CN113768872A - Tulathromycin injection and application thereof - Google Patents

Tulathromycin injection and application thereof Download PDF

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CN113768872A
CN113768872A CN202111228810.9A CN202111228810A CN113768872A CN 113768872 A CN113768872 A CN 113768872A CN 202111228810 A CN202111228810 A CN 202111228810A CN 113768872 A CN113768872 A CN 113768872A
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tulathromycin
injection
cyclodextrin
stirring
beta
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CN113768872B (en
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田瑞叶
刘漫
赵新祥
王玲
李建国
汪娜
杨申永
韩丙星
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Amicogen China Biopharm Co Ltd
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Abstract

The invention discloses a tulathromycin injection and application thereof, belonging to the technical field of veterinary injection. The invention provides a tulathromycin compound injection which is characterized by consisting of tulathromycin, vitamin C, a solubilizer, a cosolvent and a solvent. The compound injection prepared by the invention is water-soluble injection, and the water solubility and the stability of the tulathromycin are improved by adopting the substituted beta-cyclodextrin as a solubilizer. Meanwhile, the injection does not need to be added with a pH regulator and an antioxidant, so that the injection has the advantages of no irritation, high safety, quick response, good solubility and the like.

Description

Tulathromycin injection and application thereof
Technical Field
The invention belongs to the technical field of veterinary injection, and particularly relates to a tulathromycin injection preparation and application thereof.
Background
Tulathromycin (Tulathromycin) is a specialized semi-synthetic macrolide antibiotic developed in the united states for animals that inhibits the biosynthesis of essential proteins by selectively binding to bacterial ribosomal RNA. They function by facilitating dissociation of the polypeptide-tRNA from the ribosome during translocation. Unlike many other macrolide antibiotics, its pharmaceutical action is retained for a longer period of time, due in part to the presence of 3 amino groups in its structure. The tulathromycin is a broad-spectrum antibacterial drug and is very sensitive to various pathogenic bacteria causing respiratory diseases of pigs and cows, such as pasteurella haemolytica, pasteurella multocida, actinobacillus pleuropneumoniae, mycoplasma, haemophilus parasuis, bordetella bronchiseptica and the like, and bovine infectious keratoconjunctivitis caused by moraxella bovis.
At present, the macrolide medicines which are widely used in animal production and have good effects at home comprise tilmicosin and tylosin, but with the prolonging of the use time and the non-standard medicine use, the medicine resistance of different degrees appears in many areas, the drug effect of the tylosin is stronger than that of the macrolide medicines which are widely used in markets such as the tilmicosin, the tylosin and the like, the macrolide medicines generally have the inhibiting effect on bacteria, and the tylosin has the antibacterial and bactericidal effects. The tulathromycin has the advantages of excellent pharmacokinetic characteristic, quick absorption, short peak reaching time, high bioavailability, very high tissue concentration in the lung, long elimination half-life period, lasting drug effect, slow release effect, capability of providing whole-course treatment by single intramuscular injection or subcutaneous administration, and wide application prospect in veterinary clinic. The drug is marketed in the European Union and the United states in 2004, and is allowed to be used in animal production for the first time in No. 957 bulletin of 2008 of Ministry of agriculture in China.
The tulathromycin injection is difficult to dissolve in water and easy to dissolve in an acid solution, so most of the tulathromycin injection on the market at present is a solution type injection preparation prepared by an organic solvent/water cosolvent and under an acid condition, the injection is slightly acidic and has large irritation, and the problems of injection pain, injection part swelling and the like are often caused during injection; compared with a solution type injection, the oily injection prepared from the tulathromycin has the defects of slow response and inconvenience for treating acute severe infected animals; meanwhile, the antioxidant is added into the formula of the tulathromycin injection, so that the stability of the medicine is improved, but the safety of the medicine is reduced.
Therefore, the problem to be solved in the field is to provide a water-soluble tulathromycin compound injection which has no irritation, good safety, quick response and good solubility.
