Preparation method of aspirin enteric-coated tablets based on specific particle size screening

Abstract

The application discloses a preparation method of aspirin enteric-coated tablets based on specific particle size screening and belongs to the technical field of pharmaceutical preparations. In aspirin raw materials used in the enteric-coated tablets, the mass percentage of particles with a particle size between a three-number sieve aperture of 355 mu m plus or minus 13 mu m and a seven-number sieve aperture of 125 mu m plus or minus 5.8 mu m accounts for more than 90% of the total particles; the enteric-coated tablets comprise aspirin, a filling agent, a disintegrating agent and an enteric-coated layer. The application precisely controls the proportion of aspirin raw material particles with a particle size between a three-number sieve and a seven-number sieve to be more than 90%, and optimizes the selection of auxiliary materials and the process parameters of the preparation, such as the parameters of direct mixing, direct compression of powder and enteric-coated coating and the like, based on the raw material with a specific particle size range, so that the synergistic effect of each link is ensured, and the product quality is improved. The preparation method of the aspirin enteric-coated tablets based on specific particle size screening has the advantages of stable preparation process, high dissolution rate, good quality stability and the like, and improves the overall quality and curative effect of the medicine.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a preparation method of aspirin enteric-coated tablets based on specific particle size screening. BACKGROUND

[0002] As a commonly used clinical drug, aspirin enteric-coated tablets are intended to ensure that the drug is not released in the stomach, effectively released in the intestinal environment and exert its pharmacological effect. However, there are still some problems to be solved in the production and quality control of current aspirin enteric-coated tablets.

[0003] In terms of raw material particle size, the prior art generally lacks strict control of the precise range of particle size distribution. The particle size of aspirin raw material varies, with a wide distribution, resulting in poor uniformity of the mixture of the drug and excipients during the preparation process. When the particle size difference of the raw material is large, the smaller particles are prone to agglomeration, and the larger particles are difficult to fully integrate with the excipients, affecting the overall quality of the tablets. This unevenness is manifested in unstable compressibility during tabletting, and is prone to problems such as cracking and loose tablets, which seriously affect production efficiency and product quality.

[0004] From the perspective of dissolution rate, the particle size of the raw material has a key influence on the dissolution speed and extent of the drug in the intestine. If the particle size is too large, the contact area between the drug and the dissolution medium is small, and the dissolution process is slow, which cannot meet the clinical demand for rapid drug effect; if the particle size is too small, although the contact area is increased, agglomeration may occur, which also hinders the dissolution of the drug. Therefore, a suitable particle size range is crucial for optimizing the dissolution rate, but the prior art often ignores the precise definition and control of this range.

[0005] In addition, in the preparation process, traditional wet granulation and dry granulation processes have many drawbacks, such as the hydrolysis of aspirin in wet granulation and the complex process of dry granulation. In summary, the existing aspirin enteric-coated tablets have deficiencies in raw material particle size control, tabletting performance, dissolution rate and quality stability, which seriously affect product quality and efficacy, and need to be improved and solved by innovative methods. In view of this, in view of the above problems, after in-depth research, the present application is produced. SUMMARY

[0006] The present application aims to provide a preparation method of aspirin enteric-coated tablets based on specific particle size screening, to solve the problems of deficiencies in raw material particle size control, tabletting performance, dissolution rate and quality stability of existing aspirin enteric-coated tablets, which seriously affect product quality and efficacy.

[0007] To achieve the above-mentioned purpose, the present application provides the following technical solutions: An aspirin enteric-coated tablet, the proportion of aspirin raw material particles between No. 3 and No. 7 sieves is more than 90%, and the tablet comprises the following excipients: microcrystalline cellulose, corn starch, and sodium carboxymethyl cellulose; the enteric-coated tablet is prepared by a method comprising the following steps: Step (1): the particle size of aspirin raw material is adjusted by using air flow crushing technology, the parameters such as air flow pressure and feeding speed are precisely controlled, the particles between No. 3 and No. 7 sieves are collected by a screening device, and the particle size distribution is detected by an instrument to ensure that the proportion of particles between No. 3 and No. 7 sieves is more than 90%; Step (2): the aspirin of step (1) is mixed with microcrystalline cellulose, corn starch, and sodium carboxymethyl cellulose to obtain a total mixture; Step (3): the total mixture of step (2) is tableted to obtain aspirin enteric-coated tablet elements; Step (4): the aspirin enteric-coated tablet elements of step (3) are enteric-coated to obtain aspirin enteric-coated tablets.

