CH666407A5 - SYNERGISTIC MEDICINE COMBINATION AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

DESCRIPTION The invention relates to a new, antimicrobial drug combination and a method for its production.

Oxolinic acid (5-ethyl-5,8-dihydro-8-oxo-l, 3-dioxo-lo- [4,5-g] quinoline-7-carboxylic acid) and nalidixic acid (1-ethyl-1,4- dihydro-7-methyl-4-oxo-l, 8-naphthyridine-3-carboxylic acid) have been known for a long time in human medicine and in veterinary medicine. In human medicine, they are primarily used to treat urinary tract disorders, while they are important in veterinary medicine for combating infections caused by Gram-negative bacteria.

Combinations of oxolinic acid or nalidixic acid and antibiotics or other organic acids have also become known. Bartoloni and co-workers reported the combined use of oxolinic acid or nalidixic acid and trimethoprim (Bartoloni, E., Castelli, M., Genedani, M., Genedani, S., Bertoni, V .: Drug Exp. Clin. Res. 6 (4th ), 311-316 [1980]).

Japanese Patent No. 81,150,016 describes anti-microbial combinations of oxolinic acid and other organic acids for the treatment of infections caused by E. coli.

Tiamulin is a relatively new active substance, an antibiotic (14-deoxy- 14 - [(2-diethylaminoethyl) -mercaptoacetoxy] -mutilin-hydrogen fumarate), which is used primarily against diseases of the respiratory tract and digestive organs of pigs, but also used to cure udder inflammation of cows caused by mycoplasmas (Burch, DGS, Haard, RW, Taskor, JB: Vet. Ree. 10, 236-237 [1983]).

The action of tiamulin against Gram-positive bacteria (Staphylococcus, Streptococcus, Mycoplasma, Treponema) is also known from British Patent No. 2,027,590.

However, as microbiological studies showed, the spectrum of action of tiamulin against gram-negative bacteria is relatively narrow (Forster, J., Pickles, G .: IPVS conference, Zagrab, June 13-15, 1978).

It has now been found that when tiamulin hydrogen fumarate and oxolinic acid and / or nalidixic acid are used in combination, there is a pronounced increase in activity, a synergistic effect, in addition to the additive activity resulting from the different activity ranges.

The invention accordingly relates to a new, synergistic combination of medicaments, the tiamulin hydrogen fumarate and organic acids which are effective against bacteria and protozoa, preferably oxolinic acid and / or nalidixic acid, or their water-soluble salts in a ratio between 1-5: 5-1 and optionally inert, solid and / or liquid carriers, extenders and auxiliaries.

To demonstrate the synergism, the minimum inhibitory concentration and the minimum bactericidal concentration of both the individual components and the combination for different microorganisms were measured in vitro. The results are summarized in Tables 1 and 2.

15

20th

25th

30th

35

40

45

Table 1

Test organism

Tiamulin

Oxolinic acid

combination

Intensi

MIC

MBC

MIC

MBC

MIC

MBC

crossing

Staphylococcus

aureus

25th

100

25th

50

5

25th

4-10 x

Listeria

monocytogenes

50

100

100

100

5

25th

20-40 times

Salmonella

typhi mur.

200

> 200

1

10th

1

1

2-400 x

Klebsiella

pneumoniae

> 200

> 200

5

10th

5

5

2-80 x

Table 2

666 407

Test organism

Tiamulin

Nalidixic acid

combination

Intensi

MIC

MBC

MIC

MBC

MIC

MBC

crossing

Staphylococcus

aureus

25th

100

5

> 200

5

-5

2-10 x

Listeria

monocytogenes

50

100

> 200

> 200

50

100

2-8 x

Salmonella

typhi-murium

200

> 200

10th

10th

10th

10th

2-40 x

Klebsiella

pneumoniae

> 200

> 200

50

50

50

50

2-4 x

The results of the tests carried out in vitro clearly show the synergism of the combination. The intensification of the effect is primarily pronounced in the cultures of Staphylococcus aureus, Listeria monocytogenes, Klebsiella pneumoniae and Salmonella. It is generally two to four times, but can reach values up to four hundred times in some cases.

The invention further relates to a process for the preparation of the new, synergistically active pharmaceutical preparations. For the purposes of the invention, the 25 active ingredients are homogenized with one another, if appropriate, carriers, extenders and auxiliaries are added, and the mixture is optionally formulated into the customary dosage forms. For use per os, the active ingredient mixture, as a powder or as granules, is mixed into the drinking water 30 of the animals or into the feed. Capsules for intrauterine use and liquid formulations for intracysternal use are particularly suitable as parenteral forms of administration.

