Carbocisteine tablets and process for their preparation
By using glycine as a co-solvent and a compound stabilizer system of sodium bisulfite and propylene glycol alginate, the preparation process was optimized, solving the stability and dissolution problems of carboxymethylcysteine tablets, achieving rapid drug release and improved stability, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG NEW TIME PHARMA CO LTD
- Filing Date
- 2026-04-15
- Publication Date
- 2026-06-05
AI Technical Summary
Existing carbocysteine tablets have shortcomings in terms of stability and dissolution, resulting in unstable efficacy and incomplete drug absorption, which affects clinical efficacy.
Glycine was used as a co-solvent, combined with a complex stabilizer system of sodium bisulfite and propylene glycol alginate. Through precise premix preparation and process parameter control, the types and ratios of disintegrants were optimized, resulting in a simple and controllable preparation process.
It significantly improves the dissolution and stability of carboxycysteine tablets, ensuring rapid and full release of the drug in vivo, improving bioavailability, and reducing the risk of quality fluctuations during the production process.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a carboxycysteine tablet and its preparation method. Background Technology
[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
[0003] Chronic bronchitis, bronchial asthma, and chronic obstructive pulmonary disease (COPD) are respiratory diseases with high global prevalence. They often cause symptoms such as thick sputum and difficulty expectorating, severely impacting patients' respiratory function and quality of life, and even endangering their lives. The core pathological mechanisms of these diseases include airway mucus hypersecretion, inflammatory response, and oxidative stress damage. Therefore, there is an urgent need for safe and effective expectorants to improve mucus secretion, reduce sputum viscosity, promote sputum expectoration, alleviate clinical symptoms, and reduce the risk of acute exacerbations.
[0004] Carbocysteine, as a mucus modifier, has a thiol group (-SH) in its molecular structure. Its core mechanism of action is: (1) regulating the secretion of bronchial glands, increasing the secretion of low-viscosity salivary mucin, reducing the production of high-viscosity fucose, reducing sputum viscosity, and making it easier to cough up. (2) having antioxidant and anti-inflammatory properties, it can scavenge oxygen free radicals, reduce the damage of oxidative stress to airway cells, inhibit the release of inflammatory factors, and alleviate airway inflammatory reactions. (3) promoting the movement of cilia in the respiratory mucosa, enhancing airway clearance function, and helping to improve ventilation efficiency. Carbocysteine tablets have become a commonly used drug in clinical expectorant treatment due to their rapid onset of action, high safety, and wide applicability. They are widely used in the treatment of sputum viscosity-related symptoms in adults and children.
[0005] Although the clinical value of carbocysteine is clear, the existing carbocysteine tablets have the following shortcomings in terms of formulation performance and stability: (1) Poor stability: The thiol group in the carbocysteine molecule is easily oxidized, leading to drug degradation and affecting efficacy. In addition, the formulation may experience discoloration and content reduction during storage, requiring strict control of storage conditions. (2) Poor dissolution: Carbocysteine is poorly soluble in water, with a solubility of only 1.6 mg / mL in water. It is a poorly soluble drug, so dissolution is a key factor affecting drug absorption.
[0006] Existing formulations often fail to achieve ideal dissolution rates, leading to incomplete drug absorption and low bioavailability, thus hindering their full clinical efficacy. Therefore, developing a carboxycysteine tablet with high stability and good dissolution rate, along with its preparation method, is of great significance for enhancing the clinical application value of this drug. Summary of the Invention
[0007] In view of the technical defects in stability and dissolution of carbocysteine tablets in the prior art, the core objective of this invention is to provide a carbocysteine tablet with excellent dissolution, high stability and simple and controllable preparation process and its corresponding preparation method, so as to overcome the shortcomings of the prior art and improve the clinical application value of the drug.
[0008] The carboxymethylcysteine tablets of the present invention, by weight, have the following formulation: Active ingredient: 10-25 parts of carboxymethylcysteine. 10-50 parts of filler, selected from one or more of starch, mannitol, lactose, microcrystalline cellulose, sorbitol, and maltodextrin, preferably a combination of lactose, microcrystalline cellulose, and maltodextrin. 2-8 parts of disintegrant, selected from one or more of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone carboxymethyl cellulose, and sodium alginate, preferably a combination of crospovidone and sodium carboxymethyl starch. 1-3 parts of solubilizer, glycine. 0.5-1.5 parts of stabilizer, a compound system of sodium bisulfite and propylene glycol alginate, wherein sodium bisulfite is 0.3-1.0 parts and propylene glycol alginate is 0.2-0.5 parts. 0.25-1 part of lubricant, selected from one or more of micronized silica gel, talc, and magnesium stearate, preferably magnesium stearate.
