Solid oral quick-release preparation containing edaravone and dextroborneol

Abstract

The invention discloses solid particles of edaravone and dextroborneol prepared by a wet granulation process and a solid oral quick-release preparation prepared from the solid particles. The solid particles comprise edaravone, dextroborneol, polyethylene glycol and other pharmaceutic adjuvants. According to the present invention, the dextroborneol and the polyethylene glycol are co-dissolved in the absolute ethyl alcohol, and the wet granulation is performed with the edaravone and the pharmaceutical excipients, such that the process feasibility is significantly improved, and the particles with different particle sizes can be prepared according to the absolute ethyl alcohol use amount so as to prepare the oral quick-release tablets with different dosage forms, the dissolving-out speed of the prepared solid particle dextroborneol is obviously improved, and the stability of edaravone is also improved at the same time.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulations, specifically relating to a stable, rapidly releasing solid oral immediate-release formulation containing edaravone and dextroborneol based on a wet granulation process. Background Technology

[0002] Edaravone is a marketed neuroprotective agent. Its chemical name is 3-methyl-1-phenyl-2-pyrazoline-5-one, and its structural formula is as follows: .

[0003] Studies have shown that edaravone has antioxidant activity, which can significantly improve neurological deficit symptoms in animals with cerebral ischemia-reperfusion injury, reduce infarct area, reduce the degree of brain damage, alleviate cerebral edema, and inhibit lipid peroxidation in damaged brain tissue.

[0004] The core structure of edaravone is a pyrazolinone ring (3-methyl-1-phenyl-2-pyrazolin-5-one), containing an enol tautomer, which may contain unsaturated double bonds or free radical reaction sites. These reactive groups readily participate in free radical chain reactions, initiating intermolecular or intramolecular polymerization. At high concentrations or under specific conditions, they themselves may become initiation sites for free radical reactions, leading to chain growth. Increased polymerization temperature accelerates molecular thermal motion, increases the probability of collisions with reactive groups, and promotes free radical generation and chain initiation. After 15 days at high temperature, impurity III increased from <0.05% to 0.5%. The main impurities are as follows:

[0005]

[0006] Dextroborneol is the main component of borneol, a commonly used traditional Chinese medicine. Its chemical name is (+)-2-borneol, and its structural formula is as follows: .

[0007] Borneol possesses the effects of "reviving the mind and opening the orifices," "aromatic dispersion," and "guiding the medicine upwards," and is often used as a "guide drug" to enhance the therapeutic effects of other drugs. The *Compendium of Materia Medica* states that borneol "is weak when used alone, but becomes effective when used as an adjuvant." Animal and in vitro experiments have shown that borneol promotes the crossing of drugs across the blood-brain barrier.

[0008] Cerebrovascular diseases, especially ischemic cerebrovascular diseases, are acute illnesses requiring rapid relief; therefore, injection is the preferred method for emergency treatment. Chinese patent document CN101848711A, entitled "A Pharmaceutical Composition and Its Application in the Preparation of Drugs for Treating Cerebrovascular Diseases," discloses the application of a specific ratio of edaravone and (+)-2-borneol injection in the preparation of drugs for treating cerebrovascular diseases, particularly ischemic cerebrovascular diseases. This composition shows better efficacy compared to edaravone injection alone. However, intramuscular or intravenous injection can cause pain and irritation at the injection site, and requires administration by qualified medical personnel, thus limiting its application and making it unsuitable for patients who develop the disease outside of a hospital.

[0009] Sublingual formulations are absorbed directly through the sublingual mucosa. The sublingual mucosa has a large surface area and strong permeability, and numerous capillaries converge there, leading to the internal jugular vein and then directly into the bloodstream via the superior vena cava. This results in rapid drug absorption, fast onset of action, accurate dosing, and convenient use, avoiding the first-pass effect of oral medications. Compared to injections, sublingual tablets significantly improve the convenience of medication administration and patient compliance. Chinese patent document CN 109906077 B, entitled "Sublingual Pharmaceutical Composition of Edaravone and (+)-2-Brunol," discloses a sublingual tablet containing edaravone and dextroborneol. In the preparation process, dextroborneol is dissolved in an organic solution, and the excipient is dissolved in an aqueous solution. The two are combined, stirred, and allowed to stand, then freeze-dried, and finally compressed with edaravone using a direct compression process. This process is energy-intensive and has low production capacity. Furthermore, because dextroborneol is easily sublimated, the freeze-drying process results in significant dextroborneol loss.