Disclosure of Invention
The invention discloses a tulathromycin injection and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a tulathromycin compound injection mainly comprises the following components: tulathromycin, vitamin C, solubilizer and cosolvent, and the balance solvent;
preferably, the component contents are as follows:
Figure BDA0003315214810000021
preferably, the solubilizer is substituted beta-cyclodextrin; preferably, the substituted beta-cyclodextrin is any one of hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin or glucosyl-beta-cyclodextrin; more preferably, the substituted beta-cyclodextrin is glucosyl-beta-cyclodextrin;
preferably, the weight ratio of the substituted beta-cyclodextrin to the tulathromycin is 1: 1;
preferably, the content of the cosolvent component is 3-5 g/L;
preferably, the cosolvent is one or two of meglumine, tromethamine or nicotinamide;
preferably, the cosolvent is tromethamine and meglumine,
preferably, the weight ratio of the tromethamine to the meglumine is as follows: 2: 1;
preferably, the solvent is water for injection;
preferably, the preparation method of the tulathromycin compound injection comprises the following steps:
the method comprises the following steps: taking a solvent accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the solvent, adding a solubilizer and a cosolvent, and stirring for dissolving; adding vitamin C, stirring and dissolving completely, wherein the pH value of the solution is 1.3-1.8;
step two: slowly adding tulathromycin into the dissolving solution obtained in the step one, heating to dissolve, and stirring for clathrating for a certain time; then adding the rest solvent, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection. The pH value of the injection is 5.0-5.5.
Preferably, the solvent is water for injection;
preferably, the pore size of the sterile filtration is 0.22 μm;
preferably, in the second step, the inclusion time is 30min to 120min, and preferably, the inclusion time is 30min to 40 min.
Preferably, in the second step, the temperature during heating is 50-60 ℃;
preferably, the heating time is 30 min;
preferably, the temperature during heating is 60 ℃;
preferably, in the third step, the pH range is 5.0 to 5.5, and preferably, the pH is 5.2.
In conclusion, the invention discloses a tulathromycin injection and application thereof. The invention provides a tulathromycin compound injection, which consists of tulathromycin, vitamin C, solubilizer, cosolvent and solvent. The compound injection prepared by the invention is water-soluble injection, and the water solubility and the stability of the tulathromycin are improved by adopting the substituted beta-cyclodextrin as a solubilizer. Meanwhile, the injection does not need to be added with a pH regulator and an antioxidant, so that the injection has the advantages of no irritation, high safety, quick response, good solubility and the like.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Figure BDA0003315214810000041
EXAMPLE 1 Compound injection of tulathromycin
Figure BDA0003315214810000042
Figure BDA0003315214810000051
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Comparative example 1
Figure BDA0003315214810000052
The preparation method comprises the following steps: the same as in example 1.
Comparative example 2
Figure BDA0003315214810000061
The preparation method comprises the following steps: the same as in example 1.
Comparative example 3
Figure BDA0003315214810000062
The preparation method comprises the following steps: the same as in example 1.
The samples prepared in example 1 and comparative examples 1 to 3 were compared for stability examination under the conditions of (1) high temperature of 60 ℃ for 10 days, (2) strong illumination of 5000Lx for 10 days, and the detection indexes were properties, contents, and pH values. The results are as follows:
results at day 0:
Figure BDA0003315214810000063
Figure BDA0003315214810000071
results at 10 days at elevated temperature:
Figure BDA0003315214810000072
light illumination 10 days results:
Figure BDA0003315214810000073
as can be seen from the analysis of the stability test results in tables 1-3, the stability of the sample prepared in example 1 is higher than that of the samples prepared in comparative examples 1-3, so that the stability of the tulathromycin is improved by including the tulathromycin with the glucosyl-beta-cyclodextrin adopted in example 1 of the invention.
