Pharmaceutical formulation of deudextromethorphan bupropion, preparation method therefor, and pharmaceutical use thereof

Abstract

Provided are a pharmaceutical formulation of deudextromethorphan bupropion, a preparation method therefor, and pharmaceutical use thereof. The formulation is a double-layer tablet, which comprises a deudextromethorphan immediate-release portion and a bupropion sustained-release portion.

Description

A pharmaceutical preparation of deuterated dextromethorphan bupropion, its preparation method and pharmaceutical uses Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a deuterated dextromethorphan bupropion pharmaceutical preparation, its preparation method, and its pharmaceutical uses. Background Technology

[0002] The applicant's previous patent application CN114340608B disclosed a pharmaceutical composition and its application, wherein the pharmaceutical composition contains deuterated dextromethorphan or a salt thereof, and bupropion or a salt thereof, wherein the mass ratio of deuterated dextromethorphan or a salt thereof, calculated as deuterated dextromethorphan, and bupropion or a salt thereof, calculated as bupropion, is 1:1-10, and is intended for pharmaceutical use including depression. CN116459255A discloses the use of deuterated dextromethorphan in combination with bupropion in the preparation of a drug for agitation in Alzheimer's disease (AD). Currently, there is no corresponding formulation implementation scheme.

[0003] WO2024006906A1 discloses a pharmaceutical formulation comprising 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide, wherein the formulation contains a polymer comprising poly(acrylic acid), poly(acrylic acid), or combinations or copolymers thereof.

[0004] WO2024006812A1 discloses a pharmaceutical composition comprising bupropion and cysteine, wherein the molar ratio of bupropion to cysteine ​​is from about 0.5:1 to about 2:1, preferably 1:1.

[0005] Further research is needed to develop suitable drug formulations for use in treating related diseases in patients. Summary of the Invention

[0006] To address the problems that this invention aims to solve, a pharmaceutical formulation with satisfactory dissolution effect and stable quality is provided for further use in mammals to exert its therapeutic effect.

[0007] First, the present invention provides a pharmaceutical preparation comprising: deuterated dextromethorphan or a pharmaceutically acceptable salt thereof, bupropion or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients, wherein the sum of the mass percentages of the drug and the excipients is 100%, wherein:

[0008] The drug formulation is a bilayer tablet, wherein deuterdextromethorphan is the fast-release fraction and bupropion is the slow-release fraction;

[0009] The rapid-release portion contains one or more disintegrants selected from crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; the slow-release portion contains one or more sustained-release materials selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and carbomer. Crospovidone is a more preferred disintegrant, and crospovidone models include crospovidone (XL), etc.

[0010] As a preferred embodiment of the present invention, the amount of the disintegrant is 2%-15% of the rapid release portion, more preferably 5%-12%, and even more preferably 8%-12%.

[0011] As a preferred embodiment of the present invention, the amount of the slow-release material is 10%-50% of the slow-release portion, more preferably 10%-40%, and even more preferably 15%-35%.

[0012] The use of disintegrants in this invention ensures that the immediate-release layer rapidly swells and disperses into small particles upon contact with water, promptly detaching from the sustained-release layer before it hydrates and forms a gel, thus avoiding interference from the sustained-release portion. The active ingredient can dissolve and be absorbed at a relatively fast rate. Cross-linked povidone is a preferred disintegrant, exhibiting high disintegrant power even with very low water absorption, rapidly demonstrating high capillary activity and excellent hydration ability, with almost no tendency to gel. Tablets prepared using cross-linked povidone as a disintegrant disintegrate rapidly and dissolve quickly and completely.

[0013] Non-sustained-release formulations contain active ingredients that dissolve rapidly, and the body cannot maintain a sustained effective concentration, requiring multiple doses. Adding sustained-release materials allows for control over the rate at which the active ingredient is released from the tablet. Adjusting the amount of sustained-release material in the tablet allows for formulations with different release rates, thus prolonging drug release time, reducing fluctuations in blood drug concentration, decreasing the frequency of dosing, achieving the desired absorption effect, and improving patient compliance.