[0009] The carboxymethylcysteine tablets of the present invention are prepared through the following steps, the core of which lies in the precise preparation of the premix and the control of process parameters in each step: (1) Preparation of premix: Weigh the prescribed amount of glycine and sodium bisulfite, mix them evenly, and then add them to purified water at a constant temperature of 40-50℃. Stir until completely dissolved. Then add the prescribed amount of propylene glycol alginate and continue stirring for 30-40 minutes to allow the components to fully react. Dry the resulting mixture at 60℃ to constant weight. After drying, pulverize and sieve the solid material to obtain the premix. This step allows the cosolvent and stabilizer to form a composite system, laying the foundation for improving drug dissolution and stability in the future.
[0010] (2) Material mixing: Weigh the formula amount of carboxymethylcysteine, filler and disintegrant, pass them through an 80-mesh sieve, and place them together with the premixed mixture prepared above in a mixing device. Mix until the system is uniform to ensure that each functional component is dispersed in a consistent manner.
[0011] (3) Blending: Add the formula amount of lubricant to the uniformly mixed material and blend to obtain a free-flowing powder to be compressed.
[0012] (4) Tableting: Put the powder to be compressed into the tablet press, adjust the appropriate tableting parameters (pressure, speed, etc.), and compress it to form the tablet. Carboxymethylcysteine tablets are then obtained.
[0013] Compared with the prior art, the present invention has the following significant technical effects: (1) Significantly improved dissolution rate: By selecting glycine as a dedicated solubilizer and optimizing the type and ratio of disintegrants, and in conjunction with a specific preparation process, the dissolution efficiency of the carboxymethylcysteine tablets of this invention is significantly improved. According to the dissolution test method in the Chinese Pharmacopoeia, the dissolution rate can reach more than 95% after 30 minutes, ensuring rapid and sufficient release of the drug in vivo and improving bioavailability.
[0014] (2) Significantly enhanced stability: The present invention uses a compound stabilizer system of sodium bisulfite and propylene glycol alginate. The two work together to exert antioxidant and degradation-inhibiting effects. At the same time, the premixing preparation process enables the stabilizer and the drug to form an effective protective mechanism, which significantly improves the stability of the formulation.
[0015] (3) The preparation process is simple and controllable: The preparation method of the present invention has clear steps and clear process parameters. No special equipment is required, which is suitable for industrial production. The optimized design of each step can ensure the uniformity of product quality and reduce the risk of quality fluctuations during the production process. Detailed Implementation
[0016] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.
[0017] Example 1: Carboxymethylcysteine tablets formula:
[0018] Preparation method: (1) Preparation of premix: Weigh glycine and sodium bisulfite, mix them evenly, put the mixed material into purified water at a constant temperature of 40-50℃, stir until completely dissolved, add the formula amount of propylene glycol alginate, continue stirring for 30-40 minutes, dry the resulting mixture at 60℃ to constant weight, crush the dried solid material, and sieve it to obtain the premix. (2) Material mixing: Weigh carboxymethylcysteine, filler, disintegrant, and place them in a mixing device with the premixed mixture prepared above, and mix until the system is homogeneous; (3) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (4) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets. Carboxymethylcysteine tablets are then obtained.
[0019] Example 2: Carboxymethylcysteine tablets formula:
[0020] Preparation method: (1) Preparation of premix: Weigh glycine and sodium bisulfite, mix them evenly, put the mixed material into purified water at a constant temperature of 40-50℃, stir until completely dissolved, add the formula amount of propylene glycol alginate, continue stirring for 30-40 minutes, dry the resulting mixture at 60℃ to constant weight, crush the dried solid material, and sieve it to obtain the premix. (2) Material mixing: Weigh carboxymethylcysteine, filler, disintegrant, and place them in a mixing device with the premixed mixture prepared above, and mix until the system is homogeneous; (3) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (4) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets. Carboxymethylcysteine tablets are then obtained.
[0021] Example 3: Carboxymethylcysteine tablets formula:
[0022] Preparation method: (1) Preparation of premix: Weigh glycine and sodium bisulfite, mix them evenly, put the mixed material into purified water at a constant temperature of 40-50℃, stir until completely dissolved, add the formula amount of propylene glycol alginate, continue stirring for 30-40 minutes, dry the resulting mixture at 60℃ to constant weight, crush the dried solid material, and sieve it to obtain the premix. (2) Material mixing: Weigh carboxymethylcysteine, filler, disintegrant, and place them in a mixing device with the premixed mixture prepared above, and mix until the system is homogeneous; (3) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (4) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets. Carboxymethylcysteine tablets are then obtained.
