Dopamine hydrochloride injection and preparation method thereof

Abstract

The invention is suitable for the technical field of pharmaceutical preparations, and provides a dopamine hydrochloride injection and a preparation method thereof.The preparation method comprises the steps that part of water for injection is added into a liquid preparation tank, inert gas is synchronously filled, the temperature is controlled to be 20-30 DEG C, and inert gas is continuously filled in the subsequent liquid preparation process; the preparation method comprises the following steps: adding calcium chloride and sodium glycerophosphate into water for injection, stirring and dissolving completely, adding sodium acetate, dopamine hydrochloride and citric acid, and stirring and dissolving; and adding the water for injection to full dose and uniformly stirring. The dopamine hydrochloride injection obtained by sequentially adding the calcium chloride, the sodium glycerophosphate, the sodium acetate, the dopamine hydrochloride and the citric acid into the water for injection and stirring and dissolving at a specific temperature is low in impurity amount, and in an accelerated test stability investigation, the characters, the pH value, related substances, the content and the like have no obvious change, and the quality stability is high; in addition, sodium pyrosulfite is not contained, so that the adverse reaction caused by an antioxidant can be avoided, and the safety is high.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a dopamine hydrochloride injection and a preparation method thereof. Background Art

[0002] The chemical name of dopamine hydrochloride is 4-(2-aminoethyl)-1,2-benzenediol hydrochloride. It can be used in myocardial infarction, endotoxin sepsis, trauma and other situations. It can also regulate diseases caused by renal failure, heart surgery, congestive heart failure and other reasons.

[0003] At present, most of the dopamine hydrochloride injections that are often used as reference preparations and the dopamine hydrochloride injections that are widely sold on the market use sodium metabisulfite as an auxiliary material stabilizer. Sodium metabisulfite is a white or yellow crystalline powder or small crystals with a strong SO 2 The smell has obvious irritating effect on the skin and mucous membranes, and can cause symptoms of conjunctivitis and bronchitis. In addition, people with allergies or asthma are very sensitive to it, and direct skin contact can cause burns. Since sodium metabisulfite can cause great damage to the human body, its dosage must be strictly limited.

[0004] It can be seen from this that the existing dopamine hydrochloride injection generally contains sodium metabisulfite and has low safety. Summary of the invention

[0005] The purpose of the embodiments of the present application is to provide a dopamine hydrochloride injection and a preparation method thereof, aiming to solve the problem that the existing dopamine hydrochloride injection generally contains sodium metabisulfite and has low safety.

[0006] The embodiment of the present application is implemented as follows: a method for preparing dopamine hydrochloride injection, comprising:

[0007] Add a portion of the prepared water for injection into the liquid preparation tank, and simultaneously fill it with inert gas to make the dissolved oxygen less than 2 mg / L, control the temperature at 20-30°C, and continue to fill it with inert gas during the subsequent liquid preparation process;

[0008] Add calcium chloride and sodium glycerophosphate to the water for injection, turn on the stirring device to dissolve them completely, add sodium acetate, dopamine hydrochloride and citric acid and stir to dissolve;

[0009] Add water for injection to the full amount and stir evenly. After filtering, filling and sterilization, dopamine hydrochloride injection is obtained.

[0010] Preferably, the mass ratio of sodium glycerophosphate to calcium chloride is 1:(0.5-0.7).

[0011] Preferably, the mass ratio of the sodium glycerophosphate to calcium chloride is 1:0.6.

[0012] Preferably, the mass ratio of dopamine hydrochloride, sodium glycerophosphate, sodium acetate and citric acid is 40:(4-6):(1-3):(0.03-0.07).

[0013] Preferably, the mass ratio of dopamine hydrochloride, sodium glycerophosphate, sodium acetate and citric acid is 40:5:2:0.05.

[0014] Another aspect of the embodiments of the present application further provides a dopamine hydrochloride injection, wherein the dopamine hydrochloride injection is prepared by the above-mentioned method for preparing dopamine hydrochloride injection.

