An adrenaline injection and a method for preparing the same

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to an adrenaline injection and a preparation method thereof. The application provides an adrenaline injection, 1 mg of adrenaline, 9 mg of sodium chloride, 0.02%-0.5% of dihydrolipoic acid, 0.05%-0.5% of disodium edetate, and appropriate hydrochloric acid are contained in each 1 mL of the injection, and the rest is water for injection. The dihydrolipoic acid and the disodium edetate are innovatively added in the prescription as antioxidants, and the antioxidants synergistically play a stabilizing role. The prescription process of the application has good applicability and high stability, the injection can be subjected to terminal sterilization, and the safety and effectiveness of the product in the clinical use can be fully ensured.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to an adrenaline injection solution and its preparation method. Background Technology

[0002] Adrenaline is an important catecholamine hormone and neurotransmitter that produces rapid and strong physiological effects by non-selectively activating α and β adrenaline receptors. It is mainly used in emergency situations such as cardiac arrest, anaphylactic shock, hypotension with septic shock, and bronchial asthma, and is a widely used emergency drug in clinical practice.

[0003] The core structure of adrenaline lies in the catechol group (catechol structure) and the β-hydroxyethylamine side chain. The catechol structure determines its chemical instability, making it easily oxidized by oxygen, light, or metal ions to adrenaline quinone, which then polymerizes and changes color. The β-hydroxyethylamine side chain contains a chiral carbon, giving it two optical isomers: L-adrenaline (R-configuration) and D-adrenaline (S-configuration). L-adrenaline is the naturally occurring form, has a stronger active ingredient, and its activity is significantly higher than that of D-adrenaline. Under high-temperature conditions, L-adrenaline can be converted to the S-configuration, resulting in a significant reduction in efficacy.

[0004] In existing technologies, most commercially available epinephrine injections both domestically and internationally use inorganic salts containing sulfite groups, such as sodium metabisulfite, as antioxidants. These effectively prevent the oxidative degradation of epinephrine during production, storage, and use. However, there are compatibility issues; these antioxidants readily react with epinephrine to form epinephrine sulfonated impurities, leading to excessive impurities in the epinephrine injection within its shelf life. Furthermore, sulfite antioxidants in the formulation may induce or worsen asthma symptoms during clinical use, further impacting product safety. Some patents reduce the content of adrenaline sulfonated impurities in the product by removing antioxidants from the formulation or replacing sodium metabisulfite with other easily oxidized components. However, this method requires extremely high oxygen content in the product. For example, patent CN117357469B uses vitamin C instead of sodium metabisulfite as an antioxidant. This patent requires specialized equipment in the solution preparation and filling processes to evacuate the solution tanks, production lines, containers, and pipelines to control the oxygen content of the product. Due to the large scale of commercial production, this method is difficult to apply to commercial production, has extremely high equipment requirements, and consumes a lot of energy. At the same time, current commercial production equipment is difficult to effectively control the dissolved oxygen in the finished product to maintain a low level. Even if the dissolved oxygen level can be reduced by continuous nitrogen purging during the solution preparation process, the dissolved oxygen will rise rapidly during the filling stage due to the contact of the drug solution with air.

[0005] To further ensure the sterility of injectable solutions, both my country and the EU recommend terminal sterilization during production, with an F0 > 12 being preferred. However, epinephrine exists in two configurations. Under high temperatures, the highly active L-epinephrine is converted into the less effective D-epinephrine, thus affecting the product's efficacy. Patents such as CN113332239B, CN117530919A, and CN102335125A use high-temperature sterilization, which greatly increases the risk of isomerization and affects the product's effectiveness in clinical use. The process stability of epinephrine injection solutions in existing technologies needs to be optimized.

[0006] Therefore, there is an urgent need to develop an adrenaline injection solution with good stability, low impurity content, and low irritation, as well as an adrenaline injection solution preparation process with high process reproducibility, low oxygen content, and tolerance to terminal high-temperature sterilization. Summary of the Invention

[0007] In view of the deficiencies of the prior art, the present invention provides an adrenaline injection solution and its preparation method to solve the problems existing in the prior art.

