Bromhexine hydrochloride oral solution and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a bromhexine hydrochloride oral solution and a preparation method thereof. The chitosan quaternary ammonium salt and the polyoxyethylene 60 hydrogenated castor oil are added into the bromhexine hydrochloride oral solution, the chitosan quaternary ammonium salt and the polyoxyethylene 60 hydrogenated castor oil are matched to obtain the oral solution with excellent stability, and the oral solution shows better product stability in an acceleration test and a long-term test; the method for preparing the bromhexine hydrochloride oral solution is simple and easy to implement, low in cost and more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a bromhexine hydrochloride oral solution and a preparation method thereof. BACKGROUND

[0002] Bromhexine hydrochloride, the chemical structural formula is as follows:

[0003]

[0004] The chemical name is N-methyl-N-cyclohexyl-2-amino-3,5-dibromo benzylamine hydrochloride, which is a white or white crystalline powder; slightly soluble in methanol, slightly soluble in ethanol, and extremely slightly soluble in water. It is a semi-synthetic product obtained by structural modification of Vasicine, has strong mucolytic effect, can inhibit the secretion of tracheal and bronchial mucous glands, and reduce the secretion of sputum. In clinical practice, bromhexine hydrochloride is used for acute and chronic bronchitis, asthma, bronchiectasis, and emphysema, especially for white sputum coughing difficulty and critical emergencies caused by extensive obstruction of small bronchial sputum.

[0005] Bromhexine hydrochloride oral solution is an oral preparation developed by Sanofi Company. Compared with other drug forms of bromhexine hydrochloride, this dosage form has the advantages of convenient oral administration and rapid drug efficacy after administration. Patients have high compliance to bromhexine hydrochloride oral solution, and the oral solution has been widely used in clinical practice.

[0006] However, the commercially available bromhexine hydrochloride oral solution still has the problem of poor stability. It will slowly degrade during storage, and is prone to precipitation and solution discoloration, affecting the safety and efficacy of the drug. In order to solve this problem, some improvement schemes are reported in the prior art. For example, patent CN103893116B discloses a bromhexine hydrochloride oral solution composition, which improves the stability of the oral solution by specific proportions of cooling alcohol, maltitol and xylitol components. However, the preparation process is complex, the cost is high, and high-dose sugar alcohol can easily cause abdominal distension, diarrhea and other gastrointestinal problems in sensitive people. Patent CN118557517A discloses a bromhexine hydrochloride oral solution, which re-formulates the composition of the oral solution by adding low-dose tremella polysaccharide, astaxanthin and momordica grosvenori extract. Although the amount of sugar alcohol is reduced, the preparation process of momordica grosvenori extract is complex (involving enzymolysis, fermentation, and post-ripening processes), and astaxanthin is expensive and not suitable for industrial production.

[0007] Therefore, it is of great clinical significance and market value to develop a bromhexine hydrochloride oral solution with better stability, simpler preparation process and lower cost. SUMMARY

[0008] In view of the deficiencies in the prior art, the present application provides a bromhexine hydrochloride oral solution with excellent stability, and the preparation process of the bromhexine hydrochloride oral solution is simple, the cost is low, and the bromhexine hydrochloride oral solution is more suitable for industrial production.

[0009] To achieve the above-mentioned object, the present application provides the following technical solutions.

[0010] A bromhexine hydrochloride oral solution comprises the following components: bromhexine hydrochloride, chitosan quaternary ammonium salt, a solubilizing agent, a pH adjusting agent, and purified water; wherein the solubilizing agent comprises polyoxyethylene 60 hydrogenated castor oil.

[0011] In a preferred embodiment of the present application, the solubilizing agent further comprises polyethylene glycol 15 hydroxystearate.

