CN118178667B - Nanometer liquid preparation of macrolide medicine, preparation method and application thereof - Google Patents

Abstract

The present invention relates to the field of medical technology, and in particular to a nano-liquid preparation of macrolide drugs, and a preparation method and application thereof. The nano-liquid preparation provided by the present invention is different from the prior art which generally uses sweetness, saltiness, umami, etc. alone or in combination to mask the bitterness of drugs. The nano-liquid preparation provided by the present invention creatively uses the natural bitterness of plants that livestock and poultry like or accept to improve the palatability of drugs. Through the synergistic effect between cosolvents and plant extracts, the dispersion and dissolution of macrolide drugs with low solubility and poor palatability in water are improved, and the difficulties of low solubility and poor palatability of macrolide drugs in aqueous solutions are overcome, and the consistency of bioavailability of macrolide drugs is ensured. The preparation has good dispersibility and the size and morphology of the nanoparticles of the preparation are uniform. At the same time, the present invention only uses water as a solvent, does not require an organic solvent, is environmentally friendly and safe, greatly reduces the risk of macrolide drugs in clinical applications, and ensures clinical efficacy.

Description

A nano-liquid preparation of macrolide drugs and its preparation method and application

Technical Field

The present invention relates to the field of medical technology, and in particular to a nano liquid preparation of a macrolide drug and a preparation method and application thereof.

Background technique

Macrolide drugs are a very important class of broad-spectrum veterinary antibiotics with good anti-infective properties and few side effects. They are widely used in livestock and poultry veterinary clinics. According to the different carbon-containing mother nuclei of their macrocyclic structures, they can be divided into three categories: 14-membered rings, 15-membered rings, and 16-membered rings. The main varieties are lincomycin, oleandomycin, erythromycin, tilmicosin, gaminomycin, tylosin, clindamycin, azithromycin, spiramycin, gitamycin, josamycin, tylosin, etc. This type of drug is widely used to prevent and treat respiratory and gastrointestinal infections in livestock and poultry, such as bovine respiratory diseases, mastitis, arthritis and otitis media caused by bovine mycoplasma infection, swine asthma caused by mycoplasma hyopneumoniae, porcine proliferative enteritis caused by Lawsonia intracellularis, and chicken chronic respiratory diseases caused by mycoplasma gallinarum. They can also be used as growth improvers.

Due to the characteristics of their molecular structure, this type of macrolide drug usually has very low water solubility and is generally insoluble or slightly soluble in water. For example, the solubility of tacrolimus in water is about 12 μg/mL. Such low water solubility brings great difficulties to drug formulation. The formulation problems caused by extremely low water solubility and the resulting low bioavailability have brought many restrictions to the formulation and clinical application of this series of drugs, seriously affecting the efficacy of their drugs.

In addition to low water solubility, another difficulty in developing veterinary liquid preparations of macrolide drugs is that these drugs taste very bitter and have extremely poor palatability. If their bitterness is not masked and their palatability is not improved, animals will refuse to eat or drink, resulting in reduced bioavailability and serious impact on the efficacy of the drug.

At present, there are solid preparations such as capsules (including soft capsules, which are oil-soluble matrices), tablets (dispersible tablets), granules, dry suspensions, and freeze-dried powder injections on the market. In addition to being inconvenient for animals to take medicine, solid preparations also have disadvantages such as bioavailability being affected by the dissolution of active ingredients, and the dissolution of active ingredients is affected by many other factors (such as preparation disintegration time, animal gastric juice volume, gastric acid pH, gastric contents, etc.). If it is made into a liquid preparation, it is not only convenient for animals to take medicine through drinking water, but also there is no dissolution problem, the bioavailability is relatively stable, and therefore the efficacy is more accurate. Liquid preparations have not been developed on the market because macrolide drugs have low solubility in aqueous solutions and poor palatability.

Summary of the invention

In order to solve the above problems, the present invention provides a nano-liquid preparation of macrolide drugs and its preparation method and application. The nano-liquid preparation provided by the present invention overcomes the difficulties of low solubility and poor palatability of macrolide drugs in aqueous solution, ensures the consistency of bioavailability of macrolide drugs, greatly reduces the risk of macrolide drugs in clinical application, and ensures clinical efficacy.

