WO2010069493A1

WO2010069493A1 - Improved combination of active agents comprising an antibiotic and a non-steroidal anti-inflammatory drug (nsaid)

Info

Publication number: WO2010069493A1
Application number: PCT/EP2009/008734
Authority: WO
Inventors: Kristine Fraatz; Iris Heep; Stefan Hofmann; Martina Rehagen
Original assignee: Bayer Animal Health Gmbh
Priority date: 2008-12-18
Filing date: 2009-12-08
Publication date: 2010-06-24
Also published as: AR074674A1

Abstract

The invention relates to novel combination formulations in veterinary medicine, comprising a quinolone antibiotic and a non-steroidal anti-inflammatory drug (NSAID). The formulations, particularly injection solutions comprising a quinolone antibiotic and an anti-inflammatory substance, are particularly well suited for parenteral treatment of bacterial infections in animals such as cattle, swine, dogs, and cats.

Description

Improved drug combination containing an antibiotic and a non-steroidal anti-inflammatory drug (NSAID)

The invention relates to novel combination formulations in veterinary medicine containing a quinolone antibiotic and a non-steroidal anti-inflammatory drug (NSAID). The formulations, in particular injection solutions containing a quinolone antibiotic and an anti-inflammatory substance are particularly suitable for the parenteral treatment of bacterial infections in animals such. Cattle, pigs, dogs, cats.

Bacterial infections of the respiratory tract of bovine (BRD, bovine respiratory disease) are one of the main causes of high economic losses in cattle breeding, breeding and milk production worldwide. Losses are caused by decreased daily gains, reduced fertility, and increased mortality, along with not inconsiderable treatment costs. Manheimia haemolytica, Pasteurella multocida and Haemophilus somnis play a role in the pathogenesis of FRG as causative germs.

Comparable to BRD in cattle are the bacterial infections of the respiratory tract of the pig (SRD, swine respiratory disease), caused by e.g. P. multocida, H. parasuis, Bordetella bronchiseptica, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis and mycoplasma.

The disease is characterized in both species by a pronounced inflammatory process, which can lead to irreparable lung damage. The treatment should therefore both eliminate the causal bacterial pathogens and minimize the inflammatory process. The standard therapy so far includes the use of a suitable antibiotic, such. As enrofloxacin (Baytril ^®), and in serious clinical diseases beyond the use of NSAIDs such. B. ketoprofen (Romefen ^®).

Comparable therapy is also performed in the presence of acute bovine mastitis, metritis, or pork mastitis metritis agalactia, as these bacterial infections are all associated with severe inflammatory processes and are life-threatening to the affected animals.

Basically, there is a need for improved therapeutic options for bacterial infections, especially for animals, especially those associated with strong inflammatory processes.

The invention relates to a combination comprising a quinolone antibiotic and a non-steroidal anti-inflammatory agent. The invention further relates to medicaments containing this combination and the preparation of these medicaments.

Quinolone antibiotics are antibiotic quinolones, preferably fluoroquinolones; These include, but are not limited to, compounds disclosed in the following documents: US 4,670,444 (Bayer AG), US 4,472,405 (Riker Labs), US 4,730,000 (Abbott), US 4,861,779

(Pfizer), US 4,382,892 (Daiichi), US 4,704,459 (Toyama), as concrete examples of quinolones may be mentioned pipemic acid and nalidixic acid; as examples of fluoroquinolones may be mentioned:

Amifloxacin, benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin,

Enoxacin, Enrofloxacin, Fleroxacin, Ibafloxacin, Levofloxacin, Lomefloxacin, Marbofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Orbifloxacin, Pefloxacin, Temafloxacin, Tosufloxacin,

Sarafloxacin, sparfloxacin.

