Composition with synergistic functions of alternative antibodies and antibacterial drugs and application of composition

Abstract

The invention discloses a composition with an antibiotic replacement and antibacterial drug synergistic function and application. The composition is prepared from the following raw materials in parts by weight: 5-10 parts of tea leaves, 5-10 parts of pericarpium citri reticulatae, 1-5 parts of radix paeoniae rubra and 1-5 parts of radix saposhnikoviae. The composition can be used instead of antibiotics, can significantly reduce the diarrhea rate, death rate and feed conversion ratio of animals, and effectively improves the average weight gain of the animals; the composition can also be used in combination with antibacterial drugs, and has a synergistic effect on the antibacterial drugs, so that the dosage of the antibacterial drugs is reduced. Therefore, the composition provided by the invention is a natural pharmaceutical composition with double effects of resisting substitution and synergism at the same time, and can be produced and applied to preparation of resisting substitution preparations or antibacterial drug synergism preparations for animals in a large scale.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary drug preparations, and in particular to a composition having the functions of replacing antibiotics and enhancing the synergy of antibacterial drugs and its application. Background Art

[0002] With the emergence of super pathogens, the threat to humans from bacteria is increasing. In the process of animal husbandry, a large number of antibiotics are used for a long time for the purpose of disease prevention, treatment and growth promotion, which has become one of the most direct factors inducing bacterial resistance. Since my country's restriction and ban on antibiotics, the use of antibiotics has become very strict, resulting in an increasing trend in the incidence and mortality of infectious diseases in animals. Therefore, the market is in urgent need of efficient, safe and non-resistant alternative antibiotic products. Summary of the invention

[0003] The purpose of the present invention is to solve the above technical problems and provide a composition and application having the functions of replacing antibiotics and enhancing the synergy of antibacterial drugs.

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

[0005] One of the purposes of the present invention is to provide a composition with antibiotic substitution and antibacterial drug synergistic function, which is composed of the following raw materials in parts by weight: 5-10 parts of tea leaves, 5-10 parts of tangerine peel, 1-5 parts of red peony root and 1-5 parts of siler.

[0006] The second object of the present invention is to provide a method for preparing the above-mentioned composition. After the raw materials are dried, they are weighed according to proportion, 10 times the amount of 80% ethanol is added to fully soak, the mixture is decocted for 30 minutes and then filtered, the filtrate is stored, the filter residue is extracted once again by the same method, the two filtrates are combined, and the mixture is concentrated under reduced pressure to a density of 1.1-1.2, and stored at low temperature to obtain an extract of the composition.

[0007] The third object of the present invention is to provide an enteric-coated solid dispersion, which comprises the above-mentioned composition.

[0008] A fourth object of the present invention is to provide a method for preparing the above-mentioned enteric-coated solid dispersion, comprising the following steps:

[0009] S1. Prepare an extract of the composition according to the preparation method of claim 2, mix the extract with the coating solution in a ratio of 1:2-1:5, and dissolve it in an organic solvent to obtain a solution;

[0010] S2, using spray drying method, converting the solution in S1 into powder by atomization, the inlet air temperature is controlled at 50-70℃, the exhaust air temperature is controlled at 40-60℃, and the atomization pressure is set to 1.5-2.5bar;

[0011] S3. Enteric coating the powder in S2 using a fluidized bed or spray coating device, maintaining the coating temperature at 30-50° C. and controlling the coating weight increment at 5-10%, to prepare an enteric solid dispersion.

[0012] Preferably, the organic solvent in S1 is ethanol or isopropanol.

[0013] Preferably, 5% polyethylene glycol (PEG) and 2% triacetin are added to the coating material, and the coating solution is prepared after mixing, and the concentration of the coating solution is 10-15%; the coating material is one of hydroxypropyl methylcellulose (HPMCP), polyacrylic acid resin (Eudragit L) or polyacrylic acid resin (S series).

[0014] More preferably, the particle size distribution of the enteric solid dispersion is 50-200 μm.

[0015] A fifth object of the present invention is to provide the use of the above composition in the preparation of antibiotic substitutes or antibacterial drug synergistic preparations for animals.

[0016] The sixth object of the present invention is to provide the use of the above-mentioned enteric solid dispersion in the preparation of antibiotic replacement preparations or antibacterial drug synergistic preparations for animals.