[0010] Chinese patent document CN 110693882 A, entitled "A Sublingual Pharmaceutical Composition," discloses a method for preparing sublingual tablets. Dextroborneol is a needle-like crystal, difficult to pulverize, and has poor water solubility. This process uses conventional excipients and a direct compression tableting process, which results in uneven mixing of dextroborneol and poor dissolution.

[0011] Under current technology, it is impossible to obtain ideal sublingual tablets of edaravone and (+)-2-borneol using common excipients and preparation methods. Therefore, developing formulations and processes for energy-saving, high-capacity, and rapid-release oral immediate-release formulations remains an urgent problem to be solved. Summary of the Invention

[0012] This invention addresses the shortcomings of existing technologies by adding polyethylene glycol to the formulation, which not only improves the stability of edaravone but also enhances the solubility of dexborneol. Furthermore, the sublimation problem of dexborneol during production is solved by employing anhydrous ethanol wet granulation and controlling the drying temperature during one-step granulation. This results in solid granules containing edaravone and dexborneol, which can be further combined with different functional excipients to prepare various solid oral dosage forms to meet the needs of different patients and improve patient compliance.

[0013] The specific technical solution of this invention is as follows:

[0014] A solid granule containing edaravone and dexborneol, comprising edaravone, dexborneol, polyethylene glycol, and other pharmaceutical excipients, wherein the weight parts of each component are as follows: edaravone 10-100 parts, dexborneol 1-10 parts, polyethylene glycol 0.1-30 parts, and other pharmaceutical excipients 20-360 parts, wherein the other pharmaceutical excipients are selected from one or more of fillers, disintegrants, and lubricants, and are prepared by the following method:

[0015] (1) Dissolve polyethylene glycol in anhydrous ethanol and then add dexborneol to dissolve it to prepare a drug-containing adhesive solution;

[0016] (2) Edaravone and pharmaceutical excipients are mixed and added to a wet mixing granulator. After premixing, a drug-containing binder solution is added to form a soft mass. The granulated soft mass is added to a fluidized bed and dried at 20~40℃. The dried granules are then granulated to obtain solid granules containing edaravone and dextromethorphan.

[0017] The solid particles of the present invention preferably contain polyethylene glycol with a molecular weight of 500-4000 Da, more preferably 3350 Da.

[0018] Preferably, in step (1), the ratio of polyethylene glycol to anhydrous ethanol is 0.1~30g: 20~500ml.

[0019] In a preferred embodiment, the solid particles of the present invention comprise 10-100 parts edaravone, 1-10 parts dexborneol, 0.1-30 parts polyethylene glycol, 5-100 parts filler, 2-50 parts disintegrant, 0.1-2 parts lubricant, and 20-500 parts anhydrous ethanol. More preferably, the solid particles comprise 20-70 parts edaravone, 3-8 parts dexborneol, 0.3-20 parts polyethylene glycol, 10-50 parts filler, 3-25 parts disintegrant, 0.1-1 part lubricant, and 30-200 parts anhydrous ethanol.

[0020] The present invention also aims to provide a solid oral immediate-release formulation containing edaravone and dextroborneol, which is prepared from the solid particles described in the present invention.

[0021] The solid oral immediate-release formulation is a tablet, granule, or capsule. Preferably, the tablet is selected from sublingual tablets, dispersible tablets, or orally disintegrating tablets.

[0022] The solid oral immediate-release formulation includes the solid particles described in this invention, as well as one or more of fillers, binders, disintegrants, and lubricants.

[0023] The filler of this invention is selected from one or more of mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, sorbitol, and corn starch; the binder is selected from one or more of hydroxypropyl methylcellulose, povidone K30, copovidone, hydroxypropyl cellulose, and polyethylene glycol; the disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; and the lubricant is selected from one or more of talc, silica, magnesium stearate, and sodium stearate fumarate.

