Ephedrine hydrochloride injection and preparation process thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an ephedrine hydrochloride injection and a preparation process thereof. The formula of the ephedrine hydrochloride injection consists of ephedrine hydrochloride, sodium chloride, an antioxidant, a pH regulator and water for injection, the antioxidant is one of ascorbic acid or thioglycerol, and the ephedrine hydrochloride injection is prepared by an optimized preparation process. The invention has the characteristics of small harm to human body, low impurity content, stable quality and safety.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to an ephedrine hydrochloride injection and its preparation process. Background Art

[0002] Ephedrine hydrochloride injection is a sympathomimetic drug, which has the effects of vasoconstriction, blood pressure elevation, bronchial dilation, etc. Clinically, it is mainly used for: correcting hypotension during anesthesia, adjuvant treatment of bronchial asthma, and relieving nasal mucosal congestion (such as rhinitis). Due to its rapid onset and definite effect, ephedrine hydrochloride injection has important application value in operating rooms, emergency departments and other scenarios. However, the existing preparations still have problems such as poor stability, easy oxidation, and large injection irritation, which affect the safety and effectiveness of clinical use.

[0003] The phenolic hydroxyl group in the ephedrine hydrochloride molecule is easily oxidized and degraded under the catalysis of light, high temperature or metal ions, resulting in a decrease in drug efficacy and even the generation of harmful impurities (such as quinone compounds). The existing prescriptions lack antioxidants, and the solution may turn color (yellow → brown) after long-term storage, affecting the drug safety and shelf life. Moreover, the traditional preparation process (such as dissolution → filtration → sealing) does not consider oxygen isolation and metal ion control, resulting in the possible introduction of oxidation risks during the production process; the method of simply relying on low pH (adjusted with hydrochloric acid) to inhibit oxidation has limited effects and may increase injection irritation.

[0004] In view of the above problems, the present invention proposes to introduce a highly efficient and low-toxic antioxidant into the basic formula of the existing ephedrine hydrochloride injection, and further optimize the process, which can inhibit the oxidative degradation of the product, make the product more stable during production and storage, and improve the drug safety. Summary of the Invention

[0005] The first object of the present invention is to provide a formula of ephedrine hydrochloride injection with better antioxidant effect and better long-term storage performance.

[0006] The second object of the present invention is to provide a preparation process of the above ephedrine hydrochloride injection with better antioxidant effect and better long-term storage performance.

[0007] To solve the above technical problems, the present invention discloses an ephedrine hydrochloride injection, which comprises the following components: ephedrine hydrochloride, sodium chloride, antioxidant, pH regulator, and injection water, wherein the antioxidant is one of ascorbic acid or thioglycerol.

[0008] In some preferred embodiments, the contents of the components are 4.7 mg / ml of ephedrine hydrochloride, 7.5 mg / ml of sodium chloride, 0.4 - 0.6 mg / ml of ascorbic acid or 0.5 - 1.0 mg / ml of thioglycerol, and the pH value of the injection is 4.6 - 6.0.

[0009] The present invention also provides a preparation process for the above-mentioned ephedrine hydrochloride injection, which specifically includes the following steps: (1) Add sodium chloride, antioxidant, and ephedrine hydrochloride to an appropriate amount of injection water, mix well, and adjust the pH value of the solution to 4.6 - 6.0; (2) Filter the solution using a filter membrane, fill with nitrogen before filling, fill, fill with nitrogen after filling, and seal; (3) Sterilize.

[0010] In some preferred embodiments, the antioxidant in step (1) is one of ascorbic acid or thiodiglycerol.

[0011] In some preferred embodiments, the ascorbic acid is 0.4 - 0.6 mg / ml, and the thiodiglycerol is 0.5 - 1.0 mg / ml.

[0012] In some preferred embodiments, the nitrogen filling flow rate before filling in step (2) is 10 - 15 L / min, and the nitrogen filling flow rate after filling is 8 - 15 L / min.

[0013] Positive effects of the present invention: 1. Oxidation degradation problem: By optimizing the type and concentration of the antioxidant, the shelf life of the preparation is significantly extended; 2. Process compatibility: Ensure the activity of the injection during sterilization (such as autoclaving at 121°C) and long-term storage; 3. Safety: Avoid the allergy risk of traditional antioxidants (such as sulfites), improve clinical applicability; Inhibit the generation of oxidation degradation impurities in the product, and improve product safety. Specific embodiments

[0014] The sources of the reagents are shown in Table 1: Table 1 Sources of reagents

[0015] The following is a detailed description of the present invention in combination with examples. The examples are intended to explain rather than limit the technical solutions of the present invention.

