Compound tylosin tartrate injection and preparation method thereof

Abstract

The invention discloses a compound tylosin tartrate injection. Every 100 ml of the injection contains 10 to 20 g of tylosin tartrate, 3 to 8 g of gentamicin sulfate, 0.05 to 0.2 g of dexamethasone sodium phosphate, 0.1 to 0.5 g of sodium hydrogen sulfite, 20 to 50 g of an organic solvent, 3 to 10 g of a stabilizing agent and the balance of water for injection. The compound tylosin tartrate injection provided by the invention is advanced and reasonable in prescription design, the preparation process is simple and easy to operate, and the obtained preparation is good in stability and small in irritation, can be used for treating infection caused by microorganisms sensitive to tylosin and / or gentamicin, and not only can achieve the purpose of powerful sterilization, but also can quickly relieve surface symptoms.

Description

Technical Field

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

[0002] Tylosin, also known as Tylosin and Tylosin, is a macrolide antibiotic obtained from the culture fluid of Streptomyces freundii in the United States in 1959. It is an animal-specific antibiotic that is effective against mycoplasma and most Gram-positive bacterial infections. It is mainly used to treat and prevent various respiratory, intestinal, reproductive and locomotor system infections caused by pathogens such as mycoplasma, Staphylococcus aureus, Bacillus pyogenes, Pneumococcus, Erysipelothrix, Haemophilus parahaemolyticus, Neisseria meningitidis, Pasteurella, spirochetes, cocci, etc. It has a good effect on preventing and treating secondary mycoplasma infections in livestock and poultry during viral disease outbreaks, and its effect is better than erythromycin, bethromycin and tylosin. As an animal-specific antibiotic, tylosin not only has good efficacy and low toxic side effects, but also has the functions of promoting growth and weight gain, prevention and treatment. It is favored and widely used by owners and veterinarians of pig farms, cattle farms, sheep farms and poultry farms around the world.

[0003] Gentamycin sulfate is a broad-spectrum aminoglycoside antibiotic that has a good antibacterial effect on both Gram-positive and Gram-negative bacteria. It is mainly used to prevent and treat inflammation such as enteritis, peritonitis, mastitis, and bronchopneumonia caused by bacilli and cocci.

[0004] Dexamethasone sodium phosphate is an adrenal cortex hormone drug with anti-inflammatory, anti-allergic, anti-rheumatic and immunosuppressive effects. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a compound tylosin tartrate injection, which has an advanced and reasonable prescription design, a simple and easy-to-operate preparation process, and a preparation having good stability, low irritation and good efficacy.

[0006] After research, the present invention provides the following technical solutions:

[0007] 1. Compound tylosin tartrate injection, each 100ml injection contains 10-20g tylosin tartrate, 3-8g gentamicin sulfate, 0.05-0.2g dexamethasone sodium phosphate, 0.1-0.5g sodium bisulfite, 20-50g organic solvent, 3-10g stabilizer, and the balance is water for injection.

[0008] Preferably, the organic solvent is a mixture of propylene glycol and N,N-dimethylformamide, and the weight ratio of propylene glycol to N,N-dimethylformamide is 2-5:1-4; and the stabilizer is benzyl alcohol.

[0009] As the best technical solution, each 100 ml injection contains 15 g of tylosin tartrate, 6 g of gentamicin sulfate, 0.1 g of dexamethasone sodium phosphate, 0.2 g of sodium bisulfite, 20 g of propylene glycol, 10 g of N,N-dimethylformamide, 5 g of benzyl alcohol, and the balance is water for injection.

[0010] The present invention prepares a compound preparation by combining tylosin tartrate, gentamicin sulfate and dexamethasone sodium phosphate. Tylosin tartrate mainly acts on bacterial 50S ribosomal subunits, inhibits bacterial protein synthesis by blocking transpeptidation and mRNA displacement. The mechanism of action of gentamicin sulfate is to firmly bind to specific proteins on bacterial riboprotein subunits, interfere with riboprotein function, prevent protein synthesis, and cause errors in the code on mRNA to synthesize non-functional proteins. The two have different action sites, and combined use can synergistically inhibit protein synthesis, achieve the purpose of strong bactericidal effect, and enhance the therapeutic effect. Glucocorticoid dexamethasone sodium phosphate has anti-inflammatory, anti-stress and glucose production effects, and further adding dexamethasone sodium phosphate can quickly relieve surface symptoms. Tylosin tartrate and dexamethasone sodium phosphate can also improve the blood drug concentration of dexamethasone when used in combination. The compound tylosin tartrate injection of the present invention can be used to treat infections caused by microorganisms sensitive to tylosin and / or gentamicin, such as respiratory tract infections (pneumonia, bronchopneumonia), mastitis, foot rot, erysipelas, endometritis, arthritis, general gastrointestinal infections, etc.

