CN112516085A

CN112516085A - Tilmicosin solution and preparation method and use method thereof

Info

Publication number: CN112516085A
Application number: CN202011334422.4A
Authority: CN
Inventors: 赵一阳; 黎剑坤; 刘肖娟; 王振兴; 谭志坚; 符德文
Original assignee: Foshan Standard Bio Tech Co Ltd
Current assignee: Foshan Standard Bio Tech Co Ltd
Priority date: 2020-11-25
Filing date: 2020-11-25
Publication date: 2021-03-19
Anticipated expiration: 2040-11-25
Also published as: CN112516085B

Abstract

The invention discloses a tilmicosin solution, a preparation method and a use method thereof, wherein the tilmicosin solution comprises the following raw materials in percentage by weight: 10 to 50 percent of tilmicosin, 4 to 10 percent of mixing agent, 1 to 3 percent of solubilizer, 8 to 15 percent of emulsifier, 2 to 5 percent of co-emulsifier, 1 to 3 percent of flavoring agent, 0.5 to 2 percent of taste blocker, 8 to 20 percent of oil phase and the balance of water; the emulsifier is composed of a natural emulsifier and a nonionic surfactant. The tilmicosin solution disclosed by the invention is high in tilmicosin content and good in taste, can be used for pigs, can stimulate the pigs to drink water, can be directly used for drinking water administration of the pigs, and has a wide application prospect.

Description

Tilmicosin solution and preparation method and use method thereof

Technical Field

The invention relates to the technical field of veterinary drugs, and particularly relates to a tilmicosin solution, and a preparation method and a use method thereof.

Background

Tilmicosin belongs to the 4 th generation macrolide antibiotics and belongs to the special use for animals. Tilmicosin is widely applied to infectious diseases caused by sensitive bacteria such as cattle, sheep, pigs, chickens and the like. The tilmicosin preparation recorded in the PRC (national animal pharmacopoeia) comprises three tilmicosin premixes, a tilmicosin solution and a tilmicosin premix, wherein the tilmicosin premix is generally mixed for administration, and has the problems of inconvenient operation, uneven mixing, incapability of well controlling the administration dosage and the like. The rural part of agriculture requires that most of medicines are stopped being added into commercial feed from 7 months to 1 day in 2020, and the medicine field mixing and administration become very inconvenient along with the popularization and the popularization of the automatic feeding of the breeding industry.

However, the mixed drinking administration of tilmicosin also has problems, and the existing veterinary drug quality standard of tilmicosin solution is stipulated as follows: [ DOSAGE AND ADMINISTRATION ] in terms of tilmicosin. Mixing and drinking: chicken 75mg per 1L water. The medicine is taken for 3 days. However, the veterinary drug quality standard does not have the instructions and requirements for the use of pigs. And the number of taste buds of the pigs is 3-4 times that of the pigs, the tilmicosin is very sensitive, the tilmicosin is bitter, the water drinking amount of the pigs can be reduced due to the direct mixing of the ordinary tilmicosin solution, the treatment effect cannot be achieved, and the normal growth and development are influenced.

Disclosure of Invention

The invention aims to solve the technical problem of providing a tilmicosin micro-emulsion solution which has high tilmicosin content and can be used for pigs.

The invention also aims to solve the technical problem of providing a tilmicosin micro-emulsion solution which has good taste and can stimulate the drinking water of pigs.

The technical problem to be solved by the invention is to provide a method for preparing a tilmicosin solution, which is easy to prepare and short in preparation time, and the prepared tilmicosin solution is high in tilmicosin content and stable in property.

The invention also aims to solve the technical problem of providing a method for using the tilmicosin solution, wherein the tilmicosin solution is added into an automatic drinking line of a pig farm, and the method is suitable for disease prevention, control and treatment through the drinking line in large-scale pig breeding.

In order to solve the technical problems, the invention provides a tilmicosin solution which comprises the following raw materials in percentage by weight: 10 to 50 percent of tilmicosin, 4 to 10 percent of mixing agent, 1 to 3 percent of solubilizer, 8 to 15 percent of emulsifier, 2 to 5 percent of co-emulsifier, 1 to 3 percent of flavoring agent, 0.5 to 2 percent of taste blocker, 8 to 20 percent of oil phase and the balance of water;

the emulsifier consists of a natural emulsifier and a nonionic surfactant;

the flavoring agent comprises sweetener and/or aromatic.

