DE3515185A1 - SYNERGISTIC COMBINATION MEDICINAL PRODUCTS - Google Patents

Description

DR.STEPHAN G. BESZfDES PATENT ADVOCATE

VNR: 101265 APPROVED REPRESENTATIVE ALSO AT THE EUROPEAN PATENT OFFICE

PROFESSIONAL REPRESENTATIVE ALSO BEFORE THE EUROPEAN PATENT OFFICE

DACHAU NEAR MÖNCHEN

BOX 1168

MONCHENER STRASSE 8OA Federal Republic of Germany

TELEPHONE: D ACHAU 08131/4371 TELEX: 527537 bepat d

Postschectckonta MQnchen (bank code 700 100 80)

Account No. 1 368 71-601 Bank account no. 906 370 at Sparkasse Dachtu

(Sort code 700 515 40)

{VIA Bayerische LandesbanV

Girozentrale, Munich)

P 2 289

Patent application and description

for patent application

HAJDÜSAGI AGRAHIPARI EGYESÜLriö

Nadudvar, Hungary

concerning

Combination medicinal products with a synergistic effect

BAD ORiGfNAL

description

The invention relates to new antimicrobial synergistic properties acting combination drugs.

1- (ethyl) -1,4-di- (hydro) -6,7- (methylenedioxy) -4- - (oxo) -quinoline-3-carboxylic acid [5-ethyl-5,8-dihydro-8- oxo- -i ^ -dioxolo - ^^ - gJchinolin ^ -carboxylic acid} <"oxolinic acid) and the 1- (ethyl) -7- (methyl) -4- (oxo) -1,4-di- (hydro) -1,8- -naphthyridine-3- (carboxylic acid) {i-ethyl-1,4-dihydro-7- -methyl-4-OXO-1, e-naphthyridine ^ -carboxylic acid} {nalidixic acid) are known for a long time in human medicine and in veterinary medicine alike. In human medicine They are primarily used to treat urinary tract disorders while they are used for the Veterinary medicine to combat gram-negafcive Bacteria-evoked infection-η are important.

There are also combinations of 1- (ethyl) -1,4-di- (hydro) - -6,7- (methylenedioxy) -4- (oxo) -quinoline-3-carboxylic acid <CCbcolins ^: iure)> or 1- (ethyl) -7- (methyl) -4- (oxo) - -1,4-di- (hydro) -1,8-nachfchyridin-3- (carbons- iure ^v) Otfslidixinsäure) and become known antibiotics or other organic acids . Bartoloni et al. Reported on the combined use of 1- (ethyl) -1,4-di- - (hyd ro) -6,7- ( ^ e ethylenedioxy) -4- (oxo) -quinoline-3-carb acidic ^ oxolinic acid) or 1- (ethyl) -7- (methyl) - -4- (oxo) -1,4-di- (hydro) -1,8-naphthyridine-3- (carboxylic acid) ^ Na ¹ idixic acid) and 5- [3 ', 4', 5'-tri- (methoxy) -benzyl] - -pyridine-2,4-di- [amine] <fTrimethoprim> reported (Bartoloni, E., Castelli, M., Genedani , M., Genedani, S., Bertoni, V .: Drug Exp. Clin. Res. 6 ^ (4), [1980], 311-316).

In Japanese patent 81150016 anti-

- 5 -BAD ORiGfNAL

microbial combinations of 1- (ethyl) -1,4 ~ di- (hydro) - -6,7- (methylenedioxy) -4- (oxo) -quinoline-3-carboxylic acid <0xolinic acid> and other organic acids for treatment of infections caused by E. coli.

-'14 - [[2 "(diethylamino) -ethyl] -mercapto- -acetoxy} -mutilin-hydrogen fumarate ^ Tiamulin-hydrogen fumarai ^ is a relatively new active ingredient, an antibiotic, which is primarily used against respiratory diseases and the digestive organs of pigs, but also to cure those caused by mycoplasma Udder inflammation of cows is used (Burch, D. G. S., Haard, R. W., Taskor, J. B .: Vet. Rec. 1_0, [1983], 236 to 237).

