HU201668B - Method for producing veterinary preparation and fodder premixture of synergetic effect serving for making more economical breeding of animals - Google Patents

Abstract

The present invention relates to a method for increasing the yield of farm animals, preferably poultry and pigs, and to certain macrolide anabolic antibiotics, preferably kitamycin and a quinolone carboxylic acid, for the prophylaxis and treatment of various gastrointestinal and respiratory diseases such as various pox infections and poultry and porcine mycoplasmosis. flumequin and / or oxolinic acid for the preparation of a veterinary composition and a feed mixture comprising 20: 1 to 1:20, preferably 5: 1 to 1: 1. EN 201 668 A Scope of the description: 5 pages without drawing -1-

Description

FIELD OF THE INVENTION The present invention relates to a process for the production of an antibacterial synergistically active veterinary drug and feed compound for the production of animals, preferably farm animals, especially poultry and pigs, to increase their meat yield, to prevent certain bacterial diseases, is a mixture of its salts.

Macrolide antibiotics (critromycin, cisacamycin, tylosin, olcandomycin, spiramycin) are well-known cyclic compounds containing laclon. Of these, erythromycin [Anlibiot. and Chcmothcr. 2. U.S. Patent 281 (1952) 2,653,899] and tylosin (Anlibiot. and Chcmothcr. 11, 328 (1961), 3,178,341], which is a mixture of at least eight biologically active components. Macrolide antibiotics are mainly active against Gram-positive bacteria and mycoplasmas, while others (eg tylosin) also have pronounced trcponema-cllcncs activity.

Among the quinolone carboxylic acid derivatives (oxolinic acid, nalidixic acid, flumcquin, norfioxacin, ciprofioxacin, enrofloxacin and esters of compounds c), oxolinic acid [Antimicr. Ag., Chcmothcr. 2. U.S. Patent 3,287,458, 475 (1967)] and nalidixic acid [J. Med Pharm. Chem., 5,1063 (1962) 3,149,104. U.S. Pat. No. 5,191,191] have long been known compounds in both human and veterinary medicine.

Newer members within compound c of fiumcquin [Antimicr. Ag. Chcmohcr. 13, 479 (1978)], norfloxaxin [J. Antimicr. Chcmothcrm. 11: 369 (1983)], ciprofioxacin [Antimicr. Ag. Chcmothcrm 25 319 (1984)] and cnrofloxacin (Schccr, M. Bauditz, R .: Baytril (BAY Vp 2674) - Antibactic activity as a serum and tissues in calves (PVS Congrcss, 1986, 1986)). .

These compounds are mainly effective against gram-negative bacteria. The compounds are used in human medicine mainly for the treatment of urinary tract infections and in veterinary medicine mainly for the control of enteric, urinary and respiratory diseases caused by Gram-negative germs.

Esters, in particular alkyl esters of quinolone carboxylic acids, have similar pharmacological effects, and hence the mention of quinolone carboxylic acids includes their esters.

The antibacterial activity of macrolide antibiotics is enhanced in combination with aminoglycoside antibiotics (U.S. Patent No. 4,379,781).

The oxolinic acid described herein is 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid;

nalidixic acid: 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid;

flumcquin: 1- (4,5-dichloro-2-ticnyl) -2- (1H-cis-bulylamino) -ctanol;

norfioxacin: 1-ethyl-6-fluoro-4-oxo-7-pipcrazino-1,4-dihydroquinoline-3-carboxylic acid;

ciprofioxacin: 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-hypcrazin-1-yl-quinoline-3-carboxylic acid.

(Acid addition salts of the disclosed compounds are also known.) In the following, when describing the above compounds and their effects, the salts thereof are also encompassed herein.

Our studies have found that when a macrolide antibiotic is preferably used in combination with oxolinic acid and / or flumcquin, the antimicrobial activity of the compounds with different spectrum of activity is enhanced in a synergistic manner in many bacterial strains.

In our experiments we have found that the use of ready-to-use anti-bacterial products increases the meat yield of the animals, improves the nutrition of the forage and prevents the occurrence of certain bacterial diseases.

The present invention relates to a method for increasing the yield of animals, preferably poultry and pigs, and to increasing the yield of certain digestive and respiratory tract. for the preparation of a synergistic antimicrobial agent for the prevention of diseases such as various mycobacterial infections and poultry and porcine mycoplasmosis, characterized in that a macrolide antibiotic is a quinolone carboxylic acid derivative and / or biologically acceptable salts thereof: A mixture of 20, preferably 5: 1 to 1: 1, is mixed with the usual carrier, diluent diluents for veterinary preparations.