As an improvement of the scheme, the tilmicosin solution comprises the following raw materials in percentage by weight: 30-50% of tilmicosin, 4-10% of a mixing agent, 1-3% of a solubilizer, 8-15% of an emulsifier, 2-5% of a co-emulsifier, 1-3% of a flavoring agent, 0.5-2% of a taste blocker, 8-20% of an oil phase and the balance of water;

the emulsifier is composed of a natural emulsifier and a nonionic surfactant, wherein the mass ratio of the natural emulsifier to the nonionic surfactant is 1: (1.1-3).

The flavoring agent comprises a sweetening agent and an aromatic, and the mass ratio of the sweetening agent to the aromatic is 5 (1-4).

As a modification of the above scheme, the natural emulsifier is selected from one or more of lecithin, soybean phospholipid, hydrogenated soybean phospholipid, lanolin, wool acid, casein, beeswax and cholesterol, gum arabic, tragacanth gum, gelatin, casein and cholesterol;

the nonionic surfactant is selected from one or more of long-chain fatty alcohol polyoxyethylene ether, long-chain fatty alcohol polyoxyethylene ester, polyoxyethylene polyol fatty acid ester, polyol long-chain fatty acid ester, alkylphenol polyoxyethylene, fatty acid polyoxyethylene ester, polyoxyethylene alkylamine, polyoxyethylene alkylamide, fatty glyceride and polyglycerol fatty acid ester.

As an improvement of the scheme, the nonionic surfactant is one or more selected from Tween 80, span 60, glyceryl monostearate, polyoxyethylene octylphenol ether and polyoxyethylene nonylphenol ether.

As an improvement of the scheme, the mixture comprises a substance I and a substance II, wherein the mass ratio of the substance I to the substance II is (1-2): 1;

the substance I is selected from one or more of polyethylene glycol 4000, polyethylene glycol 6000, polyoxyethylene castor oil, polyoxyethylene monooleate, vinylpyrrolidone-vinyl acetate copolymer, soybean lecithin and pentaerythritol tetraacetate;

the substance II is one or more selected from sucrose, mannitol, xylitol, d-xylose, maltitol, fructose, glucose, glucan and alpha-lactose.

As a modification of the above, the sweetener comprises a natural sweetener and/or a synthetic sweetener;

the natural sweetener comprises one or more of sucrose, fructose, lactose, glucose, simple syrup, aromatic syrup, glycerol, sorbitol, mannitol, stevioside, glycyrrhizin, disodium glycyrrhizinate, tripotassium glycyrrhizinate, and trisodium glycyrrhizinate;

the synthetic sweetener comprises one or more of sodium cyclamate, aspartame, sodium cyclamate, neohesperidin dihydrochalcone, thaumatin, Ixeransis, saccharin and saccharin sodium.

As an improvement of the scheme, the aromatic comprises a natural aromatic extract aromatic and/or a synthetic aromatic with sweet milk flavor, fruit flavor, liquorice flavor and grain flavor;

the natural spice extract aromatic is one or more selected from lemon extract, herba Menthae extract, cortex Cinnamomi Japonici extract, ethyl maltol, ethyl vanillin, isoamyl acetate, ethyl acetate, vanillin, ethyl vanillin, and citronellal.

As an improvement of the scheme, the taste blocker is selected from one or more of pepper extract, pepper extract and chili extract.

The coemulsifier is one or more selected from ethylene glycol, propylene glycol, butanediol, ethanol, isopropanol, glycerol, n-butanol and polyglycerol ester.

The solubilizer is organic acid, and the organic acid is one or more selected from citric acid, succinic acid, salicylic acid and glycyrrhizic acid;

the oil phase is selected from one or more of isopropyl myristate, liquid paraffin, olive oil, ethyl acetate, caprylate, caprate, ethyl oleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, soybean oil and peanut oil.

Correspondingly, the invention also provides a preparation method of the tilmicosin solution, which comprises the following steps of:

heating the mixture to be molten;

mixing tilmicosin and a solubilizer, adding the mixture into the mixture, and heating the mixture to be molten to obtain a drug-loaded compound A;

uniformly mixing the emulsifier, the co-emulsifier and the oil phase substance to obtain an oil phase substance B;

dissolving correctant and taste blocking agent in the rest amount of water to obtain water phase substance C;

adding the drug-loaded compound A into the oil phase substance B, and stirring for 0.7-1.2 hours to obtain a mixture D;

and dropwise adding the water-phase substance C into the mixture D until the mixture D becomes clear and transparent, thus obtaining the tilmicosin microemulsion solution.

Correspondingly, the invention also provides a using method of the tilmicosin solution, and the tilmicosin solution is used for drinking water administration of pigs; wherein the content of the first and second substances,

adding the tilmicosin solution to an automatic drinking line of a pig farm.

