EP1993549A1

EP1993549A1 - Medicament formulations comprising fluoroquinolones

Info

Publication number: EP1993549A1
Application number: EP07711642A
Authority: EP
Inventors: Iris Heep; Kristine Fraatz; Hans-Jürgen HAMANN; Markus Edingloh
Original assignee: Bayer Animal Health GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2006-03-08
Filing date: 2007-02-23
Publication date: 2008-11-26
Also published as: AU2007222676A1; US20090163484A1; NZ571047A; RU2008139633A; ECSP088722A; KR20080110599A; CA2644981A1; DE102006010642A1; BRPI0708692A2; US20150080387A1; SV2008003018A; CR10274A; ZA200807486B; JP2009529014A; MX2008011489A; WO2007101560A1; CA2644981C; CN101400351A

Abstract

The invention relates to medicament formulations in liquid form, comprising fluoroquinolones and antioxidant sulphur compounds. The formulations are suitable especially for parenteral applications and feature, inter alia, good compatibility.

Description

Drug formulations containing fluoroquinolones

The invention relates to pharmaceutical formulations in liquid form containing fluroquinolones and antioxidant sulfur compounds. The formulations are particularly suitable for parenteral applications and are u. a. through good compatibility.

The chemical stability of solutions may e.g. be increased by using antioxidants. In this case, the oxidative degradation of an ingredient can be prevented. This is also common and especially for injection solutions. Common antioxidants here include u.a. the sulfites. DE-A-19500784, EP-A-0187315 or EP-A-1121933 describe injection solutions with sulphites. Eye drops are also provided as solutions with sulfites, as described in EP-A-0804267. DE-A-2364470 describes the use of sulphites which have a

To prevent discoloration of the formulation. So far, the use of such sulfites to improve the local compatibility of injection solutions is not described. Solutions that are not well tolerated must be given intravenously in practice, for example, as an infusion. However, this is problematic in carrying out particularly in the treatment of animals. There are also numerous attempts, e.g. by formulation as liposomes to increase compatibility, as shown in WO 98/33482. Cyclodextrins are also an often-explored possibility to improve solubility or compatibility of formulations; see EP-A-0209768. If a formulation can not be improved in its compatibility, it may be necessary to use a local anesthetic in the application, as described in GB-A-1 143330; or to avoid oily formulations EP-A-1121933.

Solutions for parenteral application to animals have the peculiarity that they are applied in different ways depending on the animal species. So it is e.g. In Europe, injection solutions are administered subcutaneously to pigs and intramuscularly to dogs or cats. Not only the animal species but also the different forms of application lead to an increased requirement as far as the compatibility is concerned (EP-A-1121933). From the

Compatibility, for example in cattle, may not necessarily be compatible with e.g. Cats or dogs are closed (WO 01/81358). To ensure broad applicability, it therefore makes sense to improve the local tolerability of injection solutions so that they can also be used in sensitive animal species.

It is therefore not surprising that most injection solutions with fluoroquinolones are not available for dogs or cats due, among other things, to the lack of tolerability. In order to make the compatibility as good as possible, it is advisable to keep the pH of the solutions as neutral as possible (about 7.4), but this contradicts the solubility of fluoroquinolones. Also at this pH range, particle formation of the betaine form of the fluoroquinolones is frequently observed, which is why solutions, if they should already be tolerated, but then are not storable long and it comes to particle formation. This can be avoided, for example by avoiding freeze-dried products. However, freeze-dried products are cumbersome to handle in practice and often only have a shelf life of the reconstituted solution of a maximum of 4 weeks after onset, or must be discarded directly due to the possible particle formation. The advantage is therefore a ready to use solution as an injection solution, also known as "ready to use - formulation".

Furthermore, it is necessary that after administration, as described in WO 99/29322, the fluoroquinolone in the appropriate amount passes into the serum. Again, this is not a matter of course with injectable formulations of fluoroquinolones and may also depend on the particular animal species.

There have been found directly usable (ready to use) injectable formulations containing fluoroquinolones which contain a sufficient concentration of fluoroquinolone which, when stored under pharmaceutical conditions, is stable and free of particulate formation, which are well tolerated, especially in dogs, and have favorable serum kinetics ,

The subject of the invention is therefore:

A pharmaceutical formulation in liquid form comprising:

(a) a fluoroquinolone

(b) an antioxidant sulfur compound

(c) optionally further pharmaceutical excipients and / or additives

Fluoroquinolones include 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 may be mentioned: benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin,

Enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin,

Moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, pipemidic acid, temafloxacin, toufloxacin, sarafloxacin, sparfloxacin.