A preferred group of fluoroquinolones are those of the formula (I) or (I-):

in which

X is hydrogen, halogen, C _1-4 -alkyl, C _M -alkoxy, NH ₂ , Y stands for radicals of the structures

stands in which R ^{4 is} optionally substituted by hydroxy or methoxy straight or branched Q-Gi-alkyl, cyclopropyl, acyl having 1 to 3 carbon atoms, R ^{5 is} hydrogen, methyl, phenyl, thienyl or pyridyl, R ^{6 is} hydrogen or C _{M is} alkyl, R ^{7 is} hydrogen or 0 ,. _4- alkyl,

R ^{8 is} hydrogen or Q _-4 -alkyl, and R ^{1 is} an alkyl radical having 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-

Fluorophenyl, 2,4-difluorophenyl or methylamino, R ^{2 is} hydrogen or alkyl optionally substituted by methoxy or 2-methoxyethoxy having 1 to 6 carbon atoms and cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl, R ^{3 is} hydrogen , Methyl or ethyl is and

A is nitrogen, = CH-, = C (halo) -, = C (OCH ₃ ) -, = C (CH ₃ ) - or = C (CN), B is oxygen, optionally substituted by methyl or phenyl = NH or = CH ₂ ,

Z is = CH- or = N-, and their pharmaceutically acceptable salts, hydrates and complex compounds.

The compounds of formulas (I) and (II) may be in the form of their racemates or in enantiomers

Shapes are present.

Preference is given to compounds of the formula (I) in which

A is = CH- or = C-CN, R! represents optionally halogen-substituted C 1 -C 6 -alkyl or cyclopropyl,

R ² represents hydrogen or Ci _-4 -alkyl group,

Y for residues of the structures

in which R ^{4 stands} for optionally hydroxyl-substituted straight-chain or branched C ₁ -C ₃ -alkyl, oxalkyl having 1 to 4 C atoms, R ^{5 is} hydrogen, methyl or phenyl,

R ^{7 is} hydrogen or methyl,

R ⁶ and R ^{8 are} hydrogen and their pharmaceutically usable hydrates, salts and complex compounds.

Particular preference is given to compounds of the formula (I) in which

A is = CH- or = C-CN, R ^{1 is} cyclopropyl, R ^{2 is} hydrogen, methyl or ethyl, Y is radicals of the structures

stands in which

R ^{4 is} methyl, optionally hydroxy-substituted ethyl, R ^{5 is} hydrogen or methyl,

R ^{7 is} hydrogen or methyl, R ⁶ and R ^{8 are} hydrogen and their pharmaceutically acceptable salts, hydrates and complex compounds.

Suitable salts are pharmaceutically usable acid addition salts and basic salts.

Examples of pharmaceutically usable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. Furthermore, the compounds according to the invention can be bound to acidic or basic ion exchangers. Suitable pharmaceutically usable basic salts are the alkali metal salts, for example the sodium or potassium salts, the alkaline earth metal salts, for example the magnesium or calcium salts; the zinc salts, the silver salts and the guanidinium salts. Furthermore, basic organic compounds can be used to salt with quinolones, for example, ammonia or mono-, di-, trialkylamines and their derivatives such as triethylamine, triethanolamine, 2-aminoethanol, N-methylglucamine (meglumine), cyclic amines such as Morpholine, piperazine or too basic amino acids, especially arginine, lysine, or their decarboxylation products, such as cholamine.

Hydrates are understood as meaning both the hydrates of the fluoroquinolones themselves and the hydrates of their salts.

Complex compounds are understood to mean, in particular, the compounds in which the quinolone is bonded to the coordination sphere via the carbonyl, carboxyl or, if appropriate, an amine function or via the cyano group with two or three positively charged metal ions or transition metal ions and ions of the boron. These complexes can be mononuclear or polynuclear.

Particularly preferred fluoroquinolones which may be mentioned are the compounds described in WO 97/31001, in particular 8-cyano-1-cyclopropyl-7 - ((1S, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl) 6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (pradofloxacin) having the formula

Pradofloxacin is preferred in its free form as anhydrate, e.g. In modification B (see WO 00/31076) or as trihydrate (cf., WO 2005/097789).

Particular preference is given to using enrofloxacin:

1-Cyclopropyl-7- (4-ethyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

Besides enrofloxacin and pradofloxacin, preferred quinolone anti-infectives include marbofloxacin, danofloxacin, orbifloxacin, difloxacin and ibafloxacin. Also conceivable is the use of the active ingredient ciprofloxacin otherwise used in human medicine.

