Sodium sulfadiazine injection and preparation method thereof

Abstract

The invention relates to a sulfadiazine sodium injection and a preparation method thereof. The invention discloses a sulfadiazine sodium injection and a preparation method thereof, the sulfadiazine sodium injection is characterized in that every 1000ml of the injection contains 200g of sulfadiazine sodium, anhydrous disodium hydrogen phosphate and nicotinamide, preferably, 2.5 g of anhydrous disodium hydrogen phosphate and 6.4 g of nicotinamide are contained in every 1000ml of the injection, preferably, the injection also contains 2g of sodium thiosulfate, and the preferable specification is 2ml: 0.4 g or 5ml: 1g. The sulfadiazine sodium injection prepared according to a prescription process disclosed by the invention can keep very low insoluble particles, and can be used for preparing the injection. The quality stability is extremely high and is obviously superior to that in the prior art.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a sulfadiazine sodium injection and a preparation method thereof. Background Art

[0002] Sulfadiazine sodium is a medium-acting sulfonamide antibacterial drug, which has antibacterial effects on many Gram-positive and Gram-negative bacteria. It has antibacterial effects on non-enzyme-producing Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella, Salmonella, Shigella, Neisseria gonorrhoeae, Neisseria meningitidis, and Haemophilus influenzae. In addition, it also has activity against Chlamydia trachomatis, Nocardia asteroides, Plasmodium, and Toxoplasma gondii in vitro. The antibacterial activity of this product is the same as that of sulfamethoxazole.

[0003] The currently commonly used clinical dosage form of sulfadiazine sodium is an injection, with specifications of 2ml∶0.4g and 5ml∶1g. Sulfadiazine sodium has a relatively high alkalinity, with a pH value of 9.6 - 6.4, and the alkalinity of the prepared injection according to the national standard is also pH 9.5 - 11.0, belonging to strong alkalinity. The general packaging material for existing injections is a glass ampoule bottle, but the glass ampoule bottle has poor alkali resistance, which will cause an increase in insoluble particles in the injection, and even film shedding. Insoluble particles are extremely likely to cause adverse reactions such as allergies, posing a relatively high safety risk. Summary of the Invention

[0004] The purpose of the present invention is to provide a sulfadiazine sodium injection and a preparation method thereof, which have lower insoluble particles and stable quality indicators compared with the prior art, and are significantly superior to the prior art.

[0005] The solution adopted by the present invention to solve the above technical problems is:

[0006] The sulfadiazine sodium injection contains 200g of sulfadiazine sodium, as well as disodium hydrogen phosphate anhydrous and nicotinamide in every 1000ml of the injection.

[0007] Preferably, the dosage of disodium hydrogen phosphate anhydrous in every 1000ml of the injection is 2.5g, and the dosage of nicotinamide is 6.4g.

[0008] Preferably, every 1000ml of the sulfadiazine sodium injection also contains 2g of sodium thiosulfate, which can further increase the stability of the injection.

[0009] Preferably, the specifications of the sulfadiazine sodium injection are 2ml:0.4g or 5ml:1.0g.

[0010] The present invention also provides a preparation method for the above sulfadiazine sodium injection, including the following steps:

[0011] (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 600 ml of injection water at 55°C - 60°C;

[0012] (2) Maintain the temperature at 55°C - 60°C, and successively add the prescribed amounts of nicotinamide and sodium sulfadiazine, stir to dissolve, and add injection water to 1000 ml;

[0013] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and sterilize to obtain sodium sulfadiazine injection.

[0014] Preferably, the sterilization conditions are 121°C for 15 minutes.

[0015] The inventor of the present invention unexpectedly found that the combined use of nicotinamide and anhydrous disodium hydrogen phosphate as excipients for sodium sulfadiazine injection is beneficial to maintaining the stability of sodium sulfadiazine injection with lower insoluble particles, and at the same time has high stability, achieving unexpected technical effects. In particular, the best effect is achieved with a specific ratio of adding 2.5 g of anhydrous disodium hydrogen phosphate and 6.4 g of nicotinamide per 1000 ml. Specific Embodiments

[0016] For a better understanding of the present invention, the following examples further illustrate the present invention, but the content of the present invention is not limited to the following examples.

[0017] Example 1

[0018] According to the prescribed amounts in Table 1 below, prepare the injection according to the following method:

[0019] (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 600 ml of injection water at 55°C;

[0020] (2) Maintain the temperature at 55°C, successively add the prescribed amounts of nicotinamide and sodium sulfadiazine, stir to dissolve, and add injection water to 1000 ml;

[0021] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification of 3 ml: 0.5 g, and then sterilize at 121°C for 15 minutes to obtain sodium sulfadiazine injection.