[0014] As a preferred embodiment of the present invention, the slow-release portion contains one or more of cysteine ​​hydrochloride, glycine hydrochloride, sodium metabisulfite, citric acid, and tartaric acid, in an amount of 1 / 5 to 1 / 10 of the sustained-release material, which can stabilize bupropion. Preferably, the slow-release portion contains cysteine ​​hydrochloride. The applicant's research has found that this not only stabilizes bupropion, but also that if the amount of cysteine ​​hydrochloride in the sustained-release portion exceeds the range selected in this invention, it will cause hydrolysis of the sustained-release material, weakening its long-term stability and sustained-release effect.

[0015] As a preferred embodiment of the present invention, the rapid release portion and / or the slow release portion contain a certain amount of a flow aid, wherein the flow aid is selected from silica, talc, etc., and the flow aid is 0.05%-3% of the rapid release portion, more preferably 0.5%-1.5%, and the flow aid is 0.00%-2% of the slow release portion, more preferably 0.3%-0.7%.

[0016] A flow aid is an excipient that reduces friction between powders or granules, thereby improving material flowability. In tablet manufacturing, flow aids are typically added to increase the material flow rate during compression, allowing for rapid and uniform filling of the die, maintaining stable tablet weight, and achieving better weight variation. Especially in bilayer tableting, precise control of each layer's weight is crucial. Excessive weight variation can affect the accuracy of dosage in each layer and cause significant fluctuations in pressure and hardness, potentially leading to interlayer separation or cracking. In this invention, the addition of silica and talc significantly improves material flowability and enhances the feasibility of the bilayer tableting process.

[0017] As a preferred embodiment of the present invention, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, dicalcium phosphate, pregelatinized starch, etc.

[0018] Preferably, the filler comprises 50%-90% of the fast-release portion, more preferably 50%-70%; the filler comprises 15%-60% of the slow-release portion, more preferably 20%-50%; one embodiment is that when the filler contains lactose and microcrystalline cellulose, the mass ratio of lactose to microcrystalline cellulose is 3:1-1:2, more preferably 2.5-1.5:1.

[0019] Fillers are a very important component of tablets. The powder properties and crystalline forms of most active ingredients are not conducive to tableting and compression molding. Therefore, fillers with good flowability and compressibility are needed to improve the flowability and compressibility of drug powders, or to prepare them into granules through dry or wet processes to meet the requirements of formulation production for powder particle size.

[0020] As a preferred embodiment of the present invention, the rapid release portion contains a certain amount of adhesive, which is selected from povidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., and the amount used is 0.5%-8% of the rapid release portion, more preferably 1%-3%; preferably povidone, such as povidone (K29 / 32).

[0021] The addition of binders can uniformly bind the main components and other excipients together, preventing stratification during the formulation process and avoiding uneven content. Simultaneously, granulation can form dense, uniform particles, thereby improving material flowability and tablet compressibility.

[0022] As a preferred embodiment of the present invention, the rapid release portion and / or the slow release portion further contain one or both of a colorant and a lubricant.

[0023] The colorant is selected from yellow iron oxide, red iron oxide, etc., and the lubricant is selected from magnesium stearate, stearic acid, sodium stearate, behenic acid glyceride, etc.

[0024] As a preferred embodiment of the present invention, the colorant is 0.05%-0.2% of the fast-release portion;

[0025] As a preferred embodiment of the present invention, the lubricant is 0.1%-3% of the fast-release portion; the lubricant is 0.5%-3% of the slow-release portion.

[0026] In multilayer tablets, colorants are typically added to differentiate the materials in each layer. Similar colors can easily cause confusion and production failures. Multilayer tablet presses usually require multiple feeders, and several materials are simultaneously present on the press's rotary table, each layer having a different color. This allows for rapid identification of mixed materials during compression, preventing interlayer contamination. Therefore, the use of colorants is essential.