[0015] The embodiment of the present application provides a method for preparing dopamine hydrochloride injection, which is prepared by successively adding calcium chloride, sodium glycerophosphate, sodium acetate, dopamine hydrochloride and citric acid in specific proportions to water for injection at a specific temperature and stirring and dissolving the mixture, wherein the dopamine hydrochloride injection has low impurities, and during the accelerated test stability investigation, the properties, pH value, related substances and contents thereof do not change significantly, and the quality stability is high; in addition, the dopamine hydrochloride injection does not contain sodium pyrosulfite, and thus can avoid adverse reactions caused by its antioxidant, and thus has high safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is a SEM image of the bottom of the bottle corresponding to the 6-month accelerated dopamine hydrochloride injection sample provided in the examples of the present application;

[0017] Figure 2 This is a SEM image of the bottle corresponding to the 6-month accelerated dopamine hydrochloride injection sample provided in the examples of the present application;

[0018] Figure 3 This is a SEM image of the bottleneck corresponding to the 6-month accelerated dopamine hydrochloride injection sample provided in the examples of the present application. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solution and advantages of the present application more clearly understood, the present application is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0020] In order to solve the problem that the existing dopamine hydrochloride injection generally contains sodium metabisulfite and has low safety, the embodiment of the present application provides a method for preparing dopamine hydrochloride injection. The dopamine hydrochloride injection is obtained by adding calcium chloride, sodium glycerophosphate, sodium acetate, dopamine hydrochloride and citric acid to water for injection at a specific temperature, stirring and dissolving them. The dopamine hydrochloride injection has low impurities, and during the accelerated test stability investigation, the properties, pH value, related substances and contents do not change significantly, and the quality stability is high. In addition, since it does not contain sodium metabisulfite, the adverse reactions caused by its antioxidant can be avoided, and the dopamine hydrochloride injection has high safety.

[0021] Specifically, the preparation method of dopamine hydrochloride injection provided in the embodiment of the present application comprises the following steps:

[0022] Add a portion of the prepared water for injection into the liquid preparation tank, and simultaneously fill it with inert gas to make the dissolved oxygen less than 2 mg / L, control the temperature at 20-30°C, and continue to fill it with inert gas during the subsequent liquid preparation process;

[0023] Add calcium chloride and sodium glycerophosphate to the water for injection, turn on the stirring device to dissolve them completely, add sodium acetate, dopamine hydrochloride and citric acid and stir to dissolve;

[0024] Add water for injection to the full amount and stir evenly. After filtering, filling and sterilization, dopamine hydrochloride injection is obtained.

[0025] Among them, since each excipient needs to be mixed and reacted under certain temperature conditions, the control of the preparation temperature during the preparation process has a certain impact on the stability of the injection. When the preparation temperature is controlled at 20-30°C, the properties and pH of the injection are stable within 16 hours, and there is no significant difference in related substances. When the preparation temperature reaches 35°C, the properties of the injection are stable within 8 hours, the pH decreases slightly, and the related substances increase slightly.

[0026] Wherein, the mass ratio of the sodium glycerophosphate to calcium chloride is 1:(0.5-0.7), preferably 1:0.6.

[0027] Wherein, the mass ratio of dopamine hydrochloride, sodium glycerophosphate, sodium acetate and citric acid is 40:(4-6):(1-3):(0.03-0.07), preferably 40:5:2:0.05.

[0028] It is worth noting that the order of adding sodium glycerophosphate, calcium chloride, dopamine hydrochloride, sodium acetate and citric acid into water for injection has a great influence on the stability of the resulting dopamine hydrochloride injection. It is necessary to ensure that sodium acetate, dopamine hydrochloride and citric acid are added only after calcium chloride and sodium glycerophosphate are completely dissolved in water for injection. In addition, the ratio of sodium glycerophosphate, calcium chloride, dopamine hydrochloride, sodium acetate and citric acid also has a certain influence on the stability of the resulting dopamine hydrochloride injection.

[0029] Wherein, the inert gas is nitrogen.

