Ambroxol hydrochloride syrup and preparation process thereof

Abstract

The invention discloses ambroxol hydrochloride syrup and a preparation process thereof, and belongs to the technical field of pharmaceutical preparations. The ambroxol hydrochloride syrup comprises ambroxol hydrochloride, a stabilizing cosolvent, a sweetening agent, a preservative, a pH regulator, essence and a solvent. Wherein the stable cosolvent is a composition of propylene glycol, meglumine and propylene carbonate, and the sweetening agent is a composition of cane sugar and a functional sweetening agent. The preparation process comprises the steps of low-temperature pretreatment of the main drug and the stable cosolvent, dissolution and mixing of the auxiliary materials, pH adjustment and essence addition, constant-volume filtration, encapsulation and the like. Through the synergistic effect of a composite stable cosolvent system and a specific preparation process, the storage stability of ambroxol hydrochloride is remarkably improved, meanwhile, the taste of the preparation is optimized, the preparation is wide in applicable crowd, the preparation process is simple and controllable, and good clinical application value and industrialization prospects are achieved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an ambroxol hydrochloride syrup and its preparation process. 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] Ambroxol hydrochloride, a metabolite of bromhexine, is derived from the plant extract of *Dracaena cochinchinensis*, namely, dracaena alkaloid. It is an active substance with mucolytic, anti-inflammatory, and local analgesic effects, and is widely used clinically to treat sore throat and respiratory diseases accompanied by thick mucus, including chronic bronchitis, asthmatic bronchitis, acute exacerbations of bronchial asthma, bronchiectasis, and pulmonary tuberculosis. It can effectively increase respiratory fluid volume, reduce mucus secretion, promote the secretion of pulmonary surfactant and ciliary movement, and also has a certain antitussive effect, significantly improving symptoms such as thick sputum and difficulty coughing. It is suitable for both adults and children.

[0004] With the diversification of clinical needs, the formulations of ambroxol hydrochloride have continuously evolved. Currently, commercially available products include solid dosage forms (such as tablets and capsules), injections, inhaled solutions, syrups, and oral solutions. While solid dosage forms are convenient for storage and transportation, they have significant limitations: tablets or capsules need to be broken down for children, making precise dosage control difficult, and the pungent taste of the drug itself leads to poor compliance in children; furthermore, solid dosage forms require disintegration and dissolution in the body before absorption, resulting in a slower onset of action and failing to quickly relieve acute cough and wheezing symptoms. Injections, although fast-acting, are invasive and inconvenient to administer, making them unsuitable for routine home treatment, especially for children and elderly patients.

[0005] Compared to solid dosage forms and injections, syrups and oral solutions are among the preferred oral dosage forms in clinical practice due to their advantages such as convenient administration, easy and accurate dosage measurement, no need for disintegration process, large contact area with the human body, rapid absorption, and rapid onset of action. To address the shortcomings of solid dosage forms, targeted research and development has been conducted in related technical fields. For example, Chinese patent CN101352417A discloses an ambroxol hydrochloride oral solution, which improves the taste of the formulation and enhances children's compliance by adding sodium benzoate as a preservative and combining it with a flavoring agent composed of steviol glycosides, citric acid, sucrose, and flavoring. At the same time, it optimizes the preparation process and ensures a certain degree of product stability. Chinese patent CN116459204A discloses an ambroxol hydrochloride cough syrup that is essentially free of glycerol and preferably essentially free of sugar alcohols. By eliminating glycerol and sugar alcohol excipients that easily lead to the degradation of ambroxol hydrochloride, the degradation rate of the drug is significantly reduced, storage stability is greatly improved, and no additional stabilizers are required, simplifying the formulation composition.

[0006] Although existing technologies have improved the convenience and stability of ambroxol hydrochloride preparations, they still suffer from deficiencies such as insufficient overall compatibility and inadequate stability. Therefore, developing an ambroxol hydrochloride syrup with high storage stability, pleasant taste, wide applicability, and a simple and controllable preparation process, along with its preparation technology, has significant clinical value and application prospects. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of existing ambroxol hydrochloride preparations, such as insufficient overall compatibility of formulations and poor storage stability, and to provide an ambroxol hydrochloride syrup with high storage stability, wide applicability to a wide range of people, and simple and controllable preparation process, so as to meet the clinical demand for efficient, safe and convenient oral preparations.

