CN108310045B

CN108310045B - Compound preparation for preventing and treating mastitis of dairy cows in dry period and preparation method and application thereof

Info

Publication number: CN108310045B
Application number: CN201810298838.1A
Authority: CN
Inventors: 周淑贞; 陶映娴; 林孝崇; 焦伟丽
Original assignee: Foshan Nanhai Eastern Along Pharmaceutical Co ltd
Current assignee: Foshan Nanhai Eastern Along Pharmaceutical Co ltd
Priority date: 2018-03-30
Filing date: 2018-03-30
Publication date: 2021-12-03
Anticipated expiration: 2038-03-30
Also published as: CN108310045A

Abstract

The invention provides a compound preparation for preventing and treating mastitis of dairy cows in a dry period, and a preparation method and application thereof. In the compound preparation, the cefquinome and the traditional Chinese medicine extract are used in a matching way, so that the compound preparation not only can realize synergistic interaction, but also has the effects of resisting bacteria and diminishing inflammation, can overcome the defects of slow treatment effect and insufficient effect of the traditional Chinese medicine, can avoid the problem of western medicine residue, and fully exerts the respective characteristics of the traditional Chinese medicine and the western medicine. Meanwhile, the preparation method of the compound preparation is simple and convenient in process and is suitable for industrial production.

Description

Compound preparation for preventing and treating mastitis of dairy cows in dry period and preparation method and application thereof

Technical Field

The invention relates to the field of veterinary drugs, and particularly relates to a compound preparation for preventing and treating mastitis of dairy cows in a dry period, and a preparation method and application thereof.

Background

The mastitis of the dairy cows is the most common disease of the dairy cows in recent years, is one of the most serious diseases causing the economic loss of the dairy industry, and has great harm to the dairy cow breeding industry. There are about a billion cows throughout the world, about one third of which suffer from various types of breast disease, resulting in altered milk quality. The main cause of mastitis in cows is infection by pathogenic microorganisms, of which 5 pathogenic types, staphylococcus aureus, streptococcus agalactiae, streptococcus dysgalactiae, streptococcus uberis and various gram-negative bacteria are the most common.

The mastitis of the dairy cow not only affects the milk yield of the dairy cow and the nutritional ingredients of the milk, but also contains a large amount of pathogenic bacteria in the milk of the sick dairy cow, and if a consumer drinks the milk which is not sterilized tightly, the body is easy to be discomforted; secondly, cow's milk is rich in proteins, fats and sugars, and mammary tissue with mastitis is invaded by pathogenic bacteria, resulting in the loss of some nutrients.

Cow mastitis can be classified into clinical mastitis and recessive mastitis. Clinical symptoms of clinical mastitis are manifested by swelling, fever, congestion, pain, obstructed milk discharge, scanty milk, even cessation of secretion, swollen lymph nodes and the like of the breasts of sick cattle. The milk contains milk clot or flocculent mass, and the heavy one is mixed with blood and pus. The sick cattle do not want to stand up, and the hind limbs are opened when the sick cattle walk, and young animals are refused to breast-feed and manually milking. The cow suffers from appetite, rumination decrease and lassitude, and also can infect other mammary glands along with the development of the course of the cow, the lactation yield is sharply reduced, and the milk mixed with floccules is squeezed out of a clear water sample. Recessive mastitis has no obvious clinical symptoms, is not easy to be found, is not obvious by visual observation, and only shows that the somatic cell number of milk is increased, the milk yield is reduced, and the components of the milk are changed, thereby influencing the quality of the milk, and the diagnosis can be confirmed after the laboratory examination; recessive mastitis develops into clinical mastitis if not treated in time or treated improperly, even blind cows are led to be rejected when serious.

The key to prevent the recessive mastitis of the dairy cattle is to prevent the infection of the dairy cattle in the dry period and to prevent the inflammatory reaction of mammary tissues. The dry period is the best period for treating and preventing mastitis, as the cow stops producing milk, the mammary gland tissue is in a repair stage and can be regenerated before parturition, the mastitis treatment in the dry period can reduce the incidence rate of clinical mastitis during parturition, the treatment effect is favorably improved, the influence on the milk quality is avoided, and if the treatment of intramammary infection is not carried out, the bacteria in the dry period can be kept static until the postpartum or early lactation period is resuscitated to cause the mastitis.

Antibiotics are listed as the first choice drugs for treating mastitis all over the world for a long time, but because the antibiotics have single components and are repeatedly used for a long time, bacteria are easy to generate drug resistance, so that the curative effect is reduced; another disadvantage is that high doses of antibiotic preparations cause problems with antibiotic residues in milk, which can be harmful to human health. The pure traditional Chinese medicine preparation has no residue, small toxic and side effects, does not generate drug resistance after long-term use, can overcome the defect of using antibiotics, but has slow effect and slow effect, needs to be taken for a long time, and has far lower antibacterial effect than the antibiotics. Therefore, the development of a preparation for preventing and treating the mastitis of the animals, which has no residue, quick response and lasting drug effect, is urgent.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The cefquinome and the traditional Chinese medicine extract are used in a matched mode, so that the compound preparation has the synergistic effect, has the antibacterial and anti-inflammatory effects, can overcome the defects of slow treatment effect and insufficient effect of the traditional Chinese medicine, can avoid the problem of western medicine residue, and fully exerts respective characteristics of the traditional Chinese medicine and the western medicine.

