Oxytetracycline injection and preparation method thereof

Abstract

The invention discloses an oxytetracycline injection and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the oxytetracycline is firstly micronized, then sprayed with water, frozen, heated and dried, soaked in a solution containing a surfactant, taken out and dried, and pretreated oxytetracycline is obtained; s2, water for injection is taken and heated, an antioxidant is added for dissolution, then a complexing agent is added, stirring is performed for dissolution, and a first solution is obtained; adding an organic solvent into the first solution, heating, adding the pretreated oxytetracycline, stirring and dissolving to obtain a second solution; adding a stabilizer into the second solution, and adjusting the pH value; and then supplementing the water for injection to obtain the injection. The oxytetracycline raw medicine powder is micronized to a specific particle size range, then freeze drying is performed to make the oxytetracycline raw medicine powder loose and porous, and compatibilization of the surfactant is further combined, so that the solubility and the stability of the oxytetracycline raw medicine powder are greatly improved in the subsequent injection preparation process.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to oxytetracycline injection and a preparation method thereof. Background Art

[0002] Oxytetracycline is a broad-spectrum tetracycline antibiotic that has good efficacy against infections caused by Gram-positive bacteria, Gram-negative bacteria, mycoplasma, chlamydia, rickettsia, etc. Oxytetracycline is slightly soluble in water, soluble in methanol, ethanol and propanedione, and relatively stable in the air, but it tends to turn darker when exposed to light. Whether under acidic or alkaline conditions, its preparations are prone to darkening, precipitation and decreased potency when heated or stored for a long time. This is because its aqueous solution undergoes isomerization, dehydration, hydrolysis and oxidation reactions under different conditions. In an acidic environment, the hydroxyl group on C6 and the hydrogen on C5 undergo a trans-elimination reaction to produce an orange-yellow dehydrate; in an alkaline environment, an isomer of the lactone structure is formed, which turns dark or black. Therefore, oxytetracycline injection is unstable and needs to be improved. Summary of the invention

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

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

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

[0006] S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant, take out and dry, to obtain pretreated oxytetracycline;

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

[0008] S3: adding an organic solvent to the first solution, heating to 50-70° C., adding pretreated oxytetracycline, stirring to dissolve, to obtain a 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 100 ml, and then coarsely filter and finely filter the obtained drug crystal, fill with nitrogen and seal in a brown bottle to obtain an injection solution.

[0010] Preferably, the micronization treatment is specifically: crushing the oxytetracycline powder at 3-8°C to a particle size D90 of less than 8 μm and a particle size D50 of 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 sorbitan fatty acids, 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 is introduced into the mixture so that its dissolved oxygen content does not exceed 0.5 ppm; and pretreated oxytetracycline is added under conditions of continuous nitrogen filling and stirring.

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

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

[0019] The beneficial effects of the present invention are as follows: the present invention micronizes the oxytetracycline technical powder to a specific particle size range, and then freeze-dries it to make it loose and porous, and further combines the volume expansion of a surfactant, so that the solubility and stability of the subsequent injection are greatly improved; furthermore, the present invention adopts a mixed solvent of α-pyrrolidone and dimethylacetamide, which has less irritation on the one hand, and on the other hand, the complexation with oxytetracycline improves the stability of the injection; in addition, the use of an antioxidant and a nitrogen atmosphere to reduce the oxygen content greatly improves the stability of the injection, so that the color of the injection remains amber for a long time. DETAILED DESCRIPTION

[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. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0021] Example 1

[0022] S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant at a concentration of 20wt%, take out and dry, to obtain pretreated oxytetracycline;

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

[0024] S3: Add 30 g of organic solvent to the first solution, heat to 60° C., introduce nitrogen gas into the first solution so that the dissolved oxygen content does not exceed 0.5 ppm; add 18 g of pretreated oxytetracycline under continuous nitrogen filling and stirring, stir and dissolve to obtain 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, and then coarsely filter and finely filter the obtained drug liquid crystal, fill it with nitrogen and seal it in a brown bottle to obtain an injection solution.

[0026] The micronization treatment specifically includes: crushing the oxytetracycline powder at 5°C until the particle size D90 is less than 8 μm and the 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 solvent comprises α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0031] The stabilizer is ethanolamine.

[0032] Example 2

[0033] S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant at a concentration of 25wt%, take out and dry, to obtain pretreated oxytetracycline;

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

[0035] S3: Add 30 g of organic solvent to the first solution, heat to 60° C., introduce nitrogen gas into the first solution so that the dissolved oxygen content does not exceed 0.5 ppm; add 18 g of pretreated oxytetracycline under continuous nitrogen filling and stirring, stir and dissolve to obtain 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, and then coarsely filter and finely filter the obtained drug liquid crystal, fill it with nitrogen and seal it in a brown bottle to obtain an injection solution.

[0037] The micronization treatment specifically includes: crushing the oxytetracycline powder at 5°C until the particle size D90 is less than 8 μm and the 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 solvent comprises α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0042] The stabilizer is ethanolamine.

