Preparation composition of ambroxol hydrochloride and preparation method thereof

Abstract

The invention discloses an ambroxol hydrochloride preparation composition and a preparation method thereof, the ambroxol hydrochloride preparation composition contains hydroxyethyl cellulose, and the weight-average molecular weight of the hydroxyethyl cellulose is selected from 900000 to 1100000. By improving the prescription raw materials and the prescription process, the production equipment requirement and cost are greatly reduced while the product quality is ensured, and the preparation method is very suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to a formulation composition of ambroxol hydrochloride and its preparation method. Background Technology

[0002] Ambroxol hydrochloride is a new generation of mucolytic agent, mainly used clinically for thick sputum and difficulty in expectoration caused by acute and chronic respiratory diseases (such as acute and chronic bronchitis, bronchial asthma, bronchiectasis, and pulmonary tuberculosis). Boehringer Ingelheim first used it in August 1978. It is marketed as the trade name of ambroxol hydrochloride, in the form of an oral solution, with a strength of 15mg / 5mL.

[0004] Ambroxol hydrochloride oral solution uses hydroxyethyl cellulose as a thickener at a high concentration (approximately 4 mg of hydroxyethyl cellulose per 1 mL of product). Existing information does not disclose the weight-average molecular weight of the hydroxyethyl cellulose. However, hydroxyethyl cellulose generally agglomerates after absorbing water, making it difficult to disperse evenly in the preparation container and causing stability issues, resulting in substandard product quality. To overcome these problems, existing technologies typically improve the pre-dissolution method of hydroxyethyl cellulose. For example, document CN117618344A discloses an ambroxol hydrochloride oral solution in which hydroxyethyl cellulose is pre-dissolved in water and then heated to 60-90°C while stirring to accelerate complete dissolution. Similarly, document CN119385928A discloses an ambroxol hydrochloride oral solution in which the hydroxyethyl cellulose is pre-dissolved in 40% purified water, and the pre-dissolution process also requires heating to 60°C. Afterwards, it needs to be circulated in a colloid mill for 20 minutes, and then stirred for another 70 minutes. For example, literature CN118178319A discloses an oral solution of ambroxol hydrochloride, in which hydroxyethyl cellulose is first dissolved separately (first added to purified water at 20-35℃, stirred and dispersed, then heated to 40-60℃ and stirred to dissolve), and then subjected to high-speed shearing treatment (shearing conditions are 2000-2500 rpm, shearing time is 5-15 min), which can disperse hydroxyethyl cellulose and improve its dispersibility.

[0005] However, these methods have not yielded ideal improvements in practice. Heating hydroxyethyl cellulose during pre-dissolution alters its viscosity characteristics, resulting in significant differences in viscosity between the prepared ambroxol hydrochloride oral solution and the reference formulation. Furthermore, it leads to stability issues with the prepared ambroxol hydrochloride oral solution, particularly high-temperature stability. The use of colloid rods and high-speed shearing devices further increases the requirements for production equipment.

[0006] Pharmaceutical-grade hydroxyethyl cellulose (HEC) is a nonionic, water-soluble polymer with a wide molecular weight range, typically around 9 × 10⁻⁶. 4 -7×10 6 The existing technologies have not studied the dispersion effect and stability of hydroxyethyl cellulose with different molecular weights on ambroxol hydrochloride.

[0007] In summary, it is essential to develop a formulation composition for ambroxol hydrochloride that is highly stable, has simple and mild processing conditions. Summary of the Invention

[0008] In view of this, the purpose of the present invention is to provide a formulation composition of ambroxol hydrochloride and a method for preparing the same, which can be prepared using a simple and mild process to obtain a formulation composition of ambroxol hydrochloride with high stability.

[0009] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0010] In a first aspect, the present invention relates to a formulation composition of ambroxol hydrochloride, the raw material of which contains hydroxyethyl cellulose, said hydroxyethyl cellulose having a weight-average molecular weight selected between 900,000 and 1,100,000, preferably between 950,000 and 1,050,000. Commercially available alternatives include, for example, Natrosol 250HX sold by Ashland. TM Hydroxyethyl cellulose.