The implementation of the invention has the following beneficial effects:

the invention has important effects by compounding the natural emulsifier and the nonionic surfactant, wherein the nonionic surfactant has good pH stability and neutralizes the defect that the natural emulsifier is greatly influenced by pH; secondly, the natural emulsifier is easy to form a polymer film, the nonionic surfactant can effectively reduce the water-oil interfacial tension, the formed molecular microemulsion has strong stability, high efficiency and safety, the addition amount of the emulsifier can be controlled to be about 8-15 percent, the formula is lower than that of a common formula, and the toxic and side effects are greatly reduced.

The component forms of the substance I and the substance II in the mixture can increase the solubility of the original medicine, improve the tilmicosin content in a finished product, shorten the preparation time, reduce the dosage of the emulsifier, facilitate the preparation and reduce the toxicity.

According to the invention, the organic acid is added into the tilmicosin solution to serve as the tilmicosin solubilizer, so that the material is selected safely, and the solubility of tilmicosin is increased.

The taste modifier and the taste blocker are added into the tilmicosin solution, so that the materials are selected safely; the flavoring agent (sweetener and/or aromatic agent) and taste blocker are properly matched, and are administered by inducing smell, stimulating sweet taste, paralyzing taste buds to a certain extent, and finally by stimulating drinking water.

The tilmicosin solution can be mixed and drunk through a drinking water line to serve as an optimal administration mode, is convenient to administer, is uniformly distributed, is suitable for large-scale cultivation, and has wide application prospects under the large background of future large-scale cultivation.

The invention adopts a melting method to prepare tilmicosin raw materials into a dispersion body, so that the tilmicosin is uniformly dispersed in a water-soluble carrier, and the solubility of the tilmicosin is increased, so that the content of the tilmicosin reaches 10-50 percent, even reaches 30-50 percent; in addition, the method can also shorten the preparation time, reduce the dosage of the co-emulsifier, facilitate the preparation and reduce the toxicity.

The tilmicosin solution prepared by the invention is an O/W type molecular microemulsion solution, and the tilmicosin is in an internal oil phase, so that the bitter taste of the tilmicosin is effectively inhibited; the sweetener and the taste blocker are in water phase, so the medicine is suitable for drinking water administration; the prepared molecular microemulsion solution can be mixed with water in any ratio, can be used for automatic drinking water line administration, does not block pipelines, is convenient to operate, can well regulate and control the drug dosage and drinking amount of pigs, and is suitable for disease prevention, control and treatment in large-scale breeding.

The preparation method of the tilmicosin solution combines the preparation technology of the solid dispersion and the preparation technology of the emulsion, adopts a melting method under the coordination of the solubilizer to quickly disperse the tilmicosin in the mixture, increases the solubility of the tilmicosin, shortens the preparation time, reduces the dosage of the auxiliary emulsifier, is convenient to prepare, and reduces the toxicity.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail below.

The invention provides a tilmicosin solution which comprises the following raw materials in percentage by weight: 10 to 50 percent of tilmicosin, 4 to 10 percent of mixing agent, 1 to 3 percent of solubilizer, 8 to 15 percent of emulsifier, 2 to 5 percent of co-emulsifier, 1 to 3 percent of flavoring agent, 0.5 to 2 percent of taste blocker, 8 to 20 percent of oil phase and the balance of water; the emulsifier consists of a natural emulsifier and a nonionic surfactant; the flavoring agent comprises sweetener and/or aromatic.

Further, the invention provides a tilmicosin solution which comprises the following raw materials in percentage by weight: 30-50% of tilmicosin, 4-10% of a mixing agent, 1-3% of a solubilizer, 8-15% of an emulsifier, 2-5% of a co-emulsifier, 1-3% of a flavoring agent, 0.5-2% of a taste blocker, 8-20% of an oil phase and the balance of water; the emulsifier consists of a natural emulsifier and a nonionic surfactant; the flavoring agent comprises sweetener and/or aromatic.

It should be noted that the tilmicosin solution of the present invention is preferably a tilmicosin microemulsion solution.

The mixture comprises a substance I and a substance II, wherein the mass ratio of the substance I to the substance II is (1-2): 1; the substance I is selected from one or more of polyethylene glycol 4000, polyethylene glycol 6000, polyoxyethylene castor oil, polyoxyethylene monooleate, vinylpyrrolidone-vinyl acetate copolymer, soybean lecithin and pentaerythritol tetraacetate; the substance II is one or more selected from sucrose, mannitol, xylitol, d-xylose, maltitol, fructose, glucose, glucan and alpha-lactose.

The solubilizer is organic acid selected from one or more of citric acid, succinic acid, salicylic acid and glycyrrhizic acid.

