Carbocisteine oral solution and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations for treating respiratory system diseases, and particularly relates to a carbocisteine oral solution and a preparation method thereof. The carbocisteine oral solution disclosed by the invention is prepared from carbocisteine, sorbitan tristearate, tragacanth gum, a sweetening agent and water. By optimizing a prescription and a preparation process, the solubility of carbocisteine is remarkably improved, and the carbocisteine oral solution is not added with a preservative, is qualified in microbial limit, can achieve the same effect as a carbocisteine oral solution added with the preservative, and is high in stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations for treating respiratory diseases, and specifically relates to a carbocysteine ​​oral solution and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Carbocysteine ​​is a mucus regulator that mainly affects the secretion of bronchial glands at the cellular level, increasing the secretion of low-viscosity salivary mucins and reducing the production of high-viscosity fucoxanthins, thereby reducing the viscosity of sputum and making it easier to cough up. Specifically, carbocysteine ​​is an expectorant that is mainly used to treat symptoms such as thick sputum and difficulty in expectoration caused by diseases such as chronic bronchitis and bronchial asthma. It can also be used to treat bronchiectasis, tuberculosis, and asthma combined with excessive bronchial secretions. In addition, it can also be used to prevent and treat postoperative difficulty in expectoration and pneumonia complications, as well as to prevent non-suppurative otitis and deafness in children. Its main mechanism of action is to inhibit blood-gas barrier dysfunction by selectively antagonizing pulmonary surfactant and protein carriers of the blood-gas barrier. At the same time, it can also break the mucopolysaccharide fibers in sputum, reduce the viscosity of sputum, and make sputum easier to cough up. In addition, carbocysteine ​​can enhance the clearance ability of bronchial mucosal ciliary epithelial cells, reduce the retention of sputum in the respiratory tract, and promote the excretion of fine particles and harmful substances from the lungs. Common dosage forms include tablets, granules, solutions, etc.

[0004] Liquid preparations refer to liquid dispersion systems for oral or external use in which drugs are dispersed in a certain form in a liquid medium. They have the following advantages: (1) large dispersion and fast absorption; (2) reduced drug irritation. However, since carbocysteine ​​has a low solubility in water (only about 0.16%), although the solubility of carbocysteine ​​after salt formation is improved, its aqueous solution is acidic. In actual application, it is found that after long-term storage, the solution will change from a clear state to a flocculent state and degrade impurities, which poses a hidden danger to drug safety.

[0005] The Chinese patent with publication number CN114617840A discloses a carbocysteine ​​oral solution, which comprises 2-3% carbocysteine, 5-10% pregelatinized starch, 5-20% saccharin sodium, 1-3% sodium hydroxide and 0.2-0.3% sodium methyl paraben as a preservative. The carbocysteine ​​oral solution has excellent long-term stability and good taste. The pregelatinized starch increases its taste and solubility to prevent the precipitation of insoluble raw materials. The oral solution is still stable and clear after being stored at room temperature for 36 months, and the content of the active ingredient decreases to between 0.1% and 0.3%.

[0006] Chinese patent publication number CN109498555A discloses a carbocysteine ​​oral solution and a preparation method thereof. Cyclodextrin inclusion technology is used to improve the water solubility of carbocysteine. A pH regulator, a flavoring agent, a mucilage agent and a preservative are added to obtain a carbocysteine ​​oral solution with a smooth taste and sweet and sour taste.

[0007] Chinese patent publication number CN115137693A discloses an oral carbocysteine ​​preparation and a preparation method thereof, which is an oral preparation prepared from raw materials and auxiliary materials including the following weight percentages: 50-75 parts of carbocysteine ​​and 3-15 parts of hydroxyethyl cellulose; or 50-75 parts of carbocysteine ​​and 1-15 parts of xanthan gum, thereby reducing the safety risks during storage and use.

[0008] Most of the existing technologies have the following three defects: (1) containing preservatives, which poses a safety risk; (2) poor stability; and (3) low solubility of carbocysteine. Summary of the invention

[0009] To overcome the deficiencies of the prior art, the present invention provides a carbocysteine ​​oral solution which is free of preservatives and has high safety and stability.

[0010] The invention provides a prescription and preparation method of a carbocysteine ​​oral solution, wherein the carbocysteine ​​oral solution is composed of 500 parts by weight of carbocysteine, 80 to 120 parts by weight of sorbitan tristearate, 30 to 70 parts by weight of tragacanth gum, a sweetener and water. The preparation method comprises the following steps: (1) dissolving sorbitan tristearate in a proper amount of buffer solution A with a pH value of 8.0 to 9.0, mixing tragacanth gum with a proper amount of water, stirring to prepare a viscous substance, and uniformly mixing the viscous substance with the buffer solution containing sorbitan tristearate to obtain a solution 1; (2) micronizing carbocysteine, adding the viscous substance to the solution 1 obtained in step (1) and uniformly mixing the viscous substance, then adding buffer solution B to adjust the pH value to 6.0 to 7.0, adding water to the full amount, and introducing an inert gas to obtain the solution 1.