Non-steroidal anti-inflammatory drugs, also referred to as non-steroidal anti-inflammatory drugs or NSAIDs, include: salicylic acid derivatives such as salicylic acid, acetylsalicylic acid, diflunisal, salicylsalicylate (salsalate), magnesium salicylate, amides of salicylic acid; Acetic acid derivatives, for example, indomethacin, diclofenac, lonazolac, bromfenac, tolmetin, etodolac, aceclofenac, oxametacin; Propionic acid derivatives, for example ibuprofen, flurbiprofen, ketoprofen, dexketoprofen (an analgesic), naproxen, tiaprofenic acid, suprofen, fenoprofen, carprofen, fenbufen, ketorolac, oxaprozin, loxoprofen, suprofen, indoprofen, alminoprofen, pirprofen; Oxicams, for example piroxicam, tenoxicam, meloxicam, lornoxicam; Anthranilic acid derivatives, for example mefenamic acid, flufenamic acid, meclofenamic acid; Coxibs such as celecoxib, rofecoxib, etoricoxib, valdecoxib, parecoxib, lumiracoxib; Sulfonanilides such as nimesulide, or compounds such as oxaceprol, aceclofenac. Another example of an NSAID is flunixin.

Non-steroidal anti-inflammatory drugs and analgesics for the purposes of this invention are also pharmaceutically active metabolites of the abovementioned compounds and their prodrug compounds, for example acetamicin or nabumetone.

Occasionally non-acidic antipyretic analgesics such as paracetamol, metamizole, phenylbutazone or flupirtine are sometimes referred to as NSAIDs in the literature, although their anti-inflammatory activity is low. According to the invention, these compounds should also be regarded as non-steroidal anti-inflammatory agents in a broader sense and can be used accordingly in the combinations according to the invention. Of the compounds mentioned, metamizole is preferred for the combinations according to the invention.

Preferred NSAIDs for the purposes of this invention are ketoprofen, flunixin and meloxicam.

Particularly preferred is ketoprofen:

For all pharmaceutically active ingredients, as explained in more detail above for the quinolones, the corresponding pharmaceutically acceptable salts, hydrates, solvates and optionally various modifications may be used.

For the purposes of the invention, the Na ⁺ and K ⁺ salts of quinolones and ketoprofen are particularly preferred.

Optically active substances may be used in the form of their stereoisomers or as a mixture of stereoisomers, e.g. as pure or enriched enantiomers or as racemates.

The combinations according to the invention and medicaments containing them enable the improved treatment of bacterial infections, especially in animals. They are preferably suitable for the treatment of bacterial infections which are accompanied by inflammation. For example, they are suitable for the treatment of bacterial infections z. B. the respiratory tract, such. B. Germany or SRD in cattle or pigs; bacterial infections of the udder in mammals or bacterial infections of the uterus of animals.

For the combinations according to the invention, in particular of enrofloxacin and ketoprofen, improved efficacy can be expected since, surprisingly, the serum pharmacokinetic profile of the antibiotic in the combination is advantageously altered.

The serum-kinetic profile of the antibiotic in these formulations surprisingly shows a substantial increase in peak serum concentrations (C _m, _*) of the quinolone antibiotic compared with the single preparation (z. B. when comparing a Enrofloxacin / ketoprofen formulation with the commercial product Baytril ^® in Cattle and pig). Among other things, the expected efficacy of a quinolone is derived from its peak serum concentrations (McKellar QA, Sanchez Bruni SF, Jones DG (2004), Pharmacokinetic / pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine., J. vet. Pharmacol. Therap. 27, 503-514), one can conclude an improved antibacterial efficacy of the combination over the single preparation. This improved efficacy was demonstrated in initial clinical trials (see Tables 1 and 2, Figures 1 and 2).

