Compound sulfamonomethoxine sodium injection and preparation method thereof

Abstract

The invention discloses a compound sulfamonomethoxine sodium injection. Every 100 ml of the compound sulfamonomethoxine sodium injection is prepared from 17 g to 23 g of sulfamonomethoxine sodium, 3.8 g to 4.3 g of trimethoprim, 0.12 g to 0.15 g of sodium thiosulfate, 0.24 g to 0.28 g of sodium hydroxide, 30 g to 50 g of polyethylene glycol-400, 10 g to 15 g of glycerol formal and the balance of water for injection. The compound sulfamonomethoxine sodium injection is high in content and good in stability, and compared with a low-content injection, the compound sulfamonomethoxine sodium injection can reduce the dosage and avoid animal stress; the irritation of an injection part can be reduced, and animals recover faster; the injection liquid suction difficulty can be reduced, the injection time is shortened, and medication is more convenient and faster; and the packaging cost can be reduced, the manpower and material resource cost of medication is reduced, resources are saved, and the environment is protected.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and relates to a compound sulfamethoxazole sodium injection, and also relates to a preparation method thereof. Background Art

[0002] Sulfonamide sodium is a sulfonamide antibacterial drug that has a strong inhibitory effect on most Gram-positive and Gram-negative bacteria. Bacteria develop resistance to this drug slowly, and it is currently the sulfonamide drug with the strongest antibacterial effect both in vivo and in vitro.

[0003] Trimethoprim is a lipophilic, weakly alkaline pyrimethamine-type antibacterial agent. It is easy to cause bacterial resistance when used alone and is generally not used alone. It is mainly used as a sulfonamide enhancer and is used in combination with sulfonamide drugs to form a compound preparation.

[0004] In clinical practice, sulfamethoxazole sodium is used together with trimethoprim to enhance the antibacterial effect. The two are usually made into injections or powders for use together. Since the intramuscular injection method of injection is more convenient and quick, more users prefer injections.

[0005] Since trimethoprim is insoluble in water, the preparation of the injection requires the use of a certain organic solvent, and the injections prepared by selecting different organic solvents are quite different. In the prior art, due to different processes such as temperature and feeding sequence, the final injection may also have problems such as dark color and poor stability. At the same time, the low-content compound sulfamethoxazole sodium injection in the current pharmacopoeia standard has the problem of too large injection volume during use in large animals. If the injection volume is too large, the difficulty of injection will increase accordingly, and may be accompanied by animal stress response; if there is too much liquid medicine at the injection site, the absorption is slow, and the irritation of the drug may hinder the animal's movement and prolong the recovery time; in addition, the difficulty of aspirating the liquid medicine during use increases, and the longer injection time is also a problem that needs to be considered. Therefore, it is necessary to invent a compound sulfamethoxazole sodium injection with high content and good stability. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a compound sulfamethoxazole sodium injection, which has a high content and good stability, can reduce the dosage of the medicine and avoid animal stress; can reduce the irritation of the injection site and the animal recovers faster; can reduce the difficulty of aspirating the injection liquid and the injection time, and the medication is more convenient and quick; and can also reduce the packaging cost, reduce the manpower and material cost of medication, save resources and protect the environment.

[0007] After research, the present invention provides the following technical solutions:

[0008] 1. Compound sulfamethoxine sodium injection. Each 100 ml of injection contains sulfamethoxine sodium 17-23 g, trimethoprim 3.8-4.3 g, sodium thiosulfate 0.12-0.15 g, sodium hydroxide 0.24-0.28 g, polyethylene glycol-400 30-50 g, glycerol formal 10-15 g, and the balance is water for injection.

[0009] As one of the preferred embodiments, each 100 ml injection contains 19 g of sulfamethoxazole sodium, 3.9 g of trimethoprim, 0.13 g of sodium thiosulfate, 0.27 g of sodium hydroxide, 40 g of polyethylene glycol-400, 11 g of glycerol formal, and the balance is water for injection.

