An oral preparation of acetylcysteine and a method for preparing the same

Abstract

The application provides an oral preparation of acetylcysteine and a preparation method thereof, and the preparation formula comprises acetylcysteine 25% (w / w), povidone k300 0.5-1.5% (w / w), diluent 35-45% (w / w), disintegrant 3-10% (w / w), filling agent 10-15% (w / w), sodium bicarbonate 8-13% (w / w), glidant 0.5-1.5% (w / w), flavoring agent 2-4% (w / w), lubricant 0.5-1.5% (w / w), and the total of the mass percentages of the components is 1. The acetylcysteine is pre-coated, and then mixed with other auxiliary materials, and the powder is directly compressed to obtain a tablet, the types of the auxiliary materials are reasonably selected, the ratio is scientific, the finished product has good quality stability and rapid disintegration, the preparation process is simple and convenient, and the preparation process is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to an oral acetylcysteine ​​preparation and its preparation method. Background Technology

[0002] Acetylcysteine ​​is a thiol derivative with strong mucolytic and free radical scavenging effects, resulting in good expectorant efficacy. Clinically, it is often used for expectorant treatment in patients with chronic respiratory diseases such as chronic bronchitis, chronic obstructive pulmonary disease, and emphysema.

[0003] The dosage forms of acetylcysteine ​​available in China include granules, capsules, film-coated tablets, and effervescent tablets, but these have several problems. First, chronic respiratory diseases are often accompanied by symptoms such as cough and airway obstruction, which require timely relief. However, conventional oral preparations require water to take, which is inconvenient, and the drug disintegrates, dissolves, and is absorbed slowly, which is not conducive to rapid symptom relief. Second, sputum secretion affects swallowing, especially for the elderly, children, and other patients with swallowing difficulties, resulting in poor medication adherence.

[0004] Orally disintegrating tablets rapidly disintegrate and disperse in saliva within the mouth, entering the digestive tract. Compared to conventional oral solid dosage forms, they offer advantages such as ease of administration, rapid onset of action, and less irritation to the digestive tract mucosa, making them suitable for children, the elderly, and other patients with swallowing difficulties, thus improving compliance. Furthermore, orally disintegrating tablets can be used in anhydrous conditions, making them more convenient for patients working outdoors or at heights; they also reduce the risk of tracheal obstruction or suffocation caused by physical blockage during conventional oral administration.

[0005] Currently, there are few research reports on orally disintegrating acetylcysteine ​​tablets both domestically and internationally, and no products are on the market. The main reason is that orally disintegrating tablets have high requirements for excipients and disintegration properties, and the disintegrants are often hygroscopic. Acetylcysteine ​​is chemically unstable, easily oxidized, and sensitive to moisture and heat. During conventional preparation techniques, it easily absorbs moisture and is exposed to heat, leading to a significant increase in impurities, decreased product stability, and the risk of reduced active ingredient content or even reduced efficacy.

[0006] Patent CN201110088945.X, "An Acetylcysteine ​​Granule and Its Preparation Process" (application date 2011.04.11, publication date 2011.08.10), describes a method that uses acrylic resin to coat acetylcysteine ​​before mixing it with other excipients for granulation, thus solving the problem of poor stability of granules due to moisture sensitivity. However, orally disintegrating tablets and granules have different requirements for excipients and preparation processes. Simply adding the corresponding excipients for orally disintegrating tablets to the granule preparation process is insufficient to solve the problems of poor quality, disintegration performance, and drug stability of orally disintegrating tablets.

[0007] Patent EP2983650A1, "ORALPHARMACEUTICAL COMPOSITION COMPRISINGTASTE-MASKEDN-ACETYLCYSTEINE (Oral Pharmaceutical Composition Containing Taste-Making Acetylcysteine)" (Application Date: April 11, 2014; Publication Date: February 17, 2016), discloses an acetylcysteine ​​taste-masking granule. It uses triglycerides and polysorbate to hot-melt coat acetylcysteine, thereby achieving a taste-masking effect. However, it fails to solve the problem of poor stability caused by the sensitivity of raw materials to moisture and heat during the preparation of orally disintegrating tablets. Furthermore, hot-melt coating technology has high requirements for the melting point and operating temperature of the coating material. This coating material is complex, used in large quantities (20%-70%), and has poor water solubility. It is unclear whether such a complex composition can meet the performance requirements of rapid disintegration of orally disintegrating tablets and the stability requirements of the finished product during long-term storage.

[0008] Therefore, how to provide an acetylcysteine ​​orally disintegrating tablet with better quality and stability, rapid disintegration, simple preparation process, and suitability for industrial production is an urgent problem to be solved. Summary of the Invention

[0009] The purpose of this invention is to provide an oral formulation of acetylcysteine ​​and its preparation method. The orally disintegrating acetylcysteine ​​tablets provided by this invention have higher quality, better stability, rapid disintegration, and a simple preparation process, making them suitable for large-scale industrial production and overcoming the shortcomings of existing technologies.