In the combinations according to the invention, quinolone antibiotics and nonsteroidal anti-inflammatory agents are usually in weight ratios (quinolone antibiotic: non-steroidal anti-inflammatory agent) of 100: 1 to 1: 100, preferably 50: 1 to 1:50, particularly preferably 50: 1 to 1: 1, in particular 30: 1 to 1: 1 before. In the treatment, the combinations according to the invention per application are usually in dosages of 1 to 100 mg, preferably 2 to 50 mg, more preferably 5 to 30 mg quinolone per kg body weight, and 0.1 to 60 mg, preferably 0.5 to 50 mg , more preferably 2 to 10 mg non-steroidal anti-inflammatory drugs per kg body weight applied. High-potency non-steroidal anti-inflammatory agents may preferably be administered in dosages of 0.1 to 20 mg, more preferably 0.2 to 10 mg per kg of body weight. Non-steroidal anti-inflammatory drugs with comparatively low potency can preferably be administered in dosages of 10 to 100 mg, more preferably 20 to 70 mg per kg of body weight.

The combination can be applied once or several times. The treatment is preferably as a single dose. Depending on the infection, the treatment duration can be extended to several days. Dose and dosage scheme depend on the type and course of the present bacterial infection and can range from several times a day, several days, once to several times daily over several days in different dosages.

For example, for the treatment of bovine bacterial infections, the combination according to the invention is administered once or several times in dosages of 2 to 50 mg quinolone per kg body weight and 1 to 20 mg nonsteroidal anti-inflammatory drugs per kg body weight. Preferably, the combinations are administered to cattle at doses of 5 to 30 mg / kg of quinolone and 2 to 10 mg / kg of nonsteroidal anti-inflammatory drug; even more suitable are doses of 5 to 20 mg / kg of quinolone and 3 to 7 mg / kg of nonsteroidal anti-inflammatory drug. In cattle, it is preferable to administer by injection, in particular intravenously, subcutaneously or intramuscularly.

For the treatment of bacterial infections of the pig, the combination according to the invention is administered once or several times in doses of 2 to 50 mg of quinolone per kg of body weight and of 1 to 20 mg of nonsteroidal anti-inflammatory agent per kg. Preferably, the formulations are administered to swine at a dose of 5 to 30 mg / kg of quinolone and 2 to 10 mg / kg of nonsteroidal anti-inflammatory drug; even more suitable are doses of 5 to 20 mg / kg of quinolone and 3 to 7 mg / kg of nonsteroidal anti-inflammatory drug. In pigs, it is preferably applied by injection, in particular intramuscularly.

If necessary, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of administration route, on the active ingredients used, on the individual behavior towards the drugs, on the formulation and the treatment scheme. Thus, in some cases it may be sufficient to make do with less than the abovementioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these to several single doses.

If appropriate, it may be expedient to supplement the combination according to the invention by adding one or more further components.

The formulations according to the invention may optionally contain further substances, in particular useful for the animal organism, such as builders, minerals or immunostimulating substances.

As builders may be mentioned, inter alia, vitamins, such. Vitamin B 12 and Vitamin C.

As minerals are exemplified calcium and magnesium compounds.

Immunostimulating substances are, for example, pharmacologically acceptable organic phosphonic acid derivatives with immunostimulating action, such as e.g. Toldimfos and in particular butaphosphane.

The combination according to the invention is characterized by good compatibility.

The term "combination" in the sense of the invention is understood to mean a dosage form which contains all components (so-called fixed combinations) or a combination pack which contains the components separately from one another In the primary packaging means, the two components are each in separate containers, Such separate packaging of the two components in a common primary packaging means is also referred to as a kit.

The active compounds of the combination according to the invention can be converted in a known manner into the usual pharmaceutical forms (formulations).

As a further formulation variant for the combination according to the invention, a fixed combination (also known as a "fixed combination") is preferably suitable. "Fixed combination" is understood here to mean those pharmaceutical forms in which the two components are present together in a defined formulation in a defined ratio. Such fixed combinations can be realized, for example, as solutions, tablets, dragees, pills, capsules, powders and / or granules. The active compounds of the combination according to the invention are particularly suitable for being formulated in a fixed combination, in particular in the form of a liquid dosage form for parenteral administration.

