A bromhexine hydrochloride injection and a preparation method thereof

Abstract

This invention provides a bromhexine hydrochloride injection and its preparation method, relating to the field of pharmaceutical technology. Each 1000 mL of bromhexine hydrochloride injection comprises the following components: 2-4 g of bromhexine hydrochloride, 5-12 g of L-cysteine ​​hydrochloride, 10-50 g of trehalose, 1.5-6.5 g of excipients, 3-5 g of sodium chloride, a pH adjuster, and the remainder being water for injection. This invention utilizes a combination of trehalose, L-cysteine ​​hydrochloride, tartaric acid, citric acid, and calcium sodium edetate, which produces a significant synergistic effect, better stabilizing the bromhexine hydrochloride injection system. This effectively protects the integrity of bromhexine hydrochloride during storage, preventing its degradation, and allows for effective control of the content of related substances during long-term storage, thus improving the safety of the drug.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a bromhexine hydrochloride injection and its preparation method. Background Technology

[0002] Bromhexine hydrochloride, chemically known as N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine hydrochloride, is a commonly used clinical drug for respiratory diseases and a widely used mucolytic expectorant. Currently, it is available in various dosage forms in China, including tablets, injections, and powder for injection. Bromhexine hydrochloride injection is a commonly used dosage form due to its rapid onset of action and high bioavailability, and is widely used in clinical treatment.

[0003] However, bromhexine hydrochloride is only slightly soluble in ethanol or chloroform, and very slightly soluble in water. It is also sensitive to pH, easily crystallizing at pH values ​​above 5.0. Furthermore, because the bromhexine hydrochloride molecule contains primary aromatic amino and cyclohexylamine functional groups that are sensitive to oxygen, light, and heat, it is highly susceptible to oxidative and thermal degradation in aqueous solutions, producing various related substances. Excessive levels of these substances can affect the drug's efficacy and safety. Simultaneously, bromhexine hydrochloride may react with excipients, generating unique, unknown impurities that require strict control. This presents significant challenges to the preparation and storage of the injection solution. Summary of the Invention

[0004] In view of this, the present invention proposes a bromhexine hydrochloride injection and its preparation method.

[0005] The technical solution of this invention is implemented as follows: A bromhexine hydrochloride injection, wherein each 1000 mL of bromhexine hydrochloride injection comprises the following components: 2-4 g of bromhexine hydrochloride, 5-12 g of L-cysteine ​​hydrochloride, 10-50 g of trehalose, 1.5-6.5 g of adjuvants, 3-5 g of sodium chloride, a pH adjuster, and the balance being water for injection; wherein the pH adjuster adjusts the pH of the bromhexine hydrochloride injection to 3.5-4.5.

[0006] Furthermore, each 100 mL of bromhexine hydrochloride injection consists of the following components: 2-4 g of bromhexine hydrochloride, 5-10 g of L-cysteine ​​hydrochloride, 10-20 g of trehalose, 1.6-3.5 g of adjuvants, 3-5 g of sodium chloride, pH adjuster, and the remainder being water for injection.

[0007] Furthermore, each 100 mL of bromhexine hydrochloride injection consists of the following components: 2 g of bromhexine hydrochloride, 8 g of L-cysteine ​​hydrochloride, 20 g of trehalose, 3.3 g of adjuvants, 3.5 g of sodium chloride, pH adjuster, and the remainder being water for injection.

[0008] Furthermore, the additive is composed of tartaric acid, citric acid, and sodium calcium edetate in a mass ratio of 0.5~3:1~3:0.1~0.5.

[0009] Furthermore, the content of tartaric acid in each 1000 mL of bromhexine hydrochloride injection is 0.5~3 g; the content of citric acid in each 1000 mL of bromhexine hydrochloride injection is 1~3 g; and the content of calcium sodium edetate in each 1000 mL of bromhexine hydrochloride injection is 0.1~0.5 g.

[0010] Furthermore, the pH adjuster is a 0.1~0.2 mol / L hydrochloric acid or sodium hydroxide solution.

[0011] Furthermore, the pH adjuster is a 0.1 mol / L sodium hydroxide solution.

[0012] The preparation method of bromhexine hydrochloride injection includes the following steps: S1. Heat 40-60% of the prescribed amount of water for injection to 50-60°C, then add the excipients and sodium chloride and stir to mix well. Cool down to 30-35°C and add bromhexine hydrochloride under a nitrogen atmosphere and stir to mix well to obtain drug solution I. S2. Add L-cysteine ​​hydrochloride and trehalose to the mixed drug solution and stir to dissolve to obtain drug solution II; S3. Adjust the pH value of drug solution II with pH adjuster, add the remaining prescription amount of water for injection to make up the volume, stir evenly to obtain drug solution III, add activated carbon for filtration, and then pass through microfiltration, filling and sterilization to obtain bromhexine hydrochloride injection.