The mixture can be used as a carrier to increase the content of tilmicosin in the solution. According to the invention, organic acid is added into the tilmicosin solution to serve as a tilmicosin solubilizer, so that the tilmicosin solubilizer is safe in material selection, sour and sweet in taste, can stimulate drinking water of pigs, and can increase the solubility of tilmicosin.

The emulsifier is composed of a natural emulsifier and a nonionic surfactant. The invention has important effects by compounding the natural emulsifier and the nonionic surfactant, wherein the nonionic surfactant has good pH stability and neutralizes the defect that the natural emulsifier is greatly influenced by pH; secondly, the natural emulsifier is easy to form a polymer film, the nonionic surfactant can effectively reduce the water-oil interfacial tension, the formed molecular microemulsion has strong stability, high efficiency and safety, the addition amount of the emulsifier can be controlled to be about 8-15 percent, the formula is lower than that of a common formula, and the toxic and side effects are greatly reduced.

The mass ratio of the natural emulsifier to the nonionic surfactant plays an important role in preparing the tilmicosin solution, if the mass ratio of the natural emulsifier to the nonionic surfactant is too small or too large, the ratio of the natural emulsifier to the nonionic surfactant is unbalanced, the formation of a polymer film and a molecular microemulsion is influenced, the addition amount of the emulsifier is increased finally, and the stability and the water solubility of the tilmicosin solution are reduced.

Preferably, the mass ratio of the natural emulsifier to the nonionic surfactant is 1: (1.1-3).

Preferably, the mass ratio of the natural emulsifier to the nonionic surfactant is 1: (1.1-2).

The natural emulsifier is selected from one or more of lecithin, soybean phospholipid, hydrogenated soybean phospholipid, lanolin, wool acid, casein, beeswax and cholesterol, gum arabic, tragacanth gum, gelatin, casein and cholesterol.

The nonionic surfactant is selected from one or more of long-chain fatty alcohol-polyoxyethylene ether, long-chain fatty alcohol-polyoxyethylene ester, polyoxyethylene polyol fatty acid ester, polyol long-chain fatty acid ester, alkylphenol ethoxylate, fatty acid-polyoxyethylene ester, polyoxyethylene alkylamine, polyoxyethylene alkylamide, fatty glyceride and polyglycerol fatty acid ester.

Further, the nonionic surfactant is selected from one or more of tween 80, span 60, glyceryl monostearate, polyoxyethylene octylphenol ether and polyoxyethylene nonylphenol ether.

Sweeteners of the present invention include natural sweeteners and/or synthetic sweeteners; the natural sweetener comprises one or more of sucrose, fructose, lactose, glucose, simple syrup, aromatic syrup, glycerol, sorbitol, mannitol, stevioside, glycyrrhizin, disodium glycyrrhizinate, tripotassium glycyrrhizinate, and trisodium glycyrrhizinate; the synthetic sweetener comprises one or more of sodium cyclamate, aspartame, sodium cyclamate, neohesperidin dihydrochalcone, thaumatin, Ixeransis, saccharin and saccharin sodium.

Preferably, the mass ratio of the natural sweetener to the synthetic sweetener is 1 (1.5-3.5).

The aromatic of the invention comprises natural aromatic extract aromatic and/or synthetic aromatic with sweet milk flavor, fruit flavor, liquorice flavor and grain flavor; the natural spice extract aromatic is one or more selected from lemon extract, herba Menthae extract, cortex Cinnamomi Japonici extract, ethyl maltol, ethyl vanillin, isoamyl acetate, ethyl acetate, vanillin, ethyl vanillin, and citronellal.

Preferably, the mass ratio of the sweetening agent to the flavoring agent is 5 (1-4).

The taste blocker is selected from one or more of pepper extract, pepper extract and hot pepper extract.

According to the invention, the oil phase substance is added into the tilmicosin solution, so that the tilmicosin can be uniformly dispersed in the water-soluble carrier, and the solubility of the tilmicosin is increased, so that the content of the tilmicosin reaches 10-50%, even 30-50%; in addition, the dosage of the auxiliary emulsifier can be reduced, and the toxicity can be reduced.

Correspondingly, the invention also provides a preparation method of the tilmicosin solution, which comprises the following steps:

adding 4-10% of the mixture into a container for heating according to the weight percentage, and stirring until the mixture is molten; adding 10-50% of tilmicosin and 1-3% of solubilizer into a container, and stirring until the tilmicosin and the solubilizer are molten to obtain a drug-loaded compound A;

mixing 8-15% of emulsifier, 2-5% of co-emulsifier and 8-20% of oil phase substance, and uniformly stirring to obtain oil phase substance B;

dissolving 1-3% of flavoring agent and 0.5-0.5% of taste blocking agent in the balance of water to obtain a water phase substance C;

The preparation method of the invention also comprises the following steps:

adding 4-10% of the mixture into a container for heating according to the weight percentage, and stirring until the mixture is molten; mixing 10-50% of tilmicosin and 1-3% of solubilizer, adding the mixture into a container, and stirring until the mixture is molten to obtain a drug-loaded compound A;

mixing 1-3% of flavoring agent and 0.5-0.5% of taste blocking agent to obtain a mixed substance C;

and adding the mixture C into the mixture D, and fully stirring to obtain the tilmicosin self-microemulsion solution.

