FR2563432A1 - New antibacterial and antiprotozoal pharmaceutical compositions comprising tiamulin acid fumarate and process for preparing them - Google Patents

Abstract

The present invention relates to new antibacterial and antiprotozoal pharmaceutical compositions. These compositions comprise tiamulin acid fumarate and antibacterial/antiprotozoal organic acids, or a pharmaceutically acceptable, water-soluble derivative of the latter, in a weight ratio of 1:5 to 5:1, mixed with non-toxic, inert solid or liquid vehicles. Use in human medicine and in veterinary therapy.

Description

 The present invention relates to new antibacterial and antiprotozoal pharmaceutical compositions and to a process for preparing them.

 Oxolinic acid (5-ethyl-5,8-dihydro acid 8-oxo-1, 3-dioxolo4, Sgjquinoline-7-carboxylic) and nalidixic acid (1-ethyl-1,4-dihydro-7- acid methyl-4-oxo-1,8-naphthyridine-3-carboxylic) are compounds well known in human medicine, as well as in veterinary therapy. They are mainly used as urinary tract antiseptics in the field of human medicine. These compounds are applied to fight against infections caused by gram-negative bacteria in the veterinary art.

 There are known combinations of oxolinic acid or nalidixic acid with antibiotics and other organic acids, too. The simultaneous application of oxolinic acid or nalidixic acid with trimethoprim, is described by Bartolini et al.

CBartolini et al., Drug. Exp. Clin. Res. 6, 311-316 (1980).

 Tiamulin (14-deoxy-14 ((2-diethylamino-ethyl)) -mercapto-acetoxyl-mutiline fumarate is a relatively new antibiotic in the veterinary art. It is mainly used in the treatment of respiratory and gastrointestinal disorders It successfully treats swine pneumonia and dysentery, caused by Mycoplasma EBurch et al., Vet. Rec. 10, 236-237 (1983).

 The effect of tiamulin on gram-positive bacteria (Staphylococcus, Streptococcus), Mycoplasma and Treponema is described in British Patent No. 2,027,590.

 The range of activity of tiamulin against gram-negative bacteria is relatively narrow, according to the results of microbiological tests (Forster, J. and Pickles, G., IPVS Congress, Zagreb, June 13- 15, 1978).

 The object of the present invention is to prepare pharmaceutical combinations of known antibiotics which not only considerably reduce expenditure, but manifest the individual effect of two or more components in a synergistic manner.

 It has now been found that by applying tiamulin acid fumarate with antibacterial and antiprotozoal organic acids, preferably oxolinic acid and / or naliGixic acid, a clear synergy can be observed with respect to certain strains side of the curative characteristics of the distinct components whose activity ranges are different (for example, an inhibition effect in vitro on Streptococci and E. coli).

 On the basis of these facts, the present invention relates to new pharmaceutical compositions exerting a synergistic effect and useful for treating respiratory, gastrointestinal and urogenital infections in domestic animals, which include the antibiotic tiamulin fumarate acid and organic acids. antibacterials, antiprotozoa, preferably oxolinic acid or nalidixic acid or a derivative thereof, water soluble and pharmaceutically acceptable, in a weight ratio of 1: 5 to 5: 1 , mixed with pharmaceutically acceptable solid or liquid carriers.

 The present invention also provides a process for the preparation of a novel synergistic antibacterial-antiprotozoal composition useful for the treatment of respiratory, gastrointestinal and urogenital infections in domestic animals, according to which tiamulin acid fumarate is mixed with an antibacterial organic acid. -antiprotozoan, preferably oxolinic acid or nalidixic acid, or a pharmaceutically acceptable water-soluble salt thereof, in a weight ratio of 5: 1 to 1: 5 and with carriers inert, non-toxic used in veterinary art.

 Microbiological tests are carried out to study the inhibitory effect in vitro of the active compounds vis-à-vis different strains of bacteria and to establish their synergy. The same pathogen isolates were used as test organisms to aid understanding. The minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (CBM) of tiamulin and oxolinic acid or nalidixic acid were determined. The results are collated in Tables I and II. The ICD and CBM values are expressed in g / ml.

TABLE I
Intensification of the antibacterial activity of the combination of tiamulin and
oxolinic acid, in a weight ratio of 1: 1
Test organism Tiamulin Oxolinic acid Combination Factor
intensification
CIM CBM CIM CBM CIM CBM
Staphylococcus aureus 25 100 25 50 5 25 4 - 10x
Listeria monocytogens 50 100 100 100 5 25 8 - 40x
Salmonella typhi-murium 200 200 1 10 1 1 2 - 400x
Klebsiella pneumoniae 200 200 5 10 5 5 2 - 80x
TABLE I
Intensification of the antibacterial activity of the combination of tiamulin and
nalidixic acid, in a weight ratio of 1: 1
Test organism Tiamulin Nalidixic acid Combination Factor
CIM CBM CIM CBM CIM CBM intensification
Staphylococcus aureus 25 100 5 200 5 5 2 - 80x
Listeria monocytogens 50 100 200 200 50 100 2 - 8x
Salmonella typhi-murium 200 200 10 10 10 10 2 - 40x
Klebsiella pneumoniae 200 200 50 50 50 50 2 - 80x
In vitro tests demonstrate the synergistic effect presented by the combination vis-à-vis certain strains of bacteria. The intensification of the effect is clearly shown against Staphylococcus aureus, Listeria monocytogenes, Klebsiella pneumoniae and Salmonella typhi-murium.

The factor of this intensification is 2 to 8 times on average, but it can even reach the rate of 400 times.