[0008] The technical problem to be solved by this invention is that the adrenaline injection solution prepared in the prior art has high content of sulfonated impurities and oxidized impurities, and is highly irritating. This invention provides an adrenaline injection solution and its preparation method, which has high formulation stability, good process reproducibility, and can withstand terminal sterilization, thus fully ensuring the safety and efficacy of the injection solution prepared by this invention in clinical use.

[0009] In a first aspect, in order to achieve the above-mentioned objective, the present invention provides an adrenaline injection solution comprising adrenaline, sodium chloride, dihydrolipoic acid, disodium edetate, hydrochloric acid, and water for injection.

[0010] In some preferred embodiments, each 1 mL of the injection solution contains 1 mg of adrenaline, 9 mg of sodium chloride, 0.02%~0.5% of dihydrolipoic acid, 0.05%~0.5% of disodium edetate, and an appropriate amount of hydrochloric acid, with the remainder being water for injection.

[0011] In some preferred embodiments, each 1 mL of the injection solution contains 1 mg of adrenaline, 9 mg of sodium chloride, 0.02% to 0.5% of dihydrolipoic acid, 0.1% to 0.2% of disodium edetate, and an appropriate amount of hydrochloric acid, with the remainder being water for injection.

[0012] In some preferred embodiments, each 1 mL of the injection solution contains 1 mg of adrenaline, 9 mg of sodium chloride, 0.05%~0.2% of dihydrolipoic acid, 0.1%~0.2% of disodium edetate, and an appropriate amount of hydrochloric acid, with the remainder being water for injection.

[0013] On the other hand, the present invention also provides a method for preparing an adrenaline injection, comprising the following steps:

[0014] (1) Add an appropriate amount of water for injection and fill the water for injection with nitrogen to control dissolved oxygen;

[0015] (2) Add sodium chloride, dihydrolipoic acid and disodium edetate in sequence, stir to dissolve, and then add adrenaline; (3) Slowly add hydrochloric acid solution until all components are completely dissolved, adjust the pH, and add water for injection to make up the volume;

[0016] (4) The medicine solution obtained in step (3) is filtered, bottled, freeze-dried and sterilized to obtain the finished product.

[0017] In some preferred embodiments, step (3) involves adjusting the pH to 3-5, preferably to 3.8-4.5.

[0018] In some preferred embodiments, step (4) freeze drying involves setting the shelf temperature of the freeze dryer to 0°C to 20°C and maintaining it for 20 min to 60 min; setting the pressure of the freeze dryer to 5 mbar to 30 mbar and maintaining it for 10 min to 60 min.

[0019] In some preferred embodiments, step (4) freeze drying involves setting the shelf temperature of the freeze dryer to 2°C to 15°C and maintaining it for 15 min to 25 min; setting the pressure of the freeze dryer to 8 mbar to 25 mbar and maintaining it for 15 min to 50 min.

[0020] In some preferred embodiments, step (4) involves filtration, in which the drug solution is filtered through 0.45 μm and 0.22 μm filter membranes.

[0021] In some preferred embodiments, step (1) controls dissolved oxygen to ≤2.5 mg / L, preferably, to ≤1.5 mg / L.

[0022] In some preferred embodiments, after adding water for injection in step (1), the water temperature is controlled to be ≤45℃, preferably ≤40℃.

[0023] In some preferred embodiments, after freeze-drying in step (4), inert gas is filled into the freeze-drying chamber to restore the pressure to atmospheric pressure, and the freeze-drying and inert gas filling steps are repeated 1 to 3 times.

[0024] In some preferred embodiments, the inert gas is argon or nitrogen, preferably nitrogen.

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] (1) High safety: Lipoic acid is an endogenous nutrient that can be synthesized by the human body. Dihydrolipoic acid and lipoic acid can be interconverted. Appropriate use is beneficial to human health and is not likely to induce allergies such as asthma. Using dihydrolipoic acid as one of the antioxidants is generally safe and well tolerated.

[0027] (2) Strong antioxidant capacity: Dihydrolipoic acid is the reduced form of lipoic acid, and lipoic acid is the oxidized form of dihydrolipoic acid. Both have good antioxidant effects; disodium edetate also has antioxidant effects; together they constitute a powerful antioxidant system.