[0013] Furthermore, the amount of activated carbon added is 0.05% to 0.1% of the mass of the drug solution III.

[0014] Furthermore, the microfiltration involves sequentially passing the drug solution III through 0.45μm and 0.22μm microporous membranes.

[0015] Furthermore, the sterilization is performed at 115℃~121℃ for 15~30 minutes.

[0016] When using the bromhexine hydrochloride injection of the present invention, it can be administered directly via intravenous drip according to clinical needs, or diluted with conventional infusion solutions such as 5% glucose injection or 0.9% sodium chloride injection.

[0017] Compared with the prior art, the beneficial effects of the present invention are: This invention utilizes a compound of trehalose, L-cysteine ​​hydrochloride, tartaric acid, citric acid, and calcium sodium edetate to produce a significant synergistic effect, thereby better stabilizing the bromhexine hydrochloride injection system. This effectively protects the integrity of bromhexine hydrochloride during storage, prevents its degradation, and allows for effective control of the content of related substances during long-term storage, thus improving the safety of the drug.

[0018] In this invention, trehalose does not undergo Maillard-type dehydration condensation with the free amino groups of bromhexine hydrochloride, thus eliminating the formation of adduct impurities between the drug and excipients at the source. Trehalose can form a stable system with bromhexine hydrochloride and water molecules through hydrogen bonds, reducing the chemical potential of the drug molecules in solution and slowing down the hydrolysis rate and thermal degradation. Furthermore, L-cysteine ​​hydrochloride can react with dissolved oxygen in the injection solution, effectively protecting the free amino groups in the bromhexine hydrochloride molecules from oxidative attack and preventing oxidative degradation of the drug molecules. L-cysteine ​​hydrochloride and trehalose have a synergistic protective effect, preventing the reaction and degradation of bromhexine hydrochloride drug molecules through multiple pathways and improving the stability of the solution system. In addition, the use of tartaric acid, citric acid, and calcium sodium edetate in specific proportions as excipients effectively stabilizes the pH environment of the injection system, effectively inhibiting the precipitation of bromhexine hydrochloride and the generation of related substances. Detailed Implementation

[0019] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0020] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0021] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0022] Example 1 This embodiment provides a bromhexine hydrochloride injection, and the prescription dosage is shown in Table 1 below: Table 1

[0023] The preparation method of this injection solution includes the following steps: S1. Heat 60% of the prescribed amount of water for injection to 60°C, then add the excipients and sodium chloride and stir to mix well. Cool down to 30°C and add bromhexine hydrochloride under a nitrogen atmosphere and stir to mix well to obtain drug solution I. S2. Add L-cysteine ​​hydrochloride and trehalose to the mixed drug solution and stir to dissolve to obtain drug solution II; S3. Adjust the pH of drug solution II to 3.8 with a pH adjuster, add the remaining prescription amount of water for injection to make up the volume, stir evenly to obtain drug solution III, add 0.1% of pharmaceutical activated carbon according to the total mass of drug solution III, stir for 15 min, filter to remove carbon, and then pass through microfiltration successively through 0.45μm and 0.22μm microporous membranes for filtration and filling. During the entire filtration and filling process, nitrogen gas is continuously introduced for protection and dissolved oxygen content is monitored online to ensure that dissolved oxygen ≤0.5mg / L. Then sterilize at 121℃ for 15 min to obtain bromhexine hydrochloride injection.

[0024] Example 2 This embodiment provides a bromhexine hydrochloride injection, and the prescription dosage is shown in Table 2 below: Table 2

[0025] The preparation method of this injection solution includes the following steps: S1. Heat 50% of the prescribed amount of water for injection to 50°C, then add the excipients and sodium chloride and stir to mix well. Cool down to 35°C and add bromhexine hydrochloride under a nitrogen atmosphere and stir to mix well to obtain drug solution I. S2. Add L-cysteine ​​hydrochloride and trehalose to the mixed drug solution and stir to dissolve to obtain drug solution II; S3. Adjust the pH of drug solution II to 4.5 with a pH adjuster, add the remaining prescribed amount of water for injection to make up the volume, stir evenly to obtain drug solution III, add 0.05% of pharmaceutical activated carbon according to the total mass of drug solution III, stir for 20 min, filter to remove carbon, and then pass through microfiltration successively through 0.45μm and 0.22μm microporous filter membranes, and fill. During the entire filtration and filling process, nitrogen gas is continuously introduced for protection and dissolved oxygen content is monitored online to ensure that dissolved oxygen ≤0.5mg / L. Then sterilize at 115℃ for 30 min to obtain bromhexine hydrochloride injection.