[0010] This invention provides an oral formulation of acetylcysteine, characterized in that the oral formulation of acetylcysteine ​​comprises the following components and their mass percentages: acetylcysteine ​​25%, povidone K30 0.5-1.5%, diluent 35-45%, disintegrant 3-10%, filler 10-15%, sodium bicarbonate 8-13%, flow aid 0.5-1.5%, flavoring agent 2-4%, and lubricant 0.5-1.5%, wherein the total mass percentage of the components is 100%.

[0011] Furthermore, the oral acetylcysteine ​​formulation is an orally disintegrating tablet.

[0012] Furthermore, the diluent is one or more of mannitol, sorbitol, and lactose.

[0013] Furthermore, the disintegrant is one or more of crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose.

[0014] Furthermore, the filler is one or more of microcrystalline cellulose, starch, and sucrose.

[0015] Furthermore, the flow aid is either talc or colloidal silica.

[0016] Furthermore, the lubricant is at least one of sodium stearate fumarate and magnesium stearate.

[0017] Furthermore, the flavoring agent is aspartame and lemon flavoring. Preferably, the mass ratio of the flavoring agent aspartame to lemon flavoring is 1-2:0.75-2.

[0018] The present invention also provides a method for preparing the above-mentioned oral acetylcysteine ​​preparation, comprising the following steps: pre-coating acetylcysteine ​​with povidone K30, then mixing it evenly with other excipients, and directly compressing the powder into tablets to obtain the orally disintegrating tablets.

[0019] Furthermore, the preparation method of the acetylcysteine ​​orally disintegrating tablets includes the following steps:

[0020] (1) Pass the acetylcysteine ​​raw material through a 60-150 mesh sieve for later use; take the amount of acetylcysteine ​​in the formulation, atomize and spray it into polyvinyl ketone K30 at 20-30℃ for coating, and obtain acetylcysteine ​​coated granules.

[0021] (2) Weigh out the other excipients except lubricant according to the formula amount, mix them evenly with the coating particles in step (1), add the lubricant according to the formula amount, mix evenly, and directly compress into tablets to obtain the acetylcysteine ​​orally disintegrating tablets.

[0022] Furthermore, in step (1) of the preparation method, acetylcysteine ​​is passed through a 60-100 mesh sieve, and the coating process temperature is 25-30℃. The resulting acetylcysteine-coated particles have a coating weight gain of 2-6% based on the mass of acetylcysteine.

[0023] Furthermore, the hardness of the prepared oral disintegrating tablets is 65-90 N.

[0024] To address the issue of acetylcysteine's sensitivity to moisture and heat, this invention involves coating acetylcysteine ​​with other excipients and then directly compressing it into orally disintegrating tablets. Compared to wet granulation tableting, this invention eliminates the need for softening and drying processes, thus resolving the problems of poor product stability caused by moisture and prolonged drying during preparation. Compared to dry granulation tableting, this invention avoids the mechanical heat generated during the briquetting, pulverizing, and re-granulation of raw materials and excipients, which can affect the stability of the active pharmaceutical ingredient. Compared to freeze-drying technology, this invention does not require special equipment and process conditions and avoids the problem of inaccurate dosage caused by tablets being easily damaged by external forces during storage, transportation, or administration due to their low hardness and high brittleness.

[0025] Compared with the prior art, the technical advantages of the present invention are as follows:

[0026] 1. The acetylcysteine ​​orally disintegrating tablets (hereinafter referred to as "orally disintegrating tablets") provided by the present invention have stable quality, reasonable selection of excipients and scientific ratio, significantly improve the compressibility and flowability of materials, have a short disintegration time and good taste; and meet the requirements of the 2020 edition of the Chinese Pharmacopoeia for hardness, friability, compressibility, content uniformity, disintegration time, etc.

[0027] As shown in Table 1, the pharmacopoeia stipulates that the content uniformity limit is 15%. When it is greater than 15%, the content difference between tablets is large and the efficacy is unstable. The friability of tablets shall not exceed 1%. When the compression rate is <20%, the material has good flowability. When the compression rate is >40%, the flowability will decrease to the point that it is not easy to flow out of the container automatically. Orally disintegrating tablets should disintegrate completely within 60 seconds.

[0028] The orally disintegrating tablets 1-3 prepared within the scope of protection of this invention have a hardness of 60-70N, a compression rate of less than or equal to 20%, a content uniformity of less than or equal to 6%, and a disintegration time of less than or equal to 55s, all of which meet the relevant requirements of the pharmacopoeia.