[0030] Among them, 0.22μm filter membrane is used for filtration. This application investigates the content, clarity, color and pH changes of the intermediate solution after filtering through 0.22μm PVDF filter membrane and 0.22μm PES filter membrane of different materials. The results show that the intermediate solution has no significant changes in properties, pH and content after filtering through 0.22μm PVDF filter membrane (diameter 100mm) and 0.22μm PES filter membrane (diameter 100mm). PES and PVDF filter membranes have no adsorption on the main drug and have good compatibility.

[0031] Among them, sterilization was carried out at a temperature of 121°C for 15 minutes. This application investigated the properties, related substances and pH changes under three different sterilization processes: 115°C, 30 minutes; 121°C, 8 minutes and 121°C, 15 minutes. The results showed that after the intermediate solution was filtered through a 0.22μm PES filter membrane and filled in a borosilicate glass ampoule, there was no significant difference in the properties, related substances and pH under the three different sterilization processes of 115°C, 30 minutes; 121°C, 8 minutes and 121°C, 15 minutes. The sterilization process of overkilling method (F0≥12) was selected.

[0032] In addition, the headspace oxygen level needs to be controlled during potting. After nitrogen filling and liquid preparation, this application is divided into three groups according to the headspace oxygen level during melting and sealing: no nitrogen filling, partial nitrogen filling, and absolute nitrogen filling. The pH and related substances on the 0th day after sterilization of each group are investigated, and the pH and related substances change after 5 days. The results show that under the condition of no nitrogen filling, the pH drops to 3.2 after 0-day sterilization, and the total impurities are 0.09%. The pH drops to 2.7 after 5 days. Under the condition of partial nitrogen filling, the pH drops to 3.6 after 5 days, and under the condition of absolute nitrogen filling, the pH does not change significantly after 5 days. Therefore, in order to ensure the pH of this product and control the growth of related substances, the headspace oxygen level needs to be controlled.

[0033] The following are specific examples of the embodiments of the present application, which are not intended to limit the scope of the present application. In addition, it should be noted that the numerical values ​​given in the following examples are as accurate as possible.

[0034] Example 1

[0035] Add about 800g of water for injection to the preparation tank (start of nitrogen filling), control the temperature at 25±5℃, take samples to detect the dissolved oxygen content, introduce nitrogen to make the dissolved oxygen less than 2mg / L, and continue to fill nitrogen during the subsequent preparation process; add 2.4g of calcium chloride and 4g of sodium glycerophosphate to the water for injection, turn on the stirring device (stirring speed: 30Hz, about 225r / min), and stir to dissolve it completely; add 1g of sodium acetate, 40g of dopamine hydrochloride and 0.03g of citric acid, stir to dissolve it completely; add the remaining water for injection to the batch (1000g), and stir and mix for 10min at the same time. After the preparation is completed, continue to fill with nitrogen, take the solution for inspection of each sample according to the sampling plan, and take the intermediate product for inspection at the same time. After the intermediate product is qualified, filter and potting are carried out. During the potting process, the nitrogen in the headspace of the tank is always pressurized, but the bottom nitrogen filling and stirring are not turned on.

[0036] Example 2

[0037] Add about 800g of water for injection to the preparation tank (start of nitrogen filling), control the temperature at 25±5℃, take samples to detect the dissolved oxygen content, introduce nitrogen to make the dissolved oxygen less than 2mg / L, and continue to fill nitrogen during the subsequent preparation process; add 3g of calcium chloride and 5g of sodium glycerophosphate to the water for injection, turn on the stirring device (stirring speed: 30Hz, about 225r / min), and stir to dissolve it completely; add 2g of sodium acetate, 40g of dopamine hydrochloride and 0.05g of citric acid, stir to dissolve it completely; add the remaining water for injection to the batch (1000g), and stir and mix for 10min at the same time. After the preparation is completed, continue to fill with nitrogen, take the solution for inspection according to the sampling plan, and take the intermediate product for inspection at the same time. After the intermediate product is qualified, filter and potting are carried out. During the potting process, the nitrogen in the headspace of the tank is always pressurized, but the bottom nitrogen filling and stirring are not turned on.

