Dopamine hydrochloride injection and preparation method thereof

Abstract

The present application relates to a kind of dopamine hydrochloride injection and its preparation method, which is composed of the following raw materials by mass percentage: dopamine hydrochloride 2%, nicotinamide 0.2-0.5%, glycerol 0.5-1%, and the rest is water for injection.The present application has the advantages that the prepared dopamine hydrochloride injection has fewer impurities decomposed during long-term storage, more stable quality, and higher drug safety.

Description

Technical Field

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

[0002] Dopamine hydrochloride injection is a common emergency treatment drug, indicated for shock syndromes caused by myocardial infarction, trauma, endotoxin sepsis, cardiac surgery, renal failure, congestive heart failure, etc.; and for shock that cannot be corrected after blood volume resuscitation, especially shock with oliguria and normal or low peripheral vascular resistance. Because it can increase cardiac output, it is also used for heart failure unresponsive to digitalis and diuretics.

[0003] Dopamine hydrochloride is a white or off-white lustrous crystal; it gradually decomposes upon exposure to air and light, releasing impurities and darkening in color. When formulated as dopamine hydrochloride injection, this readily decomposable property affects the safety of the drug.

[0004] Most commercially available dopamine hydrochloride injections currently use sodium bisulfite to inhibit decomposition, but this still fails to achieve the desired effect. Dopamine hydrochloride still decomposes during long-term storage, leading to a decrease in content, an increase in impurities, and affecting product safety. Summary of the Invention

[0005] The purpose of this invention is to overcome the above-mentioned defects and provide a dopamine hydrochloride injection and its preparation method. The dopamine hydrochloride injection prepared by this invention has fewer impurities decomposed during long-term storage, more stable quality, and higher drug safety.

[0006] This invention is achieved through the following technical solution: providing a dopamine hydrochloride injection solution, which, by mass percentage, is composed of the following raw materials: 2% dopamine hydrochloride, 0.2-0.5% nicotinamide, 0.5-1% glycerol, with the balance being water for injection. The optimal composition is: 2% dopamine hydrochloride, 0.3% nicotinamide, 0.8% glycerol, with the balance being water for injection.

[0007] Another method for preparing the above-mentioned dopamine hydrochloride injection is provided, and the specific preparation steps are as follows:

[0008] Step S1: Preparation process;

[0009] Add nicotinamide and glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0010] Step S2: Filling process;

[0011] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0012] Step S3: Sterilization process;

[0013] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0014] The beneficial effects of this invention are as follows: This invention enables dopamine hydrochloride injection to decompose with fewer impurities during long-term storage, resulting in more stable quality and higher drug safety; This invention uses a combination of nicotinamide and glycerin to inhibit the generation of impurities, which is superior to using nicotinamide and glycerin alone, achieving unexpected results. Detailed Implementation

[0015] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0016] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0017] Example 1

[0018]

[0019]

[0020] Process:

[0021] Step S1: Preparation process;

[0022] Add nicotinamide to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0023] Step S2: Filling process;

[0024] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0025] Step S3: Sterilization process;

[0026] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0027] Example 2

[0028] Material composition Prescription ratio Dopamine hydrochloride 20g glycerin 10g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0029] Process:

[0030] Step S1: Preparation process;

[0031] Add glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0032] Step S2: Filling process;

[0033] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0034] Step S3: Sterilization process;

[0035] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0036] Example 3

[0037] Material composition Prescription ratio Dopamine hydrochloride 20g Niacinamide 2g glycerin 5g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0038] Process:

[0039] Step S1: Preparation process;

[0040] Add nicotinamide and glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0041] Step S2: Filling process;

[0042] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0043] Step S3: Sterilization process;

[0044] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0045] Example 4

[0046] Material composition Prescription ratio Dopamine hydrochloride 20g Niacinamide 5g glycerin 10g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0047] Process:

[0048] Step S1: Preparation process;

[0049] Add nicotinamide and glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0050] Step S2: Filling process;

[0051] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0052] Step S3: Sterilization process;

