Pharmaceuticals containing fluoroquinolones
View Patent ↗The invention relates to the use of quaternary ammonium compounds for preventing precipitations of fluoroquinolones from their solutions and to stable, tolerated pharmaceuticals which are particularly suitable for parenteral use and which contain, in dissolved form, a fluoroquinolone and a quaternary ammonium compound.
1. A method of treating a bacterial infection in an animal comprising injecting a waterbased formulation into the animal, wherein the injectable formulation comprises
i) at least 50% (w/v) water,
ii) 1 to 15% (w/v) pradofloxacin or a salt or hydrate thereof, and
iii) a quaternary ammonium compound,
wherein the waterbased formulation is a solution.
2. The method of claim 1 , wherein the quaternary ammonium compound is of the general formula (III)
[R 1 R 2 R 3 R 4 N] + X − (III)
where
R 1 to R 4 are identical or different and represent C 1-18 -alkyl which can optionally be interrupted once or more than once by oxygen and which can optionally be substituted by hydroxyl or by an aryl radical which is optionally substituted by one or more halogen atoms or C 1-8 -alkyl radicals, or
R 1 to R 4 may, as the result of the cyclization of three radicals, form 5- or 6-membered heterocyclic radicals optionally mono- or polysubstituted by C 1-4 -alkyl or C 1-4 -alkenyl, which optionally have attached to them an aryl radical optionally substituted by halogen, amino or dimethylamino, and
X is selected from the group consisting of a sulphate and halide.
3. The method of claim 1 , wherein the quaternary ammonium compound is selected from the group consisting of benzalkonium chloride, n-(C 12 -C 18 )-alkylbenzyldimethylammonium chloride with an average molecular weight of approximately 380, benzethonium chloride, dichlorobenzyldimethylalkylammonium chloride, benzoxonium chloride, cetrimonium bromide, dioctyldimethylammonium chloride, di-n-decyldimethylammonium chloride, cetylpyridinium chloride, and thiazoline iodide.
4. The method of claim 1 wherein the formulation comprises a single dose of pradofloxacin.
5. The method of claim 1 wherein the pH of the formulation is 4 to 7.6.
6. The method of claim 1 wherein the formulation comprises 0.005 to 3.0% (w/v) of the quaternary ammonium compound.
7. The method of claim 1 wherein the formulation further comprises at least one antioxidant, wetting agent, osmolarity agent, colorant, preservative, co-solvent, poloxamers, lecithin, polyvinylpyrrolidone, or complexing agent.
8. The method of claim 1 wherein the formulation is injected into the animal subcutaneously, intramuscularly, intravenously, intramammarially, or intraperitoneally.
9. The method of claim 1 wherein the animal treated is a livestock animal, a breeding animal, a zoo animal, a laboratory animal, an experimental animal, or a pet animal.
10. The method of claim 9 wherein the animal treated is a pet animal which is a horse, a rabbit, a cat, or a dog.
11. The method of claim 1 wherein the pradofloxacin is in enantiomeric form.
12. The method of claim 1 , wherein the formulation comprises at least 70% (w/v) water.
13. The method of claim 1 , wherein the quaternary ammonium compound is selected from benzalkonium chloride and benzethonium chloride.
14. The method of claim 1 , wherein the formulation further comprises from 1% to 10% (w/v) of a cosolvent selected from pharmaceutically tolerated alcohols, dimethyl sulphoxide, ethyl lactate, ethyl acetate, triacetin, N-methylpyrrolidone, propylene carbonate, propylene glycol, glycofurol, dimethylacetamide, 2-pyrrolidone, isopropylidene glycerol, glycerine formal, glycerin, polyethylene glycols, and mixtures thereof.
15. The method of claim 14 , wherein the cosolvent is a pharmaceutically tolerated alcohol.
16. The method of claim 15 , wherein the pharmaceutically tolerated alcohol is selected from ethanol, benzyl alcohol, and n-butanol.
17. The method according to claim 1 , wherein the injectable formulation is stable under pharmaceutical storage conditions and free of particle formation.
18. The method according to claim 1 , wherein the animal is a cat or dog and the injectable formulation is tolerated locally by cat or dog following parenteral administration.
19. The method according to claim 1 , wherein the injectable formulation has a serum-pharmacokinetic profile of C max of at least 3.8 μg/mL, T max of at least 1.5 hours, t 1/2 of at least 4.6 hours, AUC inf of at least 31.0 h*μg/mL, and AUC last of at least 30.7 h*μg/mL.
20. A method of treating a bacterial infection in an animal comprising of injecting a waterbased formulation into the animal, the injectable formulation consisting of:
at least 50% (w/v) water, 1 to 15% (w/v) pradofloxacin or a salt or hydrate thereof,
a quaternary ammonium compound, and
optionally one or more of: an antioxidant, a wetting agent, an osmolarity agent, a colorant, a preservative, a co-solvent, a poloxamer, a lecithin, a polyvinylpyrrolidone, or a complexing agent,
wherein the injectable waterbased formulation is a solution and is stable under pharmaceutical storage conditions and free of particle formation.
21. The method of claim 1 , wherein pradofloxacin is the only antibiotically active substance present in the formulation.
22. The method of claim 21 , wherein the quaternary ammonium compound is benzalkonium chloride.
23. An injectable formulation comprising i) at least 50% (w/v) water, ii) 1-15% (w/v) an antibiotically active substance consisting of pradofloxacin or a salt or hydrate thereof, and a quaternary ammonium compound, wherein the waterbased formulation is a solution.