CN110693826A - Long-acting oxytetracycline injection for livestock and preparation method thereof - Google Patents
Long-acting oxytetracycline injection for livestock and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a veterinary long-acting oxytetracycline injection and a preparation method thereof, wherein the veterinary long-acting oxytetracycline injection contains oxytetracycline dihydrate, magnesium oxide, sodium formaldehyde sulfoxylate, glycerol methylal, polyvinylpyrrolidone K12, polyethylene glycol-400, monoethanolamine and water for injection. The veterinary long-acting terramycin injection provided by the invention adopts the combined action of low-impurity-content and high-purity terramycin dihydrate, sodium formaldehyde sulfoxylate, magnesium oxide and glycerol methylal to improve the stability of the injection and prolong the storage time of the injection. After intramuscular injection, the peak value of blood concentration can be reached in a short time by adopting the polyethylene glycol-400, so that intramuscular injection is easier. By adopting polyvinylpyrrolidone K12, the medicine is slowly released, the action time of the medicine is prolonged, the injection interval time is prolonged, the injection dosage is reduced, and the stress response of animals is reduced.
Description
Technical Field
The invention relates to a preparation for veterinary injection, in particular to a long-acting oxytetracycline injection for veterinary use and a preparation method thereof.
Background
Terramycin is a broad-spectrum antibiotic of tetracycline, which not only has inhibitory action on gram-positive bacteria and gram-negative bacteria, but also has inhibitory action on pick, mycoplasma, chlamydia, spirochete, actinomycetes and some protozoa. Has strong effect on gram-positive bacteria such as staphylococcus, hemolytic streptococcus, bacillus anthracis, clostridium tetani, clostridium clostridia and the like, and is sensitive to gram-negative bacteria such as escherichia coli, salmonella, brucella, pasteurella and the like. The oxytetracycline injection is originally developed and researched by the pharmaceutical company of the pfeizu america, and the veterinary oxytetracycline injection with two specifications of 10% and 20% is also approved by the department of agriculture in 2013, but has many problems in the practical application process.
The inventor finds that the oxytetracycline injection in the prior art has at least the following problems in experiments and experimental processes, and the oxytetracycline injection in the prior art has high viscosity at low temperature, so that the filtration and sterilization process in the production link cannot be smoothly carried out, and the injection is difficult in clinical use. Under the condition of high temperature, the effective components in the oxytetracycline injection are unstable, ring-opening cracking is easy to occur, and the active components are irreversibly damaged. In addition, the oxytetracycline injection has the problem of low effective content, so that the action time of the medicine is short, multiple injections and large-amount administration are needed, the animal stress is caused, the death of the animal is possibly caused, and irreparable loss is caused to farmers.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a long-acting oxytetracycline injection for animals. The injection has high quality stability, prolongs the storage time of the injection, effectively solves the problem that the effective content is reduced because the injection is easy to discolor and precipitate after long-term storage, and has quick absorption after intramuscular injection and slow release of active pharmaceutical ingredients in animal bodies, thereby achieving the purpose of long-acting, reducing the administration times and lowering the production cost of farmers.
Aiming at the defects in the prior art, the second purpose of the invention is to provide a preparation method of the veterinary long-acting oxytetracycline injection. The method has scientific design and simple operation, and is suitable for industrial large-scale production.
In order to achieve the above purpose, the solution adopted by the invention is as follows:
the long-acting oxytetracycline injection for the livestock comprises 11-32g of oxytetracycline dihydrate, 1.5-1.9g of magnesium oxide, 0.4-0.8g of sodium formaldehyde sulfoxylate, 20-40g of glycerol methylal, 1-5g of polyvinylpyrrolidone K12(PVP K12), 20-40g of polyethylene glycol-400 (PEG-400), 1.2-1.8g of monoethanolamine and the balance of water for injection, wherein each 100ml of the long-acting oxytetracycline injection for the livestock contains the oxytetracycline dihydrate, the magnesium oxide, the sodium formaldehyde sulfoxylate and the polyethylene glycol-400.
The veterinary long-acting oxytetracycline injection disclosed by the invention further preferably comprises the following components in proportion: the injection comprises the following components in each 100 ml: 22g of oxytetracycline dihydrate, 1.7g of magnesium oxide, 0.5g of sodium formaldehyde sulfoxylate, 30g of glycerol formal, K122 g of polyvinylpyrrolidone, 20g of polyethylene glycol-40020 g of monoethanolamine and the balance of water for injection.