[0008] Preferably, in the raw material particle size treatment of step (1), the air flow pressure during air flow crushing is 0.8-1.0 MPa, and the feeding speed is 4-5 kg / h.

[0009] Preferably, the mixing machine of step (1) is a fixed hopper mixing machine, a V-shaped mixing machine, or a three-dimensional mixing machine.

[0010] Preferably, about 60% of the prescription amount of aspirin, microcrystalline cellulose, corn starch, and sodium carboxymethyl cellulose are sequentially added to the mixing machine during mixing of step (2), and the remaining aspirin is added.

[0011] Preferably, the mixing of step (2) is direct mixing, that is, the mixing speed is set to 6 rpm, and the mixing time is 20 min.

[0012] Preferably, the tableting of step (3) is carried out by using a double-discharge high-speed tablet press, the tableting speed is 40-120 thousand tablets / hour, the feeding speed is set to 40-80 rpm, and the average pressure is 5-30 KN.

[0013] Preferably, the coating liquid for the coating process of step (4) is prepared by using acrylic resin III as the main coating material, 10% diethyl phthalate as the plasticizer, and 3% talc as the anti-adhesive agent.

[0014] Preferably, the coating process of step (4) is carried out by controlling the coating weight increase to be about 10%-12%.

[0015] The application also provides an application of the aspirin enteric-coated tablets, which is the application of the aspirin enteric-coated tablets in improving the drug dissolution and ensuring the smooth preparation process.

[0016] Compared with the prior art, the innovation and beneficial effects of the present application are as follows: The present application aims to systematically solve the core problems of the existing aspirin enteric-coated tablets, such as tabletting difficulty, poor dissolution, and poor quality stability, caused by the wide particle size control of raw drug and complex process.

[0017] I. Core technical innovation

[0018] Precise control of particle size: The present application innovatively defines and strictly controls the particle size distribution of aspirin raw drug, requiring that the mass percentage of particles between the three and seven sieves is more than 90%. This precise control is achieved through the combination of airflow crushing and sieving technology, laying a solid foundation for subsequent processes.

[0019] Revolutionary simplification of process: The wet granulation method which easily causes hydrolysis of aspirin or the dry granulation method with complex process is abandoned, and the core process of "direct mixing + powder direct compression" is adopted. This process not only fundamentally avoids the generation of hydrolysis by-products salicylic acid, but also greatly simplifies the production process.

[0020] Optimization of the adaptability of excipients: Based on the specific particle size of the raw drug, the excipients such as microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose are optimized and the best dosage range is determined, ensuring the best match between the raw drug and the excipients in terms of flowability, compressibility and disintegration.

[0021] II. Significant beneficial effects brought about

[0022] The above-mentioned technical innovations work together to bring the following multiple beneficial effects: Significant improvement in dissolution performance: The specific and uniform particle size range greatly increases the effective surface area of the drug in the intestinal environment. The data of the examples show that the dissolution of the product of the present application in pH 6.8 buffer is as high as 98.9% in 90 minutes, which is much better than that of the comparative examples (the highest is only 78.5%), ensuring that the drug can act quickly and has high bioavailability.

[0023] Great improvement in production feasibility: The uniformity of particle size makes the powder flow well, and after direct mixing, the tablets can be directly compressed, effectively solving the tabletting problems such as cracking and loose tablets. The production process is smooth, the production efficiency is high, and it is more suitable for large-scale production, reducing the production cost.

[0024] The product quality stability is excellent: the precise particle size control and the simplified dry process jointly ensure the chemical stability (low salicylic acid content) and the physical stability (consistent dissolution behavior) of the product during storage. This means that the product is reliable in quality during the entire validity period, significantly reduces the commercial risk caused by quality fluctuations, and ensures the safety of patients taking the medicine.