[0028] (3) Good formulation stability: Dihydrolipoic acid has a long chain structure of 8 carbons, and the two ends of the carbon chain are 2 mercapto groups and one carboxyl group respectively; In addition to its antioxidant effect, disodium edetate has a long chain structure of 8 atoms in the main chain and the carbon atoms at the end of the main chain all contain carboxyl groups; Dihydrolipoic acid and disodium edetate both have large spatial structures, and the steric hindrance of the two works together to exert a stabilizing effect, inhibiting the conversion of highly active L-adrenaline into less active S-adrenaline at high temperature. The experimental results of this invention show the advantages of the dihydrolipoic acid / disodium edetate combination stabilizer. Attached Figure Description

[0029] Figure 1 The attached image shows the histopathological findings of the negative sample group 72 hours after the last administration of the muscle stimulation test.

[0030] Figure 2 The following is a histopathological image of the sample group in Example 1, taken 72 hours after the last administration of muscle irritation test.

[0031] Figure 3 The following is a histopathological image of the sample group in Example 3, taken 72 hours after the last administration of muscle irritation test.

[0032] Figure 4 The accompanying image shows the histopathological findings of the control group 72 hours after the last administration of the muscle irritation test.

[0033] Figure 5 The image shows the histopathological findings of the negative sample group 72 hours after the last administration of the subcutaneous irritation test.

[0034] Figure 6 The following is a histopathological chart of the sample group in Example 1, taken 72 hours after the last administration of the subcutaneous irritation test.

[0035] Figure 7 The following are the histopathological images of the sample group in Example 3, taken 72 hours after the last administration, showing the subcutaneous irritation test.

[0036] Figure 8The image shows the histopathological findings of the comparative sample group 72 hours after the last administration of the subcutaneous irritation test.

[0037] Figure 9 The accompanying image shows the histopathological findings of the control group 1, 17 days after the last administration of the subcutaneous irritation test. Detailed Implementation

[0039] The present invention will be further described below with reference to the embodiments. However, the scope of protection of the present invention should not be considered as limited to the specific embodiments described below. Any process improvements made by those skilled in the art based on this method are within the scope of protection of the present invention.

[0040] Note: All percentages of material usage mentioned in this article are w / w.

[0041] Example 1: Preparation of Adrenaline Injection

[0042] prescription:

[0043]

[0044] Process:

[0045] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1.5mg / L;

[0046] (2) Add sodium chloride, dihydrolipoic acid and disodium edetate to (1) in sequence, stir until dissolved, then add the raw material adrenaline and disperse evenly;

[0047] (3) Slowly add 4% hydrochloric acid solution until the raw materials in (2) are completely dissolved, and adjust the pH to 4.2;

[0048] (4) Add water for injection to bring the volume to the maximum.

[0049] (5) The drug solution was filtered through 0.45 and 0.22 μm filter membranes;

[0050] (6) The filtered drug solution is filled into borosilicate glass vials for injection, and after partially sealing with rubber stoppers, it is transferred to a freeze dryer;

[0051] (7) Set the shelf temperature of the freeze dryer to 7.5℃ and maintain it for 30 minutes;

[0052] (8) Set the pressure of the freeze dryer to 15±3 mbar and maintain it for 30 min;

[0053] (9) Fill the freeze-drying chamber with nitrogen to restore the pressure to atmospheric pressure;

[0054] (10) Repeat steps (8) to (9) above twice; then press and cap the plug.

[0055] (11) Place the product after it is taken out of the box in a sterilizer and sterilize it at 121℃ for 12 minutes to obtain the finished product.

[0056] Example 2: Preparation of Adrenaline Injection

[0057] prescription:

[0058]

[0059] Process:

[0060] Same as Example 1.

[0061] Example 3: Preparation of Adrenaline Injection Solution

[0062] prescription:

[0063]

[0064] Process:

[0065] Same as Example 1.

