Edaravone dispersible tablet and preparation method thereof

Abstract

The invention provides an edaravone dispersible tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, and the preparation method comprises the following steps: taking 52.5% by weight of edaravone, 0.5-5% by weight of a disintegrating agent, 0.5-5% by weight of a flow aid, 0.5-5% by weight of a sweetening agent, 0.25-5% by weight of a lubricant and the balance of a lactose microcrystalline cellulose co-treatment substance, directly and uniformly mixing, and tabletting to obtain the edaravone dispersible tablet. The lactose and microcrystalline cellulose co-treatment material integrates the advantages of lactose and cellulose, the fluidity and compressibility of total mixed powder can be guaranteed, the tablet weight difference of the tabletting process is reduced, the feasibility of mass production is guaranteed, and the production efficiency and the qualification rate of the tabletting process are improved; compared with a traditional solid dispersion process, the method has the advantages that solvent treatment, fluidized bed granulation or high-temperature drying steps are not needed, and preparation production can be completed only through direct mixing and tabletting processes, so that the influence of a humid and hot environment on the API stability is fundamentally avoided, and the product is more stable.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an edaravone dispersible tablet and a preparation method thereof. Background Art

[0002] Edaravone is a multi-target neuroprotective agent with strong free radical scavenging ability. It can block the damage of neurons caused by oxidative stress by neutralizing reactive oxygen species such as hydroxyl radicals and superoxide anions. Clinically, it is mainly used to treat acute cerebral infarction, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and other diseases.

[0003] In the early stage, the edaravone preparations were mainly injection preparations (such as CN03156779.7). By adding water-soluble fillers (such as mannitol, lactose) and antioxidants (L-cysteine salt), freeze-dried powder injections were prepared, which solved the problem of poor stability of aqueous injections. However, the injection administration method has problems such as low patient compliance and high medical costs, and there is an urgent need to develop oral alternative dosage forms.

[0004] In the prior art, the development of edaravone oral solid preparations faces multiple challenges. For example, although the solid dispersion process disclosed in the patent CN116262107A improves the dissolution and bioavailability through fluidized bed granulation combined with solvent system treatment, its process is complex: the active ingredient needs to be co-dissolved with a polymer and a reducing agent in a methanol-water system, and then undergoes granulation, drying and tabletting processes, resulting in the risk of generating degradation products such as edaravone dimers due to the exposure of the API to a humid and hot environment. And because this process requires the use of organic solvents, fluidized bed granulation, etc., explosion-proof workshops and fluidized bed granulation-related equipment need to be equipped, and the early investment in workshop equipment is large. The complex process limits its potential for industrial application. Summary of the Invention

[0005] In view of the above problems, the present invention provides an edaravone dispersible tablet and a preparation method thereof, which improve the production efficiency, drug stability of edaravone and reduce the production cost by controlling the preparation process of edaravone and adding appropriate pharmaceutical excipients.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] An edaravone dispersible tablet, calculated by weight percentage, the raw materials for preparing the edaravone dispersible tablet include:

[0008] Edaravone 52.5%;

[0009] Excipients: disintegrant 0.5 - 5%, glidant 0.5 - 5%, sweetener 0.5 - 5%, lubricant 0.25 - 5% and the balance of lactose microcrystalline cellulose co-processed product.

[0010] Furthermore, the raw materials for preparing the edaravone dispersible tablets by weight percentage include:

[0011] Edaravone 52.5%;

[0012] Excipients: disintegrant 1.5 - 3.0%, glidant 2.0 - 3.0%, sweetener 2.0 - 3.0%, lubricant 2.0 - 3.0% and the balance of lactose microcrystalline cellulose co-processed product.

[0013] Furthermore, the disintegrant is at least one of sodium carboxymethylcellulose cross-linked, sodium carboxymethyl starch and polyvinylpyrrolidone cross-linked.

[0014] Furthermore, the lubricant is magnesium stearate and / or talc powder.

[0015] Furthermore, the glidant is silicon dioxide.

