CN111494312A - Oral liquid for preventing and treating chicken colibacillosis and preparation method thereof - Google Patents
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Abstract
The invention belongs to the field of preparations, and particularly relates to an oral liquid for preventing and treating chicken colibacillosis and a preparation method thereof. The application provides an oral liquid for preventing and treating chicken colibacillosis, which comprises the following raw materials: 10-20 g of 3, 4-dihydroxy benzoic acid, 2-4 ml of additive, 2-10g of sweetener, 2-7 g of florfenicol and 100ml of solvent. 3, 4-dihydroxy benzoic acid is stably existed in the oral liquid and is not easy to oxidize by adding the sweetening agent, the solvent dimethylacetamide and the additive lactic acid. Simultaneously, the preparation method of the oral liquid is also provided, and the method is simple and suitable for industrial application.
Description
Technical Field
The invention belongs to the field of preparations, and particularly relates to an oral liquid for preventing and treating chicken colibacillosis and a preparation method thereof.
Disclosure of Invention
Colibacillosis in chicken is a common disease caused by Escherichia coli, and is characterized by causing pericarditis, perihepatitis, air sacculitis, peritonitis, salpingitis, synovitis, Escherichia coli granuloma, omphalitis and other pathological changes.
3, 4-Dihydroxybenzoic acid [ (HO)2C6H3COOH]Is the main component of protocatechuic acid, has a relative molecular mass of 154.12, and mainly comprises the following sources: is extracted from acanthopanax, schisandra, eucommia bark, holly and other plants; biosynthesis is carried out by taking glucose as a substrate in a shikimic acid pathway in microorganisms. Has antioxidant, antibacterial, antiinflammatory, and antiviral effects, and has been used in medicine and health promotion fields. 3, 4-dihydroxy benzoic acid has not been approved to be formally applied to livestock and poultry, but related animal experiments are available. Protocatechuic acid is fed, so that stress and inflammatory reaction of weaned piglets can be relieved, intestinal flora is improved, intestinal injury is relieved, and survival rate and weight gain are improved; improving intestinal flora of yellow feather broilers and increasing weight; relieving the heat stress of the poultry and lightening the oxidative damage; reducing the content of malondialdehyde in the liver of the broiler chicken, and improving the total antioxidant capacity in the liver; inhibiting virus propagation such as avian influenza, newcastle disease, infectious bursal disease, infectious bronchitis, etc., improving immunity of chicken, and reducing death rate.
3, 4-Dihydroxybenzoic acidThe antibacterial mechanism of (a) is: (1) the hydroxyl groups can be combined with lipid bilayers of cell membranes to influence the interaction of cell membrane phospholipid and protein, and change the structure, function and permeability of the cell membranes. (2) Form stable complex with iron, and the lack of iron can reduce the activity of metalloenzyme such as heme enzyme and riboside reductase, and inhibit the growth of pathogenic bacteria such as Escherichia coli. (3) The hydroxyl group is easy to be broken, and the given electron can enable O2Is activated into O-2Causing lipid peroxidation of bacterial cell membranes, and O-2Production of H under the action of SOD2O2(ii) a Divalent iron ion (Fe) in pathogenic bacteria such as Escherichia coli and Staphylococcus aureus2+) More OH is easily generated by Fenton reaction, and excessive OH grafting acts on DNA to cause breakage, thereby causing bacterial apoptosis.
3, 4-dihydroxy benzoic acid has certain in vitro antibacterial action, but the antibacterial action is weaker than that of antibiotics, for example, the MIC range of the 3, 4-dihydroxy benzoic acid to escherichia coli, staphylococcus aureus and pseudomonas aeruginosa is 0.5-3.0 mg/m L, the inventor carries out the antibacterial test on escherichia coli (CMCC 44103), the MIC of the inventor is 0.5mg/m L, the antibacterial effect of the traditional Chinese medicine extract containing the component is worse, and protocatechuic acid, mequindox and clinafloxacin are combined to have synergistic effect on fish-derived streptococcus as an antibiotic synergist, but the synergistic effect on the escherichia coli is not reported.