The effect of 14 — deoxy-14 - [[2- (diethylamino) ethyl] - -mercapto-acetoxyj-mutilin-hydrogenfumcrates (Tiamulin- -hydrofumarates) against gram-positive bacteria (Staphylococcus, Streptococcus, Mycoplasma and Treponema) is also known from British patent specification 2,027,590.

As microbiological investigations showed, however, the activity spectrum of the 14-deoxy-14 ~ [[2- (diethylamino) ethyl] -mercapto-acetoxy} -mutilin-hydrogenfumarates _<(h-t Tianiulin ydrogenfumarates)> against gram-negative bacteria is relatively eng (Forster, J., Pickles, G .: IPVS Conference, Zagreb, June 13-15, 1978).

The invention is based on the object of 14 — deoxy- -14 - {[2- (diethylamino) ethyl] -mercapto-acetoxy3-mutilin- -hydrogenfumerate <! tiamulin hydrogenfumerate) containing Combination medicinal products that have the individual effects of Combine 2 or more components in a synergistic way and also reduce the effort enable to create.

The above has surprisingly been achieved by the invention.

It was found, surprisingly, that with the combined use of 14-deoxy-i ^ - ^^ - idiäthylamino ^ äthylJ-mercapto-acetoxy ^ i-mutilin hydrogen fumarate {Tiamulin hydrogen fumarate) organic acids effective against bacteria and protozoa, especially 1- (ethyl) -1,4, - -di (hydro) -6,7- (fiethylenedioxy) -4- (oxo) -quinoline-3-carboric acid (Oxolinic acid) and / or 1- (ethyl) -7- (methyl) -4- (oxo) - _1, Z | - di (hydro) -1,8-naphthyridine-3- (carboxylic acid) (NaIidixic acid ") In addition to the additive effect resulting from the different spectrum of effects, a pronounced one Increased effectiveness, a synergistic effect occurs.

The invention therefore relates to synergistically acting combination medicaments with an antibacterial effect and antiprotozoal effects with a content of 14-deoxy- -14 {[2- (diethylamino) ethyl] -mercapto-acetoxyJ-mutilin- -hydrogenfumerate (Tiamulin-hydrogenfumaraO, if necessary together with 1 or more conventional pharmaceutical inert non-toxic solid and / or liquid carriers, Extender and / or auxiliary substance (s), which are characterized are that they besides that

_a ) i / j.- Deoxy-14- [[2- (diethylamino) -ethyl] -mercapto- -acetoxyj-mutilin hydrogen fumarate <(tiamulin hydrogen fumarate)

b) 1 or more effective against bacteria and protozoa organic acid (s) and / or water-soluble derivative (s) thereof,

if necessary, in the case of spatially separated

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are of a) and b) in one and the same packaging or packaging Application unit, included, the weight ratio of a): b) 5 * 1 to 1: 5.

The combination medicaments according to the invention preferably contain as organic effective against bacteria and protozoa Acid (s) {components) b) J 1- (ethyl) -1,4 ~ di- (hydro) - -6,7- (niettE7len.dioxy) -4- (oxo) -quinoline-3-carboxylic acid ^ oxolinic acid) and / or 1- (ethyl) -7- (methyl) -4- (oxo) -1,4-di- - (hydro) -1,8-naphthyridine-3- (carboxylic acid) (nalidixic acid).

As a water-soluble derivative (s) of the organic acid (s) ^ Components) b)] can or can in the invention Combination medicaments [a] pharmaceutically usual [s], advantageously [a] salt (s), preferably with [a] alkali metal (s), such as sodium and / or potassium, and / or ammonium salt (s), and / or complex (s), preferably with [a] metal (s), in particular heavy metal (s), and / or amide (s) and / or ester.

After an advantageous. In an embodiment of the invention, the combination medicaments according to the invention contain lactose as a carrier. It is preferred that they contain the active ingredient mixture from a) and b) and the milk sugar in weight ratios of 5 ^: 1 to 1:50, in particular 3: 1 to 1: 3, especially 3: 1 to 1: 1.