[0008] The ambroxol hydrochloride syrup of this invention comprises the following components per 100 ml: Main drug: Ambroxol hydrochloride 0.6g; Stabilizing solubilizer: 8-27g, a combination of propylene glycol, meglumine, and propylene carbonate, preferably 5-15g propylene glycol, 2-9g meglumine, and 1-3g propylene carbonate; Sweetener: 40-60g, a combination of sucrose and functional sweetener, wherein the functional sweetener is selected from at least one of sucralose, aspartame, steviol glycosides, sorbitol, maltitol, and acesulfame potassium; Preservative: 0.1-0.5g, selected from sodium benzoate, At least one of ethylparaben, potassium sorbate, sodium dehydroacetate, and benzyl alcohol; pH adjuster: appropriate amount, selected from at least one of citric acid-sodium citrate buffer pair, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, tartaric acid-sodium tartrate buffer pair, and acetate-sodium acetate buffer pair; flavoring: 0.01-0.2g, selected from at least one of strawberry flavoring, orange flavoring, blueberry flavoring, banana flavoring, peppermint flavoring, peach flavoring, and pineapple flavoring; solvent: water, added to 100ml.

[0009] The preparation process of ambroxol hydrochloride syrup of the present invention includes the following steps: (1) Pretreatment of the active pharmaceutical ingredient and stabilizing cosolvent: Take propylene glycol, meglumine and propylene carbonate, mix them at 5-15℃, stir to form a homogeneous and transparent mixture, and after returning to room temperature, add ambroxol hydrochloride to dissolve and obtain the active pharmaceutical ingredient solution; if the dissolution is incomplete and turbidity occurs, ultrasonic dissolution can be used. (2) Dissolving and mixing excipients: Take 60% of the total amount of purified water, heat it and add sweetener and preservative, stir until completely dissolved and dispersed; after cooling, slowly pour the excipient solution into the main drug solution while stirring to form a preliminary mixture; (3) pH adjustment and fragrance addition: Dissolve the pH adjuster in a small amount of water, add it to the initial mixture, adjust the pH to 4-6, cool and add the fragrance, and stir well; (4) Volume adjustment, filtration and filling: Add purified water to 100ml, stir and mix well, filter, collect the clear filtrate, quantitatively fill, seal and sterilize under aseptic conditions.

[0010] Compared with the prior art, the technical advantages of the present invention are as follows: (1) Significantly improved stability: This invention innovatively employs a composite stabilizing cosolvent system composed of propylene glycol, meglumine, and propylene carbonate. The synergistic effect of these three components effectively inhibits the degradation of ambroxol hydrochloride during storage. Simultaneously, a specific low-temperature pretreatment process further enhances the stability of the active pharmaceutical ingredient. Accelerated and long-term tests have verified that the ambroxol hydrochloride content in the embodiments of this invention decreases only slightly, and it maintains high efficacy even after long-term storage, demonstrating superior stability compared to existing technologies and commercially available formulations.

[0011] (2) Suitable taste and high compliance: The combination of sucrose and functional sweeteners is used as a sweetener, which not only ensures the appropriate sweetness, but also avoids the taste defects caused by a single sweetener; combined with a variety of natural flavorings, it effectively masks the pungent taste of ambroxol hydrochloride itself, significantly improves the taste of the preparation, and is especially suitable for children and patients who are sensitive to taste, thus improving medication compliance. Attached Figure Description

[0012] Figure 1 Stability of ambroxol hydrochloride syrup (accelerated test).

[0013] Figure 2 Stability of ambroxol hydrochloride syrup (long-term test). Detailed Implementation

[0014] 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.

[0015] Example 1 Ambroxol Hydrochloride Syrup formula: Preparation process: (1) Pretreatment of the active pharmaceutical ingredient and stabilizing cosolvent: Take propylene glycol, meglumine, and propylene carbonate and place them in a clean, low-temperature reactor; start the low-temperature constant temperature stirrer, set the temperature to 10℃ and the speed to 180r / min, and stir for 18 minutes until a uniform and transparent mixture is formed. After returning to room temperature, add ambroxol hydrochloride in 3 portions, stirring at 280r / min for 5 minutes after each addition until it is completely dissolved into a clear liquid. If it is turbid, use 120W ultrasonic waves to assist in dissolving for 4 minutes to obtain the active pharmaceutical ingredient solution.