[0010] As one of the preferred embodiments, each 100 ml injection contains 23 g of sulfamethoxazole sodium, 4.1 g of trimethoprim, 0.14 g of sodium thiosulfate, 0.28 g of sodium hydroxide, 50 g of polyethylene glycol-400, 15 g of glycerol formal, and the balance is water for injection.

[0011] 2. The preparation method of the compound sulfamethoxazole sodium injection comprises the following steps:

[0012] 1) Mix polyethylene glycol-400 and glycerol formal, heat to 85°C, add trimethoprim, stir to dissolve completely, stop heating, cool to below 50°C, and set aside;

[0013] 2) Take part of the water for injection, adjust the temperature to 50°C, add sodium hydroxide and sodium thiosulfate, stir to dissolve completely, add sulfamethoxine sodium, stir to dissolve completely, then add the solution obtained in step 1), stir to mix, add water for injection to make up to volume, adjust the pH value to 10.2-10.4 with 10% (g / ml) sodium hydroxide solution or 10% (g / ml) hydrochloric acid solution, filter, fill with nitrogen and sterilize to obtain compound sulfamethoxine sodium injection.

[0014] Since sulfamethoxine sodium is soluble in water and trimethoprim is insoluble in water, a suitable organic solvent or a composite organic solvent is selected to make the two form a stable compound preparation. The present invention selects polyethylene glycol-400 as an organic solvent. Polyethylene glycol-400 is a polymer of ethylene oxide hydrolyzate, which is miscible with water and ethanol and has stable chemical properties. The addition of cosolvent glycerol formal can not only promote the dissolution of trimethoprim, produce a sustained release effect after entering the body, but also ensure the stability of the obtained preparation under high and low temperature conditions, while avoiding the safety risks caused by the addition of propylene glycol, etc., and reducing the irritation of the solution.

[0015] The present invention selects sodium hydroxide as a pH regulator to maintain the pH value of the injection within the legal range of 9.0 to 11.0, thereby ensuring the long-term stability of sulfamethoxine sodium and trimethoprim. Comparative experimental results show that without adding a pH regulator, the pH value of the preparation is lower than 9.0 and the pH is unstable.

[0016] The present invention selects sodium thiosulfate as an antioxidant. Since sulfonamide drugs are derivatives with p-aminobenzenesulfonamide as the basic structure, the aromatic primary amines in the structure are easily oxidized by oxygen in the air. Under the catalysis of sunlight and heavy metals, the oxidation reaction is accelerated, and the color of the drug becomes darker when exposed to light, especially under alkaline conditions. The 2017 edition of the "Quality Standards for Veterinary Drugs" stipulates that the pH range of compound sulfamethoxazole sodium injection is 9.0-11.0. Therefore, after experimental screening, sodium thiosulfate is used as an antioxidant to reduce the possibility of oxidation of the preparation, reduce the precipitation of related substances, and ensure the stability of the preparation under high temperature and related conditions.

[0017] For the preparation process of injection, after experimental screening, the best heating temperature of step 1) trimethoprim is 85°C. A lower temperature will cause incomplete dissolution of trimethoprim and easy precipitation. A too high temperature will cause the color of the preparation to darken, which does not meet the requirements of the pharmacopoeia; the best feeding and mixing temperature of step 2) is 50°C. Adding an antioxidant at a high temperature will rapidly oxidize and turn yellow, resulting in a darker color of the preparation, and there is no obvious difference at a lower temperature. The present invention also studies the feeding order of related materials. If the auxiliary materials such as pH regulators and antioxidants are dissolved first and then trimethoprim is added thereto and heated to dissolve, the antioxidant will be consumed, resulting in a darker color of the finished product and a decrease in stability. If trimethoprim is first heated and dissolved with an organic solvent and then cooled and mixed with pH regulators, antioxidants, sulfamethoxazole sodium, etc., the effect is better and the stability of the preparation content and related parameters can be ensured.