According to another advantageous embodiment of the invention, the combination medicaments according to the invention contain as a carrier (s) 1 or more physiologically compatible liquid diluents, in particular Water, 1 or more vegetable oil (s) and / or dimethylformamide. It is preferred that they contain the active ingredient mixture from a) and b) the liquid diluent (s) in weight ratios of 1: 1 to 1:25, in particular 1: 8 to 1:25.

Combinations of the embodiment mentioned last with that mentioned in the penultimate paragraph are also very advantageous .

According to a preferred embodiment of the invention, the combination medicaments according to the invention contain the active substance mixture of a) and b) in amounts of 5 to 15 mg / kg of body weight in dosage units or dosage units suitable for oral administration.

According to another preferred embodiment of the invention, the combination medicaments according to the invention contain the active substance mixture of a) and b) in dosage units or dose units suitable for intrauterine administration, in particular capsules, in amounts of 4 to 6 g, especially 5 g, suitable as a daily dose for Λ animals G.

The combination medicaments according to the invention can be prepared in such a way that in a known manner a) with b) in weight ratios of 5: 1 to 1: 5 and if necessary with the T-ager, Extender and / or auxiliary substance (s), optionally as or is or are mixed into solutions, expediently with homogenization, and optionally the mixture is prepared into dosage or dose units.

For oral use, the active ingredient mixture is used as Powder or as granules, mixed in the drinking water of the animals or in the feed. As peirenteral forms of administration are in particular capsules for intrauterine use and liquid preparations for intracysternal use suitable.

To demonstrate the synergism, the minimum inhibitory concentration and the bactericidal minimum

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centering of both the individual components and the Combinations measured in terms of different microorganisms. The results are shown in Tables 1 below and 2 put together. The degree of intensification in Table 1 =

Minimum concentration of 14-deoxy-14 - {[2- (diethylamino) ethyl] -mercapto-acetoxy} -mutilin · -hydrogen-

fumarate {Tiamulin-HydroKenfumarat} _O

Minimum concentration of the inventive combination of 14-deoxy-14- £ [2- (diethylamino) ethyl] - -mercapto-acetoxyj-mutilin-hydrogen fumarate <(Tiamulin hydrogen fumarate) and 1- (ethyl) -1,4-di- (hydro) - -6,7- (niethylenedioxy) -4- (oxo) -quinoline-3-carboxylic acid (Oxolinic acid)

respectively

Minimum concentration of 1- (ethyl) -1,4-di- (hydro) - -6,7- (si ^: 2fchyleadioxy) -4- (oxo) -quinoline-3-carbon-

acid ^ oxolin ^ ure ^ _t P

Minimum concentration of the invention. combination from 14-deoxy-14 - {[2- (diethylamino) -äthylj- -nercapto-acetoxyj-mutilin-hydrogenfunaarat <! Ti ^ - mulin hydrogen fumarate) and 1- (ethyl) -1, ^ - di- (hydro) - -G ^ -Cmethylenedioxy) - ^ - (oxo) -quinoline-J-carboxylic acid {Oxolinic acid>.

the degree of intensification in Table 2 =

Minimum concentration of 14-deoxy-14 - [[2- (diethylamino) ethyl] -mercapto-acetoxyj-mutilin-hydrogen-

fumarate CTiamulin hydrogen fumarate) _# P

Minimum concentration of the inventive combination of 14-deoxy-i4 - {[2 ~ (diethylamino) ethyl] - -mercapto-acetoxyj-mutilin-hydrogen fumarate <^ Tiamulin hydrogen fumarate) and 1- (ethyl) -7- (methyl) - -4- (oxo) -1,4-di- (hydro) -1,8-naphthyridine-3- (carboxylic acid) ^ ialidixins ^ iure ^ - 10 -

respectively

Minimum concentration of 1- (ethyl) -7- (methyl) -4- - (oxo) -1,4-di- (hydro) ~ 1,8-naphthyridine-3- (carbon-

acid) ^ nalidixic acid) _t ~

Minimum concentration of the combination according to the invention from 14-deoxy-14- £ [2- (diethylamino) ethyl] - -mercepto-acetoxy] mutilin hydrogen fumarate ^ TiamuIin hydrogen fumarate) and 1- (ethyl) -7- (methyl) - -4- (oxo) -1,4-di- (hydro) -1,8-naphthyridine-3- (carboxylic acid) (Nalidixic acid)