[0011] Compared with other weight-average molecular weight hydroxyethyl celluloses, the present invention uses hydroxyethyl cellulose with a weight-average molecular weight between 900,000 and 1,100,000, which results in better stability of the prepared ambroxol hydrochloride formulation, especially better high-temperature stability.

[0012] In some embodiments, the formulation composition of ambroxol hydrochloride further contains benzoic acid, sucralose, flavoring, and water. Preferably, the formulation composition of ambroxol hydrochloride consists of ambroxol hydrochloride, hydroxyethyl cellulose, benzoic acid, sucralose, flavoring, and water. The water is preferably purified water.

[0013] The dosage form of the ambroxol hydrochloride formulation of the present invention is preferably an aqueous solution, wherein the content of ambroxol hydrochloride is 1-10 mg / mL; the content of benzoic acid is 0.1-1 mg / mL; the content of hydroxyethyl cellulose is 1-10 mg / mL; the content of sucralose is 0.5-5 mg / mL; and the content of flavor is 0.5-2 mg / mL. Preferably, the content of ambroxol hydrochloride is 2-8 mg / mL; the content of benzoic acid is 0.3-0.8 mg / mL; the content of hydroxyethyl cellulose is 1-10 mg / mL; the content of sucralose is 0.5-1.5 mg / mL; and the content of flavor is 0.5-1.5 mg / mL. More preferably, the content of ambroxol hydrochloride is 3-6 mg / mL; the content of benzoic acid is 0.4-0.6 mg / mL; the content of hydroxyethyl cellulose is 3-6 mg / mL; the content of sucralose is 0.8-1.3 mg / mL; and the content of flavor is 0.8-1.3 mg / mL.

[0014] In a second aspect, the present invention relates to a method for preparing an oral solution of ambroxol hydrochloride, comprising the following steps: sieving hydroxyethyl cellulose and adding it to a mixed solution containing benzoic acid, sucralose and ambroxol hydrochloride.

[0015] In some implementation schemes, to ensure uniform dispersion and product stability, the sieving is performed through a sieve of not less than 30 mesh, preferably through a sieve of 30-80 mesh; to further improve production efficiency, it is more preferably through a sieve of 30-60 mesh.

[0016] The ambroxol hydrochloride oral solution provided by this invention exhibits good solubility and easy dispersion of the flavoring. Therefore, it can be added to the solution system before or after the addition of hydroxyethyl cellulose without affecting product quality. The following description exemplifies the method of simultaneous addition with sucralose and ambroxol hydrochloride (i.e., before the addition of hydroxyethyl cellulose), but this invention is not limited thereto.

[0017] In some embodiments, the preparation method of the ambroxol hydrochloride oral solution includes the following steps:

[0018] S1: Mix benzoic acid with some purified water until completely dissolved, and set aside;

[0019] S2: Add sucralose, flavoring, and ambroxol hydrochloride to the benzoic acid solution prepared in step S1 in any order, and stir until completely dissolved to obtain mixed solution one;

[0020] S3: After passing hydroxyethyl cellulose through a 30-80 mesh sieve, add it to the mixed solution two of step S2 under stirring conditions. After the addition is completed, keep stirring for 0.1-1 hours to obtain mixed solution two.

[0021] S4: Add the remaining amount of purified water to the mixed solution from step S3, mix well, and obtain mixed solution three;

[0022] S5: After filtering and filling the mixed solution obtained in step S4, ambroxol hydrochloride oral solution is obtained.

[0023] In some embodiments, the purified water used in step S1 is 70-90% of the prescription amount, preferably 75-85%, and most preferably 80%.

[0024] In some embodiments, step S3 preferably involves passing hydroxyethyl cellulose through a 30-60 mesh sieve, more preferably through a 40-60 mesh sieve.