[0053] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0054] Example 5

[0055] Material composition Prescription ratio Dopamine hydrochloride 20g Niacinamide 3g glycerin 8g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0056] Process:

[0057] Step S1: Preparation process;

[0058] Add nicotinamide and glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0059] Step S2: Filling process;

[0060] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0061] Step S3: Sterilization process;

[0062] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0063] Example 6

[0064]

[0065]

[0066] Process:

[0067] Step S1: Preparation process;

[0068] Add nicotinamide and glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0069] Step S2: Filling process;

[0070] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0071] Step S3: Sterilization process;

[0072] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0073] Comparative Example 1

[0074] Material composition Prescription ratio Dopamine hydrochloride 20g Sodium bisulfite 10g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0075] Process:

[0076] Step S1: Preparation process;

[0077] Sodium bisulfite is added to the mixing tank according to the prescription amount, and then 40% of the total weight of the dopamine hydrochloride injection solution is added to it. The mixture is stirred and dissolved. Then, 60% of the total weight of the dopamine hydrochloride injection solution is added, and dopamine hydrochloride is added. The mixture is stirred and dissolved, and then water for injection is added to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0078] Step S2: Filling process;

[0079] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0080] Step S3: Sterilization process;

[0081] The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

[0082] Comparative Example 2

[0083] Comparative Example 2 was prepared using conventional methods, and the formulation is as follows:

[0084] Material composition Prescription ratio Dopamine Hydrochloride Injection 20g Sodium bisulfite 5g Water for Injection Adjust the volume to 1000ml headspace Nitrogen

[0085] Process:

[0086] Step S1: Preparation process;

[0087] Sodium bisulfite is added to the mixing tank according to the prescription amount, and then 40% of the total weight of the dopamine hydrochloride injection solution is added to it. The mixture is stirred and dissolved. Then, 60% of the total weight of the dopamine hydrochloride injection solution is added, and dopamine hydrochloride is added. The mixture is stirred and dissolved, and then water for injection is added to make up the volume to obtain the dopamine hydrochloride mixed solution.

[0088] Step S2: Filling process;

[0089] The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection.

[0090] Step S3: Sterilization process;

[0091] The dopamine hydrochloride injection solution obtained in step S2 was autoclaved at 121°C for 15 minutes, and leak was checked to obtain the dopamine hydrochloride injection solution.

[0092] Example 1

[0093] The content of dopamine hydrochloride obtained in Examples 1-6 and Comparative Examples 1-2 was determined using the following method:

[0094] Preparation of test solution: Accurately measure an appropriate amount of this product and quantitatively dilute it with the mobile phase to prepare a solution containing 30 μg of dopamine hydrochloride per 1 ml.

[0095] Preparation of reference solution: Weigh an appropriate amount of dopamine hydrochloride reference standard accurately, dissolve and quantitatively dilute it in the mobile phase to prepare a solution containing 30 μg of dopamine hydrochloride per 1 ml.

[0096] Measurement conditions:

[0097] For system suitability solution, take appropriate amounts of dopamine hydrochloride and 4-ethylcatechol, dissolve and dilute them in the mobile phase to prepare a mixed solution containing approximately 6 μg of each in 1 ml.

[0098] The chromatographic conditions were as follows: octadecylsilane-bonded silica gel was used as the stationary phase; the mobile phase was 0.005 mol / L sodium dodecyl sulfate-acetonitrile-glacial acetic acid-0.1 mol / L disodium ethylenediaminetetraacetate (700:300:10:2); the detection wavelength was 280 nm; and the injection volume was 20 μl.

[0099] System suitability requirements: In the system suitability solution chromatogram, the resolution between the dopamine peak and the 4-ethylcatechol peak should be greater than 3.0.

[0100] Assay Method and Calculation: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the amount of dopamine hydrochloride per ml by peak area using the external standard method, divide by the labeled amount (40 mg / ml), and calculate the percentage. The limit requirement is 95%–105% to be considered acceptable.