[0025] In summary, the present application successfully prepares an aspirin enteric-coated tablet with high dissolution rate, stable production, and reliable quality through the systematic scheme of "raw material control-process simplification-excipient optimization", which has outstanding technical progress and commercial value. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The figure is the index result of the aspirin enteric-coated tablet of Example 1 of the present application; Figure 2 The figure is the index result of the aspirin enteric-coated tablets of Comparative Examples 1-3 of the present application; Figure 3 The figure is the dissolution curve detection result of the reference preparation and the experimental group (0.1M hydrochloric acid + pH6.8 phosphate buffer, n=12) of the present application; Figure 4 The figure is the dissolution curve of the reference preparation and the process verification of three batches (0.1M hydrochloric acid + pH6.8 phosphate buffer) of the present application. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0028] Please refer to Figures 1-4 The present application provides a technical solution: an aspirin enteric-coated tablet, the particle size of aspirin raw material is more than 90% between the No. 3 sieve and the No. 7 sieve, and the tablet includes the following excipients: microcrystalline cellulose, corn starch, and cross-linked sodium carboxymethyl cellulose; the enteric-coated tablet is prepared by the method including the following steps: Step (1): the particle size of aspirin raw material is adjusted by using airflow crushing technology, the parameters such as airflow pressure and feeding speed are accurately controlled, the particles with the particle size between the No. 3 sieve and the No. 7 sieve are collected by a screening device, and the particle size distribution is detected by an instrument to ensure that the particle percentage between the No. 3 sieve and the No. 7 sieve is more than 90%; Step (2): the aspirin of step (1) is mixed with microcrystalline cellulose, corn starch, and cross-linked sodium carboxymethyl cellulose to obtain a total mixture. Step (3): the total mixture of step (2) is tabletted to obtain aspirin enteric-coated tablet element tablet; Step (4): the aspirin enteric-coated tablet element tablet obtained in step (3) is enteric-coated to obtain aspirin enteric-coated tablet.

[0029] In the step (1) raw material particle size treatment, the airflow pressure is 0.8-1.0 MPa and the feeding speed is 4-5 kg / h during the airflow crushing.

[0030] The step (1) mixing machine is a fixed hopper mixing machine, a V-shaped mixing machine or a three-dimensional mixing machine.

[0031] In the step (2) mixing, about 60% of the prescription amount of aspirin, microcrystalline cellulose, corn starch and cross-linked sodium carboxymethyl cellulose are sequentially added into the mixing machine, and the remaining aspirin is added.

[0032] The step (2) direct mixing is that the mixing rotation speed is 6 rpm and the mixing time is 20 min.

[0033] The step (3) tabletting is that the tabletting is performed by using a double-discharge high-speed tabletting machine, the tabletting speed is 40-120 thousand tablets / hour, the feeding rotation speed is set to 40-80 rpm, and the average pressure is 5-30 KN.

[0034] In the step (4) coating process, the coating liquid is prepared by taking acrylic resin III as the main coating material, 10% diethyl phthalate as the plasticizer and 3% talcum powder as the anti-adhesive agent according to the weight of the tablet core to prepare the enteric-coating liquid.

[0035] In the step (4) coating process, the coating weight increase is controlled to be about 10%-12%.

[0036] The application also provides an application of the aspirin enteric-coated tablet, which is the application of the aspirin enteric-coated tablet in improving the drug dissolution rate and ensuring the smooth preparation process.

[0037] The product detection is compared by combining specific examples and comparative examples, and the product detection is as follows: The finished product free salicylic acid detection method is Chinese Pharmacopoeia 2020 edition four-part general rule 0512. In order to ensure the product quality, the internal control is that the free salicylic acid content is not more than 1.5% of the aspirin marked amount.

[0038] The finished product dissolution rate detection method is Chinese Pharmacopoeia 2020 edition four-part general rule 0931 first method 1; in order to ensure the product quality, the internal control is that the release rate in the acid is not more than 10% of the marked amount for 2 h, and the release rate in the buffer is not less than 75% of the marked amount for 90 min.

[0039] Example 1

[0040] 1. Raw material particle size treatment: Take the initial aspirin raw material and use a laser particle size analyzer to determine the particle size distribution. It is found that the particles in the size range between the No. 3 sieve and the No. 7 sieve account for 40%. The raw material is placed in an air flow pulverizer, the air flow pressure is set to 0.8 MPa, and the feeding speed is 5 kg / h. The pulverized raw material is sieved by a vibrating sieve separator, and the particles between the No. 3 sieve and the No. 7 sieve are collected. The particle size distribution is detected again, and the particles in the size range account for 92%.