[0022] Table 1 Injections with Different Prescribed Amounts of Nicotinamide and Anhydrous Disodium Hydrogen Phosphate

[0023]

[0024] Conduct the stress test on the above 8 prescription samples, place them at 60°C and under strong light (4500 lx ± 500 lx) for 10 days respectively, sample and test on the 10th day respectively, compare the results with those on the 0th day, and examine the insoluble particles of the samples. The results are shown in Tables 2 - 3:

[0025] Table 2 Results of 60°C Stability Test

[0026]

[0027] Table 3 Results of High Intensity Light (4500 LX) Stability Test

[0028]

[0029] It can be seen from the test results in Table 2 - Table 3 that the combined use of disodium hydrogen phosphate anhydrous and nicotinamide is beneficial to reducing the insoluble particles in sulfadiazine sodium injection. In particular, the best effect is achieved with a specific ratio of 2.5 g of disodium hydrogen phosphate anhydrous and 6.4 g of nicotinamide per 1000 ml. That is, even a very small change in the dosage will produce significantly different technical effects.

[0030] Example 2

[0031] Preparation of Sulfadiazine Sodium Injection (Specification: 2 ml: 0.4 g)

[0032] Prescription:

[0033] Sulfadiazine Sodium: 200 g

[0034] Disodium Hydrogen Phosphate Anhydrous: 2.5 g

[0035] Nicotinamide: 6.4 g

[0036] Water for Injection q.s. to 1000 ml

[0037] Manufactured into 500 vials

[0038] Process:

[0039] (1) Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of water for injection at 55°C;

[0040] (2) Maintain the temperature at 55°C, and successively add the prescribed amounts of nicotinamide and sulfadiazine sodium, stir to dissolve, and add water for injection to 1000 ml;

[0041] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and then sterilize at 121°C for 15 minutes to obtain sulfadiazine sodium injection.

[0042] Example 3

[0043] Preparation of Sulfadiazine Sodium Injection (Specification: 2 ml: 0.4 g)

[0044] Prescription:

[0045] Sulfadiazine Sodium: 200 g

[0046] Disodium hydrogen phosphate anhydrous: 2.5 g

[0047] Nicotinamide: 6.4 g

[0048] Water for injection q.s. to 1000 ml

[0049] Manufactured into 500 vials

[0050] Process:

[0051] (1) Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of water for injection at 60°C;

[0052] (2) Maintain the temperature at 60°C, and successively add the prescribed amounts of nicotinamide and sodium sulfadiazine, stir to dissolve, and add water for injection to 1000 ml;

[0053] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and then sterilize at 121°C for 15 minutes to obtain sodium sulfadiazine injection.

[0054] Example 4

[0055] Preparation of sodium sulfadiazine injection (Specification: 2 ml: 0.4 g)

[0056] Prescription:

[0057] Sodium sulfadiazine: 200 g

[0058] Disodium hydrogen phosphate anhydrous: 2.5 g

[0059] Nicotinamide: 6.4 g

[0060] Water for injection q.s. to 1000 ml

[0061] Manufactured into 500 vials

[0062] Process:

[0063] (1) Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of water for injection at 58°C;

[0064] (2) Maintain the temperature at 58°C, and successively add the prescribed amounts of nicotinamide and sodium sulfadiazine, stir to dissolve, and add water for injection to 1000 ml;

[0065] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and then sterilize at 121°C for 15 minutes to obtain sodium sulfadiazine injection.

[0066] Example 5

[0067] Preparation of Sulfadiazine Sodium Injection (Specification: 5 ml: 1 g)

[0068] Prescription:

[0069] Sulfadiazine Sodium: 200 g

[0070] Disodium Hydrogen Phosphate Anhydrous: 2.5 g

[0071] Nicotinamide: 6.4 g

[0072] Water for Injection q.s. to 1000 ml

[0073] Manufactured into 200 vials

[0074] Process:

[0075] (1) Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of water for injection at 55 °C;

[0076] (2) Maintain the temperature at 55 °C, and successively add the prescribed amounts of nicotinamide and sulfadiazine sodium, stir to dissolve, and add water for injection to 1000 ml;

[0077] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and then sterilize at 121 °C for 15 minutes to obtain sulfadiazine sodium injection.

[0078] Example 6

[0079] Preparation of Sulfadiazine Sodium Injection (Specification: 5 ml: 1 g)

[0080] Prescription:

[0081] Sulfadiazine Sodium: 200 g

[0082] Disodium Hydrogen Phosphate Anhydrous: 2.5 g

[0083] Nicotinamide: 6.4 g

[0084] Water for Injection q.s. to 1000 ml

[0085] Manufactured into 200 vials

[0086] Process:

[0087] (1) Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of water for injection at 60 °C;

[0088] (2) Maintain the temperature at 60 °C, and successively add the prescribed amounts of nicotinamide and sulfadiazine sodium, stir to dissolve, and add water for injection to 1000 ml;

[0089] (3)Measure the pH value and content of the solution, filter it with a 0.22 µm filter element, fill it into ampoules according to the specifications, and then sterilize it at 121 °C for 15 minutes to obtain sodium sulfadiazine injection.