The self-microemulsion solution can be added into water to form microemulsion for subsequent use.

The invention adopts a melting method to prepare tilmicosin raw materials into a dispersion body, so that the tilmicosin is uniformly dispersed in a water-soluble carrier, and the solubility of the tilmicosin is increased, so that the content of the tilmicosin reaches 10-50 percent, even 30-50 percent; in addition, the method can also shorten the preparation time, reduce the dosage of the co-emulsifier, facilitate the preparation and reduce the toxicity.

The tilmicosin solution prepared by the invention is an O/W type molecular microemulsion solution, has good water solubility, can be used for automatic drinking water line administration, does not block a pipeline, is convenient to operate, can well regulate and control the drug dosage and drinking amount of pigs, and is suitable for disease prevention, control and treatment in large-scale breeding.

In the O/W type molecular microemulsion solution, the tilmicosin with bitter taste is in the inner oil phase, so that the bitter taste of the tilmicosin is inhibited; the sweetener and the taste blocker are mainly in a water phase, realize olfactory sensation induction drinking, sweet stimulation and certain degree of paralytic taste buds under the action of the aromatic, finally carry out drinking water administration in a drinking water stimulation mode, do not reduce drinking water, and achieve the purpose of drinking water administration treatment.

Correspondingly, the invention also provides a using method of the tilmicosin solution, which comprises the following steps: the tilmicosin solution is used for drinking water administration of animals, and is particularly suitable for drinking water administration of animals sensitive to bitter taste; further drinking water administration for pigs; the tilmicosin solution of the present invention is further added to an automatic drinking line of a pig farm. Preferably, the addition amount of the tilmicosin solution is 0.5-1.5 ml/L.

Because the tilmicosin solution is O/W type molecular microemulsion and has good water solubility, the tilmicosin solution can be added into an automatic drinking line of a pig farm for administration, does not block pipelines, is convenient to operate, can well regulate and control the drug dosage and drinking amount of pigs, and is suitable for disease prevention, control and treatment in large-scale breeding.

The invention will be further illustrated by the following specific examples

Example 1

The formula of the tilmicosin solution comprises the following components:

tilmicosin 30%

Polyethylene glycol 60003%

2 percent of sucrose

1.5 percent of citric acid

Casein 4%

6 percent of glycerin monostearate

Ethanol 4%

Olive oil 13%

Glycyrrhizin 0.5%

Aike-Bentan 0.5%

Ethyl vanillin 0.5%

1 percent of pepper extract

The balance of water.

The preparation method comprises the following steps:

heating polyethylene glycol 6000 and sucrose to 60 deg.C, and stirring to melt;

adding citric acid and tilmicosin, and continuously stirring until the mixture is completely melted to obtain a drug-loaded compound A;

mixing casein, glyceryl monostearate, anhydrous ethanol and olive oil, and stirring to obtain oil phase substance B;

mixing glycyrrhizin, Ipomoea batatas, ethyl vanillin, and fructus Zanthoxyli extract with water to obtain water phase substance C;

adding the drug-loaded compound A into the oil phase substance B, and stirring for 1 hour to obtain a mixture D;

Example 2

The formula of the tilmicosin solution comprises the following components:

tilmicosin 40.0%

4.5 percent of poloxamer

3 percent of sucrose

2 percent of citric acid

Lecithin 5%

Tween 807.5%

4.5 percent of 1, 2-propylene glycol

11 percent of isopropyl myristate

Stevioside 1%

Aspartame 0.5%

0.5% of lemon extract

1.5 percent of pepper extract

The balance of water.

The preparation method comprises the following steps:

heating poloxamer and sucrose to 60 ℃, and stirring until the poloxamer and the sucrose are molten;

mixing lecithin, tween 80, 1, 2-propylene glycol and isopropyl myristate, and stirring to obtain oil phase substance B;

mixing stevioside, aspartame, lemon extract and pepper extract with water to obtain water phase substance C;

and dropwise adding the water-phase substance C into the mixture D until the mixture D becomes clear and transparent, thus obtaining the tilmicosin solution.