[0027] Lubricants reduce friction between granules or tablets and the die, allowing tablets to be easily ejected during compression and resulting in a smooth, glossy tablet appearance. Otherwise, problems such as die sticking, tablet defects, and in severe cases, compression cannot continue.

[0028] As a preferred embodiment of the present invention, the dosage of deuterated dextromethorphan or its pharmaceutically acceptable salt is 10-60 mg, preferably 15-50 mg, calculated as deuterated dextromethorphan; the dosage of bupropion or its pharmaceutically acceptable salt is 40-160 mg, preferably 50-150 mg, calculated as bupropion.

[0029] In one embodiment, the amount of deuterdextromethorphan or its pharmaceutically acceptable salt is 15%-35% of the pharmaceutical preparation based on deuterdextromethorphan; the amount of bupropion or its pharmaceutically acceptable salt is 30%-50% of the pharmaceutical preparation based on bupropion.

[0030] The mass ratio of deuterated dextromethorphan or its pharmaceutically acceptable salt to bupropion or its pharmaceutically acceptable salt is 1-10:1-10. As one embodiment, the amount of deuterated dextromethorphan or its pharmaceutically acceptable salt, calculated based on deuterated dextromethorphan or its salt, and the amount of bupropion or its pharmaceutically acceptable salt, calculated based on bupropion or its salt, are in a mass ratio of 1-10:1-10, preferably 1:1-10, including: 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4.75, 1:5, 1:5.25, and 1:1. 5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10, specifically, 15:62.5; 20:50; 30:125; 40:100; 45:100; 45:125; 45:150; 50:110, and 15mg:62.5mg; 20mg:50mg; 30mg:125mg; 40mg:100mg; 45mg:100mg; 45mg:125mg; 45mg:150mg; 50mg:110mg, etc.

[0031] In one embodiment, the dosage of deuterated dextromethorphan or its pharmaceutically acceptable salts, calculated as deuterated dextromethorphan, includes 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, and 50 mg; the dosage of bupropion or its pharmaceutically acceptable salts, calculated as bupropion, includes 50 mg, 62.5 mg, 75 mg, 87.5 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, and 150 mg, etc.

[0032] When the proportion of the active ingredients deuterdextromethorphan and bupropion in the drug composition is reduced, the total weight of the drug formulation can also be reduced accordingly, to a certain proportion or appropriately adjusted.

[0033] As a preferred embodiment of the present invention, the pharmaceutical salt of deuterated dextromethorphan is selected from... ; pharmaceutically acceptable salts of bupropion are selected from .

[0034] As a preferred embodiment of the present invention, the dosage of the pharmaceutical preparation is calculated based on the salt content of the compound.

[0035] The present invention further provides a coated pharmaceutical formulation, wherein the aforementioned pharmaceutical formulation is further coated with one or more coating agents.

[0036] As a preferred technical solution, a film coating premix (gastric-soluble Opadry 295F640024-CN) is used for coating, and the tablet core weight increases by about 1-3% after coating.

[0037] This invention further provides a method for preparing a pharmaceutical formulation, wherein the rapid-release portion and / or slow-release portion are independently selected from powder direct compression, dry or wet granulation followed by compression to obtain bilayer tablets, which are then further coated. The formulation method includes fluidized bed granulation.

[0038] The formulation equipment and pharmaceutical excipients or reagents described in this invention can all be obtained commercially.

[0039] The present invention further provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of neurological disorders.

[0040] Furthermore, the neurological disorders include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, and treatment-resistant bipolar depression.

[0041] More specifically, depression includes bipolar disorder, seasonal affective disorder, mania, anxiety disorder, attention deficit disorder, attention deficit hyperactivity disorder, attention deficit / hyperactivity disorder, bipolar and manic disorders, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychogenic sexual dysfunction, pseudobulbar mood, and mood instability.