[0012] In a specific embodiment of the present application, the chitosan quaternary ammonium salt is a medium-substituted chitosan quaternary ammonium salt, i.e., the degree of substitution is 0.4-0.7; the degree of substitution (DS, also referred to as DQ) of the chitosan quaternary ammonium salt refers to the proportion of the amino groups in the chitosan molecules that are substituted by quaternary ammonium groups; i.e., a degree of substitution of 0.7 means that the proportion of the amino groups in the chitosan molecules that are substituted by quaternary ammonium groups accounts for 70%; the classification criteria for the degree of substitution of the chitosan quaternary ammonium salt are low-substituted DQ≤0.4, medium-substituted 0.4

[0013] The bromhexine hydrochloride oral solution of the present application comprises the following components per 100 parts of the oral solution: 0.2-0.6 parts of bromhexine hydrochloride, 1-2 parts of chitosan quaternary ammonium salt, 2-6 parts of a solubilizing agent, 0.1-1.0 parts of a pH adjusting agent, and the balance of purified water; preferably, the bromhexine hydrochloride oral solution of the present application comprises the following components per 100 parts: 0.4 parts of bromhexine hydrochloride, 1.5 parts of chitosan quaternary ammonium salt, 4 parts of a solubilizing agent, 0.5 parts of a pH adjusting agent, and the balance of purified water.

[0014] In a specific embodiment of the present application, the pH adjusting agent is selected from one or more of tartaric acid, lactic acid, citric acid, and malic acid.

[0015] In a preferred embodiment of the present application, the bromhexine hydrochloride oral solution further comprises a flavoring agent selected from one or more of sucralose, steviol glycoside, abasitan, and cyclamate; the amount of the flavoring agent can be known according to the general level of cognition of those skilled in the art.

[0016] Another aspect of the present application provides a preparation method of the above-mentioned bromhexine hydrochloride oral solution, which specifically comprises the following steps:

[0017] (1) adding solubilizer into purified water, stirring until completely dissolved to obtain solution A;

[0018] (2) adding bromhexine hydrochloride into solution A of step (1) to obtain a uniform suspension; then adding pH adjuster into the suspension, stirring to dissolve to obtain solution B;

[0019] (3) adding chitosan quaternary ammonium salt into purified water at 10-15℃, stirring until completely dissolved to obtain solution C; adding solution C into solution B obtained in step (2) and diluting with purified water to obtain a total solution; here, chitosan quaternary ammonium salt is dissolved in purified water at 10-15℃ to avoid molecular chain breakage caused by high temperature;

[0020] (4) filtering the total solution of step (3) and filling to obtain bromhexine hydrochloride oral solution.

[0021] In a specific embodiment of the present application, step (2) further comprises the process of adding flavoring agent, which can be selected from flavoring agents commonly used in oral solution preparations in the art, preferably, the flavoring agent is selected from one or more of sucralose, steviol glycoside, acesulfame potassium and cyclamate.

[0022] Compared with the prior art, the present application has the following beneficial effects:

[0023] (1) The present application adds chitosan quaternary ammonium salt and polyoxyethylene 60 hydrogenated castor oil into bromhexine hydrochloride oral solution to obtain a bromhexine hydrochloride oral solution with excellent stability, which shows good product stability in accelerated test and long-term test; and the applicant has also found that adding polyethylene glycol 15 hydroxystearate into the bromhexine hydrochloride oral solution of the present application can further improve the stability of the product.

[0024] (2) Compared with the complex biological preparation process involving monk fruit extract in the prior art, the preparation method of the bromhexine hydrochloride oral solution provided by the present application is simpler, easier and lower in cost. DETAILED DESCRIPTION

[0025] In order to better understand the technical solutions of the present application, the following further describes the embodiments. However, those skilled in the art should recognize that the present application is not limited to these embodiments.

[0026] Embodiment 1

[0027]

[0028] The preparation method is as follows:

[0029] (1) Polyoxyl 60 hydrogenated castor oil is added to purified water, and stirred until completely dissolved to obtain solution A;

[0030] (2) Bromhexine hydrochloride is added to solution A of step (1) to obtain a uniform suspension; tartaric acid is further added to the suspension, and stirred until dissolved to obtain solution B;

[0031] (3) Chitosan quaternary ammonium salt is added to purified water at 10-15°C, and stirred until completely dissolved to obtain solution C; solution C is added to solution B obtained in step (2), and diluted with purified water to obtain a total solution;

[0032] (4) The total solution of step (3) is filtered and filled to obtain bromhexine hydrochloride oral solution.