In order to achieve the above object, the present invention provides the following technical solutions:

The invention provides a nano liquid preparation of a macrolide drug, comprising the following components: a macrolide drug, a cosolvent, a plant water extract and water; the cosolvent comprises one or more of dextran, ammonium alginate, poloxamer, sodium dodecyl sulfonate, sodium dodecyl sulfate, polyethylene glycol and polysorbate 80; the raw materials for preparing the plant water extract comprise one or more of dandelion, bitter dish, bitter Zhai Po, chrysanthemum intermittent, nephrolepis chinensis, chicory, chicory, sonchus oleraceus and scutellaria baicalensis.

Preferably, the macrolide drugs include one or more of lincomycin, oleandomycin, erythromycin, tilmicosin, gaminomycin, tylosin, clindamycin, azithromycin, spiramycin, gitamycin, josamycin and tyvalomycin.

Preferably, the mass ratio of the macrolide drug to the cosolvent is 1:0.5-2; the mass ratio of the macrolide drug to the plant extract is 1:0.5-2; the mass ratio of the macrolide drug to water is 2-10:100.

Preferably, the nano liquid preparation comprises the following components: 1-10 wt.% of macrolide drug, 3-15 wt.% of cosolvent, 1-10 wt.% of plant water extract and the balance of water.

Preferably, the method for preparing the plant water extract comprises decoction; and the extraction ratio of the plant water extract is 5-200:1.

The present invention provides a method for preparing the nano liquid preparation described in the above technical solution, comprising: mixing the macrolide drug, a cosolvent, a plant water extract and water to obtain the nano liquid preparation.

Preferably, the mixing method comprises:

Dissolving the macrolide drug and the cosolvent in water by ultrasonication to obtain a first solution;

The first solution and the plant water extract are mixed for a second time to obtain the nano liquid preparation.

Preferably, the ultrasonic dissolution time is 5 to 30 minutes, and the ultrasonic dissolution power is 400 to 600W.

Preferably, the second mixing method comprises stirring; the stirring time is 5 to 60 minutes.

The present invention provides the use of the nano liquid preparation described in the above technical solution or the nano liquid preparation prepared by the preparation method described in the above technical solution in the preparation of veterinary drugs.

Beneficial effects:

The invention provides a nano liquid preparation of a macrolide drug, comprising the following components: a macrolide drug, a cosolvent, a plant water extract and water; the cosolvent comprises one or more of dextran, ammonium alginate, poloxamer, sodium dodecyl sulfonate, sodium dodecyl sulfate, polyethylene glycol and polysorbate 80; the raw materials for preparing the plant water extract comprise one or more of dandelion, bitter dish, bitter Zhai Po, chrysanthemum intermittent, nephrolepis chinensis, chicory, chicory, sonchus oleraceus and scutellaria baicalensis. The nano liquid preparation provided by the present invention is different from the prior art which generally uses sweetness, saltiness, umami and the like alone or in combination to mask the bitterness of the drug. It creatively uses the natural plant bitterness that livestock and poultry like or accept to improve the palatability of the drug. Through the synergistic effect between the cosolvent and the plant extract, the dispersibility and solubility of the macrolide drugs in water are improved, the difficulties of low solubility and poor palatability of the macrolide drugs in aqueous solution are overcome, and the consistency of the bioavailability of the macrolide drugs is ensured; the preparation has good dispersibility and the size and morphology of the nanoparticles of the preparation are uniform. At the same time, the present invention only uses water as a solvent, does not require an organic solvent, is environmentally friendly and safe, greatly reduces the risk of macrolide drugs in clinical applications, and ensures clinical efficacy.

Furthermore, the preparation method of the nano liquid preparation provided by the present invention has the advantages of mild reaction conditions, no need for high temperature and high pressure in the preparation process and simple operation.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the embodiments are briefly introduced below.

FIG1 is a physical diagram of different drug preparations and a diagram of the Tyndall phenomenon;

FIG2 is a SEM image of particles in the nano liquid preparation prepared in Example 1 of the present invention;

FIG3 is a particle size distribution diagram of the nano liquid preparation prepared in Example 1 of the present invention;

FIG. 4 is a picture of the liquid preparations prepared in Comparative Examples 1 and 2 of the present invention after being shaken and left to stand for 10 min.