[0024] The advantages and positive effects of this invention are as follows:

[0025] Through extensive exploratory experiments, this invention unexpectedly discovered that polyethylene glycol can improve the stability of edaravone and the solubility of dextromethorphan. The related substances content was optimized from approximately 0.4% in the previously disclosed technology to less than 0.05%, and the solubility improved from less than 80% dissolution within 15 minutes to complete dissolution. This ensures the safety and effectiveness of the product.

[0026] This invention selects anhydrous ethanol as the solvent for wet granulation, and by controlling the material temperature during fluidized drying, it avoids the sublimation of dextromethorphan and ensures that the ethanol residue is within the acceptable range, resulting in high production efficiency and suitability for large-scale production. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] Comparative Example 1: Preparation of Edaravone Dexborneol Tablets by Direct Compression Method

[0029] The preparation was carried out according to the method described in Example 4 of CN 110693882 A.

[0030] 1. Prescription

[0031]

[0032] 2. Process

[0033] Mixing: Add dextroborneol, edaravone, β-cyclodextrin, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate to an HTD50 mixer manufactured by Shandong Xinma Pharmaceutical Equipment Co., Ltd., and mix at 15 rpm for 10 minutes to obtain the final mixture.

[0034] Tableting: Tableting was performed using an S60 rotary tablet press from Shandong Xinma Pharmaceutical Equipment Co., Ltd.

[0035] 3. Examine the overall mixing uniformity, dissolution rate, and stability of related substances under high temperature conditions of the tablet mixture.

[0036] 4. Results

[0037] The results are shown in Table 1.

[0038] Table 1 Summary of Results

[0039]

[0040] Comparative Example 1 High Temperature Stability Data

[0041]

[0042] The results above show that, using the existing direct compression process, the mixing uniformity of dexborneol is poor, resulting in large differences in tablet weight, low hardness, poor compressibility, and poor stability of edaravone. Furthermore, there is a significant difference in the dissolution rates of edaravone and dexborneol, which affects the synergistic effect of the drugs.

[0043] Examples 1-9: Preparation of Edaravone Dexborneol Tablets by Wet Granulation

[0044] Due to the numerous problems with existing technologies and processes, this embodiment disperses dextroborneol in different solvents for wet granulation to improve the problem of poor mixing uniformity, and examines its effect on the dissolution of the two drugs.

[0045] 1. Prescription

[0046] Prescription composition (mg)

[0047]

[0048] Dispersing solvent

[0049]

[0050] 2. Process

[0051] Edaravone, mannitol, microcrystalline cellulose, and croscarmellose sodium were added to a wet granulator and premixed for 3 minutes. Then, dextromethorphan alcohol dispersions in different solvents were added to prepare a soft mass. After granulation, the soft mass was dried in a fluidized bed at an inlet air temperature of 30°C for 20 minutes. The dried granules were then granulated to obtain dry granules.

[0052] Dry granules, silica, and magnesium stearate were added to an HTD50 mixer from Shandong Xinma Pharmaceutical Equipment Co., Ltd., and mixed at 15 rpm for 10 minutes to obtain the final mixture.

[0053] Tableting: Tableting was performed using an S60 rotary tablet press from Shandong Xinma Pharmaceutical Equipment Co., Ltd.

[0054] 3. Results

[0055]

[0056] Results of high-temperature stability tests in Examples 1-9

[0057]

[0058] 4. Conclusion

[0059] The results above show that using different solvents for wet granulation can solve the problems of unstable tablet weight, unqualified mixing of dexborneol, and large differences in tablet weight. However, problems such as low hardness, poor compressibility, large differences in dissolution rates between edaravone and dexborneol, and poor stability of edaravone still exist. A comprehensive comparison of the performance of different solvents in terms of tablet hardness, dissolution rate, and stability shows that using anhydrous ethanol as the solvent resulted in the greatest improvement in dexborneol dissolution and the slowest impurity growth rate.

