Promethazine hydrochloride injection and preparation method thereof

Abstract

The invention belongs to the technical field of chemical medicine preparations, and particularly relates to a promethazine hydrochloride injection and a preparation method, the promethazine hydrochloride injection comprises the following components by weight concentration: 20-30 mg / mL of promethazine hydrochloride, 0.4-0.6 mg / mL of anhydrous sodium sulfite, 0.6-0.8 mg / mL of sodium pyrosulfite and 0.03-0.07 mg / mL of thioglycerol; the stability of the injection can be improved.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical medicine preparations, and particularly relates to a promethazine hydrochloride injection and a preparation method thereof. Background Art

[0002] Promethazine hydrochloride is a phenothiazine derivative. Because its chemical structure contains a phenothiazine mother ring and low-valent sulfur, it is extremely easy to be oxidized into quinone-like compounds and sulfoxides. Therefore, the dry product will turn blue over time in the air, and the aqueous solution will oxidize more rapidly. Promethazine hydrochloride can competitively block histamine H1 receptors to produce antihistamine effects, counteract histamine-induced capillary dilation, reduce its permeability, and relieve wheezing caused by bronchial smooth muscle contraction. It is stronger and more lasting than diphenhydramine hydrochloride. In addition, because promethazine hydrochloride can easily enter the brain tissue, it has a significant sedative effect and can enhance the central inhibitory effects of hypnotics, analgesics and anesthetics.

[0003] However, the promethazine hydrochloride injection prepared by the existing preparation method has a high level of promethazine hydrochloride impurities and a low level of sterility assurance, and the solution color is prone to being unqualified during its stability period.

[0004] Therefore, in order to improve the quality of promethazine hydrochloride injection and the stability of the drug, it is necessary to develop a preparation method for promethazine hydrochloride injection that can withstand terminal sterilization and has good stability.

[0005] Patent application publication number CN103637981 A discloses a promethazine hydrochloride injection, which contains 1-4g promethazine hydrochloride, 0.05-1g antioxidant, 0.4-0.8g osmotic pressure regulator, appropriate pH regulator and the remainder of water for injection per 100ml, wherein the antioxidant is one or more of sodium bisulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, thiourea, cysteine, methionine and vitamin C, the osmotic pressure regulator is sodium fluoride or glucose, the amount of pH regulator is based on adjusting the pH of the injection to 4-5.5, and the pH regulator can be selected from conventional sodium hydroxide solution (10wt%), sodium carbonate solution (10wt%) or ammonia water (10wt%). The stability of the above injection needs to be improved. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a promethazine hydrochloride injection and a preparation method to improve the stability of the injection.

[0007] The embodiment of the present invention provides a promethazine hydrochloride injection, comprising the following components in weight concentrations: 20-30 mg / mL of promethazine hydrochloride, 0.4-0.6 mg / mL of anhydrous sodium sulfite, 0.6-0.8 mg / mL of sodium pyrosulfite and 0.03-0.07 mg / mL of thioglycerol.

[0008] Preferably, the components are included in the following weight concentrations: promethazine hydrochloride 25 mg / mL, anhydrous sodium sulfite 0.5 mg / mL, sodium pyrosulfite 0.7 mg / mL and monothioglycerol 0.05 mg / mL.

[0009] The embodiment of the present invention provides a method for preparing the promethazine hydrochloride injection, comprising adding anhydrous sodium sulfite, sodium pyrosulfite and thioglycerol to water for injection after nitrogen filling, and stirring evenly; then adding promethazine hydrochloride, stirring evenly, filtering, and sterilizing to obtain the promethazine hydrochloride injection.

[0010] Preferably, anhydrous sodium sulfite, sodium pyrosulfite and monothioglycerol are added to the water for injection after nitrogen filling, and the dissolved oxygen content is controlled to be ≤0.5 mg / L during the stirring process.

[0011] Preferably, during the preparation process of the promethazine hydrochloride injection, the nitrogen filling state is maintained.

[0012] Preferably, the sterilization method is sterilization at 121°C for 10-20 minutes.

[0013] Preferably, after sterilization, the residual oxygen content above the solution in the container is controlled to be less than 1%.

[0014] Preferably, the stirring speed during uniform stirring is 20-30 r / s, and the stirring time is 5-10 min.

[0015] Preferably, the filter element is a polyethersulfone filter element.

[0016] The beneficial effects of the present invention are that anhydrous sodium sulfite, sodium pyrosulfite and thioglycerol are added to the promethazine hydrochloride injection, which can effectively improve the stability of the injection, reduce impurities during long-term storage, effectively reduce residual oxygen content, and control changes in pH value.

[0017] The present invention selects thioglycerol as an antioxidant, which can significantly reduce residual oxygen and impurities compared with antioxidants such as vitamin C.