Detailed ways

The invention provides a nano liquid preparation of a macrolide drug, comprising the following components: a macrolide drug, a cosolvent, a plant water extract and water; the cosolvent comprises one or more of dextran, ammonium alginate, poloxamer, sodium dodecyl sulfonate, sodium dodecyl sulfate, polyethylene glycol and polysorbate 80; the poloxamer preferably comprises one or more of poloxamer 407, poloxamer 124 and poloxamer 188; the raw materials for preparing the plant water extract comprise one or more of dandelion, bitter dish, bitter vine, chrysanthemum, nephrolepis, chicory, chicory, sonchus, sonchus and radix scutellariae; the method for preparing the plant water extract preferably comprises decoction; the extraction ratio of the plant water extract is preferably 5-200:1, that is, 5-200 parts by weight of the preparation raw materials are decocted with water to obtain 1 part by weight of the water extract.

Unless otherwise specified, the present invention has no special requirements on the sources of the components of the nano liquid preparation, and commercially available products known to those skilled in the art may be used.

In the present invention, the macrolide preferably includes one or more of lincomycin, oleandomycin, erythromycin, tilmicosin, gamithromycin, tylosin, clindamycin, azithromycin, spiramycin, gitamycin, josamycin and tylosin, and more preferably includes one or more of lincomycin, oleandomycin, erythromycin, spiramycin, gamithromycin, tylosin, clindamycin and azithromycin; the mass ratio of the macrolide to the cosolvent is preferably 1:0.5~2, and more preferably 1:1~2; the mass ratio of the macrolide to the plant extract is preferably 1:0.5~2, and more preferably 1:0.6~1; the mass ratio of the macrolide to water is preferably 2~10:100, and more preferably 2.5~8:100.

In terms of mass percentage, the nano liquid preparation preferably comprises the following components: 1-10wt.% of macrolide drugs, 3-15wt.% of cosolvents, 1-10wt.% of plant water extracts and the balance of water, and further preferably comprises 2.5-8wt.% of macrolide drugs, 5-10wt.% of cosolvents, 2.5-6wt.% of plant water extracts and the balance of water.

The present invention improves the solubility of unstable, poorly soluble, and poorly palatable macrolide drugs in water through the action of a cosolvent, forming nanometer-sized particles with uniform size. The nanometer size has the characteristics of allowing efficient delivery, which can improve the solubility and bioavailability of macrolide drugs; and the nano liquid preparation provided by the present invention creatively utilizes the natural plant bitterness that livestock and poultry like or accept to improve the palatability of the drug, thereby facilitating animals to take drugs through drinking water and improving drug utilization. The present invention provides a new form for the dosage form of macrolide drugs and the intake of veterinary drugs, and has broad application prospects.

The present invention provides a method for preparing the nano liquid preparation described in the above technical solution, comprising: mixing the macrolide drug, a cosolvent, a plant water extract and water to obtain the nano liquid preparation.

The present invention preferably dissolves the macrolide drug and the cosolvent in water by ultrasonication to obtain a first solution. In the present invention, the ultrasonic dissolution time is preferably 5 to 30 minutes, more preferably 8 to 15 minutes, and more preferably 10 minutes; the ultrasonic dissolution power is preferably 400 to 600 W, and more preferably 500 W.

After obtaining the first solution, the present invention performs a second mixing of the first solution and the plant water extract to obtain the nano liquid preparation. In the present invention, the second mixing method includes preferably stirring; the stirring time is preferably 5 to 60 minutes, more preferably 8 to 20 minutes, and more preferably 10 minutes.

The invention dissolves a macrolide drug and a cosolvent in water, and then adds a plant water extract, so that the uniform mixed liquid obtained is a macrolide drug nano liquid preparation with improved palatability by using a plant extract; the subsequent addition of the plant water extract can ensure a sufficient and effective interaction between the macrolide drug and the cosolvent, and reduce the amount of the cosolvent used; the preparation method provided by the invention uses only water as a solvent, does not require the use of an organic solvent, does not require high temperature and high pressure conditions, is environmentally friendly and safe, has mild reaction conditions, and is simple to operate.

The present invention provides the use of the nano liquid preparation described in the above technical solution or the nano liquid preparation prepared by the preparation method described in the above technical solution in the preparation of veterinary drugs.

In order to further illustrate the present invention, a nano-liquid preparation of a macrolide drug provided by the present invention, a preparation method thereof and an application thereof are described in detail below in conjunction with the accompanying drawings and examples, but they should not be construed as limiting the scope of protection of the present invention.