[0029] Orally disintegrating tablets 4 and 5 were prepared by replacing povidone K30 in formulation 2 of the present invention with acrylic resin and hydroxypropyl methylcellulose, respectively; orally disintegrating tablet 9 was prepared by removing the coating material povidone K30 from formulation 2. The hardness, compressibility, content uniformity, and disintegration time of the above three tablets all meet the pharmacopoeia requirements. It is evident that the type of coating material has a relatively small impact on the above indicators.

[0030] Orally disintegrating tablet 6, prepared using the same excipients as orally disintegrating tablet 2 but in different proportions, exhibits a 50% decrease in hardness, a compression ratio >20%, nearly doubled content uniformity, reduced material flowability, poor compressibility, and a 2.4-fold increase in disintegration time, failing to meet pharmacopoeia requirements. Orally disintegrating tablets 7 and 8, prepared using the same excipients as orally disintegrating tablet 2 but in different proportions of sodium bicarbonate, show a 1.3-fold increase in content uniformity and a compression ratio >20%; however, material flowability decreases, with orally disintegrating tablet 7 exhibiting a 2-fold increase in disintegration time. This demonstrates that the direct compression method for preparing orally disintegrating tablets places high demands on the properties of diluents, disintegrants, and fillers, requiring not only strong disintegration performance but also good flowability and compressibility.

[0031] The active pharmaceutical ingredient (API) of the orally disintegrating tablet formulation 2 of this invention is uniformly mixed with other excipients and then directly compressed into an orally disintegrating tablet. This is then coated with povidone K30 to obtain orally disintegrating tablet 10, which exhibits a 69% reduction in hardness, a compression rate >20%, and poor surface smoothness with fine lines. This is because the premixed coating of acetylcysteine ​​and povidone K30 increases the flowability of the API, improving its compressibility, content uniformity, and disintegration in the tablet. However, after changing the process flow, the effect of povidone K30 on the API is not achieved, and the tablets prepared from the specific formulation with high disintegration properties are easily affected by the coating process, becoming loose and reducing hardness. Therefore, premixing the API with povidone K30 is a crucial step in achieving better compressibility and content uniformity in orally disintegrating tablets.

[0032] The orally disintegrating tablets provided by this invention, under a specific excipient composition, exhibit superior hardness, compressibility, content uniformity, and disintegration time compared to other formulations. In particular, the specific content of sodium bicarbonate not only promotes disintegration but also reduces compressibility and content uniformity, increases material flowability, and improves the quality of orally disintegrating tablets.

[0033] Table 1. Quality test results of acetylcysteine ​​orally disintegrating tablets

[0034]

[0035]

[0036] 2. The present invention uses a method of coating acetylcysteine ​​with povidone K30, and then directly compressing the powder into tablets after mixing with excipients, which also improves the stability of acetylcysteine ​​orally disintegrating tablets.

[0037] Acetylcysteine ​​is unstable under wet and heat conditions and is prone to producing impurities. The orally disintegrating tablets 1-3 prepared within the scope of this invention exhibit significantly lower levels of related substances than the limits under high temperature and high humidity environments, demonstrating good product stability.

[0038] Orally disintegrating tablets 4 and 5 were prepared by replacing povidone K30 in formulation 2 of this invention with acrylic resin and hydroxypropyl methylcellulose, respectively. Under high temperature and high humidity conditions, the N,S-diacetylcysteine ​​content of orally disintegrating tablets 4 and 5 was 80 times and 70 times that of orally disintegrating tablet 2, respectively; the contents of cystine, L-cysteine ​​and other related substances were significantly increased. Among them, the total impurity content of orally disintegrating tablets 4 and 5 increased by 24 times and 15 times, respectively, compared with orally disintegrating tablet 2, far exceeding the limits for related substances in the pharmacopoeia.

[0039] The orally disintegrating tablet 9 obtained by removing the coating from orally disintegrating tablet 2 of this invention has an N,S-diacetylcysteine ​​content that is 50 times higher than that of orally disintegrating tablet 2 under high temperature and high humidity conditions. The content of other related substances increases by more than 10 times, and the content of N,N'-diacetylcysteine, the total known impurities, other individual impurities, and the total impurities all significantly exceed the limits for related substances. Combining orally disintegrating tablets 2, 4, 5, and 9, it is evident that acetylcysteine ​​can only be effectively isolated from other excipients after premixing with povidone K30, reducing the reaction between the active pharmaceutical ingredient and alkaline excipients and the impact during preparation, thereby reducing impurity generation, effectively controlling drug stability, and mitigating the impact of high temperature and high humidity on the impurity content of the drug.