[0018] The present invention controls the concentrations of anhydrous sodium sulfite, sodium pyrosulfite and thioglycerol, and can significantly reduce residual oxygen and impurities compared with other concentration ranges. DETAILED DESCRIPTION

[0019] The present invention is further described below with reference to specific embodiments, but these embodiments should not be construed as limiting the present invention.

[0020] Example 1: Promethazine Hydrochloride Injection Prescription composition: Component prescription Promethazine hydrochloride 4000g Anhydrous sodium sulfite 80g Sodium metabisulfite 112g Thioglycerol 8g Add water for injection to 160L.

[0021] The preparation method is: Add 80% of the prepared water for injection into the preparation tank, fill nitrogen into the bottom, monitor the dissolved oxygen content of the water for injection online, and start feeding when the dissolved oxygen content is ≤0.5 mg / L, add the prescribed amount of anhydrous sodium sulfite, sodium metabisulfite and thioglycerol, stir for 5 minutes until completely dissolved, then add the prescribed amount of promethazine hydrochloride, stir for 5 minutes until completely dissolved, filter through 0.45µm and 0.22µm polyethersulfone filter elements, and fill with nitrogen before and after filling in 2ml colorless borosilicate ampoule, control the residual oxygen content in the upper part of the liquid to be ≤1.0%, perform melt sealing, and sterilize at 121°C for 15 minutes to obtain promethazine hydrochloride injection.

[0022] The samples were tested in accordance with the standards of promethazine hydrochloride injection in the 2020 edition of the Chinese Pharmacopoeia, and the prepared samples were subjected to stability testing. The test results are shown in Table 1 below.

[0023] Table 1

[0024] It can be seen from the test data in Table 1 above that the promethazine hydrochloride injection sample prepared in this embodiment has good stability, and the quality of the sample is stable after accelerated sampling for 6 months.

[0025] Comparative Example 1 Prescription composition Component prescription amount Promethazine hydrochloride 250g Anhydrous sodium sulfite 5g Sodium metabisulfite 7g Add water for injection to 10L.

[0026] The preparation method is: Add 80% of the prepared amount of water for injection into the preparation tank, fill nitrogen into the bottom, monitor the dissolved oxygen content of the water for injection online, and start feeding when the dissolved oxygen content is ≤0.5 mg / L, add the prescribed amount of anhydrous sodium sulfite and sodium metabisulfite, stir for 5 minutes until completely dissolved, then add the prescribed amount of promethazine hydrochloride, stir for 5 minutes until completely dissolved, filter through 0.45µm and 0.22µm polyethersulfone filter elements, and fill with nitrogen before and after filling in 2ml colorless borosilicate ampoule, control the residual oxygen content in the upper part of the liquid to be ≤1.0%, perform melt sealing, and sterilize at 121°C for 15 minutes to obtain promethazine hydrochloride injection.

[0027] The samples were tested in accordance with the standards for promethazine hydrochloride injection in the 2020 edition of the Chinese Pharmacopoeia, and the prepared samples were subjected to stability testing. The test results are shown in Table 2 below.

[0028] Table 2

[0029] According to the test data in Table 2 above, it can be seen that the quality of the promethazine hydrochloride injection sample prepared in this embodiment is unstable after accelerated sampling for 6 months, indicating that no thioglycerol is added to the prescription, the antioxidant capacity of the drug is poor, and the requirement for drug stability cannot be met.

[0030] Comparative Example 2 Prescription composition Component prescription Promethazine hydrochloride 1.5g Anhydrous sodium sulfite 30mg Sodium bisulfite 42mg Vitamin C 3mg Add water for injection to 60 ml.

[0031] The preparation method is: Add 80% of the prepared amount of water for injection into the preparation tank, fill nitrogen into the bottom, monitor the dissolved oxygen content of the water for injection online, and start feeding when the dissolved oxygen content is ≤0.5 mg / L, add the prescribed amount of anhydrous sodium sulfite and sodium metabisulfite, stir for 5 minutes until completely dissolved, then add the prescribed amount of promethazine hydrochloride, stir for 5 minutes until completely dissolved, filter through 0.45µm and 0.22µm polyethersulfone filter elements, and fill with nitrogen before and after filling in 2ml colorless borosilicate ampoule, control the residual oxygen content in the upper part of the liquid to be ≤1.0%, perform melt sealing, and sterilize at 121°C for 15 minutes to obtain promethazine hydrochloride injection.

[0032] The samples were tested in accordance with the standards for promethazine hydrochloride injection in the 2020 edition of the Chinese Pharmacopoeia, and the prepared samples were subjected to stability testing. The test results are shown in Table 3 below.