[0011] It should be noted that the present invention adjusts pH twice, and it is found that the first adjustment of pH is about 8 to 9, and the second adjustment of pH is about 6 to 7, which can improve the solubility and dispersibility of carbocysteine, and can also improve the stability and antibacterial ability of carbocysteine ​​oral solution. In addition, a comparative experiment on nitrogen gas flow is also conducted, and it is found that nitrogen gas flow does not greatly affect the stability and antibacterial property of carbocysteine ​​oral solution, and nitrogen gas flow is only an auxiliary effect to exclude oxygen.

[0012] In many embodiments, the sweetener is selected from at least one of sucrose, monosaccharide syrup, saccharin sodium, sucralose, aspartame, neotame, and mannitol. It should be noted that the selection of sweeteners is a routine skill of those skilled in the art, and R&D personnel can adjust the type and amount according to needs.

[0013] In the above preparation method, the buffer solution A is selected from one of sodium barbital-hydrochloric acid buffer solution, Tris-hydrochloric acid buffer solution, and glycine-sodium hydroxide buffer solution. The buffer solution B is selected from one of potassium dihydrogen phosphate-sodium hydroxide buffer solution, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, and citric acid-sodium citrate buffer solution.

[0014] In a preferred embodiment, the pH of the buffer solution A is 8.5, and the pH of the buffer solution B is 6.5.

[0015] In an embodiment, the inert gas is nitrogen.

[0016] Generally, the toxicity of surfactants is in the order of "cationic surfactants > anionic surfactants > nonionic surfactants". Therefore, the present invention screened nonionic surfactants and unexpectedly found that Span 65 (sorbitan tristearate) mixed with tragacanth gum at a certain pH value can enhance the ability to dissolve and disperse carbocysteine.

[0017] Meanwhile, the carbocysteine ​​oral solution provided by the present invention does not contain any preservatives, has a qualified microbial limit, can achieve the same effect as the carbocysteine ​​oral solution containing preservatives, and has high stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : Changes in the contents of related substances in long-term tests of carbocisteine ​​oral solutions of Examples 1 to 3 and Comparative Examples 1 to 8. DETAILED DESCRIPTION

[0019] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Example 1 Carbocisteine ​​oral solution

[0021] formula:

[0022] Carbocisteine ​​500mg

[0023]

[0024] Preparation method:

[0025] (1) dissolving sorbitan tristearate in an appropriate amount of sodium barbital-hydrochloric acid buffer solution with a pH of 8.5, mixing tragacanth gum with an appropriate amount of water, stirring to make a viscous substance, and uniformly mixing with the buffer solution containing sorbitan tristearate to obtain solution 1;

[0026] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0027] Example 2 Carbocisteine ​​oral solution

[0028] formula:

[0029]

[0030] Preparation method:

[0031] (1) dissolving sorbitan tristearate in a proper amount of Tris-HCl buffer solution having a pH of 8.0, mixing tragacanth gum with a proper amount of water, stirring to form a viscous substance, and uniformly mixing the viscous substance with the buffer solution containing sorbitan tristearate to obtain solution 1;

[0032] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add potassium dihydrogen phosphate-sodium hydroxide buffer to adjust the pH to 6.0, add water to the total amount, and introduce nitrogen to obtain the product.

[0033] Example 3 Carbocisteine ​​oral solution

[0034] formula:

[0035]

[0036]

[0037] Preparation method:

[0038] (1) dissolving sorbitan tristearate in an appropriate amount of glycine-sodium hydroxide buffer solution having a pH of 9.0, mixing tragacanth gum with an appropriate amount of water, stirring to form a viscous substance, and uniformly mixing the viscous substance with the buffer solution containing sorbitan tristearate to obtain solution 1;

[0039] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add citric acid-sodium citrate buffer to adjust the pH to 7.0, add water to the total amount, and introduce nitrogen to obtain the product.

