HU191399B - Process for the production of new compound medicine of synergic effect - Google Patents

Abstract

The invention relates to a synergistic anti-septic-antiprotozoal drug composition useful for the treatment of respiratory, gasto-intestinal and urogenital infections of domestic animals. The composition comprises tiamulin hydrogen fumarate and microbiologically active organic acids, preferably oxolinic acid and nalidixic acid or a pharmaceutically acceptable water-soluble derivate thereof in a weight ratio of 1:5 to 5:1. The active components are admixed or diluted with a carrier used in veterinary therapy and formulated for oral or parenteral use.

Description

The present invention relates to a process for the preparation of a novel pharmaceutical composition for parenteral treatment of respiratory, urinary and other bloodstream infections in domestic animals.

The preparation of a synergistic pharmaceutical composition of the invention is characterized by mixing the water-soluble pharmacologically active salt of tiamulin hydrogen fumarate, lleomycin or streptoinicin with an inert, non-toxic carrier in a ratio of 1: 1 to 5: 1.

The use of neomycin and streptomycin, alone or in combination, to treat infections of various origins is widespread in veterinary medicine.

Thus, streptomycin, alone or in combination with penicillin (Stredipen inj.), is used parenterally for the treatment of respiratory diseases.

Among the neomycin formulations, Neomast A.U.V. and Nestrepina A.U.V. for mastitis, Exuter Μ. P. effervescent tablet or combination of capsules (Septimetrine) for bee treatment.

The use of neomycin by parenteral injection is limited because it has been reported in the literature to cause nplplotoxicity, azotemia and oliguria (Kuhhnann 1979, Deutsche Med. Wschr. 104. 50. 1783-1787). In this case, it is advisable to reduce the therapeutic dose in order to avoid adverse side effects, which may, on the one hand, lead to ineffective treatment and on the other hand to the development of resistance.

In particular, treatment is ineffective when Mycoplasma is involved in the production of urinary, respiratory, and other infections, as neomycin is ineffective (Ulrich, Briand, 1977, Acta Pathol. Microbiol. Scand. B 85, 5, 347349).

No. 2027590, incorporated herein by reference. It is known from the British patent for the preparation of tiamulin hydrogen fumarate in parenteral dosage form. Based on its spectrum of action, it is effective in treating not only mycoplasma pneumonia but also swine dysentery (Burch, D. G. S. Heard, T. W. Tasker, J. B. 1983. Vet. Rec. 10 Sep 236-237).

It is therefore an object of the present invention to provide a combination of drugs which, on the one hand, enhances the anti-mycoplasma effect of tiamulin by increasing its spectrum of action in combination with certain antibiotics and, on the other hand, effectively against pathogens that cause urinary tract, respiratory and other infections.

Experiments were carried out on different pathogenic strains grown from sick animals and found that the minimum inhibitory value of each active ingredient was different. The data for the assays are tabulated, showing the minimum inhibitory (MIC) and minimal bactericidal (MBC) concentrations of each drug in the same culture, expressed as mg / f.

Table 1 gives MICs and MBCs for neomycin. This shows that the preparation alone is Listeria, Klebsiella, Pasteurella and Borde1. spreadsheet

Antibacterial activity of chemotherapeutic agents expressed in mg / l

Tribe neomycin MIC MBC Staphylococcus aureus 10 25 Streptococcus zooepidemicus 10 25 Listeria monocytogenes 5 5 Corynebacterium pyogenes 25 50 E. coli 5 10 E. coli (calf) > 200 > 200 Klebsiella pneumoniae 5 5 Salmonella typhimurium 10 25 Proteus vulgaris 100 200 Pasteurella multocida 1 5 Pasteurella haemolytica 5 10 Brodetella bronchiseptica 5 5 Pseudomonas aeruginosa 25 50 Mycoplasma gallisepticum > 200 > 200 Mycoplasma hyorhinis > 200 > 200

Table 2

Antibacterial activity of chemotherapeutic agents expressed in mg / l

tiamulin MIC MBC

Staphylococcus aureus 25 100 Streptococcus zooepidemicus <0.5 <0.5 Listeria monocytogenes 50 100 Corynebacterium pyogenes - - E. coli 50 100 E. coli (calf) > 200 > 200 Klebsiella pneumoniae > 200 > 200 Salmonella typhimurium 200 > 200 Proteus vulgaris > 200 > 200 Pasteurella multocida 25 25 Pasteurella haemolytica 10 10 Ihodclclln bronchiseptica 50 200 Pseudomonas aeruginosa > 200 > 200 Mycoplasma gallisepticum <0.5 < 0.5 Mycoplasma hyorhinis 0.5 1

tella species, while the susceptibility of E. coli strains to neomycin is variable depending on the animal species.

