CA1336822C

CA1336822C - Intramuscular injection forms of gyrase inhibitors

Info

Publication number: CA1336822C
Application number: CA000596557A
Authority: CA
Inventors: Norbert Pollinger; Peter Serno; Wolfram Hofmann; Dieter Beermann
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1988-04-15
Filing date: 1989-04-13
Publication date: 1995-08-29
Anticipated expiration: 2012-08-29
Also published as: CN1037272A; ES2038359T3; DE3902079A1; DK169772B1; IL89928A; DE58901663D1; EP0337231B1; KR900015736A; AU3275389A; IE60407B1; NZ228708A; GR3005415T3; HUT54048A; AU610380B2; EP0337231A2; IE891201L; EP0337231A3; IL89928A0; US5023257A; JPH01316321A

Abstract

Ciprofloxacin and related gyrase inhibitors are tolerated well if administered intramuscularly in the form of an aqueous suspension of the betaine form having an approximate neutral pH value or in the form of an oily suspension of the betaine or salts thereof.
Oily suspensions which contain the active material in water-soluble form, eventually in form of the hydrochlorides, lactates, mesilates, methanesulfonates and other salts, are capable of releasing the active compound very rapidly, particu-larly when the wettability of the oily carrier medium is in-creased by addition of interfacially surface active materials.

Description

The invention relates to intramuscular injection forms which contain, as the active compound, gyrase inhibitors from the group comprising quinolone- and 1,8-naphthyridone-3-carboxylic acids, their preparation and their use as medicaments.
Tablets for peroral administration and relatively large volume infusion solutions (O.ZZ strength/50, 100 ml) and infusion concentrates (1% strength/10 ml) contain-ing, for example, ciprofloxacin as the active substance have so far been available. In contrast, no satisfactory formulation has to date been developed for intramuscular administration. Solutions of, for example, ciprofloxacin of up to 5~ strength for intramuscular administration are thus very poorly tolerated because of their non-physio-logical pH in the acid or alkaline range. After intra-muscular injection of aqueous acid or alkaline solutions, considerable intolerances and damage up to necroses have been found in the muscular tissue.
Surprisingly, it has now been found that cipro-2û floxacin is tolerated ~ell follo~ing intramuscularadministration if it is administered in the form of an aqueous suspension of the betaine form having an approximate neutral pH value or in the form of an oi1y suspension of the betaine or salts thereof Moreover it has been found sur-prisingly that oi1y suspensions which contain ciprofloxacin inwater-soluble form, eventually in form of the hydrochlorides, 1actates, mesi1ates, methanesulfonates and other salts, are hle of rp~ c;~g the active compound very rapidly, particu-larly when the wettability of the oi1y carrier medium is in-creased by addition of interfacially surface active materialsTo the contrary aqueous suspensions which contain the active compound in the form of betaine ensure protracted release of the active compound.
Regulation and control of release of the active com-pound is possible via choice of particle size and the combina-tion of auxi1iaries respectively.
The invention relates to intramuscular injection formulations of gyrase inhibitors containing 0.05 to 70 by ~eight of a gyrase inhibitor of the general formula Le A 25 940 - 1 -~ 336822 R ~ COOR2 (I) in which R1 stands for methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-di-fluoroPhenyl, R stands for hydrogen, alkyl having 1 to 4 carbon atoms or (S-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R3 stands for methyl or a cyclic amino group, such as ~ C ~ N-, R4-N N-, N-~ S N-, R4_N ~ N-~ R4_N ~ N-1 r--~ N ~ N- ~`N-N ~ N-, ~ , ~herein R stands for hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFCl2-S-, CFCl2-S02-, CH30-C0-S-, benzyl, 4-aminobenzyl or CH~
J~CH2 ' ~0 Le A 25 940 - 2 -R5 stands for hydrogen or methyl, R6 stands for hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyloxymethyl, R7 stands for hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl or hydroxymethyl and R stands for hydrogen, methyl, ethyl or chlorine, X stands for fluorine, chlorine or nitro and A stands for N or C-R6, ~herein R6 stands for hydrogen, halogen, such as fluorine or chlorine, methyl or nitro or, together ~ith R1, can also form a bridge having the structure 0-CH2-CH-CH3, -S-CH2-CH-CH3 or -CH2-CH2-CH-CH3 ~