The second purpose of the invention is to provide a preparation method of the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

a compound preparation for preventing and treating mastitis of dairy cows in a dry period is mainly prepared from the following raw materials: cefquinome and/or cefquinome salt, traditional Chinese medicine extract and auxiliary materials; wherein the traditional Chinese medicine extract comprises: one or more of birch bark extract, sargentgloryvine stem extract, honeysuckle stem extract, cowherb seed extract and snakegourd fruit extract;

preferably, the formulation is a breast implant;

preferably, the cefquinome salt is cefquinome sulfate;

preferably, the traditional Chinese medicine extract is a water extract of traditional Chinese medicine;

preferably, the Chinese medicinal extract comprises: one or more of birch bark extract, caulis Sargentodoxae extract, and caulis Lonicerae extract.

Preferably, in the compound preparation of the present invention, the adjuvant includes: antioxidant, synergist, thickener, and solvent.

Preferably, in the compound preparation of the present invention, the antioxidant includes: vitamin E oil, benzyl alcohol, BHT, propyl gallate, and one or more of BHA;

and/or, the synergist comprises: one or more of LIPONIC EG-1, isopropyl myristate, propylene glycol, and sorbitol; more preferably, the potentiator comprises LIPONIC EG-1;

and/or, the thickener comprises: one or more of vaseline, stearic acid, glyceryl monostearate, medium chain triglyceride, hydrogenated castor oil, PEG, and poloxamer; more preferably, the thickener comprises: glyceryl monostearate and hydrogenated castor oil;

and/or, the vehicle comprises: one or more of soybean oil for injection, medicinal castor oil, medicinal cottonseed oil, or liquid paraffin.

Preferably, the compound preparation provided by the invention comprises the following raw materials in percentage by weight:

1-5% of cefquinome and/or cefquinome salt, 1-5% of a traditional Chinese medicine extract and 90-98% of auxiliary materials.

2-3.5% of cefquinome and/or cefquinome salt, 2-4% of a traditional Chinese medicine extract, 0.05-0.3% of an antioxidant, 0.5-4% of a synergist, 1-20% of a thickener and 75-95% of a solvent;

more preferably, the compound preparation of the invention comprises the following raw materials by weight percent: 2-3.5% of cefquinome and/or cefquinome salt, 2-4% of a traditional Chinese medicine extract, 0.05-0.3% of an antioxidant, 0.5-4% of a synergist, 1.5-17% of a thickener and 78-90% of a solvent;

further preferably, the compound preparation of the invention comprises the following raw materials by weight percent: 3.5% of cefquinome and/or cefquinome salt, 4% of traditional Chinese medicine extract, 0.1% of antioxidant, 1% of synergist, 13% of thickener and the balance of solvent.

Preferably, in the compound preparation of the present invention, the thickener is glyceryl monostearate and hydrogenated castor oil;

more preferably, the mass ratio of the glyceryl monostearate to the hydrogenated castor oil is 1: 3-3: 1;

more preferably, the mass ratio of the glyceryl monostearate to the hydrogenated castor oil is 5: 8-8: 5.

Meanwhile, the invention also provides a preparation method of the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period, and the preparation method comprises the following steps:

mixing cefquinome and/or cefquinome salt, the traditional Chinese medicine extract and auxiliary materials, and then carrying out colloid grinding to obtain the compound preparation for preventing and treating mastitis of dairy cows in the dry period.

Preferably, the preparation method of the invention comprises the following steps:

adding the synergist and the thickener into the solvent, heating and stirring until the solution is clear, and then keeping the temperature and stirring;

cooling, adding cefquinome and/or cefquinome salt, the traditional Chinese medicine extract and an antioxidant, stirring uniformly, and grinding colloid to obtain the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period.

Similarly, the invention also provides application of the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period in preparing medicaments for treating the mastitis of the dairy cows.

Furthermore, the invention also provides a medicine or a pharmaceutical composition containing the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period.

Compared with the prior art, the invention has the beneficial effects that:

(1) the compound preparation has wide antibacterial spectrum and can exert long-acting effect during the period of dry milk;

(2) the compound preparation can reduce the dosage of antibiotics, the drug resistance of bacteria and drug residues in vivo, can quickly resist over resistance after being developed, and does not influence the quality of milk;

(3) the compound preparation has good drug fluidity, good drug release and convenient drug delivery;

(4) in the compound preparation, the medicine can be well dispersed in the matrix, the particle size of the medicine is 90 percent less than 10 mu m after the preparation carrier is emulsified, and in addition, the addition of the synergist can promote the distribution and absorption of the medicine in breast tissues and improve the bioavailability of the medicine;

(5) the compound preparation has good stability and unchanged viscosity after long-term storage; the preparation method is rapid, simple and convenient, low in cost and strong in operability.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

In view of the defects of the existing medicines in the prevention and treatment of the mastitis of the dairy cows, the invention particularly provides a novel compound preparation for preventing and treating the mastitis of the dairy cows in the dry period, so as to solve the defects of the existing medicines.

Specifically, the compound preparation provided by the invention comprises the following raw materials: cefquinome and/or cefquinome salt, traditional Chinese medicine extract and auxiliary materials;

wherein, the traditional Chinese medicine extract is: one or more of birch bark extract, sargentgloryvine stem extract, honeysuckle stem extract, cowherb seed extract and snakegourd fruit extract; preferably, the traditional Chinese medicine extract is: one or more of birch bark extract, caulis Sargentodoxae extract, and caulis Lonicerae extract; more preferably, the traditional Chinese medicine extract is: birch bark extract, caulis Sargentodoxae extract, and caulis Lonicerae extract;

further, the traditional Chinese medicine extract is a water extract of traditional Chinese medicine; the water extract of the traditional Chinese medicine can be prepared by the following method: picking raw medicinal materials, washing with water, placing into an extraction tank, adding 8 times of distilled water by weight, soaking for 30min, heating and decocting for 3 times, each time for 2h, and mixing the filtrates obtained by 3 times of water extraction to obtain extractive solution; spray drying the extractive solution to obtain Chinese medicinal extract powder with particle size not greater than 200 meshes.