[0038] Example 3

[0039] Add about 800g of water for injection to the preparation tank (start of nitrogen filling), control the temperature at 25±5℃, take samples to detect the dissolved oxygen content, introduce nitrogen to make the dissolved oxygen less than 2mg / L, and continue to fill nitrogen during the subsequent preparation process; add 3.6g of calcium chloride and 6g of sodium glycerophosphate to the water for injection, turn on the stirring device (stirring speed: 30Hz, about 225r / min), and stir to dissolve it completely; add 3g of sodium acetate, 40g of dopamine hydrochloride and 0.07g of citric acid, stir to dissolve it completely; add the remaining water for injection to the batch (1000g), and stir and mix for 10min at the same time. After the preparation is completed, continue to fill with nitrogen, take the solution for inspection according to the sampling plan, and take the intermediate product for inspection. After the intermediate product is qualified, filter and potting are carried out. During the potting process, the nitrogen in the headspace of the tank is always pressurized, but the bottom nitrogen filling and stirring are not turned on.

[0040] The dopamine hydrochloride injection samples prepared in the above Examples 1-3 were placed under different temperature conditions (30° C., 70° C.) for 15 days and then sampled for testing to investigate the stability of the samples. The results are shown in Table 1.

[0041] Table 1

[0042]

[0043]

[0044] In summary, the embodiments of the present application successively add calcium chloride, sodium glycerophosphate, sodium acetate, dopamine hydrochloride and citric acid in specific proportions as excipients to water for injection for mixing reaction, and the obtained dopamine hydrochloride injection has low impurities and high quality stability.

[0045] Example 4: Investigation of liquid preparation temperature

[0046] Since each auxiliary material needs to be mixed and reacted under certain temperature conditions, the control of the preparation temperature during the preparation process has a certain influence on the stability of the injection. The present application conducts the following investigation on the preparation temperature, specifically: the preparation process is the same as in Example 2 above, nitrogen filling is maintained throughout the process, and the effects of the preparation temperatures of 20°C, 30°C, 35°C, and 40°C on the properties, pH, and related substances of dopamine hydrochloride injection are investigated respectively. The results are shown in Table 2 below.

[0047] Table 2: Stability results of different solution temperatures

[0048]

[0049]

[0050] In summary, it can be seen from Table 2 that when the preparation temperature is controlled at 20-30℃, the properties and pH of the injection are stable within 16 hours and there is no significant difference in related substances, while when the preparation temperature reaches 35℃, the properties of the injection are stable within 8 hours, the pH decreases slightly, and the related substances increase slightly. Taking into account the dissolution rate, related substances and physical and chemical properties, combined with the actual operation of the workshop, the preparation temperature of 25℃±5℃ was selected.

[0051] Example 5: Laboratory scale-up production

[0052] Add about 81kg of water for injection to the preparation tank (start of nitrogen filling), control the temperature at 25±5℃, take samples to test the dissolved oxygen content, introduce nitrogen to make the dissolved oxygen less than 2mg / L, and continue to fill nitrogen during the subsequent preparation process; add 300g of calcium chloride and 500g of sodium glycerophosphate to the water for injection, turn on the stirring device (stirring speed: 30Hz, about 225r / min), and stir to dissolve it completely; add 200g of sodium acetate, 4kg of dopamine hydrochloride and 5g of citric acid, stir to dissolve it completely; add the remaining water for injection to the batch (100kg), and stir and mix for 10min at the same time. After the preparation is completed, continue to fill with nitrogen, take the solution for inspection according to the sampling plan, and take the intermediate product for inspection at the same time. After the intermediate product is qualified, it is filtered and potted. During the potting process, the nitrogen in the headspace of the tank is always pressurized, but the bottom nitrogen filling and stirring are not turned on. The laboratory enlarged product (nitrogen filling sterilization) was tested for influencing factors, and the results are shown in Table 3-4 below.