The 3, 4-dihydroxy benzoic acid has poor solubility in cold water, the dissolution amount in 100ml of water is less than 0.1g, the use of the 3, 4-dihydroxy benzoic acid in the chicken raising industry is limited, because the existing large-scale chicken farm generally adopts drinking water for administration, and the medicine with poor water solubility is difficult to popularize. The patent CN201110045158.7 discloses that protocatechuic acid is prepared into a liquid preparation for preventing and treating livestock and poultry viral diseases, the liquid preparation method is that protocatechuic acid, ethanol and tween are dissolved according to the weight-volume ratio of 1: 3: 4, and glycerol can be added as a solvent. However, if the preparation of the invention is mixed with chicken for drinking, four defects are caused: (1) when the medicine is diluted by 10 times of water, turbidity appears, the medicine is diluted again and still turbid, and precipitates become oil drops after the medicine is placed for 1 day, so that the medicine dosage is not uniform; (2) the drinking time of chicken comprises 4h centralized drinking or 12-24h drinking, even if the preparation is diluted by 1:100 times at one time (difficult to operate in an actual farm), the preparation can reach a clear state, but the color of the preparation can be changed into light yellow to yellow in 12-24h in water due to the oxidation of phenolic hydroxyl, the drug effect is unstable, and the preparation is not suitable for drinking in 12-24 h; (3) the potential safety hazard of medication exists when the Tween is used in an overdose manner; (4) after being diluted by water, the chicken tastes extremely bitter and is refused to drink.
3, 4-dihydroxy benzoic acid is a traditional Chinese medicine component with excellent antibacterial effect, and the following problems need to be solved for applying the 3, 4-dihydroxy benzoic acid to the prevention and treatment of chicken colibacillosis: (1) the in vitro bacteriostasis test of the escherichia coli standard strain cannot be limited, and the in vitro bacteriostasis of the escherichia coli standard strain on a chicken colibacillus clinical isolate strain is further researched; (2) on the premise of good in-vitro antibacterial action, the oral solution with stable quality during storage and application is prepared; (3) the problem that the water drinking amount of the chicken is greatly reduced due to bitter taste is solved, and the chicken drinking water is suitable for normal drinking of the chicken; (3) performing in-vivo efficacy test on the target animal chicken to achieve the aim of safely and effectively preventing and treating chicken colibacillosis; (4) the synergistic effect of the antibacterial agent and the antibacterial agent is researched, and the curative effect is improved.
Disclosure of Invention
Aiming at the problems, the application provides the oral liquid for preventing and treating the chicken colibacillosis, and 3, 4-dihydroxy benzoic acid stably exists and is not easy to oxidize under the action of adding a sweetening agent, a solvent of dimethyl acetyl and an additive of lactic acid. Simultaneously, the preparation method of the oral liquid is also provided, and the method is simple and suitable for industrial application.
The technical scheme of the invention is as follows: (claims)
1. An oral liquid for preventing and treating chicken colibacillosis is characterized by comprising the following raw materials: 10-20 g of 3, 4-dihydroxy benzoic acid, 2-4 ml of additive, 2-10g of sweetener, 2-7 g of florfenicol and 100ml of solvent.
2. The oral liquid for preventing and treating chicken colibacillosis according to claim 1, wherein the additive is lactic acid.
3. The oral liquid for preventing and treating chicken colibacillosis according to claim 1, wherein the sweetener is dissolved in a solvent.
4. The oral liquid for preventing and treating chicken colibacillosis according to claim 1, wherein the solvent is an aprotic polar solvent.
5. The oral liquid for preventing and treating chicken colibacillosis according to claim 1 or 4, wherein the solvent is one or a mixture of two of dimethylacetamide and dimethylformamide.
5. The oral liquid for preventing and treating chicken colibacillosis according to claim 1 or 3, wherein the sweetening agent is: a mixture of rebaudioside and glycyrrhizin.
6. The oral liquid for preventing and treating chicken colibacillosis according to claim 1 or 3, wherein the florfenicol and the glycyrrhizin, in combination with the 3, 4-dihydroxybenzoic acid, can exert a synergistic effect (partial synergistic or additive effect) on the antibacterial activity of escherichia coli.