Preferably, the cefquinome salt is cefquinome sulfate.

Meanwhile, preferably, the compound preparation is a breast injection, and the injection mode is convenient for administration of the dairy cow.

Wherein, cefquinome is a cephalosporin antibiotic, achieves the bactericidal effect by inhibiting the synthesis of cell walls, has broad-spectrum antibacterial activity, is stable to I-type beta-lactamase around cytoplasm and has low affinity. In vitro antibacterial test shows that the product can inhibit common gram-positive and gram-negative bacteria including Escherichia coli, Staphylococcus aureus, and Streptococcus. Cefquinome is poor in oral absorption, rapid in intramuscular and subcutaneous injection absorption, short in peak reaching time and high in bioavailability. Currently approved by the european union pharmaceutical committee for veterinary use (CVMP) for the clinical treatment of mastitis in dairy cows.

The fructus trichosanthis is a fruit of trichosanthes kirilowii maxim of Cucurbitaceae, is sweet and cold, mainly treats heat clearing and phlegm removing, chest stuffiness relieving and stagnation eliminating, dryness moistening and intestine lubricating, can be used for treating acute mastitis, swelling and pain without pus formation, and has the effects of chest stuffiness relieving, swelling subsiding and stagnation eliminating. The decoction or infusion has been proved to have the inhibition effect on gram-negative intestinal pathogenic bacteria such as escherichia coli and the like in vitro, and also has a certain inhibition effect on staphylococcus, diplococcus pneumoniae, alpha hemolytic streptococcus, influenza bacillus and the like.

The semen Vaccariae is the mature seed of herba Vaccinii Bracteati of Caryophyllaceae, and has effects of promoting blood circulation, dredging channels, promoting lactation, relieving swelling, inducing diuresis, and treating stranguria. For promoting lactation, the medicine is used for treating lactation failure after delivery; it is good at activating blood, unblocking meridians and promoting lactation, so it can be used for swelling and pain of acute mastitis.

The sargentgloryvine stem is bitter and flat, has the effects of clearing and activating the channels and collaterals, dissipating blood stasis and relieving pain, regulating qi and promoting blood circulation, killing parasites and the like, and is mainly used for treating abdominal pain caused by intestinal carbuncle, swelling and pain caused by acute mastitis and the like in clinical application.

The birch bark is bitter and flat, has effects of clearing heat, promoting diuresis, eliminating phlegm, relieving cough, and removing toxic substance, and can be used for treating acute mastitis, skin sore, and prurigo.

In traditional Chinese veterinary medicine, mastitis is called as acute mastitis, and due to pathogenic toxin accumulation and heat transformation, milk collaterals are not smooth, milk is stagnated, and the breast has symptoms of redness, swelling, heat, pain and the like, and the main treatment principles are heat clearing, detoxifying, blood circulation activating and blood stasis removing. In terms of the traditional veterinary medicine channels and collaterals, except for traumatic mastitis, excessive heat of stomach channels of yangming meridians, liver channel threshold of jueyin and chong and ren meridians are disordered, and the mastitis is only caused by unsmooth breast channels, milk stagnation, fever and putrefaction. The general therapeutic principle is therefore: clearing away heat and toxic materials, resisting bacteria, relieving inflammation, dredging channels, promoting blood circulation, relieving swelling and pain, activating collaterals, and promoting lactation.

In the invention, the cefquinome or the cefquinome salt and a specific traditional Chinese medicine extract or a traditional Chinese medicine extract composition are used together, so that the cefquinome and the traditional Chinese medicine extract composition have a synergistic interaction effect, and have an obvious effect of preventing and treating mastitis. The cefquinome or the cefquinome salt has broad-spectrum sterilization and bacteriostasis in breasts, has quick response and infection elimination, and the traditional Chinese medicine extract or the traditional Chinese medicine extract composition has the functions of clearing heat, diminishing inflammation, detoxifying and relieving pain, so that the effects of promoting lactation, eliminating stagnation and reducing swelling are achieved, the cefquinome and the traditional Chinese medicine extract have synergistic effect, the mastitis in the dry period can be treated for a long time, the mastitis in the lactation period is prevented, no antibiotic residue exists, and the cefquinome or the cefquinome salt is safer and more effective.

Further preferably, in the compound preparation provided by the invention, the dosage percentages of the raw materials are respectively as follows: 1-5% of cefquinome and/or cefquinome salt, 1-5% of a traditional Chinese medicine extract and 90-98% of auxiliary materials;

provided that the sum of the amounts of the raw materials is 100%.

Preferably, in the compound preparation provided by the invention, the auxiliary materials specifically comprise the following components: antioxidant, synergist, thickener, and solvent.