According to the invention, the macrolide antibiotic is 1-100 mg / kg, preferably 3060 mg / kg in poultry, 5-20 mg / kg in pigs, and 0.5-50 mg / kg in quinolone carboxylic acid derivative, preferably 5-15 mg / kg in poultry. per kg bodyweight and 2.510 mg / kg body weight in pigs.

The macrolide anlibiotic is kilasamycin and / or tylosin and / or erythromycin and / or, if desired, the biologically acceptable salts thereof and flumequinl and / or oxolinic acid and / or nalidixacin and / or norfloxacin and / or ciprofloxacin and / or enrof and / or their bioavailable salts and / or esters.

The composition is mixed in a dose of 1 to 150 mg / kg, preferably 10 to 50 mg / kg of active ingredient, and is administered orally or parenterally.

According to the invention, the treatment is preferably carried out as follows:

1. In the treatment of poultry, the animals are treated with a macrolide anlibiotic, preferably kilasamycin and a quinolone carboxylic acid derivative at daytime and then during the fattening period 1 or if necessary (particularly in turkeys) for 1 to 5 days, preferably 3 days. , preferably with a combination of flumcquin. Application of the procedure to increase the meat yield of the animals in the respiratory tract! disease and coli infections. Alternatively, the combination of the macrolide antibiotic and the quinolone carboxylic acid derivative may be used in the diet during the first days of life and then during the fattening period for an additional 1, if necessary 2 to 3 to 10 days, preferably 3 to 5 days.

2. The pigs have been weaned for 3 to 14 days, preferably 5 to 10 days, after weaning and, if necessary, during subsequent stages of fattening, with the addition of a macrolide antibiotic oxolinic acid.

GB 201 668 The bination is treated through the feed. A further application is the use of a combination of a macrolide antibiotic and a macrolide-containing antibiotic and a quinolone-quinoic acid derivative for 3-14 days, preferably 5-10 days, dissolved in drinking water.

The application of the method increases the meat yield of the animals, improves the sales of feed and significantly reduces the incidence of colic and enzootic pneumonia.

3. Cows and ewes are treated with a combination of a macrolide antibiotic, preferably chitazamycin, and a quinolone carboxylic acid derivative, preferably oxolinic acid, for intra-uterine treatment for a period of 1-5 days after birth to prevent and treat bacterial infections of the uterus. The procedure accelerates the rate of uterine volumization, prevents bacterial uterine infections, and allows animals to become pregnant again within a short period of time.

4. Cows are treated intracisternally for a period of 1-5 days following the combination of a macrolide antibiotic, preferably chitamycin and a quinolone carboxylic acid derivative, preferably oxolinic acid, for prevention and treatment of bacterial mastitis, after dryness and during lactation. By using this procedure, the incidence of clinical and subclinical mastitis can be greatly reduced and the amount of milk produced increased.

The main advantages of the process according to the invention are as follows:

(a) the yields of animals may be increased and the profitability of production may be increased.

(b) control of certain bacterial infections of the gastrointestinal tract, the respiratory tract, the urinary tract and the uterus is more effective and cost-effective than at present.

FIELD OF THE INVENTION The present invention relates to any process for the preparation of a feed or nutrient mixture and a medicated premix comprising a combination of a macrolide antibiotic and a quinolone carboxylic acid derivative in addition to the known feed, feed, and feed components.

The feed and nutritional mixtures may contain from 0.01% to 10% of said active compounds. Some examples of commercially available nutrition and nutritional products which may include the following active ingredients include:

(a) Intensive broiler starter feed

(b) Intensive broiler rearing feed

(c) Hybrid turkey starter feed

(d) Hybrid turkey breeder I. nutrition

(e) Pig moor

(f) Hybrid broiler starter uniform premix (g) Piglet uniform premix.

The invention further provides a process for the preparation of feed additives.

A 20: 1 to 1:20, preferably 5: 1 to 1: 1 mixture of a macrolide antibiotic and a quinoline 10 carboxylic acid derivative and / or salts or esters thereof is admixed with the usual ingredient in the compound feed.

The macrolide antibiotic is chitamycin and / or tylosin and / or erythromycin and / or, if desired, their biologically usable salts and flumcquin and / or oxolinic acid and / or nalidixic acid and / or norfloxacin and / or ciprofloxacin and / or enrofloxacin and / or the biologically acceptable salts and / or esters thereof.

The composition is mixed and administered orally in a dose of 1 to 150 mg / kg, preferably 10 to 5 mg / kg of active ingredient.