[0016] Furthermore, the sweetener is stevioside.

[0017] A preparation method of the above-mentioned edaravone dispersible tablets, which is to directly mix edaravone with excipients and then press tablets to obtain the edaravone dispersible tablets.

[0018] Furthermore, the preparation method is to take a filler, a disintegrant, a sweetener, a glidant, a part of the lubricant and edaravone, mix them for the first time, then granulate and mix, and then add the remaining lubricant and mix well. The obtained total mixed powder is directly pressed into tablets to obtain the edaravone dispersible tablets.

[0019] Furthermore, during the first mixing process, the amount of the lubricant added is 1 / 3 - 1 / 2 of the total amount of the lubricant used.

[0020] The beneficial effects of an edaravone dispersible tablet and its preparation method of the present invention are as follows:

[0021] The present invention proposes an innovative direct mixing process scheme. By selecting lactose microcrystalline cellulose co-processed product as the core filler, the lactose microcrystalline cellulose co-processed product combines the brittle deformation of monohydrate lactose and the plastic deformation characteristics of microcrystalline cellulose, ensuring the fluidity and compressibility of the total mixed powder, and significantly improving the production efficiency and qualification rate of the tablet pressing process;

[0022] Compared with the traditional solid dispersion process, the present invention does not require solvent treatment, fluidized bed granulation or high-temperature drying steps, and only needs direct mixing and tablet pressing processes to complete the preparation production, fundamentally avoiding the influence of the humid and hot environment on the stability of API and making the product more stable;

[0023] The lactose microcrystalline cellulose co-processed product used in the present invention combines the advantages of lactose and cellulose, can ensure the fluidity and compressibility of the total mixed powder, reduces the tablet weight variation in the tableting process, and ensures the feasibility of large-scale production. This process innovation not only reduces the equipment procurement and maintenance costs, but also improves the process stability by reducing the production links, providing a better solution for the large-scale production of edaravone oral preparations;

[0024] The present invention uses at least one of croscarmellose sodium, sodium carboxymethyl starch, and crospovidone as a disintegrant, which can accelerate the disintegration of the dispersible tablets through capillary action and ensure the dissolution behavior of the dispersible tablets prepared by the present invention;

[0025] The present invention does not require the pretreatment of the active substance, nor does it require the granulation process during production, which can effectively improve the production efficiency of the product. The equipment used is simple and does not require complex equipment, which can reduce the equipment operation loss cost and labor cost. Detailed implementation manners

[0026] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar promotions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0027] Example 1 An edaravone dispersible tablet and its preparation method

[0028] This example is an edaravone dispersible tablet and its preparation method, which are specifically as follows:

[0029] I. Prescription (for 100,000 tablets) of the edaravone dispersible tablet is as follows:

[0030] Table 1 List of prescriptions for edaravone dispersible tablets

[0031] Prescription Composition Prescription Ratio Prescription 1 Edaravone 52.5%(w / w) 5.25kg Lactose Microcrystalline Cellulose Coprocessate 37.5%(w / w) 37.5kg Croscarmellose Sodium 2.5%(w / w) 250g Silica 2.5%(w / w) 250g Stevioside 2.5%(w / w) 250g Magnesium Stearate 2.5%(w / w) 250g

[0032] Among them, the lactose microcrystalline cellulose co-processed product is purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.

[0033] II. Preparation method of the edaravone dispersible tablet

[0034] S1. Weighing of materials: Weigh the above-mentioned amounts of raw and auxiliary materials in sequence according to the principle of adding auxiliary materials first and then raw materials, namely lactose microcrystalline cellulose co-processed product, croscarmellose sodium, stevioside, silicon dioxide, magnesium stearate, and edaravone;

[0035] S2. Mixing: Place the lactose microcrystalline cellulose co-processed product (filler), croscarmellose sodium (disintegrant), stevioside (sweetener), silicon dioxide (glidant), 1 / 3 of magnesium stearate (lubricant), and edaravone into the mixing barrel in sequence and mix for 50 revolutions for the first time. The mixed material obtained is granulated by a rapid granulator. After granulation, the material is transferred into the mixing barrel and mixed for another 100 revolutions. After mixing, the remaining magnesium stearate (lubricant) is added and mixed for 50 revolutions to obtain the total mixed powder.