[0066] Example 4: Preparation of Adrenaline Injection

[0067] prescription:

[0068]

[0069] Process:

[0070] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1.5mg / L;

[0071] (2) Add sodium chloride, dihydrolipoic acid and disodium edetate to (1) in sequence, stir until dissolved, then add the raw material adrenaline and disperse evenly;

[0072] (3) Slowly add 4% hydrochloric acid solution until the raw materials in (2) are completely dissolved, and adjust the pH to 4.5;

[0073] (4) Add water for injection to bring the volume to the maximum.

[0074] (5) The drug solution was filtered through 0.45 and 0.22 μm filter membranes;

[0075] (6) The filtered drug solution is filled into borosilicate glass vials for injection, and after partially sealing with rubber stoppers, it is transferred to a freeze dryer;

[0076] (7) Set the shelf temperature of the freeze dryer to 15°C and maintain it for 20 minutes;

[0077] (8) Set the pressure range of the freeze dryer to 25±3 mbar and maintain it for 50 min;

[0078] (9) Fill the freeze-drying chamber with nitrogen to restore the pressure to atmospheric pressure;

[0079] (10) Repeat steps (8) to (9) above 3 times; then press and cap the cap;

[0080] (11) Place the product after it is taken out of the box in a sterilizer and sterilize it at 121℃ for 12 minutes to obtain the finished product.

[0081] Example 5: Preparation of Adrenaline Injection

[0082] prescription:

[0083]

[0084] Process:

[0085] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1.5mg / L;

[0086] (2) Add sodium chloride, dihydrolipoic acid and disodium edetate to (1) in sequence, stir until dissolved, then add the raw material adrenaline and disperse evenly;

[0087] (3) Slowly add 4% hydrochloric acid solution until the raw materials in (2) are completely dissolved, and adjust the pH to 3.8;

[0088] (4) Add water for injection to bring the volume to the maximum.

[0089] (5) The drug solution was filtered through 0.45 and 0.22 μm filter membranes;

[0090] (6) The filtered drug solution is filled into borosilicate glass vials for injection, and after partially sealing with rubber stoppers, it is transferred to a freeze dryer;

[0091] (7) Set the shelf temperature of the freeze dryer to 2°C and maintain it for 25 minutes;

[0092] (8) Set the pressure range of the freeze dryer to 8±3 mbar and maintain it for 15 min;

[0093] (9) Fill the freeze-drying chamber with nitrogen to restore the pressure to atmospheric pressure;

[0094] (10) Repeat steps (8) to (9) once; then press and cap the plug.

[0095] (11) Place the product after it is taken out of the box in a sterilizer and sterilize it at 121℃ for 15 minutes to obtain the finished product.

[0096] Comparative Example 1: Preparation of Adrenaline Injection

[0097] prescription:

[0098]

[0099] Process:

[0100] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1mg / L;

[0101] (2) Add sodium chloride, disodium edetate, sodium hydroxide and tartaric acid to (1) in sequence and stir until dissolved. Slowly add 4% hydrochloric acid solution and then add adrenaline and stir until dissolved. The pH of the solution is 4.0.

[0102] (3) Add water for injection to bring the volume to the maximum.

[0103] (4) The drug solution is sterilized by passing through 0.45 and two 0.22 μm filter membranes;

[0104] (5) The filtered drug solution is filled into borosilicate glass vials for injection, the headspace residual oxygen is controlled below 3.5%, and then the vials are pressed and capped.

[0105] Comparative Example 2: Preparation of Adrenaline Injection (Batch No.: 250207)

[0106] prescription:

[0107]

[0108] Process:

[0109] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1.5mg / L;

[0110] (2) Add sodium chloride, disodium edetate, sodium hydroxide and tartaric acid to (1) in sequence and stir until dissolved. Slowly add 4% hydrochloric acid solution and then add adrenaline and stir until dissolved. The pH of the solution is 4.0.

[0111] (3) Add water for injection to bring the volume to the maximum.