The veterinary medicinal product is administered orally and / or parenterally. The ratio of the quinolone carboxylic acid derivative to the macrolide antibiotic in the veterinary composition may be 20: 1 to 1:20, preferably 5: 11: 1.

The daily dosage of the preparation is 1-150 mg / kg, preferably 1-50 mg / kg of active ingredient.

Microbiological studies were performed to evaluate the in vitro inhibitory effect of each active compound or combination thereof on different bacterial strains. The results are summarized in Table 1.

In vitro studies clearly demonstrated the synergistic effect of the combination on certain bacterial strains. The enhancement is mainly expressed in cultures of Staphylo40 coccus aureus, Listeria monocy togenes and Bordetella bronchiseptica. The rate is usually 2-4 times, but in some cases it can reach 20 times.

In our studies of broiler chickens, we have shown that, for example, chitamycin with flumequin in the first 3 days of life and fattening 26-28. on Day 5: 1

Table 1

Antibacterial activity of chemotherapeutic agents and combinations thereof (mg / l)

Bacterium Chemotherapeutic agent species Kitasamicin MIC * MBC " oxolinic MIC MBC Kitasamicin + oxolinic MIC MBC synergism

Staphyloccoccus aureus 5 25 25 50 5 5 2-10 fold Listeria mono- cytogenes 5 5 100 100 1 5 2-10 fold E.coli 494 200 200 0.5 1 0.5 1 2x E.colill 200 200 0.5 1 0.5 1 2-4 fold Bordetella bronchiseptica 200 200 5 10 0.5 25 20 times

x - Minimum inhibitory concentration xx - Minimum bactericidal concentration

When combined at a dose of 300 mg / l via drinking water, the animals significantly increased meat yields compared to untreated controls, improved feed intake, and reduced the incidence of chronic respiratory disease and coli infections. In our studies of broiler chickens, we found that, when used in combination with 5: 1 combination of chitamycin and flumequin for 5 days, the clinical signs of chronic respiratory disease were virtually eliminated in treated animals, significantly reducing mortality and increasing meat yield and productivity. .

According to our results in broiler chickens, the combination of chitamycin and flumequin at a dose of 240 mg / kg / kg in feed for the first 10 days of life significantly increased meat yield, improved feed sales, mortality, and coli infection in broiler chickens. significantly reduced the incidence of respiratory disease.

In our studies in turkeys, we found that combination of chitamycin with flumequin in the ratio of 5: 1 for the first 3 days of life, followed by a total of 300 mg / l in drinking water during the 6th week of fattening increased the body weight gain of animals, and significantly reduced the incidence of coli infections.

In our experiments in fattening pigs, we found that in combination with oxitic acid in a 2: 1 ratio, at a dose of 300 mg / kg body weight and after 10 to 10 days after transfer to the fattening farm, the use of significantly reduced the incidence of elective colic hash and enzymatic pneumonia.

In our studies of fattening pigs, we found that the combination of chitamycin and flumequin in a 2: 1 ratio in the feed at a dose of 300 mg / kg.kg, after 10 days after introduction into fattening, significantly increased the meat yield of the animals, significantly reduced the incidence of coli infections and enzootic pneumonia.

In our experiments in fattening pigs, it was found that when applied with flumequin 2: 1 in a ratio of 180 mg / l for 7 days, it significantly reduced the clinical symptoms of enzootic pneumonia, significantly increased the yield of pigs and improved feed sales.

In our studies of cows, we found that a 1: 1 combination of chitamycin and oxolinic acid encapsulated in the uterus of newly born cows accelerated the rate of involution and prevented the development of uterine inflammation and fetal retardation. 1 capsule contained 3 g of the active ingredient.

In our experiments on cows, we found that a 3: 1 combination of chitamycin and oxolinic acid, when formulated as a suitable vehicle for oestrus, delivers inflammatory udder quarters in 3 days to animals with acute mastitis.

In our studies on cows, we found that a 3: 1 combination of chitacamycin and oxolinic acid, when formulated as an udder formulation with appropriate carriers, 1 time during the dry period 4 weeks prior to expected parturition, infused into the udder quarters with bacterial infections.

The invention is illustrated by the following non-limiting examples.

Example 1

Drinking water containing 250 mg / l of chitamycin and 50 mg / l of flumequine in broiler chickens for life 1-3 and 26-28. day for 3 to 3 days. (In addition to increasing meat yields, the procedure also greatly reduces the incidence of chronic gastrointestinal disease and coli infections.)