A preparation method of the long-acting oxytetracycline injection for livestock comprises the following steps:
s1, adding 10-15ml of injection water into a stainless steel barrel, adding sodium formaldehyde sulfoxylate weighed according to a formula ratio during stirring, and stirring until the sodium formaldehyde sulfoxylate is completely dissolved to obtain a standby solution A;
s2, adding 10-15ml of water for injection into a liquid preparation pot, sequentially adding the glycerol formal, the polyethylene glycol-400 and the polyvinylpyrrolidone K12 weighed according to the formula ratio while stirring, and stirring until the materials are completely dissolved to obtain a standby liquid B;
s3, adding the standby liquid A obtained in the step S1 into the standby liquid B obtained in the step S2, uniformly stirring, and heating to 70 ℃;
s4, adding magnesium oxide weighed according to the formula ratio into the solution obtained in the step S3, and stirring for more than 5 minutes to obtain a uniform mixed solution;
s5, weighing oxytetracycline dihydrate according to the formula ratio, adding the oxytetracycline dihydrate into the solution obtained in the step S4, and stirring for more than 60 minutes to completely dissolve the oxytetracycline dihydrate;
s6, after the stirred solution in the step S5 is clarified, adding the monoethanolamine weighed according to the formula ratio under stirring;
s7, cooling to below 40 ℃, adding nearly full amount of injection water, and stirring for more than 10 minutes to obtain a uniform mixed solution;
s8, adding water for injection to a constant volume of 100ml, and stirring for more than 10 minutes to form a uniform mixed solution;
s9, coarsely filtering the solution obtained in the step S8 by using a 0.45-micrometer filter element, and finely filtering the solution by using a 0.22-micrometer filter element after the solution is qualified through quality inspection;
s10, filling according to the specified dosage, and packaging after the lamp inspection is qualified.
The veterinary long-acting oxytetracycline injection and the preparation method thereof provided by the invention have the beneficial effects that:
1. the veterinary long-acting oxytetracycline injection provided by the invention adopts the oxytetracycline dihydrate with low impurity content and high purity, so that the interference impurities of the injection are effectively reduced; sodium formaldehyde sulfoxylate is adopted to prevent the injection from being oxidized and blackened, so that the storage time of the product is prolonged; magnesium oxide is combined with two free hydroxyl groups of oxytetracycline to form a chelate, so that the injection forms clear liquid and the performance stability is maintained; the technical problems that the effective components of the oxytetracycline injection are unstable, ring-opening cracking is easy to occur and the active components are irreversibly damaged under the high-temperature condition are effectively solved.
2. The long-acting oxytetracycline injection for animals provided by the invention adopts glycerol methylal as an organic solvent, so that the stability of the injection can be improved, and the viscosity of the injection can be reduced; meanwhile, the polyethylene glycol-400 is adopted, so that the oxytetracycline can be easily and quickly delivered into blood through body fluid after intramuscular injection, the blood concentration reaches the peak value within 20 minutes, and the technical problem that the oxytetracycline injection is difficult to inject in clinical use is effectively solved.
3. The veterinary long-acting oxytetracycline injection provided by the invention adopts polyvinylpyrrolidone K12, so that on one hand, the viscosity of the injection is reduced, on the other hand, when the injection is injected into animal muscles, gel can be formed at the injection part, so that the drug is slowly released, the action time of the drug is prolonged, the toxic and side effects of overhigh blood concentration on animal organisms can be reduced, the technical problem that the oxytetracycline injection is difficult to inject in clinical use is solved, the active ingredients of the drug are ensured to be slowly released in the animal bodies, the long-acting purpose is achieved, the administration times are reduced, and the production cost of farmers is reduced.
4. The preparation method of the veterinary long-acting oxytetracycline injection provided by the invention is scientific in design, simple to operate and suitable for industrial large-scale production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described below with reference to specific examples.
Example 1
The embodiment provides a veterinary long-acting oxytetracycline injection, wherein each 100ml of the veterinary long-acting oxytetracycline injection contains 11g of oxytetracycline dihydrate, 1.5g of magnesium oxide, 0.4g of sodium formaldehyde sulfoxylate, 20g of glycerol formal, polyvinyl pyrrolidone K121 g, 40g of polyethylene glycol-40040 g of monoethanolamine and the balance of water for injection.