The medicaments according to the invention are generally suitable for use in humans and animals. Preferably, they are used in livestock and animal breeding in livestock, breeding, zoo and pets, especially in mammals and poultry.

The livestock and breeding animals include mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, chinchilla, raccoon, as well as birds such as e.g. Chickens, geese, turkeys, ducks, quails, pigeons and ostriches. Examples of preferred farm animals are beef, sheep, pork, horse, turkey and chicken.

Hobby animals include dogs, cats, horses, rabbits, rodents such. Golden hamsters, guinea pigs, mice, as well as reptiles, amphibians and birds for home and zoo keeping.

The medicaments according to the invention are preferably used in farm animals, in particular in cattle and pigs.

The application can be both prophylactic, metaphylactic and therapeutic. It is usually carried out in the form of suitable preparations parenterally as an injection, for. Intramuscular, intracutaneous, subcutaneous, intravenous, intraperitoneal or oral, e.g. as a tablet, suspension, dragee or through implants. Usually, the application can also be carried out as an ointment or suspension intramammary, as well as intrauterine or rectally as a suppository, tablet or suspension. Furthermore, the dermal application is conceivable.

Formulations of the invention for parenteral administration can be prepared as a solution, emulsion or suspension.

Imaging solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly additives such as co-solvents, solubilizers, acids, bases, buffer salts, antioxidants, preservatives, isotonizing agents, absorption promoting substances, dyes, substances that improve the local compatibility, compounds containing the Influencing theological behavior of injection solutions, or adding cryoprotectants. The solutions are sterile filtered and bottled. As a solvent, the liquid formulation contains physiologically acceptable solvents such as water or water-miscible substances. Examples which may be mentioned are glycerol, propylene glycol, polyethylene glycols, compatible alcohols such as ethanol, benzyl alcohol or n-butanol, ethyl lactate, ethyl acetate, triacetin, N-methylpyrrolidone, propylene carbonate, glycofurol , Dimethylacetamide, 2-pyrrolidone, isopropylideneglycerol, or glycerol formal. Combinations of the solvents are also conceivable. Preference is given to water-based formulations in which other solvents and co-solvents may be present.

If desired, the active compounds can also be dissolved in physiologically tolerated vegetable or synthetic oils which are suitable for injection. Here are, for example, the vegetable, animal and synthetic oils such as cottonseed oil, sesame oil, soybean oil, medium chain triglycerides of a chain length of Ci ₂ -Ci ₈ , propylene glycol such as Propylenglykoloctanoat-decanoate, or paraffin called.

The formulations according to the invention may also contain co-solvents, preferably when the formulations contain water; the cosolvents can improve the solubility of certain formulation ingredients. The cosolvents are usually used in proportions of 1 to 10%, preferably from 3 to 8% (percentages in each case M / V). Examples which may be mentioned as cosolvents are: pharmaceutically acceptable alcohols, dimethyl sulfoxide, ethyl lactate, ethyl acetate, triacetin, N-methylpyrrolidone, propylene carbonate, propylene glycol, glycofurol, dimethylacetamide, 2-pyrrolidone, isopropylideneglycerol, glycerol formal, glycerol and polyethylene glycols. As Kosolvenz are particularly suitable pharmaceutically acceptable alcohols, such as. As ethanol, benzyl alcohol or n-butanol. Mixtures of the abovementioned solvents can also be used as cosolvents.

As solubilizers may be mentioned: compounds that promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters, poloxamers.

To increase or regulate the solubility of the quinolones, and especially those of the acidic NSAIDs, bases are often used in the formulations of this invention. Mention may be made here of inorganic basic compounds such as the hydroxides, carbonates, bicarbonates, sulfites and hydrogen sulfites of the alkali metals, alkaline earth metals and earth metals or basic salts of the transition metals which form water-soluble salts with the quinolones and NSAED compounds. Particular mention may be made here of the sodium or potassium salts, the alkaline earth salts, for example the magnesium or calcium salts; the zinc salts and silver salts. Furthermore, basic organic compounds can be used for salt formation such as ammonia or mono-, di-, trialkylamines and their derivatives such as triethylamine, triethanolamine, 2-aminoethanol, N-methylglucamine (meglumine), cyclic amines such as morpholine, piperazine or basic amino acids, in particular arginine , Lysine, or their decarboxylation products, such as cholamine.

