Phenylephrine hydrochloride injection and its preparation process

Abstract

The present invention relates to the pharmaceutical field, in particular to chemical drug injections. The present invention specifically discloses a phenylephrine hydrochloride injection and a preparation process thereof, wherein the prescription consists of phenylephrine hydrochloride, sodium chloride, sodium pyrosulfite, antioxidant 2, sodium citrate dihydrate, citric acid monohydrate and water for injection, wherein when antioxidant 2 is thioglycerol, the phenylephrine hydrochloride injection prepared by the optimized preparation process has the characteristics of simple ingredients, little harm to human body, low impurity content, stable quality and safety.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, in particular to chemical drug injections. Background Art

[0002] Phenylephrine hydrochloride injection is an anti-shock vasoactive drug. Currently, the marketed phenylephrine hydrochloride injection has 1ml:10mg, 5ml:50mg, 10ml:100mg, and 5ml:0.5mg specifications. The 1ml:10mg specification product is clinically suitable for the increase in blood pressure of adults with clinically important hypotension mainly caused by vasodilation under anesthesia and septic shock. Phenylephrine is an extremely unstable drug that will degrade and produce impurities in the presence of oxygen, certain acids and metals.

[0003] Patents CN102525893A and CN109394684A disclose two prescriptions for phenylephrine hydrochloride injection, one is phenylephrine hydrochloride, sodium chloride, disodium edetate; the other prescription is phenylephrine hydrochloride, sodium chloride, sodium pyrosulfite, disodium edetate; both prescriptions contain disodium edetate, and existing studies have shown that disodium edetate can combine with calcium ions to form a soluble complex to cause a decrease in calcium, and the use of disodium edetate will lead to a decrease in blood calcium. And for this variety, even if disodium edetate is used, the product of 1ml:10mg still needs sodium citrate dihydrate and citric acid monohydrate to maintain the pH value, otherwise it will cause the product to be extremely unstable, so it is necessary to further study the new prescription system and add new antioxidants to ensure the stability of phenylephrine hydrochloride injection.

[0004] In order to ensure the safety of drugs and reduce adverse reactions, it is also extremely important to effectively control the impurities of drugs. In the study of the original research 1ml:10mg phenylephrine hydrochloride injection, the applicant found that the product contained high concentrations of impurities C and impurity F after sterilization, and the structural formulas of impurities F and impurity C were confirmed as follows: , .

[0005] Impurity F is confirmed by the research of this application to be a polymer produced by sodium citrate dihydrate and citric acid monohydrate and raw materials under sterilization conditions. Impurity C is an oxidative impurity, and its generation is mainly related to the type of antioxidant, the pH value of the drug solution, the degree of nitrogen filling, etc. Impurity F is related to the dosage of sodium citrate dihydrate and citric acid monohydrate and the sterilization intensity. After the self-made product prepared according to the original research prescription is sterilized, although impurity F meets the quality standard, it is close to the upper limit of the quality standard. This application study found that the risk of impurity F in the sterilized sample can be reduced by reducing the dosage of sodium citrate dihydrate and citric acid monohydrate. From the perspective of drug development, reducing the dosage of related excipients is not a simple increase or decrease in the raw and excipients of conventional specifications of drugs. It is also necessary to comprehensively examine the drug component ratio, optimize the formula, and adjust the process to achieve better efficacy and stability; therefore, in order to ensure the safety and high quality of medication, developing a stable, safe and high-quality 1ml:10mg specification of phenylephrine hydrochloride injection is the technical problem we want to solve. Summary of the invention

[0006] The first object of the present invention is to provide a stable and standard phenylephrine hydrochloride injection having extremely low contents of impurity F and impurity C.

[0007] The second object of the present invention is to provide a preparation process for the above-mentioned phenylephrine hydrochloride injection which has extremely low content of impurity F and impurity C, is stable and meets the standards.

[0008] In order to solve the above technical problems, the present invention provides a phenylephrine hydrochloride injection, comprising the following components: phenylephrine hydrochloride, sodium chloride, sodium metabisulfite, antioxidant 2, sodium citrate dihydrate, citric acid monohydrate, and water for injection.