Table 2 shows MICs and MBCs for tiamulin hydrogen fumarate. Its effect on Gram positive bacteria is primarily Streptococcus

-2191 399 in cultures is remarkably low. It is virtually inactive against E. coli, Klebsiella, Salmonella, Proteus and Pseudomonas. According to our tiamulin measurements, mycoplasma cultures have an excellent effect even at low concentrations.

Table 3 gives MIC and MBC values for streptomycin. It can be seen that the preparation alone is effective against Corynebacterium and Klebsiella cultures, as well as cultures of Staphylococcus and Listeria, but its efficacy against E. coli is unsatisfactory.

Our studies have shown that when combined with ncomydn or streptomycin, tiamulin hydiogenic fumarate, as measured in vitro in some strains, exhibits synergism that

Table 3

Antibacterial efficacy of chemotherapeutic agents expressed in mg / l

streptomycin MIC MBC

Staphylococcus aureus 10 25 Streptococcus zooepide- 25 50 micus Listeria monoeytogenes 10 25 Corynebacterium pyogenes 5 25 E. coli 11 100 > 200 E. coli 494 200 > 200 Salmonella typhimurium 50 200 Klebsiella pneumoniae 5 5 Pasteurella is a thing of the past 25 25 Bordetella bronchiseptica 200 > 200 Pseudomonas aeruginosa 100 > 200

The composition of the preparation was calculated from the microbiological measurement data given in Tables 4 and 5.

Of the 15 strains tested, 6 showed a pronounced enhancement, as shown in Table 6.

The potency is at least 4-5-fold, but 50-100 and 200-fold, respectively. A dose reduction of this ratio is equivalent to g in vitro; tias can be assured.

The preparation is administered parenterally intrauterine

Table 4

Antibacterial activity of chemotherapeutic agents expressed in mg / l

Tribe Tiainulin + Neomycin MIC MBC Staphylococcus aureus 1 5 Streptococcus zooepidemicus <0.5 <0.5 Listeria monoeytogenes <0.5 <0.5 Corynebacterium pyogenes l 1 E coli 5 5 E coli (calf) 100 200 Klebsiella pneumoniae 5 10 Salmonella typhimurium 5 5 Pioteus vulgaris 10 25 Pasteurella is a thing of the past <0.5 <0.5 Pasteurella liaemolytica - - Bordetella bronchiseptica 5 5 Pseudomonas aeruginosa 10 10 Mycoplasma gallisepticum <0.5 <0.5 Mycoplasma hyorhinis 5 5

both therapeutically and economically significant due to dose reduction. In addition to reducing the effective dose required, the combination has the additional benefit of being effective in the treatment of respiratory and gynecological diseases associated with other protozoal and bacterial infections, mycoplasma agents, and secondary infections due to the broadening of the spectrum of action. A further advantage of the composition according to the invention is that by reducing the dose of neomycin and streptomycin, the adverse side effects of their use are reduced, while the lower dosage also reduces their otherwise long nutritional waiting time. The synergistic effect of the composition of the invention is demonstrated below by in vitro activity assays of drug combinations wherein the combinations are 1; 1 ratio contains tiamulin hydrogen fumarate and neomycin or tiamulin hydrogen fumarate and streptomycin.

Table 5

Antibacterial efficacy of chemotherapeutic agents expressed in mg / l

Tiainulin + Streptoinycin Strain -MIC MBC

Staphylococcus aureus 5 5 Stieplococcus zooepide- 1 1 mieus Listeria monoeytogenes 10 20 Corynebacterium pvogenes <0.5 5 E. coli 11 50 > 200 E. coli 494 50 > 200 Salmonella typhimurium 50 > 200 Klebsiella pneumoniae 5 10 Pasteurella is a thing of the past 10 25 Bordetella bronchiseptica 200 > 200 Pseudomonas aeruginosa 100 > 200

At a dose of 191,399 g / animal, it is recommended for the prevention of uterine inflammation after fever and for treatment of fetal envelope.