A preferred group of fluoroquinolones are those of the formula (I) or (IT): in which

X is hydrogen, halogen, C _M -alkyl, C _M -alkoxy, NH ₂ ,

for remnants of the structures

stands in which

R ^{4 represents} optionally substituted by hydroxy or methoxy straight-chain or branched C 1 -C ₄ -alkyl, cyclopropyl, acyl having 1 to 3 C-atoms,

R ^{5 is} hydrogen, methyl, phenyl, thienyl or pyridyl,

R ^{6 is} hydrogen or C _M -alkyl,

R ^{7 is} hydrogen or C _M -alkyl,

R ^{8 is} hydrogen or C _M -alkyl,

such as

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 optionally methoxy or 2-methoxyethoxy-substituted alkyl having 1 to 6 carbon atoms and cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl,

R ^{3 is} hydrogen, methyl or ethyl and

A is nitrogen, = CH-, = C (halogen) -, = C (OCH ₃ ) -, = C (CH ₃ ) - or = C (CN),

B is oxygen, optionally substituted by methyl or phenyl = NH or = CH ₂ ,

Z stands for = CH- or = N-,

and their pharmaceutically acceptable salts and hydrates.

Preference is given to compounds of the formula (I)

in which

A is = CH- or = C-CN,

R! represents optionally halogen-substituted Cj-C3-alkyl or cyclopropyl,

R ^{2 is} hydrogen or Ci. _4- alkyl,

Y for residues of the structures

stands in which

R ^{4 represents} optionally substituted by hydroxy straight-chain or branched C iC ₃ -alkyl, oxalkyl having 1 to 4 C-atoms,

R ^{5 is} hydrogen, methyl or phenyl,

R ^{6 is} hydrogen,

R ^{7 is} hydrogen or methyl, R ^{8 is} hydrogen,

and their pharmaceutically usable hydrates and salts.

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

in which

A is = CH- or = C-CN,

R! represents cyclopropyl,

R ^{2 is} hydrogen, methyl or ethyl,

Y for residues of the structures

stands in which

R ^{4 is} methyl, optionally substituted by hydroxy ethyl,

R ^{5 is} hydrogen or methyl,

R ^{6 is} hydrogen,

R ^{7 is} hydrogen or methyl,

R ^{8 is} hydrogen,

and their pharmaceutically acceptable salts and hydrates.

Marbofloxacin may be mentioned as a preferred example of a fluoroquinolone of the formula (II):

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, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (pradofloxacin) having the formula

Enrofloxacin: 1-Cyc! O -propyl-7- (4-ethyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is furthermore particularly preferably employed

Also conceivable is the use of the active substance ciprofloxacin otherwise used in human medicine.

Optically active fluoroquinolones may be in the form of their racemates or in enantiomeric forms. Both the pure enantiomers and mixtures thereof can be used according to the invention.

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

Examples of suitable pharmaceutically acceptable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methane. sulfonic 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.

Hydrates are understood as meaning both the hydrates of the fluoroquinolones themselves and the hydrates of their salts. An example is pradofloxacin, which forms a stable trihydrate (see WO 2005/097789).

Fluoroquinolones may possibly form different crystal modifications as a solid.

Advantageous for the pharmaceutical compositions of the present invention are those modifications which have corresponding solubility properties.

The fluoroquinolone is typically used in an amount for animals with a body weight up to about 80 kg of 0.1 to 15%, preferably 0.5 to 15% and particularly preferably 1 to 15%. In animals with a body weight from about 80 kg, the fluoroquinolone is typically used in a proportion of from 1 to 30%, preferably 3 to 25% and particularly preferably 4 to 20%. The percentages are given as M / V.

Antioxidative sulfur compounds are, for example: sulfites (sodium sulfite, potassium sulfite), bisulfates (such as, for example, sodium metabisulfite, potassium metabisulfite, potassium pyrosulfite, sodium pyrosulfite, acetonitrile metabisulfite, acetonitrile bisulfite), thiosulfates (such as, for example, potassium thiosulfate,

Sodium thiosulfate), as well as organic sulfur compounds (such as sodium formaldehyde sulfoxylate, thiourea, thiosorbitol, cysteine hydrochloride, cystine, cysteine, acetylcysteine, glutathione, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid).