6. A method for preparing the oral liquid according to any one of claims 1 to 4, comprising the steps of:
(1) adding an additive into a solvent accounting for 90 percent of the total amount, then adding 2/3 amounts of 3, 4-dihydroxybenzoic acid, and uniformly stirring;
(2) adding florfenicol into the solution obtained in the step (1), and uniformly stirring;
(3) heating to 40-60 deg.C, adding the rest 3, 4-dihydroxybenzoic acid, and stirring; cooling to room temperature for later use;
(4) adding 2 sweetening agents into the solution obtained in the step (3), stirring for dissolving, and adding the residual solvent to the whole volume; when in use, the water is added for dilution according to the instruction, and the mixture is uniformly stirred and is drunk by chickens.
The invention adopts lactic acid as an additive, plays a role in stabilizing 3, 4-dihydroxy benzoic acid, does not oxidize the 3, 4-dihydroxy benzoic acid, and mainly acts on the easily oxidized phenolic hydroxyl of the 3, 4-dihydroxy benzoic acid. Dimethylacetamide or dimethylformamide are aprotic polar solvents, can dissolve various compounds, are completely mutually soluble with water, ether, ketone, ester and the like, have the characteristics of high thermal stability, low possibility of hydrolysis, low corrosivity, low toxicity and the like, and are excellent catalysts in organic synthesis, so that cyclization, halogenation, cyanidation, alkylation, dehydrogenation and other reactions can be accelerated, and dimethylacetamide used as a solvent in the method can also play a role in resisting oxidation and stabilizing a solution. The sweetening agent is mainly used for improving the bitter taste of the 3, 4-dihydroxy benzoic acid and has a synergistic effect, and the selected sweetening agent is dissolved in a solvent; stevioside, a novel natural sweetener extracted from stevia rebaudiana Bertoni (or stevia rebaudiana Bertoni) of Compositae family herbaceous plants; glycyrrhizin, also known as glycyrrhizic acid, is a saponin component separated from traditional Chinese medicine licorice, is the main component of licorice and is also the effective component. Has adrenocortical hormone-like effect, has antiinflammatory, antiallergic, antibacterial, and toxic materials removing effects, and can inhibit proliferation of chicken Escherichia coli and relieve inflammation and toxicity caused by endotoxin in Escherichia coli. Florfenicol is an antibacterial drug special for animals, is used for treating bacterial diseases of pigs, chickens and fish caused by sensitive bacteria, and has obvious curative effect on respiratory system infection and intestinal tract infection.
The invention has the advantages of
1. Preparing an oral solution with stable quality during storage and application;
2. the problem that the water drinking amount of the chicken is greatly reduced due to bitter taste is solved, and the chicken drinking water is suitable for normal drinking of the chicken;
3. the effect is remarkable: performing in-vivo efficacy test on the target animal chicken to achieve the aim of safely and effectively preventing and treating chicken colibacillosis; the synergistic effect of the antibacterial agent and the antibacterial agent is researched, and the curative effect is improved.
Detailed Description
Example 1
A preparation method of an oral liquid for preventing and treating chicken colibacillosis comprises the following steps:
(1) adding 4 ml of lactic acid into 100ml of dimethylacetamide with the total amount being 90%, then adding 13.5g of 3, 4-dihydroxybenzoic acid, and uniformly stirring;
(2) adding 2 g of florfenicol into the solution obtained in the step (1), and uniformly stirring;
(3) heating to 60 ℃, adding 6.5 g of the rest 3, 4-dihydroxybenzoic acid, and uniformly stirring; cooling to room temperature for later use;
(4) adding 5g of sweetening agent stevioside and glycyrrhizin into the solution obtained in the step (3), stirring for dissolving, and stirring uniformly; adding the remaining solvent to full volume; when in use, the water is added for dilution according to the instruction, and the mixture is uniformly stirred and is drunk by chickens.
Example 2
A preparation method of an oral liquid for preventing and treating chicken colibacillosis comprises the following steps:
(1) adding 2 ml of lactic acid into 100ml of dimethylacetamide with the total amount being 90%, then adding 6.6g of 3, 4-dihydroxybenzoic acid, and uniformly stirring;
(2) adding 7 g of florfenicol into the solution obtained in the step (1), and uniformly stirring;
(3) heating to 40 ℃, adding 3.4 g of the rest 3, 4-dihydroxybenzoic acid, and uniformly stirring; cooling to room temperature for later use;
(4) adding 0.5 g of sweetening agent stevioside and 1.5 g of glycyrrhizin into the solution in the step (3) before feeding, stirring for dissolving, and stirring uniformly; adding the remaining solvent to full volume; when in use, the water is added for dilution according to the instruction, and the mixture is uniformly stirred and is drunk by chickens.