[0017] The beneficial effects of the present invention are:

[0018] 1) The present invention provides a traditional Chinese medicine composition, which can replace antibiotics, significantly reduce the diarrhea rate, mortality rate and feed-to-meat ratio of animals, and effectively increase the average weight gain of animals; the traditional Chinese medicine composition can also be used in combination with antibacterial drugs to enhance the synergy of the antibacterial drugs, thereby reducing the dosage of the antibacterial drugs.

[0019] 2) The present invention also provides a method for preparing the extract of the traditional Chinese medicine composition, which is simple, easy to operate and has high production efficiency.

[0020] 3) In order to protect the active ingredients in the extract of the above-mentioned traditional Chinese medicine composition from being destroyed by gastric acid and prevent its oxidation, and at the same time improve its absorption efficiency in the intestine, the present invention prepares the extract into an enteric solid dispersion, and the preparation process is simple and suitable for industrial large-scale production; and the prepared enteric solid dispersion has uniform particles, with a particle size distribution of 50-200 μm, and has good appearance and fluidity; the dissolution experiment shows that the 1-hour release rate in simulated gastric fluid (pH 1.2) is less than 8%, and the 2-hour release rate in simulated intestinal fluid (pH 6.8) exceeds 85%, which meets the requirements of enteric preparations; the stability test (40°C·5°C, 75%±5%RH, 6 months) shows that the extract content has no significant change, and the appearance has no significant change, which proves that the preparation has good stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the drug-time curve after intramuscular injection of 10 mg / kg.bw amoxicillin in pigs.

[0022] Figure 2 This is the drug-time curve after intramuscular oral administration of 5 mg / kg.bw enrofloxacin in ducks. DETAILED DESCRIPTION

[0023] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0024] Example 1

[0025] After drying the raw materials tea leaves, dried orange peel, red peony root and fangfeng, the following weight portions are weighed: 10 parts of tea leaves, 10 parts of dried orange peel, 5 parts of red peony root and 5 parts of fangfeng. 10 times the amount of 80% ethanol is added to the raw materials for full soaking, and the filtrate is filtered after boiling for 30 minutes, and the filtrate is stored, and the filter residue is extracted once again in the same way, and the two filtrates are combined, concentrated under reduced pressure to a density of 1.2 and stored at low temperature to obtain an extract of the composition.

[0026] Example 2

[0027] After drying the raw materials tea leaves, dried orange peel, red peony root and fangfeng, the following weight parts are weighed: 5 parts of tea leaves, 5 parts of dried orange peel, 5 parts of red peony root and 5 parts of fangfeng. 10 times the amount of 80% ethanol is added to the raw materials for full soaking, and the filtrate is filtered after boiling for 30 minutes, and the filtrate is stored, and the filter residue is extracted once again in the same way, and the two filtrates are combined, concentrated under reduced pressure to a density of 1.1 and stored at low temperature to obtain an extract of the composition.

[0028] Example 3

[0029] 1) Mix the extract of Example 1 and the coating solution in a ratio of 1:2, dissolve them in ethanol, and prepare a uniform solution or suspension;

[0030] 2) The solution was converted into powder by atomization using the spray drying method. The inlet air temperature was controlled at 60°C, the exhaust air temperature was controlled at 40°C, and the atomization pressure was set at 2.0 bar to ensure uniform particles.

[0031] 3) Use fluidized bed or spray coating equipment for enteric coating, select hydroxypropyl methylcellulose as coating material, add 5% polyethylene glycol (PEG) for solubilization, 2% triacetin for plasticization, control the concentration of coating solution at 10%, maintain the coating temperature at 50°C, and control the coating weight increment to 5% of the total weight.

[0032] The experimental results show that the obtained enteric solid dispersion particles are uniform, with a particle size distribution of 50-200μm, and have good appearance and fluidity; the dissolution experiment shows that the 1-hour release rate in simulated gastric fluid (pH 1.2) is less than 8%, and the 2-hour release rate in simulated intestinal fluid (pH 6.8) is more than 85%, which meets the requirements of enteric preparations; the stability test (40℃·5℃, 75%±5%RH, 6 months) shows that the extract content has no significant change, and the appearance properties have not changed significantly, which proves that the preparation has good stability.

[0033] Example 4

[0034] 4) Mix the extract of Example 2 with the coating solution in a ratio of 1:4, dissolve in ethanol, and prepare a uniform solution or suspension;

[0035] 5) The solution was converted into powder by atomization using the spray drying method. The inlet air temperature was controlled at 70°C, the exhaust air temperature was controlled at 50°C, and the atomization pressure was set at 2.0 bar to ensure uniform particles;

[0036] 6) Enteric coating is performed using a fluidized bed or spray coating equipment, polyacrylic acid resin (Eudragit L or S series) is used as the coating material, 5% polyethylene glycol (PEG) is added for solubilization, 2% triacetin is added for plasticization, the coating solution concentration is controlled at 15%, the coating temperature is maintained at 50° C., and the coating weight increment is controlled at 10%. Enteric solid dispersion particles are prepared.

