US 200901 63484A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0163484 A1 Heep et al. (43) Pub. Date: Jun. 25, 2009 (54) PHARMACEUTICALS CONTAINING (30) Foreign Application Priority Data FLUOROQUINOLONES (75) Inventors: Iris Heep, Köln (DE); Kristine Mar. 8, 2006 (DE) ......................... 102O06O10642.3 Rigi,R. Dormagen Publication Classification (DE); Markus Edingloh, (51) Int. Cl. Leverkusen (DE) A 6LX 3/5.395 (2006.01) Correspondence Address: A63/496 (2006.01) BSER HEALTHCARE LLC A 6LX 3L/24709 (2006.01) P.O.BOX390 A6II 47/20 (2006.01) SHAWNEE MISSION, KS 66201 (US) A6IP3L/04 (2006.01) (73) Assignee: BAYER ANIMAL, HEALTH (52) U.S. Cl. ................. 514/229.2: 514/253.08: 514/300; GMBH, LEVERKUSEN (DE) 514/769; 514/772 (21) Appl. No.: 12/280,996 (57) ABSTRACT (22) PCT Filed: Feb. 23, 2007 The invention relates to pharmaceutical formulations in liq uid form, containing fluoroquinolones and antioxidative Sul (86). PCT No.: PCT/EP2007/001568 phur compounds. The formulations are particularly Suitable S371 (c)(1), for parenteral uses and are distinguished, interalia, by good (2), (4) Date: Oct. 31, 2008 tolerance. US 2009/0163484 A1 Jun. 25, 2009 PHARMACEUTICALS CONTAINING reconstitution, or must be discarded directly as the result of FLUOROQUINOLONES the possibility of particle formation. Accordingly, a ready-to use solution is advantageous as solution for injection. 0006. It is furthermore necessary that a suitable amount of the fluoroquinolone enters the serum after the administration, 0001. The invention relates to pharmaceutical formula as this is also described in WO99/29322. Again, this is not a tions in liquid form comprising fluoroquinolones and antioxi matter of course with injectable fluoroquinolone formula dant Sulphur compounds. The formulations are particularly tions and may likewise depend on the animal species in ques Suitable for parenteral administrations and are distinguished tion. interalia by the fact that they are well tolerated. 0007. There have been found ready-to-use injectable for 0002 The chemical stability of solutions can be increased mulations containing fluoroquinolones which comprise Suf for example by using antioxidants. The oxidative degradation ficient concentration of the fluoroquinolone, which are stable of a constituent can thereby be prevented. This is also cus and free from particle formation upon storage under pharma tomary in Solutions for injection, where this is particularly the ceutical conditions, which are well tolerated, in particular by case. Antioxidants which are conventionally used here are, dogs, and which have advantageous serum kinetics. interalia, the sulphites. DE-A-19500784, EP-A-0187315 or 0008. The invention therefore relates to: EP-A-1121933 describe solutions for injection which contain a pharmaceutical formulation in liquid form containing: Sulphites. Eye drops too, when present as solutions, are pro 0009 (a) a fluoroquinolone, 0.010 (b) an antioxidative sulphur compound vided with sulphites, as this is described in EP-A-0804267. 0.011 (c) if appropriate, further pharmaceutical auxilia DE-A-2364470 describes the use of sulphites which is ries and/or additives intended to prevent decoloration of the formulation. The use 0012 Fluoroquinolones are, interalia, compounds as they of Such Sulphites for improving the local tolerance of solu are disclosed in the following documents: U.S. Pat. No. tions for injection has not been described as yet. Solutions 4,670,444 (Bayer AG), U.S. Pat. No. 4,472.405 (Riker Labs), which are not well tolerated must, in practice, be adminis U.S. Pat. No. 4,730,000 (Abbott), U.S. Pat. No. 4,861,779 tered intravenously, for example in the form of an infusion. (Pfizer), U.S. Pat. No. 4,382,892 (Daiichi), U.S. Pat. No. However, the practice of this procedure is problematic, in 4,704,459 (Toyama), the following being mentioned as spe particular when animals are treated. There has also been a cific examples: benofloxacin, binfloxacin, cinoxacin, ciprof number of attempts to increase the tolerance for example by loxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, formulating the product as liposomes, as this is described in fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbof WO 98/33482. Cyclodextrins also are a possibility, fre loxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, quently studied, in order to improve the solubilities or toler pefloxacin, pipemidic acid, temafloxacin, toSufloxacin, Sara ances of formulations; see EP-A-0209768. If the tolerance of floxacin, sparfloxacin. a formulation cannot be improved at all, it may be necessary 0013 A preferred group of fluoroquinolones are those of to use a local anaesthetic when applying it, as this is described the formula (I) or (II): in GB-A-1143330; or to use oily formulations instead; EP-A- (I) 1121933. X O 0003 Solutions for parenteral administration on animals F COOR2 are special in as far as they must be applied in different ways and means, depending on the animal species. For example, it