[0101] The results of the determination of dopamine hydrochloride content obtained in Examples 1-6 and Comparative Examples 1-2 are shown in Table 1 below:

[0102] Table 1:

[0103] Examples / Comparative Examples Dopamine hydrochloride content (%) illustrate Example 1 98.2 qualified Example 2 97.8 qualified Example 3 99.3 qualified Example 4 99.4 qualified Example 5 100.9 Best effect Example 6 98.2 qualified Comparative Example 1 95.2 Unqualified Comparative Example 2 94.3 Unqualified .

[0104] Example 2

[0105] The impurities contained in Examples 1-6 and Comparative Examples 1-2 were determined using the following method:

[0106] Preparation of test solution: Accurately measure an appropriate amount of this product and dilute it with the mobile phase to prepare a solution containing approximately 0.3 mg of dopamine hydrochloride per 1 ml.

[0107] Preparation of reference solution: Accurately measure 1 ml of the test solution and place it in a 100 ml volumetric flask. Dilute to the mark with the mobile phase and shake well.

[0108] Measurement conditions:

[0109] For system suitability solution, take appropriate amounts of dopamine hydrochloride and 4-ethylcatechol, dissolve and dilute them in the mobile phase to prepare a mixed solution containing approximately 6 μg of each in 1 ml.

[0110] The chromatographic conditions were as follows: octadecylsilane-bonded silica gel was used as the stationary phase; the mobile phase was 0.005 mol / L sodium dodecyl sulfate-acetonitrile-glacial acetic acid-0.1 mol / L disodium ethylenediaminetetraacetate (700:300:10:2); the detection wavelength was 280 nm; and the injection volume was 20 μl.

[0111] System suitability requirements: In the system suitability solution chromatogram, the resolution between the dopamine peak and the 4-ethylcatechol peak should be greater than 3.0.

[0112] For the assay, accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to three times the retention time of the main component peak.

[0113] If impurity peaks are present in the chromatogram of the test solution, the sum of the areas of all impurity peaks shall not exceed the area of ​​the main peak of the control solution (1.0%).

[0114] The results of the determination of impurity content obtained in Examples 1-6 and Comparative Examples 1-2 are shown in Tables 2 and 3 below:

[0115] Table 2 Impurity Detection Results

[0116]

[0117] Table 3 Summary of Impurity Information

[0118]

[0119] Therefore, this invention enables dopamine hydrochloride injection to decompose with fewer impurities during long-term storage, resulting in more stable quality and higher drug safety. The combination of nicotinamide and glycerin used in this invention to inhibit the generation of impurities is superior to using nicotinamide and glycerin alone, achieving unexpected results.

[0120] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. 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 dopamine hydrochloride injection solution, characterized in that, This dopamine hydrochloride injection is composed of the following raw materials by weight percentage: dopamine hydrochloride 2%, nicotinamide 0.3%, glycerin 0.8%, and the balance being water for injection; The impurity test results for this dopamine hydrochloride injection were as follows: no impurities were detected, including 4-O-methyldopamine, 3-O-methyldopamine, 2-(3,4-dimethoxyphenyl)ethylamine, and 4-ethylcatechol.

2. A method for preparing the dopamine hydrochloride injection solution according to claim 1, characterized in that, The specific preparation steps are as follows: Step S1: Preparation process; Add nicotinamide and glycerin to the mixing tank according to the prescription amount, and add water for injection accounting for 40% of the total weight of the dopamine hydrochloride injection solution. Stir to dissolve, then add water for injection accounting for 60% of the total weight of the dopamine hydrochloride injection solution, add dopamine hydrochloride, stir to dissolve, and add water for injection to make up the volume to obtain the dopamine hydrochloride mixed solution. Step S2: Filling process; The dopamine hydrochloride mixture obtained in step S1 was cooled to 2-8°C, pressurized with nitrogen for 12 hours, and then heated to 30°C. After the solution was completely reconstituted, it was filtered through a 0.22μm microporous membrane and filled into brown borosilicate glass ampoules. The ampoules were then sealed with a high-temperature flame to obtain dopamine hydrochloride injection. Step S3: Sterilization process; The dopamine hydrochloride injection obtained in step S2 is subjected to autoclaving at 121°C for 15 minutes and leak detection is performed to obtain the dopamine hydrochloride injection.

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