HU190963B - Process for production of synergyc medical preparatives containing organic acids with oxitetracylin and antimicrobatic influence - Google Patents

Abstract

The invention relates to pharmaceutical combinations with a synergistic action for the treatment of infections of the respiratory organs, of the gastrointestinal tract and of the urinary and genital organs of domestic animals with a content of 5-(hydroxy)tetracycline [oxytetracycline], where appropriate together with one or more conventional inert, non-toxic, solid and/or liquid pharmaceutical excipients, extenders and/or ancillary substance(s), which, apart from a) 5-(hydroxy)tetracycline [oxytetracycline] contain b) one or more antimicrobial organic acid(s) and/or water-soluble derivative(s) thereof, where appropriate with a) and b) being spacially separate from one another in one and the same pack or administration unit, where the a):b) ratio by weight is 0.5:10 to 10:0.5.

Description

BACKGROUND OF THE INVENTION This invention relates to novel synergistic pharmaceutical compositions for the treatment of microbial diseases in domestic animals.

The preparation of the pharmaceutical compositions of the present invention is characterized in that the oxytetracycline, oxolinic or nalidixic acid is mixed in a ratio of 0.5 to 5: 5 to 0.5, together with inert, solid and / or liquid pharmaceutical carriers and formulated for pharmaceutical use.

In cattle and pigs, juvenile diseases cause significant losses. Every year, 8 to 10,000 suckling calves and nearly 10 percent of the born piglets die during the suckling age, mainly due to bacterial infections. The diseases are mainly infections caused by gram-negative pathogens (E. coli, Klebsiella, etc.), but also Strepto- and Staphylococcosis due to reduced resistance are common.

Among the widely used tetracyclines, oxytetracycline has been used in Hungary for three decades (Tetran inj., Tetran comb. Pulvis A.U.V.). However, there was a significant increase in resistance to OTC. In strains isolated from staphylococcus aureus, the strains isolated from strains isolated from calves and chickens are approximately 20% (De Buyser, M. - Ollieuz, N .; Rec. Med. Vet., 755-8. (Heller, ED - Drabkin, N .: Brit. Vet. J., 1977, 13, 6, 572-578), the preparation alone is depreciated.

To provide a more complete effect, oxytetracycline is often used in combination (e.g. Neo-Te-Sol, Exuter M. and P. tabl. A.U.V., Neomast A.U.V., etc. in combination with neomycin).

The Gram-negative spectrum of oxolinic acid is very good (Linzenmeier, Neussel: Warner-Chillcott Madrid 1972) and can be used very effectively in E. coli infections. No. 81,150,016. The Japanese patent combination (oxolinic, nalidixic acid + pipemidic, pyromidic acid) is also recommended for the treatment of E. coli infections.

Nalidixic acid alone has good microbiological efficacy. Studies on the preparation of drug combinations have shown that it produces synergism with trimethoprim (Bertoni, V .: Drug Exp. Clin.

4. 311-316).

The present invention is based on the discovery that when oxytetracycline is used in combination with oxolinic acid or nalidixic acid, the efficacy of the individual components is maintained (e.g., in some strains against E. coli, Pasteurella, Proteus, Listeria monocytogenes, Corynebacterium pyogenes). measured, there is a clear synergy. The synergistic effect of the combination is demonstrated by microbiological assays.

Table 1 shows the bacteriostatic (MIC) and bactericidal (MBC) activity of oxytetracycline on certain bacterial strains. Table 2 shows the antibacterial values of oxolinic acid expressed in mg / l for the same strains. Table 3 shows the antibacterial values of nalidixic acid expressed in mg / l for the same strains.

Table 7

Antibacterial activity of chemotherapeutic agent expressed as mg / l oxytetracycline

MIC MBC Staphylococcus aureus <0.5 5 Streptococcus zooepidemicus 0.5 5 Listeria monocytogenes <0.5 5 Corynebacterium pyogenes 5 25 E. coli 11. 200 > 200 E. coli 494 > 200 > 200 Klebsiella pneumoniae 5 25 Salmonella typhimurium 5 50 Proteus vulgaris 25 200 Pasteurella multocida 5 5 Pasteurella haemolytica 5 5 Bordetella bronchiseptica 1 10 Pseudomonas aeruginosa 5 25 Mycoplasma gallisepticum 0.5 5 Mycoplasma hyorhinis 25 25 Table 2 Antibacterial activity of chemotherapeutic agent in mg / l expressed oxolinic MIC MBC Staphylococcus aureus 25 50 Streptococcus zooepidemicus 10 25 Listeria monocytogenes 100 100 Corynebacterium pyogenes 50 100 E. coli 11 0.5 1 E. coli 494 0.5 1 Klebsiella pneumoniae 5 10 Salmonella typhimurium 1 1 Proteus vulgaris <0.5 <0.5 Pasteurella multocida <0.5 <0.5 Pasteurella haemolytica 0.5 1 Bordetella bronchiseptica 5 10 Pseudomonas aeruginosa 25 100 Mycoplasma gallisepticum - - Mycoplasma hyorhinis - - Table 3 Antibacterial activity of chemotherapeutic agent in mg / l expressed nalidixic MIC MBC Staphylococcus aureus 50 > 200 Streptococcus zooepidemicus > 200 > 200 Listeria monocytogenes > 200 > 200