is conventional practice in Europe to administer Solutions for NYr injection Subcutaneously to pigs and intramuscularly to dogs Y A. or cats. Increased tolerance requirements must be met not RI only as the result of the animal species, but also as the result (II) of the different routes of administration (EP-A-112 1933). O The fact that they are tolerated by cattle, for example, does not F COOR2 necessarily allow the conclusion that they are tolerated by, for example, cats or dogs (WO 01/81358). In order to ensure a broad applicability, it is therefore meaningful to improve the Y local tolerance of Solutions for injection in Such a way that B Z-R they can be used even in sensitive animal species. N1 0004. It is therefore also not surprising that most solutions for injection which contain fluoroquinolones are not available in which for dogs or cats, the reason being, interalia, that they are not X represents hydrogen, halogen, C-alkyl, C-alkoxy, well tolerated. NH, 0005 To ensure that the solutions are as well tolerated as Y represents radicals of the structures possible, it is recommended to maintain their pH as neutral as possible (approx. 7.4), which, however, is in contrast with the fluoroquinolones solubility. Also, particle formation of the betaine form of the fluoroquinolones can frequently be observed in this pH range, which is why solutions, while tolerated, have a short shelflife and particle formation results. This can be avoided for example by choosing freeze-dried products instead. Freeze-dried products, however, are diffi cult to handle in practice and frequently only have a shelflife, of the reconstituted solution, of no more than 4 weeks after US 2009/0163484 A1 Jun. 25, 2009 -continued -continued H N1 1 O | H N R41 N Q9 N H H N H N 0021 in which H I0022) R' represents optionally hydroxyl-substituted straight-chain or branched C-C-alkyl, oxalkyl having 1 to 4 C atoms, 0014 in which I0023 R represents hydrogen, methyl or phenyl, 10015I R' represents optionally hydroxyl- or methoxy I0024) R' represents hydrogen, Substituted Straight-chain or branched C-C-alkyl, I0025) R' represents hydrogen or methyl, cyclopropyl, acyl having 1 to 3 C atoms, 0026 R represents hydrogen, 10016 R represents hydrogen, methyl, phenyl, thienyl and their pharmaceutically useful hydrates and salts. or pyridyl, 0027. Especially preferred compounds of the formula (I) 10017 R represents hydrogen or C-alkyl, are those 10018) R' represents hydrogen or C-alkyl, in which (0019 R represents hydrogen or C-alkyl, A represents —CH or —C CN, and R" represents cyclopropyl. R" represents an alkyl radical having 1 to 3 carbon atoms, R represents hydrogen, methyl or ethyl, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl, 2,4-di Y represents radicals of the structures fluorophenyl or methylamino, R represents hydrogen or optionally methoxy- or 2-meth oxyethoxy-Substituted alkyl having 1 to 6 carbon atoms and R8 cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonyl R methyl, pivaloyloxymethyl, R represents hydrogen, methyl or ethyl and SS- N1 A represents nitrogen, =CH-, =C(halogen)-. R41 sh. R41 N =C(OCH) , =C(CH)– or=C(CN), R5 B represents oxygen, optionally methyl- or phenyl-Substi tuted —NH or —CH, Z represents —CH or —N—, and their pharmaceutically useful salts and hydrates. N1 - O 0020 Preferred compounds of the formula (I) are those in which 41 Q9 A represents —CH or —C CN, R" represents optionally halogen-substituted C-C-alkyl or cyclopropyl. H R represents hydrogen or C-alkyl, H Y represents radicals of the structures N N R8 H R SS- N1 0028 in which I0029) R' represents methyl, optionally hydroxyl-sub R4 ---> 41 stituted ethyl, R5 0030 R represents hydrogen or methyl, I0031) R' represents hydrogen, N1 1 O I0032) R' represents hydrogen or methyl, R -N Q9 0033 R represents hydrogen, and their pharmaceutically useful salts and hydrates. US 2009/0163484 A1 Jun. 25, 2009 0034. A preferred example of a fluoroquinolone of the sium salts, the alkaline earth metal salts, for example the formula (II) which may be mentioned is marbofloxacin: magnesium or calcium salts; the Zinc salts, the silver salts and the guanidinium salts. 0041 Hydrates are taken to mean not only the hydrates of the fluoroquinolones themselves, but also the hydrates of F COOH their salts. An example which may be mentioned is pradof loxacin, which forms a stable trihydrate (see WO 2005/ 097789). 0042 Fluoroquinolones, being solids, can, under certain circumstances, form various crystal modifications. Advanta geous for the pharmaceuticals of the present invention are those modifications which have suitable solubility properties. 0043. The fluoroquinolone is typically employed in an 0035 Especially preferred fluoroquinolones which may amount, for animals with a body weight of up to approxi be mentioned are the compounds described in WO97/31001, mately 80 kg, of 0.1 to 15%, preferably 0.5 to 15% and in particular 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabi especially preferably 1 to 15%.