The antioxidant sulfur compounds are usually used in concentrations of 0.05 to 10%, preferably from 0.1 to 8% and particularly preferably from 0.5 to 5%. The

Figures in percent are given as M / V.

The liquid formulations may contain other substances which improve the local tolerance when applied. Examples include: radical scavengers or antioxidants such as vitamin E, water-soluble vitamin E esters or vitamin C, butylhydroxyanisole or butylhydroxytoluene. Complexing agents such as, for example, sodium EDTA (ethylenediaminetetraacetic acid), polyvinylpyrrolidone or cyclodextrins, of which in particular hydroxypropyl-.beta.-cyclodextrin or sulfobutyl ether .beta.-cyclodextrin, dexpanthenol, salts of Fatty acids such as sodium caprylate, salts of polyvalent cations eg: the alkaline earth metals (Me ²⁺ or Me ³⁺ ) 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, dextranes, acids such as gluconolactonic acid, lactic acid, embonic acid, citric acid, tartaric acid, mucic acid or hyaluronic acid, lecithins containing 70-100% phosphatidylcholine from soy or chicken protein or creatine or creatinine.

Substances which improve the compatibility are usually contained in concentrations of 0.05 to 10%, preferably of 0.1 to 8% and particularly preferably 0.5 to 5%. The percentages are given as M / V.

Substances which can prevent particle formation are e.g. Poloxamers, lecithins, polyvinylpyrrolidones, cosolvents, antioxidants, complexing agents or even quaternary ammonium compounds such. Benzethonium chloride or benzalkonium chloride.

Substances which improve stability, e.g. can avoid particle formation are usually used in concentrations of 0.001 to 10%, preferably 0.005 to 6% and more preferably 0.001 to 3%. The percentages are given as M / V.

As a solvent, the liquid formulation may contain 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, propylene glycol, glycofurol, dimethylacetamide, 2-pyrrolidone,

Isopropylidene glycerol, or glycerol formal. It is also possible to use mixtures of different solvents. Preference is given to water-based formulations in which, of course, further solvents and co-solvents may be present.

As a solvent, the liquid formulation can also contain oils in the form of an emulsion in addition to water or water-miscible substances. These include 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 octanoate decanoate or paraffin called.

The solvency is usually in concentrations of 99.8 to 72% or 98.9 to 55%, preferably 99.4 to 81% or 96.9 to 67% and particularly preferably 98.8 to 87% or 94.5 to 77% used. The percentages are given as M / V.

The pH of the liquid formulations is usually 2-11, preferably 3-8 and more preferably 4-8. The medicaments may also contain co-solvents, preferably when the formulations contain water. These are usually used in proportions of 1 to 10 wt .-%, preferably from 3 to 8%. 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.

Preservatives may be included in the liquid formulation, e.g. 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, benzalkonium chloride, benzethonium chloride or cetylpyridinium chloride.

Depending on the nature of the formulation and the form of administration, the medicaments according to the invention may contain further customary pharmaceutically acceptable additives and auxiliaries. As examples may be mentioned

• antioxidants such as phenols (tocopherols, as well as vitamin E and vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol lOOO succinate)), butylhydroxyanisole, butylhydroxytoluene, octyl and dodecyl gallate), organic acids (ascorbic acid, citric acid .

Tartaric acid, lactic acid) and their salts and esters

Wetting agents such as, for example, fatty acid salts, fatty alkyl sulfates, fatty alkyl sulfonates, linear alkylbenzenesulfonates, fatty alkyl polyethylene glycol ether sulfates, fatty alkyl polyethylene glycol ethers, alkylphenol polyethylene glycol ethers, alkyl polyglycosides, fatty acid N-methylglucamides, polysorbates, sorbitan fatty acid esters and poloxamers.

• substances for isotonization, e.g. Sodium chloride, glucose or glycerin.

• Pharmaceutically acceptable dyes such as iron oxides, carotenoids, etc.

In addition to the fluoroquinolones, the formulations according to the invention may contain further pharmaceutical active ingredients. For example, the fluoroquinolones can also be used in combination, for example, with analgesics, in particular the so-called NSAIDs (nonsteroidal, anti-inflammatory substances) are used. Such NSAEDs may be, for example: meloxicam, flunixin, ketoprofen, carprofen, metamizole or (acetyl) salicylic acid.

The medicaments according to the invention can be prepared by dispersing the fluoroquinolone in the solvent after the antioxidative sulfur compound, and also adding further substances to improve the compatibility and, if appropriate, to avoid particle formation. Kosolventien and other ingredients such. Preservatives may already be added to the solvent or added later.