[0037] Example 5

[0038] The enteric-coated solid dispersion prepared in Example 3 was used to treat piglet weaning diarrhea. The enteric-coated solid dispersion was added to the feed at a ratio of 2-5‰, and the piglets were fed the medicated feed from 3 days before weaning to 1 week after weaning. The feed without drug addition was used as a negative control, and the feed with 2‰ neomycin sulfate was used as a positive control. There were 20 piglets in each group, and the diarrhea rate and mortality rate of the piglets, weight gain after weaning, feed intake and feed-to-meat ratio were counted respectively. The groups and results are shown in Table 1. As can be seen from the results, the effect of the alternative antibiotic drug is significantly better than that of the positive control drug, the number of diarrhea, the number of deaths and the feed-to-meat ratio are significantly reduced, the average weight gain is significantly increased, and it is dose-dependent.

[0039] Table 1 Effects of drugs on diarrhea in piglets

[0040] Group Diarrhea number (times) Number of deaths (heads) Average weight gain (g) Feed to meat ratio Negative control group 42 8 584 2.6 Positive control group 26 4 740 2.2 2‰ Antibody replacement group 12 2 950 2.0 3‰ Antibody replacement group 6 0 1130 1.7 5‰ Antibody Replacement Group 2 0 1360 1.6

[0041] Example 6

[0042] The enteric-coated solid dispersion prepared in Example 3 was used to treat salmonellosis in chickens. Negative control group: 50 one-day-old white-feathered broilers were selected and raised normally without treatment. One-day-old white-feathered broilers were selected and gavaged with clinical isolates of Salmonella to establish a Salmonella infection model, and were divided into 5 groups, each with 50 chickens, including a positive control group: Salmonella-infected chickens were gavaged with the drug doxycycline (amoxicillin 10 mg / kg body weight); model group: no gavage of drugs; experimental groups 1-3: gavage of the enteric-coated solid dispersion prepared in Example 3 for treatment, at 5 mg / kg, 10 mg / kg and 20 mg / kg body weight, respectively, based on the extract. After 1 week, the mortality and growth of the chickens were counted, and the results are shown in Table 2. It can be seen from the results that the effect of the alternative antibiotic is significantly better than that of the positive control drug, the number of deaths and feed-to-meat ratio are significantly reduced, the average weight gain is significantly increased, and it is dose-dependent.

[0043] Table 2 Effects of drugs on Salmonella infection in chicken

[0044] Group Number of deaths (individuals) Weight gain (g) Feed to meat ratio Negative control group 8 74 1.5 Model Group 23 32 1.9 Positive control group 6 86 1.6 5mg / kg 3 94 1.5 10mg / kg 1 112 1.4 20mg / kg 1 135 1.3

[0045] Example 7

[0046] The enteric solid dispersion in this example is prepared by Example 4.

[0047] Ten healthy weaned pigs were selected and divided into a control group and an enhanced group. The control group was an amoxicillin group (10 mg / kg); the enhanced group was an amoxicillin (10 mg / kg) + enteric solid dispersion group (10 mg / kg based on the extract). The pigs were given the drug by oral gavage, and blood was collected at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours after administration. The drug concentration of amoxicillin in the blood was detected by high performance liquid chromatography. The results are shown in Tables 3 and 4. Figure 1 The AUC (0-∞) increased from 22.932 mg / L*h in the control group to 41.727 mg / L*h in the enhanced group. The relative bioavailability was 182.0% of that in the control group.

[0048] Table 3 Pharmacokinetic parameters of amoxicillin

[0049]

[0050]

[0051] Example 8

[0052] The enteric solid dispersion in this example is prepared by Example 4.

[0053] Twenty healthy ducks weighing about 2 kg were selected and divided into a control group and an enhanced group. The control group was enrofloxacin group (5 mg / kg); the enhanced group was enrofloxacin (5 mg / kg) + enteric solid dispersion group (10 mg / kg according to the extract). The drugs were administered by oral gavage, and blood was collected at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 h after administration. The drug concentration of enrofloxacin in the blood was detected by high performance liquid chromatography. The results are shown in Tables 4 and Figure 2 The AUC (0-∞) increased from 6.308 mg / L*h in the control group to 10.982 mg / L*h in the enhanced group, and the relative bioavailability was 174.1% of the control group.