[0009] In some preferred embodiments, the phenylephrine hydrochloride injection is composed of the following components: 10 mg / mL phenylephrine hydrochloride, 3.5 mg / mL sodium chloride, 2 mg / mL sodium metabisulfite, 0.4 mg / mL antioxidant 2, 2 mg / mL sodium citrate dihydrate, and 0.5 mg / mL citric acid monohydrate.

[0010] In some preferred embodiments, the antioxidant 2 is selected from one or more combinations of monothioglycerol, sodium bisulfite, and cysteine.

[0011] In some preferred embodiments, the antioxidant 2 is selected from monothioglycerol.

[0012] The present invention also provides a preparation process of the above-mentioned phenylephrine hydrochloride injection, comprising the following steps:

[0013] (1) Add water for injection into the liquid preparation tank, adjust the water temperature, and fill with nitrogen for 30 minutes;

[0014] (2) Add the prescribed amount of sodium chloride, sodium metabisulfite, antioxidant 2, sodium citrate dihydrate, and citric acid monohydrate in sequence, stir until completely dissolved, add the prescribed amount of phenylephrine hydrochloride, mix evenly, and take the filtered solution to test the pH value;

[0015] (3) Filling and sterilization.

[0016] In some preferred embodiments, the water temperature in step (1) is adjusted to 20-30°C.

[0017] In some preferred embodiments, the pH value of the drug solution sampled and tested in step (2) is controlled in the range of 4.5 to 5.5.

[0018] In some preferred embodiments, nitrogen is required to be filled before and after filling in step (3), and the flow rate of the nitrogen before filling is 10-15 L / min, and the flow rate of the nitrogen after filling is 8-15 L / min, to ensure that the residual oxygen in the headspace is less than 6.0%.

[0019] In some preferred embodiments, the sterilization parameters in step (3) are a sterilization temperature of 121° C. and a sterilization time of 15 minutes.

[0020] In some preferred embodiments, the preparation process is specifically as follows: take an appropriate amount of water for injection, adjust the water temperature to 20-30°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content is <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Detect the pH value of the drug solution, which should be adjusted to within the range of 4.5 to 5.5. Use water for injection to make up the volume, continue to fill with nitrogen after filtering the drug solution, and the dissolved oxygen content is <1.0 mg / L.

[0021] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 15min.

[0022] The beneficial effects achieved by the present invention are as follows:

[0023] Provide an injection solution that is available immediately and has extremely low content of impurity F and impurity C and stable pH value of the drug solution. According to the properties of the raw materials and product characteristics, sodium citrate dihydrate, citric acid monohydrate, and antioxidants are optimized, and the production process parameters are strictly controlled. On the basis of meeting the quality standard requirements, the product also greatly reduces the risk of impurity C and impurity F, improves the stability of the product pH value, improves the sterility assurance level, and maximizes the safety and effectiveness of the product. The injection solution has stable quality and is more suitable for commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 HPLC chromatogram of process 7 sample DETAILED DESCRIPTION

[0025] The sources of reagents are as follows:

[0026]

[0027] The present invention is described in detail below with reference to embodiments, which are intended to explain but not to limit the technical solutions of the present invention.

[0028] Example 1 Screening of buffer component ratios

[0029] Table 1 Each 1 ml injection contains the following components

[0030]

[0031] The above samples were prepared according to the following preparation methods and then measured:

[0032] Take an appropriate amount of water for injection, adjust the water temperature to 20-30℃, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be less than 1.0mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, and sodium metabisulfite, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be in the range of 4.0-6.0. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and continue to fill with nitrogen, and the dissolved oxygen content should be less than 1.0mg / L. Fill the drug solution at 1ml / vial, and perform nitrogen protection before and after filling. After filling, the sample is sterilized at 121℃ for 12min. The test results are shown in Table 2:

[0033] Table 2

[0034]

[0035] The results show that when the dosage of citric acid monohydrate and sodium citrate dihydrate is very small, although the content of impurity F is reduced, the pH value of the sample drops significantly after sterilization, which is extremely unstable, the content of impurity C is relatively high, and the total impurity content is high. The prescription of sample 2 can not only maintain the pH value of the liquid stable, but also control the impurities at a low level. Therefore, the dosage of citric acid monohydrate is determined to be 0.5 mg / ml, and the dosage of sodium citrate dihydrate is determined to be 2 mg / ml. Therefore, the antioxidant screening continues on this basis.