Wherein the antioxidant is: one or more of vitamin E oil, benzyl alcohol, BHT (dibutyl hydroxy toluene), propyl gallate, and BHA (butyl hydroxy anisole);

and/or, the synergist is: one or more of LIPONIC EG-1, isopropyl myristate, propylene glycol, and sorbitol; preferably, the synergist is LIPONIC EG-1;

and/or, the thickener is: one or more of vaseline, stearic acid, glyceryl monostearate, medium chain triglyceride, hydrogenated castor oil, PEG (preferably PEG400), and poloxamer (preferably poloxamer 407);

preferably, the thickening agent is divided into a thickening agent A and a thickening agent B; wherein the thickening agent A is: one or more of vaseline, stearic acid, or glyceryl monostearate; the thickening agent B is: one or more of medium chain triglycerides, hydrogenated castor oil, PEG, and poloxamer; in the present invention, it is also more preferable to use thickener a and thickener B in combination;

further preferably, in the present invention, the thickener used is: glyceryl monostearate and hydrogenated castor oil;

and/or the solvent is: the solvent can be one or more of soybean oil for injection, castor oil for injection, cottonseed oil for injection, or liquid paraffin, for example: medicinal castor oil/medicinal castor oil & soybean oil for injection/medicinal castor oil & medicinal cottonseed oil/medicinal castor oil & liquid paraffin/medicinal soybean oil for injection/medicinal soybean oil & medicinal cottonseed oil/medicinal cottonseed oil & liquid paraffin;

meanwhile, in the compound preparation, the dosage of the raw materials is as follows according to the weight percentage:

2-3.5% of cefquinome and/or cefquinome salt, such as but not limited to 2.2, 2.5, 2.7, 3.0, 3.2, or 3.4%; 2-4% of the Chinese medicinal extract, for example, but not limited to, 2.2, 2.5, 2.7, 3.0, 3.2, 3.5, or 3.7%, etc.; 0.05 to 0.3% of an antioxidant, for example, but not limited to, 0.07, 0.1, 0.12, 0.15, 0.170.2, 0.22, 0.25, 0.27, or 0.29%; 0.5 to 4% of a synergist, for example, but not limited to, 0.7, 1.0, 1.2, 1.5, 1.7, 2.0, 2.2, 2.5, 2.7, 3.0, 3.2, 3.5, or 3.7%, etc.; 1 to 20% of a thickener, for example, but not limited to, 1.5, 3, 3.5, 5, 7, 10, 12, 15, 17, 19%, or the like; and 75-95% of a solvent, for example, but not limited to, 77, 80, 82, 85, 87, 90, or 92%; provided that the sum of the use amount of the raw materials is 100 percent.

Preferably, the raw materials are used in the following weight percentage: 2-3.5% of cefquinome and/or cefquinome salt, 2-4% of a traditional Chinese medicine extract, 0.05-0.3% of an antioxidant, 0.5-4% of a synergist, 1.5-17% of a thickener and 78-90% of a solvent; provided that the sum of the amounts of the raw materials is 100%.

More preferably, the raw materials are used in the following weight percentage: 3.5% of cefquinome and/or cefquinome salt, 4% of traditional Chinese medicine extract, 0.1% of antioxidant, 1% of synergist, 13% of thickener and the balance of solvent.

Wherein, more preferably, the thickening agent is glycerol monostearate and hydrogenated castor oil in a mass ratio of 5: 8;

more preferably, the traditional Chinese medicine extract comprises a birch bark extract (namely, 2% by mass), a sargentgloryvine stem extract (namely, 1% by mass) and a honeysuckle stem extract (namely, 1% by mass) in a mass ratio of 2:1: 1.

The preparation method of the compound preparation is simple and convenient, and the steps can be referred as follows: mixing cefquinome and/or cefquinome salt, the traditional Chinese medicine extract and auxiliary materials, and then carrying out colloid grinding to obtain the compound preparation for preventing and treating mastitis of dairy cows in the dry period.

adding the synergist and the thickener into the solvent, heating and stirring (preferably, the heating temperature is 85-110 ℃) until the solution is clear, and then keeping the temperature and stirring (preferably, the stirring time is 5-25 min);

and then stopping heating, adding cefquinome and/or cefquinome salt, a traditional Chinese medicine extract and an antioxidant after cooling (preferably to 15-30 ℃), uniformly stirring, and carrying out colloid grinding (the grinding time is preferably 20-25 min), thus obtaining the compound preparation for preventing and treating the mastitis of the dairy cow in the dry period.

The compound preparation prepared by the method is a breast injection, and can be used for treating and preventing mastitis of dairy cows in the dry period caused by staphylococcus aureus, streptococcus, escherichia coli and the like. The preparation adopts adjuvant formula, has good slow release property, is beneficial to drug suspension, has good drug fluidity, is convenient for administration, can be slowly released after administration, can be retained in breast for a long time after once drug injection, has the longest time effect of more than 20 days, and is convenient and simple to use; the preparation method is simple and is suitable for the requirement of large-scale industrial production.

Furthermore, in the actual treatment process, the compound preparation can be used by single injection, or can be used together with other oral administration and/or injection, thereby achieving the purpose of comprehensive treatment.

Example 1

According to the mass percentage: 3.5% of cefquinome sulfate, 2% of a birch bark water extract, 1% of a sargentgloryvine stem water extract, 1% of a honeysuckle stem water extract, 0.1% of vitamin E oil, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, the compound breast injectant of example 1 was prepared as follows:

adding LIPONIC EG-1, glyceryl monostearate and hydrogenated castor oil into solvent, heating to 100 deg.C, stirring until the solution is clear, and stirring at constant temperature for 25 min;

stopping heating, cooling to 25 deg.C, adding cefquinome sulfate, birch bark water extract, caulis Sargentodoxae water extract, caulis Lonicerae water extract, and vitamin E oil, stirring, and colloid-grinding for 20 min.

Example 2

According to the mass percentage: 2.5% of cefquinome sulfate, 3% of a birch bark water extract, 1.5% of a sargentgloryvine stem water extract, 1.5% of a honeysuckle stem water extract, 0.1% of propyl gallate, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of medicinal cottonseed oil, and appropriate amounts of the raw materials are respectively weighed.

Then, referring to the method of example 1, the compound breast injectant of example 2 was obtained.