[0053] Table 3: Results of factors affecting laboratory scale-up (specification: 5ml:100mg)

[0054]

[0055]

[0056] Table 4: Results of factors affecting laboratory scale-up (specification: 2.5ml:50mg)

[0057]

[0058]

[0059] In summary, from Tables 3-4, it can be seen that there is no significant difference in the properties, API content and related substances of the laboratory-made amplified preparations of 5ml:100mg and 2.5ml:50mg when placed at high temperature for 10 days, 30 days and under light conditions.

[0060] In addition, the present application prepared 6 batches of dopamine hydrochloride injection samples according to the process of Example 5 for leaching test, wherein the accelerated stability test conditions were: 40°C ± 2°C, 75% RH ± 5% RH; the long-term stability test conditions were: 30°C ± 2°C, 65% RH ± 5% RH; the results showed:

[0061] For 6 batches of dopamine hydrochloride injection samples, after accelerated and long-term testing for 6 months, all elements in the dopamine hydrochloride injection were less than 20.01% of the sample analysis evaluation threshold, and there was no obvious change in pH, indicating that the probability of the packaging material (medium borosilicate glass ampoules) causing safety risks due to the migration of toxic elements is extremely low.

[0062] After 6 months of accelerated stability testing, the results of Si element measurement of 6 batches of dopamine hydrochloride injection samples were all less than the control threshold (5973.0μg / L) indicating flake-off. Further electron microscopy scanning was performed to observe the flake-off on the inner surface. After comparison with the positive control, no obvious signs of erosion or flake-off were found. The scanning electron microscopy images of the bottom, body, and neck of the bottle corresponding to the 6 batches of dopamine hydrochloride injection samples were respectively Figure 1-Figure 3 Therefore, only the scanning electron microscope images of the bottom, body and neck of the bottle corresponding to one batch of dopamine hydrochloride injection samples are given.

[0063] After stability testing, the 6 batches of dopamine hydrochloride injection samples showed no significant changes in bottle appearance, pH value, inner surface methylene blue staining, electron microscope scanning, and insoluble particles, all of which met the requirements, indicating that the drug had no significant corrosive effect on the inner surface of the container.

[0064] The above data show that the migration content of each toxic component is less than the sample analysis evaluation threshold, indicating that this packaging material will not affect the safety of drug use in June.

[0065] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the present application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the attached claims.

[0066] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing dopamine hydrochloride injection, characterized in that: include: Add a portion of the prepared water for injection into the liquid preparation tank, and simultaneously fill it with inert gas to make the dissolved oxygen less than 2 mg / L, control the temperature at 20-30°C, and continue to fill it with inert gas during the subsequent liquid preparation process; Add calcium chloride and sodium glycerophosphate to the water for injection, turn on the stirring device to dissolve them completely, add sodium acetate, dopamine hydrochloride and citric acid and stir to dissolve; Add water for injection to the full amount and stir evenly. After filtering, filling and sterilization, dopamine hydrochloride injection is obtained.

2. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: The mass ratio of the sodium glycerophosphate to calcium chloride is 1:(0.5-0.7).

3. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: The mass ratio of the sodium glycerophosphate to calcium chloride is 1:0.

6.

4. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: The mass ratio of dopamine hydrochloride, sodium glycerophosphate, sodium acetate and citric acid is 40:(4-6):(1-3):(0.03-0.07).

5. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: The mass ratio of dopamine hydrochloride, sodium glycerophosphate, sodium acetate and citric acid is 40:5:2:0.

05.

6. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: The inert gas is nitrogen.

7. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: Filter using a 0.22 μm filter membrane.

8. The method for preparing dopamine hydrochloride injection according to claim 1, characterized in that: Sterilize at 121°C for 15 min.

9. A dopamine hydrochloride injection, characterized in that: The dopamine hydrochloride injection is prepared by the preparation method of the dopamine hydrochloride injection according to any one of claims 1 to 8.

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