[0112] (4) The drug solution was filtered through 0.45 and 0.22 μm filter membranes;

[0113] (5) The filtered drug solution is filled into borosilicate glass vials for injection, and after partially sealing with rubber stoppers, it is transferred to a freeze dryer;

[0114] (6) Set the shelf temperature of the freeze dryer to 7.5℃ and maintain it for 30 minutes;

[0115] (7) Set the pressure of the freeze dryer to 15±3 mbar and maintain it for 30 min;

[0116] (8) Fill the freeze-drying chamber with nitrogen to restore the pressure to atmospheric pressure;

[0117] (9) Repeat steps (7) to (8) twice; then press and cap the cap.

[0118] (10) Place the product after it is taken out of the box in a sterilizer and sterilize it at 121℃ for 12 minutes to obtain the finished product.

[0119] Comparative Example 3: Preparation of Adrenaline Injection

[0120] prescription:

[0121]

[0122] Process:

[0123] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1.5mg / L;

[0124] (2) Add sodium chloride and disodium edetate to (1) in sequence, stir until dissolved, and then add the raw material adrenaline and disperse evenly;

[0125] (3) Slowly add 4% hydrochloric acid solution to adjust the pH to 4.0;

[0126] (4) Add water for injection to bring the volume to the maximum.

[0127] (5) The drug solution was filtered through 0.45 and 0.22 μm filter membranes;

[0128] (6) The filtered drug solution is filled into borosilicate glass vials for injection, and after partially sealing with rubber stoppers, it is transferred to a freeze dryer;

[0129] (7) Set the shelf temperature of the freeze dryer to 7.5℃ and maintain it for 30 minutes;

[0130] (8) Set the pressure of the freeze dryer to 15±3 mbar and maintain it for 30 min;

[0131] (9) Fill the freeze-drying chamber with nitrogen to restore the pressure to atmospheric pressure;

[0132] (10) Repeat steps (8) to (9) above twice; then press and cap the plug.

[0133] (11) Place the product after it is taken out of the box in a sterilizer and sterilize it at 121℃ for 12 minutes to obtain the finished product.

[0134] Comparative Example 4: Preparation of Adrenaline Injection

[0135] prescription:

[0136]

[0137] Process:

[0138] (1) Add 80% water for injection, control the water temperature to ≤40℃, and fill the water for injection with nitrogen to control dissolved oxygen to ≤1.5mg / L;

[0139] (2) Add sodium chloride and sodium metabisulfite to (1) in sequence, stir until dissolved, and then add adrenaline and disperse evenly;

[0140] (3) Slowly add 4% hydrochloric acid solution to adjust the pH to 4.0;

[0141] (4) Add water for injection to bring the volume to the maximum.

[0142] (5) The drug solution was filtered through 0.45 and 0.22 μm filter membranes;

[0143] (6) The filtered drug solution is filled into borosilicate glass vials for injection, and after partially sealing with rubber stoppers, it is transferred to a freeze dryer;

[0144] (7) Set the shelf temperature of the freeze dryer to 7.5℃ and maintain it for 30 minutes;

[0145] (8) Set the pressure of the freeze dryer to 15±3 mbar and maintain it for 30 min;

[0146] (9) Fill the freeze-drying chamber with nitrogen to restore the pressure to atmospheric pressure;

[0147] (10) Repeat steps (8) to (9) above twice; then press and cap the plug.

[0148] (11) Place the product after it is taken out of the box in a sterilizer and sterilize it at 121℃ for 12 minutes to obtain the finished product.

[0149] Example 6: Sample stability test results

[0150] The samples prepared in Examples 1 to 4 above were subjected to stability tests under accelerated conditions (40℃ / 75%RH) and long-term conditions (25℃ / 60%RH), respectively. The detailed results are shown in the table below:

[0151] Table 1. Results of stability test on samples

[0152]

[0153] In the samples of Examples 1 to 5, there were no significant changes in the relevant substances and isomers; in the samples of Comparative Examples 1 and 4, the sulfonated impurities and oxidized impurities increased significantly; in the samples of Comparative Examples 2 and 3, the oxidized impurities increased significantly; and in the sample of Comparative Example 3, the isomers increased significantly.