Example 2

For the first 10 days of life, broiler chickens are fed with feed containing 200 mg / kg bodyweight of chitamycin and 40 mg / kg body weight of flumequin. (The procedure significantly increases the meat yield of the animals, significantly reduces the number of deaths and the occurrence of coli infections and chronic respiratory disease.)

Example 3

Turkeys are given drinking water containing 250 mg / l tylosin and 50 mg / l enrofloxacin for 1 to 3 days of life, and for 6 to 3 weeks of fattening. (This procedure significantly reduces the number of deaths and the incidence of coli and mycoplasma infections in addition to increasing the meat yield of the animals.)

Example 4

The fattening pigs are fed with feed containing 200 mg / kg of chitamycin and 100 mg / kg of oxolinic acid for 10 to 10 days after selection and after transfer to the fattening farm. (The method significantly reduces the incidence of colic diarrhea and enzootic pneumonia, as well as increasing meat yields in animals.)

Example 5

Freshly calved cows were placed in the uterus for 3 days containing 1.5 chitamycin and 1.5 g palidixic acid. (The procedure accelerates the rate of involution and prevents uterine inflammation and fetal retardation.)

Example 6

A pulv is prepared using erythromycin cs norfloxacin as active ingredients. The composition of pulvis is as follows:

erythromycin thiocyanate 25.0 g norfloxacin 5.0 g sucrose 70.0 g

100.0 g

The preparation is used in the prevention or treatment of diseases caused by E.coli and mycoplasmas in chickens, turkeys and pigs, dissolved in drinking water or mixed with feed at a dose of 10-50 mg / kg.

HU 201 668 A

Example 7

A drug premix is prepared using the active ingredients of the cytacamycin and oxolinic acid sample. The composition of the medicated premix is as follows:

chitamycin tartrate 20.0 g oxolinic acid 10.0 g wheat flour 970.0 g

1000.0 g

The medicated premix is mixed at a concentration of 1% with feed for fattening pigs, and the feed thus prepared is fed to the animals after selection and then introduced into the fattening farm for 10 to 10 days.

Example 8

Cytamycin and ciprofloxacin are used as active ingredients in the preparation of a bee capsule. The composition of the bee capsule is as follows:

cisacamycin tartrate 1.5 g ciprofloxacin 1.5 g lactose 2.0 g

5.0 g

Example 9

Utilization of chitamycin and oxolinic acid as active ingredients provides an udder preparation. The composition of the preparation is as follows:

chitamycin tartrate 0.75 g oxolinic acid 0.25 g oleum helianthi 2.00 g ccra alba 0.25 g glycerol monostearate 0.25 g

Miglyol - 812 ad 11.00 g

The preparation is filled into a plastic syringe and the contents of 1 syringe per quarter of the cows are fed into the udder during the dry period.

Claims (6)

A process for the preparation of an animal having an antimicrobial synergistic antimicrobial agent for the prevention of the production of animals, preferably poultry and swine, and for the prevention of certain gastrointestinal diseases such as various coliforms and poultry and swine mycoplasmosis, and a mixture of a quinolone carboxylic acid derivative and / or biologically acceptable salts thereof in a ratio of 20: 1 to 1:20, preferably 5: 1 to 1: 5, with the usual carriers, carriers and diluents for veterinary preparations. Process according to claim 1, characterized in that the macrolide antibiotic is chitamycin and / or tylosin and / or erythromycin and / or, if desired, their biologically acceptable salts and flumequine and / or oxolinic acid and / or nalidixic acid and / or or norfloxacin and / or ciprofioxacin and / or enrofloxacin and / or their bioavailable salts and / or esters. The process according to claim 1, characterized in that the composition is mixed in a dose of 1150 mg / kg, preferably 10-50 mg / kg of active ingredient. A process for the preparation of a compound feed comprising mixing a mixture of a macrolide antibiotic and a quinolone carboxylic acid derivative and / or salts or esters thereof in a ratio of 20: 1 to 1:20, preferably 5: 11: 1, with a conventional ingredient of the compound. 5. A process according to claim 4, wherein the macrolide antibiotic is chitamycin and / or tylosin and / or erythromycin and / or, if desired, their biologically acceptable salts and flumequine and / or oxolinic acid and / or nalidixic acid and / or quinolone carboxylic acid derivatives. or norfloxacin and / or ciprofioxacin and / or enrofloxacin and / or their bioavailable salts and / or esters. The process according to claim 4, characterized in that the composition is mixed in a dose of 1150 mg / kg, preferably 10-50 mg / kg of active ingredient.