Particularly preferred bases in the sense of the formulations according to the invention are NaOH, KOH or arginine.

Preservatives may be included in the liquid formulation. Examples of preservatives which may be mentioned are: Aromatic or aliphatic alcohols such as benzyl alcohol, ethanol, n-butanol, phenol, cresols, chlorobutanol, para-hydroxybenzoic acid esters (in particular the methyl and propyl esters), salts or the free acids of the carboxylic acids such as sorbic acid, benzoic acid , Lactic acid or propionic acid, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride or cetylpyridinium chloride, mercury compounds such as thiomersal.

Dyes are all animal-approved dyes that may be dissolved or suspended, such as carotenoids or certain vitamins, such as vitamin B 12.

Absorption promoting substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.

As antioxidants, for example, sulfites and bisulfites (Na-sulfϊt, Na-metabisulfit), organic sulfur compounds (cystine, cysteine, cysteine hydrochloride, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid, glutathione) phenols (tocopherols, as well as vitamin E and vitamin E-TPGS (d-alpha-tocopherylpolyethylene glycol-lOOO-succinate)), butylhydroxyanisole, butylhydroxytoluene, octyl- and dodecylgallate), organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid) and their salts and esters. Synergists of these antioxidants may be: amino acids (eg alanine, arginine, methionine, cysteine), citric acid, tartaric acid, edetic acid or its salts, phosphoric acid derivatives or polyalcohols and polyethers (polyethylene glycol).

Sunscreen agents are e.g. Substances from the class of benzophenones or novantisolic acid.

Viscosity modifiers may be added to modify the fluidity of the injection solutions. They serve to regulate the theological properties or to set a yield point. For example its: cellulose derivatives such as hydroxypropyl, hydroxyethylmethyl or methylcellulose, gum arabic, carboxymethylcelluloses and their salts, polyacrylic acids and their salts, polyvinyl alcohol, co-polymers polymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, polyvinylpyrrolidone, gelatin, poloxamers, starch, hydroxyethyl starch, dextrans, alginates. In order to increase the flowability optionally, low molecular weight solvents such as ethanol are used, or glycerol, to increase the viscosity optionally.

The liquid formulations for injection may contain substances which improve the local tolerance when applied. Examples include: The above antioxidants or free-radical scavengers such as vitamin E, water-soluble vitamin E esters or vitamin C, sodium disulfide or acetylcysteine. Complexing agents such as cyclodextrins (eg hydroxyproyplecyclodextrin), sodium EDTA (sodium salt of ethylenediaminetetraacetic acid), polyvinylpyrrolidone, dexpanthenol, salts of fatty acids such as sodium caprylate, salts of polyvalent metal cations (eg Me ²⁺ or Me ³⁺ ), in particular the alkaline earth metals and especially magnesium in its salt forms, amino acids and especially arginine or lysine, poloxamers, poloxamines, cosolvents such as n-butanol, glycerol, polyethylene glycol, propylene glycol or dimethylacetamide, dextrans, creatine, creatinine, acids such as gluconolactonic acid, lactic acid, embonic acid, citric acid, tartaric acid, mucic acid or hyaluronic acid, lecithins containing 70-100% of phosphatidylcholine from soy or egg white. Of the above-mentioned substances, the salts of polyvalent metal cations are preferably used, preferably the alkaline earth metal salts, in particular magnesium salts.

Optionally, substances may be added for isotonization or freezing point regulation, e.g. may be mentioned: sodium chloride, glycerol, carbohydrates such as sorbitol or glucose.

The injection solution may also contain pharmaceutically active substances or builders which are oil soluble and therefore in the form of an emulsion.

Emulsions are either water-in-oil type or oil-in-water type.

