HU200559B - Process for producing composition suitable for preventing and curing diseases of the digestive and respiratory organs of domestic animals - Google Patents

Abstract

In the process according to the invention, 2- (4-aminobenzene sulfonamido) thiazole (sulfatiazole), 2- (4-aminobenzenesulfonamido) -4,6-dimethylpyrimidine (sulfadimidine), 4-amino, One or more of N- (5-chloropyrazin-1-benzenesulfonamide sodium monohydrate (sulfachlorpyrazine sodium monohydrate), 3- (4-amino-benzenesulfonamido) -5-methyl-ooxazole (sulfamethoxazole), [(3,4,5-trimethoxyphenyl) methyl] -2,4-pyrimidin-diamine (trimethoprim), and 15 - {[5-dideoxy-2,3-di- (O-methyl / 3- D-allopyranosyl) oxy] methyl} -6 - ([3,6-dideoxy-4-O-2,6-dideoxy-3-C-methyl-c-L-ribohexapyranosyl) -3- (dimethyl) -amino) -15-D-glucopyranosyl] oxy-16-ethyl-4-hydroxy-5,6-dimethyl-2,10-dioxoxyacyclohexadeca-11,13-dien-7-acetaldehyde (tylosin) ) or a physiologically acceptable salt thereof, [3aS- (3aC, 4 /}, 5oC, 6 <x, 8/3, 9oC, 9dC / 3, 10S *)] - ([2- (dimethylamino) ethylthio] ] -6-ethenyl-decahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a, 9-propano-3ah-cyclopentacyclooctene-8-yl} ester fumarate (dynamite) lin), a leukomycin [R- (R *, R *)] tartrate (trubin) mixed in a weight ratio of from 1 to 20: 1 to 4: 20 to 1, together with the usual carrier and excipients to form a pharmaceutical composition. EN 200559 A Scope of the description: 6 pages without drawing -1-

Description

The present invention relates to a novel pharmaceutical composition for the treatment of microbial diseases in domestic animals with a synergistic effect. The composition is particularly useful for the prevention or treatment of digestive and respiratory diseases in piglets of choice, broiler chickens, geese, ducks, turkeys.

E. coli and Treponema and Mycoplasma strains play a major role in the digestive tract disease and loss of weaned piglets. Similarly to poultry, Mycoplasma strains and, in the secondary, E.coli germs, are the cause of economic damage. There are currently no formulations that simultaneously kill E.coli and Treponema strains and eliminate Mycoplasma infections.

In the last decade, the use of trimethoprim in combination with trimethoprim has been a major contributor to the prevention of newborn coli enteritis. potential sulfonamides. One of the disadvantages of currently available formulations in Hungary (Veosulfotrim pulv. AUV, Sumetrolim inj. AUV, 25 Neophykoccin sol. Conc. AUV, Potesept paste AUV, Potesept suspension AUV) is the loss of efficacy due to long-term frequent use, and the unique application. Trimetropim, an ingredient of the potential sulfonamides, is insoluble in water, so the product could only be used orally or mixed with feed. 35

Large-scale large-scale patient populations - now incorporating technology - can be treated in the simplest form and with high safety through drinking water. However, this requires water-soluble formulations, i.e. water-dispersible formulations.

In our studies, we found that the combination of sulfonamides and trimetropim is optimal only if it has similar pharmacokinetic properties (absorption, distribution, elimination) in the animal species. Based on these considerations and results, pigs have found a mixture of sulfathiazole or sulfadimidine or sulfamethoxazole with trimethoprim and poultry preferred a mixture of sulfachlorpyrazine sodium monohydrate and trimethoprim.

It has also been found that the spectrum of potency of the sulfonamides is broadened and 55, especially in the case of Gram-positive pathogens, are enhanced when an antibiotic, preferably a macrolide antibiotic, is mixed with the potential sulfonamide.

Accordingly, the present invention relates to a process for the preparation of a pharmaceutical composition for treating gastrointestinal and respiratory diseases in domestic animals.

The process is characterized in that one or more sulfonamides, 5 - [(3,4,5-trimethoxyphenyl) ~ 65

-methyl] -2,4-pyrimidinediamine (trimethoprim) and a macrolide antibiotic (1-20) :( 1-4) :( 20-1) in weight ratio with the usual carrier and other excipients to form a pharmaceutical composition.

Preferred sulfonamides are 2- (4-aminobenzenesulfonamido) -4,6-dimethylpyrimidine (sulfadimidine), 2- (4-aminobenzenesulfonamido) -4,6-dimethylpyrimidine (sulfathiazole), 3- (4-Amino-benzenesulfonamido) -5-methyl-isoxazole (sulfamethoxazole) (pig), or 4-amino-N- (5-chloropyrazinyl) -benzenesulfonamide sodium monohydrate (sulfachloropira2ine sodium monohydrate) ( poultry).