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

[0012] 1) Propylene glycol, N,N-dimethylformamide and benzyl alcohol are mixed uniformly;

[0013] 2) dissolving sodium bisulfite in part of the water for injection, adding tylosin tartrate, stirring to dissolve, adding the solution obtained in step 1), stirring evenly, to obtain a mixed solution;

[0014] 3) Add gentamicin sulfate to part of the water for injection and stir to dissolve;

[0015] 4) Add dexamethasone sodium phosphate to part of the water for injection and stir to dissolve;

[0016] 5) Add the solution obtained in step 3) and step 4) to the mixed solution obtained in step 2), stir evenly, adjust the pH to 4.5-6.5 with 20% (g / ml) NaOH solution or 10% (g / ml) HCl solution, make up to volume with water for injection, filter, fill with nitrogen, and sterilize to obtain the compound tylosin tartrate injection.

[0017] The beneficial effects of the present invention are as follows: the present invention provides a compound tylosin tartrate injection, the prescription design is advanced and reasonable, the preparation process is simple and easy to operate, the obtained preparation has good stability and low irritation, and can be used to treat infections caused by microorganisms sensitive to tylosin and / or gentamicin, which can not only achieve the purpose of strong bactericidal effect, but also can quickly relieve surface symptoms. DETAILED DESCRIPTION

[0018] 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.

[0019] Example 1 Preparation of compound tylosin tartrate injection

[0020] Each 100 ml of compound tylosin tartrate injection contains 15 g of tylosin tartrate, 6 g of gentamicin sulfate, 0.1 g of dexamethasone sodium phosphate, 0.2 g of sodium bisulfite, 20 g of propylene glycol, 10 g of N,N-dimethylformamide, 5 g of benzyl alcohol, and the balance is water for injection.

[0021] The preparation method of compound tylosin tartrate injection comprises the following steps:

[0022] 1) Propylene glycol, N,N-dimethylformamide and benzyl alcohol are mixed uniformly;

[0023] 2) dissolving sodium bisulfite in part of the water for injection, adding tylosin tartrate, stirring to dissolve, adding the solution obtained in step 1), stirring evenly, to obtain a mixed solution;

[0024] 3) Add gentamicin sulfate to part of the water for injection and stir to dissolve;

[0025] 4) Add dexamethasone sodium phosphate to part of the water for injection and stir to dissolve;

[0026] 5) Add the solution obtained in step 3) and step 4) to the mixed solution obtained in step 2), stir evenly, adjust the pH to 4.5-6.5 with 20% (g / ml) NaOH solution or 10% (g / ml) HCl solution, make up to volume with water for injection, filter with a microporous filter membrane with a pore size of 0.45 μm, fill with nitrogen and seal, sterilize at 121° C. for 20 minutes to obtain the compound tylosin tartrate injection.

[0027] Example 2 Preparation of compound tylosin tartrate injection

[0028] Each 100 ml of compound tylosin tartrate injection contains 10 g of tylosin tartrate, 4 g of gentamicin sulfate, 0.06 g of dexamethasone sodium phosphate, 0.1 g of sodium bisulfite, 15 g of propylene glycol, 9 g of N,N-dimethylformamide, 3 g of benzyl alcohol, and the balance is water for injection.

[0029] The preparation method of compound tylosin tartrate injection is the same as that of Example 1.

[0030] Example 3 Preparation of Compound Tylosin Tartrate Injection

[0031] Each 100 ml of compound tylosin tartrate injection contains 20 g of tylosin tartrate, 8 g of gentamicin sulfate, 0.15 g of dexamethasone sodium phosphate, 0.3 g of sodium bisulfite, 30 g of propylene glycol, 20 g of N,N-dimethylformamide, 10 g of benzyl alcohol, and the balance is water for injection.

[0032] The preparation method of compound tylosin tartrate injection is the same as that of Example 1.

[0033] Example 4 Stability Study of Compound Tylosin Tartrate Injection

[0034] According to the "Guidelines for Stability Testing of Veterinary Drugs", the stability of the compound tylosin tartrate injection prepared in Examples 1, 2, and 3 was investigated.

[0035] 1. High temperature test

[0036] The compound tylosin tartrate injection was placed in a forced air drying oven at 60°C for 10 days, and samples were taken for testing on the 10th day.

[0037] The results are shown in Table 1. After being placed at 60° C. for 10 days, except that the color of the compound tylosin tartrate injection prepared in Example 3 was slightly darkened, the pH value and content of the compound tylosin tartrate injection prepared in Examples 1, 2, and 3 did not change significantly.

[0038] Table 1 High temperature test results

[0039]

[0040]

[0041] 2. Accelerated testing

[0042] The compound tylosin tartrate injection was placed 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 samples were taken for testing at the end of the 1st, 2nd, 3rd and 6th month.

[0043] The results are shown in Table 2. After being placed at 40±2°C and 75±5% for 6 months, the properties, pH value and content of the compound tylosin tartrate injection prepared in Examples 1, 2 and 3 did not change significantly.

[0044] Table 2 Accelerated test results

[0045]

[0046] 3. Long-term trials

[0047] The compound tylosin tartrate injection was placed 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 samples were taken for testing at the end of the 3rd, 6th, 9th, 12th and 18th months.