[0033] Example 2

[0034]

[0035]

[0036] The preparation method is as follows:

[0037] (1) Polyoxyl 60 hydrogenated castor oil and macrogol 15 hydroxystearate are added to purified water, and stirred until completely dissolved to obtain solution A;

[0038] (2) Bromhexine hydrochloride is added to solution A of step (1) to obtain a uniform suspension; lactic acid and stevioside are further added to the suspension, and stirred until dissolved to obtain solution B;

[0039] (3) Chitosan quaternary ammonium salt is added to purified water at 10-15°C, and stirred until completely dissolved to obtain solution C; solution C is added to solution B obtained in step (2), and diluted with purified water to obtain a total solution;

[0040] (4) The total solution of step (3) is filtered and filled to obtain bromhexine hydrochloride oral solution.

[0041] Example 3

[0042]

[0043] The preparation method is as follows:

[0044] (1) Polyoxyl 60 hydrogenated castor oil is added to purified water, and stirred until completely dissolved to obtain solution A;

[0045] (2) Bromhexine hydrochloride is added to solution A of step (1) to obtain a uniform suspension; citric acid and abasitan are further added to the suspension, and stirred until dissolved to obtain solution B;

[0046] (3) add the chitosan quaternary ammonium salt to purified water at 10-15 °C in an appropriate amount, stir until completely dissolved to obtain solution C; add solution C to solution B obtained in step (2), and dilute with purified water to obtain a total solution;

[0047] (4) filter the total solution of step (3), fill, and obtain the bromhexine hydrochloride oral solution.

[0048] Example 4

[0049]

[0050]

[0051] The preparation method is as follows:

[0052] (1) add polyoxyethylene 60 hydrogenated castor oil and macrogol 15 hydroxystearate to purified water in an appropriate amount, stir until completely dissolved to obtain solution A;

[0053] (2) add bromhexine hydrochloride to solution A of step (1) to obtain a uniform suspension; then add malic acid and sodium cyclamate to the suspension, stir and dissolve to obtain solution B;

[0054] (3) add the chitosan quaternary ammonium salt to purified water at 10-15 °C in an appropriate amount, stir until completely dissolved to obtain solution C; add solution C to solution B obtained in step (2), and dilute with purified water to obtain a total solution;

[0055] (4) filter the total solution of step (3), fill, and obtain the bromhexine hydrochloride oral solution.

[0056] Example 5

[0057]

[0058] The preparation method is as follows:

[0059] (1) add polyoxyethylene 60 hydrogenated castor oil and macrogol 15 hydroxystearate to purified water in an appropriate amount, stir until completely dissolved to obtain solution A;

[0060] (2) add bromhexine hydrochloride to solution A of step (1) to obtain a uniform suspension; then add tartaric acid and sucralose to the suspension, stir and dissolve to obtain solution B;

[0061] (3) add the chitosan quaternary ammonium salt to purified water at 10-15 °C in an appropriate amount, stir until completely dissolved to obtain solution C; add solution C to solution B obtained in step (2), and dilute with purified water to obtain a total solution;

[0062] (4) filter the total solution of step (3), fill, and obtain the bromhexine hydrochloride oral solution.

[0063] Comparative Example 1-Comparative Example 6

[0064]

[0065] Comparative Example 1-Comparative Example 6 were prepared according to the method of Example 1.

[0066] Comparative Example 1 does not contain chitosan quaternary ammonium salt; Comparative Example 2 does not contain polyoxyethylene 60 hydrogenated castor oil; Comparative Example 3 and Comparative Example 4 replace chitosan quaternary ammonium salt with maltitol and hydroxybenzoate, respectively; Comparative Example 5 and Comparative Example 6 replace polyoxyethylene 60 hydrogenated castor oil with poloxamer 188 and polysorbate 80, respectively, compared with the bromhexine hydrochloride oral solution of Example 1.

[0067] Stability Investigation

[0068] According to the requirements of the Stability Test Guiding Principles of Appendix XIX C of Chinese Pharmacopoeia 2010 Edition, the bromhexine hydrochloride oral solutions of Example 1-Example 5 and Comparative Example 1-Comparative Example 6 of the present application were investigated for stability; the changes in the properties of the bromhexine hydrochloride oral solutions and the contents of related substances after 0 days, 6 months of acceleration (temperature 40℃±2℃, relative humidity 75%±5%) and 12 months of long-term storage (temperature 30℃±2℃, relative humidity 65%±5%) were investigated, respectively, and the specific investigation results are shown in the following tables:

[0069] Table 1 Test results of bromhexine hydrochloride oral solution at 0 days

[0070]

[0071]

[0072] Table 2 Acceleration test results of bromhexine hydrochloride oral solution

[0073]

[0074]

[0075] Table 3 Long-term test results of bromhexine hydrochloride oral solution

[0076]

[0077] From the above stability test results, it can be seen that in the embodiments 1-5 of the present application, by using the combination of chitosan quaternary ammonium salt and polyoxyethylene 60 hydrogenated castor oil, the bromhexine hydrochloride oral solution obtained can maintain good product stability in 0 days, the accelerated test and the long-term storage test, the content of related substances does not change obviously, and the safety of patients can be ensured. The bromhexine hydrochloride oral solution in Comparative Examples 1-6 does not simultaneously add chitosan quaternary ammonium salt and polyoxyethylene 60 hydrogenated castor oil, the content of related substances is high, and the content of related substances increases obviously in the accelerated test and the long-term storage test, and even the solution flocculation occurs, the product stability is poor, and the product quality cannot be guaranteed.

[0078] It should be understood that the above specific embodiments of the present application are only used for illustrative or explanatory purposes of the principles of the present application, and do not constitute a limitation of the present application. Therefore, any modification, equivalent replacement, improvement, etc. made without departing from the spirit and scope of the present application shall be included in the protection scope of the present application. In addition, the appended claims of the present application are intended to cover all variations and modifications falling within the scope and boundary of the appended claims, or the equivalent forms of such scope and boundary.

Claims

1. A bromhexine hydrochloride oral solution, characterized in that, The oral solution comprises the following components: bromhexine hydrochloride, chitosan quaternary ammonium salt, solubilizer, pH regulator and purified water; wherein the solubilizer comprises polyoxyethylene 60 hydrogenated castor oil.

2. The bromhexine hydrochloride oral solution according to claim 1, characterized in that, The solubilizer further comprises macrogol 15 hydroxystearate.

3. The bromhexine hydrochloride oral solution according to claim 1, characterized in that, The chitosan quaternary ammonium salt is a medium-substituted chitosan quaternary ammonium salt.

4. The bromhexine hydrochloride oral solution according to claim 1, characterized in that, Each 100 parts of the bromhexine hydrochloride oral solution comprises the following components by weight: 0.2-0.6 parts of bromhexine hydrochloride, 1-2 parts of chitosan quaternary ammonium salt, 2-6 parts of solubilizer, 0.1-1.0 parts of pH regulator and the balance of purified water.

5. The bromhexine hydrochloride oral solution according to claim 4, characterized in that, Each 100 parts of the bromhexine hydrochloride oral solution comprises the following components by weight: 0.4 parts of bromhexine hydrochloride, 1.5 parts of chitosan quaternary ammonium salt, 4 parts of solubilizer, 0.5 parts of pH regulator and the balance of purified water.

6. The oral solution of bromhexine hydrochloride according to any one of claims 1 to 5, characterized in that, The pH regulator is selected from one or more of tartaric acid, lactic acid, citric acid and malic acid.

7. The bromhexine hydrochloride oral solution according to claim 1, characterized in that, The oral solution further comprises a flavoring agent.

8. The bromhexine hydrochloride oral solution according to claim 7, characterized in that, The flavoring agent is selected from one or more of sucralose, steviol glycoside, abasatan and cyclamate.

9. A process for the preparation of the oral solution of bromhexine hydrochloride according to claim 1, characterized by, Specifically comprising the following steps: (1) adding the solubilizer to an appropriate amount of purified water, stirring until completely dissolved to obtain solution A; (2) adding bromhexine hydrochloride to solution A of step (1) to obtain a uniform suspension; then adding the pH regulator to the suspension, stirring to dissolve to obtain solution B; (3) adding chitosan quaternary ammonium salt to an appropriate amount of 10-15℃ purified water, stirring until completely dissolved to obtain solution C; adding solution C to solution B obtained in step (2) and diluting with purified water to obtain a total solution; (4) filtering the total solution of step (3) and filling to obtain the bromhexine hydrochloride oral solution.

10. The method of preparing bromhexine hydrochloride oral solution according to claim 9, characterized by, The step (2) further comprises the process of adding a flavoring agent.

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