[0016] Example 1 Screening of antioxidant types Table 2 Prescription for antioxidant screening

[0017] The above samples were prepared according to the following preparation methods and then determined: Measure 360 ml of water for injection into a container, add 3 g of sodium chloride, and add the corresponding antioxidant, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto, stir to dissolve, adjust the pH value of the solution to 4.5 - 7.0 with hydrochloric acid / sodium hydroxide solution, make up the volume with water for injection to obtain 400 ml of the preparation, and then check and adjust the pH value to 4.5 - 7.0. The obtained solution was filtered through an appropriate filter membrane, dispensed into containers and sterilized. The stability of the samples was investigated, and the test results are shown in Table 3: Table 3 Test Results of Samples for Antioxidant Screening

[0018] As can be seen from the table, the related substances of the formulations with thiodiglycerol or ascorbic acid added are superior to those of other formulations without antioxidants or with other antioxidants added.

[0019] Example 2 Screening of Antioxidant Dosage Table 4 Prescriptions for Investigating Antioxidant Dosage

[0020] The above samples were prepared according to the following preparation methods and then determined. Measure 360 ml of water for injection into a beaker, add 3 g of sodium chloride, and add the corresponding antioxidant, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto, stir to dissolve, adjust the pH value of the solution to 4.5 - 7.0 with hydrochloric acid / sodium hydroxide solution, make up the volume with water for injection to obtain 400 ml of the preparation, and then check and adjust the pH value to 4.5 - 7.0. The obtained solution was filtered through an appropriate filter membrane, dispensed into containers and sterilized. The stability of the samples was investigated, and the test results are shown in Table 5: Table 5 Test Results of Samples for Investigating Antioxidant Dosage

[0021] As can be seen from the table, among Samples 9 - 13, the formulations with thiodiglycerol at 0.5 - 1.0 mg / ml (Samples 10 - 12) have relatively lower impurities and a smaller increase amplitude. The formulations with thiodiglycerol at 0.3 mg / ml (Sample 9) and thiodiglycerol at 1.5 mg / ml (Sample 13) have a significantly larger increase amplitude of impurities after 12 days of light exposure, indicating that the optimal dosage of thiodiglycerol is 0.5 - 1.0 mg / ml.

[0022] Among samples 14 to 18, the ascorbic acid 0.4 - 0.6 mg / ml formulations (samples 15 and 16) had lower impurities and a smaller growth rate. For the ascorbic acid 0.2 mg / ml formulation (sample 14), the growth of methcathinone hydrochloride was obvious after 12 days of light exposure. For the ascorbic acid 0.8 mg / ml formulation (sample 17) and 1.2 mg / ml formulation (sample 18), the growth of unknown single impurity and total impurities was significant after 12 days of light exposure, indicating that the optimal ascorbic acid dosage was 0.4 - 0.6 mg / ml in the formulation.

[0023] Example 3 Process Optimization Process 1: According to the formulation of sample 10, measure 360 ml of injection water into a beaker, add 3 g of sodium chloride and 0.2 g of thiodiglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto and stir to dissolve. Adjust the pH value of the solution to 3.5 - 4.5 with hydrochloric acid or sodium hydroxide solution, and make up the injection water to obtain 400 ml of the preparation. Then check the pH value and adjust it to 3.5 - 4.5. Filter the obtained solution through an appropriate filter membrane, dispense it into containers and sterilize it to obtain the sample of Process 1.

[0024] Process 2: According to the formulation of sample 10, measure 360 ml of injection water into a beaker, add 3 g of sodium chloride and 0.2 g of thiodiglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto and stir to dissolve. Adjust the pH value of the solution to 4.6 - 6.0 with hydrochloric acid or sodium hydroxide solution, and make up the injection water to obtain 400 ml of the preparation. Then check the pH value and adjust it to 4.6 - 6.0. Filter the obtained solution through an appropriate filter membrane, dispense it into containers and sterilize it to obtain the sample of Process 2.

[0025] Process 3: According to the formulation of sample 10, measure 360 ml of injection water into a beaker, add 3 g of sodium chloride and 0.2 g of thiodiglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto and stir to dissolve. Adjust the pH value of the solution to 6.1 - 7.5 with hydrochloric acid or sodium hydroxide solution, and make up the injection water to obtain 400 ml of the preparation. Then check the pH value and adjust it to 6.1 - 7.5. Filter the obtained solution through an appropriate filter membrane, dispense it into containers and sterilize it to obtain the sample of Process 3.

[0026] Process 4: According to the prescription of Sample 10, measure 360 ml of water for injection into a beaker, add 3 g of sodium chloride and 0.2 g of thiodiglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto and stir to dissolve. Adjust the pH value of the solution to 4.6 - 6.0 with hydrochloric acid or sodium hydroxide solution, and make up with water for injection to obtain 400 ml of the preparation. Then check the pH value and adjust it to 4.6 - 6.0. Filter the obtained solution through an appropriate filter membrane, divide it into containers, fill nitrogen into the containers before filling the liquid medicine with a nitrogen filling flow rate of 0 - 9 L / min, fill nitrogen above the liquid level in the containers after filling with a nitrogen filling flow rate of 0 - 7 L / min, seal immediately after filling and nitrogen filling, and sterilize the prepared sample to obtain the sample of Process 4.