15 - {[6-dideoxy-2,3-di- (O-methyl- (3-D-allopyranosyl) oxy] methyl) -6 - {[3,6-dideoxy-4-O- ( 2,6-dideoxy-3-C-methyl-o-C-L-ribohexapyranosyl) -3- (dimethylamino) - (3-D-glucopyranosyl) oxy} -16-ethyl-4-hydroxy-5,9- dimethyl-2,10-dioxooxacyclohexadeca-11,13-diene-7-acetaldehyde (tylosin) or a physiologically acceptable salt thereof, [3aS- (3aol, 4/3, 5cC, 6cC, 8/3, 9oC, 9oC / 3). , 10S *)] - ([2- (diethylamino) ethylthio] -6-ethenyl-decahydro-5,6-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a, 9-propane -3aH-cyclopentacycloocten-8-yl} ester fumarate (dynamutilin), or leukomycin [R- (R *, R *)], which is not chemically named (37280-56-1) under the chemical abstracts. tartrate (trubin) The weight ratio between the three components of the composition is (1-20) :( 1-4) :( 20-1), preferably 5: 1: 5.

The active ingredients are supplemented with the usual carriers and excipients, for example glycerol, propylene glycol, lactic acid, waxes, surfactants. The total active ingredient content of the concentrate prepared by mixing the components may be 1-30%, preferably 10-20%. Preferably, the concentrate is added to the drinking water of the animals.

Advantages of the process according to the invention are as follows:

(a) gastrointestinal and respiratory diseases of weaned piglets and poultry may be effectively treated and / or treated; prevented

b) preventive dosing prevents the disease, thus increasing the yield of the animals and increasing the profitability of the production,

(c) the water-soluble form makes the preparation easy and safe to use.

The in vitro inhibitory effect of each active compound or combination thereof on different bacterial strains was measured by microbiological assays. The results are summarized in Tables 1 and 2. Table 2 shows that the effect of the combination is far beyond the sum of the effects of the individual components.

-2EN 200559 Table A of Table 1

Anti-bacterial effect of chemotherapeutic agents (mg / l)

chemotherapy agent Bacterium Sulfamethaxazole Szulfaklór- pyrazine trimethoprim tylosin species MIC MBC MIC MBC MIC MBC MIC MBC Staphylococcus aureus > 200 > 200 > 200 > 200 10 100 0.5 0.5 Streptococcus zooepidemicus > 200 > 200 > 200 > 200 100 200 0.5 0.5 E. coli 11 > 200 > 200 > 200 > 200 25 50 100 200 Pasteurella multocida 50 50 0.5 50 5 10 0.5 10

The magnitude of the enhancement is given in Table 2.

Table 2

Antibacterial Effect (mg / l) and Degree of Effectiveness of Combinations of Chemotherapeutic Agents

Bacterium species Trimethoprim (0,6) Tylosin (1) Effect- reinforcement Sulphachloropyrazine (5) Trimethoprim (5) Citasamycin (1) Effect reinforcement MIC MBC MIC MBC Staphylococcus aureus 0.5 1 > 4.6 5 5 > 11 Streptococcus zooepidemius 0.5 1 > 4.6 5 10 > 11 E. coli 11 25 50 > 7.5 25 100 > 2.2 Pasteurella multocida 0.5 5 > 4.6 5 10 > 11

As can be seen from Table 2, the triple combination in the tested strains provides favorable in vitro potency enhancement, which has been confirmed by field studies using the formulations described in the examples.

The invention is further illustrated by the following examples. The control groups in the examples, unless otherwise indicated, were not treated animals but treated with standard prophylactic formulations (sulfotrim and doxulan). The experiments thus provide an opportunity to compare the composition of the invention with the compositions of the prior art.

Example 1

A liquid composition is prepared from the following ingredients

tilozintartarát 4.50 g Sulfamethaxazole 3.30 g trimetropim 1.30 'g glycerol 40.00 ml carbowax-400 40.00 ml propylene glycol 20.00 ml milk week 1.00 ml

100.00 ml

HU 200559 A

The components are mixed well and homogenized with the liquid components. A light yellow, clear transparent material is obtained. Preferred addition is 2.5 ml to 1000 ml of drinking water for pigs.

Operational efficacy studies were also conducted with the experimental formulation. 200 selected piglets with an average body weight of 7 kg were treated with medicated drinking water for 5 days to prevent diarrhea caused by E. coli. As controls, 300 piglets of similar weight were included in the assays under the same conditions. We found that treatment resulted in excellent results, with 30% more morbidity and 7% more mortality in the control group.