[0023] Example 4: Carboxymethylcysteine tablets formula:
[0024] Preparation method: (1) Preparation of premix: Weigh glycine and sodium bisulfite, mix them evenly, put the mixed material into purified water at a constant temperature of 40-50℃, stir until completely dissolved, add the formula amount of propylene glycol alginate, continue stirring for 30-40 minutes, dry the resulting mixture at 60℃ to constant weight, crush the dried solid material, and sieve it to obtain the premix. (2) Material mixing: Weigh carboxymethylcysteine, filler, disintegrant, and place them in a mixing device with the premixed mixture prepared above, and mix until the system is homogeneous; (3) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (4) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets. Carboxymethylcysteine tablets are then obtained.
[0025] Comparative Example 1: Carbocysteine Tablets formula:
[0026] Preparation method: Same as Example 1.
[0027] Comparative Example 2: Carbocysteine Tablets formula:
[0028] Preparation method: Same as Example 1.
[0029] Comparative Example 3: Carbocysteine Tablets formula:
[0030] Preparation method: Same as Example 1.
[0031] Comparative Example 4: Carbocysteine Tablets formula:
[0032] Preparation method: Same as Example 1.
[0033] Comparative Example 5: Carbocysteine Tablets formula:
[0034] Preparation method: Same as Example 1.
[0035] Comparative Example 6: Carbocysteine Tablets formula:
[0036] Preparation method: Same as Example 1.
[0037] Comparative Example 7: Carbocysteine Tablets formula:
[0038] Preparation method: Same as Example 1.
[0039] Comparative Example 8: Carbocysteine Tablets Formula: Same as Example 1.
[0040] Preparation method: (1) Material mixing: Weigh carboxymethylcysteine, solubilizer, stabilizer, filler and disintegrant and place them in a mixing device and mix until the system is homogeneous; (2) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (3) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets, thus obtaining carboxymethylcysteine tablets.
[0041] Comparative Example 9: Carbocysteine Tablets Formula: Same as Example 1.
[0042] Preparation method: (1) Preparation of premix: Weigh glycine and sodium bisulfite, mix them evenly, put the mixed material into purified water at a constant temperature of 40-50℃, stir until completely dissolved, add the formula amount of propylene glycol alginate and carboxymethylcysteine, continue stirring for 30-40 minutes, dry the resulting mixture at 60℃ to constant weight, crush the dried solid material, and sieve to obtain the premix; (2) Material mixing: Weigh the filler and disintegrant, and place them in a mixing device with the premixed mixture prepared above, and mix until the system is homogeneous; (3) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (4) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets. Carboxymethylcysteine tablets are then obtained.
[0043] Commercially available formulation: Carbocysteine tablets, National Drug Approval Number H44021061 Carbocysteine tablets dissolution The dissolution rate of carbocysteine tablets was determined according to the Dissolution and Release Determination Method (General Chapter 0931, Method 1) in the Chinese Pharmacopoeia. Dissolution conditions: 1000 ml of phosphate buffer (pH 6.6) was used as the dissolution medium, and the rotation speed was 100 rpm. The procedure was followed, and samples were taken after 30 minutes. Test solution: 10 ml of the dissolution solution was taken, filtered, and the filtrate was collected. Reference solution: Approximately 12.5 mg of carbocysteine reference standard was accurately weighed, placed in a 50 ml volumetric flask, dissolved and diluted to the mark with the dissolution medium, and shaken well. Assay: Accurately measure 2 ml (0.25 g specification) or 5 ml (0.1 g specification) of the test solution and 2 ml of the reference solution, and place them in separate 50 ml volumetric flasks. Accurately add 2 ml of 2% ninhydrin solution and 2 ml of dissolution medium, shake well, heat in a water bath for 15 minutes, remove, cool, dilute with water to the mark, shake well, and measure the absorbance at a wavelength of 567 nm using ultraviolet-visible spectrophotometry (General Rule 0401). Calculate the dissolution amount of each tablet.
[0044] Table 1. Dissolution of Carboxymethylcysteine Tablets
[0045] Table 1 shows the dissolution rate of carboxymethylcysteine tablets. The carboxymethylcysteine tablets of the present invention exhibit superior release performance during dissolution, and the active ingredient can be released more quickly and fully, which can better meet the dissolution efficiency required for in vivo absorption.
[0046] Stability of carboxymethylcysteine tablets Accelerated testing conditions: temperature 40℃±2℃, relative humidity 75%±5%, 6 months. The carbocysteine content in carbocysteine tablets was determined according to the Chinese Pharmacopoeia.