[0060] Examples 10-16 Adhesive Screening

[0061] Based on wet granulation using anhydrous ethanol as the solvent for dexborneol, the effects of different binders on tablet compressibility, dissolution and stability were further investigated.

[0062] 1. Prescription

[0063] Prescription composition (mg)

[0064]

[0065] 2. Process

[0066] Edaravone, mannitol, microcrystalline cellulose, and different binders were added to a wet granulator and premixed for 3 minutes. Then, an anhydrous ethanol solution of dextromethorphan was added to prepare a soft mass. After granulation, the soft mass was dried in a fluidized bed at an inlet air temperature of 30°C for 20 minutes. The dried granules were then granulated to obtain dry granules.

[0067] The dry granules, silica, and magnesium stearate were added to an HTD50 mixer from Shandong Xinma Pharmaceutical Equipment Co., Ltd., and mixed at 15 rpm for 10 minutes to obtain the final mixture.

[0068] Tableting: Tableting was performed using an S60 rotary tablet press from Shandong Xinma Pharmaceutical Equipment Co., Ltd.

[0069] 3. Results

[0070]

[0071] Results of high-temperature stability tests in Examples 10-16

[0072]

[0073] 4. Conclusion

[0074] This embodiment addressed the issue of poor compressibility by screening adhesives. Unexpectedly, it was discovered that samples prepared using polyethylene glycol 3350 and polyethylene glycol 600 showed significantly improved stability. However, the addition of the adhesive slowed tablet disintegration, and the dissolution of dexborneol remained slower than that of edaravone, which was detrimental to the synergistic effect of the drugs.

[0075] Examples 17-23: Screening of Disintegrants

[0076] Based on the use of polyethylene glycol 3350 or polyethylene glycol 600 as binders, the use of disintegrants was further increased to investigate the effects of different disintegrants on drug dissolution and stability, in order to screen for disintegrants that are compatible with the binder to improve the drug dissolution rate.

[0077] 1. Prescription

[0078] Prescription composition (mg)

[0079]

[0080] 2. Process

[0081] Edaravone, mannitol, microcrystalline cellulose, and disintegrant were added to a wet granulator and premixed for 3 minutes. An anhydrous ethanol solution containing dextromethorphan and binder was then added to prepare a soft mass. After granulation, the soft mass was dried in a fluidized bed at an inlet air temperature of 30°C for 20 minutes. The dried granules were then granulated to obtain dry granules.

[0082] Dry granules, silica, and magnesium stearate were added to an HTD50 mixer from Shandong Xinma Pharmaceutical Equipment Co., Ltd., and mixed at 15 rpm for 10 minutes to obtain the final mixture.

[0083] Tableting: Tableting was performed using an S60 rotary tablet press from Shandong Xinma Pharmaceutical Equipment Co., Ltd.

[0084] 3. Results

[0085]

[0086] Results of high-temperature stability tests in Examples 17-23

[0087]

[0088] 4. Conclusion

[0089] Using polyethylene glycol 3350 or 600 as a binder and crospovidone as a disintegrant, the dissolution rates of edaravone and dexborneol were adjusted to be more consistent. Edaravone and dexborneol exhibited similar dissolution rates at 5, 10, and 15 minutes, and were essentially completely dissolved by 15 minutes, ensuring a simultaneous and rapid onset of action for the drug combination. Furthermore, edaravone in this formulation also exhibited good stability.

[0090] Examples 24-28: Process Research

[0091] The effects of temperature and time during granulation on ethanol residue and dextromethorphan content were investigated.

[0092] 1. Prescription

[0093] Prescription composition (mg)

[0094]

[0095] 2. Process

[0096] Edaravone, mannitol, microcrystalline cellulose, and disintegrant were added to a wet granulator and premixed for 3 minutes. Then, an anhydrous ethanol solution containing dextromethorphan and polyethylene glycol 3350 was added to prepare a soft mass. After granulation, the soft mass was dried in a fluidized bed. The dried granules were then granulated to obtain dry granules.

[0097] Dry granules, silica, and magnesium stearate were added to an HTD50 mixer from Shandong Xinma Pharmaceutical Equipment Co., Ltd., and mixed at 15 rpm for 10 minutes to obtain the final mixture.