[0040] Based on orally disintegrating tablet 2, a modified process was used to produce orally disintegrating tablet 10, which involved mixing and compressing the raw materials and excipients before coating. This resulted in a significant increase in the content of related substances under high temperature and high humidity conditions. Specifically, the content of N,S-diacetylcysteine ​​was 60 times that of orally disintegrating tablet 2. The content of N,N'-diacetylcysteine, the total known impurities, other individual impurities, and the total impurities were all more than 10 times higher than in orally disintegrating tablet 2, failing to meet the related substance limits. Comparison of the test results of orally disintegrating tablets 2, 4, 5, and 9 indicates that the type, content, and order of coating materials are key technologies of this invention. Adjusting the formulation has a significant impact on the stability, content uniformity, and disintegration of the finished orally disintegrating tablet.

[0041] Orally disintegrating tablet 8 was prepared by adjusting the sodium bicarbonate content outside the protected range, based on orally disintegrating tablet 2. Under high temperature and high humidity conditions, the N,S-diacetylcysteine ​​content was 70 times that of orally disintegrating tablet 2, and the content of other related substances increased by more than 10 times, including a 14-fold increase in total impurities, all of which failed to meet the related substance limits. This demonstrates that the sodium bicarbonate content has a significant impact on the stability of the finished orally disintegrating tablet product.

[0042] The orally disintegrating tablets 1-3 prepared by the formulation of this invention are pre-coated with povidone K30. Under specific formulation composition, content and preparation process, the relationship between orally disintegrating tablet quality, disintegration performance and stability can be balanced. This effectively solves the technical problem that acetylcysteine ​​is easy to absorb moisture and heat, resulting in poor stability of the finished product. It also obtains acetylcysteine ​​orally disintegrating tablets with suitable hardness and compressibility, good content uniformity and stability, few impurities and rapid disintegration.

[0043] Table 2. Results of stability tests on acetylcysteine ​​orally disintegrating tablets.

[0044]

[0045]

[0046] 3. The preparation method of this invention is simple and easy to operate, and the drug has uniform quality and stable properties, making it suitable for large-scale industrial production and possessing good market prospects. Detailed Implementation

[0047] The present invention will be further described below with reference to the embodiments. The embodiments are illustrative and do not constitute a limitation on the scope of protection of the present invention.

[0048] Example 1: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets

[0049] 1. Formula

[0050] Acetylcysteine ​​orally disintegrating tablets were prepared using the formulation in Table 3.

[0051] Table 3. Formulation of Acetylcysteine ​​Orally Disintegrating Tablets, Part 1

[0052] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 colloidal silica 4 1 Povidone K30 2 0.5 Aspartan 8 2 Mannitol 158 39.5 Lemon flavoring 4 1 Sodium carboxymethyl starch 30 7.5 Sodium stearate 2 0.5 microcrystalline cellulose 50 12.5 magnesium stearate 2 0.5 Sodium bicarbonate 40 10 —— —— ——

[0053] 2. Preparation method

[0054] (1) Pass the acetylcysteine ​​raw material through a 60-mesh sieve and set aside; take the amount of acetylcysteine ​​in the formulation, atomize and spray it into the ethanol solution of povidone K30 for coating, and obtain acetylcysteine ​​coated particles. The coating weight gain is 2% based on the mass of acetylcysteine; the temperature of the coating process is controlled at 25-30℃.

[0055] (2) Weigh out the other excipients except lubricant according to the formula amount, mix them evenly with the coating particles in step (1), add the lubricant according to the formula amount, mix evenly, and compress the powder directly into tablets to obtain the oral disintegrating tablet 1.

[0056] Example 2: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets 2

[0057] 1. Formula

[0058] Acetylcysteine ​​orally disintegrating tablets were prepared using the formulation in Table 4.

[0059] Table 4. Formulations of Acetylcysteine ​​Orally Disintegrating Tablets (2 groups)

[0060] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 Sodium bicarbonate 35 8.75 Povidone K30 6 1.5 colloidal silica 6 1.5 Mannitol 142 35.5 Aspartan 6 1.5 Cross-linked polyvinylpyrrolidone 40 10 Lemon flavoring 3 0.75 microcrystalline cellulose 60 15 magnesium stearate 2 0.5

[0061] 2. Preparation method

[0062] (1) Pass the acetylcysteine ​​raw material through a 100-mesh sieve and set aside; take the amount of acetylcysteine ​​in the formulation, atomize and spray it into the ethanol solution of povidone K30 for coating, and obtain acetylcysteine ​​coated particles. The coating weight gain is 6% based on the mass of acetylcysteine; the temperature of the coating process is controlled at 25-30℃.

[0063] (2) Weigh out the other excipients except lubricant according to the formula amount, mix them evenly with the coating particles in step (1), add the lubricant according to the formula amount, mix evenly, and compress the powder directly into tablets to obtain the oral disintegrating tablet 2.

[0064] Example 3: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets 3

[0065] 1. Formula

[0066] Acetylcysteine ​​orally disintegrating tablets were prepared using the formulation in Table 5.