Example 1

A nano-liquid preparation of a macrolide drug, wherein the raw materials for preparation are as follows: 2.5 g of a macrolide drug, 5 g of a cosolvent, 2.5 g of a plant water extract, and 90 g of pure water; the macrolide drug is lincomycin, the cosolvent is poloxamer 407, and the plant water extract is a dandelion water extract (purchased from Xi'an Huilin Biotechnology Co., Ltd., item number 231217);

The preparation method is as follows:

Take an appropriate amount of pure water, add macrolide drugs and cosolvents, dissolve under 500W ultrasound for 10 minutes, and obtain a clear and transparent liquid (B in Figure 1). Then add the plant water extract, add an appropriate amount of water to completely dissolve, stir evenly (stirring time 10 minutes), and add pure water to 100 g to obtain the nano liquid preparation (C in Figure 1).

Test Example 1

2.5 g of lincomycin and 97.5 g of pure water were mixed and dissolved by ultrasonic treatment at 500 W for 10 min. The result is shown in A in FIG1 . As shown in FIG1 , macrolide drugs have low solubility in water and poor dispersibility. The nano liquid preparation prepared by the present invention overcomes the problem of low solubility of macrolide drugs in aqueous solution, has good dispersibility, and ensures the consistency of bioavailability of macrolide drugs.

Example 2

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 5 g of a macrolide drug, 5 g of a cosolvent, 3 g of a plant water extract, and 87 g of pure water; the macrolide drug is azithromycin, the cosolvent is dextran, and the plant water extract is a water extract of Ipomoea australis (purchased from Xi'an Kangzhicui Biotechnology Co., Ltd., item number kzc231012);

The preparation method is the same as that of Example 1.

Example 3

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 6 g of a macrolide drug, 8 g of a cosolvent, 4 g of a plant water extract, and 82 g of pure water; the macrolide drug is erythromycin, the cosolvent is sodium dodecyl sulfate, and the plant water extract is a water extract of Kuzhaipo (purchased from Shaanxi Tianyun Biotechnology Co., Ltd., item number TY231104);

The preparation method is the same as that of Example 1.

Example 4

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 8 g of a macrolide drug, 10 g of a cosolvent, 5 g of a plant water extract, and 77 g of pure water; the macrolide drug is oleandomycin, the cosolvent is ammonium alginate, and the plant water extract is a water extract of Sophora flavescens (purchased from Xi'an Huilin Biotechnology Co., Ltd., item number 230923);

The preparation method is the same as that of Example 1.

Example 5

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 6 g of a macrolide drug, 10 g of a cosolvent, 6 g of a plant water extract, and 78 g of pure water; the macrolide drug is gamithromycin, the cosolvent is sodium dodecyl sulfate, and the plant water extract is a water extract of Herba Cibotii (purchased from Xi'an Aoti Biotechnology Co., Ltd., item number xat231128);

The preparation method is the same as that of Example 1.

Example 6

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 6 g of a macrolide drug, 10 g of a cosolvent, 6 g of a plant water extract, and 78 g of pure water; the macrolide drug is spiramycin, the cosolvent is polyethylene glycol, and the plant water extract is a water extract of Chrysanthemum intermittentum (purchased from Xi'an Xinlu Biotechnology Co., Ltd., item number XL230910);

The preparation method is the same as that of Example 1.

Example 7

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 6 g of a macrolide drug, 10 g of a cosolvent, 6 g of a plant water extract, and 78 g of pure water; the macrolide drug is tylosin, the cosolvent is poloxamer 124, and the plant water extract is a chicory water extract (purchased from Xi'an Huilin Biotechnology Co., Ltd., item number 231022);

The preparation method is the same as that of Example 1.

Example 8

A nano-liquid preparation of a macrolide drug, prepared from the following raw materials: 6 g of a macrolide drug, 10 g of a cosolvent, 6 g of a plant water extract, and 78 g of pure water; the macrolide drug is gamithromycin, the cosolvent is polysorbate 80, and the plant water extract is a water extract of chokecherry (purchased from Shaanxi Guanchen Biotechnology Co., Ltd., item number 231025);

The preparation method is the same as that of Example 1.

Example 9

A nano-liquid preparation of a macrolide drug, the preparation raw materials are as follows: 6g of a macrolide drug, 10g of a cosolvent, 6g of a plant water extract and 78g of pure water; the macrolide drug is clindamycin, the cosolvent is poloxamer 188, and the plant water extract is a Sonchus oleraceus water extract (purchased from Shaanxi Ciyuan Biotechnology Co., Ltd., item number cy230926);

The preparation method is the same as that of Example 1.