[0018] The beneficial effects of the present invention are as follows: the present invention provides a high-content, stable compound sulfamethoxine sodium injection. Compared with the existing low-content compound sulfamethoxine sodium injection, the former increases the drug concentration, not only reducing the dosage of the drug by half to avoid animal stress; reducing the irritation of the injection site of the animal, and the animal recovering faster; it can also reduce the difficulty of injecting the injection, reduce the injection time, improve the efficiency of medication, and make medication more convenient and quick. In addition, in today's environment where large-scale breeding enterprises in China are increasing, the scale of breeding is gradually expanding, and the demand for drugs in various large-scale breeding farms is increasing, the selection of high-content injection can reduce packaging costs at the production end, and can reduce the human and material costs of medication for breeding enterprises at the clinical use end. At the same time, the packaging discarded after the use of the drug is reduced, and it can also effectively save resources and protect the environment. DETAILED DESCRIPTION

[0019] In order to make the objectives, technical solutions and beneficial effects of the present invention more clear, the preferred embodiments of the present invention are described in detail below.

[0020] Example 1 Preparation of Compound Sulfadiazine Sodium Injection

[0021] Every 100 ml of compound sulfamethoxine sodium injection contains 19 g of sulfamethoxine sodium, 3.9 g of trimethoprim, 0.13 g of sodium thiosulfate, 0.27 g of sodium hydroxide, 40 g of polyethylene glycol-400, 11 g of glycerol formal, and the balance is water for injection.

[0022] The preparation method of compound sulfamethoxazole sodium injection comprises the following steps:

[0023] 1) Mix polyethylene glycol-400 and glycerol formal, heat to 85°C, add trimethoprim, stir to dissolve completely, stop heating, cool to below 50°C, and set aside;

[0024] 2) Take part of the water for injection, adjust the temperature to 50°C, add sodium hydroxide and sodium thiosulfate, stir to dissolve completely, add sulfamethoxine sodium, stir to dissolve completely, then add the solution obtained in step 1), stir to mix, add water for injection to make up to volume, adjust the pH to 10.2-10.4 with 10% (g / ml) sodium hydroxide solution or 10% (g / ml) hydrochloric acid solution, first filter with a microporous membrane with a pore size of 0.45 μm, then filter with a microporous membrane with a pore size of 0.22 μm, fill with nitrogen and seal, and sterilize at 115°C for 30 min to obtain compound sulfamethoxine sodium injection.

[0025] Example 2 Preparation of Compound Sulfadiazine Sodium Injection

[0026] Every 100 ml of compound sulfamethoxine sodium injection contains 23 g of sulfamethoxine sodium, 4.1 g of trimethoprim, 0.14 g of sodium thiosulfate, 0.28 g of sodium hydroxide, 50 g of polyethylene glycol-400, 15 g of glycerol formal, and the balance is water for injection.

[0027] The preparation method of compound sulfamethoxazole sodium injection comprises the following steps:

[0028] 1) Mix polyethylene glycol-400 and glycerol formal, heat to 85°C, add trimethoprim, stir to dissolve completely, stop heating, cool to below 50°C, and set aside;

[0029] 2) Take part of the water for injection, adjust the temperature to 50°C, add sodium hydroxide and sodium thiosulfate, stir to dissolve completely, add sulfamethoxine sodium, stir to dissolve completely, then add the solution obtained in step 1), stir to mix, add water for injection to make up to volume, adjust the pH to 10.2-10.4 with 10% (g / ml) sodium hydroxide solution or 10% (g / ml) hydrochloric acid solution, first filter with a microporous membrane with a pore size of 0.45 μm, then filter with a microporous membrane with a pore size of 0.22 μm, fill with nitrogen and seal, and sterilize at 115°C for 30 min to obtain compound sulfamethoxine sodium injection.

[0030] Example 3 Stability Study of Compound Sulfadiazine Sodium Injection

[0031] According to the "Guidelines for Stability Testing of Veterinary Drugs", the stability of the compound sulfamethoxazole sodium injection prepared in Examples 1 and 2 was investigated.

[0032] 1. Strong light exposure test

[0033] Place the compound sulfamethoxazole sodium injection in a light box at an illumination of 4500±500lx for 10 days, and take samples for testing on the 5th and 10th days.

[0034] The results are shown in Table 1. After being placed under 4500±500lx for 10 days, the appearance, content and pH value of the compound sulfamethoxazole sodium injection prepared in Examples 1 and 2 did not change significantly, and the inspection items such as identification, visible foreign matter and sterility all met the requirements.