[0067] Table 5. Three formulations of acetylcysteine ​​orally disintegrating tablets

[0068] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 Sodium bicarbonate 50 12.5 Povidone K30 4 1 colloidal silica 2 0.5 Mannitol 174 43.5 Aspartan 4 1 Cross-linked carboxymethyl cellulose sodium 12 3 Lemon flavoring 8 2 microcrystalline cellulose 40 10 Sodium stearate 6 1.5

[0069] 2. Preparation method

[0070] (1) Pass the acetylcysteine ​​raw material through a 150-mesh sieve and set aside; take the amount of acetylcysteine ​​in the formulation, atomize and spray it into the ethanol solution of povidone K30 for coating, and obtain acetylcysteine ​​coated particles. The coating weight gain is 4% based on the mass of acetylcysteine; the temperature during the coating process is controlled at 20-30℃.

[0071] (2) Weigh out the other excipients except lubricant according to the formula amount, mix them evenly with the coating particles in step (1), add the lubricant according to the formula amount, mix evenly, and compress the powder directly into tablets to obtain the oral disintegrating tablet 3.

[0072] Example 4: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets 4

[0073] Based on the formulation and preparation method of Example 2, the coating material povidone K30 was replaced with acrylic resin, and the specific formulation is shown in Table 6, for the preparation of acetylcysteine ​​orally disintegrating tablets. Based on the preparation method of Example 2, the povidone K30 ethanol solution was replaced with a polypropylene resin ethanol solution for the preparation of acetylcysteine ​​orally disintegrating tablets 4.

[0074] Table 6. Four formulations of acetylcysteine ​​orally disintegrating tablets

[0075] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 Sodium bicarbonate 35 8.75 acrylic resin 6 1.5 colloidal silica 6 1.5 Mannitol 142 35.5 Aspartan 6 1.5 Cross-linked polyvinylpyrrolidone 40 10 Lemon flavoring 3 0.75 microcrystalline cellulose 60 15 magnesium stearate 2 0.5

[0076] Example 5: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets

[0077] Based on the formulation of Example 2, the coating material povidone K30 was replaced with hydroxypropyl methylcellulose, and the lubricant magnesium stearate was replaced with sodium stearate fumarate. The specific formulation is shown in Table 7. Based on the preparation method of Example 2, the ethanol solution of povidone K30 was replaced with an aqueous solution of hydroxypropyl methylcellulose in ethanol (hydroxypropyl methylcellulose is insoluble in anhydrous ethanol) for the preparation of acetylcysteine ​​orally disintegrating tablets.

[0078] Table 7. Five formulations of acetylcysteine ​​orally disintegrating tablets

[0079] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 Sodium bicarbonate 35 8.75 Hydroxypropyl methylcellulose 6 1.5 colloidal silica 6 1.5 Mannitol 142 35.5 Aspartan 6 1.5 Cross-linked polyvinylpyrrolidone 40 10 Lemon flavoring 3 0.75 microcrystalline cellulose 60 15 Sodium stearate 2 0.5

[0080] Example 6: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets 6

[0081] 1. Formula

[0082] Acetylcysteine ​​orally disintegrating tablets were prepared using the formulation in Table 8.

[0083] Table 8. Six Formulations of Acetylcysteine ​​Orally Disintegrating Tablets

[0084]

[0085]

[0086] 2. Preparation method

[0087] (1) Pass the acetylcysteine ​​raw material through a 150-mesh sieve and set aside; take the amount of acetylcysteine ​​in the formulation, atomize and spray it into the ethanol solution of povidone K30 for coating, and obtain acetylcysteine ​​coated particles. The weight gain of the coating is 12% based on the mass of acetylcysteine; the temperature of the coating process is controlled at 25-30℃.

[0088] (2) Weigh out the other excipients except lubricant according to the formula amount, mix them evenly with the coating particles in step (1), add the lubricant according to the formula amount, mix evenly, and compress the powder directly into tablets to obtain the oral disintegrating tablet 6.

[0089] Example 7: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets 7

[0090] Acetylcysteine ​​orally disintegrating tablets 7 were prepared using the formulation in Table 9 and the preparation method in Example 2.

[0091] Table 9. Seven Formulations of Acetylcysteine ​​Orally Disintegrating Tablets

[0092] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 Sodium bicarbonate 20 5 Povidone K30 6 1.5 colloidal silica 6 1.5 Mannitol 178 44.5 Aspartan 8 2 Cross-linked polyvinylpyrrolidone 12 3 Lemon flavoring 8 2 microcrystalline cellulose 60 15 magnesium stearate 2 0.5

[0093] Example 8: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets

[0094] Acetylcysteine ​​orally disintegrating tablets 8 were prepared using the formulation in Table 10 and the preparation method in Example 2.