[0043] Example 3

[0044] S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant at a concentration of 30wt%, take out and dry, to obtain pretreated oxytetracycline;

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

[0046] S3: Add 30 g of organic solvent to the first solution, heat to 60° C., introduce nitrogen gas into the first solution so that the dissolved oxygen content does not exceed 0.5 ppm; add 18 g of pretreated oxytetracycline under continuous nitrogen filling and stirring, stir and dissolve to obtain 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, and then coarsely filter and finely filter the obtained drug liquid crystal, fill it with nitrogen and seal it in a brown bottle to obtain an injection solution.

[0048] The micronization treatment specifically includes: crushing the oxytetracycline powder at 5°C until the particle size D90 is less than 8 μm and the 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 solvent comprises α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0053] The stabilizer is ethanolamine.

[0054] Example 4

[0055] S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant at a concentration of 25wt%, take out and dry, to obtain pretreated oxytetracycline;

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

[0057] S3: Add 30 g of organic solvent to the first solution, heat to 60° C., introduce nitrogen gas into the first solution so that the dissolved oxygen content does not exceed 0.5 ppm; add 18 g of pretreated oxytetracycline under continuous nitrogen filling and stirring, stir and dissolve to obtain 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, and then coarsely filter and finely filter the obtained drug liquid crystal, fill it with nitrogen and seal it in a brown bottle to obtain an injection solution.

[0059] The micronization treatment specifically includes: crushing the oxytetracycline powder at 8° C. until the particle size D90 is less than 8 μm and the 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 solvent comprises α-pyrrolidone and dimethylacetamide in a mass ratio of 1:1.

[0064] The stabilizer is ethanolamine.

[0065] Example 5

[0066] S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant at a concentration of 20wt%, take out and dry, to obtain pretreated oxytetracycline;

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

[0068] S3: Add 30 g of organic solvent to the first solution, heat to 60° C., introduce nitrogen gas into the first solution so that the dissolved oxygen content does not exceed 0.5 ppm; add 18 g of pretreated oxytetracycline under continuous nitrogen filling and stirring, stir and dissolve to obtain 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, and then coarsely filter and finely filter the obtained drug liquid crystal, fill it with nitrogen and seal it in a brown bottle to obtain an injection solution.

[0070] The micronization treatment specifically includes: crushing the oxytetracycline powder at 5°C until the particle size D90 is less than 8 μm and the 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 solvent comprises α-pyrrolidone and dimethylacetamide in a mass ratio of 1:3.

[0075] The stabilizer is ethanolamine.

[0076] Comparative Example 1

[0077] Different from Example 2, oxytetracycline was not pretreated.

[0078] Comparative Example 2

[0079] Different from Example 2, the sample was not immersed in a solution containing a surfactant.

[0080] Comparative Example 3

[0081] The difference from Example 2 is that in step S3, no nitrogen is introduced for stirring.

[0082] The above embodiments and comparative examples were subjected to performance tests, and the test results are shown in Table 1.

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

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

[0085]

[0086]

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

[0088] From the analysis of Comparative Examples 1 and 2, it can be seen 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 combining it with the volume expansion of a surfactant, its solubility and stability are greatly improved when the injection is subsequently prepared; furthermore, the present invention adopts a mixed solvent of α-pyrrolidone and dimethylacetamide, which on the one hand has less irritation, and on the other hand, it complexes with oxytetracycline to improve the stability of the injection; the analysis of Comparative Example 3 also uses an antioxidant and a nitrogen atmosphere to reduce the oxygen content, which greatly improves the stability of the injection and keeps its color amber for a long time.

[0089] The above-mentioned embodiments only express the preferred implementation modes of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, various other corresponding changes and deformations can be made according to the technical solutions and concepts described above, and all these changes and deformations should fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing oxytetracycline injection, characterized in that: The following steps are involved: S1: firstly micronize oxytetracycline, then spray water, freeze, heat and dry, immerse in a solution containing a surfactant, take out and dry, to obtain pretreated oxytetracycline; S2: Take water for injection, heat it to 55-65°C, add antioxidant to dissolve, then add complexing agent, stir and dissolve to obtain the first solution; S3: adding an organic solvent to the first solution, heating to 50-70° C., adding pretreated oxytetracycline, stirring to dissolve, to obtain a 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 100 ml, and then coarsely filter and finely filter the obtained drug crystal, fill with nitrogen and seal in a brown bottle to obtain an injection solution.

2. The method for preparing oxytetracycline injection according to claim 1, characterized in that: The micronization treatment specifically includes: crushing the oxytetracycline powder at 3-8°C until the particle size D90 is less than 8 μm and the D50 is less than 4 μm.

3. The method for preparing oxytetracycline injection according to claim 1, characterized in that: The concentration of the solution containing the surfactant is 20-30 wt %.

4. The method for preparing oxytetracycline injection according to claim 1, characterized in that: The surfactant is one of fatty acid sorbitan, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether and poloxamer.

5. 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.

6. The method for preparing oxytetracycline injection according to claim 1, characterized in that: In step S3, the organic solvent is α-pyrrolidone and dimethylacetamide.

7. The method for preparing oxytetracycline injection according to claim 1, characterized in that: In step S3, nitrogen is introduced into the mixture so that the dissolved oxygen content does not exceed 0.5 ppm; and pretreated oxytetracycline is added under conditions of continuous nitrogen filling and stirring.

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

9. A oxytetracycline injection, characterized in that: The method is prepared by any one of claims 1 to 8.

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