[0040] Comparative Example 1 Carbocisteine ​​Oral Solution

[0041] formula:

[0042]

[0043] Preparation method:

[0044] (1) mixing tragacanth gum with an appropriate amount of a sodium barbital-hydrochloric acid buffer solution having a pH of 8.5, stirring, and uniformly mixing with a buffer solution containing sorbitan tristearate to obtain a solution 1;

[0045] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0046] Comparative Example 2 Carbocisteine ​​Oral Solution

[0047] formula:

[0048]

[0049] Preparation method:

[0050] (1) dissolving sorbitan tristearate in an appropriate amount of sodium barbital-hydrochloric acid buffer solution having a pH of 8.5 to obtain solution 1;

[0051] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0052] Comparative Example 3 Carbocisteine ​​Oral Solution

[0053] formula:

[0054]

[0055] Preparation method:

[0056] (1) dissolving sorbitan tristearate in an appropriate amount of sodium barbital-hydrochloric acid buffer solution with a pH of 8.5, mixing tragacanth gum with an appropriate amount of water, stirring to make a viscous substance, and uniformly mixing with the buffer solution containing sorbitan tristearate to obtain solution 1;

[0057] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0058] Comparative Example 4 Carbocisteine ​​Oral Solution

[0059] formula:

[0060]

[0061] Preparation method:

[0062] (1) dissolving Tween 80 in an appropriate amount of sodium barbital-hydrochloric acid buffer solution with a pH of 8.5, mixing tragacanth gum with an appropriate amount of water, stirring to form a viscous substance, and mixing the mixture evenly with the buffer solution containing Tween 80 to obtain solution 1;

[0063] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0064] Comparative Example 5 Carbocisteine ​​Oral Solution

[0065] formula:

[0066]

[0067]

[0068] Preparation method:

[0069] (1) dissolving sorbitan tristearate in an appropriate amount of sodium barbital-hydrochloric acid buffer solution with a pH of 8.5, mixing gum arabic with an appropriate amount of water, stirring to make a viscous substance, and uniformly mixing with the buffer solution containing sorbitan tristearate to obtain solution 1;

[0070] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0071] Comparative Example 6 Carbocisteine ​​Oral Solution

[0072] formula:

[0073]

[0074] Preparation method:

[0075] (1) dispersing sorbitan tristearate and tragacanth gum in an appropriate amount of water, adding an appropriate amount of sodium barbital-hydrochloric acid buffer solution with a pH of 8.5 to obtain solution 1;

[0076] (2) Powder carbocysteine, add it to the solution 1 of step (1) and mix well, then add disodium hydrogen phosphate-potassium dihydrogen phosphate buffer to adjust the pH to 6.5, add water to the total amount, and introduce nitrogen to obtain the product.

[0077] Comparative Example 7 Carbocisteine ​​Oral Solution

[0078] formula:

[0079]

[0080]

[0081] Preparation method:

[0082] (1) dissolving sorbitan tristearate in an appropriate amount of sodium barbital-hydrochloric acid buffer solution with a pH of 8.5, mixing tragacanth gum with an appropriate amount of water, stirring to make a viscous substance, and uniformly mixing with the buffer solution containing sorbitan tristearate to obtain solution 1;

[0083] (2) Carbocisteine ​​is micronized and added to the solution 1 of step (1) and mixed evenly. Then, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer is added to adjust the pH to 6.5. Methylparaben is added and water is added to the total amount. Nitrogen is introduced to obtain the product.

[0084] Comparative Example 8 Commercially available carbocisteine ​​oral solution (National Medicine Standard H41020535)

[0085] Quality evaluation of carbocisteine ​​oral solution in embodiments and comparative examples

[0086] A long-term test was designed, and the carbocisteine ​​oral solutions of Examples 1 to 3 and Comparative Examples 1 to 8 were placed at 25° C. and 60% relative humidity for 12 months for long-term test investigation.

[0087] Determination of the content of active ingredient carbocisteine

[0088] The content of carbocisteine ​​is determined by UV-visible spectrophotometry (General Chapter 0401 of the Chinese Pharmacopoeia). Test solution: Take the product, accurately measure an appropriate amount, and quantitatively dilute it with phosphate buffer (pH6.6) to make a solution containing 0.2 mg per 1 ml. Reference solution: Take an appropriate amount of carbocisteine ​​reference, accurately weigh it, dissolve it in phosphate buffer (pH6.6) and quantitatively dilute it to make a solution containing 0.2 mg per 1 ml. Determination method: Accurately measure 2 ml of the test solution and the reference solution, respectively, and place them in 50 ml volumetric bottles, accurately add 1 ml of 2% ninhydrin solution and 2 ml of phosphate buffer (pH6.6), mix well, heat in a boiling water bath for 15 minutes, take it out, cool it quickly, dilute it to the scale with water, shake it well, measure the absorbance at a wavelength of 567 nm, and calculate.

[0089] The microbial limit is determined according to the microbial counting method for microbial limit inspection of non-sterile products in the Chinese Pharmacopoeia.

