Oxytetracycline Injection and its Preparation Method

Abstract

This invention discloses an oxytetracycline injection and its preparation method, relating to the field of pharmaceutical formulation technology. First, oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, and then immersed in a solution containing a surfactant. After drying, pretreated oxytetracycline is obtained. S2: Water for injection is heated, an antioxidant is added to dissolve it, and then a complexing agent is added and stirred to dissolve, forming a first solution. An organic solvent is added to the first solution, heated, and the pretreated oxytetracycline is added and stirred to dissolve, forming a second solution. A stabilizer is added to the second solution, and the pH is adjusted. Then, water for injection is added to obtain the injection solution. This invention, by micronizing the oxytetracycline technical powder to a specific particle size range and then freeze-drying it to make it loose and porous, combined with the solubilization effect of surfactants, significantly improves the solubility and stability of the subsequent injection solution preparation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to an oxytetracycline injection and its preparation method. Background Technology

[0002] Oxytetracycline is a tetracycline broad-spectrum antibiotic, effective against infections caused by Gram-positive bacteria, Gram-negative bacteria, mycoplasma, chlamydia, and rickettsia. Oxytetracycline is slightly soluble in water but soluble in methanol, ethanol, and propylene glycol. It is relatively stable in air, but its color darkens easily upon exposure to light. Regardless of acidic or alkaline conditions, its preparations tend to darken in color, precipitate, and decrease in potency upon heating or prolonged storage. This is due to isomerization, dehydration, hydrolysis, and oxidation reactions occurring in its aqueous solution under different conditions. In acidic environments, the hydroxyl group at C6 reacts with the hydrogen at C5 in a trans-elimination reaction, producing an orange-yellow dehydrated product; in alkaline environments, it forms an isomer with a lactone structure, turning dark black or black. Therefore, oxytetracycline injection is unstable and requires improvement. Summary of the Invention

[0003] The purpose of this invention is to at least solve one of the technical problems existing in the prior art, and to provide an oxytetracycline injection and its preparation method.

[0004] The technical solution of the present invention is as follows:

[0005] A method for preparing oxytetracycline injection includes the following steps:

[0006] S1: First, the oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, immersed in a solution containing surfactant, removed and dried to obtain pretreated oxytetracycline;

[0007] S2: Take water for injection, heat it to 55-65℃, add the antioxidant to dissolve it, then add the complexing agent, stir to dissolve, and this is the first solution;

[0008] S3: Add an organic solvent to the first solution, heat to 50-70℃, add pretreated oxytetracycline, stir to dissolve, and obtain the second solution;

[0009] S4: Add a stabilizer to the second solution and adjust the pH to 8.0-9.0; then add water for injection to 100ml, then filter the obtained drug solution coarsely and finely, fill with nitrogen and seal in a brown bottle to obtain the injection solution.

[0010] Preferably, the micronization process specifically involves pulverizing oxytetracycline powder at 3-8°C until its particle size D90 is less than 8 μm and D50 is less than 4 μm.

[0011] Preferably, the concentration of the solution containing the surfactant is 20-30 wt%.

[0012] Preferably, the surfactant is one of fatty acid sorbitan derivatives, polysorbates, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, and poloxamer.

[0013] Preferably, in step S2, the antioxidant is sodium formaldehyde sulfoxylate;

[0014] The complexing agent is magnesium chloride or magnesium oxide.

[0015] Preferably, in step S3, the organic solvent is α-pyrrolidone and / or dimethylacetamide.

[0016] Preferably, in step S3, nitrogen gas is introduced into the mixture so that the dissolved oxygen content does not exceed 0.5 ppm; pretreated oxytetracycline is added under conditions of continuous nitrogen purging and stirring.

[0017] Preferably, in step S4, the stabilizer is ethanolamine.

[0018] The present invention also discloses an oxytetracycline injection solution, which is prepared by any of the preparation methods described above.

[0019] The beneficial effects of this invention are as follows: By micronizing the oxytetracycline technical powder to a specific particle size range and then freeze-drying it to make it loose and porous, and further combining it with the solubility enhancement of surfactants, the solubility and stability of the injection solution are greatly improved in the subsequent preparation. Furthermore, this invention uses a mixed solvent of α-pyrrolidone and dimethylacetamide, which has less irritation and, on the other hand, complexes with oxytetracycline, improving the stability of the injection solution. In addition, the use of antioxidants and a nitrogen atmosphere to reduce oxygen content greatly improves the stability of the injection solution, allowing it to maintain its amber color for a long time. Detailed Implementation

[0020] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0021] Example 1

[0022] S1: First, oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, then immersed in a 20wt% solution containing surfactant, then removed and dried to obtain pretreated oxytetracycline;

[0023] S2: Take water for injection, heat it to 60°C, add 8g of antioxidant to dissolve it, then add 10g of complexing agent, stir to dissolve, and this is the first solution;

[0024] S3: Add 30g of organic solvent to the first solution, heat to 60℃, and purge with nitrogen gas to ensure that the dissolved oxygen content does not exceed 0.5ppm; under continuous nitrogen purging and stirring, add 18g of pretreated oxytetracycline, stir to dissolve, and this is the second solution;

[0025] S4: Add 8g of stabilizer to the second solution and adjust the pH to 8.2-8.7; then add water for injection to 100ml, then filter the obtained drug solution coarsely and finely, fill with nitrogen and seal in a brown bottle to obtain the injection solution.