[0047] Table 2. Accelerated Test Carbohydrate Content
[0048] Table 2 shows that, under harsh accelerated storage conditions, the carboxymethylcysteine tablets of the present invention can maintain the content of the active ingredient well, exhibiting outstanding stability and the active ingredient is not easily degraded. In contrast, under the same conditions, the content of the active ingredient in Comparative Examples 1-9 and commercially available formulations decreased more significantly, indicating insufficient stability under high temperature and high humidity environments, making it difficult to guarantee the efficacy concentration during storage.
[0049] Long-term test conditions: temperature 25℃±2℃, relative humidity 60%±10%, 12 months.
[0050] Table 3. Carbohydrate content in long-term trials
[0051] Table 3 shows that the carbocysteine tablets of the present invention maintain good stability during long-term storage, with a small decrease in the content of the active ingredient, and can maintain a stable level of efficacy over a relatively long period. In contrast, the content of the active ingredient in the comparative ratios and commercially available formulations continues to decrease with prolonged storage time, and the efficacy may be significantly affected after long-term storage, making it impossible to guarantee the consistency of the medication effect.
[0052] Appearance of carboxymethylcysteine tablets Accelerated and long-term tests were conducted to examine the appearance changes of carboxymethylcysteine tablets.
[0053] Table 4. Appearance changes of carboxymethylcysteine tablets
[0054] Table 4 shows that the carboxymethylcysteine tablets of the present invention maintained stable appearance during both accelerated and long-term tests, remaining consistently white or off-white tablets without significant discoloration, spots, or other abnormal changes. This performance indirectly confirms the stability of its components. In contrast, Comparative Examples 1-9 and commercially available formulations all exhibited varying degrees of appearance changes during storage, mostly manifesting as yellowing and the appearance of light-colored spots, with the changes becoming more pronounced over time, reflecting a lack of stability.
Claims
1. A carboxymethylcysteine tablet, characterized in that, The carboxymethylcysteine tablets, by weight, consist of: 10-25 parts carboxymethylcysteine, 10-50 parts filler, 2-8 parts disintegrant, 1-3 parts solubilizer, 0.5-1.5 parts stabilizer, and 0.25-1 part lubricant.
2. The carboxymethylcysteine tablets according to claim 1, characterized in that, The co-solvent is glycine.
3. The carboxymethylcysteine tablets according to claim 1, characterized in that, The stabilizer is sodium bisulfite and propylene glycol alginate.
4. The carboxymethylcysteine tablets according to claim 1, characterized in that, The stabilizer is 0.3-1.0 parts of sodium bisulfite and 0.2-0.5 parts of propylene glycol alginate.
5. The carboxymethylcysteine tablets according to claim 1, characterized in that, The filler is selected from one or more of starch, mannitol, lactose, microcrystalline cellulose, sorbitol, and maltodextrin. Preferably, the filler is lactose, microcrystalline cellulose, or maltodextrin.
6. The carboxymethylcysteine tablets according to claim 1, characterized in that, The disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone sodium carboxymethyl cellulose, and sodium alginate. Preferably, the disintegrant is crospovidone or sodium carboxymethyl starch.
7. The carboxymethylcysteine tablets according to claim 1, characterized in that, The lubricant is selected from one or more of micronized silica gel, talc, and magnesium stearate, preferably magnesium stearate.
8. A method for preparing the carboxymethylcysteine tablets according to claim 1, characterized in that, The preparation method includes the following steps: (1) Preparation of premix: Glycine and sodium bisulfite are mixed evenly and dissolved in purified water at 40-50℃. Propylene glycol alginate is added and stirred. The mixture is dried, pulverized and sieved to obtain the premix. (2) Material mixing: Weigh carboxymethylcysteine, filler, disintegrant, and premix and mix them; (3) Blending: Add lubricant to the above mixture and blend. (4) Tableting.
9. The preparation method according to claim 8, characterized in that, The preparation method includes the following steps: (1) Preparation of premix: Weigh glycine and sodium bisulfite, mix them evenly, put the mixed material into purified water at a constant temperature of 40-50℃, stir until completely dissolved, add the amount of propylene glycol alginate in the formula, continue stirring for 30-40 minutes, dry the resulting mixture at 60℃ to a semi-dry state, then raise the temperature to 80℃ to dry to a constant weight, crush the dried solid material, and sieve it to obtain the premix; (2) Material mixing: Weigh carboxymethylcysteine, filler, disintegrant, and place them in a mixing device with the premixed mixture prepared above, and mix until the system is homogeneous; (3) Blending: Add lubricant to the above uniformly mixed material and blend to obtain the powder to be compressed into tablets; (4) Tableting: Put the powder to be compressed into the tablet press, adjust the tableting parameters, and compress it to form the tablets. Carboxymethylcysteine tablets are then obtained.