[0154] Compared to Comparative Example 1, which uses metabisulfite and disodium edetate as antioxidants, Comparative Example 2, which uses only dihydrolipoic acid as an antioxidant, Comparative Example 3, which uses only disodium edetate as an antioxidant, and Comparative Example 4, which uses only sodium metabisulfite as an antioxidant, the adrenaline injection prepared in Examples 1 to 5 using a combination of dihydrolipoic acid and disodium edetate as an antioxidant has low or undetectable levels of sulfonated impurities, oxidized impurities, and isomers, and low headspace oxygen and dissolved oxygen content. In other words, the adrenaline injection prepared using a combination of dihydrolipoic acid and disodium edetate as an antioxidant has good stability and high safety.

[0155] Example 7: In vivo safety test

[0156] Special safety tests were conducted on the finished products prepared in Examples 1, 3, and Comparative Example 1. The experimental results showed that the combination of dihydrolipoic acid and disodium edetate as stabilizers in the formulation of this product has high safety. The specific results of the special safety tests are as follows:

[0157] 1. Muscle stimulation test

[0158] 1-1 Experimental Objective:

[0159] The adrenaline injection was used to conduct a muscle irritation test on rabbits to observe the local reaction at the administration site (muscle) after contact with the test product, and to compare it with the control product (comparative sample 1) to provide a reference for safe clinical application.

[0160] 1-2 Experimental Methods:

[0161] Eighteen New Zealand white rabbits were randomly divided into three groups (Example 1 sample group, Example 3 sample group, and Comparative Example 1 sample group) using a stratified randomization method based on body weight, with six rabbits in each group, half male and half female. A self-comparison method was used, and according to the grouping, each animal received an intramuscular injection of 1 mg / mL of the drug in the left quadriceps femoris muscle, while the right quadriceps femoris muscle received an equal volume of sodium chloride injection as a negative control. The administration volume was 0.3 mL / side / rabbit, administered once daily for three consecutive days. During the experiment, the injection site was observed for congestion, swelling, or other reactions before each administration and at 24 h, 48 h, and 72 h after the last administration. At 72 h after the last administration and on day 17, three animals from each group were euthanized, and bilateral quadriceps femoris muscles were harvested for gross necropsy and histopathological examination.

[0162] The grading criteria, average scores, and levels for muscle stimulation tests are as follows:

[0163]

[0164] Experimental results 1-3:

[0165] No obvious abnormalities were observed in the negative control, Example 1 sample group, and Example 3 sample group 72 hours after the last administration. Microscopic examination of the quadriceps femoris muscle in one-third of the animals in the Comparative Example 1 sample group revealed moderate patchy necrosis of muscle fibers with inflammatory cell infiltration, mild multifocal regeneration / fibrosis, mild focal mineralization, and mild multifocal hemorrhage in the interstitial muscle bundles. The average scores for the negative control, Example 1, Example 3, and Comparative Example 1 sample groups were 0.33, 0.33, 0.33, and 1.00, respectively, corresponding to the stimulation response levels of no irritation, no irritation, no irritation, and slight irritation. The corresponding histopathological images are attached. Figure 1 ~Appendix Figure 4 Seventeen days after the last administration, no obvious abnormalities were found in the injection sites of the quadriceps femoris muscles in all four groups under microscopic examination. That is, the sample groups of Example 1 and Example 3 did not cause muscle irritation at the injection site; the sample group of Comparative Example 1 caused slight muscle irritation at the injection site, which subsided 17 days after drug withdrawal.

[0166] 2. Subcutaneous irritation test:

[0167] 2-1 Experimental Objective:

[0168] The subcutaneous stimulation test of adrenaline injection was used to observe the local reaction of rabbits after subcutaneous injection of adrenaline injection and to compare it with the control (comparative sample 1) to provide a reference for safe clinical application.