[0026] The micronization process specifically involves pulverizing oxytetracycline powder at 5°C until its particle size D90 is less than 8 μm and D50 is less than 4 μm.

[0027] The surfactant is Tween 80.

[0028] The antioxidant is sodium formaldehyde sulfoxylate.

[0029] The complexing agent is magnesium chloride.

[0030] The organic solvents are α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0031] The stabilizer is ethanolamine.

[0032] Example 2

[0033] S1: First, oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, then immersed in a 25wt% solution containing surfactant, then removed and dried to obtain pretreated oxytetracycline;

[0034] S2: Take water for injection, heat it to 60°C, add 8g of antioxidant to dissolve it, then add 10g of complexing agent, stir to dissolve, and this is the first solution;

[0035] S3: Add 30g of organic solvent to the first solution, heat to 60℃, and purge with nitrogen gas to ensure that the dissolved oxygen content does not exceed 0.5ppm; under continuous nitrogen purging and stirring, add 18g of pretreated oxytetracycline, stir to dissolve, and this is the second solution;

[0036] S4: Add 8g of stabilizer to the second solution and adjust the pH to 8.2-8.7; then add water for injection to 100ml, then filter the obtained drug solution coarsely and finely, fill with nitrogen and seal in a brown bottle to obtain the injection solution.

[0037] The micronization process specifically involves pulverizing oxytetracycline powder at 5°C until its particle size D90 is less than 8 μm and D50 is less than 4 μm.

[0038] The surfactant is Tween 80.

[0039] The antioxidant is sodium formaldehyde sulfoxylate.

[0040] The complexing agent is magnesium chloride.

[0041] The organic solvents are α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0042] The stabilizer is ethanolamine.

[0043] Example 3

[0044] S1: First, oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, then immersed in a 30wt% solution containing surfactant, then removed and dried to obtain pretreated oxytetracycline;

[0045] S2: Take water for injection, heat it to 60°C, add 8g of antioxidant to dissolve it, then add 10g of complexing agent, stir to dissolve, and this is the first solution;

[0046] S3: Add 30g of organic solvent to the first solution, heat to 60℃, and purge with nitrogen gas to ensure that the dissolved oxygen content does not exceed 0.5ppm; under continuous nitrogen purging and stirring, add 18g of pretreated oxytetracycline, stir to dissolve, and this is the second solution;

[0047] S4: Add 8g of stabilizer to the second solution and adjust the pH to 8.2-8.7; then add water for injection to 100ml, then filter the obtained drug solution coarsely and finely, fill with nitrogen and seal in a brown bottle to obtain the injection solution.

[0048] The micronization process specifically involves pulverizing oxytetracycline powder at 5°C until its particle size D90 is less than 8 μm and D50 is less than 4 μm.

[0049] The surfactant is Tween 80.

[0050] The antioxidant is sodium formaldehyde sulfoxylate.

[0051] The complexing agent is magnesium chloride.

[0052] The organic solvents are α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0053] The stabilizer is ethanolamine.

[0054] Example 4

[0055] S1: First, oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, then immersed in a 25wt% solution containing surfactant, then removed and dried to obtain pretreated oxytetracycline;

[0056] S2: Take water for injection, heat it to 60°C, add 8g of antioxidant to dissolve it, then add 10g of complexing agent, stir to dissolve, and this is the first solution;

[0057] S3: Add 30g of organic solvent to the first solution, heat to 60℃, and purge with nitrogen gas to ensure that the dissolved oxygen content does not exceed 0.5ppm; under continuous nitrogen purging and stirring, add 18g of pretreated oxytetracycline, stir to dissolve, and this is the second solution;

[0058] S4: Add 8g of stabilizer to the second solution and adjust the pH to 8.2-8.7; then add water for injection to 100ml, then filter the obtained drug solution coarsely and finely, fill with nitrogen and seal in a brown bottle to obtain the injection solution.

[0059] The micronization process specifically involves pulverizing oxytetracycline powder at 8°C until its particle size D90 is less than 8 μm and D50 is less than 4 μm.

[0060] The surfactant is Tween 80.

[0061] The antioxidant is sodium formaldehyde sulfoxylate.

[0062] The complexing agent is magnesium chloride.

[0063] The organic solvents are α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0064] The stabilizer is ethanolamine.