Alternatively, cosolvents, preservatives, substances which influence the compatibility or particle formation, can also first be dissolved in the solvent and subsequently the fluoroquinolone can be added first. Also, the antioxidant sulfur compound can be dispersed with or after the fluoroquinolone.

The pharmaceutical preparations according to the invention are generally suitable for use in humans and animals. They are preferably used in animal husbandry and animal breeding in livestock, breeding, zoo, laboratory, experimental and hobby animals.

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 and birds such as e.g. Chickens, geese, turkeys, ducks, pigeons and bird species for home and zoo keeping.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

The hobby animals include rabbits, hamsters, guinea pigs, mice, horses, reptiles, corresponding birds, dogs and cats.

Furthermore, fish are called, namely useful, breeding, aquarium and ornamental fish of all ages, living in fresh and salt water.

The preparations according to the invention are preferably used in hobby animals such as horses, cats and dogs. In particular, they are suitable for use in cats and dogs.

Examples of preferred farm animals are beef, sheep, pork, goat and chicken. Particularly preferred farm animals are beef and pork.

The application can be both prophylactic and therapeutic. The formulations described herein can be delivered in various ways to the target organism (human or animal). They can be administered, for example, parenterally, in particular by injection (eg subcutaneously, intramuscularly, intravenously, intramammary, intraperitoneally), dermally, orally, rectally, vaginally or nasally, with parenteral administration-in particular by injection-being preferred.

The formulations are preferably added as solutions, suspensions or emulsions.

The medicaments according to the invention are distinguished by good stability and good solubility of the active ingredient. Furthermore, they have good compatibility and suitable serum kinetics in animals, in particular after parenteral administration.

Examples

The formulations of the following examples are prepared by mixing or dissolving the indicated starting materials in Aqua per injections. The pH of the solutions can be adjusted by adding acids or bases. The solutions for injection are sterile filtered and transferred into suitable containers. Pradofloxacin can be used as anhydrate or as

Trihydrate are used; the numerical values are calculated respectively for the anhydrate.

(Percentages in percent by weight based on the total volume of the finished preparation, [M / V])

example 1

3.0% pradofloxacin

0.1% poloxamer F68

0.2% sodium bisulfite

3% n-butanol

1.6% sodium hydroxide (1N) 2.7% sodium chloride ad 100% Aqua per injection

3.0 g of pradofloxacin, 0.1 g of poloxamer, 0.2 g of sodium disulfite, 3 g of n-butanol, 2.7 g of sodium chloride are dissolved in about 80 g of aqua per injection, the pH is checked and optionally 1, 6 g of 1N sodium hydroxide adjusted to pH 7.4. It is then adjusted to the final weight of 100 ml with the remaining Aqua per injection.

Example 2

3% pradofloxacin 0.1% poloxamer F68 0.5% sodium disulfite 3% n-butanol

2.4% sodium chloride

4.6% 1N sodium hydroxide ad 100% Aqua per injection

3 g of pradofloxacin, 0.1 g of poloxamer, 0.5 g of sodium disulfite, 3 g of n-butanol, 2.4 g of sodium chloride are dissolved in about 80 g of water per injection, the pH is checked and with 4.6 g of sodium hydroxide adjusted to pH 7.4. Subsequently, with the remaining Aqua per injection on the Final weight set to 100 ml.

Example 3

3% pradofloxacin 0.2% sodium disulfite 3% n-butanol

20% N-methylpyrrolidone ad 100% Aqua per injection

70 g of Aqua per injection are mixed with 3 g of n-butanol and 20 g of N-methylpyrrolidone. In it are dissolved 0.2% sodium disulfite and then 3 g of pradofloxacin. The remaining 3.8 g of Aqua per injection are adjusted to the final weight of 100 ml.

Example 4

1% enrofloxacin 0.5% sodium disulfite 1, 4% benzyl alcohol 1.4 g IN-KOH

3% magnesium chloride hexahydrate ad 100% Aqua per injection

70 g of Aqua per injection are mixed with 1.4 g of benzyl alcohol and 3 g of magnesium chloride hexahydrate. In it, 0.5% sodium disulfite and 1.4 g of IN-KOH are dissolved and then 1 g of enrofloxacin. With the remaining 22.7 g Aqua per injection is set to the final weight.