[0025] In some implementations, the addition of hydroxyethyl cellulose in step S3 is completed within 0.1-1 hour, preferably within 0.2-0.8 hours, and more preferably within 0.2-0.6 hours.

[0026] In some implementations, the stirring frequency in steps S2 and S3 is controlled within 20-60Hz, preferably 25-50Hz.

[0027] In some implementations, the preparation temperature for steps S1-S5 is 10-30°C, preferably room temperature.

[0028] In some implementations, the filtration described in step S5 is performed through a filter cartridge with a pore size of less than 10 μm.

[0029] In a third aspect, the present invention provides a method for preparing ambroxol hydrochloride oral solution, comprising the following steps:

[0030] S1: Mix benzoic acid with 70-90% purified water (based on the prescription volume) until completely dissolved, and set aside.

[0031] S2: Add sucralose, flavoring, and ambroxol hydrochloride to the benzoic acid obtained in step S1 in any order.

[0032] In the solution, stir at a stirring frequency of 20-60 Hz until completely dissolved to obtain mixed solution one;

[0033] S3: At room temperature, hydroxyethyl cellulose is passed through a 30-80 mesh sieve and then added to the mixture under a stirring frequency of 20-60 Hz.

[0034] After adding the materials to the second mixed solution of step S2, keep stirring for 0.1-1 hours to obtain the second mixed solution.

[0035] S4: Add the remaining amount of purified water to the mixed solution from step S3, mix well, and obtain mixed solution three;

[0036] S5: After filtering and filling the mixed solution obtained in step S4 through a filter with a pore size of less than 10 μm, ambroxol hydrochloride oral solution is obtained.

[0037] Fourthly, the present invention provides the use of the ambroxol hydrochloride formulation composition as described in the first aspect above, or the ambroxol hydrochloride oral solution prepared by the preparation methods described in the second and third aspects above, in the preparation of medicaments for treating acute and chronic respiratory diseases accompanied by thick sputum and difficulty in expectoration. Further preferred applications are in the preparation of medicaments for treating acute and chronic bronchitis, bronchial asthma, bronchiectasis, and pulmonary tuberculosis.

[0038] The beneficial effects of this invention are as follows:

[0039] This invention, through screening of hydroxyethyl cellulose in ambroxol hydrochloride formulations, obtained an ambroxol hydrochloride formulation composition with better stability. In addition, this invention also optimizes the production process of ambroxol hydrochloride oral solution, especially the feeding method of hydroxyethyl cellulose, which greatly reduces the requirements and costs of production equipment while ensuring product quality, making it very suitable for large-scale industrial production. Detailed Implementation

[0040] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0041] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0042] Unless otherwise specified, in the following examples and comparative examples, all fillings are in oral liquid pharmaceutical polyester bottles (100mL), except for the reference preparation.

[0043] In the following examples and comparative examples, the turbidity was compared with turbidity standard solution No. 1 (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0902, Method I), and the color was compared with yellow standard colorimetric solution No. 2 (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0901, Method I); related substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), and the structural formula of impurity B is as follows:

[0044]

[0045] For example, the flavoring used in the following embodiments and comparative examples is peach flavoring, but other common pharmaceutical flavorings in the art (such as strawberry flavoring, cherry flavoring, lemon flavoring, etc.) can be substituted and added instead, and the present invention is not limited thereto.

[0046] The Natrosol 250HX model used in the following examples and comparative examples TM Natrosol with a weight-average molecular weight of 1,000,000 and a model number of 250M TM Natrosol with a weight-average molecular weight of 720,000 and a model number of 250G TM The weight-average molecular weight is 300,000.

[0047] Example 1

[0048] The prescription for Example 1 is shown in Table 1 below:

[0049] Table 1:

[0050]

[0051] The preparation method is as follows:

[0052] S1: Add 25% of the prescribed amount of purified water to the preparation tank, turn on the stirrer at room temperature, adjust the frequency to 25Hz, add all the benzoic acid to the preparation tank, continue to add purified water (total of 75% of the prescribed amount), adjust the speed to 50Hz, until the benzoic acid is completely dissolved, and set aside.