The pharmaceutical combinations 35 according to the invention can be used against the infectious agents listed below in cattle, calves, pigs, piglets, rabbits, dogs:

- Inflammation of the intestine caused by Salmonella, Klebsiella, E. coli; 40

Uterine inflammation caused by Proteus, E. coli, Streptococcus, Staphylococcus;

Udder inflammation caused by Streptococcus, Staphylococcus, Gram-negative pathogens such as E. coli, Klebsiella, Mycoplasma; 45

- in diseases of the digestive organs and airways of pigs (e.g. diarrhea caused by E. coli, dysentery, pneumonia caused by mycoplasma);

- Diseases of the digestive organs and airways 50 in rabbits and poultry (infections caused by E. coli, etc.).

The following dosages are recommended for oral administration:

55 water-soluble preparation containing 60% active substance against intestinal inflammation

Calves 400 mg / animal and day

Piglet 350 mg / litter and day against intestinal inflammation and urinary tract infections in dogs depending on the size of the animal 200 - 400 60 mg / day and animal, with a treatment duration of 3 days.

To mix it into the feed, a premix containing 60% active ingredients is added to the feed for five days:

65

against inflammation of the digestive organs and the airways and against dysentery

Pigs 200-400 mg / kg feed against infections of the digestive organs and the respiratory tract

Rabbits 150-250 mg / kg feed,

Poultry 300-400 mg / kg feed.

For intrauterine treatment, the mixture containing 60% of active ingredients is administered in a daily dose of 5 g, preferably in capsules, for five days.

The invention is illustrated by the following examples, but is not limited to the examples.

example 1

1.5 g of Tiamulin hydrogen fumarate, 1.5 g of oxolinic acid and 2.0 g of lactose are mixed together and filled into a capsule. Capsules of this type were administered intra-uterine to cows which had just calved over three days. In the 24 treated animals, the regression proceeded faster, uterine inflammation and embryos did not remain. The treatment is suitable for preventing bacterial inflammation.

Example 2

0.6 g of Tiamulin hydrogen fumarate, 3.0 g of nalidixic acid and 1.4 g of lactose are mixed together. The ratio of the two active ingredients to one another is 1: 5. Based on the pure active ingredient, 10-20 mg / kg body weight of this preparation are administered orally.

The mixture was suspended in 100 ml of water. Five litters of piglets (50 piglets) were treated. Each animal (healthy and sick animals) received 1 ml (= 0.036 g) of the suspension per os. The diarrhea of the sick animals stopped after the first treatment. There were no new illnesses and relapses.

Example 3

10.0 g of tiamulin hydrogen fumarate, 2.0 g of oxolinic acid and 100.0 ml of oil suitable for injections are processed into a suspension.

10 ml of this suspension were infused into each teat channel of 5 cows suffering from inflammation of the udder. The symptoms of acute inflammation (swollen, warm udders, macroscopically noticeable changes in milk) improved significantly after the first treatment. A week after the third application, a bacteriological examination was carried out, the result of which was negative.

s

Claims (8)

666 407 1. Synergistic drug combinations with antibacterial and antiprotozoal action, characterized in that they contain tiamulin hydrogen fumarate and organic acids which are active against bacteria and protozoa, or their water-soluble salts in a ratio of 1-5: 5-1. 2. Pharmaceutical combination according to claim 1, characterized in that it contains oxolinic acid and / or nalidixic acid or their water-soluble salts. 2nd PATENT CLAIMS 3. Pharmaceutical combination according to claim 1 or 2, characterized in that it contains inert, solid and / or liquid carriers, extenders and auxiliaries. 4. Pharmaceutical combination according to one of claims 1 to 3, characterized in that it contains in dosage units suitable for intrauterine administration, preferably in capsules, which contains a daily dose for an animal of 5 g. 5. A process for the preparation of new, synergistic drug combinations with antibacterial and antiprotozoal action according to claim 1, characterized in that that one mixes tiamulin hydrogen fumarate and organic acids effective against bacteria and protozoa, or their water-soluble salts in a weight ratio between 1-5: 5-1. 6. The method according to claim 5, characterized in that oxolinic acid and / or nalidixic acid or its water-soluble salts are used as organic acids effective against bacteria and protozoa. 7. The method according to claim 5 or 6, characterized in that the active ingredients with inert, solid and / or liquid carriers, extenders and auxiliaries mixed. 8. The method according to any one of claims 5 to 7, characterized in that the mixture of the components is formulated into metering units.