Concerning the intensification it should be noted that in each case in the combination according to the invention the amounts of the constituents are half of the amounts that of 14-deoxy- -14- ^ 2- (diethylamino) -ethyl] ~ tnercapto-acetoxy} -mutilin- -hyorogenic fumarate (Tiamulin hydrogen fumarate) or 1- (ethyl) -1,4-di- (hydro) -6,7- (methylenedioxy) - ~ 4- (oxo) -quinoline-3-carboxylic acid <oxolinic acid> {in the table 1; or ν on 14-deoxy-14- '[2- (diethylamino) -ethyl] -aercapto-acetoxy _J - -mutilin-hydi ogenfum ^ rat \ Tiair; ulin-hydrogenfuic6rat)> or the 1- (ethyl) - -7- (n! Ethyl) -4- (oxo) - ⁱ 1,4-di- (hydro) -1,8-naphthyridine-3- - (carboxylic acid) (Kalidixic acid> ^ in Table 2j were used ; if the value for the combination is the same as for 14-deoxy-14-i [2- (diethylamino) - -äthylj-mercapto-acetoxy] mutilin hydrogen fumarate <tiamulin hydrogen fumarate) or for 1- (ethyl) - -1,4-di- (hydro) -6,7- (methylenedioxy) -A- (oxo) -quinoline-3- -carboxylic acid <TOxolinic acid> | in Table 1] or 1- (ethyl) -7- ( methyl) -4- (oxo) -1,4-di- (hydro) -1,8- -naphthyridine-3- (carboxylic acid) ^ nalidixinic acid) ^ .n Table 2Jr, this means a 2-fold intensification. The range of the degree of intensification is formed from the thus obtained lowest value of the degree of intensification in the respective microorganism as the lower value and from the thus obtained highest value of the degree of intensification in the respective microorganism as the upper value. BADORlGfNAL

- 11 Table 1

Intensification of the antibacterial effect in the case of a combination of 14-deoxy-14 - ^ [2- (diethylamino) -
-äthylj-mercapto-acetoxyj-mutilin-hydrogen fumarate <fTiamulin-hydrogenfuinarat) {component a)} and 1- (ethyl) -
-1,4-di- (hydro) -6,7- (methylenedioxy) -4- (oxo) -quinoline-3-carboxylic acid ^ oxolinic acid) {component b)] by weight

ratio of 1 y 1

Investigated 14-deoxy-14 - {[2- (di- Bactericidal 1- (ethyl) -1,4-di- Bactericidal Combination of 14-deoxy-14- Bactericidal area Microorganism ethylamino) ethyl] - minimum con - (hydro) -6.7- Minimum con - {[2- (diethylamino) ethyl] - Minimum con of -mercapto-acetoxyj- centration - (methylenedioxy) - centering -mercapto-acetoxy} -mutilin- centering Degree -mut ilin-hydrogen- in -4- (oxo) -quinoline- in -hydrogen fumarate ^ tiamulin- in the fumarate ^ tiamulin- / ig / ml -3-carboxylic acid / ig / ml -hydrogen fumarate ^ 25th Int en- hydrogen fumarate) ^ Oxo1ic acid) [Component a) j 25th sivation minimum minimum and 1 inhibit- inhibit- 1- (Xthyl) -1,4-di- (hydro) -6,7- 5 centrate. centraticn - (methylenedioxy) -4- (oxo) - in in -quinoline-3-carboxylic acid / ig / ml / ig / ml <0xolic acid ^ 100 50 {Component b) j 100 100 in a weight ratio of 1: 1 > 200 10 Minimum inhibit- > 200 10 centering in / ig / ml Staphylococcus aureus 25th 25th 5 4 to 10 χ Listeria monocytogenes 50 100 5 8 to 40 χ Salmonella typhi-murium 200 1 1 2 to 400 χ Klebsieila pneumoniae > 200 5 5 2 to 80 χ