[0053] S2: Add sucralose, flavoring and ambroxol hydrochloride to the benzoic acid solution obtained in step S1 in sequence, and stir at a frequency of 50 Hz until the materials are completely dissolved to obtain mixed solution one;

[0054] S3: After passing hydroxyethyl cellulose through a 30-40 mesh sieve, add the hydroxyethyl cellulose to the mixed solution one from step S2 within 30 minutes under stirring conditions (stirring frequency 50Hz). After the addition is completed, keep stirring for 30 minutes to obtain mixed solution two.

[0055] S4: Add the remaining amount of purified water to the mixed solution two from step S3, mix well, and obtain mixed solution three;

[0056] S5: After filtering the mixed solution obtained in step S4 through a 5μm pore size filter, it is filled using a filling machine to obtain ambroxol hydrochloride oral solution.

[0057] Comparative Example 1

[0058] Replace the hydroxyethyl cellulose in the formulation of Example 1 with Natrosol, type 250M. TM The preparation method is the same as in Example 1.

[0059] Comparative Example 2

[0060] Replace the hydroxyethyl cellulose in the formulation of Example 1 with Natrosol, type 250G. TM The preparation method is the same as in Example 1.

[0061] The ambroxol hydrochloride oral solutions prepared in Example 1 and Comparative Examples 1-2 were placed at high temperature (60°C) for 30 days. The stability of the products of Example 1 and Comparative Examples 1-2 was investigated using properties and related substances as indicators. The results are shown in Table 2 below:

[0062] Table 2:

[0063]

[0064] Analysis of Table 2 above shows that the ambroxol hydrochloride oral solution of Example 1 has significantly lower levels of related substances after being placed at 60°C for 30 days, especially with the total impurities remaining essentially unchanged compared to day 0. In contrast, the related substances in Comparative Examples 1-2 are significantly higher than those in Example 1, with a total impurity change rate exceeding 120%. Therefore, the results in Table 2 indicate that using hydroxyethyl cellulose with a weight-average molecular weight of 1,000,000 results in a more stable high-temperature ambroxol hydrochloride oral solution.

[0065] Example 2-3

[0066] The prescriptions for Examples 2-3 are shown in Table 3 below:

[0067] Table 3:

[0068]

[0069]

[0070] The preparation method is as follows:

[0071] S1: Add 30% of the prescribed amount of purified water to the preparation tank, turn on the stirrer at room temperature, adjust the frequency to 25Hz, add all the benzoic acid to the preparation tank, continue to add purified water (total of 80% of the prescribed amount), adjust the speed to 50Hz, until the benzoic acid is completely dissolved, and set aside.

[0072] S2: Add sucralose, ambroxol hydrochloride, and flavoring sequentially to the benzoic acid solution obtained in step S1, and stir at a frequency of 50 Hz until the materials are completely dissolved to obtain mixed solution one;

[0073] S3: After passing hydroxyethyl cellulose through a 60-mesh sieve, add the hydroxyethyl cellulose to the mixed solution one from step S2 within 45 minutes under stirring conditions (stirring frequency 50Hz). After the addition is completed, keep stirring for 30 minutes to obtain mixed solution two.

[0074] S4: Add the remaining amount of purified water to the mixed solution two from step S3, mix well, and obtain mixed solution three;

[0075] S5: After filtering the mixed solution obtained in step S4 through a 5μm pore size filter, it is filled using a filling machine to obtain ambroxol hydrochloride oral solution.

[0076] The ambroxol hydrochloride oral solution prepared in Examples 2-3 was compared with reference preparation A. 15 mg / 5 mL) and reference preparation B ( Influencing factor test (30mg / 5mL):

[0077] Influencing factor test: The ambroxol hydrochloride oral solution prepared in Examples 2-3, along with reference preparations A and B, were placed upright and inverted under high temperature (60℃) and strong light (5000 lux ± 500 lux, 25℃), respectively, and samples were taken at 10 days and 30 days, respectively; low temperature cycling test and freeze-thaw cycle test were conducted, and samples were taken at 12 days. The indicators examined were appearance and related substances. The results are shown in Table 4 below:

[0078] Table 4

[0079]

[0080]

[0081] Analysis of Table 4 above shows that, compared with the reference preparation, the ambroxol hydrochloride oral solution of Examples 2-3 is stable under high temperature, light, low temperature freeze-thaw and cycling conditions, has lower levels of related substances, and has better stability.