[0065] Example 5

[0066] S1: First, oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, then immersed in a 20wt% solution containing surfactant, then removed and dried to obtain pretreated oxytetracycline;

[0067] S2: Take water for injection, heat it to 60°C, add 8g of antioxidant to dissolve it, then add 10g of complexing agent, stir to dissolve, and this is the first solution;

[0068] S3: Add 30g of organic solvent to the first solution, heat to 60℃, and purge with nitrogen gas to ensure that the dissolved oxygen content does not exceed 0.5ppm; under continuous nitrogen purging and stirring, add 18g of pretreated oxytetracycline, stir to dissolve, and this is the second solution;

[0069] S4: Add 8g of stabilizer to the second solution and adjust the pH to 8.2-8.7; then add water for injection to 100ml, then filter the obtained drug solution coarsely and finely, fill with nitrogen and seal in a brown bottle to obtain the injection solution.

[0070] The micronization process specifically involves pulverizing oxytetracycline powder at 5°C until its particle size D90 is less than 8 μm and D50 is less than 4 μm.

[0071] The surfactant is Tween 80.

[0072] The antioxidant is sodium formaldehyde sulfoxylate.

[0073] The complexing agent is magnesium chloride.

[0074] The organic solvents are α-pyrrolidone and dimethylacetamide in a mass ratio of 1:3.

[0075] The stabilizer is ethanolamine.

[0076] Comparative Example 1

[0077] Unlike Example 2, no oxytetracycline was pretreated.

[0078] Comparative Example 2

[0079] Unlike Example 2, it was not immersed in a solution containing surfactant.

[0080] Comparative Example 3

[0081] Unlike Example 2, nitrogen gas was not introduced for stirring in step S3.

[0082] Performance tests were conducted on the above embodiments and comparative examples, and the test results are shown in Table 1.

[0083] Stability test method: The compound oxytetracycline injection obtained in the example was placed at a temperature of 60℃±2℃ and a relative humidity of 75%±5% for 15 days. The required equipment should be able to control the temperature ±2℃ and relative humidity ±5%, and be able to detect the actual temperature and humidity. Samples were taken on days 0, 5, 10, and 15 during the test period, and the change rate of oxytetracycline content on days 5, 10, and 15 compared to day 0 was measured. The change rate = (m... n -m0) / m0*100%.

[0084] Table 1. Performance test results of the examples and comparative examples.

[0085]

[0086]

[0087] As can be seen from the table above, the performance of the embodiment is better than that of the comparative example. The main reasons may be as follows:

[0088] Analysis of Comparative Examples 1 and 2 shows that by micronizing the oxytetracycline technical powder to a specific particle size range and then freeze-drying it to make it loose and porous, and further combined with the solubilization of surfactants, its solubility and stability are greatly improved when it is subsequently formulated into an injection solution. Furthermore, the present invention uses a mixed solvent of α-pyrrolidone and dimethylacetamide, which has less irritation and, on the other hand, improves the stability of the injection solution by complexing it with oxytetracycline. Analysis of Comparative Example 3 shows that the use of antioxidants and the use of a nitrogen atmosphere to reduce oxygen content further improves the stability of the injection solution and allows it to maintain its amber color for a long time.

[0089] The embodiments described above are merely preferred embodiments of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various other corresponding changes and modifications based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing oxytetracycline injection, characterized in that, Includes the following steps: S1: First, the oxytetracycline is micronized, then sprayed with water, frozen, heated and dried, immersed in a solution containing surfactant, removed and dried to obtain pretreated oxytetracycline; The micronization process specifically involves pulverizing oxytetracycline powder at 3-8°C until its particle size D90 is less than 8μm and D50 is less than 4μm. The concentration of the surfactant-containing solution is 20-30 wt%; S2: Take water for injection, heat it to 55-65℃, add the antioxidant to dissolve it, then add the complexing agent, stir to dissolve, and this is the first solution; S3: Add an organic solvent to the first solution, heat to 50-70℃, add pretreated oxytetracycline, stir to dissolve, and obtain the second solution; S4: Add a stabilizer to the second solution and adjust the pH to 8.0-9.0; then add water for injection to 100ml, then filter the obtained drug through coarse and fine filtration, fill with nitrogen and seal in a brown bottle to obtain the injection solution; The surfactant is a polysorbate; In step S3, the organic solvent is α-pyrrolidone and dimethylacetamide; In step S3, nitrogen gas is introduced into the mixture so that the dissolved oxygen content does not exceed 0.5 ppm; pretreated oxytetracycline is added under conditions of continuous nitrogen purging and stirring.

2. The method for preparing oxytetracycline injection according to claim 1, characterized in that, In step S2, the antioxidant is sodium formaldehyde sulfoxylate; The complexing agent is magnesium chloride or magnesium oxide.

3. The method for preparing oxytetracycline injection according to claim 1, characterized in that, In step S4, the stabilizer is ethanolamine.

4. An oxytetracycline injection solution, characterized in that, It is prepared by any one of the preparation methods described in claims 1-3.

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