[0054] Table 4 Pharmacokinetic parameters of enrofloxacin

[0055] parameter unit Duck control group Duck Enhancer Group AUC(0-t) mg / L*h 6.264±0.172 10.841±0.236 AUC(0-∞) mg / L*h 6.308±0.179 10.982±0.243 AUMC(0-t) 13.928±0.43 47.876±2.097 AUMC(0-∞) 14.626±0.452 52.498±2.386 MRT(0-t) h 2.224±0.056 4.415±0.129 MRT(0-∞) h 2.319±0.055 4.779±0.15 VRT(0-t) h^2 3.982±0.148 19.283±0.56 VRT(0-∞) h^2 5.145±0.223 28.566±2.027 t1 / 2z h 1.741±0.169 4.106±0.414 Tmax h 0.625±0.177 0.675±0.169 CLz / F L / h / kg 1.586±0.044 0.911±0.02 Vz / F L / kg 3.979±0.333 5.397±0.554 Zeta 0.402±0.042 0.17±0.019 Cz (tail point regression value) mg / L 0.017±0.004 0.023±0.006 Cmax mg / L 2.496±0.129 2.734±0.156

[0056] In summary, the Chinese medicine composition of the present invention is a natural medicine composition with the dual effects of replacing antibiotics and enhancing the synergy of antibacterial drugs. It can be used alone or in combination with antibacterial drugs to reduce the dosage of antibacterial drugs. At the same time, it has the characteristics of being cheap and easy to obtain, simple in process and reliable in effect, providing a powerful supplement for the prevention and treatment of bacterial infection diseases in clinical practice.

[0057] The specification and drawings of the present invention are considered to be illustrative rather than restrictive. On the basis of the present invention, those skilled in the art can make some substitutions and modifications to some of the technical features according to the disclosed technical content without creative labor, all of which are within the protection scope of the present invention.

Claims

1. A composition having the function of replacing antibiotics and enhancing the synergy of antibacterial drugs, characterized in that: The invention is composed of the following raw materials in parts by weight: 5-10 parts of tea leaves, 5-10 parts of dried orange peel, 1-5 parts of red peony root and 1-5 parts of siler.

2. The method for preparing the composition according to claim 1, characterized in that: After the raw materials are dried, they are weighed according to proportion, 10 times the amount of 80% ethanol is added to fully soak, decocted for 30 minutes and then filtered, the filtrate is stored, the filter residue is extracted once again in the same way, the two filtrates are combined, concentrated under reduced pressure to a density of 1.1-1.2, and stored at low temperature to obtain an extract of the composition.

3. An enteric solid dispersion, characterized in that: The enteric solid dispersion comprises the composition according to claim 1.

4. The method for preparing the enteric solid dispersion according to claim 3, characterized in that: The following steps are involved: S1. Prepare an extract of the composition according to the preparation method of claim 2, mix the extract with the coating solution in a ratio of 1:2-1:5, and dissolve it in an organic solvent to obtain a solution; S2, using spray drying method, converting the solution in S1 into powder by atomization, the inlet air temperature is controlled at 50-70℃, the exhaust air temperature is controlled at 40-60℃, and the atomization pressure is set to 1.5-2.5bar; S3. Enteric coating the powder in S2 using a fluidized bed or spray coating device, maintaining the coating temperature at 30-50° C. and controlling the coating weight increment at 5-10%, to prepare an enteric solid dispersion.

5. The preparation method according to claim 4, characterized in that: The organic solvent in S1 is ethanol or isopropanol.

6. The preparation method according to claim 4, characterized in that: 5% polyethylene glycol (PEG) and 2% triacetin are added to the coating material, and the coating solution is prepared after mixing. The concentration of the coating solution is 10-15%. The coating material is one of hydroxypropyl methylcellulose (HPMCP), polyacrylic acid resin (Eudragit L) or polyacrylic acid resin (S series).

7. The preparation method according to claim 4, characterized in that: The particle size distribution of the enteric solid dispersion is 50-200 μm.

8. Use of the composition according to claim 1 in the preparation of antibiotic replacement preparations or antibacterial drug synergistic preparations for animals.

9. Use of the enteric solid dispersion according to claim 3 in the preparation of antibiotic replacement preparations or antibacterial drug synergistic preparations for animals.

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