[0035] Table 1 Strong light irradiation test results

[0036]

[0037] 2. High temperature test

[0038] Place the compound sulfamethoxazole sodium injection in a forced air drying oven at 60°C for 10 days, and take samples for testing on the 5th and 10th days.

[0039] The results are shown in Table 2. After being placed at 60°C for 10 days, the appearance, content and pH value of the compound sulfamethoxazole sodium injection prepared in Examples 1 and 2 did not change significantly, and the inspection items such as identification, visible foreign matter and sterility all met the requirements.

[0040] Table 2 High temperature test results

[0041]

[0042]

[0043] 3. Accelerated testing

[0044] Place the compound sulfamethoxazole sodium injection in a constant temperature and humidity chamber at a temperature of 40±2°C and a relative humidity of 75±5% for 6 months, and take samples for testing at the end of the 1st, 2nd, 3rd and 6th month.

[0045] The results are shown in Table 3. After being placed at 40±2°C and 75±5% for 6 months, the appearance, content and pH value of the compound sulfamethoxazole sodium injection prepared in Examples 1 and 2 did not change significantly, and the inspection items such as identification, visible foreign matter and sterility all met the requirements.

[0046] Table 3 Accelerated test results

[0047]

[0048] 4. Long-term trials

[0049] Place the compound sulfamethoxazole sodium injection in a constant temperature and humidity chamber at a temperature of 30±2°C and a relative humidity of 65±5% for 18 months, and take samples for testing at the end of the 3rd, 6th, 9th, 12th and 18th month.

[0050] The results are shown in Table 4. After being placed at 30±2°C and 65±5% for 18 months, the appearance, content and pH value of the compound sulfamethoxazole sodium injection prepared in Examples 1 and 2 did not change significantly, and the inspection items such as identification, visible foreign matter and sterility all met the requirements.

[0051] Table 4 Long-term test results

[0052]

[0053]

[0054] The above stability test results show that the high-content compound sulfamethoxazole sodium injection prepared by the present invention has good stability.

[0055] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present invention.

Claims

1. Compound sulfamethoxazole sodium injection, characterized in that: Each 100 ml of injection solution contains 17-23 g of sulfamethoxazole sodium, 3.8-4.3 g of trimethoprim, 0.12-0.15 g of sodium thiosulfate, 0.24-0.28 g of sodium hydroxide, 30-50 g of polyethylene glycol-400, 10-15 g of glycerol formal, and the balance is water for injection.

2. The compound sulfamethoxazole sodium injection according to claim 1, characterized in that: Each 100 ml of injection solution contains 19 g of sulfamethoxazole sodium, 3.9 g of trimethoprim, 0.13 g of sodium thiosulfate, 0.27 g of sodium hydroxide, 40 g of polyethylene glycol-400, 11 g of glycerol formal, and the balance is water for injection.

3. The compound sulfamethoxazole sodium injection according to claim 1, characterized in that: Each 100 ml of injection solution contains 23 g of sulfamethoxazole sodium, 4.1 g of trimethoprim, 0.14 g of sodium thiosulfate, 0.28 g of sodium hydroxide, 50 g of polyethylene glycol-400, 15 g of glycerol formal, and the balance is water for injection.

4. The method for preparing the compound sulfamethoxazole sodium injection according to any one of claims 1 to 3, characterized in that: The following steps are involved: 1) Mix polyethylene glycol-400 and glycerol formal, heat to 85°C, add trimethoprim, stir to dissolve completely, stop heating, cool to below 50°C, and set aside; 2) Take part of the water for injection, adjust the temperature to 50°C, add sodium hydroxide and sodium thiosulfate, stir to dissolve completely, add sulfamethoxine sodium, stir to dissolve completely, then add the solution obtained in step 1), stir to mix, add water for injection to make up to volume, adjust the pH to 10.2-10.4 with 10% (g / ml) sodium hydroxide solution or 10% (g / ml) hydrochloric acid solution, filter, fill with nitrogen, and sterilize to obtain compound sulfamethoxine sodium injection.

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