[0033] Table 3

[0034] According to the test data in Table 3 above, it can be seen that the quality of the promethazine hydrochloride injection sample prepared in this embodiment is unstable after accelerated sampling for 6 months, indicating that the combination of sodium bisulfite, sodium sulfite and vitamin C antioxidants added to the prescription is not as good as the combination of anhydrous sodium sulfite, sodium pyrosulfite and thioglycerol, and the antioxidant capacity of the drug is poor, which cannot meet the requirement of drug stability.

[0035] Comparative Example 3 Commercially available promethazine hydrochloride injection Commercially available promethazine hydrochloride injection was purchased from Tianjin Jinyao Pharmaceutical Co., Ltd.

[0036] The samples were tested in accordance with the standards for promethazine hydrochloride injection in the 2020 edition of the Chinese Pharmacopoeia, and the prepared samples were subjected to stability testing. The test results are shown in Table 4 below.

[0037] Table 4

[0038] According to the test data in Table 4 above, it can be seen that the stability of the commercially available products is poor, and the samples accelerated for 3 months showed instability.

[0039] Comparative Example 4 Prescription composition Component prescription amount Promethazine hydrochloride 4000g Anhydrous sodium sulfite 56g Sodium metabisulfite 112g Thioglycerol 8g Add water for injection to 160L.

[0040] The preparation method is the same as Example 1.

[0041] The samples were tested in accordance with the standards for promethazine hydrochloride injection in the 2020 edition of the Chinese Pharmacopoeia, and the prepared samples were subjected to stability testing. The test results are shown in Table 5 below.

[0042] Table 5

[0043] According to the test data in Table 5 above, it can be seen that the 0-day test quality of the promethazine hydrochloride injection sample prepared in this embodiment does not meet the requirements, indicating that the amount of anhydrous sodium sulfite added to the prescription is too small, the antioxidant capacity of the drug is poor, and the requirement for drug stability cannot be met.

[0044] Comparative Example 5 Prescription composition Component prescription amount Promethazine hydrochloride 4000g Anhydrous sodium sulfite 80g Sodium metabisulfite 80g Thioglycerol 8g Add water for injection to 160L.

[0045] The preparation method is the same as Example 1.

[0046] The samples were tested with reference to the promethazine hydrochloride injection standard of the 2020 edition of the "Chinese Pharmacopoeia", and the prepared samples were subjected to stability testing. The test results are shown in Table 6 below.

[0047] Table 6

[0048] According to the test data in Table 6 above, it can be seen that the 0-day test quality of the promethazine hydrochloride injection sample prepared in this embodiment does not meet the requirements, indicating that the amount of sodium metabisulfite added in the prescription is too small, the antioxidant capacity of the drug is poor, and the requirement for drug stability cannot be met.

[0049] It can be judged from the above test results that the present application improves the product quality of promethazine hydrochloride injection by adopting anhydrous sodium sulfite, sodium metabisulfite and thioglycerol as excipients and strictly controlling the preparation process, and can ensure the stability of the product quality of promethazine hydrochloride injection within the validity period.

[0050] A person skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the concept of the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0051] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the protection scope of the present application.

Claims

1. A promethazine hydrochloride injection, characterized in that: The invention comprises the following components in weight concentrations: promethazine hydrochloride 20-30 mg / mL, anhydrous sodium sulfite 0.4-0.6 mg / mL, sodium pyrosulfite 0.6-0.8 mg / mL and thioglycerol 0.03-0.07 mg / mL.

2. The promethazine hydrochloride injection according to claim 1, characterized in that: The composition comprises the following components in weight concentrations: promethazine hydrochloride 25 mg / mL, anhydrous sodium sulfite 0.5 mg / mL, sodium pyrosulfite 0.7 mg / mL and monothioglycerol 0.05 mg / mL.

3. A method for preparing promethazine hydrochloride injection as claimed in claim 1 or 2, characterized in that: Add anhydrous sodium sulfite, sodium pyrosulfite and thioglycerol to the nitrogen-filled water for injection, and stir evenly; then add promethazine hydrochloride, stir evenly, filter, and sterilize to obtain promethazine hydrochloride injection.

4. The preparation method according to claim 3, characterized in that: Add anhydrous sodium sulfite, sodium metabisulfite and monothioglycerol to the water for injection after nitrogen filling, and control the dissolved oxygen content to ≤0.5 mg / L during the stirring process.

5. The preparation method according to claim 3, characterized in that: During the preparation process of the promethazine hydrochloride injection, the nitrogen filling state is maintained.

6. The preparation method according to claim 3, characterized in that: The sterilization method is to sterilize at 121°C for 10-20 minutes.

7. The preparation method according to claim 3, characterized in that: After sterilization, the residual oxygen content above the solution in the container is controlled to be less than 1%.

8. The preparation method according to claim 3, characterized in that: The stirring speed is 20-30r / s when stirring evenly, and the stirring time is 5-10min.

9. The preparation method according to claim 3, characterized in that: The filter element is a polyethersulfone filter element.

Images