[0042] The present invention further provides the use of the aforementioned pharmaceutical composition in the preparation of a medicine for the prevention and / or treatment of dementia, including but not limited to Alzheimer's disease (including AD agitation), Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0043] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms, including agitation. Agitation can occur in Alzheimer's disease and may manifest as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior can include, but is not limited to, incoherent rambling, inappropriate emotional reactions, attention demands, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, agitation, tearing, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive bodily movements, hoarding, stalking, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0044] The advantages of this invention over the prior art include:

[0045] (1) The pharmaceutical preparation provided by the present invention has a good dissolution effect and can meet the drug concentration required for once-daily administration.

[0046] (2) The pharmaceutical preparation provided by the present invention has good quality stability.

[0047] (3) The raw materials and excipients of the present invention have undergone extensive screening in order to achieve the aforementioned objectives. Among them, one or a combination of disintegrants, sustained-release materials, and stabilizers is particularly important for the overall implementation of the formulation of the present invention. Detailed Implementation

[0048] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0049] Unless otherwise stated, in the embodiments, deuterated dextromethorphan refers to Bupropion refers to Deuterated dextromethorphan hydrobromide monohydrate (as C 18 H 19 Based on the dosage of D6NO·HBr·H2O, bupropion is administered according to the dosage of bupropion hydrochloride (C). 13 H 18 The dosage of ClNO·HCl is measured. Formulations of different strengths can be prepared and tested according to the proportions (%) in the examples.

[0050] Example 1

[0051]

[0052] & Process: Add lactose, dextromethorphan hydrobromide, microcrystalline cellulose, povidone and yellow iron oxide into a mixing tank and mix evenly. Add an appropriate amount of water and granulate by wet method. Dry to obtain inner granules. Then add silicon dioxide, crosslinked povidone and magnesium stearate in sequence and mix to obtain granules A.

[0053] # Process: Add bupropion hydrochloride, microcrystalline cellulose, and hydroxypropyl methylcellulose to a mixer and mix evenly; dissolve cysteine ​​hydrochloride in part of purified water as the first granulation solution; add a certain amount of purified water as the second granulation solution, and perform fluidized bed spray granulation. Add silica (if any) and magnesium stearate and mix evenly to obtain granules B.

[0054] A double-layer tablet press was used to add particles A and B into different chambers to prepare double-layer tablets. The double-layer tablets were further coated with a film coating premix (gastric-soluble Opadry 295F640024-CN). After coating, the tablet core weight increased by about 2%.

[0055] Example 2

[0056]

[0057] & Process: Add lactose, dextromethorphan hydrobromide, microcrystalline cellulose, povidone, and yellow iron oxide to a mixing tank and mix evenly. Add an appropriate amount of water and granulate by wet method. Dry to obtain inner granules. Then add silicon dioxide, crosslinked povidone, and magnesium stearate in sequence and mix to obtain granules A.

[0058] # Process: Add bupropion hydrochloride, microcrystalline cellulose, and hydroxypropyl methylcellulose to a mixer and mix evenly; dissolve cysteine ​​hydrochloride in part of purified water as the first granulation solution; add a certain amount of purified water as the second granulation solution, and use fluidized bed spray granulation. Add silica and magnesium stearate and mix evenly to obtain granules B.

[0059] A double-layer tablet press was used to add particles A and B into different chambers to prepare double-layer tablets. The double-layer tablets were further coated with a film coating premix (gastric-soluble Opadry 295F640024-CN). After coating, the tablet core weight increased by about 2%.

[0060] Example 3

[0061]

[0062] & Process: Add lactose, dextromethorphan hydrobromide, microcrystalline cellulose, povidone, and yellow iron oxide to a mixing tank and mix evenly. Add an appropriate amount of water and granulate by wet method. Dry to obtain inner granules. Then add silicon dioxide, crosslinked povidone, and magnesium stearate in sequence and mix to obtain granules A.

[0063] #Process: Add bupropion hydrochloride, microcrystalline cellulose, and hydroxypropyl methylcellulose to a mixer and mix evenly; dissolve cysteine ​​hydrochloride in part of purified water as the first granulation solution; add a certain amount of purified water as the second granulation solution, and use fluidized bed spray granulation. Add silica and magnesium stearate and mix evenly to obtain granules B.