The preparation method comprises the following steps: adding 10ml of water for injection into a stainless steel barrel, adding 0.4g of sodium formaldehyde sulfoxylate in the stirring process, and stirring until the sodium formaldehyde sulfoxylate is completely dissolved to obtain a standby solution A; adding 10ml of water for injection into a liquid preparation pot, sequentially adding 20g of glycerol formal, 40g of polyethylene glycol-400 and 1g of polyvinylpyrrolidone K12 while stirring, and stirring until the mixture is completely dissolved to obtain a standby liquid B; adding the standby liquid A into the standby liquid B, uniformly stirring, and heating to 70 ℃; adding 1.5g of magnesium oxide, stirring for more than 5 minutes to obtain a uniform mixed solution, adding 11g of oxytetracycline dihydrate, and stirring for more than 60 minutes to completely dissolve the oxytetracycline dihydrate; after the solution is clarified, 1.2g of monoethanolamine is added under stirring; cooling to below 40 deg.C, adding injectable water to approximate full volume, stirring for more than 10min, adding injectable water to constant volume of 100ml after mixing, and stirring for more than 10min to obtain uniform mixed solution; then, a 0.45 mu m filter core is adopted for rough filtration, and after the quality inspection is qualified, the filter core with the size of 0.22 mu m is adopted for fine filtration; filling according to the specified dosage, and packaging after the lamp inspection is qualified.
Example 2
The embodiment provides a veterinary long-acting oxytetracycline injection, wherein each 100ml of the veterinary long-acting oxytetracycline injection contains 22g of oxytetracycline dihydrate, 1.7g of magnesium oxide, 0.5g of sodium formaldehyde sulfoxylate, 30g of glycerol formal, K125 g of polyvinylpyrrolidone, 20g of polyethylene glycol-40020 g of monoethanolamine and the balance of water for injection.
The preparation method comprises the following steps: adding 15ml of water for injection into a stainless steel barrel, adding 0.5g of sodium formaldehyde sulfoxylate in the stirring process, and stirring until the sodium formaldehyde sulfoxylate is completely dissolved to obtain a standby solution A; adding 15ml of water for injection into a liquid preparation pot, sequentially adding 30g of glycerol methylal, 20g of polyethylene glycol-400 and 5g of polyvinylpyrrolidone K12 while stirring, and stirring until the mixture is completely dissolved to obtain a standby liquid B; adding the standby liquid A into the standby liquid B, uniformly stirring, and heating to 70 ℃; adding 1.7g of magnesium oxide, stirring for more than 5 minutes to obtain a uniform mixed solution, adding 22g of oxytetracycline dihydrate, and stirring for more than 60 minutes to completely dissolve the oxytetracycline dihydrate; after the solution is clarified, 1.4g of monoethanolamine is added under stirring; cooling to below 40 deg.C, adding injectable water to approximate full volume, stirring for more than 10min, adding injectable water to constant volume of 100ml after mixing, and stirring for more than 10min to obtain uniform mixed solution; then, a 0.45 mu m filter core is adopted for rough filtration, and after the quality inspection is qualified, the filter core with the size of 0.22 mu m is adopted for fine filtration; filling according to the specified dosage, and packaging after the lamp inspection is qualified.
Example 3
The embodiment provides a veterinary long-acting oxytetracycline injection, wherein each 100ml of the veterinary long-acting oxytetracycline injection contains 22g of oxytetracycline dihydrate, 1.7g of magnesium oxide, 0.5g of sodium formaldehyde sulfoxylate, 30g of glycerol formal, polyvinyl pyrrolidone K122 g, 20g of polyethylene glycol-40020 g of monoethanolamine and the balance of water for injection.
The preparation method comprises the following steps: adding 15ml of water for injection into a stainless steel barrel, adding 0.5g of sodium formaldehyde sulfoxylate in the stirring process, and stirring until the sodium formaldehyde sulfoxylate is completely dissolved to obtain a standby solution A; adding 15ml of water for injection into a liquid preparation pot, sequentially adding 30g of glycerol methylal, 20g of polyethylene glycol-400 and 2g of polyvinylpyrrolidone K12 while stirring, and stirring until the mixture is completely dissolved to obtain a standby liquid B; adding the standby liquid A into the standby liquid B, uniformly stirring, and heating to 70 ℃; adding 1.7g of magnesium oxide, stirring for more than 5 minutes to obtain a uniform mixed solution, adding 22g of oxytetracycline dihydrate, and stirring for more than 60 minutes to completely dissolve the oxytetracycline dihydrate; after the solution is clarified, 1.4g of monoethanolamine is added under stirring; cooling to below 40 deg.C, adding injectable water to approximate full volume, stirring for more than 10min, adding injectable water to constant volume of 100ml after mixing, and stirring for more than 10min to obtain uniform mixed solution; then, a 0.45 mu m filter core is adopted for rough filtration, and after the quality inspection is qualified, the filter core with the size of 0.22 mu m is adopted for fine filtration; filling according to the specified dosage, and packaging after the lamp inspection is qualified.