Example 3
A preparation method of an oral liquid for preventing and treating chicken colibacillosis comprises the following steps:
(1) adding 3 ml of lactic acid into 100ml of dimethylacetamide with the total amount being 90%, then adding 10g of 3, 4-dihydroxybenzoic acid, and uniformly stirring;
(2) adding 5g of florfenicol into the solution obtained in the step (1), and uniformly stirring;
(3) heating to 50 ℃, adding 5g of the rest 3, 4-dihydroxybenzoic acid, and uniformly stirring; cooling to room temperature for later use;
(4) adding 2 g of sweetening agent stevioside and 3 g of glycyrrhizin into the solution obtained in the step (3), stirring for dissolving, and uniformly stirring; adding the remaining solvent to full volume; when in use, the water is added for dilution according to the instruction, and the mixture is uniformly stirred and is drunk by chickens.
Example 4
A preparation method of an oral liquid for preventing and treating chicken colibacillosis comprises the following steps:
(1) adding 3 ml of lactic acid into 100ml of dimethylacetamide with the total amount being 90%, then adding 10g of 3, 4-dihydroxybenzoic acid, and uniformly stirring;
(2) heating to 50 ℃, adding 5g of the rest 3, 4-dihydroxybenzoic acid, and uniformly stirring; cooling to room temperature for later use;
(3) adding 2 g of sweetening agent stevioside and 3 g of glycyrrhizin into the solution obtained in the step (3), stirring for dissolving, and uniformly stirring; adding the remaining solvent to full volume; when in use, the water is added for dilution according to the instruction, and the mixture is uniformly stirred and is drunk by chickens.
Comparative example 1
A preparation method of an oral liquid for preventing and treating chicken colibacillosis comprises the following steps:
(1) adding 10g of 3, 4-dihydroxybenzoic acid into 100ml of dimethylacetamide with the total amount of 90%, and uniformly stirring;
(2) adding 5g of florfenicol into the solution obtained in the step (1), and uniformly stirring;
(3) heating to 50 ℃, adding 5g of the rest 3, 4-dihydroxybenzoic acid, and uniformly stirring; cooling to room temperature for later use;
(4) adding 2 g of sweetening agent stevioside and 3 g of glycyrrhizin into the solution obtained in the step (3), and uniformly stirring; and (5) sparsely stirring uniformly.
Examples of the effects of the invention
Clarity and stability of diluted solution
Taking examples 1-4 and comparative examples 1-2 as examples, diluting 10 times, 100 times, 200 times and 400 times, and standing overnight; the results show that the oral liquid prepared in the embodiments 1 to 4 of the invention has good clarity and stability; whereas comparative example 1, the discoloration was severe.
II, in-vitro bacteriostasis test: the oral liquid formulation of example 4 is adopted to prepare a standard drug sensitive tablet without dilution, the drug content (4 mug/tablet) is contained, and a drug sensitive test is carried out on clinically separated escherichia coli with strong drug resistance, and the results are as follows: the sensitivity rate of the invention is 100 percent, and the sensitivity rate of common antibiotics is 0-43 percent. The results are shown in Table 1.
TABLE 1 results of bacteriostasis of E.coli isolates from various sources, example 4 and other antibiotics
Third, the therapeutic effect
The oral liquids of examples 1-3 and comparative examples 1-2 were used to treat the colibacillosis of artificially infected chickens (Shouguang isolates) at a dose of 40mg of 3, 4-dihydroxybenzoic acid per 1kg of body weight: the chicken mortality rate of examples 1-3 decreased from 70% to 10%; mortality of example 4 was 20%; the mortality rate of the comparative example 1 is 10% (lactic acid only has effect on the stability of the product, has no obvious effect on the direct drenching drug effect, and the curative effect is reduced because the raw materials are unstable and discolor when drinking water for chickens all day).
EXAMPLE 4 in vitro antibacterial synergy test on E.coli in combination with antibacterial
4.1 the test was carried out by the drug sensitive paper strip method. The drug sensitive tablet of the antibacterial drug is sold in the market; the glycyrrhizin drug sensitive tablet is self-made, and each tablet contains 10 microgram of glycyrrhizin; the drug sensitive tablet is self-made, and each tablet contains 4 mu g of 3, 4-dihydroxy benzoic acid; the combined drug sensitive tablet is prepared by dripping the drug sensitive tablet (containing 4 mu g of 3, 4-dihydroxybenzoic acid) on a commercially available drug sensitive tablet, and drying at low temperature. Coli used a standard strain (CMCC 44103). The results are shown in Table 2.