[0082] Example 4 and Comparative Examples 3-5

[0083] The formulations for Example 4 and Comparative Examples 3-5 are the same, as shown in Table 5 below:

[0084] Table 5:

[0085]

[0086]

[0087] The preparation method of Example 4 is as follows:

[0088] S1: Add 30% of the prescribed amount of purified water to a glass beaker, turn on the stirrer at room temperature, adjust the frequency to 25Hz, add all the benzoic acid to the preparation tank, continue to add purified water (total of 80% of the prescribed amount), adjust the speed to 34Hz, until the benzoic acid is completely dissolved, and set aside.

[0089] S2: Add sucralose, flavoring and ambroxol hydrochloride to the benzoic acid solution obtained in step S1 in sequence, and stir at a frequency of 34 Hz ​​until the materials are completely dissolved to obtain mixed solution one;

[0090] S3: After passing hydroxyethyl cellulose through a 40-mesh sieve, add the hydroxyethyl cellulose to the mixed solution one from step S2 within 30 minutes under stirring conditions (stirring frequency 34Hz). After the addition is completed, keep stirring for 30 minutes to obtain mixed solution two.

[0091] S4: Add the remaining amount of purified water to the mixed solution two from step S3, mix well, and obtain mixed solution three;

[0092] S5: After filtering the mixed solution obtained in step S4 through a 5μm pore size filter, measure 100mL of the solution using a 100mL graduated cylinder and fill it into a container, then manually screw on the cap.

[0093] The preparation methods of Comparative Examples 3-5 are basically the same as those of Example 4, except that the way hydroxyethyl cellulose is added is changed, as shown in Table 6 below:

[0094] Table 6:

[0095]

[0096] The ambroxol hydrochloride oral solutions prepared in Example 4 and Comparative Examples 4-5 were placed at high temperature (60°C) for 30 days. The stability of the products of Example 4 and Comparative Examples 4-5 was investigated using appearance and related substances as indicators. The results are shown in Table 7 below:

[0097] Table 7:

[0098]

[0099] Analysis of Tables 6-7 above shows that by sieving hydroxyethyl cellulose at a suitable mesh size, the present invention can significantly improve the dispersibility of hydroxyethyl cellulose in the ambroxol hydrochloride mixed solution, which is beneficial to improving the stability of the prepared ambroxol hydrochloride oral solution. Furthermore, the hydroxyethyl cellulose feeding process in the production process of the present invention does not require a high-power stirrer or other complex procedures, which greatly improves production efficiency, reduces equipment costs, and is very suitable for large-scale industrial production.

[0100] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A formulation composition of ambroxol hydrochloride, comprising hydroxyethylcellulose, characterized in that, The weight-average molecular weight of the hydroxyethyl cellulose is selected between 900,000 and 1,100,000, preferably between 950,000 and 1,050,000.

2. The formulation composition according to claim 1, characterized in that, It also contains benzoic acid, sucralose, flavoring, and water.

3. The formulation composition according to claim 1, characterized in that, It is composed of ambroxol hydrochloride, hydroxyethyl cellulose, benzoic acid, sucralose, flavoring and water.