Example 2

A liquid composition is prepared from the following ingredients

tilozintartarát 3.50 g sulfathiazole 10.00 g Sulfamethaxazole 10.00 g trimetropim 4.00 g tween-80 40,00ml glycerol 20.00 ml propylene glycol 60.00 ml carbowax-400 80.00 ml lactic acid 2.00 ml

200.00 ml

The components are mixed well and homogenized with the liquid components. Pigs are treated with the drug stock solution for 5 days at a dose of 5 ml ad 1000 ml drinking water. In the field trials, 250 weaned piglets were treated with 250 control animals. The control group showed that the control group developed respiratory symptoms and the animals coughed. About 30% higher morbidity was observed in this group, and mortality was 5% higher.

Example 3

A liquid composition is prepared from the following ingredients

tilozintartarát 20.0 g szulfaklórpirazin- -sodium monohydrate 20.0 g trimetropim 4.0 g propylene glycol 22.0 ml carbowax-400 158.0 ml lactic acid 2.0 ml

200.00 ml

The components are pulverized, mixed well, and homogenized with the liquid components. The preparation is suitable for the treatment of poultry at a concentration of 2.5 ml / 1000 ml of drinking water.

Example 4

A liquid composition is prepared from the following ingredients

tilozintartarát 4.00 g sulfamethoxazole 12.00 g trimetropim 2.40 g glycerol 30.00 ml propylene glycol 31,00 ml triethylene 31,00 ml milk week 1.00 ml

100.00 ml

The pale yellow clear solution is added to pigs' drinking water at a rate of 2.5 ml per liter. In the field observations, in which a control group of 250 weaners was treated with 250 animals for 4 days, the consumption of medicated drinking water reduced the incidence of gastrointestinal disorders. In the treated group, morbidity was 15% despite treatment, and 2% of the sick animals died. In the control group, the morbidity rate was 30% with a mortality of 7%.

Thus, the use of medicated drinking water could reduce the economic loss caused by diarrhea.

Example 5

Liquid Composition The following ingredients are prepared: Tylosin tartrate 5.00 g Sulfachlorpyrazine sodium monohydrate 5.00 g Trimethoprim 1.00 g Glycerol 30.00 ml Propylene glycol 32.00 ml Triethylene glycol 32.00 ml Lactic acid 1.00 ml

100.00 ml

The components are mixed well and homogenized with the liquid components. The drug is treated with a stock solution of poultry at 5.0 ml ad 1000 ml drinking water for 4 days. Under large-scale conditions, 3-week-old chickens were divided into two groups. 500 animals were watered with the above medicated drinking water for 4 days, and another 500 birds were left untreated. The control group was breathing5

EN 200559 Organic symptoms (cough, sneezing = mycoplasmosis) have occurred while the health of the treated flock was clinically satisfactory.

Example 6

Liquid composition is prepared from the following ingredients tylosin tartrate 10.00 g sulfachloropyridazine sodium monohydrate 10.00 g trimethoprim 2.00 g glycerol 30.00 ml propylene glycol 60.00 ml

100.00 ml

The components are pulverized, mixed well, and homogenized with the liquid components. From the pale yellow, clear solution

2.5 ml was added to 1 liter of drinking water for 500 days to 500-500 3-week-old chickens kept under large-scale conditions. In contrast to the conti-ol group, no respiratory symptoms were observed in the treated flock.

Example 7

A liquid composition is prepared from the following ingredients tylosin tartrate 10.00 g sulfamethoxazp 30.00 g trimethoprim 6.00 g glycerol 155.00 ml propylene glycol 310.00 ml

500.00 ml

The components are mixed well and homogenized until dissolved in the liquid mixture. A pale yellow, transparent mixture is obtained, from which 5 to 5 ml per liter of pig water is added. The recommended treatment period is 5 days. We used the experimental drug as a prophylaxis. One group of animals was treated and the other was left untreated. At 4 weeks post-treatment, we found that diarrhea and respiratory tract 10 days after the end of treatment in the control group! symptoms have occurred. The disease rate reached 30% and 7% of the animals died. In contrast, the drug-protected pig population was not clinically detectable.

Example 8

A liquid composition is prepared from the following Ingredients tylosin tartrate 30.00 g sulfochloropyrazine sodium monohydrate 30.00 g trimethoprim 6.00 g glycerol 85.00 ml propylene glycol 170.00 ml

300.00 ml

The powdered ingredients are thoroughly mixed and then homogenized with the liquid ingredients. Add 2.5 ml of the dense yellow solution to the poultry in 1 liter of drinking water.

Example 9

A liquid composition is prepared from the following Ingredients tylosin tartrate 10.00 g sulfathiazole, 30.00 g trimetropim 6.00 g glycerol 56.00 ml propylene glycol 112.00 ml

200.00 ml

The ingredients of the powder mixture are thoroughly mixed and then homogenized until dissolved in the liquid phase. We recommend 5 ml of the preparation per liter of drinking water for pigs. Medication is recommended for 5 days.