[0016] (2) Dissolving and mixing excipients: Take 60% of the total amount of purified water, heat it to 42°C, add sweetener while stirring at 200r / min, and stir for 12 minutes until dissolved; add preservative and continue stirring for 7 minutes until evenly dispersed; cool the excipient solution to 23°C, slowly pour it into the main drug solution, and stir at 250r / min for 10 minutes while pouring to form a preliminary mixture.

[0017] (3) pH adjustment and fragrance addition: Dissolve the pH adjuster in a small amount of water, add it dropwise to the initial mixture, and stir while adding until the pH is 5.0. Continue stirring for 5 minutes. Cool the mixture to 18°C, add the fragrance, and stir at 190 r / min for 9 minutes until uniform.

[0018] (4) Volume adjustment, filtration and filling: Add purified water to 100ml, stir for 10 minutes to mix well; filter, collect the clear filtrate; fill quantitatively under aseptic conditions, seal and sterilize.

[0019] Example 2 Ambroxol Hydrochloride Syrup formula: Preparation process: (1) Pretreatment of the active pharmaceutical ingredient and stabilizing cosolvent: Take propylene glycol, meglumine, and propylene carbonate and place them in a clean, low-temperature reactor; start the low-temperature constant temperature stirrer, set the temperature to 5℃ and the speed to 150r / min, stir for 15 minutes until a uniform and transparent mixture is formed, and after returning to room temperature, add ambroxol hydrochloride in 3 portions, stirring at 250r / min for 5 minutes after each addition until completely dissolved into a clear liquid. If it is turbid, use 100W ultrasonic waves to assist in dissolving for 5 minutes to obtain the active pharmaceutical ingredient solution.

[0020] (2) Dissolving and mixing excipients: Take 60% of the total amount of purified water, heat it to 40°C, add sweetener while stirring at 200r / min, and stir for 10 minutes until dissolved; add preservative and continue stirring for 5 minutes until evenly dispersed; cool the excipient solution to 20°C, slowly pour it into the main drug solution, and stir at 250r / min for 10 minutes while pouring to form a preliminary mixture.

[0021] (3) pH adjustment and fragrance addition: Dissolve the pH adjuster in a small amount of water, add it dropwise to the initial mixture, and stir while adding until pH=4.0, and continue stirring for 5 minutes; cool the mixture to 15℃, add the fragrance, and stir at 180r / min for 8 minutes until uniform.

[0022] (4) Volume adjustment, filtration and filling: Add purified water to 100ml, stir for 10 minutes to mix well; filter, collect the clear filtrate; fill quantitatively under aseptic conditions, seal and sterilize.

[0023] Example 3 Ambroxol Hydrochloride Syrup formula: Preparation process: (1) Pretreatment of the active pharmaceutical ingredient and stabilizing cosolvent: Take propylene glycol, meglumine, and propylene carbonate and place them in a clean, low-temperature reactor; start the low-temperature constant temperature stirrer, set the temperature to 15℃ and the speed to 200r / min, and stir for 20 minutes until a uniform and transparent mixture is formed. After returning to room temperature, add ambroxol hydrochloride in 3 portions, stirring at 300r / min for 5 minutes after each addition until it is completely dissolved into a clear liquid. If it is turbid, use 150W ultrasonic waves to assist in dissolving for 3 minutes to obtain the active pharmaceutical ingredient solution.

[0024] (2) Dissolving and mixing excipients: Take 60% of the total amount of purified water, heat it to 45°C, add sweetener while stirring at 200r / min, and stir for 15 minutes until dissolved; add preservative and continue stirring for 8 minutes until evenly dispersed; cool the excipient solution to 25°C, slowly pour it into the main drug solution, and stir at 250r / min for 10 minutes while pouring to form a preliminary mixture.

[0025] (3) pH adjustment and fragrance addition: Dissolve the pH adjuster in a small amount of water, add it dropwise to the initial mixture, and stir while adding until pH=5.0, and continue stirring for 5 minutes; cool the mixture to 20℃, add the fragrance, and stir at 200r / min for 10 minutes until uniform.

[0026] (4) Volume adjustment, filtration and filling: Add purified water to 100ml, stir for 10 minutes to mix well; filter, collect the clear filtrate; fill quantitatively under aseptic conditions, seal and sterilize.