Example 2: compound injection of tulathromycin
Figure BDA0003315214810000081
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 50 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 1 h; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 3: compound injection of tulathromycin
Figure BDA0003315214810000082
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 1 h; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 4: compound injection of tulathromycin
Figure BDA0003315214810000091
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 5: compound injection of tulathromycin
Figure BDA0003315214810000101
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 6: compound injection of tulathromycin
Figure BDA0003315214810000102
Figure BDA0003315214810000111
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the formula amount of glucose-beta-cyclodextrin, tromethamine and nicotinamide, stirring for dissolving, adding the formula amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 7: compound injection of tulathromycin
Figure BDA0003315214810000112
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the formula amount of glucose-beta-cyclodextrin and tromethamine, stirring for dissolving, adding the formula amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 8: compound injection of tulathromycin
Figure BDA0003315214810000121
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of the glucosyl-beta-cyclodextrin and the meglumine, stirring for dissolving, adding the prescription amount of the vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 9: compound injection of tulathromycin
Figure BDA0003315214810000122
Figure BDA0003315214810000131
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin and nicotinamide, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 10: compound injection of tulathromycin
Figure BDA0003315214810000132
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 11: compound injection of tulathromycin
Figure BDA0003315214810000141
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 12: compound injection of tulathromycin
Figure BDA0003315214810000142
Figure BDA0003315214810000151
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the rest of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
Example 13: compound injection of tulathromycin
Figure BDA0003315214810000152
The preparation method comprises the following steps:
the method comprises the following steps: taking injection water accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the injection water, adding the prescription amount of glucose-beta-cyclodextrin, tromethamine and meglumine, stirring for dissolving, adding the prescription amount of vitamin C, and stirring for completely dissolving;
step two: slowly adding the tulathromycin with the prescription amount, heating to 60 ℃ until the tulathromycin is completely dissolved, and stirring for inclusion for 30 min; then cooling to room temperature, adding the formula amount of thioglycerol, supplementing the balance amount of water for injection, and stirring and mixing uniformly;
step three: and (5) filtering and sterilizing the solution obtained in the step two by using a 0.22-micron microporous filter membrane to obtain the tulathromycin and vitamin C compound injection.
The content, isomer A, B and pH of the tulathromycin complex injection prepared in examples 1 to 13 were measured, and the results are shown in the following table:
TABLE 1
Figure BDA0003315214810000161
Figure BDA0003315214810000171
Analysis of the sample detection results of examples 1-3 shows that both tylosin isomer A, B are maintained in a certain range (87.0-92.0% of tylosin isomer A, 8.0-13.0% of tylosin isomer B) at a heating temperature of 60 ℃ and a heating time of 30min-1h, and that both tylosin and vitamin C are relatively stable; analysis on the sample detection results of the examples 1, 4 and 5 shows that when the weight ratio of the glucosyl-beta-cyclodextrin to the tulathromycin is 1:1, the solubilization effect of the glucosyl-beta-cyclodextrin to the tulathromycin is better; the detection results of the samples of comparative examples 1 and 6-11 show that the cosolvent is preferably tromethamine and meglumine, the addition amount of the tromethamine and the meglumine is 3g/L, and the ratio is 2: 1; the test results of the samples of comparative examples 1 and 13 show that the stability of the tulathromycin and the vitamin C is not obviously different when the antioxidant (thioglycerol) is added and the antioxidant is not added. In summary, the heating temperature and heating time are preferably 60 ℃ for 30min, and the weight ratio of the glucosyl-beta-cyclodextrin to the tulathromycin is preferably 1: 1.
Example 14: compound injection of tulathromycin
Figure BDA0003315214810000172
The preparation method comprises the following steps: the same as in example 1.
The tulathromycin complex injection prepared in example 14 was used as a sample, and an accelerated test and a long-term test were conducted to examine the stability of the tulathromycin complex injection. The experimental results are shown in the following tables (tables 2 and 3):
TABLE 2 accelerated test (40. + -. 2 ℃ C.) data
Figure BDA0003315214810000181
TABLE 3 Long-term test (25. + -. 2 ℃ C.) data
Figure BDA0003315214810000182
The data (tables 2 and 3) of an accelerated test (40 +/-2 ℃) and a long-term test (25 +/-2 ℃) show that the characteristics, the pH value and the like of the sample of the tulathromycin composite injection have no obvious change after the tulathromycin composite injection is placed for 6 months in the accelerated test and is placed for 12 months in the long-term test, and all quality indexes such as the content of tulathromycin and vitamin C in the sample are qualified, so that the composite injection prepared from tulathromycin and glucose-beta-cyclodextrin forms an inclusion compound and the composite injection and the vitamin C have good quality stability.