They are prepared by dissolving the active ingredients either in the hydrophobic or in the hydrophilic phase and homogenized with the aid of suitable emulsifiers and other excipients such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances, with the solvent of the other phase ,

As hydrophobic phase (oils) may be mentioned: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, Triglyceride mixture with vegetable fatty acids of chain length Cg. \ 2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of Cg / C \ _Q fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a medium chain branched fatty acid with saturated fatty alcohols of chain length C ^ gC ^ g, isopropyl myristate, isopropyl palmitate, caprylic / capric esters of saturated fatty alcohols of chain length C \ 2 -C \ g, isopropyl stearate, oleyl oleate, oleic acid, ethyl oleate, ethyl lactate, waxy fatty acid esters such as dibutyl phthalate, adipic acid adipate, the latter related ester mixtures, inter alia Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids, e.g. Oleic acid and its mixtures.

As the hydrophilic phase may be mentioned: water, alcohols such as e.g. Propylene glycol, glycerol, sorbitol and their mixtures.

Emulsifiers _^ including surfactants, mention may be made, for example: fatty acid salts, fatty, fatty alkylsulfonates, linear Aklylbenzolsulfonate, ether sulfates Fettalkylpolyethylenglycol-, Fettalkylpolyethylenglycolether, Alkylphenolpolyethylenglycolether, glycosides alkylpolyglycosides, fatty acid N-methlyglucamide, poloxamers, dioctylsulfosuccinate, polyoxiethylierte and not polyoxiethylierte mono- and difatty of glycerol, polyoxyethylated and non-polyoxyethylated monofatty acid esters of propylene glycol, polyoxyethylated and non-polyoxyethylated mono-, di-, triflic acid esters of sorbitol and its mono- and dianhydrides (polysorbates), polyethylene glycol fatty acid esters, polyoxyethylated and non-polyoxyethylated castor oils and derivatives thereof, salts of cholic acid and their derivatives Derivatives, sucrose stearates; cationic surfactants such as cetyltrimethylammonium chloride; ampholytic surfactants such as di-Na-N-lauryl-.beta.-iminodipropionate or lecithin and mixtures thereof.

As further auxiliaries may be mentioned:

Viscosity-increasing and emulsion-stabilizing substances such as carboxymethyl cellulose,

Methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin,

Gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances listed, and all other viscosity-regulating substances mentioned above. In special cases, the injection solution may also contain other pharmaceutically active substances or builders that are not sufficiently oil or water soluble and are therefore present in finely divided, suspended form as a solid.

Suspensions are prepared by suspending the active ingredient in a carrier liquid optionally with the addition of further auxiliaries, such as wetting agents, dyes, substances which promote absorption, preservatives, antioxidants, light stabilizers.

As carrier liquids, all homogeneous solvents and solvent mixtures may be mentioned.

Suitable wetting agents (dispersants) are the emulsifiers specified above. Optionally, further stabilizers may be added to prevent crystal growth and aggregation of the suspended particles, for example, lecithins, phosphatidyl cholines, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone,

Carboxymethylcellulose and its salts, methyl, hydroxyethyl, hydroxypropyl and ethylcellulose, gelatin, pectins, sorbitol, dextran, natural and derivatized polysaccharides.

As further auxiliaries mentioned above.

According to a preferred embodiment, the combinations according to the invention are formulated as aqueous solutions.

These include:

1 to 25% m / V, preferably 3 to 20% m / V, more preferably 9 to 16% m / V of quinolone

0.1 to 10% m / V, preferably 0.2 to 8% m / V, more preferably 0.3 to 7% m / V of non-steroidal anti-inflammatory agent.

0.1 to 10% m / V, preferably 0.5 to 5% m / V, particularly preferably 0.5 to 3% m / V n-butanol.

The abovementioned aqueous solutions are made alkaline with base, to a pH of 9 to 13, preferably 10.5 to 12.5. As bases come z. B. in question: basic amino acids, such as. As arginine or alkali metal hydroxides such as sodium hydroxide or potassium hydroxide. More preferably, potassium hydroxide is used. Examples

Biological example

In clinical pharmacokinetic studies in cross-over design according to GSP standards, in which the serum concentration-time profiles of the test formulation (according to Formulation Example 1) were compared to the commercial product, the following PK parameters could be determined.