Example 5

5% pradofloxacin (trihydrate) 0.1% poloxamer F68 3% n-butanol 0.5% sodium disulfite

9% 1N hydrochloric acid ad 100% Aqua per injection

80 g of Aqua per injection are mixed with 0.5 g of sodium bisulfite, 3 g of n-butanol and 0.1 g of poloxamer. Therein, 5 g of pradofloxacin (trihydrate, calculated as pure pradofloxacin) are dissolved. If necessary, it is adjusted to a pH of 5 with approx. 9 g of acid and the remaining weight per injection is set to the final weight of 100 ml.

Example 6

2% pradofloxacin (trihydrate) 0.1% poloxamer F68

3% n-butanol 0.5% sodium disulfite 2.6% sodium chloride 9% 1N sodium hydroxide ad 100% aqua per injection

80 g of Aqua per injection are mixed with 0.5 g of sodium bisulfite, 3 g of n-butanol, 2.6 g of sodium chloride and 0.1 g of poloxamer. It dissolves 2 pradofloxacin (trihydrate, calculated as pure pradofloxacin). If necessary, it is adjusted to a pH of 7.4 with approx. 2.4 g sodium hydroxide and the remaining weight per injection is adjusted to the final weight of 100 ml.

Compatibility in vivo

The formulations described herein have demonstrated improved local tolerance to other formulations in the clinical trial. Drug-dependent tissue irritation and swelling at the injection site are dependent on the formulation used in their expression. Table 1 below lists selected examples.

Table 1:

Formulation Local reactions, dog

1-36 days post adm.

n spontaneously mild moderately difficult

Example 2

6 0

3% pradofloxacin with Na disulfite (SC, 3 ml)

Example 6

8 0

2% pradofloxacin with Na-disulfite (SC, 9 mg / kg)

Example 2

6 0

3% pradofloxacin with Na-disulfite (SC, 9 mg / kg)

Example 2

6 0

3% pradofloxacin with Na disulfite (IM, 9 mg / kg)

SC = subcutaneously, IM = intramuscular

Serum pharmacokinetic profile

The formulation has an influence on the serum pharmacokinetic (PK) profile. Different formulations show significant differences in the serum concentration-time curve. For quinolones, fast absorption, high peak concentration, and long elimination phase curves are preferred. Table 2 below lists various formulations and shows their influence on the PK profile.

Table 2:

Formulation PK parameters (arithmetic mean)

C _max T _max t _{l / 2} AUC _lnf MRTi _as ,

(μg / mL) (hr) (hr) (h * μg / mL) (hr)

Example 6

2% pradofloxacin with Na disulfite 2.7 3.3 7.9 36.0 13.3

(SC, 9 mg / kg)

Example 2

3% pradofloxacin with Na disulfite 2.7 2.3 5.1 28.0 8.4

(IM, 9 mg / kg)

SC = subcutaneously, IM = intramuscular

Claims

claims

1. Drug formulation in liquid form comprising:

(a) a fluoroquinolone

(B) an antioxidant sulfur compound (c) optionally further pharmaceutical excipients and / or additives

2. Drug formulation according to claim 1, containing as antioxidant sulfur compound a sulfite, in particular sodium sulfite, potassium sulfite; a bisulfite, especially sodium metabisulfite, potassium metabisulfite, potassium pyrosulfite, sodium pyrosulfite, aceto sodium metabisulfite, acetone sodium bisulfite; a thiosulfate, especially potassium thiosulfate, sodium thiosulfate; or an organic sulfur compounds, in particular sodium formaldehyde sulfoxylate, thiourea, thiosorbitol, cysteine hydrochloride, cystine, cysteine, acetylcysteine, glutathione, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid.

3. A pharmaceutical formulation according to any one of the preceding claims, containing sodium disulfite.

4. A pharmaceutical formulation according to one of the preceding claims, containing as fluoroquinolone ciprofloxacin, enrofloxacin, pradofloxacin or marbofloxacin

5. A pharmaceutical formulation according to claim 4, containing pradofloxacin.

6. A pharmaceutical formulation according to claim 4, containing enrofloxacin.

7. A pharmaceutical formulation according to claim 4, containing marbofloxacin.

8. Use of pharmaceutical formulations according to one of the preceding claims for the preparation of medicaments for combating bacterial diseases.

9. Use according to claim 8 for the preparation of medicaments suitable for injection for combating bacterial diseases.

10. Use according to claim 8 or 9 for the preparation of medicaments with improved

Compatibility.