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Continuation of Table 3

nalidixic MIC MBC Corynebacterium pyogenes - - E. coli 11 (swine) 10 10 E. coli 494 (calf) 25 25 Klebsiella pneumoniae 50 50 Salmonella typhimurium 10 10 Proteus vulgaris - - Pasteurella multocida 1 1 Pasteurella haemolytica - - Bordetella bronchiseptica 50 50 Pseudomonas aeruginosa > 200 > 200

The experiments were hereinafter carried out using a combination of oxytetracycline with oxolinic acid or nalidixic acid. The in vitro experiments with the combinations clearly demonstrated the synergistic effect of the combination on certain bacterial strains (Table 4-5). The 1: 1 oxytetracycline-oxolinic acid composition results in a doubling, 10-fold, and 40-fold potency in Streptococcus, Klebsiella, and Bordetella cultures (Table 6). The efficiency of oxytetracycline and nalidixic acid in a 1: 1 ratio can be up to 800-fold (Table 7).

Pharmaceutical compositions having a synergistic effect according to the invention may be formulated for both oral and parenteral administration.

The formulations are prepared by homogenizing the active ingredients and then gradually mixing with smaller quantities of the carrier. The carrier may also contain one or more additives commonly used in veterinary medicine.

The composition is administered orally in powder or granule form in drinking water or in feed, parenterally, preferably in capsule form, intrauterine, in liquid form, intracysterally.

The synergistic drug combination of the present invention is preferably cattle, calf, pig, pig, rabbit, dog

- uterine infections caused by Proteus, E. coli, Streptococcus, Staphylococcus,

- calf, pig E. coli, Klebsiella, Salmonella spp. intestinal inflammation,

Table 4

Antibacterial activity of a chemotherapeutic agent expressed in mgf

Oxytetracycline + Oxolinic acid (1: 1) MIC MBC Staphylococcus aureus <0.5 5 Streptococcus zooepidemicus <0.5 <0.5 Listeria monocytogenes 1 10 Corynebacterium pyogenes 5 25 E. coli 11 0.5 1 E. coli 494 0.5 1 Klebsiella pneumoniae 5 5 Salmonella typhimurium 1 5 Proteus vulgaris 0.5 0.5 Pateurella multocida <0.5 <0.5 Bordetella bronchiseptica 1 5 Pseudomonas aeruginosa 10 50 Mycoplasma gallisepticum - - Mycoplasma hyorhinis - -

Table 5

Antibacterial activity of chemotherapeutic agent expressed in mg / l

Oxytetracycline + Nalidixic Acid (I: 1)

MIC MBC Staphylococcus aureus <0.5 <0.5 Streptococcus zooepidemicus <0.5 <0.5 Listeria monocytogenes <0.5 1 Corynebacterium pyogenes <0.5 1 E. coli 11 5 10 E. coli 494 10 10 Klebsiella pneumoniae 10 10 Salmonella typhimurium 5 10 Proteus vulgaris - - Pasteurella multocida - - Pasteurella haemolytica - - Bordetella bronchiseptica <0.5 1 Pseudomonas aeruginosa 10 ⁵⁰

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Table 6

Effectiveness in combination

oxitetra- cyclin oxolinic oxytetracycline + oxolinic acid (1: 1) effect- reinforcement MIC MBC MIC MBC MIC MIC Streptococcus zooepidemicus 0.5 5 10 25 <0.5 <0.5 2-40- fold Klebsiella pneumoniae 5 25 5 10 5 5 4-10- fold Bordetella bronchiseptica 1 10 5 10 1 5 2-40- fold 7th spreadsheet Oxitetra- cyclin nalidixic Oxytetracycline + Nalidixic Acid (1: 1) effect- reinforcement MIC MBC MIC MBC MIC MBC Staphylococcus aureus <0.5 5 50 200 <0.5 <0.5 2-800- tight Streptococcus zooepidemicus 0.5 5 > 200 > 200 <0.5 <0.5 2-800- tight E. coli (11) > 200 > 200 10 10 5 10 4-400- tight E. coli (494) 200 > 200 25 25 10 10 5-40- fold Salmonella typhimurium 5 50 10 10 5 10 2-10- fold Bordetella bronchiseptica 1 10 50 50 <0.5 1 4-200- tight

- swine infection by E. coli caused by Salmonella,

- porcine Streptococcus, Staphylococcus, Pasteurella, Salmonella, Bordetella spp. respiratory diseases,

- rabbit, poultry E. coli, Salmonella spp. For the treatment of gastrointestinal diseases caused by the invention, it is recommended that the invention not be limited to some of the diseases, animal species and pathogens listed and exemplified herein.