[0027] Process 5: According to the prescription of Sample 10, measure 360 ml of water for injection into a beaker, add 3 g of sodium chloride and 0.2 g of thiodiglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride thereto and stir to dissolve. Adjust the pH value of the solution to 4.6 - 6.0 with hydrochloric acid or sodium hydroxide solution, and make up with water for injection to obtain 400 ml of the preparation. Then check the pH value and adjust it to 4.6 - 6.0. Filter the obtained solution through an appropriate filter membrane, divide it into containers, fill nitrogen into the containers before filling the liquid medicine with a nitrogen filling flow rate of 10 - 15 L / min, fill nitrogen above the liquid level in the containers after filling with a nitrogen filling flow rate of 8 - 15 L / min, seal immediately after filling and nitrogen filling, and sterilize the prepared sample to obtain the sample of Process 5.

[0028] The samples prepared by the above processes were subjected to detection and stability investigation, and the detection and investigation results are shown in Tables 6 - 7: Table 6 Comparison of Detection Results of Samples of Process 1 / 2 / 3

[0029] It can be seen from the table that the impurities and the growth rate of impurities in the samples of Process 1 and Process 3 are significantly higher than those in the samples of Process 2, indicating that the product has the best stability when the pH value of the liquid preparation is between 4.6 and 6.0.

[0030] Table 7 Comparison of Detection Results of Samples of Process 2 / 4 / 5

[0031] It can be seen from the table that there is almost no growth of impurities in the samples of Process 5, and its stability is better than that of the samples of Process 2 and Process 4. It shows that pre - filling nitrogen at 10 - 15 L / min and post - filling nitrogen at 8 - 15 L / min can make the samples more stable. In addition, according to the actual commercial production situation, if the nitrogen flow rate continues to increase, the impact force of nitrogen on the liquid medicine will increase, causing the liquid medicine to splash, which will increase the risk of contamination and cause quality problems of the samples; at the same time, when the samples obtain the same quality and stability, using too large a nitrogen flow rate will cause certain resource waste. Therefore, the optimal nitrogen filling flow rate range is pre - filling nitrogen at 10 - 15 L / min and post - filling nitrogen at 8 - 15 L / min.

[0032] Stability study: The following samples were subjected to stability investigation under high temperature and light conditions, and pH, related substances, and content were detected. Among them, the related substances were statistically analyzed for methcathinone hydrochloride, pseudoephedrine hydrochloride, the largest single impurity of others, and the total impurity of others, and the stability of each ephedrine hydrochloride injection was investigated.

[0033] Table 8 Detection results of pH value

[0034] Table 9 Detection results of methcathinone hydrochloride content (%)

[0035] Table 10 Detection results of the largest single impurity content of others (%)

[0036] Table 11 Detection results of the total impurity content of others (%)

[0037] For the remaining indicators (content, pseudoephedrine hydrochloride), each sample was stable and had comparable stability.

[0038] According to the research results in Tables 8 - 11, it can be seen that the impurities in the purchased reference preparation and the self - made reference preparation increased significantly during the stability investigation. The impurities in the best sample (Sample 10) increased to a certain extent but were significantly better than those in the purchased reference preparation or the self - made reference preparation; the impurities in the best - process sample (Sample of Process 5) prepared by the optimized process hardly increased during the stability investigation, and the impurity stability was further optimized compared with the best sample. In addition, by comparing the pH values of different samples during the stability period, the change range of the best - process sample was smaller than that of the purchased reference preparation or the self - made reference preparation, indicating that the pH index of the best - process sample was more stable. Thus, it shows that the best - process sample has significant advantages in terms of quality and stability.

Claims

1. An ephedrine hydrochloride injection, characterized in that, It contains the following components: ephedrine hydrochloride, sodium chloride, antioxidant, pH regulator, and water for injection; the antioxidant is one of ascorbic acid or thioglycerol.

2. The ephedrine hydrochloride injection according to claim 1, characterized in that, The contents of the components are as follows: ephedrine hydrochloride is 4.7 mg / ml, sodium chloride is 7.5 mg / ml, ascorbic acid is 0.4 - 0.6 mg / ml or thioglycerol is 0.5 - 1.0 mg / ml, and the pH value of the injection solution is 4.6 - 6.

0.

3. The preparation process of ephedrine hydrochloride injection as described in claim 1 or 2, characterized in that, It includes the following steps: (1) Add sodium chloride, antioxidant, and ephedrine hydrochloride to an appropriate amount of water for injection, mix well, and adjust the pH value of the solution to 4.6 - 6.0; (2) Filter the solution using a filter membrane, fill with nitrogen before filling, fill, fill with nitrogen after filling, and seal; (3) Sterilize.

4. A preparation process as claimed in claim 3, characterized in that, The antioxidant in step (1) is one of ascorbic acid or thioglycerol.

5. A preparation process as described in claim 4, characterized in that, The ascorbic acid is 0.4 - 0.6 mg / ml or the thioglycerol is 0.5 - 1.0 mg / ml.

6. A preparation process as described in claim 3, characterized in that, The nitrogen filling flow rate before filling in step (2) is 10 - 15 L / min, and the nitrogen filling flow rate after filling is 8 - 15 L / min.

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