Comparative Example 1

A liquid preparation of a macrolide drug, prepared by the following raw materials: 2.5 g of a macrolide drug, 5 g of a cosolvent and 92.5 g of pure water; the macrolide drug is lincomycin, and the cosolvent is β-cyclodextrin;

The preparation method is as follows: add a macrolide drug and a cosolvent into pure water, and dissolve them by ultrasonication at 500W for 10 minutes to obtain the liquid preparation.

The prepared liquid preparation was shaken (A in FIG. 4 ) and allowed to stand for 10 min (B in FIG. 4 ). The results are shown in A and B in FIG. 4 . It can be seen from A and B in FIG. 4 that if the co-solvent is not properly selected and the plant water extract is missing, a transparent mixed solution will not be obtained and the mixed solution will quickly separate.

Comparative Example 2

A liquid preparation of a macrolide drug similar to Example 1, the only difference being that the cosolvent is β-cyclodextrin.

The liquid preparation prepared in Comparative Example 2 was shaken (C in FIG. 4 ) and then allowed to stand for 10 min (D in FIG. 4 ). The results are shown in C and D in FIG. 4 . It can be seen from C and D in FIG. 4 that even if the co-solvent is not properly selected, a transparent mixed solution cannot be obtained, and the mixed solution will separate quickly.

Comparative Example 3

A nano liquid preparation similar to Example 2, the only difference being that the bitter disc extract in Example 2 is replaced with a stevia extract of the same specification (purchased from Henan Shuangchen Biotechnology Co., Ltd., item number hnsc231012).

Example 10

The morphology and particle size of the particles in the nanofluid preparation prepared in Example 1 were characterized using a scanning electron microscope. The main experimental instruments in the test included: a JSM-7401F ultra-high resolution field emission scanning electron microscope (JEOL, Japan) and a Malvern Zetasizer Pro (Malvern Panalytical, UK).

Specific testing methods include:

The clear and transparent liquid (B in FIG. 1 ) prepared in Example 1 was shaken, 100 μL was taken with a pipette, and diluted to 1 mL with pure water to obtain a 10-fold dilution; then 100 μL of the 10-fold dilution was taken and diluted to 10 mL with pure water to obtain a 1000-fold dilution. 5 μL of the 1000-fold dilution was taken with a pipette, and dripped onto the surface of the silicon wafer, and after being naturally air-dried at room temperature, it was observed and photographed with a JSM-7401F ultra-high resolution field emission scanning electron microscope. The obtained results are shown in FIG. 2 , and it can be seen from FIG. 2 that the morphology of the drug-loaded nanoparticles is close to spherical, and the particle size is about 100-400 nm.

The nano liquid preparation prepared in Example 1 (C in FIG. 1 ) was shaken and diluted 20 times with pure water. The particle size was measured using a Malvern Zetasizer Pro (Malvern Panalytical, UK). The results are shown in FIG. 3 , which show that the average particle size was about 300 nm and the polydispersity index (PDI) was 0.1538.

Embodiment 11

Palatability experiment: A commercially available water-soluble preparation of macrolide drugs was prepared into a solution with the same active ingredient concentration as the liquid preparations obtained in Examples 1 to 9 and Comparative Example 3, and a drinking speed comparison experiment was carried out in a chicken farm to verify the palatability of the liquid preparations obtained in Examples 1 to 9.

An appropriate amount of a commercially available macrolide drug liquid preparation or one obtained in Examples 1 to 9 or Comparative Example 3 was added to every 1000 kg of water, so that the effective drug content in the water was 100 g. The chicken houses were numbered 1, 3, 5, 7, 9, 11 ... 33, 35, 37, 39. There were 10,000 chickens in each chicken house. The administration time was after feeding, and the water was controlled for one hour before administration, and the drinking water time was 4 hours.

The feeding results are shown in Table 1.