[0090] Example 7

[0091] Preparation of sodium sulfadiazine injection (Specification: 5 ml: 1 g)

[0092] Prescription:

[0093] Sodium sulfadiazine: 200 g

[0094] Disodium hydrogen phosphate anhydrous: 2.5 g

[0095] Nicotinamide: 6.4 g

[0096] Water for injection q.s. to 1000 ml

[0097] Manufacture 200 vials

[0098] Process:

[0099] (1)Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of water for injection at 58 °C;

[0100] (2)Maintain the temperature at 58 °C, sequentially add the prescribed amounts of nicotinamide and sodium sulfadiazine, stir to dissolve, and add water for injection to 1000 ml;

[0101] (3)Measure the pH value and content of the solution, filter it with a 0.22 µm filter element, fill it into ampoules according to the specifications, and then sterilize it at 121 °C for 15 minutes to obtain sodium sulfadiazine injection.

[0102] Example 8

[0103] Preparation of sodium sulfadiazine injection (Specification: 2 ml: 0.4 g)

[0104] Prescription:

[0105] Sodium sulfadiazine: 200 g

[0106] Disodium hydrogen phosphate anhydrous: 2.5 g

[0107] Nicotinamide: 6.4 g

[0108] Sodium thiosulfate: 2 g

[0109] Water for injection q.s. to 1000 ml

[0110] Manufacture 500 vials

[0111] Process:

[0112] (1) Dissolve the prescribed amount of anhydrous disodium hydrogen phosphate in 600 ml of injection water at 55°C;

[0113] (2) Maintain the temperature at 55°C, and successively add the prescribed amounts of nicotinamide, sodium thiosulfate, and sodium sulfadiazine, stir to dissolve, and add injection water to 1000 ml;

[0114] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specifications, and then sterilize at 121°C for 15 minutes to obtain sodium sulfadiazine injection.

[0115] The present invention provides the following test and comparison results:

[0116] 1. Sample 1 (sodium sulfadiazine injection prepared in Example 2 of the present invention, 2 ml: 0.4 g);

[0117] 2. Sample 2 (sodium sulfadiazine injection prepared in Example 8 of the present invention, 2 ml: 0.4 g);

[0118] 3. Sample 3 (commercially available sodium sulfadiazine injection, 2 ml: 0.4 g);

[0119] Samples 1 to 3 were subjected to accelerated stability investigation (40°C ± 2°C, RH 75% ± 5%) for 6 months, and the results are shown in Table 4:

[0120] Table 4 Results of accelerated test stability

[0121]

[0122] Samples 1 to 3 were subjected to long-term stability investigation (25°C ± 2°C, RH 60% ± 10%), and the results are shown in Table 5:

[0123] Table 5 Results of long-term test stability

[0124]

[0125] It can be seen from the results in Table 4 - Table 5 that the sodium sulfadiazine injection prepared by the prescription and process of the present invention maintains extremely low insoluble particles and has good stability, showing significant advantages compared with the marketed products. The sodium sulfadiazine injections prepared in other examples of the present invention also underwent the same tests and obtained similar results.

[0126] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. Sulfadiazine Sodium Injection, characterized in that: In addition to 200 g of sodium sulfadiazine in every 1000 ml of injection solution, it also contains disodium hydrogen phosphate anhydrous and nicotinamide.

2. The sulfadiazine sodium injection according to claim 1, wherein: The dosage of disodium hydrogen phosphate anhydrous in every 1000 ml of injection solution is 2.5 g, and the dosage of nicotinamide is 6.4 g.

3. The sulfadiazine sodium injection according to claim 2, characterized in that: Every 1000 ml of injection solution also contains 2 g of sodium thiosulfate.

4. The sulfadiazine sodium injection according to claim 1, wherein: The specifications of the sodium sulfadiazine injection are 2 ml: 0.4 g or 5 ml: 1 g.

5. The preparation method of the sulfadiazine sodium injection according to any one of claims 1 to 4, characterized in that, It is prepared by the following method: (1) Dissolve the prescribed amount of disodium hydrogen phosphate anhydrous in 600 ml of injection water at 55°C to 60°C; (2) Keep the temperature at 55°C to 60°C, and successively add the prescribed amounts of nicotinamide, sodium thiosulfate, and sodium sulfadiazine, stir to dissolve, and add injection water to 1000 ml; (3) Measure the pH value and content of the solution, filter it with a 0.22 µm filter element, fill it into ampoules according to the specifications, and sterilize to obtain the sodium sulfadiazine injection.

6. The preparation method of sulfadiazine sodium injection according to claim 5, characterized in that The sterilization conditions are: sterilize at 121°C for 15 minutes.

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