Example 15 irritation test
The tulathromycin compound injection prepared in example 14 is used as a medicine, and compared with a marketed 10% tulathromycin injection preparation (using an organic solvent/water as a solvent), 12 cattle and 6 pigs are injected with neck muscle respectively, and the administration doses are respectively 2.5mg/kg and 7.5mg/kg, and the specific conditions are shown in the following tables 4 and 5:
TABLE 4
Figure BDA0003315214810000191
TABLE 5
Figure BDA0003315214810000192
Comparing the stimulation experiment results of the tulathromycin composite injection prepared by the invention and the tulathromycin injection which is sold on the market and is 10 percent to the injection part of the cattle, the results show that only one cattle of 6 cattle and 3 pigs which are injected with 14 preparations have slight pain reaction when the injection dosage is slightly larger, and the rest 5 cattle and 3 pigs have no injection stimulation reaction; for 6 cattle and 3 pigs injected with 10% tulathromycin injection on the market, 5 cattle have pain reaction and local swelling at the injection part, when the administration dosage is increased, the injection part is swollen, and 2 pigs among 3 pigs have pain reaction, wherein 1 pig has local swelling at the injection part and the swelling disappears in 8 to 33 days. The irritation test result shows that the tulathromycin composite injection prepared by the invention has good histocompatibility and no obvious irritation.
EXAMPLE 16 determination of the blood concentration of Compound injection of tulathromycin
The tulathromycin complex injection prepared in example 14 was used as a drug, and compared with a preparation 1, which is a commercially available 10% tulathromycin injection preparation (organic solvent/water is used as an injection solvent), and a preparation 2 to 10% tulathromycin injection preparation (oily solvent is used as an injection solvent). Selecting 30 healthy pigs with the weight of 40-50kg, dividing the pigs into 3 groups, carrying out neck intramuscular injection on each group with the administration dose of 2.5mg/kg respectively for 10 pigs in each group, collecting blood on time, and detecting the tulathromycin content (ng/ml) in blood plasma, wherein the specific conditions are shown in the following table 6:
TABLE 6
Figure BDA0003315214810000201
As can be seen from comparison of the results of the blood concentration measurements after the injection of the three formulations in Table 6, the blood concentration of the formulation in example 14 reaches the peak faster than that of the formulation 1 tulathromycin injection (organic solvent/water is used as the injection solvent); while the peak time of the blood concentration is not obviously different when the preparation 2 tulathromycin injection preparation (oily solvent is used as injection solvent) is injected just before, the preparation in example 14 still has higher blood concentration within 48 hours at the later stage, and the drug release speed in the body is stable and the concentration is close to that within 48 hours. The analysis of the results shows that the preparation in example 14 has the advantages of quick release and sustained and controlled release compared with the preparation 1 tulathromycin injection (which takes organic solvent/water as injection solvent) and the preparation 2 tulathromycin injection (which takes oily solvent as injection solvent), and simultaneously shows that the preparation in example 14 has the characteristics of complete administration and absorption, long half-life and high bioavailability.
Example 17 efficacy comparison of the preparation of example 14 with the preparations 1 and 2 of example 16 36 pigs (body weight: about 50kg) with clinical symptoms of respiratory diseases in a large pig farm were selected and tested, and based on the clinical symptoms (see table 7), the 36 pigs were divided into 3 grades of 3-severe disease (6), 2-moderate disease (21) and 1-mild disease (9), and the 3 grades were divided into 3 groups, wherein the preparation of example 14 was injected in group 1, the preparation of injection of preparation 1 in group 2 and the preparation of injection of preparation 2 in group 3, and the dose was 2.5mg/kg for intramuscular injection in the neck. Clinical symptoms and disease recurrence and weight gain after 2 months were observed at 1, 2, 5 and 7 days after treatment and the results are shown in table 8.