[0098] Tableting: Tableting was performed using an S60 rotary tablet press from Shandong Xinma Pharmaceutical Equipment Co., Ltd.

[0099] 3. Results

[0100]

[0101] 4. Conclusion

[0102] By controlling the temperature at 20~40℃ through one-step granulation, the sublimation of dextroborneol can be avoided, ensuring that the content is qualified and that solvent residue meets the regulations.

[0103] Analytical methods

[0104] 1. Content uniformity determination

[0105] Samples were taken from 11 different locations on the mixer, and the content was measured to calculate the RSD. The content detection method is as follows:

[0106] (1) Uniformity of edaravone content

[0107] Chromatographic conditions:

[0108] Test method: ChP2020 General Rules 0512 High Performance Liquid Chromatography.

[0109] Column: Octadecylsilane-bonded silica gel as the packing material (Agilent Eclipse XDB C184.6×150mm, 3.5μm is recommended);

[0110] Mobile phase: 1% glacial acetic acid (adjusted to pH 6.0 with ammonia) - methanol (75:25);

[0111] Detection wavelength: 240nm, acquisition frequency: 2 points / sec;

[0112] Column temperature: 30℃;

[0113] Flow rate: 1.0 ml / min;

[0114] Injection volume: 20 μl;

[0115] Running time: 15 minutes.

[0116] Solution preparation:

[0117] Diluent: Methanol-0.01% phosphoric acid solution (20:80).

[0118] Reference solution: Accurately weigh approximately 20 mg of edaravone reference standard, place it in a 100 ml volumetric flask, dissolve and dilute to the mark with anhydrous ethanol, and shake well; accurately measure 3 ml, place it in a 20 ml volumetric flask, dilute to the mark with diluent, and shake well. Prepare two parallel solutions.

[0119] Stock solution for test sample: Accurately weigh one tablet of this product and place it in a 100ml volumetric flask. Add 70ml of anhydrous ethanol and sonicate for 10min to disperse and dissolve. Cool and dilute to the mark with anhydrous ethanol. Shake well and filter through a 0.45μm PVDF membrane. Discard 1ml of the initial filtrate and collect the subsequent filtrate. Prepare 5 parallel solutions.

[0120] Test solution: Accurately measure 2 ml of the filtrate, place it in a 20 ml volumetric flask, dilute to the mark with diluent, and shake well to obtain the test solution.

[0121] Determination method:

[0122] After the system is balanced, inject the sample according to the requirements in the table below (inject one injection of the accompanying control solution every 4 to 6 hours), record the chromatogram, and calculate the content of the main component of this product using the external standard method.

[0123]

[0124] System applicability requirements:

[0125] For reference solution 1, five consecutive injections should be performed, and the RSD of the main peak area should not exceed 2.0%; the theoretical plate number, calculated based on the edaravone peak, should not be less than 2000; the recovery rate of reference solution 2 should be between 98.0% and 102.0%.

[0126] Calculation formula

[0127] ① Formula for calculating the recovery rate of reference solution 2:

[0128]

[0129] In the formula:

[0130] m 对1 The sample weight of edaravone reference standard in reference solution 1, in mg;

[0131] m 对2 The sample weight of edaravone reference standard in reference solution 2, in mg;

[0132] A 对1 The average peak area of ​​the main peak in reference solution 1 (5 consecutive injections);

[0133] A 对2 : The average peak area of ​​the main peak in reference solution 2 (two consecutive injections).

[0134] ② Formula for calculating principal component content:

[0135]

[0136] In the formula:

[0137] A i : Peak area of ​​the main peak in the test solution;

[0138] A r The average peak area of ​​the main peak in reference solution 1 (5 consecutive injections);

[0139] m rThe sample weight of edaravone reference standard in reference solution 1 is [amount in mg].

[0140] Br: Content of edaravone reference standard;

[0141] Edaravone dosage: 30mg / tablet.

[0142] (2) Uniformity of dextroborneol content

[0143] Chromatographic conditions:

[0144] Test method: Gas chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0521).