[0026] Example 3 This embodiment provides a bromhexine hydrochloride injection, and the prescription dosage is shown in Table 3 below: Table 3

[0027] The preparation method of this injection solution includes the following steps: S1. Heat 40% of the prescribed amount of water for injection to 55°C, then add the excipients and sodium chloride and stir to mix well. Cool down to 30°C and add bromhexine hydrochloride under a nitrogen atmosphere and stir to mix well to obtain drug solution I. S2. Add L-cysteine ​​hydrochloride and trehalose to the mixed drug solution and stir to dissolve to obtain drug solution II; S3. Adjust the pH of drug solution II to 4.0 with a pH adjuster, add the remaining prescription volume of water for injection to make up the volume, stir evenly to obtain drug solution III, add pharmaceutical activated carbon accounting for 0.08% of the total mass of drug solution III, stir for 15 min, filter to remove carbon, and then pass through microfiltration successively through 0.45μm and 0.22μm microporous membranes for filtration and filling. During the entire filtration and filling process, nitrogen gas is continuously introduced for protection and dissolved oxygen content is monitored online to ensure that dissolved oxygen is ≤0.5mg / L. Then sterilize at 121℃ for 15 min to obtain bromhexine hydrochloride injection.

[0028] Comparative Example 1 Based on Example 1, the formulation does not contain trehalose, but remains otherwise unchanged. The dosages are shown in Table 4 below: Table 4

[0029] Comparative Example 2 Based on Example 1, the formulation does not contain L-cysteine ​​hydrochloride, and all other aspects remain unchanged. The dosages are shown in Table 5 below: Table 5

[0030] Comparative Example 3 Based on Example 1, the formulation contains no adjuvants, and all other aspects remain unchanged. The dosages are shown in Table 6 below: Table 6

[0031] Comparative Example 4 Based on Example 1, the dosage and ratio of the adjuvants were changed, while the rest remained the same.

[0032] The additive is composed of tartaric acid, citric acid, and sodium calcium edetate in a mass ratio of 0.1:5:0.

[0033] The performance of the bromhexine hydrochloride injection prepared in the above examples and comparative examples was tested.

[0034] 1. Detection Method (1) Appearance: Visually inspect the color, clarity and presence of precipitate of the injection solution.

[0035] (2) pH value determination: determined according to the method of General Chapter 0631, Part IV, Chinese Pharmacopoeia 2020 edition.

[0036] (3) Content determination: The content was determined according to the high performance liquid chromatography method (General Chapter 0512) of the 2020 edition of the Chinese Pharmacopoeia. The chromatographic conditions are as follows: Chromatographic column: Octadecylsilane bonded silica column (C18, 250mm × 4.6mm, 5μm); Mobile phase: phosphate buffer-acetonitrile, with a volume ratio of 70:30. The phosphate buffer was prepared by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 mL of water and adjusting the pH to 3.0 with phosphoric acid. Detection wavelength: 249nm; Flow rate: 1.0 mL / min; The column temperature is 30℃; The injection volume was 20 μL.

[0037] (4) Determination of related substances: The chromatographic conditions are the same as those for the content determination, according to the high performance liquid chromatography method (General Rule 0512) of the 2020 edition of the Chinese Pharmacopoeia. The chromatographic chromatogram is recorded until twice the retention time of the main component peak, and the total amount of related substances and the content of individual impurities are calculated.

[0038] 2. Testing Items (1) Initial test results The performance of the bromhexine hydrochloride injections prepared in the examples and comparative examples was tested at day 0, and the results are shown in Table 7 below.

[0039] (2) Acceleration stability The injection solutions prepared in the examples and comparative examples were placed in a constant temperature and humidity chamber at 40℃±2℃ and 75%±5% for 6 months, and then samples were taken and tested according to the detection method described in section 1 above. The results are shown in Table 8 below.

[0040] (3) Long-term stability The injection solutions prepared in the examples and comparative examples were placed in a constant temperature and humidity chamber at 25℃±2℃ and 60%±5% for 24 months, and then samples were taken and tested according to the above detection method. The results are shown in Table 9 below.

[0041] Table 7

[0042] As can be seen from the results in Table 7, the bromhexine hydrochloride injections prepared in the examples and comparative examples all meet the requirements. However, compared with Examples 1-3, the content of related substances in the bromhexine hydrochloride injections of Comparative Examples 1-4 is significantly higher than that in the bromhexine hydrochloride injections prepared in Examples 1-3. This indicates that the combination of trehalose, L-cysteine ​​hydrochloride, tartaric acid, citric acid and calcium sodium edetate can better stabilize the injection system.