Example 3

According to the mass percentage: 4% of cefquinome sulfate, 1% of a birch bark water extract, 1% of a sargentgloryvine stem water extract, 1% of a honeysuckle stem water extract, 0.1% of vitamin E oil, 1% of butyl hydroxy anisole, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, referring to the method of example 1, the compound breast injectant of example 3 was obtained.

Example 4

According to the mass percentage: 3.5% of cefquinome sulfate, 3% of a birch bark water extract, 1.5% of a sargentgloryvine stem water extract, 1.5% of a honeysuckle stem water extract, 0.1% of benzyl alcohol, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of liquid paraffin, and respectively weighing a proper amount of the raw materials.

Then, referring to the method of example 1, the compound breast injectant of example 4 was obtained.

Example 5

According to the mass percentage: 5% of cefquinome sulfate, 2% of a birch bark water extract, 1% of a sargentgloryvine stem water extract, 1% of a honeysuckle stem water extract, 0.1% of vitamin E oil, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, referring to the method of example 1, the compound breast injectant of example 5 was obtained.

Example 6

According to the mass percentage: 3.5 percent of cefquinome sulfate, 2 percent of cowherb seed water extract, 2 percent of snakegourd fruit water extract, 0.1 percent of vitamin E oil, LIPONIC EG-11 percent, 5 percent of glycerin monostearate, 8 percent of hydrogenated castor oil and the balance of soybean oil for injection, and proper amount of raw materials are respectively weighed.

Then, the compound breast injectant of example 6 was prepared by referring to the method of example 1.

Example 7

According to the mass percentage: 3.5% of cefquinome sulfate, 2% of birch bark, 1% of cowherb seed water extract, 1% of snakegourd fruit water extract, 0.1% of vitamin E oil, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, the compound breast injectant of example 7 was prepared by referring to the method of example 1.

Example 8

According to the mass percentage: 3.5% of cefquinome sulfate, 4% of birch bark water extract, 0.1% of vitamin E oil, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, the compound breast injectant of example 8 was prepared by referring to the method of example 1.

Example 9

According to the mass percentage: 3.5% of cefquinome sulfate, 2% of a birch bark water extract, 1% of a sargentgloryvine stem water extract, 1% of a honeysuckle stem water extract, 0.1% of vitamin E oil, 1% of isopropyl myristate, 5% of vaseline, 4078% of poloxamer and the balance of soybean oil for injection, and respectively weighing a proper amount of the raw materials.

Then, the compound breast injectant of example 9 was prepared by referring to the method of example 1.

Comparative example 1

According to the mass percentage: 3.5 percent of cefquinome sulfate, 0.1 percent of vitamin E oil, LI PON I C EG-11 percent, 5 percent of glycerin monostearate, 8 percent of hydrogenated castor oil and the balance of soybean oil for injection, and respectively weighing proper raw materials.

Then, the compound breast injectant of comparative example 1 was prepared by referring to the method of example 1.

Comparative example 2

According to the mass percentage: 2% of birch bark water extract, 1% of sargentgloryvine stem water extract, 1% of honeysuckle stem water extract, 0.1% of vitamin E oil, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, the compound breast injectant of comparative example 2 was prepared by referring to the method of example 1.

Comparative example 3

According to the mass percentage: 3.5 percent of rifaximin, 2 percent of birch bark water extract, 1 percent of sargentgloryvine stem water extract, 1 percent of honeysuckle stem water extract, 0.1 percent of vitamin E oil, LIPONIC EG-11 percent, 5 percent of glycerin monostearate, 8 percent of hydrogenated castor oil and the balance of soybean oil for injection, and proper amount of each raw material is respectively weighed.

Then, the compound breast injectant of comparative example 3 was prepared by referring to the method of example 1.

Comparative example 4

According to the mass percentage: 3.5% of cefquinome sulfate, 2% of water extract of houttuynia cordata, 2% of water extract of dandelion, 0.1% of vitamin E oil, LIPONIC EG-11%, 5% of glyceryl monostearate, 8% of hydrogenated castor oil and the balance of soybean oil for injection, and appropriate amounts of the raw materials are respectively weighed.

Then, the compound breast injectant of comparative example 4 was prepared by referring to the method of example 1.

Experimental example 1

On the basis of a preparation quality standard draft, the compound breast injectant of the embodiments 1-9 of the invention is subjected to temperature test, illumination test, accelerated test and long-term stability test according to the veterinary drug stability test guiding principle in the appendix of the Chinese veterinary drug dictionary 2015, main indexes and contents in characters and examinations of a sample of a conventional packaging specification preparation are examined and measured, and the validity period is calculated according to the examined result. The results show that: the preparation has the effective period of more than 24 months under the conditions of shading and sealing and the temperature of below 25 ℃, and the temporary effective period of 24 months.

(1) Temperature stability test and results thereof

The compound preparations of examples 1 to 9 were each filled in a commercially available packaging material (milk tube), sealed, placed in a refrigerator at 4 ℃ and examined for 30 days at room temperature at 25 ℃ and 40 ℃ with samples taken every 5 days. The results show that the compound preparations of all groups have no obvious agglomeration phenomenon under the conditions, maintain uniform oily paste, have no phenomena of layering, color change and the like, and show that the compound preparation has good temperature stability.

(2) Light test

The compound preparations of examples 1 to 9 were filled in glass bottles, sealed, placed in a light box or other suitable lighting device with a fluorescent lamp under a illuminance of 4500 ± 500l x for 10 days, and sampled on days 5 and 10, respectively. The results show that the compound preparations of each group can keep uniform oily paste without phenomena of discoloration, layering and the like.