Example 10

A liquid composition is prepared from the following ingredients

tilozintartarát 4.00 g sulfamethoxazole 12.00 g trimetropim 2.40 g glycerol 60.00 ml propylene glycol 100.00 ml carbowax-400 27.00 ml

200.00 ml

The liquid ingredients are weighed and mixed. The powdered ingredients were finely powdered and then combined with a small amount of the liquid mixture. The liquid phase was continuously mixed with a paste-like mixture. Slightly heated (60-65 ° C), the Compounds gave a perfectly clear pale yellow drug-containing liquid mixture. The recommended dose for pigs is 5 ml daily for 1 liter of drinking water.

HU 200559 A

Example 11

A liquid composition is prepared from the following ingredients

tilozintartarát 20.00 g szulfaklórpirazin- -sodium monohydrate 20.00 g trimetropim 4.00 g glycerol 122.70 ml propylene glycol 122.70 ml triethylene 122.70 ml

The preparation procedure detailed in Example 10 gave a pale yellow solution which was recommended to poultry for 5 days at a concentration of 5 ml / 1000 ml of drinking water for the treatment of gastrointestinal diseases.

Example 12

Trubin sulfadimidine trimethoprim polyethylene glycol-400 propylene glycol

50.00 g

50.00 g 25

10.00 g

225.00 ml 225.00 1

The powder components are mixed well and then homogenized until dissolved in the mixture of liquids. During heating, a pale yellow, clear concentrate is obtained from which 5 to 5 ml per liter is added to the drinking water of broiler chickens and other poultry. Treatment is continued for 5 days. The effect on chickens was investigated in groups of 3x500 animals and in other poultry groups of 2x500 animals. Control groups were treated conventionally. Experimental csopor- loss was 5-10% lower case ^40, while the improved takarmányhasznosltás 4-6% of normal.

For prophylaxis, the concentrate is administered at a dose of 2.5-2.5 ml / liter of drinking water for 5-10 days and between 31-36 days of age.

Example 13

The following components are formulated as a liquid pharmaceutical composition:

dynamutilin sulfachlorpyrazine sodium monohydrate trimethoprim polyethylene glycol-400 propylene glycol

50.00 g

50.00 g 10.00 g 350.00 ml 100.00 ml

The mixture of the powdered components is homogenized until dissolved in the liquids and, after gentle heating, a clear yellowish concentrate is obtained.

For the treatment of porcine dysentery and pneumonia and other gastrointestinal complications of E. coli, and for the treatment of respiratory, coccidiosis digestive diseases of poultry, the animals are watered at a concentration of 0.5% for 3-5 days. It reduces mortality by 6-10% in both animal species compared to control (conventional drug treated) patient groups.

Claims (2)

PATENT CLAIMS A process for the preparation of a water-soluble composition for the prevention and treatment of gastrointestinal and respiratory diseases in domestic animals, characterized in that 2- (4-aminobenzosulfonamido) -thiazole (sulfathiazole), 2- (4-aminobenzosulfonamido) -4,6-dimethyl -pyrimidine (sulfadimidine), 4-amino-N- (5-chloropyrazinyl) -benzenesulfonamide sodium monohydrate (sulfachlorpyrazine sodium monohydrate) 3- (4-aminobenzenesulfonamido) -5-methylisoxazole (sulfamethoxazole) one or more of these, 5 - [(3,4,5-trimethoxyphenyl) methyl] -2,4-pyrimidinediamine (trimethoprim), and 15 - {[6-dideoxy-2,3-di- ( 0-methyl-6-D-allopyranosyl) oxy] methyl} -6 - {[3,6-dideoxy-4-0- (2,6-dideoxy-3-C-methyl-alpha-L-ribo- hexopyranosyl) -3- (dimethylamino) - / 3-D-glucopyranosyl] oxy} -16-ethyl-4-hydroxy-5,9-dimethyl-2,10-dioxo-oxaciklohexadeka-ll, 13-diene Of 7-acetaldehyde (tylosin) or its physiologically acceptable salt, [3aS- (3acC, 46, 5oC, 60o, 86, 9oC, 9c, 10S *)] - {[2- (dimethylamino) ethylthio] -6 ethenyl-dek fumarate of ahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a, 9-propano-3aH-cyclopentacycloocten-8-yl} ester (dynamutilin), leukomycin [R- (R *, One of its R *)] tartrates (trubin) is mixed in a weight ratio of 1-20: 1-4: 20-1 together with the usual carrier and excipients to form a pharmaceutical composition. The process according to claim 1, wherein one or more of the sulfathiazole, sulfadimidine, sulfachlorpyrazine sodium monohydrate, sulfamethoxazole, triraetoprim and tylosin, dynamutilin, trubin are used in a ratio of 5: 1: 5.