4. The formulation composition according to claim 2 or 3, characterized in that, The dosage form is an aqueous solution, wherein the content of ambroxol hydrochloride is 1-10 mg / mL; the content of benzoic acid is 0.1-1 mg / mL; the content of hydroxyethyl cellulose is 1-10 mg / mL; the content of sucralose is 0.5-5 mg / mL; and the content of flavor is 0.5-2 mg / mL. Preferably, the content of ambroxol hydrochloride is 2-8 mg / mL; the content of benzoic acid is 0.3-0.8 mg / mL; the content of hydroxyethyl cellulose is 1-10 mg / mL; the content of sucralose is 0.5-1.5 mg / mL; and the content of flavor is 0.5-1.5 mg / mL. More preferably, the content of ambroxol hydrochloride is 3-6 mg / mL; the content of benzoic acid is 0.4-0.6 mg / mL. mg / mL; the content of hydroxyethyl cellulose is 3-6 mg / mL; the content of sucralose is 0.8-1.3 mg / mL; The content of the fragrance is 0.8-1.3 mg / mL.

5. A method for preparing an oral solution of ambroxol hydrochloride, characterized in that, The process includes the following steps: sieving hydroxyethyl cellulose and adding it to a mixed solution containing benzoic acid, sucralose and ambroxol hydrochloride.

6. The method for preparing ambroxol hydrochloride oral solution according to claim 5, characterized in that, The sieving process involves passing through a sieve of not less than 30 mesh, preferably through a sieve of 30-80 mesh, and more preferably through a sieve of 30-60 mesh.

7. The method for preparing ambroxol hydrochloride oral solution according to claim 6, characterized in that, It includes the following steps: S1: Mix benzoic acid with some purified water until completely dissolved, and set aside; S2: Add sucralose, flavoring, and ambroxol hydrochloride to the benzoic acid solution prepared in step S1 in any order, and stir until completely dissolved to obtain mixed solution one; S3: After passing hydroxyethyl cellulose through a 30-80 mesh sieve, add it to the mixed solution two of step S2 under stirring conditions. After the addition is completed, keep stirring for 0.1-1 hours to obtain mixed solution two. S4: Add the remaining amount of purified water to the mixed solution from step S3, mix well, and obtain mixed solution three; S5: After filtering and filling the mixed solution obtained in step S4, ambroxol hydrochloride oral solution is obtained.

8. The method for preparing ambroxol hydrochloride oral solution according to claim 7, characterized in that, The purified water used in step S1 is 70-90% of the prescription amount, preferably 75-85%, and most preferably 80%; the addition time of hydroxyethyl cellulose in step S3 is controlled within 0.1-1h, preferably within 0.2-0.8h, and more preferably within 0.2-0.6h; the stirring frequency in steps S2 and S3 is controlled within 20-60Hz, preferably 25-50Hz; the preparation temperature of steps S1-S5 is 10-30℃, preferably room temperature; the filtration in step S5 is performed through a filter cartridge with a pore size of less than 10μm.

9. A method for preparing the ambroxol hydrochloride formulation composition according to claim 4, characterized in that, It includes the following steps: S1: Mix benzoic acid with 70-90% purified water (based on the prescription volume) until completely dissolved, and set aside. S2: Add sucralose, flavoring, and ambroxol hydrochloride to the benzoic acid solution obtained in step S1 in any order, and stir at a stirring frequency of 20-60 Hz until completely dissolved to obtain mixed solution one; S3: At room temperature, hydroxyethyl cellulose is passed through a 30-80 mesh sieve and added to the mixed solution two of step S2 with a stirring frequency of 20-60 Hz. After the addition is completed, stirring is maintained for 0.1-1 h to obtain mixed solution two. S4: Add the remaining amount of purified water to the mixed solution from step S3, mix well, and obtain mixed solution three; S5: After filtering and filling the mixed solution obtained in step S4 through a filter with a pore size of less than 10 μm, ambroxol hydrochloride oral solution is obtained.

10. The use of the ambroxol hydrochloride formulation composition according to claims 1-4 or the ambroxol hydrochloride oral solution prepared by the preparation method according to claims 5-9 in the preparation of medicaments for treating acute and chronic respiratory diseases accompanied by thick sputum and difficulty in expectoration; more preferably, in the preparation of medicaments for treating acute and chronic bronchitis, bronchial asthma, bronchiectasis, and pulmonary tuberculosis.

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