[0145] Chromatographic column: Capillary column with β-cyclodextrin as stationary phase (Cyclosil-β, 30m×0.25mm×0.25μm or equivalent column);

[0146] Heating program: Initial temperature 100℃, maintain for 3 minutes, increase to 150℃ at 30℃ per minute, maintain for 10 minutes, then increase to 210℃ at 30℃ per minute, maintain for 10 minutes;

[0147] Carrier gas: nitrogen; Flow rate: 1.0 ml / min;

[0148] Inlet temperature: 270℃;

[0149] Flame ionization detector (FID), detector temperature: 300℃;

[0150] Injection volume: 1 μl; split ratio: 8:1.

[0151] Solution preparation:

[0152] Diluent: Anhydrous ethanol.

[0153] Internal standard solution: Weigh approximately 200 mg of methyl salicylate reference standard accurately, place it in a 100 ml volumetric flask, add anhydrous ethanol, sonicate to dissolve and dilute to the mark, shake well, and the solution is ready.

[0154] Dextromethorphanol reference standard stock solution: Accurately weigh approximately 24 mg of dextromethorphanol reference standard, place it in a 100 ml volumetric flask, add anhydrous ethanol, sonicate to dissolve and dilute to the mark, shake well, and the solution is ready. Prepare two parallel solutions.

[0155] Reference solution: Accurately measure 5 ml of dextromethorphan reference stock solution and 1 ml of internal standard solution, place them in the same 20 ml volumetric flask, dilute to the mark with anhydrous ethanol, and shake well to obtain the solution.

[0156] Test solution: Accurately weigh one tablet of this product and place it in a 100ml volumetric flask. Add 70ml of anhydrous ethanol and sonicate for 10min to disperse and dissolve. Cool, accurately add 5ml of internal standard solution, dilute to the mark with anhydrous ethanol, shake well, filter through a 0.45μm PVDF membrane, discard 1ml of the initial filtrate, and collect the subsequent filtrate. Prepare 5 parallel solutions.

[0157] Determination method:

[0158] After the system is balanced, inject the diluent 2-3 times, reference solution 1 5 times, reference solution 2 2 times, and test solution 2 times. Inject one dose of the accompanying reference solution every 4-6 hours. When the test solution injection is finished, inject one dose of the accompanying reference solution. Record the chromatogram and calculate the dextromethorphan content of the product using the external standard method.

[0159]

[0160] System applicability requirements:

[0161] Methyl salicylate and dextroborneol eluted sequentially. The average correction factor was calculated, and the relative standard deviation of the obtained correction factor should not exceed 5.0%. The theoretical plate number calculated based on the dextroborneol peak should not be less than 10,000, and the resolution between the dextroborneol peak and the methyl salicylate peak should not be less than 2.0.

[0162] Precautions:

[0163] (1) The test solution and reference solution prepared for sample testing should be sealed and stored in a refrigerator at 2~8℃ before the sample testing is completed.

[0164] (2) It is recommended to maintain the injection port before each test: bake the injection port at 300℃ for 1 hour, and replace the liner, septum and split plate if necessary.

[0165] Calculation formula

[0166] ① Formula for calculating the correction factor:

[0167]

[0168] In the formula:

[0169] M s : Sample weight of internal standard methyl salicylate, mg;

[0170] M r : Sample weight of dextromethorphan reference standard, mg;

[0171] A s Peak area of ​​methyl salicylate in the reference solution;

[0172] A rPeak area of ​​dextromethorphan in the reference solution;

[0173] B s The content of the internal standard methyl salicylate;

[0174] B r Content of dextromethorphanol reference standard.

[0175] ② Formula for calculating the content of dextromethorphan in the test sample:

[0176]

[0177] In the formula, A x : Peak area of ​​dextromethorphan in the test solution;

[0178] A' s : Peak area of ​​methyl salicylate in the test solution;

[0179] M s : Sample weight of internal standard methyl salicylate, g;

[0180] B s The content of the internal standard methyl salicylate;

[0181] f 平均 The average value of the correction factor for five consecutive injections of reference solution 1;

[0182] Dextromethorphan labeled as: 6 mg / tablet.