Table 1 Test results of drinking speed comparison experiment

Chicken house number Chicken age 4 hours water supply Add to Drug addition amount 1 15 days 268 kg Shimizu 0 g 3 15 days 216 kg Commercially available lincomycin preparations 21.6 g 5 15 days 249 kg Example 1 Lincomycin Preparation 24.6 g 7 15 days 213 kg Commercially available azithromycin preparations 21.3 g 9 15 days 256 kg Example 2 Azithromycin Preparation 25.6 g 11 15 days 225 kg Comparative Example 3 Azithromycin Preparation 22.5 g 13 15 days 212 kg Commercially available erythromycin preparations 21.2 g 15 15 days 253 kg Example 3 Erythromycin preparation 25.3 g 17 15 days 211 kg Commercially available oleandomycin preparations 21.1 g 19 15 days 253 kg Example 4 Oleandomycin preparation 25.3 g twenty one 15 days 218 kg Commercially available gamithromycin preparations 21.8 g twenty three 15 days 258 kg Example 5 Gamithromycin Preparation 25.8 g 25 15 days 213 kg Commercially available spiramycin preparations 21.3 g 27 15 days 249 kg Example 6 Spiramycin preparation 24.9 g 29 15 days 215 kg Commercially available tylosin preparations 21.5 g 31 15 days 258 kg Example 7 Tylosin Preparation 25.8 g 33 15 days 214 kg Commercially available gamithromycin preparations 21.4 g 35 15 days 242 kg Example 8 Gamithromycin Preparation 24.2 g 37 15 days 217 kg Commercially available clindamycin preparations 21.7 g 39 15 days 246 kg Example 9 Clindamycin Preparation 24.6 g

From the results in Table 1, it can be seen that when the liquid preparations prepared in Examples 1 to 9 are added to drinking water, the drinking speed of the chickens is close to the drinking speed of the control group of pure water, while the drinking water consumption speed of the chickens added with the commercially available macrolide drug water-soluble preparations and the preparations prepared in the comparative example is significantly lower than that of the control group and the groups of Examples 1 to 9. It can be determined that the liquid preparations prepared in Examples 1 to 9 have good palatability, and compared with similar commercial preparations or preparations that rely on sweetness to mask the bitterness of the drug (Comparative Example 3), the palatability is significantly improved.

In summary, the present invention improves the palatability of macrolide veterinary liquid preparations by using plant extracts, thereby facilitating and improving the animals' taking of drugs through drinking water and increasing drug utilization.

Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims (9)

1. A nano liquid preparation of a macrolide drug, characterized in that it is composed of the following components: a macrolide drug, a cosolvent, a plant water extract and water; the mass ratio of the macrolide drug to the cosolvent is 1:0.5~2; the mass ratio of the macrolide drug to the plant water extract is 1:0.5~2; the mass ratio of the macrolide drug to water is 2~10:100; the cosolvent is one or more of dextran, ammonium alginate, poloxamer, sodium dodecyl sulfate, sodium dodecyl sulfate, polyethylene glycol and polysorbate 80; the raw material for preparing the plant water extract is one or more of dandelion, bitter vegetative, chrysanthemum, nephrolepis and chicory. 2. The nano liquid preparation according to claim 1, characterized in that the macrolide drug comprises one or more of lincomycin, oleandomycin, erythromycin, tilmicosin, gaminomycin, tylosin, clindamycin, azithromycin, spiramycin, guitamycin, josamycin and tylosin. 3. The nano liquid preparation according to claim 1, characterized in that the nano liquid preparation consists of the following components: 1-10 wt.% of macrolide drug, 3-15 wt.% of cosolvent, 1-10 wt.% of plant water extract and the balance of water. 4. The nano liquid preparation according to claim 1, characterized in that the method for preparing the plant water extract comprises decoction; and the extraction ratio of the plant water extract is 5~200:1. 5. The method for preparing the nano liquid preparation according to any one of claims 1 to 4, characterized in that it comprises: mixing the macrolide drug, a cosolvent, a plant aqueous extract and water to obtain the nano liquid preparation. 6. The preparation method according to claim 5, characterized in that the mixing method comprises: Dissolving the macrolide drug and the cosolvent in water by ultrasonication to obtain a first solution; The first solution and the plant water extract are mixed for a second time to obtain the nano liquid preparation. 7. The preparation method according to claim 6, characterized in that the time of the ultrasonic dissolution is 5 to 30 minutes, and the power of the ultrasonic dissolution is 400 to 600W. 8. The preparation method according to claim 6, characterized in that the second mixing method comprises stirring; and the stirring time is 5 to 60 minutes. 9. Use of the nano liquid preparation according to any one of claims 1 to 4 or the nano liquid preparation prepared by the preparation method according to any one of claims 5 to 8 in the preparation of veterinary antibiotic drugs.