[0169] 2-2 Experimental Methods:

[0170] Eighteen New Zealand white rabbits were randomly divided into three groups (Example 1 sample group, Example 3 sample group, and Comparative Example 1 sample group) using a stratified randomization method based on body weight, with six rabbits in each group, half male and half female. A self-comparison method was used, with each group receiving a subcutaneous injection of 1 mg / mL of the drug on the left side of the neck and back. All three groups received an equal volume of sodium chloride injection solution subcutaneously on the right side of the neck and back as a negative control. The administration volume was 0.3 mL / side / rabbit, administered once daily for three consecutive days. During the experiment, the skin at the administration site was observed for reactions such as erythema, congestion, exudation, ulceration, and induration before each administration and at 24, 48, and 72 hours after the last administration. At 72 hours and 17 days after the last administration, three animals from each group were euthanized, and gross necropsy was performed at the administration site. Skin and subcutaneous connective tissue from both administration sites were collected for histopathological examination.

[0171] 2-3 Experimental Results:

[0172] Seventy-two hours after the last administration, no obvious histopathological changes were observed in the subcutaneous tissue at the administration site on the neck and back of the animals in the negative control, Example 1, and Example 3 sample groups. The corresponding histopathological images are attached. Figure 5 ~Appendix Figure 7 In Comparative Example 1, two-thirds of the animals in the sample group showed epidermal ulceration with scab formation and dermal neutrophil infiltration at the drug administration site on the neck and back. Histopathological findings are attached. Figure 8 Seventeen days after the last administration, no obvious histopathological changes were observed in the subcutaneous tissue of the neck and back of the animals in the negative control, Example 1, and Example 3 batches. In the comparative example batch, scabs were visible at the neck and back administration sites on 2 / 3 of the animals. Histopathological findings are attached. Figure 9 That is, the samples in Examples 1 and 3 did not cause irritation to the subcutaneous injection site; the sample in the comparative example caused some irritation to the subcutaneous injection site, and the irritation did not completely recover 17 days after drug withdrawal.

Claims

1. An adrenaline injection solution, characterized in that, The injection solution contains adrenaline, sodium chloride, dihydrolipoic acid, disodium edetate, hydrochloric acid, and water for injection.

2. The adrenaline injection solution according to claim 1, characterized in that, The injection solution contains 1 mg of adrenaline, 9 mg of sodium chloride, 0.02%~0.5% of dihydrolipoic acid, 0.05%~0.5% of disodium edetate, and an appropriate amount of hydrochloric acid per 1 mL, with the remainder being water for injection.

3. The adrenaline injection solution according to claim 1 or 2, characterized in that, The injection solution contains 0.1% to 0.2% disodium edetate per 1 mL.

4. The adrenaline injection solution according to any one of claims 1-3, characterized in that, Each 1 mL of injection solution contains 0.05% to 0.2% dihydrolipoic acid.

5. A method for preparing the adrenaline injection solution according to claims 1-4, characterized in that, Includes the following steps: (1) Add an appropriate amount of water for injection and fill the water for injection with nitrogen to control dissolved oxygen; (2) Add sodium chloride, dihydrolipoic acid and disodium edetate in sequence, stir to dissolve, and then add adrenaline; (3) Slowly add hydrochloric acid solution until all components are completely dissolved, adjust the pH, and add water for injection to make up the volume; (4) The medicine solution obtained in step (3) is filtered, bottled, freeze-dried and sterilized to obtain the finished product.

6. The preparation method according to claim 5, characterized in that, In step (3), the pH is adjusted to 3-5, preferably to 3.8-4.

5.

7. The preparation method according to claim 5 or 6, characterized in that, In step (4) freeze drying, the shelf temperature of the freeze dryer is set to 0℃~20℃ and maintained for 20min~60min; the pressure of the freeze dryer is set to 5mbar~30mbar and maintained for 10min~60min; preferably, after freeze drying in step (4), inert gas is filled into the freeze drying chamber to restore the pressure to normal pressure, and the freeze drying and inert gas filling steps are repeated 1~3 times.

8. The preparation method according to any one of claims 5-7, characterized in that, The sterilization step (4) is performed at 121℃ for 10 to 20 minutes.

9. The preparation method according to any one of claims 5-7, characterized in that, In step (4), the drug solution is filtered through 0.45μm and 0.22μm filter membranes.

10. The preparation method according to any one of claims 5-7, characterized in that, After adding water for injection in step (1), adjust the water temperature to ≤45℃ and control the dissolved oxygen to ≤2.5mg / L.

Images