[0043] Table 8

[0044] As shown in Table 8, the bromhexine hydrochloride injection samples prepared in Examples 1-3 of this invention exhibited good stability in the accelerated stability test, with a content of 99.0% or higher, a maximum single impurity content of ≤0.08%, and a total impurity content of ≤0.31%. In contrast, the contents of Comparative Examples 1-3 ranged from 97.2% to 98.5%, with a maximum single impurity content of ≥0.14% and a total impurity content of ≥1.25%. Comparative Example 1's formulation did not contain trehalose, Comparative Example 2's formulation did not contain L-cysteine ​​hydrochloride, Comparative Example 3's formulation did not contain any excipients, and Comparative Example 4 changed the proportion of excipients. During storage, the bromhexine hydrochloride content decreased more rapidly, and the content of related substances increased. This indicates that by combining trehalose and L-cysteine ​​hydrochloride, along with a specific proportion of excipients, the integrity of bromhexine hydrochloride during storage can be effectively protected, preventing degradation and improving storage stability.

[0045] Table 9

[0046] As shown in Table 9 of the long-term stability test results, the content of bromhexine hydrochloride injection samples in Examples 1-3 decreased relatively slowly, the content of related substances increased slowly, and the content of related substances was low. Compared with Example 1, the bromhexine hydrochloride injection samples prepared in Comparative Examples 1-4 showed varying degrees of degradation after being stored for 24 months at a temperature of 25℃±2℃ and a relative humidity of 60%±5%, and the content of other maximum single impurities and total impurities also showed varying degrees of increase, indicating poor stability.

[0047] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A bromhexine hydrochloride injection solution, characterized in that, Each 1000 mL of bromhexine hydrochloride injection consists of the following components: 2-4 g of bromhexine hydrochloride, 5-12 g of L-cysteine ​​hydrochloride, 10-50 g of trehalose, 1.5-6.5 g of adjuvants, 3-5 g of sodium chloride, pH adjuster, and the balance being water for injection; the pH adjuster adjusts the pH of the bromhexine hydrochloride injection to 3.5-4.

5.

2. The bromhexine hydrochloride injection according to claim 1, characterized in that, Each 100 mL of bromhexine hydrochloride injection consists of the following components: 2-4 g of bromhexine hydrochloride, 5-10 g of L-cysteine ​​hydrochloride, 10-20 g of trehalose, 1.6-3.5 g of adjuvants, 3-5 g of sodium chloride, pH adjuster, and the balance being water for injection.

3. The bromhexine hydrochloride injection solution according to claim 1, characterized in that, Each 100 mL of bromhexine hydrochloride injection consists of the following components: 2 g of bromhexine hydrochloride, 8 g of L-cysteine ​​hydrochloride, 20 g of trehalose, 3.3 g of adjuvants, 3.5 g of sodium chloride, pH adjuster, and the remainder is water for injection.

4. The bromhexine hydrochloride injection solution according to any one of claims 1-3, characterized in that, The additive is composed of tartaric acid, citric acid, and sodium calcium edetate in a mass ratio of 0.5~3:1~3:0.1~0.

5.

5. The bromhexine hydrochloride injection according to claim 4, characterized in that, The content of tartaric acid in each 1000 mL of bromhexine hydrochloride injection is 0.5~3g; the content of citric acid in each 1000 mL of bromhexine hydrochloride injection is 1~3g; and the content of calcium sodium edetate in each 1000 mL of bromhexine hydrochloride injection is 0.1~0.5g.

6. The bromhexine hydrochloride injection according to any one of claims 1-3, characterized in that, The pH adjuster is a 0.1~0.2 mol / L hydrochloric acid or sodium hydroxide solution.

7. The method for preparing bromhexine hydrochloride injection according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Heat 40-60% of the prescribed amount of water for injection to 50-60°C, then add the excipients and sodium chloride and stir to mix well. Cool down to 30-35°C and add bromhexine hydrochloride under a nitrogen atmosphere and stir to mix well to obtain drug solution I. S2. Add L-cysteine ​​hydrochloride and trehalose to the mixed drug solution and stir to dissolve to obtain drug solution II; S3. Adjust the pH value of drug solution II with pH adjuster, add the remaining prescription amount of water for injection to make up the volume, stir evenly to obtain drug solution III, add activated carbon for filtration, and then pass through microfiltration, filling and sterilization to obtain bromhexine hydrochloride injection.

8. The method for preparing bromhexine hydrochloride injection according to claim 7, characterized in that, The amount of activated carbon added is 0.05% to 0.1% of the mass of the drug solution III.

9. The method for preparing bromhexine hydrochloride injection according to claim 7, characterized in that, The microfiltration process involves sequentially passing the drug solution III through 0.45μm and 0.22μm microporous membranes.

10. The method for preparing bromhexine hydrochloride injection according to claim 7, characterized in that, The sterilization process involves sterilizing at 115℃~121℃ for 15~30 minutes.

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