[0036] S3. Tabletting: Take the total mixed powder and use a Ф8mm shallow arc round punch to tablet, with the tablet weight control range of ±7.5% and the friability ≤1.0% to obtain the edaravone dispersible tablets.

[0037] Take the edaravone dispersible tablets prepared in this example and the commercially available edaravone dispersible tablets (i.e., the original research formulation H004A), place them under the conditions of temperature 40°C ± 2°C and relative humidity 75% ± 5% for 6 months respectively, and sample at the end of the 1st, 2nd, 3rd, and 6th months respectively to investigate the changes in their properties, dissolution, content, and related substances. The specific results are shown in the following table.

[0038] Table 2 Summary of comparison results of accelerated experiments

[0039]

[0040] It can be seen from Table 2 that the edaravone dispersible tablets prepared in this example are placed under the conditions of temperature 40°C ± 2°C and relative humidity 75% ± 5% for 6 months. There are no obvious changes in the sample properties, dissolution, content, and related substances. The product quality meets the regulations, and the product quality is significantly higher than that of the original research product.

[0041] In summary, it can be seen that the production process of the present invention is simple, the production efficiency is high, the edaravone dispersible tablets prepared have good stability, the dissolution is about 100%, which can ensure that the drug is completely dissolved within the specified time. At the same time, the present invention can effectively reduce the equipment cost, labor cost, and time cost in the production process.

[0042] Example 2 An edaravone dispersible tablet and its preparation method

[0043] In this example, croscarmellose sodium with different proportions is used to prepare edaravone dispersible tablets, with a batch of 1000 tablets and the proportion ranging from 1.5% to 3.0%. The specific details are as follows:

[0044] Table 3 Prescription list of croscarmellose sodium with different proportions

[0045]

[0046] Respectively use the above prescriptions to prepare the corresponding edaravone dispersible tablets according to the method of Example 1;

[0047] Detection and determination method: Take the above-mentioned Edaravone Dispersible Tablets, use hydrochloric acid solution with pH 1.0 as the dissolution medium, conduct dissolution tests at a temperature of 37 °C, a volume of 900 mL, and a rotation speed of 50 rpm. Samples are taken at 5, 10, 15, 20, 30, 45, and 60 minutes to detect the dissolution amount, and the content and dissolution curve of each Edaravone Dispersible Tablet are determined. The specific results are as follows:

[0048] Table 4 Summary of dissolution comparison results

[0049]

[0050]

[0051] It can be seen from Table 4 that when the dosage of the disintegrant cross-linked carboxymethylcellulose sodium is 1.5 - 3.0% (w / w), the tablet content is about 100%, and the dissolution curve can reach 100% dissolution, indicating that the dosage of the disintegrant can be 1.5 - 3.0% (w / w).

[0052] Example 3 An Edaravone Dispersible Tablet and Its Preparation Method

[0053] In this example, cross-linked carboxymethylcellulose sodium, sodium carboxymethyl starch, and cross-linked povidone are respectively used as disintegrants to prepare Edaravone Dispersible Tablets, with a batch of 1000 tablets. The specific details are as follows:

[0054] Table 5 Prescription list of different types of disintegrants

[0055]

[0056] Respectively use the above prescriptions to prepare the corresponding Edaravone Dispersible Tablets according to the method of Example 1;

[0057] Detection and determination method: Take the above-mentioned Edaravone Dispersible Tablets, use hydrochloric acid solution with pH 1.0 as the dissolution medium, conduct dissolution tests at a temperature of 37 °C, a volume of 900 mL, and a rotation speed of 50 rpm. Samples are taken at 5, 10, 15, 20, 30, 45, and 60 minutes to detect the dissolution amount, and the content and dissolution curve of each Edaravone Dispersible Tablet are determined. The specific results are as follows:

[0058] Table 6 Summary of dissolution comparison results

[0059]

[0060] As can be seen from Table 6, when the disintegrants are cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, and cross-linked povidone, and the dosage of each is 2.5% (w / w), the tablet content is about 100%, and the dissolution curves can all reach 100% dissolution, indicating that at least one of cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, and cross-linked povidone can be used as the disintegrant.