[0064] A double-layer tablet press was used to add particles A and B into different chambers to prepare double-layer tablets. The double-layer tablets were further coated with a film coating premix (gastric-soluble Opadry 295F640024-CN). After coating, the tablet core weight increased by about 2%.

[0065] Example 4

[0066] The dissolution and release rate were determined according to the method of determination of dissolution and release rate (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method I). 900 ml of hydrochloric acid solution (pH 1.5 medium) was used as the dissolution medium, and the rotation speed was 50 rpm. Samples were taken and measured after 0.5 h, 1 h, 2 h, and 6 h.

[0067]

[0068] As can be seen from the above test results, the pharmaceutical preparation provided by the present invention has a good dissolution effect and can meet the drug concentration required for once-daily administration.

[0069] Example 5 Stability Test

[0070] Each formulation was tested for one month at 40°C and 75% accelerated conditions to assess total impurities, dissolution rate, and content. The formulations exhibited good quality stability, as shown in the table below.

[0071]

[0072] Comparative Example 1

[0073] The formulation for screening the types and dosages of deuterated dextromethorphan layer disintegrants (wherein, the bupropion layer and the preparation process of both layers are the same as in Example 1).

[0074]

[0075] The dissolution results (aqueous medium) of the bilayer tablets for the aforementioned screening of deuterated dextromethorphan layer disintegrant types and dosages are as follows:

[0076]

[0077] As shown in the table above, when croscarmellose sodium is used as a disintegrant, the dissolution rate of deuterated dextromethorphan in bilayer tablets is relatively low at 30 min when the dosage is 5% to 15%. However, when croscarmellose is used as a disintegrant, the dissolution rate of deuterated dextromethorphan in bilayer tablets is significantly increased when the dosage is 5% to 15%.

[0078] Therefore, the type and amount of disintegrant for comparative formulation 1.2 were selected, namely, the type of disintegrant was determined to be crospovidone, and more preferably, the amount was 10% of the weight of the deuterated dextromethorphan layer.

[0079] Comparative Example 2

[0080]

[0081] Dissolution test results after storage

[0082]

[0083] In the sustained-release portion, when the amount of cysteine ​​hydrochloride is 1 / 3 of that of the sustained-release material hydroxypropyl methylcellulose (Formula 2.2), the sustained-release material will be hydrolyzed, and the dissolution rate will exceed the limit after 1 hour.

[0084] Pharmacokinetics of the compound in beagle dogs compared with Example 3

[0085] 1. Experimental Materials

[0086] Beagle: Male, 7-10kg, Beijing Mars Biotechnology Co., Ltd.

[0087] Test substances: Deuterated dextromethorphan hydrobromide / bupropion = 45mg / 150mg compound tablets, deuterated dextromethorphan hydrobromide tablets, and bupropion hydrochloride tablets were prepared according to the formulation of Example 2, and tablets containing single active ingredients were prepared respectively according to the compound formulation.

[0088] Reagents: Methanol, formic acid, and propranolol (internal standard) are all commercially available.

[0089] Instrument: AB SCIEX TripleQuad5500+ triple quadrupole mass spectrometer.

[0090] 2. Experimental Methods

[0091] Five beagle dogs were used in a crossover drug administration experiment. The dogs were numbered. In the first cycle, the first three dogs received the compound tablet, and the last two dogs received dextromethorphan hydrobromide + bupropion hydrochloride tablets. After a 7-day washout period, the second cycle began. In the second cycle, the first three dogs received dextromethorphan hydrobromide + bupropion hydrochloride tablets, and the last two dogs received the compound tablet. After each cycle, approximately 0.5 mL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h in anticoagulant tubes containing EDTA-K2. The samples were centrifuged at 2000g for 10 min at 2–8°C, and the plasma was stored at -80°C for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. The stock solutions of dextromethorphan (deDM) and bupropion (BUP) were accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard series solutions, add 90 μL of blank plasma, vortex to mix, and prepare plasma samples with concentrations equivalent to 1–300 ng / mL. Perform dual-sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma, add 200 μL of acetonitrile solution containing internal standard, vortex to mix, add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and use the supernatant for LC-MS / MS detection of deDM and BUP.