(3) Thermal accelerated test

The compound preparations of examples 1 to 9 were filled in commercially available packaging materials (milk tubes), respectively, sealed, placed at 30 ℃. + -. 2 ℃ and relative humidity of 75%. + -. 5% for 6 months, and sampled at the end of 1 month, 2 months, 3 months, and 6 months, respectively, for examination. The results show that the compound preparations of each group have no phenomena of discoloration, layering and the like under the conditions, and the uniform oily paste is kept.

Experimental example 2

Clinical trial study

2.1 materials and methods

2.1.1 test drugs

Examples 1-9 and comparative examples 1-4.

2.1.2 test animals

750 cows which do not have clinical mastitis characteristics clinically and normally enter a dry period in a large cow farm are selected, and according to preparation examples 1-9 and comparative examples 1-4, a positive control group (ampicillin sodium and cloxacillin benzathine compound breast injectant) and a blank control group are divided into 15 groups, and 50 cows are selected for each group for clinical drug test.

2.2 test methods

2.2.1 methods of treatment and dosages: injecting one breast injection with corresponding formula into each breast chamber of the grouped cows, and sealing the nipples.

2.2.2 therapeutic Effect determination indexes:

(1) drug timeliness maintained during dry period

(2) Drug residue after birth

(3) Changes in somatic cell counts before and after birth

(4) Mastitis in dry period and within one month after delivery

(5) Compared with similar compound preparations, the compound preparation has comprehensive use effect

(1) Drug aging property

And extruding a small amount of milk samples from the milk area every other week from 41 days after the milk is dried, and detecting once a day according to the detection result in the later detection period. The study results of the drug effect time of breast injectant (DC) with different formulas are as follows:

from the comparison test results, the injectant groups of the embodiment of the invention have ideal drug effect time, meet the international regulation timeliness (the preparation for preventing and treating the mastitis of the dairy cows in the dry period must have long effect, the drug effect can act for 60 days in the whole dry period, and the drug effect concentration of the preparation should be maintained above 21 days), can slowly release the drug, effectively reduce the administration frequency, and can exert long effect in the dry period.

Meanwhile, as can be seen from the comparison of the effects of the compound preparations of the embodiments, the embodiment 1 and the embodiment 9 have proper drug effect time, and compared with the embodiment 1, the drug effect time is longer, so that the use of the auxiliary materials such as the thickening agent has certain influence on the treatment effect of the compound preparation, and the application of the auxiliary materials used in the embodiment 1 can further improve the timeliness of the compound preparation;

meanwhile, as can be seen from the comparison between the effects of the compound preparation in the embodiment 1 and the compound preparations in the embodiments 2 and 3, the component ratio of the western medicine extract to the traditional Chinese medicine extract (in the case that the total amount of the western medicine extract and the traditional Chinese medicine extract is equivalent) has a certain influence on the timeliness of the compound preparation, and the compound preparation has better timeliness obviously according to the ratio in the embodiment 1;

on the other hand, as can be seen from the comparison between example 1 and examples 4 and 5, the examples 4 and 5 can still detect drug residues after calving, which affects the milk quality. Therefore, the dosage and the proportion of the raw materials have important influence on the action time of the compound preparation, and the compound preparation prepared by the raw materials according to the preferable scheme of the invention has obvious longer drug effect and does not influence the quality of milk;

further, as can be seen from the time-dependent comparison between the compound preparations of examples 1 and 6-8, the composition of the ingredients of the herbal extract has a certain effect on the effect of the compound preparation, and long-acting treatment can be achieved by using appropriate herbal ingredients in combination with cefquinome.

The compound antibiotic breast injectant (positive control group) on the market has no sustained release effect.

Furthermore, as can be seen from the comparison between the effects of the example and the comparative examples 1 and 2, compared with the case that only cefquinome or the traditional Chinese medicine extract is used as the effective ingredient, the cefquinome or the traditional Chinese medicine extract can achieve a longer-lasting therapeutic effect when being used in combination;

meanwhile, the effect comparison of the embodiment and the comparative examples 3 and 4 shows that the long-acting property of the medicament can be more obviously improved by matching appropriate Chinese and western medicinal components. (2) Drug residue situation

A small amount of milk sample was expressed from the breast area daily for testing on days 1 and 2 after the start. Different formulations breast injectant (DC) drug residue findings:

medicine and food additive	Number of test heads	Number of cows without residue on the day of production	Number of cows without residue in one day after birth
				Example 1	50	50 heads (100%)	50 heads (100%)
Example 2	50	50 heads (100%)	50 heads (100%)
				Example 3	50	50 heads (100%)	50 heads (100%)
Example 4	50	46 heads (92%)	49 heads (98%)
				Example 5	50	45 heads (90%)	47 heads (94%)
Example 6	50	50 heads (100%)	50 heads (100%)
				Example 7	50	50 heads (100%)	50 heads (100%)
Example 8	50	50 heads (100%)	50 heads (100%)
				Example 9	50	50 heads (100%)	50 heads (100%)
Comparative example 1	50	50 heads (100%)	50 heads (100%)
				Comparative example 2	50	50 heads (100%)	50 heads (100%)
Comparative example 3	50	50 heads (100%)	50 heads (100%)
				Comparative example 4	50	50 heads (100%)	50 heads (100%)
Positive control group	50	50 heads (100%)	50 heads (100%)
				Blank control group	50	50 heads (100%)	50 heads (100%)

As can be seen from the above experimental results, except for the groups of examples 4 and 5, the other experimental groups did not detect any drug residue on the day of mining, and no drug residue was detected after one day of mining;

meanwhile, in the groups of examples 4 and 5, the number of cows with drug residues on the day of mining and the day after mining is also small.