[0061] Example 4 An Edaravone Dispersible Tablet and Its Preparation Method

[0062] In this example, silica with different proportions was used to prepare edaravone dispersible tablets. The batch size was 1000 tablets, and the proportion was 2 - 3%, specifically as follows:

[0063] Table 7 Prescription List of Silica with Different Proportions

[0064]

[0065] Using the above prescriptions respectively, corresponding edaravone dispersible tablets were prepared according to the method of Example 1;

[0066] Detection and determination method: Take the above-mentioned edaravone dispersible tablets, use hydrochloric acid solution with pH 1.0 as the dissolution medium, conduct dissolution tests at a temperature of 37°C, a volume of 900 mL, and a rotation speed of 50 rpm. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min to detect the dissolution amount, and the content and dissolution curve of each edaravone dispersible tablet were determined. The specific results are as follows:

[0067] Table 8 List of Dissolution Comparison Results

[0068]

[0069] As can be seen from Table 8, when the dosage of the glidant silica is 2.0 - 3.0% (w / w), the tablet content is about 100%, the dissolution curves can all reach 100% dissolution, and the weight variation meets the requirements of the Chinese Pharmacopoeia, indicating that the dosage of the glidant can be 2.0 - 3.0% (w / w).

[0070] Example 5 An Edaravone Dispersible Tablet and Its Preparation Method

[0071] In this example, stevioside with different proportions was used to prepare edaravone dispersible tablets. The batch size was 1000 tablets, and the proportion was 2.0 - 3.0%, specifically as follows:

[0072] Table 9 Prescription List of Stevioside with Different Proportions

[0073]

[0074]

[0075] Using the above prescriptions respectively, according to the method of Example 1, the corresponding edaravone dispersible tablets were prepared;

[0076] Detection and determination method: Without disclosing the prescription, 20 people were invited to taste each edaravone dispersible tablet pressed with different proportions of stevioside respectively, score and evaluate after tasting, with a full score of 5 points, and the average value was taken to judge the taste quality, and the content of the edaravone dispersible tablets was determined. The specific results are as follows:

[0077] Table 10 List of taste comparison results

[0078]

[0079] As can be seen from Table 10, when the dosage of the sweetener stevioside is 2.0 - 3.0% (w / w), the tablet content meets the requirements, and the average taste scores are 4.3 points, 3.8 points, and 3.6 points (full score 5 points), and the per capita acceptability is high, indicating that the dosage of the sweetener can be 2.0 - 3.0% (w / w).

[0080] Example 6 An edaravone dispersible tablet and its preparation method

[0081] In this example, magnesium stearate with different proportions was used to prepare edaravone dispersible tablets, with a batch of 1000 tablets, and the proportion was 2.0 - 3.0%, specifically as follows:

[0082] Table 11 List of prescriptions of magnesium stearate with different proportions

[0083]

[0084] Using the above prescriptions respectively, according to the method of Example 1, the corresponding edaravone dispersible tablets were prepared;

[0085] Detection and determination method: Taking the above edaravone dispersible tablets, using hydrochloric acid solution with pH 1.0 as the dissolution medium, carrying out dissolution tests at a temperature of 37°C, a volume of 900 mL, and a rotation speed of 50 rpm, sampling and detecting the dissolution amount at 5, 10, 15, 20, 30, 45, and 60 min, and determining the content and dissolution curve of each edaravone dispersible tablet. The specific results are as follows:

[0086] Table 12 List of dissolution comparison results

[0087]

[0088] As can be seen from Table 12, when the dosage of the lubricant magnesium stearate is 2.0 - 3.0% (w / w), the tablet shape is good, the weight difference is within ±4%, the tablet content is about 100%, and the dissolution curves all meet the regulations, indicating that the dosage of the lubricant can be 2.0 - 3.0% (w / w).