[0183] 2. Dissolution test

[0184] The dissolution and release rate were determined according to the method of determination of dissolution and release rate (ChP2025 General Chapter 4 0931 Method 2).

[0185] Dissolution conditions: 500 ml of phosphate buffer (pH 6.8) was used as the dissolution medium, the temperature was 25°C, the rotation speed was 50 rpm, and the procedure was followed. 5 ml samples were taken at 5 min, 10 min, and 15 min.

[0186] Test solution: Take the dissolution, filter it, and take the filtrate to obtain the solution.

[0187] Edaravone reference solution: Weigh approximately 20 mg of edaravone reference standard accurately, place it in a 100 ml volumetric flask, dissolve and dilute to the mark with anhydrous ethanol, and shake well; accurately measure 5 ml, place it in a 25 ml volumetric flask, dilute to the mark with diluent, and shake well to obtain the solution.

[0188] Dextromethorphan reference solution: Weigh approximately 24 mg of dextromethorphan reference standard accurately, place it in a 100 ml volumetric flask, add anhydrous ethanol, sonicate to dissolve and dilute to the mark, shake well, accurately measure 5 ml of the solution and 1 ml of the internal standard solution, place them in the same 20 ml volumetric flask, dilute to the mark with anhydrous ethanol, shake well, and the solution is ready.

[0189] Refer to the content determination method of edaravone and dextroborneol in the content uniformity determination: (1) Inject the test solution and the reference solution into the liquid chromatograph, record the chromatogram, and calculate the dissolution amount of edaravone per tablet by peak area according to the external standard method. (2) Inject the test solution and the reference solution into the gas chromatograph, record the chromatogram, and calculate the dextroborneol content per tablet by peak area according to the external standard method.

[0190] 3. Stability determination

[0191] Stability test conditions

[0192]

[0193] Related substances method for detection chromatographic conditions

[0194] Test method: ChP2020 General Rules 0512 High Performance Liquid Chromatography.

[0195] Column: Octadecylsilane-bonded silica gel as packing material (Agilent Eclipse plus C18 4.6mm×150mm, 3.5μm);

[0196] Capture column: Yuexu, 4.6mm×50mm;

[0197] Mobile phase A: 1% glacial acetic acid (adjusted to pH 6.0 with ammonia);

[0198] Mobile phase B: Methanol;

[0199] Detection wavelength: 245nm, acquisition frequency: 2 points / sec;

[0200] Column temperature: 30℃;

[0201] Flow rate: 1.0 ml / min;

[0202] Injection volume: 50 μl;

[0203] Gradient procedure:

[0204]

[0205] Solution preparation:

[0206] Diluent: Methanol-0.01% phosphoric acid solution (30:70).

[0207] Impurity I stock solution: Weigh about 3 mg of impurity I reference standard and place it in a 100 ml volumetric flask. First, add 5 ml of phosphoric acid to dissolve it, then dilute it to the mark with methanol and shake well. Accurately measure 2 ml of the solution and place it in a 20 ml volumetric flask. Dilute it to the mark with diluent and shake well to obtain the solution.

[0208] Impurity III stock solution: Weigh about 2 mg of impurity III reference standard and place it in the same 50 ml volumetric flask. Dissolve and dilute to the mark with methanol and shake well. Accurately measure 3 ml of the solution and place it in a 20 ml volumetric flask. Dilute to the mark with diluent and shake well.

[0209] System suitability solution: Accurately measure 2 ml of each of impurity I stock solution and impurity III stock solution, place them in a 20 ml volumetric flask containing approximately 6 mg of edaravone reference standard, add diluent to dissolve and dilute to the mark, and shake well to obtain the solution.

[0210] Test solution: Take 1 tablet of this product, place it in a 100ml volumetric flask, add 70ml of diluent, sonicate for 10 minutes, cool, dilute to the mark with diluent, shake well, filter through a 0.45μm PVDF filter membrane, discard the initial filtrate, and take the subsequent filtrate to obtain the test solution.