Therefore, the compound breast injectant has ideal drug residue effect, and provides a good theoretical basis for establishing the milk abandoning period.

(3) Changes in somatic cell counts before and after birth

The somatic cell number of the postpartum somatic cell before delivery is recorded in detail before dry milk: and (4) after the production, sampling milk, measuring the somatic cell number of each cow, and comparing the change condition of the somatic cell number. Examination results of somatic cell number changes after prenatal and postnatal treatments with different formulations of breast injectants (DC):

the experimental results show that the compound preparation of each embodiment group of the invention can effectively reduce the number of somatic cells of the dairy cows and reduce the probability of mammary gland infection, and the effect is obviously better than that of a positive control group using the existing medicine;

compared with the data of the proportion that the prenatal somatic cell number of the dairy cows is more than 50 ten thousand decreased and the proportion that the postpartum somatic cell number is less than 20 ten thousand decreased in the examples 1 and 9, the group in the example 1 has a slightly better effect, so that the selection of the auxiliary materials such as the thickening agent, the synergist and the like has a certain influence on the effect of the compound preparation;

meanwhile, compared with the data of the proportion that the prenatal somatic cell number of the cows is more than 50 ten thousand reduction and the postpartum somatic cell number is less than 20 ten thousand reduction in the examples 1, 2 and 3, the group in the example 1 has obviously better effect; therefore, the proportion of the cefquinome to the traditional Chinese medicine extract (under the condition that the total amount of the cefquinome and the traditional Chinese medicine extract is equivalent) has obvious influence on the medicine effect, and better effect can be obtained according to the optimal proportion;

further, the data of the proportion of the reduction of the somatic cell number of the dairy cows in the prenatal period of more than 50 ten thousand and the proportion of the reduction of the somatic cell number of the dairy cows in the postpartum period of less than 20 ten thousand are basically equivalent;

compared with the data of the proportion that the prenatal somatic cell number of the cows is more than 50 ten thousand reduction and the postpartum somatic cell number is less than 20 ten thousand reduction in the examples 1, 6 to 8, the group in the example 1 has obviously better effect; therefore, the composition of the components of the traditional Chinese medicine extract not only influences the timeliness of the compound preparation, but also has certain influence on the effect of preventing the mammary gland infection; obviously, the traditional Chinese medicine extract in the preferred embodiment is used in combination, so that better mastitis prevention/treatment effect can be achieved.

Further, as shown in example 1, the comparison of the data of the proportion of the reduction of the prenatal somatic cell number of the cows of more than 50 ten thousand and the proportion of the reduction of the postpartum somatic cell number of less than 20 ten thousand in comparative examples 1 and 2 shows that compared with the case that cefquinome or a traditional Chinese medicine extract is used alone as a drug effective component, the combination of the cefquinome and the traditional Chinese medicine extract can obviously achieve a better effect of preventing/treating the mammary gland infection;

similarly, as can be seen from the comparison of the proportion data of the reduction of the prenatal somatic cell number of the cows higher than 50 ten thousand and the proportion data of the reduction of the postpartum somatic cell number lower than 20 ten thousand in example 1, comparative examples 3 and 4, although a certain treatment/prevention effect can be achieved by adopting the combination of other western medicines and traditional Chinese medicine extracts, the effect of example 1 is obviously better, so that the formula of the invention can achieve a more ideal effect.

(4) Mastitis in dry period and within one month after delivery

The milk cow mastitis has a series of inflammatory reactions such as red, swelling, heat, pain and the like in the determination standard during the dry period and within one month after delivery, milk is thin, watery, beer-shaped, flocculus, pustule, blood-shaped, rice-shaped pustule, palpation is different in hardness and softness, the body temperature is increased, the appetite is reduced, and the lactation yield is reduced. Change of pH value of milk: normal milk is 6.5-6.7, while mastitis occurs close to about 7.4.

According to the experimental control results, the compound preparation of each group in the embodiment of the invention can effectively prevent and treat the mastitis of the dairy cattle, and the prevention and treatment effect of the compound preparation is obviously better than that of the positive control group using the existing medicine.

Meanwhile, as shown by comparison of the control effects of the mastitis of the cows in different example groups, the incidence rate of the mastitis of the cows in the examples 1, 4 and 5 is lowest, however, the damage of the cow udder (blood milk) can be caused by the high concentration of the effective component in the examples 4 and 5;

meanwhile, as can be seen from comparison of the data in the embodiment 1, the embodiment 2 and the embodiment 3, according to the preferable mixture ratio in the embodiment 1, a better cow mastitis prevention and treatment effect can be realized, and thus, it can be known that the mixture ratio of the raw materials has a certain influence on the treatment effect of the compound preparation;

furthermore, as can be seen from comparison of data in examples 1, 6, 7 and 8, the preferred herbal extracts of the present invention can achieve better effect of preventing and treating mastitis in dairy cows, and thus, the use of herbal extracts has a significant effect on the effect of the compound preparation of the present invention.

Similarly, as can be seen from comparison of data in example 1 and comparative examples 1 and 2, compared with a pharmaceutical preparation prepared from a single western medicine/traditional Chinese medicine extract, the optimal mastitis prevention and treatment effect can be achieved by using the cefquinome and the traditional Chinese medicine extract in a matching manner;

meanwhile, as can be seen from comparison of the control effect data of the group of the embodiment 1 and the comparative examples 3 and 4, the better control effect on the mastitis of the dairy cattle can be obtained by matching appropriate western medicines and traditional Chinese medicine components.