if appropriate as a salt ~ith an acid or base or as a pro-drug, in aqueous or oily suspension.
Not only a systemic action, ~hich can be con-trolled with respect to time, depending on the composi-tion of the formulation, can be achieved ~ith the intra-muscular injections containing gyrase inhibitors. In addition, local infection foci can also be reached by the direct route and treated in a targeted manner over rela-tively long periods of time.
The gyrase inhibitors can be used in the aqueous and oily injection forms as such or as a salt ~ith an acid or base. It is also possible to use them as a pro-drug, for example in the form of esters.
The formulations according to the invention con-tain 0.05-70Z by weight, preferably 2.5-50% by ~eight, of the active compound.
The suspensions according to the invention for intramuscular injection particularly preferably contain 10-60Z ~eight/weight of the active compound of the above formula.
Le A 25 940 The formulations mentioned contain, in particu-lar, ciprofloxacin, norfloxacin, pefloxacin, amifloxacin, pirfloxacin, ofloxacin, fleroxacin, lomefloxacin andlor enoxacin. The formulations according to the invention especially preferably also contain the active compounds of European Patent Applications 153,163, 106,489, 153,828, 195,316, 167,763 and 126,355.
The follo~ing active compounds may be mentioned in particular: 6-chloro-7-[3-(4-chlorophenyl)-1-piperaz-inyl]-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quino-linecarboxylic acid, 6-chloro-1-cyclopropyl-8-fluoro-7-C3-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-t3-(4-bromophenyl)-1-piperaz-inyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-t3-(4-methylphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 7-t3-(4-biphenylyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-t3-(4-methoxyphenyl)-1-piperaz-inyl]-4-oxo-3-quinolinecarboxylic acid, 6-chloro-1-cyclo-propyl-8-fluoro-1,4-dihydro-7-t3-(4-hydroxyphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylic acid, 8-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-t(4-nitrophenyl)-1-piperazinyl~-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-t3-(4-piperi-dinophenyl)-1-piperazinyl~-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-t3-(3,4-dimethoxyphenyl)-1-piperazinyl]-3-quinolinecar-boxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oxo-7-t3-(3,4,5-trimethoxyphenyl)-1-piperazinyl]-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-t3-(2-thienyl)-1-piperazinyl]-Le A 25 940 ~ 33682~