[0095] Table 10. Eight Formulations of Acetylcysteine ​​Orally Disintegrating Tablets

[0096] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 Sodium bicarbonate 64 16 Povidone K30 6 1.5 colloidal silica 2 0.5 Mannitol 142 35.5 Aspartan 8 2 Cross-linked polyvinylpyrrolidone 32 8 Lemon flavoring 4 1 microcrystalline cellulose 40 10 magnesium stearate 2 0.5

[0097] Example 9: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets

[0098] 1. Formula

[0099] Using the formulation in Table 11, acetylcysteine ​​orally disintegrating tablets were prepared without coating the active pharmaceutical ingredient.

[0100] Table 11. Nine formulations of acetylcysteine ​​orally disintegrating tablets

[0101] composition Mass (g) percentage(%) composition Mass (g) percentage(%) Acetylcysteine 100 25 colloidal silica 6 1.5 Mannitol 148 37 Aspartan 6 1.5 Cross-linked polyvinylpyrrolidone 40 10 Lemon flavoring 3 0.75 microcrystalline cellulose 60 15 magnesium stearate 2 0.5 Sodium bicarbonate 35 8.75 —— —— ——

[0102] 2. Preparation method

[0103] Pass the acetylcysteine ​​raw material through a 100-mesh sieve and set aside; take the formulation amount of acetylcysteine ​​and other excipients except lubricant, mix them evenly, then add the formulation amount of lubricant, mix evenly, and directly compress the powder into tablets to obtain orally disintegrating tablets 9.

[0104] Example 10: Preparation of Acetylcysteine ​​Orally Disintegrating Tablets 10

[0105] Acetylcysteine ​​orally disintegrating tablets were prepared using the formulation of Example 2, by compression followed by coating.

[0106] 1. Formula

[0107] The same formulation as in Example 2.

[0108] 2. Preparation method

[0109] (1) Pass the acetylcysteine ​​raw material through a 100-mesh sieve and set aside; take the formulation amount of acetylcysteine ​​and other excipients except lubricant, mix them evenly, then add the formulation amount of lubricant, mix evenly, and directly compress the powder into tablets.

[0110] (2) The tablets in step (1) were coated with polyvinyl ketone K30 ethanol solution to prepare oral disintegrating tablets 10.

[0111] Example 11: Quality assessment of orally disintegrating tablets

[0112] The acetylcysteine ​​orally disintegrating tablets prepared in Examples 1-10 were subjected to in vitro disintegration, hardness, friability, and stability tests.

[0113] 1. Experimental Methods

[0114] 1.1 Hardness Test

[0115] The orally disintegrating tablets prepared in Examples 1-10 were subjected to hardness testing according to the methods in the 2020 edition of the Chinese Pharmacopoeia.

[0116] 1.2 Friability Test

[0117] Orally disintegrating tablets prepared in Examples 1-10 were tested according to the tablet friability test method in Part IV of the 2020 edition of the Chinese Pharmacopoeia. The friability should not exceed 1%.

[0118] 1.3 Compression Ratio Test

[0119] The compression ratio of the granules prepared in Examples 1-10 was determined as follows: 60g of the mixed granules were gently placed into a graduated cylinder, and the initial loose volume was measured. The granules were then brought to their most compacted state using a tapping method, and the final volume was measured. The loosest density and the densest density were calculated. Compression ratio = (densest density - loosest density) / densest density * 100%. When the compression ratio is < 20%, the flowability is good; as the compression ratio increases, the flowability decreases; when the compression ratio is > 40%, the material powder is difficult to flow out of the container.

[0120] 1.4 Content Uniformity Test

[0121] Orally disintegrating tablets prepared in Examples 1-10 were tested according to the content uniformity test method in Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0122] 1.5 Collapse Time Limit Test

[0123] Orally disintegrating tablets prepared in Examples 1-10 were tested according to the disintegration time test method in Part IV of the 2020 edition of the Chinese Pharmacopoeia. The disintegration time should be controlled within 60 seconds.

[0124] 1.6 Stability Test

[0125] Orally disintegrating tablets prepared according to Examples 1-5, 8-9 and 10, which meet general quality testing requirements, were placed in an accelerated chamber at 40°C and 75% relative humidity for 10 days for related substance investigation.

[0126] 2. Test Results

[0127] Table 1. Quality test results of acetylcysteine ​​orally disintegrating tablets

[0128] Orally disintegrating tablets Hardness (N) Friability (%) Compression ratio (%) Content uniformity (%) Disintegration time limit 1 68 ≤1.0 19 5.3 48s 2 70 ≤1.0 16 4.8 40s 3 65 ≤1.0 20 6 55s 4 69 ≤1.0 18 5.8 41s 5 68 ≤1.0 18 5.2 45s 6 35 ≤1.0 28 9.1 1 minute 35 seconds 7 65 ≤1.0 22 6.3 1 minute 25 seconds 8 60 ≤1.0 21 6.5 49s 9 64 ≤1.0 20 7 39s 10 22 ≤1.0 20 6.1 30s

[0129] The test results are shown in Table 12. The hardness, friability, compressibility, and content uniformity of orally disintegrating tablets 1-5 and 9 all meet the pharmacopoeia requirements, and their disintegration time all meet the requirement of "complete disintegration within 60 seconds". Among them, orally disintegrating tablets 1-3 were prepared under the formulation within the scope of protection of this invention, and their hardness was 60-70 N, their compressibility was less than or equal to 20%, their content uniformity was less than or equal to 6%, and their disintegration time was less than or equal to 55 s, all of which meet the relevant pharmacopoeia requirements.