TABLE 7 clinical symptom score criteria
Figure BDA0003315214810000211
TABLE 8 clinical symptom grading results
Figure BDA0003315214810000221
As can be seen from the data analysis in Table 8, the severe pigs administered with the preparation of example 14 all turned into mild moderate disease on day 3, while no moderate swine was present on day 5, 8 pigs had no clinical symptoms, and all the clinical symptoms of the sick pigs on day 7 were substantially disappeared; after the preparation 1 is administrated, 1 pig with serious clinical symptoms and 6 pigs with medium and light symptoms still remain on the 7 th day; after administration of formulation 2, 5 pigs with mild symptoms remained on day 7. The data show that the preparation in example 14 has quick response, quick disappearance of diseases and high bioavailability for pigs with respiratory diseases, and is particularly beneficial to the treatment of severe pigs.
TABLE 9 relapse and weight gain
Figure BDA0003315214810000222
Figure BDA0003315214810000231
The data analysis of table 9 shows that, after the treatment and recovery, within 2 months, all pigs in the preparation group of example 14 have no recurrent respiratory diseases, 1 pig recurrent respiratory diseases in the preparation 2 group, 3 pigs recurrent respiratory diseases in the preparation 1 group, and the weight gain of the pigs in the preparation group of example 14 is greater than that of the preparation 1 group and the preparation 2 group, so that the tulathromycin composite injection is shown to have a faster body recovery speed and a better effect than that of the preparation 1-10% tulathromycin injection (organic solvent/water is used as injection solvent) and the preparation 2-10% tulathromycin injection (oily solvent is used as injection solvent), and can enhance the immunity of the pigs.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to the above-described embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (10)

1. The tulathromycin compound injection is characterized by mainly comprising the following components: tulathromycin, vitamin C, solubilizer and cosolvent, and the balance solvent.
2. The tulathromycin composite injection as claimed in claim 1, which is characterized by comprising the following components in percentage by weight:
Figure FDA0003315214800000011
the balance being solvent.
3. The tulathromycin complex injection of claim 2, wherein the solubilizing agent is a substituted β -cyclodextrin; preferably, the substituted beta-cyclodextrin is any one of hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin or glucosyl-beta-cyclodextrin; more preferably, the substituted beta-cyclodextrin is glucosyl-beta-cyclodextrin.
4. The tulathromycin complex injection of claim 3, wherein the weight ratio of the substituted beta-cyclodextrin to the tulathromycin is 1: 1.
5. The tulathromycin composite injection as claimed in claim 2, wherein the cosolvent component is present in an amount of 3-5 g/L.
6. The tulathromycin composite injection as claimed in claim 5, wherein the cosolvent is one or two of meglumine, tromethamine or nicotinamide.
7. The method for preparing the tulathromycin complex injection as claimed in any one of claims 1 to 7, which comprises the following steps:
the method comprises the following steps: taking a solvent accounting for 90 percent of the total amount of the preparation, introducing nitrogen into the solvent, adding a solubilizer and a cosolvent, and stirring for dissolving; adding vitamin C, stirring and dissolving completely, wherein the pH value of the solution is 1.3-1.8;
step two: slowly adding tulathromycin into the dissolving solution obtained in the step one, heating to dissolve, and stirring for clathrating for a certain time; then adding the rest solvent, and stirring and mixing uniformly;
step three: and (5) sterilizing and filtering the solution obtained in the step two to obtain the tulathromycin and vitamin C compound injection. The pH value of the injection is 5.0-5.5.
8. The preparation method of tulathromycin composite injection as claimed in claim 7, wherein in the second step, the inclusion time is 30-120 min, preferably 30-40 min.
9. The method for preparing the tulathromycin composite injection as claimed in claim 7, wherein the temperature during heating is 50-60 ℃ in the second step.
10. The tulathromycin composite injection as claimed in claim 2 or 7, wherein in step three, the pH value is in the range of 5.0-5.5, preferably the pH value is 5.2.
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