Example 3

The formula of the tilmicosin solution comprises the following components:

50 percent of tilmicosin

Polyethylene glycol 60006%

4 percent of sucrose

2.5 percent of citric acid

Soybean lecithin 5%

607.5 percent of span

2 percent of isopropanol

Ethyl acetate 8%

1 percent of sodium cyclamate

Vanillin 0.5%

1% of pepper extract

The balance of water.

The preparation method comprises the following steps:

heating polyethylene glycol 6000 and sucrose to 60 deg.C, and stirring to melt;

mixing soybean phospholipid, span 60, isopropanol and ethyl acetate, and stirring uniformly to obtain an oil phase substance B;

mixing sodium cyclamate, vanillin, Capsici fructus extract and water to obtain water phase substance C;

Example 4

The formula of the tilmicosin solution comprises the following components:

tilmicosin 15%

Pentaerythritol tetraacetate 2.4%

1.6 percent of mannitol

Lecithin 2%

Tween 806%

2 percent of n-butyl alcohol

Isopropyl myristate (IPM) 10%

2.5 percent of citric acid

Mannitol 0.3%

Aike-Bentan 0.6%

0.5 percent of lemon volatile oil

Fructus Piperis extract 0.5%

Balance of water

The preparation method comprises the following steps:

heating the mixture of pentaerythritol tetraacetate and mannitol to 80 ℃, and stirring until the mixture is molten;

mixing lecithin, tween 80, n-butanol and isopropyl myristate (IPM), and stirring to obtain oil phase substance B;

mixing mannitol, Ixeris, lemon volatile oil, fructus Piperis extract and water to obtain water phase substance C;

Example 5

The formula of the tilmicosin solution comprises the following components:

10% of tilmicosin, the raw materials except the tilmicosin and the water and the content are the same as the formula of the embodiment 1, and the balance is water;

the preparation method was the same as that of example 1.

Example 6

25% of tilmicosin, the raw materials except the tilmicosin and the water and the content are the same as the formula of the embodiment 1, and the balance is water;

the preparation method was the same as that of example 1.

Comparative example 1

The raw materials and contents were the same as those of the formulation of example 1 except that glycyrrhizin and Iketam (without sweetener) were not contained, and the balance was water;

the preparation method is the same as that of example 1.

Comparative example 2

The raw materials and contents were the same as those of the formulation of example 1 except that ethyl vanillin was not contained (no fragrance), and the balance was water;

the preparation method is the same as that of example 1.

Comparative example 3

The raw materials and contents are the same as the formula of example 1 except that the pepper extract is not contained (taste blocker is not contained), and the balance is water;

the preparation method is the same as that of example 1.

Comparative example 4

The raw materials and contents were the same as those of the formulation of example 1 except that glycyrrhizin, Iketame and ethylvanillin were not contained (sweetener and aroma were not contained), and the balance was water;

the preparation method is the same as that of example 1.

Comparative example 5

The raw materials and contents are the same as the formula of example 1 except that glycyrrhizin, Iketame and Zanthoxylum bungeanum extract (no sweetener and taste blocker are contained), and the balance is water;

the preparation method is the same as that of example 1.

Comparative example 6

The raw materials and contents were the same as those of the formulation of example 1 except that ethyl vanillin and Zanthoxylum bungeanum extract were not contained (aromatics and taste blockers were not contained), and the balance was water;

the preparation method is the same as that of example 1.

Comparative example 7

The raw materials and contents were the same as those of the formulation of example 1 except that glycyrrhizin, Iketam, ethyl vanillin and Zanthoxylum extracts were not included (sweetener, aroma and taste blocker were not included), and the balance was water;

the procedure was as in example 1, except that water was added directly to the mixture D as the aqueous substance C.

Test 1

Taking 30g of tilmicosin, 60003 g of polyethylene glycol, 2g of sucrose, 1.5g of citric acid, 10g of emulsifier, 4g of absolute ethyl alcohol, 13g of olive oil, 1.5g of flavoring agent and 1g of taste blocker as formulas, respectively preparing a drug-carrying compound A, an oil-phase substance B, a water-phase substance C and a mixture D by adopting the preparation method of the invention, dropwise adding the water-phase substance C into the mixture D until the mixture D becomes clear and transparent to form a tilmicosin solution of a molecular microemulsion, and calculating the water dosage and the weight percentage of the emulsifier by adopting different emulsifiers, wherein the results are shown in the following table 1:

TABLE 1 percentage of different emulsifiers added to form a molecular microemulsion

The result shows that the compounding of the natural emulsifier and the nonionic surfactant can effectively reduce the addition of the emulsifier by 2.5-4.6%, which is beneficial to reducing the toxicity of the emulsifier and improving the biological safety.