TABLE 2 evaluation of the combined bacteriostatic effect of the drug sensitive tablets and example 4
4.2 Broth dilution checkerboard test 6 × 6 checkerboard was used, with the MIC of each drug against standard E.coli strains, to set the maximum concentration of each drug at 2 × MIC, followed by a series of double dilutions in medium, A (different antibacterial) in columns, B (3, 4-bis of the invention)Hydroxybenzoic acid) as a row, keeping the concentration of A in every 1 row of holes of a 96-well plate constant, keeping the concentration of B in the holes of the 96-well plate at 2, 1, 1/2, 1/4, 1/8 and 1/16 times of MIC (the MIC of B is 0.5mg/m L), keeping the concentration of B in every 1 row of holes constant, decreasing the concentration of A to 1/16 times of MIC, mixing uniformly, and then performing static culture at 37 ℃ for 18-24h, wherein FIC index is the partial antibacterial concentration and is used as the judgment basis, and FIC index = [ MIC ] ([ MIC ](A)/MICA]+[MIC(B)/MICB]Wherein MICA and MICB represent MIC of A and B drugs, respectively(A)And MIC(B)Represent the MIC values for each of the a and B drugs when combined. FIC index is less than or equal to 0.5, which is a synergistic effect; FIC index more than 0.5 and less than or equal to 1 is partial synergy or additive effect; FIC index is more than 1 and less than or equal to 2, which is an irrelevant effect; > 2 is antagonistic. Each group was tested in duplicate 3 times. The results are shown in Table 3.
TABLE 3 EXAMPLE 4 in vitro bacteriostatic synergy test on E.coli in combination with antibacterial agents
Note: neomycin sulfate is insoluble in dimethylacetamide but is easily soluble in water, so that neomycin sulfate cannot be mixed to prepare the same solution, but can be respectively added with water and used in combination in clinic to increase the curative effect.
Fifth, drinking water feeding test
According to the embodiment 1-4 of the invention, water is added for dilution according to the proportion of 1: 100-400 times, the chicken can drink water freely, and the water drinking amount is not changed obviously; the sweetener in example 3 was removed and the chicken was diluted as well and allowed to drink water freely, reducing the water intake by 60-90%.
Claims (7)
1. An oral liquid for preventing and treating chicken colibacillosis is characterized by comprising the following raw materials: 10-20 g of 3, 4-dihydroxy benzoic acid, 2-4 ml of additive, 2-10g of sweetener, 2-7 g of florfenicol and 100ml of solvent.
2. The oral liquid for preventing and treating chicken colibacillosis according to claim 1, wherein the additive is lactic acid.
3. The oral liquid for preventing and treating chicken colibacillosis according to claim 1, wherein the sweetener is dissolved in a solvent.
4. The oral liquid for preventing and treating chicken colibacillosis according to claim 1, wherein the solvent is an aprotic polar solvent.
5. The oral liquid for preventing and treating chicken colibacillosis according to claim 1 or 4, wherein the solvent is one or a mixture of two of dimethylacetamide and dimethylformamide.
6. The oral liquid for preventing and treating chicken colibacillosis according to claim 1 or 3, wherein the sweetening agent is: a mixture of rebaudioside and glycyrrhizin.
7. A method for preparing the oral liquid according to any one of claims 1 to 4, comprising the steps of:
(1) adding an additive into a solvent accounting for 90 percent of the total amount, then adding 2/3 amounts of 3, 4-dihydroxybenzoic acid, and uniformly stirring;
(2) adding florfenicol into the solution obtained in the step (1), and uniformly stirring;
(3) heating to 40-60 deg.C, adding the rest 3, 4-dihydroxybenzoic acid, and stirring; cooling to room temperature for later use;
(4) adding 2 sweetening agents into the solution obtained in the step (3), stirring for dissolving, and adding the residual solvent to the whole volume; when in use, the water is added for dilution according to the instruction, and the mixture is uniformly stirred and is drunk by chickens.
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