Passive assays were performed to isolate the polyresistant E. coli (OK K 36 99) and porcine E. coli strains isolated with bovine active substances and combinations thereof. The drug and its combination were considered resistant if the tested strains also increased at 200 mg / l. The results are shown in Table 8.

SALT

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Table 8

preparation Tribe passages number oxytetracycline E. coli (cattle) 0 E. coli (swine) 0 oxolinic E. coli (cattle) 11 E. coli (swine) 15 Oxytetracycline + Oxolinic acid (1: 1) E. coli (cattle) 15 E. coli (swine) ¹⁵ nalidixic E. coli (cattle) 3 E. coli (swine) 3 Oxytetracycline + Nalidixic Acid (1: 1) E. coli (cattle) 11 E. coli (swine) 12

Studies have shown that the combination can significantly delay the development of resistance.

The composition for peroral administration suggested average of 5 to 20 mg / kg administered parenterally intrauterine 1: 1 mixture of 2 g / animal on capsule ₂ and inserted.

For single treatment: from 20% active ingredient

- piglets at 50 to 200 mg in an aqueous suspension day ₃₀

- calves in a 0.6-2.5 g aqueous suspension for 3-4 days.

In case of bulk treatment: 20% by weight of the active substance in a compound feedingstuff

- pigs at a concentration of 0,06 to 0,25% for ₃₅ days,

- rabbits, poultry at a concentration of 0.04-0.15%.

In order to carry out the process according to the invention, the following examples are given. ₄₀

Example 1 oxytetracycline 500 mg oxolinic acid 500 mg lactose 3000 mg

4000 mg

The drug mixture was suspended in 0.5 l lukewarm chamomile tea and administered orally twice daily to calves. ⁵⁰

Medication was continued for four days. According to our preliminary studies, calves with enteritis were clinically cured after the second dose. The dilute bowel movement ceased, the animals improved significantly and their appetite increased.

None of the 50 animals we treated died.

Example 2 Oxytetracycline 1.0 g nalidixic acid 1.0 g

The drug mixture was filled into capsules and placed in the uterus of freshly calved cows, once daily for 3 days. In cows treated with medication, uterine involution was free of disturbances. Uterine clearance was accelerated, and the nature of the secretion did not indicate bacterial infection.

The compositions have the advantage that they can be used effectively in the treatment of infections of particularly lactating animals, with a synergistic effect and lower active ingredient concentration.

Claims (6)

CLAIMS 1. A process for the preparation of a synergistic pharmaceutical composition comprising oxytetracycline and an organic acid comprising oxytetracycline [4 (dimethylamino) -1,4,4a, 5,5a, 6,11, -12a-octahydro-3,5,6,10. 12,12a, -hexahydro-6-methyl-1,11-dioxo-2-naphthacenecarboxamide] a quinoline or naphthalidine carboxylic acid derivative, preferably oxolinic acid [1- (ethyl) -1,4-di- (hydro) -6, 7- (methylenedioxy) -4 (oxo) quinoline-3-carboxylic acid] or nalidixic acid [1 (ethyl) -7- (methyl) -4- (oxo) -1,4, -di- (hydro-1, 8-naphthyridine-3-carboxylic acid] in a ratio of 0.5 to 5: 5 to 0.5, and inert, solid and / or liquid pharmaceutical carrier (s) and formulated for pharmaceutical use. 2. The method of claim 1, wherein the oxytetracycline and oxolinic or nalidixic acid are mixed for oral administration at a concentration of 5 to 20 mg / kg of active ingredient. 3. The method of claim 1, wherein the 1: 1 mixture of active ingredients is formulated in a capsule for use in intrauterine administration in an amount of 2 g / animal. 4. The method of claim 1, wherein the 0.5 to 5% active ingredient mixture is mixed in a 1: 5 ratio with an inert solid and / or liquid carrier for veterinary use. 5. The method of claim 4, wherein the 20% active ingredient formulation is formulated for individual treatment in pigs at doses of 50-100 mg / kg / day and calves 0.6-2.5 g / day. 190,963 6. The method of claim 4, wherein the composition containing 20% of the active compound is added to the feed at a concentration of 0.06-0.25% for pigs, 0.04-0.15% for poultry, and 0.04-0.15% for poultry.