Test 2

Test animals: the weight of the long white pig is 15-20 kg, the long white pig is raised in a common animal house, and the long white pig is managed conventionally and can drink water freely.

Randomly dividing 60 pigs into 6 groups according to body weight, 10 pigs in each group, preparing 5 groups of diluents with different concentrations from the tilmicosin solution in the example 1, performing intragastric administration on each group, observing poisoning symptoms, recording death numbers, and searching a dosage range when the death rate is 0-100%, wherein the results are shown in table 2:

TABLE 2 acute toxicity test results for tilmicosin solution

Group of	Number of pigs (only)	Dosage (mg/kg. w)	Death number (only)	Mortality (%)
					1	10	2000	0	0
2	10	2200	1	10
					3	10	2410	3	30
4	10	2630	5	50
					5	10	2860	8	80
6	10	3100	10	100

The result shows that the dose range of 0-100% of the mortality rate of the tilmicosin solution is 2000-3100 mg/kg.w, LD50 is calculated by a probability unit weighted regression method, the fitting degree test P is 0.900, which shows that the fitting degree is good, the tilmicosin solution LD50 is 2576.227 mg/kg.w, and the 95% confidence limit is 2453.428-2708.391 mg/kg.w. According to the classification standard of acute toxicity of chemical substances, the medicine belongs to low-toxicity (501-5000 mg/kg. w) class medicine, and is safe in clinical application. According to the report, the domestic tilmicosin oral LD50 is known to be 2071 mg/kg.w, the tilmicosin solution LD50 is higher than the average level reported at present, and the biological safety is higher.

Test 3

The tilmicosin solution of example 2 was used as a subject, and the subject was placed in an environment of 40 ± 2 ℃ and 75% ± 5% relative humidity, and the appearance was observed at 1,2, 3, and 6 months, respectively, and the content of tilmicosin was measured and recorded as shown in table 3:

TABLE 3 acceleration test results of tilmicosin solution

The result shows that in a high-temperature and high-humidity environment, the tilmicosin solution is stable in shape, uniform in clarification, low in tilmicosin content reduction, unobvious in difference and excellent in stability.

Test 4

The tilmicosin solution of example 3 was mixed at a ratio of 1: 1000. 1: 1500. 1: 2000, carrying out a water mixing test, uniformly mixing, standing at room temperature, observing the water-soluble stable condition of the tilmicosin solution, and measuring the content of the tilmicosin on the 1 st, 3 th, 6 th and 10 th days, wherein the record is as follows:

TABLE 4 tilmicosin solution Water solubility test results

The result shows that the tilmicosin solution can be quickly dissolved to be uniform when being added into water, the standing observation is carried out for 10 days, the appearance shape is stable, the layering demulsification phenomenon is avoided, and the automatic line water mixing administration can not block a water line; the content of tilmicosin is measured and slightly reduced but the reduction amplitude is small, which shows that the aqueous solution has excellent stability and is suitable for large-scale cultivation.

Test 5

Selecting a growing white fattening middle-stage pig in one house of a certain pig farm in Guangdong province as a test object, selecting test pigs with similar development states to group, wherein the weight of the test pigs is 60-70 kg, the number of the test pigs is 10 for each group, and the test pigs are divided into 3 groups. The tilmicosin solution in example 1 was mixed with 6 kg of water per 1ml, the change of the water intake of pigs was observed, and a commercially available tilmicosin solution group was set up to mix with water in the same ratio, and a blank control group was normally drunk without adding any drug, and the results are shown in table 5:

TABLE 5 tilmicosin solution palatability test results

The results show that the water intake of pigs sensitive to taste is not reduced by using the tilmicosin solution, and the tilmicosin solution after taste correction can stimulate the pigs to drink water and has good palatability. From the results of comparative examples 1 to 7, it can be seen that the combined action and mutual coupling of the sweetener, the aromatic and the taste blocker enables the prepared microemulsion solution to be directly used for drinking water administration of pigs without affecting normal drinking water thereof. The absence of one or two or three of the components of the sweetener, aroma and taste blocker also significantly affects the water intake of the swine. In comparative example 2, the water intake of pigs was slightly better than that of the other comparative examples because the taste blocker of the present invention has a certain aromatic effect, which plays a part of the drinking inducing effect of the aromatic in addition to the taste blocker.

Test 6

The experimental animal is a 35-month-old Changbai piglet, which has no respiratory disease characteristics in clinic and normal lung respiratory sound. The swine mycoplasma virus is recovered by 10^-3The dose of the medicine is 3ml for each trachea for counteracting toxic pathogen, and the medicine is fed regularly after counteracting toxic pathogen. After 15 days, symptoms such as cough, dyspnea and the like appear, one sick piglet is randomly selected for caesarean examination, the lung has typical lesion, mycoplasma viruses are separated from lung tissues, and the success of infection is determined.