[0027] Comparative Example 1: Ambroxol Hydrochloride Syrup formula: Preparation process: Same as Example 1.

[0028] Comparative Example 2: Ambroxol Hydrochloride Syrup formula: Preparation process: Same as Example 1.

[0029] Comparative Example 3: Ambroxol Hydrochloride Syrup formula: Preparation process: Same as Example 1.

[0030] Comparative Example 4: Ambroxol Hydrochloride Syrup formula: Preparation process: Same as Example 1.

[0031] Comparative Example 5: Ambroxol Hydrochloride Syrup formula: Preparation process: Same as Example 1.

[0032] Comparative Example 6: Ambroxol Hydrochloride Syrup formula: Preparation process: Same as Example 1.

[0033] Comparative Example 7: Ambroxol Hydrochloride Syrup formula: Same as Example 1.

[0034] Preparation process: (1) Pretreatment of the active pharmaceutical ingredient and stabilizing cosolvent: Take propylene glycol, meglumine and propylene carbonate, stir at room temperature (25°C) and speed (180 r / min) for 18 minutes until a uniform and transparent mixture is formed. After returning to room temperature, add ambroxol hydrochloride in 3 portions, stirring at 280 r / min for 5 minutes after each addition until completely dissolved into a clear liquid. If it is turbid, use 120W ultrasonic wave to assist in dissolution for 4 minutes to obtain the active pharmaceutical ingredient solution.

[0035] (2) Dissolving and mixing excipients: Take 60% of the total amount of purified water, heat it to 42°C, add sweetener while stirring at 200r / min, and stir for 12 minutes until dissolved; add preservative and continue stirring for 7 minutes until evenly dispersed; cool the excipient solution to 23°C, slowly pour it into the main drug solution, and stir at 250r / min for 10 minutes while pouring to form a preliminary mixture.

[0036] (3) pH adjustment and fragrance addition: Dissolve the pH adjuster in a small amount of water, add it dropwise to the initial mixture, and stir while adding until the pH is 5.0. Continue stirring for 5 minutes. Cool the mixture to 18°C, add the fragrance, and stir at 190 r / min for 9 minutes until uniform.

[0037] (4) Volume adjustment, filtration and filling: Add purified water to 100ml, stir for 10 minutes to mix well; filter, collect the clear filtrate; fill quantitatively under aseptic conditions, seal and sterilize.

[0038] Commercially available preparation: Ambroxol Hydrochloride Syrup (National Drug Approval Number H20083322) Stability test of ambroxol hydrochloride syrup Accelerated test conditions: temperature 40℃±2℃, relative humidity 75%±5%, 6 months.

[0039] Long-term test conditions: temperature 25℃±2℃, relative humidity 60%±10%, 12 months.

[0040] The content of ambroxol hydrochloride was determined according to the high performance liquid chromatography method (General Chapter 0512) in the Chinese Pharmacopoeia.

[0041] Test solution: Accurately measure 2 ml of this product using a volumetric pipette and place it in a 100 ml volumetric flask. Rinse the inner wall of the pipette with the mobile phase, and add the washings to the volumetric flask. Dilute to the mark with the mobile phase and mix well. Accurately measure 5 ml of this solution and place it in a 20 ml volumetric flask. Dilute to the mark with the mobile phase and mix well. Reference solution: Accurately weigh an appropriate amount of ambroxol hydrochloride reference standard, dissolve it in the mobile phase, and quantitatively dilute it to prepare a solution containing approximately 30 μg per ml. System suitability solution: Dissolve approximately 5 mg of ambroxol hydrochloride in 0.2 ml of methanol, then add 40 μl of formaldehyde solution (1→100), mix well, heat in a 60°C water bath for 5 minutes, and dry under nitrogen. Dissolve the residue in 5 ml of water, dilute to 20 ml with the mobile phase, and mix well. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.01 mol / L diammonium hydrogen phosphate solution (pH adjusted to 7.0 with phosphoric acid)-acetonitrile (50:50) was used as the mobile phase; the detection wavelength was 248 nm; the injection volume was 20 μl. System suitability requirements: In the chromatogram of the system suitability solution, the resolution between the ambroxol peak and the impurity I peak (relative retention time approximately 0.8) should be greater than 4.0. Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results by peak area using the external standard method.