 The preparations according to the present invention can be applied in smaller and more economical doses thanks to their synergistic properties.

As these combinations have a wider spectrum, they can be successfully used in the treatment of respiratory diseases and other diseases of secondary bacterial complications and mycoplasma.

 The combinations of the present invention offer another advantage in that the development of toxic side effects is limited and that the downtime required to prevent the presence of drug residues in edible tissue is reduced.

These advantages arise from the use of lower doses of active components in the combinations.

 The preparations in accordance with the present invention may be produced according to known techniques, namely by - mixing or dissolving active components in carriers used in the veterinary art.

 The formulation of the preparation is chosen according to the given case. It can be applied orally, mixed with food or drinking water, mainly in large-scale units, or parenterally for individual or serial treatment.

 Parenteral application can be intramuscular, intrauterine or intn = .ln.ire. The preparation for parenteral use is spread on a support, preferably lactose, in a weight ratio of 1: 1 to 1:50 and it is then dissolved in a suitable solvent, preferably water, dimethylformamide or an oil. vegetable, in a weight ratio of 1: 1 to 1:25.

Favorable effects can be obtained with the synergistic pharmaceutical compositions in accordance with the present invention, in the following cases
enteritis due to strains Salmonella, Klebsiella
and E. coli;
metritis caused by Proteus strains,
E. coli, Streptococcus, Staphylococcus;
. mastitis caused by Streptococcus strains,
Staphylococcus, E. coli, Klebsiella and
Mycoplasma in cattle, calves and
dogs;
. digestive and respiratory diseases
pigs (for example, diarrhea due to
E. coli, swine dysentery, pneumonia
caused by Mycoplasma;
. diseases of the digestive and respiratory organs
res of rabbits and poultry (infections
by E. coli, etc.).

The oral dose, which is proposed for a water-soluble preparation containing 60.08 by weight of active ingredient, is as follows:
. in the case of enteritis:
400 mg / animal / day for calves
350 mg / l for piglets
. in the case of enteritis and infections
urinary:
200-400 mg / animal / day for dogs.

When food is treated with a premix containing 60.0% of active components, the recommended dose for continuous treatment for five days is:
in the case of infection of the digestive organs
and respiratory and swine dysentery:
200-400 mgXkg feed for pigs
in the case of infection of the digestive organs
and respiratory:
150-250 mg / kg feed for rabbits and
300-400 mg / kg feed for poultry.

 A daily dose of 5.0 g of the mixture containing 60.0% of active ingredients in capsules is proposed for intrauterine use.

 The use of the preparations in accordance with the present invention is not limited to the control of pathogenic elements or to the treatment of the species listed above or in the following examples.

Example 1
We mixed and introduced into an intrauterine capsule:
1.5 g of tiamulin acid fumarate;
1.5 g of oxolinic acid; and
2.0 g lactose.

 24 cows were treated intrauterine with these capsules for 3 consecutive days immediately following calving. Involution was faster and metritis and retention of the placenta did not develop. Bacterial infections have been prevented with this treatment.

Example 2
We mixed:
0.6 g of tiamulin acid fumarate;
3.0 g of nalidixic acid; and
1.4 g of lactose.

 The preparation was suspended in 100 ml of water.

 50 piglets from 5 piglets were treated orally with 1.0 ml of the suspension.

Clinical symptoms disappeared in all animals after the first treatment. No new cases or relapses were observed.

Example 3
Was suspended in 100.0 ml of oil for injection:
10.0 g of tiamulin acid fumarate; and
2.0 g of oxolinic acid.

 10 ml of this suspension was infused intramammally, via the teat canal, into 5 cows with mastitis. Symptoms of acute inflammation (swollen and hot udder, gross change in secreted milk, etc.) decreased significantly after the first treatment. Bacteriological tests carried out one week after the third treatment have given completely negative results.

 As is apparent from the above, the invention is in no way limited to those of its modes of implementation, production and application which have just been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the scope or the scope of the present invention.

Claims (8)

 1. Synergistic antibacterial-antiprotozoal pharmaceutical composition useful in the treatment of infectious diseases of the respiratory, gastrointestinal and urogenital tracts in domestic animals, characterized in that it comprises tiamulin fumarate acid and antibacterial-antiprotozoal organic acids or a derivative thereof pharmaceutically acceptable water soluble thereof, in a weight ratio of 1: 5 to 5: 1, mixed with inert, non-toxic solid or liquid carriers used in the veterinary art.  2. Composition according to claim 1, characterized in that the organic acid is oxolinic acid or nalidixic acid.  3. Composition according to claim 1, for oral administration, characterized in that it comprises active components in a dose of 5 to 15 mg / kg of body weight.  4. Composition according to claim 1, characterized in that the support is lactose.  5. Composition according to claim 4, for intrauterine application, characterized in that it comprises the active components in an amount of 60% by weight of the mixture introduced into a capsule, at a daily dose of 5.0 g / animal.  6. Composition according to claim 1, characterized in that the support is a sterile and purified vegetable oil, acceptable in the veterinary art.  7. Composition according to claim 6, for intra-mammary application, characterized in that the active components are in an amount of 0.2 to 2.0 g per udder.  8. Method for preparing a new synergistic antibacterial-antiprotozoal composition useful for treating respiratory, gastrointestinal and urogenital infections in domestic animals, characterized in that tiamulin acid fusnarate is mixed with an antibacterial organic acid or a propotozoan pharmaceutically acceptable water soluble salt thereof in a weight ratio of 5: 1 to 1: 5, and with inert non-toxic carriers used in veterinary art.