[0048] The results are shown in Table 3. After being placed at 30±2°C and 65±5% for 18 months, the properties, pH value and content of the compound tylosin tartrate injection prepared in Examples 1, 2 and 3 did not change significantly, indicating that the compound tylosin tartrate injection prepared in the present invention has good stability.

[0049] Table 3 Long-term test results

[0050]

[0051] Example 5 Investigation of muscle irritation of compound tylosin tartrate injection

[0052] According to the "Guidelines for Chemical Drug Irritant, Allergic and Hemolytic Effects", 9 rabbits weighing 2.5-3.5kg were selected and divided into 3 groups, 3 in each group, and fed for two weeks before the experiment to confirm that the rabbits were in good health and had no skin diseases, and were weighed and numbered. Using the self-left and right control method, the three groups of rabbits were injected with the compound tylosin tartrate injection prepared in Examples 1, 2, and 3 at the right thigh quadriceps, respectively, with an injection dose of 0.2ml / (kg bw); the same dose of normal saline was injected at the same site on the other side of the rabbit. After 48 hours of administration, the rabbits were killed, the skin was peeled off to expose the quadriceps, and the quadriceps were cut longitudinally to observe whether the injection site muscles had congestion, edema, deformation or necrosis and other irritation reactions, and the reaction level was obtained according to the muscle irritation reaction grading standard in Table 4, and the average score was calculated, and the irritation level was determined according to Table 5.

[0053] The results are shown in Table 6. Most rabbits had slight congestion at the injection site, and the congestion diameter was less than 0.5×1.0 cm. One rabbit in Example 3 had moderate congestion, and no mass or necrosis was found in all rabbits. The average scores of the compound tylosin tartrate injections prepared in Examples 1, 2, and 3 were 0.67, 1, and 1.33, respectively, and the irritation level was "mild". The injection obtained in Example 1 had the least irritation. This shows that the compound tylosin tartrate injection prepared by the present invention can be used for intramuscular injection.

[0054] Table 4 Classification criteria for muscle stimulation response

[0055] Stimulus Response Reaction level No significant changes 0 Mild congestion, less than 0.5 × 1.0 cm 1 Moderate congestion, with an area of ​​0.5 × 1.0 cm or more 2 Severe congestion with muscle degeneration 3 Necrosis and brown degeneration 4 Extensive necrosis 5

[0056] Table 5 Average scores and irritation levels

[0057] Average score Irritation level 0.0～0.4 none 0.5～1.4 slight 1.5～2.4 Mild 2.5～3.4 Moderate 3.5～4.4 Severe 4.5 and above serious

[0058] Note: Levels below mild can be used for injection; if the difference between the highest and lowest quadriceps muscle reaction levels is greater than 2, another animal should be used for re-testing.

[0059] Table 6 Results of irritation test on compound tylosin tartrate injection in rabbits

[0060]

[0061]

[0062] The above stability and irritation test data show that the compound tylosin tartrate injection prepared by the present invention has good stability, low irritation to the injection site, and can be used for intramuscular injection.

[0063] 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 tylosin tartrate injection, characterized in that: Each 100 ml of injection solution contains 10-20 g of tylosin tartrate, 3-8 g of gentamicin sulfate, 0.05-0.2 g of dexamethasone sodium phosphate, 0.1-0.5 g of sodium bisulfite, 20-50 g of organic solvent, 3-10 g of stabilizer, and the balance is water for injection.

2. The compound tylosin tartrate injection according to claim 1, characterized in that: The organic solvent is a mixture of propylene glycol and N,N-dimethylformamide, and the weight ratio of the propylene glycol to the N,N-dimethylformamide is 2-5:1-4; and the stabilizer is benzyl alcohol.

3. The compound tylosin tartrate injection according to claim 2, characterized in that: Each 100 ml of injection contains 15 g of tylosin tartrate, 6 g of gentamicin sulfate, 0.1 g of dexamethasone sodium phosphate, 0.2 g of sodium bisulfite, 20 g of propylene glycol, 10 g of N,N-dimethylformamide, 5 g of benzyl alcohol, and the balance is water for injection.

4. The method for preparing the compound tylosin tartrate injection according to any one of claims 1 to 3, characterized in that: The following steps are involved: 1) Propylene glycol, N,N-dimethylformamide and benzyl alcohol are mixed uniformly; 2) dissolving sodium bisulfite in part of the water for injection, adding tylosin tartrate, stirring to dissolve, adding the solution obtained in step 1), stirring evenly, to obtain a mixed solution; 3) Add gentamicin sulfate to part of the water for injection and stir to dissolve; 4) Add dexamethasone sodium phosphate to part of the water for injection and stir to dissolve; 5) Add the solution obtained in step 3) and step 4) to the mixed solution obtained in step 2), stir evenly, adjust the pH to 4.5-6.5 with 20% (g / ml) NaOH solution or 10% (g / ml) HCl solution, make up to volume with water for injection, filter, fill with nitrogen, and sterilize to obtain the compound tylosin tartrate injection.

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