[0041] 2. Preparation of excipients: Take 10 mg of microcrystalline cellulose per tablet; take 10 mg of corn starch per tablet; take 5 mg of cross-linked sodium carboxymethyl cellulose per tablet.

[0042] 3. Total mixing: Put the treated aspirin raw material and the above-mentioned excipients into a fixed hopper mixer, mix at a speed of 6 r / min for 20 min, and mix the materials thoroughly to obtain the total mixed material.

[0043] 4. Tabletting: Use a double-discharge high-speed tablet press to tablet, 40-120 thousand tablets / hour, the feeding speed is set to 40-80 rpm, and the average pressure is 5-30 KN.

[0044] 5. Coating: The coating liquid is prepared by taking acrylic resin III as the main coating material, 10% diethyl phthalate as the plasticizer, and 3% talc as the anti-adhesive agent. The coating weight is controlled at about 10%-12%.

[0045] 6. Detection: Free salicylic acid content: 0.03%; dissolution: ① Acid dissolution: use 0.1 mol / L hydrochloric acid solution 900 ml as the dissolution medium, the rotation speed is 100 revolutions per minute, and the basket method is used. After 2 hours, the detection result is 0.0%. ② Buffer dissolution: immediately remove the sample under the acid dissolution inspection item, use pH 6.8 phosphate buffer 900 ml as the dissolution medium, the rotation speed is 100 revolutions per minute, continue to dissolve, and after 90 minutes, the detection result is 98.9%.

[0046] Figure 1 The index results of aspirin enteric-coated tablets of Example 1.

[0047] As can be seen from the figure, the aspirin content of the aspirin enteric-coated tablets prepared by Example 1 is within the qualified range of 95.0%-105.0%, the free salicylic acid content is less than 1.5%, the dissolution in acid for 2 hours is not more than 10% of the labeled amount, and the dissolution in buffer for 90 minutes is not less than 75% of the labeled amount, all meeting the requirements of qualified products, indicating that the technical scheme of the present application is suitable for the preparation of aspirin enteric-coated tablets.

[0048] Comparative Example 1 (raw material particle size does not meet requirements)

[0049] 1. Raw material particle size treatment: A batch of aspirin raw material was selected without screening and adjusting the particle size, and the proportion of particles in the particle size range between the No. 3 sieve and the No. 7 sieve was only 30%.

[0050] 2. Preparation of excipients and preparation process: The same excipients and amounts as in Example 1 were used, and aspirin enteric-coated tablets were prepared according to the mixing, granulation, tabletting and coating process of Example 1. Tablet cracking and loose tablets occurred during tabletting.

[0051] 3. Detection: Free salicylic acid content: 0.03%; dissolution: under the same dissolution conditions as Example 1, the solubility test results in acid were 0.0%, and the solubility test results in buffer were 62.0%.

[0052] Comparative Example 2 (insufficient proportion of particle size range)

[0053] 1. Raw material particle size treatment: The same batch of aspirin raw material was treated to make the proportion of particles in the particle size range between the No. 3 sieve and the No. 7 sieve reach 70%.

[0054] 2. Preparation of excipients and preparation process: The same excipients and amounts as in Example 1 were used, and aspirin enteric-coated tablets were prepared according to the mixing, granulation, tabletting and coating process of Example 1.

[0055] 3. Detection: Free salicylic acid content: 0.03%; dissolution: under the same dissolution conditions as Example 1, the solubility test results in acid were 0.0%, and the solubility test results in buffer were 74.1%.

[0056] Comparative Example 3 (particle size distribution is too wide)

[0057] 1. Raw material particle size treatment: The same batch of aspirin raw material was treated to make the proportion of particles in the particle size range between the No. 3 sieve and the No. 7 sieve reach 90%, but the particle size distribution was wide and the coefficient of variation was large.

[0058] 2. Preparation of excipients and preparation process: The same excipients and amounts as in Example 1 were used, and aspirin enteric-coated tablets were prepared according to the mixing, granulation, tabletting and coating process of Example 1.