- 1? - Table 2

Intensification of the antibacterial effect in the case of a combination of 14-deoxy-14 - ([2- (dietbylamino) - -äthylj-mercepto-acetoxyj-mutilin-hydrogen fumarate ^ Tiamulin-hydrogen fumaret) {component a) j and 1- (ethyl) - -7- (methyl) -4- (oxo) -1,4-di- (hydro) -1,8-naphthyridine-3- (carboxylic acid) <nalidixic acid) ^ component b) j by weight

ratio of 1: 1

Investigated 14-deoxy-14 - {[2- (di- Bactericidal 1- (ethyl) -7- Bactericidal Combination of 14-deoxy-14- Bactericidal area Microorganism äthylam ino) -äthyl] - Minimum con - (methyl) -4- (oxo) - Minimum con - {[2- (diethylamino) ethyl] - Minimum con of -mercapto-acetoxyj- centering -1,4-di- (hydro) - centering -mercapto-ace.toxy] -mutilin- centering Degree -mutilin-hydrogen- in -1,8-naphthyridine- in -hydrogen fumarate v'Tiamulin- in the fumarate ^ tiamulin- / ig / ml -3- (carboxylic acid) / ig / ml -hydrogenfumrat) VJl Inten hydrogen fumarate) (Nalidixic acid) ^ Component a) j 100 sivation Minimum-. minimum and 10 inhibit- lemming 1- (ethyl) -7- (methyl) -4- (oxo) - 50 centratim centrationLon -1,4-di- (hydro) -1,8-naphthyri- in in din-3- (carboxylic acid) / ig / ml / ig / ml v'Nalidixic acid ') 100 > 200 (Component b)] 100 > 200 in a weight ratio of 1: 1 > 200 10 Minde stemming > 200 50 centering in / ig / ml Staphylococcus aureus 25th 5 VJI 2 to 80 7 Listeria monoc.vtogenes 50 > 200 50 2 to 8 χ Salmonella typhi-murium 200 10 10 2 to 40 χ Klebsieila pneumoniae > 200 50 50 2 to 8 χ

From Tables 1 and 2 above, the Synergism of the combinations. The intensification of the effect in the combinations according to the invention is at least 2 times, mostly 2 to 8 times, but it can reach values up to 400 times. The intensification the effect is in the cultures of Staphylococcus aureus, Listeria monocytogenes, and Salmonella typhi-murium Klebsieila pneumoniae particularly pronounced.

The combination medicaments according to the invention can advantageous against the infectious agents listed below in cattle, calves, pigs, piglets, rabbits and dogs are used:

I) Inflammation of the intestine caused by Salmonella, Klebsieila or E. coli.

II) By Proteus, E. coli, Streptococcus respectively Staphylococcus caused intestinal inflammation.

III) By Streptococcus, Staphylococcus or gram-negative pathogens, such as E. coli or respectively Klebsieila, or also mycoplasma Udder inflammation.

IV) In diseases of the digestive organs and the respiratory tract in pigs, for example caused by S. coli Diarrhea, dysentery or pneumonia caused by mycoplasma.

V) In diseases of the digestive organs and the respiratory tract in rabbits and poultry, such as infections by E. coli.

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The following dosages are recommended for oral administration:

Against intestinal inflammation, a water-soluble preparation containing 60% by weight of the active substance mixture, namely

for calves 400 mg / animal and day and

for piglets 350 mg / litter and day.

Against bowel inflammation and urinary tract infections

in dogs depending on the size of the

Animal

200 to 400 mg / day and animal with a treatment duration of 3 days.

For mixing into the feed, a 60 wt .-% Premix containing active ingredient mixture for 5 days Feed added:

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

in pigs 200 to 400 mg / kg feed.

Against infections of the digestive organs and the respiratory tract

in rabbits 150 to 250 mg / kg feed

medium and

for poultry 300 to 400 mg / kg feed

middle.

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For intrauterine treatment, the A mixture containing 60% by weight of the active substance mixture in a daily dose of 5 6 », preferably in capsules, 5 days administered for a long time.