[0090] Table 1 Long-term test investigation of carbocisteine ​​oral solution of Examples 1 to 3 and Comparative Examples 1 to 8

[0091]

[0092]

[0093] Table 1 shows the investigation of the stability of the effective ingredients, pH stability, physical stability and microbial limit of the carbocisteine ​​oral solutions of Examples 1 to 3 and Comparative Examples 1 to 8 in long-term tests, which shows that the carbocisteine ​​oral solutions of Examples 1 to 3 of the present invention have high stability.

[0094] Determination of related substances

[0095] The contents of related substances N, S-(dicarboxymethyl)cysteine, chloroacetic acid, carboxymethylcysteine ​​lactam, carbocysteine, cystine and hydroxybenzoic acid were determined by high performance liquid chromatography.

[0096] Figure 1 The graphs are the changes in the content of related substances in the long-term test of the carbocisteine ​​oral solutions of Examples 1 to 3 and Comparative Examples 1 to 8, showing that the carbocisteine ​​oral solutions of Examples 1 to 3 of the present invention have low impurity content and high stability.

[0097] Study on the influence of surfactant selection on HLB value

[0098] The single factor variable is the type of surfactant, and the other factors are the same as in Example 1, and the affinity of solution 1 in step (1) is determined.

[0099] A: Span 20

[0100] B: Span 60

[0101] C: Span 65

[0102] D: Span 80

[0103] E: Span 85

[0104] F: Twain 60

[0105] Table 2 Solution-HLB value

[0106]

[0107]

[0108] Study on the influence of pH on the affinity of solution 1

[0109] The single factor variable is the pH of step (1), and the other factors are the same as in Example 1, and the affinity of solution 1 in step (1) is determined.

[0110] A: pH = 3.0

[0111] B: pH = 5.0

[0112] C: pH = 7.0

[0113] D: pH = 8.0

[0114] E: pH = 9.0

[0115] F: pH = 11.0

[0116] Table 3 Solution-HLB value

[0117] HLB value A 11.2 B 10.4 C 10.1 D 7.2 E 7.8 F 10.5

[0118] The HLB value indicates the affinity of the surfactant. A high HLB value indicates better hydrophilicity, and a low HLB value indicates better lipophilicity. The above single-factor experimental study shows that pH and the type of surfactant jointly affect the HLB value of solution 1. Both too high and too low HLB values ​​are not conducive to the subsequent dissolution and dispersion of carbocysteine.

Claims

1. A carbocisteine ​​oral solution, characterized in that The carbocysteine ​​oral solution consists of carbocysteine, sorbitan tristearate, tragacanth gum, a sweetener and water.

2. The carbocisteine ​​oral solution according to claim 1, characterized in that The carbocysteine ​​oral solution consists of 500 parts by weight of carbocysteine, 80-120 parts by weight of sorbitan tristearate, 30-70 parts by weight of tragacanth gum, a sweetener and water.

3. The carbocisteine ​​oral solution according to claim 1 or 2, characterized in that The carbocysteine ​​oral solution consists of 500 parts by weight of carbocysteine, 100 parts by weight of sorbitan tristearate, 50 parts by weight of tragacanth gum, a sweetener and water.

4. The carbocisteine ​​oral solution according to claim 1, characterized in that The sweetener is selected from at least one of sucrose, simple syrup, saccharin sodium, sucralose, aspartame, neotame and mannitol.

5. A method for preparing the carbocysteine ​​oral solution according to claim 1, characterized in that: The method comprises the following steps: (1) dissolving sorbitan tristearate in a suitable amount of buffer solution A with a pH of 8.0 to 9.0, mixing tragacanth gum with a suitable amount of water, stirring to form a viscous substance, and uniformly mixing the viscous substance with the buffer solution containing sorbitan tristearate to obtain solution 1; (2) Powder carbocysteine, add it to solution 1 of step (1) and mix well, then add buffer solution B to adjust the pH to 6.0-7.0, add water to the total amount, and pass inert gas to obtain the product.

6. The method according to claim 5, characterized in that The buffer solution A is selected from one of sodium barbital-hydrochloric acid buffer solution, Tris-hydrochloric acid buffer solution, and glycine-sodium hydroxide buffer solution.

7. The method according to claim 5, characterized in that The pH of the buffer solution A is 8.

5.

8. The method according to claim 5, characterized in that The buffer solution B is selected from one of potassium dihydrogen phosphate-sodium hydroxide buffer, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer, and citric acid-sodium citrate buffer.

9. The method according to claim 5, characterized in that The pH of the buffer solution B is 6.

5.

10. The method according to claim 5, characterized in that The inert gas is nitrogen.

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