Example 4
The embodiment provides a veterinary long-acting oxytetracycline injection, wherein each 100ml of the veterinary long-acting oxytetracycline injection contains 32g of oxytetracycline dihydrate, 1.9g of magnesium oxide, 0.8g of sodium formaldehyde sulfoxylate, 40g of glycerol formal, K125 g of polyvinylpyrrolidone, 20g of polyethylene glycol-40020 g of monoethanolamine and the balance of water for injection.
The preparation method comprises the following steps: adding 10ml of water for injection into a stainless steel barrel, adding 0.8g of sodium formaldehyde sulfoxylate in the stirring process, and stirring until the sodium formaldehyde sulfoxylate is completely dissolved to obtain a standby solution A; adding 10ml of water for injection into a liquid preparation pot, sequentially adding 40g of glycerol methylal, 20g of polyethylene glycol-400 and 5g of polyvinylpyrrolidone K12 while stirring, and stirring until the mixture is completely dissolved to obtain a standby liquid B; adding the standby liquid A into the standby liquid B, uniformly stirring, and heating to 70 ℃; adding 1.9g of magnesium oxide, stirring for more than 5 minutes to obtain a uniform mixed solution, adding 32g of oxytetracycline dihydrate, and stirring for more than 60 minutes to completely dissolve the oxytetracycline dihydrate; after the solution is clarified, 1.8g of monoethanolamine is added under stirring; cooling to below 40 deg.C, adding injectable water to approximate full volume, stirring for more than 10min, adding injectable water to constant volume of 100ml after mixing, and stirring for more than 10min to obtain uniform mixed solution; then, a 0.45 mu m filter core is adopted for rough filtration, and after the quality inspection is qualified, the filter core with the size of 0.22 mu m is adopted for fine filtration; filling according to the specified dosage, and packaging after the lamp inspection is qualified.
Test one: pharmacodynamic metabolism test
Selecting 12 healthy pigs with the weight of 50 +/-2 kg, not giving any medicine or feed containing antibiotics for one week before the test, randomly dividing the pigs into 4 groups, carrying out intramuscular injection of 0.1ml of the prepared veterinary long-acting oxytetracycline injection per kilogram of the weight, collecting blood of 5ml through jugular veins at the time of 0min (before injection), 10min, 20min, 30min, 60min, 2h, 4h, 8h, 12h, 24h, 48h, 60h, 72h, 84h, 96h and 120h after the administration, separating the blood plasma, measuring the peak area of each blood plasma by using a high performance liquid chromatograph, and calculating the blood concentration of the oxytetracycline, wherein the result is shown in table 1.
TABLE 1
The test result shows that: the veterinary long-acting oxytetracycline injection prepared in example 1 has the highest content of polyethylene glycol 400, and the blood concentration reaches the peak value 20 minutes after intramuscular injection, so that the problem of difficult injection in clinical use is solved, but the drop rate of the blood concentration is higher than that of the veterinary long-acting oxytetracycline injection prepared in examples 2-3. The veterinary long-acting oxytetracycline injections prepared in examples 2 and 4 have the highest polyvinylpyrrolidone K12 content, the injections are gradually and slowly absorbed and widely distributed in animals after intramuscular injection, the oxytetracycline content can be detected in blood after 120h, and although the drug effect action time is long, the peak blood concentration cannot be reached in a short time after intramuscular injection. The veterinary long-acting oxytetracycline injection prepared in the embodiment 3 can reach the peak blood concentration 30 minutes after intramuscular injection, the blood concentration is slowly reduced along with the time lapse, the oxytetracycline content can be detected in blood after 120 hours, and the veterinary long-acting oxytetracycline injection has the advantages of easiness in intramuscular injection, capability of reaching the peak blood concentration in a short time, increase of the action time of a medicament, prolongation of the injection interval time, reduction of the injection dosage, reduction of the stress response of animals and the like.