The invention is explained in more detail with reference to the following examples.

example 1

There were 1.5 g of 14-deoxy-14 - {[2- (diethylamino) ethyl] - -mercapto-acetoxyj-mutilin-hydrogen fumarate (tiamulin- -hydrogen fumarate), 1.5 S 1- (ethyl) -1,4-di- (hydro) -6,7- - (methylenedioxy) -4 - (oxo) -quinoline-3-carboxylic acid ^ oxolinic acid) and 2.0 g of milk sugar mixed together and filled into a capsule. Such capsules were made for cows had just calved, administered intrauterine over 3 days. In the 24 treated animals the regression went faster in front of you, uterine inflammation and lagging behind of the embryo skins did not enter. The treatment was effective in preventing bacterial inflammation.

Example 2

There were 0.6 14-deoxy-14 - ^ [2- (diethylamino) ethyl] - -mercapto-acetoxyj-mutilin-hydrogen fumarate (tiamulin- -hydrogen fumarate), 3.0 g 1- (ethyl) -7- (methyl) -4- (oxo) - -1,4-di (hydro) -1,8-naphthyridine-3- (carboxylic acid) ('nalidixic acid ^ and 1.4 g of milk sugar mixed together. The weight ratio of the two active ingredients to one another was So 1: 5 · This preparation, expressed as a pure mixture of active ingredients, 10 to 20 mg / kg body weight administered orally.

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3515T85

Dps mixture was suspended in 100 ml of water. 5 litters of piglets (50 piglets) were treated. Received each animal (healthy as well as sick animal) 1 ml (= 0.036 g) of the Oral suspension. The diarrhea of the sick animals stopped after the first treatment. New diseases and there were no relapses.

Example 3

There were 10.0 14 ~ Deso: -: y - 14 - {[2- (diethylamino) ethyl] - -mercapto-acetoxyj-mutilin-hydrogen fumarate (tiamulin- -hydrogen fumarate), 2.0 g 1- (ethyl) -1,4-di- (hydro) -6,7- - (methylenedioxy) -4- (oxo) -chinoline-3-carboxylic acid <oxolinic acid ^ and 100.0 ml of oil suitable for injections made into a suspension.

10 ml of this suspension were poured into each teat canal infused from 5 cows suffering from inflammation of the udder. The symptoms of acute inflammation (swollen, warm udder, macroscopically noticeable change in milk) improved significantly after the first treatment. One week after the third administration, it was bacteriological Examination carried out, the result of which was negative.

Together

Claims (4)

Claims 1.) Synergistic combination drugs with antibacterial and antiprotozoal effects with a content of 14-deoxy - 14- £ [2- (diethylamino) - -äthylj-mercapto-acetoxyj-mutilin-hydrogen fumarate {Tiamulin hydrogen fumarate), optionally together with 1 or more conventional pharmaceutical inert non-toxic solid and / or liquid carriers, Extender and / or auxiliary substance (s), characterized in that that they besides that a) 14 ~ deoxy-14 - {[2- (diethylamino) ethyl] - -mercapto-acetoxy] mutilin hydrogen fumarate (Tiamulin hydrogen fumarate). b) i or more against bacteria and protozoa effective organic acid (ri) and / or water-soluble [sj Derivative (s) of the same * possibly with spatially separated. ·: Presence of a) and b) in one and the same. Ve: ¹ pack or application unit, the weight ratio of a): b) being 5: 1 to 1: 5. 2.) Combination medicament according to claim 1, characterized in that they are used as against bacteria and Protozoal acid (s) [component (s) b) j 1- (ethyl) -1,4-di- (hydro) -6,7- (methylenedioxy) -4 ~ - (oxo) -quinoline-3-carboxylic acid (oxolinic acid) and / Dder <1- (ethyl) -7- (methyl) -4 - (oxo) -1,4-di- (hydro) -1,8- -naphthyridine-3- (carboxylic acid) ^ nalidixic acid) contains .. - 3 - 3.) Combination medicament according to claim 1 or 2, characterized in that they use the active ingredient mixture from a) and b) in amounts of 5 to 15 mg / kg Body weight in dosage units or dosage units suitable for oral administration contain. 4.) Combination medicament according to claim 1 or 2, characterized in that it contains the active substance mixture of a) and b) in dosage units or dose units suitable for intrauterine administration, in particular capsules, in as
Daily dose for 1 animal appropriate amounts of
Contains 4 to 6 g, especially 5 gi. description