[0059] 3. Detection: Free salicylic acid content: 0.03%; dissolution: under the same dissolution conditions as Example 1, the solubility test results in acid were 0.0%, and the solubility test results in buffer were 78.5%.

[0060] Comparative Example 1 / 2 / 3, the content, free salicylic acid, and dissolution test results of the finished product are shown in Figure 2 .

[0061] What has not been described in detail in this specification is considered to be the prior art known to those skilled in the art. Although embodiments of the present application have been shown and described, it is to be understood that various modifications, substitutions, replacements and changes can be made to these embodiments without departing from the principles and spirit of the present application, and the scope of the present application is defined by the appended claims and their equivalents.

Claims

1. A high dissolution efficiency enteric coated aspirin tablet, characterized in that: The enteric-coated aspirin tablet uses aspirin raw material medicine, and the mass percentage of particles with a particle size between a No. 3 sieve (355 μm ± 13 μm) and a No. 7 sieve (125 μm ± 5.8 μm) accounts for more than 90% of the total particles; the enteric-coated aspirin tablet comprises aspirin, a filler, a disintegrant, and an enteric-coated layer.

2. The aspirin enteric coated tablet according to claim 1, wherein: The filler comprises microcrystalline cellulose, and the disintegrant comprises cross-linked sodium carboxymethyl cellulose and corn starch.

3. The aspirin enteric coated tablet according to claim 2, wherein: The amount of the cross-linked sodium carboxymethyl cellulose is 3-7 mg, and the amount of the corn starch is 8-12 mg per tablet.

4. A process for the preparation of enteric coated aspirin tablets according to any one of claims 1 to 3 based on specific particle size fractionation, characterized by The enteric-coated aspirin tablet is prepared by a method comprising the following steps: Step (1): The particle size of the aspirin raw material medicine is adjusted by using the airflow crushing technology, the airflow pressure and the feeding speed parameters are accurately controlled, the particles with a particle size between a No. 3 sieve and a No. 7 sieve are collected by using a screening device, and the particle size distribution is detected by using a laser particle size analyzer to ensure that the particles with a particle size between a No. 3 sieve and a No. 7 sieve account for more than 90%; Step (2): The aspirin, the microcrystalline cellulose, the corn starch, and the cross-linked sodium carboxymethyl cellulose are mixed to obtain a total mixture; Step (3): The total mixture is tableted to obtain enteric-coated aspirin tablets; Step (4): The enteric-coated aspirin tablets are coated to obtain the enteric-coated aspirin tablets.

5. The method of claim 4, wherein: In the raw material particle size treatment of step (1), the airflow pressure is 0.8-1.0 MPa, and the feeding speed is 4-5 kg / h during the airflow crushing.

6. The method of claim 4, wherein: In step (2), the equal-increment mixing method is used for mixing, part of the prescription amount of the aspirin, the microcrystalline cellulose, the corn starch, and the cross-linked sodium carboxymethyl cellulose are sequentially added into a mixer, and the remaining aspirin is added.

7. The method of claim 4, wherein: In step (2), the mixer used for mixing is a fixed-hopper mixer, a V-shaped mixer, or a three-dimensional mixer, the mixing speed is set to 6 rpm, and the mixing time is 20 min.

8. The method of claim 4, wherein: In step (3), the tablets are tableted by using a double-discharge high-speed tablet press, the tableting speed is 40-120 thousand tablets / hour, the feeding speed is set to 40-80 rpm, and the average pressure is 5-30 kN.

9. The method of claim 4, wherein: In step (4), the coating liquid is prepared by using acrylic resin III as the main coating material, and 10% diethyl phthalate and 3% talc are added as the plasticizer and the anti-adhesive, respectively, based on the weight of the tablet core. The coating weight is controlled to be 10%-12% during the coating process.

10. The use of the method according to any one of claims 4 to 9 for improving the dissolution of a drug and ensuring a smooth manufacturing process. The enteric-coated aspirin tablet has a dissolution property that the dissolution rate is not less than 70% within 45 minutes and the dissolution rate is not less than 85% within 90 minutes in a phosphate buffer solution with a pH of 6.8.

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