In addition to Gram positive and Gram negative agents, mycoplasma infection can be prevented by bulking in 0.5 g / udder quartile.

The composition of the invention is prepared by homogenizing the tiamulin hydrogen fumarate with the neomycin sulfate or streplomyein sulfate and then gradually, in a ratio of 1: 1 to 1:50 relative to the active ingredient, with a water-soluble, non-toxic carrier, preferably mix with milk sugar. The homogenate is dissolved in a tissue exclusion solvent. The solvent, which may be yeast, vegetable oils, dimethylformamide, is used in a ratio of 1: 10 to 1:25 relative to the active compounds. The resulting sterile solution is dispensed into ampoules into sterile glass vials.

The composition of the present invention is illustrated by the following example, but is not intended to be limiting.

EXAMPLE 1 Thiannilinebihydrogen Fumarate Neoinycin Sulphate Streptomycin Sulphate Milk Sugar Water

250mg 250mg or 250mg 500mg is given for 10 ml intra-ocular administration.

Example 2 tiamulin hydrogen fumarate neomycin sulfate streptomycin sulfate lactose water water for intrauterine treatment.

1000 mg 4000 mg or 4000 mg 1000 mg gives 20 ml

Table 6

Increased antibacterial efficacy when combined with chemotherapeutic agents

tribe neomycin tiainulin neomycin + tiamulin (1: 1) synergism MIC MBC MIC MBC MIC MBC Staphylococcus aureus 10 25 25 100 1 5 20-50-fold Listeria monoeytogenes 5 5 5 100 <0.5 <0.5 20-200-fold Proteus vulgar 100 200 200 200 10 25 20-40-fold Pasteurella multocida 1 5 25 25 <0.5 <0.5 40-100-fold Pseudomonas aeruginosa 25 50 200 200 10 10 5-40

tribe streptomycin tiamulin streptornycin tiamulin + (1: 1) synergism MIC MBC MIC MBC MIC MBC Staphylococcus aureus 10 25 25 100 5 5 4-40 times Listeria monoeytogenes 10 25 5 100 10 10 2-20-fold Pasteruella multocida 25 25 25 25 10 25 2-5 Klebsiella pneumoniae 5 5 > 200 > 200 5 10 2-80-fold

191,399

Claims (5)

Claims I. A process for the preparation of a novel drug combination comprising tiamulin hydrogen fumarate and neomycin or streptomycin for the treatment of respiratory, urinary and other bloodstream infections in domestic animals, characterized in that tiamulin hydrogen fumarate (14-deoxt-14 - [/ diethylaminoethyl (mercaptoacetoxy) mutilin hydrogen fumarate) and neoinycin (0-2,6-diamino-2,6-dideoxy) -? - L-idopyranosyl 1/1 -? - O-dC-ribofuranosyl? 5-O- (2-Amino-2-deoxy-α-D-glucopyranosyl / 1- [4 H] -2-deoxystreptamine) a water soluble pharmaceutically active salt or tiamulin and streptomycin (2,4-diguanidino-3,5, 6-trihydroxycyclohexyl-2O- (2-deoxy-2-methylamino-α-L-glucopyranosyl) -3-C-formyl-O-L-lixopentofuranoside), a water-soluble, pharmaceutically active salt thereof, in a ratio of 1: 1 to 1: 5; the resulting mixture is admixed with an inert, non-toxic carrier at a ratio of 1: 1 to 1: 50 and formulated for parenteral administration. In preparing. 2. The method of claim 1 for the preparation of a medicament for the treatment of mastitis, wherein the tiamulin and neomycin or tiamulin and streptoinycin are mixed in a ratio of 1: 1 to 1: 5 and 1.50 to 5.00 mg / up to kg body weight is mixed with the vehicle. 3. A process for the preparation of an intrauterine composition according to claim 1, wherein the tiamulin and neomycin or tiamulin and slreplomycil are mixed in a ratio of 1: 1 to 1: 5 and the mixture is 2.5-5 mg / kg. amount is mixed with the vehicle. 4. The method of claim 1, wherein the active compound combination is applied to the lactose carrier 15 in a ratio of 1: 1 to 1:50 relative to the active ingredients. 5. The process according to claim 1, wherein the halo conimimide is mixed with a liquid diluent to prevent tissue damage, preferably water, vegetable oils, dimethylformamide, in a ratio of from 1: 10 to 1:25.