And (2) test II: content stability test
The veterinary long-acting oxytetracycline injection prepared in example 3 was hermetically packaged in a brown ampoule bottle, stored in a constant temperature oven at 25 ℃ for 36 months, observed for color change and transparency at 0 month (at the completion of formulation), 1 month, 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months, respectively, and the effective content of oxytetracycline was measured, and the results are shown in table 2.
| Time of day | Appearance of the product | pH value | Content (indicated amount%) | The result of the judgment |
| 0 month | Yellow clear liquid | 8.7 | 102.5 | Qualified |
| 6 months old | Yellow clear liquid | 8.7 | 102.5 | Qualified |
| 12 months old | Yellow clear liquid | 8.6 | 102.3 | Qualified |
| 18 months old | Yellow clear liquid | 8.6 | 102.0 | Qualified |
| 24 months | Yellow clear liquid | 8.5 | 101.6 | Qualified |
| 30 months old | Yellow clear liquid | 8.5 | 101.1 | Qualified |
| 36 months old | Light brown clear liquid | 8.4 | 100.8 | Qualified |
TABLE 2
Test results show that after the veterinary long-acting oxytetracycline injection prepared in example 3 of the invention is stored for 36 months at normal temperature, the product color is slightly changed, the pH value and the oxytetracycline content are slightly reduced, but still within a specified range, which indicates that the oxytetracycline injection prepared by the invention has stable quality, is not easy to discolor and precipitate after long-term storage, has stable effective content, and has a shelf life not less than three years of the effective period.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (3)
1. A veterinary long-acting oxytetracycline injection is characterized in that: every 100ml of the injection comprises the following components: 11-32g of oxytetracycline dihydrate, 1.5-1.9g of magnesium oxide, 0.4-0.8g of sodium formaldehyde sulfoxylate, 20-40g of glycerol methylal, 121-5 g of polyvinylpyrrolidone K, 20-40g of polyethylene glycol-40020, 1.2-1.8g of monoethanolamine and the balance of water for injection.
2. The long-acting oxytetracycline injection for veterinary use according to claim 1, characterized in that: the injection comprises the following components in each 100 ml: 22g of oxytetracycline dihydrate, 1.7g of magnesium oxide, 0.5g of sodium formaldehyde sulfoxylate, 30g of glycerol formal, K122 g of polyvinylpyrrolidone, 20g of polyethylene glycol-40020 g of monoethanolamine and the balance of water for injection.
3. A preparation method of a veterinary long-acting oxytetracycline injection is characterized by comprising the following steps:
s1, adding 10-15ml of water for injection into a stainless steel barrel, adding sodium formaldehyde sulfoxylate weighed according to the formula ratio of claim 1 or 2 during stirring, and stirring until the sodium formaldehyde sulfoxylate is completely dissolved to obtain a standby solution A;
s2, adding 10-15ml of water for injection into a liquid preparation pot, sequentially adding glycerol methylal, polyethylene glycol-400 and polyvinylpyrrolidone K12 weighed according to the formula ratio of claim 1 or 2 while stirring, and stirring until the materials are completely dissolved to obtain a standby liquid B;
s3, adding the standby liquid A obtained in the step S1 into the standby liquid B obtained in the step S2, uniformly stirring, and heating to 70 ℃;
s4, adding the magnesium oxide weighed according to the formula ratio in the claim 1 or 2 into the solution obtained in the step S3, and stirring for more than 5 minutes to obtain a uniformly mixed solution;
s5, weighing the oxytetracycline dihydrate according to the formula ratio of claim 1 or 2, adding the oxytetracycline dihydrate into the solution obtained in the step S4, and stirring for more than 60 minutes to completely dissolve the oxytetracycline dihydrate;
s6, after the stirred solution in the S5 is clarified, adding the monoethanolamine weighed according to the formula ratio in the claim 1 or 2 under stirring;
s7, cooling to below 40 ℃, adding nearly full amount of injection water, and stirring for more than 10 minutes to obtain a uniform mixed solution;
s8, adding water for injection to a constant volume of 100ml, and stirring for more than 10 minutes to form a uniform mixed solution;
s9, coarsely filtering the solution obtained in the step S8 by using a 0.45-micrometer filter element, and finely filtering the solution by using a 0.22-micrometer filter element after the solution is qualified through quality inspection;
s10, filling according to the specified dosage, and packaging after the lamp inspection is qualified.
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