The experimental comparison data of (1) to (4) show that the compound preparation of the embodiment of the invention has good treatment effect on the cow mastitis, and compared with the existing medicines, the compound preparation has better treatment effect in all aspects;

meanwhile, as can be seen from the comparison of the effects of the different example groups, the effects of the compound preparations of the example groups 1, 4 and 5 on reducing the number of somatic cells and preventing and treating mastitis are obviously better than those of the other example groups, however, the drug residues are caused by the high content of the effective components in the traditional Chinese medicines of the example groups 4 and 5, so that the milk yield is influenced due to the milk abandoning period. Therefore, the compound preparation of the embodiment 1 is most preferably a prevention and treatment preparation for treating mastitis of dairy cows in a dry period.

Furthermore, as can be seen from the comparison of the comprehensive prevention and treatment effects of the compound preparations in the embodiments 1, 2-3 and 6-9, the treatment effect of the compound preparation is obviously affected no matter the traditional Chinese medicine extract is used in combination, or the proportion of western medicine components and traditional Chinese medicine extract components, or the specifically used auxiliary materials such as thickening agent and the like, but the better prevention and treatment effect of the mastitis of the dairy cow can be obviously obtained according to the formula and the raw material proportion of the embodiment 1.

Similarly, as is also apparent from the comparison of the therapeutic effects of the preparations in the examples and comparative examples, effective treatment of mastitis in dry period of cows can be achieved only by combining appropriate traditional Chinese medicine extracts and western medicine components.

A. Example 1 test results (50 test cows/200 breast areas):

remarking: formula one CMT detection before and after parturition reduces the difference: 15% + 5% +0 ═ 20%

B. Positive control test results (50 test cows/200 breast areas):

remarking: the positive control group reduces the difference in CMT detection before and after delivery: 7.5% + 5% +0 ═ 12.5

C. Mastitis occurrence within one month after delivery

From the control test data in experiment (5) it can be seen that:

1. from the CMT detection results before and after parturition, the incidence rate of recessive mastitis is reduced by 20 percent after the compound preparation in the example 1, and the difference is 12.5 percent better than that of a positive control group (similar compound breast injectant). From the results of somatic cell detection before and after delivery, the somatic cell reduction difference of < 50 ten thousand after the compound breast injectate of the example 1 is 28%, which is 16% better than that of the positive control group (the same compound breast injectate). Therefore, the compound preparation in the embodiment 1 has obvious sterilization effect and is superior to the dry milk medicine of the similar compound breast injectant.

2. The number of the blind areas of the dairy cows is not increased before and after the dry dairy medicine is used, so that the compound preparation and the control medicine can not increase the incidence rate of the blind areas and can play a role in protecting the blind areas.

3. The clinical mastitis incidence rate of the dairy cows within one month after delivery is less than 4%, but the somatic cell number of the dairy cows treated by the compound preparation of the embodiment 1 is obviously lower than that of a positive control group (like compound breast injectant dry milk medicine), so that the compound preparation of the embodiment 1 has more continuous nipple protection within 1 month after delivery.

4. In conclusion, the overall effect of the compound preparation of the embodiment 1 of the invention is obviously better than that of a positive control group (similar compound breast injectant dry milk medicine).

While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. A compound preparation for preventing and treating mastitis of dairy cows in a dry period is characterized by being prepared from the following raw materials:

3.5 percent of cefquinome sulfate, 4 percent of water extract of traditional Chinese medicines and auxiliary materials;

wherein the water extracts of the traditional Chinese medicines are as follows: 2% of birch bark water extract, 1% of sargentgloryvine stem water extract and 1% of honeysuckle stem water extract;

the compound preparation is a breast injection;

the preparation method of the water extract of the traditional Chinese medicine comprises the following steps: picking raw medicinal materials, cleaning with water, placing into an extraction tank, adding 8 times of distilled water by weight, soaking for 30min, heating and decocting for 3 times, each time for 2 hr, and mixing the filtrates of 3 water extractions to obtain extractive solution; spray drying the extractive solution to obtain Chinese medicinal plant extract powder with particle size not greater than 200 mesh, which is water extract of Chinese medicinal materials.

2. A compound preparation for preventing and treating mastitis of dairy cows in a dry period is characterized by being prepared from the following raw materials:

wherein the water extracts of the traditional Chinese medicines are as follows: 2% of birch bark water extract, 1% of cowherb seed water extract and 1% of snakegourd fruit water extract;

the compound preparation is a breast injection;

3. The compound preparation according to claim 1 or 2, wherein the adjuvant is: antioxidant, synergist, thickener, and solvent.

4. The combination formulation of claim 3, wherein the antioxidant is vitamin E oil; the synergist is LIPONIC EG-1; the thickening agent is glyceryl monostearate and hydrogenated castor oil; the solvent is soybean oil for injection.

5. The compound preparation according to claim 4, wherein the mass ratio of the glyceryl monostearate to the hydrogenated castor oil is 5: 8.

6. The preparation method of the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period as claimed in any one of claims 1 to 5, is characterized by comprising the following steps:

mixing the cefquinome, the water extract of the traditional Chinese medicine and auxiliary materials, and then carrying out colloid grinding to obtain the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period.

7. The method of claim 6, comprising the steps of:

cooling, adding cefquinome, the water extract of the traditional Chinese medicine and an antioxidant, stirring uniformly, and grinding by colloid to obtain the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period.

8. Use of the compound preparation for preventing and treating mastitis of dairy cows in a dry period as claimed in any one of claims 1 to 5 in the preparation of medicaments for treating mastitis of dairy cows.

9. A medicament or a pharmaceutical composition containing the compound preparation for preventing and treating the mastitis of the dairy cows in the dry period according to any one of claims 1 to 5.