[0089] Example 7 Edaravone Dispersible Tablets and Its Preparation Method

[0090] In this example, magnesium stearate and talc were used as lubricants respectively to prepare edaravone dispersible tablets, with a batch size of 1000 tablets. The specific details are as follows:

[0091] Table 13 Prescription List of Different Kinds of Lubricants

[0092]

[0093]

[0094] The corresponding edaravone dispersible tablets were prepared respectively according to the method of Example 1 using the above prescriptions;

[0095] Detection and determination method: Take the above-mentioned edaravone dispersible tablets, use hydrochloric acid solution with pH 1.0 as the dissolution medium, carry out the dissolution test at a temperature of 37°C, a volume of 900 mL, and a rotation speed of 50 rpm. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min to detect the dissolution amount, and the content and dissolution curve of each edaravone dispersible tablet were determined. The specific results are as follows:

[0096] Table 14 List of Dissolution Comparison Results

[0097]

[0098] It can be seen from Table 14 that when the lubricants are magnesium stearate and talc, and the dosage is 2.5% (w / w), the tablet content and dissolution curve meet the requirements, indicating that magnesium stearate and / or talc can be used as the lubricant.

[0099] Examples 8 - 11 Edaravone Dispersible Tablets and Its Preparation Method

[0100] Examples 8 - 11 are respectively an edaravone dispersible tablet and its preparation method, which are basically the same as Example 1, except that only some process parameters are different. The specific details are shown in Table 15:

[0101] Table 15 List of Process Parameters in Examples 8 - 11

[0102]

[0103] The content of other parts in Examples 8 - 11 is basically the same as that in Example 1 and will not be elaborated here.

[0104] Then, the content, weight difference, hardness, friability, dispersion uniformity and other tablet parameters of the above-mentioned edaravone dispersible tablets were detected respectively. The specific results are as follows:

[0105] Table 16 List of Dissolution Comparison Results

[0106] Test Items Example 8 Example 9 Example 10 Example 11 Content / % 99.6 100.3 99.7 99.5 Weight Variation -1.8％～2.2％ -2.5％～1.3％ -2.2％～2.3％ -1.4％～2.6％ Hardness 26.6～52.1N 25.3～49.8N 25.3～55.5N 24.5～53.4N Friability 0.25％ 0.21％ 0.24％ 0.19％ Dispersion Uniformity 2min26s 0min30s 1min28s 2min01s

[0107] As can be seen from the data content in Table 16, when the dosage of sodium carboxymethylcellulose cross-linked is 0.5 - 5%, the dosage of silicon dioxide is 0.5 - 5%, the dosage of stevioside is 0.5 - 5%, and the dosage of magnesium stearate is 0.25 - 5%, and the first addition amount of magnesium stearate is within the range of 1 / 3 - 1 / 2, the product content, weight variation, hardness, friability, and dispersion uniformity all meet the relevant requirements of the pharmacopoeia.

[0108] Comparative Example 1 An edaravone dispersible tablet and its preparation method

[0109] In this comparative example, anhydrous lactose, lactose - microcrystalline cellulose co - processed product, microcrystalline cellulose, and partially pre - gelatinized starch were respectively used as fillers to prepare edaravone dispersible tablets, with a batch size of 1000 tablets. The specific details are as follows:

[0110] Table 17 Prescription list of different types of fillers

[0111]

[0112] Using the above prescriptions respectively according to the method of Example 1, the corresponding edaravone dispersible tablets were prepared;

[0113] Then, the tablet parameters such as the content, weight variation, hardness, friability, and dispersion uniformity of each of the above - mentioned edaravone dispersible tablets were respectively detected. The specific results are as follows:

[0114] Table 18 List of dissolution comparison results

[0115] Test Items Prescription 1 Prescription 14 Prescription 15 Prescription 16 Prescription 17 Content / % 100.1 100.2 99.8 99.7 101.2 Weight Variation -2.0％～1.5％ -1.9％～1.5％ -9.0％～8.7％ -8.6％～7.4％ -7.5％～8.3％ Hardness 26.8～52.4N 28.9～48.6N 22.6～59.4N 20.5～70.5N 28.9～76.4N Friability 0.15％ 0.11％ 0.35％ 0.48％ 0.51％ Dispersion Uniformity 0min43s 1min02s 0min35s 1min25s 1min30s

[0116] As can be seen from Table 18, although the content, friability, and dispersion uniformity of each of the edaravone dispersible tablets prepared in this comparative example all meet the relevant regulations, the weight variations of the corresponding edaravone dispersible tablets prepared with Prescription 15 with lactose - microcrystalline cellulose co - processed product as the filler, Prescription 16 with microcrystalline cellulose and lactose as the filler, and Prescription 17 with partially pre - gelatinized starch as the filler all exceed the limit of ±7.5% and do not meet the pharmacopoeia standards. For Prescription 1 and Prescription 14 with lactose - microcrystalline cellulose co - processed product as the filler, the weight variations both meet the limit of ±7.5%, but an increase in the dosage of lactose - microcrystalline cellulose co - processed product in Prescription 14 will lead to an increase in cost and is not conducive to industrial production. It shows that changing the type of filler will cause the tablet weight of the edaravone dispersible tablets prepared only by mixing and tableting techniques to exceed the requirements of the pharmacopoeia and cannot be achieved. It is necessary to use a specific lactose - microcrystalline cellulose co - processed product as the filler, and the dosage exceeds 34.2% (Example 10) to realize the preparation of edaravone dispersible tablets by direct mixing and tableting processes.

[0117] Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

Claims

1. An edaravone dispersible tablet, characterized in that, The raw materials for preparing the edaravone dispersible tablets, by weight percentage, include: edaravone 52.5%; Excipients: disintegrant 0.5 - 5%, glidant 0.5 - 5%, sweetener 0.5 - 5%, lubricant 0.25 - 5% and the balance of lactose microcrystalline cellulose co-processed product.

2. The edaravone dispersible tablets according to claim 1, characterized in that, The raw materials for preparing the edaravone dispersible tablets, by weight percentage, include: edaravone 52.5%; Excipients: disintegrant 1.5 - 3.0%, glidant 2.0 - 3.0%, sweetener 2.0 - 3.0%, lubricant 2.0 - 3.0% and the balance of lactose microcrystalline cellulose co-processed product.

3. The edaravone dispersible tablets according to claim 1 or 2, characterized in that, The disintegrant is at least one of sodium croscarmellose, sodium carboxymethyl starch and crospovidone.

4. The edaravone dispersible tablets according to claim 1 or 2, characterized in that, The lubricant is magnesium stearate and / or talc powder.

5. The edaravone dispersible tablets according to claim 1 or 2, characterized in that, The glidant is silicon dioxide.

6. The edaravone dispersible tablets according to claim 1 or 2, characterized in that, The sweetener is stevioside.

7. A method for preparing the edaravone dispersible tablets according to any one of claims 1-6, characterized in that, The preparation method is to directly mix edaravone with the excipients and then press tablets to obtain the edaravone dispersible tablets.

8. The preparation method of the edaravone dispersible tablets according to claim 7, wherein, The preparation method is to take the filler, disintegrant, sweetener, glidant, part of the lubricant and edaravone, mix them for the first time, then granulate and mix, and then add the remaining lubricant and mix evenly. The total mixed powder obtained is directly pressed into tablets to obtain the edaravone dispersible tablets.

9. The preparation method of edaravone dispersible tablets according to claim 7, characterized in that, During the first mixing process, the amount of lubricant added is 1 / 3 - 1 / 2 of the total amount of lubricant used.

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