[0036] Example 2 Antioxidant Screening

[0037] Table 3 Each 1 ml injection contains the following components

[0038]

[0039] Take appropriate amount of water for injection in the above prescription, adjust the water temperature to 20-30℃, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be less than 1.0mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be within the range of 4.0-6.0. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and continue to fill with nitrogen, and the dissolved oxygen content should be less than 1.0mg / L.

[0040] According to the filling solution of 1ml / vial, nitrogen protection is carried out before and after filling. After filling, the sample is sterilized at 121℃ for 12min. After sterilization, pH and impurity tests are carried out. The test results are shown in Table 4:

[0041] Table 4

[0042]

[0043] It can be seen from the above table that the content of impurity C in sample 8 after the improved prescription is the lowest. Therefore, the antioxidant effect is best when the antioxidant is sodium metabisulfite and thioglycerol in combination. At this time, impurity F and total impurities are also the lowest, and the pH stability of the solution is better.

[0044] Example 3 Process Optimization

[0045] Process 1: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 30-40°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be within the range of 4.0-6.0. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen, and the dissolved oxygen content should be <1.0 mg / L;

[0046] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 12min to obtain process 1 sample;

[0047] Process 2: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 20-30°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be within the range of 4.0-6.0. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen, and the dissolved oxygen content should be <1.0 mg / L;

[0048] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling, to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 12min to obtain the process 2 sample;

[0049] Process 3: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 10-20°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be within the range of 4.0-6.0. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen, and the dissolved oxygen content should be <1.0 mg / L;

[0050] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 12min to obtain the process 3 sample;

[0051] Process 4: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 20-30°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, and adjust the pH value of the drug solution to the range of 3.5-4.4 with hydrochloric acid solution. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen. The dissolved oxygen content should be <1.0 mg / L;

[0052] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 12min to obtain process 4 sample;

[0053] Process 5: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 20-30°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be within the range of 4.5-5.5. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen, and the dissolved oxygen content should be <1.0 mg / L;

[0054] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 12min to obtain process 5 sample;

[0055] Process 6: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 20-30°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, and adjust the pH value of the drug solution to 5.6-6.6 with sodium hydroxide solution. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen, and the dissolved oxygen content should be <1.0 mg / L;

[0056] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 12min to obtain process 6 sample;

[0057] Process 7: According to the prescription of sample 8, take an appropriate amount of water for injection, adjust the water temperature to 20-30°C, fill the water for injection with nitrogen for more than 30 minutes, and the dissolved oxygen content should be <1.0 mg / L. Add the prescribed amount of sodium chloride, sodium citrate dihydrate, citric acid monohydrate, sodium metabisulfite, and antioxidant 2, stir until completely dissolved, then add the prescribed amount of raw materials, and stir until the raw materials are completely dissolved. Check the pH value of the drug solution, which should be within the range of 4.5-5.5. Use water for injection to make up the volume, filter the drug solution through a 0.22μm filter membrane, and then continue to fill with nitrogen, and the dissolved oxygen content should be <1.0 mg / L;

[0058] According to the filling solution of 1ml / vial, nitrogen filling protection is carried out before and after filling, and the nitrogen filling flow rate is 10-15L / min before filling and 8-15L / min after filling to ensure that the residual oxygen in the headspace is less than 6.0%. After filling, the sample is sterilized at 121℃ for 15min to obtain process 7 sample;

[0059] The samples prepared by the above process were sterilized and then tested for impurities. The test results are shown in Table 5:

[0060] Table 5

[0061]

[0062] This application investigates the effects of water temperature, pH value and sterilization conditions on product quality. The results in Table 8 show that there is no significant difference in the pH value and related substances of the samples after sterilization under the conditions of water temperature of 20-30°C, pH value of 4.5-5.5, and 121°C for 15 minutes. This shows that the prescription of this application is extremely stable under this preparation method and can withstand long-term high-temperature sterilization. Moreover, 121°C, 12 minutes and 121°C, 15 minutes are both over-killing methods. The sterilization condition of 121°C, 15 minutes provides a higher sterility guarantee for the product. The HPLC chromatogram of the process 7 sample is shown below. Figure 1 shown.