[0130] Orally disintegrating tablets 4 and 5 were prepared by replacing povidone K30 in formulation 2 of the present invention with acrylic resin and hydroxypropyl methylcellulose, respectively; orally disintegrating tablet 9 was prepared by removing the coating material povidone K30 from formulation 2. The hardness, compressibility, content uniformity, and disintegration time of the above three tablets all meet the pharmacopoeia requirements. It is evident that the type of coating material has a relatively small impact on the above indicators.

[0131] Based on orally disintegrating tablet 2, orally disintegrating tablet 6 was prepared by using formulations with the same excipients but outside the scope of protection. This resulted in tablet 6 with a 50% reduction in hardness, a compression ratio >20%, reduced material flowability, poor compressibility, nearly doubled content uniformity, and a 2.4-fold increase in disintegration time (>60s), failing to meet pharmacopoeia requirements. Therefore, the preparation of orally disintegrating tablets using the direct powder compression method places high demands on the properties of diluents, disintegrants, and fillers. Besides strong disintegration performance, good flowability and compressibility are also required. Formulations 1-3 within the scope of protection of this invention are superior in terms of hardness, compression ratio, content uniformity, and disintegration speed.

[0132] Based on orally disintegrating tablet 2, orally disintegrating tablets 7 and 8 were prepared by adjusting the content of sodium bicarbonate outside the protected range and other excipients. The content uniformity of these tablets increased by 1.3 times, and the compression rate was greater than 20%. However, the material flowability was low, with orally disintegrating tablet 7 exhibiting a disintegration time that increased by 2 times (>60s), failing to meet pharmacopoeia requirements. This demonstrates that a specific amount of sodium bicarbonate in the formulation can reduce the compression rate, increase the flowability of the material, and decrease the content uniformity.

[0133] Based on orally disintegrating tablet 2, the povidone K30 coating step was removed, and the mannitol content was adjusted to prepare orally disintegrating tablet 9, which showed an approximately 1.5-fold increase in content uniformity. Orally disintegrating tablet 10 was prepared by mixing acetylcysteine ​​with other excipients, adding a lubricant, directly compressing the powder, and then coating with povidone K30. This resulted in a 69% reduction in hardness, a compression rate >20%, and poor tablet surface smoothness with fine lines. It is evident that premixing and coating with acetylcysteine ​​and povidone K30 increases the flowability of the active pharmaceutical ingredient (API), reduces the reaction between the API and alkaline excipients, and improves the compressibility, content uniformity, and disintegration rate of the API in tablets. However, after changing the process flow, the effect of povidone K30 on the API is not achieved, and tablets prepared from specific formulations with high disintegration rates are easily affected by the coating process, becoming loose and showing reduced hardness. Therefore, premixing the API with povidone K30 is a necessary step for achieving better compressibility and content uniformity in orally disintegrating tablets.

[0134] Table 2. Results of stability tests on acetylcysteine ​​orally disintegrating tablets.

[0135]

[0136] The test results are shown in Table 13. Orally disintegrating tablets 1-3 prepared using the formulation and preparation method within the scope of protection of this invention were placed in a high temperature and high humidity accelerated chamber for 10 days. The content of related substances in these tablets all met the limit requirements, and the finished products showed good stability.

[0137] Orally disintegrating tablets 4 and 5 were prepared by replacing povidone K30 in formulation 2 of this invention with acrylic resin and hydroxypropyl methylcellulose, respectively. Under high temperature and high humidity conditions, the N,S-diacetylcysteine ​​content of orally disintegrating tablets 4 and 5 was 80 times and 70 times that of orally disintegrating tablet 2, respectively; the contents of cystine, L-cysteine ​​and other related substances were significantly increased. Among them, the total impurity content of orally disintegrating tablets 4 and 5 increased by 24 times and 15 times, respectively, compared with orally disintegrating tablet 2, far exceeding the limits for related substances in the pharmacopoeia.