[0092] 3. Data Processing

[0093] After detecting blood drug concentrations by LC-MS, pharmacokinetic parameters were calculated using WinNonlin software and a non-compartmental model method.

[0094] 4. Experimental Results

[0095] The absorption of the self-developed compound tablet (deDM content 45mg, BUP content 150mg) in five beagle dogs was investigated. The results are shown in Table 1.

[0096] Table 1. Comparison of compound tablets, dextromethorphan hydrobromide tablets and bupropion hydrochloride tablets in beagle dogs.

[0097]

[0098] The results showed that the AUC of deDM and BUP in plasma of beagle dogs after administration of the compound tablets was significantly reduced. last and C max All were higher than the equivalent doses of dextromethorphan hydrobromide tablets and bupropion hydrochloride tablets.

[0099] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation contains: deuterated dextromethorphan or its pharmaceutically acceptable salt, bupropion or its pharmaceutically acceptable salt, and one or more pharmaceutical excipients: The drug formulation is a bilayer tablet, wherein deuterdextromethorphan is the fast-release fraction and bupropion is the slow-release fraction; The rapid-release portion contains one or more disintegrants selected from crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; the slow-release portion contains one or more sustained-release materials selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and carbomer; preferably, the amount of the disintegrant is 2%-15% of the rapid-release portion; and the amount of the sustained-release material is 10%-50% of the slow-release portion.

2. The pharmaceutical preparation according to claim 1, characterized in that, The slow-release portion contains one or more of the following: cysteine ​​hydrochloride, glycine hydrochloride, sodium metabisulfite, citric acid, and tartaric acid, in an amount that is 1 / 5 to 1 / 10 of the sustained-release material.

3. The pharmaceutical preparation according to claim 2, characterized in that, The slow-release portion contains cysteine ​​hydrochloride.

4. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, The rapid release portion and / or slow release portion contain a certain amount of a flow aid, which is selected from silica and talc; preferably, the flow aid is 0.05%-3% of the rapid release portion and 0.00%-2% of the slow release portion.

5. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, The rapid-release portion and / or the slow-release portion contain a certain amount of filler, said filler being selected from one or more of lactose, microcrystalline cellulose, mannitol, dicalcium phosphate, pregelatinized starch, etc. Preferably, the filler comprises 50%-90% of the fast-release portion and 15%-60% of the slow-release portion.

6. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, The fast-release portion and / or the slow-release portion contain a certain amount of binder, which is selected from povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, etc., and the amount used is 0.5%-8% of the fast-release portion.

7. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, The fast-release portion and / or slow-release portion further contain one or both of a colorant and a lubricant.

8. The pharmaceutical preparation according to claim 7, characterized in that, The colorant is selected from yellow iron oxide, red iron oxide, etc., and the lubricant is selected from magnesium stearate, stearic acid, sodium stearate, behenic acid glyceride, etc.

9. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, The pharmaceutical preparation is further coated with one or more coating agents.

10. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, The mass ratio of deuterated dextromethorphan or its pharmaceutically acceptable salt to bupropion or its pharmaceutically acceptable salt is 1-10:1-10.

11. The pharmaceutical preparation according to any one of claims 1-3, characterized in that, Deuterated dextromethorphan medicinal salts are selected from ; pharmaceutically acceptable salts of bupropion are selected from .

12. A method for preparing a pharmaceutical formulation according to any one of claims 1-11, characterized in that, The rapid release portion and / or slow release portion are independently selected from powder direct pressing process, dry or wet granulation, followed by pressing to obtain a double-layer tablet, which is then further coated.

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