[0211] Control solution: Accurately measure 1 ml of the filtrate and place it in a 50 ml volumetric flask. Dilute to the mark with diluent and shake well. Accurately measure 1 ml of the filtrate and place it in a 20 ml volumetric flask. Dilute to the mark with diluent and shake well.

[0212] Sensitivity solution: Accurately measure 5 ml of the control solution, place it in a 10 ml volumetric flask, dilute to the mark with diluent, and shake well to obtain the solution.

[0213] Determination method:

[0214] After the system is balanced, inject the diluent 2-3 times and each of the other solutions 1 time, record the chromatogram, and calculate the relevant substances according to the self-comparison method with correction factors.

[0215]

[0216] System applicability requirements:

[0217] In the sensitivity solution chromatogram, the signal-to-noise ratio of the main peak should be greater than 10; in the system suitability solution chromatogram, impurities VI, VIII, and edaravone should elute in sequence, and the theoretical plate number, calculated based on edaravone, should not be less than 2000.

[0218] Calculation formula

[0219] Calculate the relevant substances using the self-comparison method with correction factors:

[0220]

[0221] In the formula:

[0222] A 杂 : Peak area of ​​impurities in the test solution;

[0223] A 对 : Area of ​​the main peak in the control solution;

[0224] f: Correction factor for each impurity.

[0225]

Claims

1. Solid particles comprising edaravone and dextromethorphan, characterized in that, The solid particles comprise edaravone, dextromethorphan, polyethylene glycol and other pharmaceutical excipients, and the weight parts of each component are as follows: 10-100 parts of edaravone, 1-10 parts of dextromethorphan, 0.1-30 parts of polyethylene glycol, and 20-360 parts of other pharmaceutical excipients, wherein the other pharmaceutical excipients are selected from one or more of fillers, disintegrants and lubricants, and the solid particles are prepared by the following method: (1) dissolving polyethylene glycol as a binder in anhydrous ethanol, and then adding dextromethorphan to prepare a binder solution containing drugs; (2) mixing edaravone with pharmaceutical excipients in a wet granulator, adding the binder solution containing drugs after premixing to prepare soft material, and then adding the granulated soft material into a fluidized bed for drying at 20-40°C, and finally drying and granulating the particles to obtain solid particles containing edaravone and dextromethorphan.

2. The solid particles of claim 1, wherein The molecular weight of the polyethylene glycol is 500-4000 Da.

3. The solid particles of claim 2, wherein The molecular weight of the polyethylene glycol is 3350 Da.

4. The solid particles of claim 1, wherein The ratio of polyethylene glycol to anhydrous ethanol in step (1) is 0.1-30 g: 20-500 ml.

5. The solid particles of claim 1, wherein The fillers are selected from one or more of mannitol, microcrystalline cellulose, lactose, calcium hydrogen phosphate, sorbitol and corn starch; the disintegrants are selected from one or more of sodium carboxymethyl starch, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, carboxymethyl cellulose calcium and low-substituted hydroxypropyl cellulose; and the lubricants are selected from one or more of talc, silicon dioxide, magnesium stearate and sodium stearyl fumarate.

6. The solid particles of claim 5, wherein The solid particles comprise 10-100 parts of edaravone, 1-10 parts of dextromethorphan, 0.1-30 parts of polyethylene glycol, 5-100 parts of fillers, 2-50 parts of disintegrants, 0.1-2 parts of lubricants and 20-500 parts of anhydrous ethanol.

7. The solid particles of claim 6, wherein The solid particles comprise 20-70 parts of edaravone, 3-8 parts of dextromethorphan, 0.3-20 parts of polyethylene glycol, 10-50 parts of fillers, 3-25 parts of disintegrants, 0.1-1 parts of lubricants and 30-200 parts of anhydrous ethanol.

8. A solid oral immediate release formulation comprising edaravone and dextromethorphan, characterized in that The solid particles are prepared from the solid particles of any one of claims 1-7.

9. The solid oral immediate release formulation of claim 8, wherein The solid oral immediate-release preparation is a tablet, granules or a capsule.

10. The solid oral immediate release formulation according to claim 9, wherein The tablet is a sublingual tablet, a dispersible tablet or an oral disintegrating tablet.

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