[0138] The orally disintegrating tablet 9 obtained from the decoating step of orally disintegrating tablet 2 of this invention has an N,S-diacetylcysteine ​​content that is 50 times higher than that of orally disintegrating tablet 2 under high temperature and high humidity conditions. The content of other related substances increases by more than 10 times, and the contents of N,N'-diacetylcysteine, the total known impurities, other individual impurities, and the total impurities all significantly exceed the limits for related substances. Combining orally disintegrating tablets 2, 4, 5, and 9, it is evident that acetylcysteine ​​can only be effectively isolated from other excipients after premixing with povidone K30, reducing the reaction between the active pharmaceutical ingredient and alkaline excipients and the impact during preparation, thereby reducing impurity generation, effectively controlling drug stability, and mitigating the impact of high temperature and high humidity on the impurity content of the drug.

[0139] Based on orally disintegrating tablet 2, a modified process was used to produce orally disintegrating tablet 10, which involved mixing and compressing the raw materials and excipients before coating. This resulted in a significant increase in the content of related substances under high temperature and high humidity conditions. Specifically, the content of N,S-diacetylcysteine ​​was 60 times that of orally disintegrating tablet 2. The content of N,N'-diacetylcysteine, the total known impurities, other individual impurities, and the total impurities were all more than 10 times higher than in orally disintegrating tablet 2, failing to meet the related substance limits. Comparison of the test results of orally disintegrating tablets 2, 4, 5, and 9 indicates that the type, content, and order of coating materials are key technologies of this invention. Adjusting the formulation has a significant impact on the stability, content uniformity, and disintegration of the orally disintegrating tablets.

[0140] Based on orally disintegrating tablet 2, orally disintegrating tablet 8 was prepared by adjusting the sodium bicarbonate content outside the protected range. Under high temperature and high humidity conditions, the content of related substances increased significantly, with N,S-diacetylcysteine ​​being 70 times that of orally disintegrating tablet 2, and the content of other related substances increasing by more than 10 times, all failing to meet the pharmacopoeia limits. This indicates that the sodium bicarbonate content is related to the stability of acetylcysteine ​​orally disintegrating tablets; only within a specific ratio range can multiple requirements such as disintegration time and stability be simultaneously met.

[0141] In summary, based on the general quality and stability test results in Example 11, it can be seen that the present invention, under specific formulation and preparation process, produces acetylcysteine ​​orally disintegrating tablets with suitable hardness and compressibility, good content uniformity and stability, few impurities, and rapid disintegration; and solves the problem of poor stability of finished products due to the sensitivity of acetylcysteine ​​to moisture and heat, and reduces the content of impurities generated during storage.

Claims

1. An acetylcysteine ​​orally disintegrating tablet, characterized in that, The orally disintegrating tablets are composed of the following components and their mass percentages: acetylcysteine ​​25% (w / w), povidone K30 0.5-1.5% (w / w), diluent 35-45% (w / w), disintegrant 3-10% (w / w), filler 10-15% (w / w), sodium bicarbonate 8-13% (w / w), glidant 0.5-1.5% (w / w), flavoring agent 2-4% (w / w), and lubricant 0.5-1.5% (w / w), the total mass percentage of the components being 100%. The preparation method of the orally disintegrating tablets includes the following steps: acetylcysteine ​​is pre-coated with povidone K30, the coated particles are mixed evenly with other excipients except lubricant, then lubricant is added and mixed evenly, and the powder is directly compressed into tablets to obtain the orally disintegrating tablets. The diluent is one or more of mannitol, sorbitol, and lactose, and the filler is one or more of microcrystalline cellulose, starch, and sucrose.

2. The orally disintegrating tablet according to claim 1, characterized in that, The disintegrant is one or more of crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose.

3. The orally disintegrating tablet according to claim 1, characterized in that, The flow aid is either talc or colloidal silica.

4. The orally disintegrating tablet according to claim 1, characterized in that, The lubricant is at least one of sodium stearate fumarate and magnesium stearate.

5. The orally disintegrating tablet according to claim 1, characterized in that, The flavoring agents are aspartame and lemon flavoring.

6. The orally disintegrating tablet according to claim 1, characterized in that, The preparation method includes the following steps: (1) Pass the acetylcysteine ​​raw material through a 60-150 mesh sieve for later use; take the amount of acetylcysteine ​​in the formulation, atomize and spray it into polyvinylpyrrolidone K30 at 20-30℃ for coating, and obtain acetylcysteine ​​coated granules. (2) Weigh out the other excipients except lubricant according to the formula amount, mix them evenly with the coating particles in step (1), add the lubricant according to the formula amount, mix evenly, and compress into tablets to obtain the acetylcysteine ​​orally disintegrating tablets.

7. The orally disintegrating tablet according to claim 6, characterized in that, In step (1), acetylcysteine ​​is passed through a 60-100 mesh sieve, and the coating process temperature is 25-30℃. The resulting acetylcysteine-coated granules have a weight gain of 2-6% based on the mass of acetylcysteine.

8. The orally disintegrating tablet according to any one of claims 6 or 7, characterized in that, The prepared acetylcysteine ​​orally disintegrating tablets had a hardness of 65-90 N.

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