[0042] Table 1 Ambroxol Hydrochloride Content in Accelerated Test Process Table 1 shows the accelerated degradation test results. The ambroxol hydrochloride syrups of Examples 1-3 of this invention maintained stable content throughout the test period with minimal decrease, consistently remaining at a high level, demonstrating excellent anti-degradation ability. In contrast, the ambroxol hydrochloride syrups of Comparative Examples 1-7 and commercially available formulations all showed significant decreases in ambroxol hydrochloride content to varying degrees. The most significant decreases were observed in the comparative examples where the stabilizing cosolvent was replaced or key components were missing. This indicates that the propylene glycol, meglumine, and propylene carbonate composite stabilizing cosolvent system used in this invention, along with the specific pretreatment process, effectively inhibits the degradation of ambroxol hydrochloride under accelerated conditions, significantly improving the short-term storage stability of the formulation.

[0043] Table 2 Ambroxol Hydrochloride Content During Long-Term Tests Table 2 shows that the ambroxol hydrochloride syrups of Examples 1-3 of this invention exhibited no significant decrease in content during long-term storage, demonstrating outstanding stability and maintaining efficacy over a long period. In contrast, the contents of Comparative Examples 1-7 and commercially available ambroxol hydrochloride syrups all showed a gradual decreasing trend with prolonged storage time, further confirming that the formulation composition of this invention, especially the synergistic effect of the composite stabilizing cosolvent and preparation process, effectively ensures the stability of ambroxol hydrochloride syrup under long-term storage conditions, surpassing existing technologies and commercially available products.

Claims

1. An ambroxol hydrochloride syrup, characterized in that, The formula for the ambroxol hydrochloride syrup is as follows: 0.6g of ambroxol hydrochloride, 8-27g of stabilizing cosolvent, 40-60g of sweetener, 0.1-0.5g of preservative, appropriate amount of pH adjuster, and 0.01-0.2g of flavoring, with solvent added to 100ml; the stabilizing cosolvent is a combination of propylene glycol, meglumine, and propylene carbonate.

2. The ambroxol hydrochloride syrup as described in claim 1, characterized in that, The stabilizing cosolvent is 5-15g of propylene glycol, 2-9g of meglumine, and 1-3g of propylene carbonate.

3. The ambroxol hydrochloride syrup as described in claim 1, characterized in that, The sweetener is a combination of sucrose and functional sweeteners.

4. The ambroxol hydrochloride syrup as described in claim 3, characterized in that, The functional sweetener is selected from at least one of sucralose, aspartame, steviol glycosides, sorbitol, maltitol, and acesulfame potassium.

5. The ambroxol hydrochloride syrup as described in claim 1, characterized in that, The preservative is selected from at least one of sodium benzoate, ethylparaben, potassium sorbate, sodium dehydroacetate, and benzyl alcohol.

6. The ambroxol hydrochloride syrup as described in claim 1, characterized in that, The pH adjuster is selected from at least one of the following: citrate-sodium citrate buffer pair, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, tartaric acid-sodium tartrate buffer pair, and acetate-sodium acetate buffer pair.

7. The ambroxol hydrochloride syrup as described in claim 1, characterized in that, The fragrance is selected from at least one of the following: strawberry fragrance, orange fragrance, blueberry fragrance, banana fragrance, mint fragrance, peach fragrance, and pineapple fragrance.

8. The ambroxol hydrochloride syrup as described in claim 1, characterized in that, The solvent is water.

9. A preparation process for ambroxol hydrochloride syrup as described in claim 1, characterized in that, The preparation process includes the following steps: (1) Pretreatment of active pharmaceutical ingredient and stabilizing cosolvent: Take propylene glycol, meglumine and propylene carbonate, mix them at 5-15℃, restore to room temperature, add ambroxol hydrochloride to dissolve, and obtain active pharmaceutical ingredient solution; (2) Dissolving and mixing excipients: Take purified water, heat it, add sweetener and preservative, and stir evenly; after cooling, pour it into the drug solution to form a preliminary mixture; (3) pH adjustment and fragrance addition: Dissolve the pH adjuster in a small amount of water, add it to the preliminary mixture until the pH is 4-6, cool, add the fragrance, and stir well; (4) Volume adjustment, filtration and filling.

10. The preparation process according to claim 9, characterized in that, The temperature in step (1) is 10℃.

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