for preparing the pharmaceutical composition includes the following steps: 1) Mix bupropion or its salt with a sustained-release agent and a filler evenly and then granulate; 2) Mix the prepared granules with cysteine ​​or its salt and a filler and optional flow aid, and then granulate. The granulation is carried out using a ≥1.0mm sieve, mixing evenly, and then adding a lubricant and mixing to obtain the final product. The granulation process is fluidized bed granulation, with the material temperature controlled at 33-43℃, and the moisture content of the resulting granules controlled at ≤3%. The mass ratio of the filler in step 1) to the filler in step 2) is 0.2-10:1, preferably 0.5-8:1, and more preferably 1-6:

1.

5. A method for improving the viscosity of cysteine ​​hydrochloride during the preparation of a pharmaceutical composition containing bupropion, wherein the particle size of cysteine ​​hydrochloride is controlled to be D90≥0.25mm during the preparation of the pharmaceutical composition.

6. A dextromethorphan-bupropion pharmaceutical composition, said pharmaceutical composition comprising bupropion or a salt thereof and cysteine ​​or a salt thereof, dextromethorphan or a salt thereof, wherein the particle size of cysteine ​​or its salt is controlled to be D during the preparation of the pharmaceutical composition. 90 ≥0.25mm.

7. The pharmaceutical composition of claim 6, further satisfying one or more of the following conditions: The mass ratio of bupropion or its salt to dextromethorphan or its salt in the pharmaceutical composition is 0.1-10:1, preferably 0.5-5:1, and more preferably 2-3:1; The pharmaceutical composition is a bilayer tablet, with bupropion or its salt and dextromethorphan or its salt in different layers; The bupropion layer comprises bupropion or a salt thereof and cysteine ​​or a salt thereof; The content of bupropion or its salt in the bupropion layer is 10-40 wt%, preferably 15-35 wt%, more preferably 20-30 wt%; The cysteine ​​or its salt content in the bupropion layer is 5-35 wt%, preferably 10-30 wt%, more preferably 12-25 wt%; The bupropion layer also contains one or more of a sustained-release agent, a filler, a flow aid, and a lubricant; The sustained-release agent in the bupropion layer is selected from one or more of hydroxypropyl methylcellulose, carbomer, carbomer homopolymer, carbomer interpolymer, polyoxyethylene, sodium alginate, and methylcellulose. The sustained-release agent in the bupropion layer contains 3-25 wt%, preferably 5-20 wt%, and more preferably 10-15 wt%. The filler in the bupropion layer is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, microcrystalline cellulose colloidal silica co-treated material, anhydrous dicalcium phosphate, and sorbitol; The filler content in the bupropion layer is 10-70 wt%, preferably 20-60 wt%, and more preferably 30-50 wt%. The lubricant in the bupropion layer is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc. The lubricant content in the bupropion layer is 0.1-5 wt%, preferably 0.5-3 wt%, and more preferably 0.7-2 wt%. The flow aid in the bupropion layer is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide. The content of the bupropion layer in the glidant is 0.1-5 wt%, preferably 0.2-3 wt%, and more preferably 0.5-1.5 wt%. The dextromethorphan layer includes dextromethorphan or its salt, as well as one or more of fillers, disintegrants, flow aids and lubricants; The content of dextromethorphan or its salt in the dextromethorphan layer is 10-40 wt%, preferably 15-35 wt%, and more preferably 20-30 wt%. The filler in the dextromethorphan layer is selected from one or more of mannitol, lactose, corn starch, microcrystalline cellulose, anhydrous dicalcium phosphate, and sorbitol; The content of the filler in the dextromethorphan layer is 45-85 wt%, preferably 50-75 wt%, and more preferably 55-70 wt%. The disintegrant in the dextromethorphan layer is selected from one or more of crospovidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. The content of the disintegrant in the dextromethorphan layer is 1-10 wt%, preferably 2-8 wt%, and more preferably 3-7 wt%. The flow aid in the dextromethorphan layer is selected from one or more of magnesium aluminum metasilicate, magnesium aluminum silicate, and silicon dioxide. The content of the glidin in the dextromethorphan layer is 0.5-10 wt%, preferably 1-8 wt%, and more preferably 2-7 wt%. The lubricant in the dextromethorphan layer is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc. The content of the lubricant in the dextromethorphan layer is 0.1-6 wt%, preferably 0.5-5 wt%, and more preferably 1-4 wt%.

8. The method for preparing a dextromethorphan-bupropion pharmaceutical composition according to any one of claims 6-7, wherein the particle size of cysteine ​​or its salt is controlled to be D90≥0.25mm during the preparation of the pharmaceutical composition.

9. The method for preparing the pharmaceutical composition according to claim 8, further satisfying one or more of the following conditions: The cysteine ​​or its salt is mixed with a filler and optional flow aid and then granulated, wherein the granulation is performed using a sieve with a diameter of ≥1.0 mm. The process includes the following steps: 1) Preparation of the immediate-release layer: Dextromethorphan or its salt is mixed evenly with one or more of the following: filler, disintegrant, and glidant. Lubricant is then added and the mixture is mixed evenly for later use. 2) Preparation of the sustained-release layer: ① Bupropion or its salt is mixed evenly with the sustained-release agent and filler and then granulated. ② The prepared granules are mixed with cysteine ​​or its salt and filler, and optionally a glidant, and then granulated. Granulation is performed using a ≥1.0mm sieve, and the mixture is mixed evenly. Lubricant is then added and the mixture is mixed evenly for later use. 3) Preparation of the double-layer tablet: The sustained-release layer is first gently pressed, and then the immediate-release layer material is filled in. The tablets are then pressed into shape in one step. The hardness of the tablets made from the double-layered sheets is controlled within the range of 80N~170N; It further includes a coating step after the preparation of the bilayer sheet.

10. The use of a pharmaceutical composition comprising bupropion as described in any one of claims 1-2 and the use of a pharmaceutical composition comprising dextromethorphan and bupropion as described in any one of claims 6-7 in the preparation of an NMDA receptor antagonist drug; or in the preparation of a 5-HT and / or NE reuptake inhibitor drug; preferably in the preparation of a drug for depression, Alzheimer's-related agitation, dementia-related agitation and anxiety, neuropathic pain, or diabetic peripheral neuropathy.

Images