According to the report, the ratio of daily feed and water intake of pigs is 1: 2-2.5, the usage amount of the tilmicosin premix on the pig is calculated by tilmicosin, the materials are stirred, 200-400 g of the tilmicosin premix is added into every 1000kg of feed, a treatment test is carried out by using 30% tilmicosin solution in the embodiment 1, and 3 test dose groups are determined through conversion, wherein the test dose groups are respectively a low dose group 1 by using the tilmicosin: 4000, normal dose group 1: 2000 and high dose group 1: 1000, mixing water according to a corresponding proportion and freely drinking for 15 days.

Taking the disappearance of the characteristic features of the typical diseases of the respiratory tract as cure, the weakening of the characteristic as effective, the non-weakening of the characteristic or the death of the suckling pigs as ineffective, dividing 30 sick pigs into 3 groups, recording the treatment effect of low, normal and high dose tilmicosin solution, and recording the weight gain condition of the pigs before and after administration, the results are shown in tables 6 and 7:

TABLE 6 statistics of therapeutic effect of tilmicosin solution on swine mycoplasmal disease piglets

TABLE 7 statistics of piglet weight gain before and after tilmicosin solution administration

Group of	Initial average body weight (kg)	Terminal average body weight (kg)	Average daily gain (kg)
				Low dose group	17.39±1.56	22.15±1.34	0.32±0.07
Normal dose group	17.43±1.04	23.50±1.61	0.41±0.04
				High dose group	17.32±1.75	23.89±1.48	0.44±0.05

The results show that in order to reduce the generation of drug resistance, the clinical application recommends that the medium dosage is used for treatment, namely, 30 percent tilmicosin solution is freely drunk by adding 1L of water into 1ml of water, and the good treatment effect can be achieved on respiratory diseases caused by mycoplasma hyopneumoniae infection.

While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

Claims

1. The tilmicosin solution is characterized by comprising the following raw materials in percentage by weight: 10 to 50 percent of tilmicosin, 4 to 10 percent of mixing agent, 1 to 3 percent of solubilizer, 8 to 15 percent of emulsifier, 2 to 5 percent of co-emulsifier, 1 to 3 percent of flavoring agent, 0.5 to 2 percent of taste blocker, 8 to 20 percent of oil phase and the balance of water;

the emulsifier consists of a natural emulsifier and a nonionic surfactant;

the flavoring agent comprises sweetener and/or aromatic.

2. The tilmicosin solution according to claim 1, which comprises the following raw materials in percentage by weight: 30-50% of tilmicosin, 4-10% of a mixing agent, 1-3% of a solubilizer, 8-15% of an emulsifier, 2-5% of a co-emulsifier, 1-3% of a flavoring agent, 0.5-2% of a taste blocker, 8-20% of an oil phase and the balance of water;

3. Tilmicosin solution according to claim 1 or 2, wherein the natural emulsifying agent is selected from one or more of lecithin, soya lecithin, hydrogenated soya lecithin, lanolin, wool acid, casein, beeswax and cholesterol, gum arabic, tragacanth, gelatin, casein, cholesterol;

4. The tilmicosin solution according to claim 3, wherein the non-ionic surfactant is one or more selected from the group consisting of Tween 80, span 60, glyceryl monostearate, polyoxyethylene octylphenol ether and polyoxyethylene nonylphenol ether.

5. The tilmicosin solution according to claim 1 or 2, wherein the mixture comprises a substance I and a substance II, wherein the mass ratio of the substance I to the substance II is (1-2): 1;

6. The tilmicosin solution according to claim 1 or 2, wherein the sweetener comprises a natural sweetener and/or a synthetic sweetener;

7. Tilmicosin solution according to claim 1 or 2, wherein said aroma comprises natural aroma extract aroma and/or synthetic aroma of the sweet milk, fruit, licorice, cereal or nut type;

8. Tilmicosin solution according to claim 1 or 2, wherein the taste blocker is selected from one or more of zanthoxylum bungeanum maxim extract, piper nigrum extract, capsicum extract.

9. A preparation method of a tilmicosin solution is characterized by comprising the following steps of:

heating the mixture to be molten;

10. A method for using a tilmicosin solution, which is characterized in that the tilmicosin solution as claimed in any one of claims 1 to 8 is used for drinking water administration of pigs; wherein the content of the first and second substances,

adding the tilmicosin solution to an automatic drinking line of a pig farm.