Table 1. Serum pharmacokinetics of enrofloxacin (Baytril 10% inj. Versus

Combination formulation) after subcutaneous injection in cattle

Formulation T tl / 2 AUC _last MRT _last n

(mg / L) (hr) (hr) (mg * hr / L) (hr)

Baytril 10% 2.26 2.0 9.60 33.49 13.00 9 Combination 2.96 1.0 9.44 35.29 12.52 9

Table 2. Serum pharmacokinetics of enrofloxacin (Baytril 10% inj. Versus combination formulation) after intramuscular injection into swine

Formulation Wiax T tl / 2 AUC _last MRT _last n

(mg / L) (hr) (hr) (mg * hr / L) (hr)

Baytril 10% 1.49 4.0 4.73 19.96 9.53 9 Combination 2.01 4.0 3.19 21.97 7.89 9

The results are shown graphically in Figures 1 and 2:

Figure 1: Mean serum concentration-time profile of enrofloxacin (Baytril 10% inj versus combination formulation) after subcutaneous injection in cattle.

Figure 2. Mean serum concentration-time profile of enrofloxacin (Baytril 10% inj. Versus combination formulation) after intramuscular injection in pigs. formulation Examples

The percentages for the formulations described herein are given by weight per volume (grams of the subject substance per 100 ml of finished formulation).

example 1

10% enrofloxacin / 4% ketoprofen

production:

The starting materials are dissolved one after the other with stirring in the order indicated above:

- Presentation of 85g water for injections - Addition of 2.7g KOH 85%

- Add 10g of enrofloxacin

- Addition of 4g ketoprofen

- Addition of Ig n-butanol

- Adjust the pH with the remaining KOH to 11.8 (± 0.2) - Make up to final volume (100 ml) with water for injection

Example 2

15% enrofloxacin / 6% ketoprofen

production:

- Submission of 75g of water for injections

- Addition of 4.0g KOH 85%

- Add 15g of enrofloxacin

- Addition of 6g ketoprofen

- Addition of 3 g of n-butanol

- Adjust the pH with the remaining KOH to 11.0 (± 0.2)

- Fill up to final volume (100ml) with water for injections.

Example 3

10% enrofloxacin / 3.67% flunixin meglumine

Preparation: The starting materials are dissolved successively in the above-mentioned order with stirring:

- Presentation of 85g of water for injections

- Addition of 1.9g KOH 85%

- Add 10g of enrofloxacin

- Addition of 3.65 g flunixin meglumine - Addition of 3 g n-butanol

- Adjust the pH with the remaining KOH to 10.5 (± 0.2) Filling to final volume (100ml) with water for injections Example 4

10% enrofloxacin / 0.5% meloxicam

production:

- Presentation of 85g of water for injections

- Addition of 1.8g KOH 85%

- Add 10g of enrofloxacin

- Addition of 0.5g meloxicam

- Addition of 3 g of n-butanol

- Adjust the pH with the remaining KOH to 11.0 (± 0.2) Fill to final volume (100ml) with water for injections.

Claims

claims

1. Combination containing a quinolone antibiotic and a nonsteroidal anti-inflammatory.

A combination according to claim 1, wherein the non-steroidal anti-inflammatory agent is ketoprofen.

A combination according to any one of the preceding claims wherein the quinolone antibiotic is enrofloxacin.

4. Use of the combination according to any one of the preceding claims for the preparation of medicaments for the treatment of bacterial diseases.

5. Medicaments containing a combination according to one of claims 1 to 3.

A drug according to claim 5 suitable for injection containing 1-30% m / V of the quinolone antibiotic and 0.5-45% m / V of the nonsteroidal anti-inflammatory drug.

7. Medicament according to claim 6, containing 10 - 30% m / V enrofloxacin and 2-8% m / V ketoprofen.