[0063] Comparative Example

[0064] Comparative Sample 1, Comparative Sample 2, Comparative Sample 3, and Comparative Sample 4 were prepared according to the methods of Examples 1 to 4 in Patent CN102525893A;

[0065] Comparative Sample 5, Comparative Sample 6, Comparative Sample 7 and Comparative Sample 8 were prepared respectively according to the methods of Examples 1 to 4 in patent CN109394684A.

[0066] Test Example 1 Impurity Determination

[0067] The above samples were tested for related substances by high performance liquid chromatography, the chromatographic column was octadecylsilane bonded silica gel, and gradient elution was used for detection. The detection wavelength was 215nm. The results of the relevant content detection of the samples are shown in Table 6:

[0068] Table 6

[0069]

[0070] The results show that the pH values ​​of samples 1 to 8 before and after sterilization are significantly different, which causes an increase in impurities in the injection. In the reference preparation, the content of impurity F is high due to the excessive content of sodium citrate dihydrate and citric acid monohydrate, and the impurity C generated by oxidation is also relatively high. Therefore, the prescription of the process 7 sample of this application, which adds a suitable amount of buffer and an additional antioxidant, plus the optimized process, can maintain the pH of the liquid well, making the impurities and injection quality better.

[0071] Test Example 2 Stability Determination

[0072] Using pH value, impurity C, impurity F and other impurities as detection indicators, the following samples were tested for sample content under high temperature and light conditions to investigate the stability of each phenylephrine hydrochloride injection;

[0073] Table 7 PH value test results

[0074]

[0075] It can be seen from the pH measurement results that the pH value of the process 7 sample in the present application shows good stability under high temperature and light conditions, and its effect is equivalent to that of the reference preparation.

[0076] Table 8 Impurity C content test results

[0077]

[0078] It can be seen from the detection results of impurity C that the impurity C of the sample of process 7 of the present application shows excellent effects under high temperature and light conditions, and its content is much lower than the prescription and reference preparation disclosed in the prior art.

[0079] Table 9 Impurity F content test results

[0080]

[0081] It can be seen from the detection results of impurity F that the impurity F in the process 7 sample of the present application shows excellent effect under high temperature and light conditions compared with the reference preparation, and its content is much lower than that of the reference preparation.

[0082] Table 10

[0083]

[0084] It can be seen from the results in Table 10 that this product only contains impurities C and F, and no other impurities are detected.

Claims

1. A phenylephrine hydrochloride injection, characterized in that: It is composed of the following components: 10 mg / mL phenylephrine hydrochloride, 3.5 mg / mL sodium chloride, 2 mg / mL sodium metabisulfite, 0.4 mg / mL monothioglycerol, 2 mg / mL sodium citrate dihydrate, 0.5 mg / mL citric acid monohydrate.

2. A process for preparing phenylephrine hydrochloride injection as claimed in claim 1, characterized in that: The following steps are involved: (1) Add water for injection into the liquid preparation tank, adjust the water temperature, and fill with nitrogen for 30 minutes; (2) Add the prescribed amount of sodium chloride, sodium metabisulfite, thioglycerol, sodium citrate dihydrate, and citric acid monohydrate in sequence, stir to dissolve completely, add the prescribed amount of phenylephrine hydrochloride and mix evenly. The pH value of the filtered solution should be controlled in the range of 4.5 to 5.5; (3) Filling and sterilization.

3. A preparation process as claimed in claim 2, characterized in that: In the step (1), the water temperature is adjusted to 20-30°C.

4. A preparation process as claimed in claim 2, characterized in that: In the step (3), nitrogen filling is required before and after filling, and the nitrogen flow rate before filling is 10-15 L / min, and the nitrogen flow rate after filling is 8-15 L / min, and the residual oxygen in the headspace is less than 6.0%.

5. A preparation process as claimed in claim 2, characterized in that: The sterilization parameters in step (3) are a sterilization temperature of 121° C. and a sterilization time of 15 min.

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