3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl,6-fluoro-1,4-dihydro-4-oxo-7-piperidino-3-quinolinecarboxy-lic acid, 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (active compound B), 6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, 7-(4-acetyl-1-piperazinyl)-6,8-dichloro-1-cyclo-propyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-(4-acetyl-1-piperazinyl)-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-morpholino-3-quinolinecarboxylic acid, 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-3-quinoline-carboxylic acid, 8-chloro-1-cyclopropyl-7-(4-ethyl-3-oxo-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-quinoline-carboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,4-dimethyl-1-piperazinyl)-3-quinolinecarboxy-lic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-3-methyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-t4-(2-hydroxyethyl)-3-methyl-1-piperazinyl]-3-quinoline-carboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-t4-(3-hydroxypropyl)-3-methyl-1-piperazinyl]-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2,5-dimethyl-1-piperazinyl)-3-quinoline-carboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-2,5-dimethyl-1-piperazinyl)-3-quinoline-Le A 25 940 carboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)-3-quinolinecarboxy-(ic acid (active compound A), 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,4,5-trimethyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-ethyl-3,5-dimethyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-ethyl-1-piperazinyl)-3-quinoline-carboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-n-propyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-aminopyrrolidinyl)-3-quinolinecarboxylic acid (active compound C), 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-isopropyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-isobutyl-1-pipereazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-(3-methyl-4-n-propyl-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-4-isopropyl)-1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-n-butyl-3-methyl-1-piperazinyl)-3-quinolinecarboxylic acid and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-mor-pholinyl-3-quinolinecarboxylic acid, and their pharma-ceutically usable acid addition salts, alkali metal salts, alkaline earth metal salts or hydrates.
Finally, ciprofloxacin or enrofloxacin are also particularly preferably`employed as the active compound in the formulations according to the invention.
In addition to water for injection purposes, aqueous suspens;ons for intramuscular injection can furthermore also contain as the liquid excipient, for example, ethanol, glycerol, propylene glycol, polyethyl-ene glycol and triethylene glycol. Yarious substances such as phosphate, citrate, tris, ascorbate, acetate, succinate, tartrate, gluconate and lactate buffers can Le A 25 940 be used for adjusting the pH as far as possible to within the physiological ran~e of about pH 7.4 or for buffering.
The pH of the aqueous formulations according to the inven-tion is 4.5 - 8.5, preferably 6.5 - 7.5. The osmolality of the aqueous suspensions is 200 - 900 m osmol/kg, preferably 260 - 390 m osmol/kg, and can be adjusted to suit isotonic conditions by additions of NaC1, g1ucose, fructose, g1ycero1, sorbitol, mannitol, sucrose or xylitol or mixtures of these substances.
It is moreover possible to use other formulating agents, such as thickeners ~for example methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrol;done, gelatine and the like), absorption agents, light screens, absorp-15 tion inhibitors, crystallization retarders, complexing agents (for example NaEDTA, phosphates, nitrates, ace-tates, citrates and others), antioxidants (ascorbic acid, sulphite compounds, L-cysteine, thiodipropionic acid, thiolactic acid, monothioglycerol, propyl gallate and others) and preservatives (PHB esters, phenol and derivatives, organomercury compounds, chlorobutanol, benzyl alcohol, ethanol, 1,3-butanediol, benzalkonium chloride, chlorhexidine salts, benzoic acid and salts, sorbic acid and others). Local anaesthetics, such as, 25 for example, procaine HCl, lidocaine HCl and others, can be added to the aqueous suspensions if appropriate.
~ hen preparing the aqueous suspensions, it must be ensured that the particle size is 0.5 - 150 ~m, in particular 4-40 ~m. Control of the release of active compound from the intramuscular suspension depot can be achieved by controlled mixing of different particle size classes of the active substance.
In the case of aqueous suspensions, the particle sizes of 90Z of the particles are preferably 10-20 ~m.
35 The viscosity of the aqueous suspensions is 5 - 500 mPa-s, preferably lO - 130 mPa-s.

Le A 25 940 - 7 -Aqueous suspensions of gyrase inhibitors can be prepared in various ways. On the one hand, the active compounds from the gyrase inhibitor class can be incorpo-rated in micronized form into the aqueous excipient medium, the auxiliaries mentioned being included; in this procedure, it should strictly be ensured that no crystal growth occurs beyond the limits mentioned. If appropriate, the active compound must be prepared in the form of one of its stable hydrate stages and further processed to a sus-pension. If final sterilization by heat is not possible,manufacture must be carried out under aseptic conditions using pretreated active compounds and auxiliaries. Final sterilization, as by radiation is possible.

Aqueous suspensions of gyrase inhibitors of the quinolone type can moreover be prepared by controlled precipitation from a solution; there is the possibility, for example, of dissolving the active compound in a physiologically tolerated acid from the group consisting of hydrochloric ac;d, methanesulphonic acid, propionic acid, succinic acid, glutaric acid, citric acid, fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid, phosphoric acid, adipic acid, hydroxyacetic acid, sulphuric acid, nitric acid, acetic acid, malic acid, L-aspartic acid, lactic acid, isethionic acid, lactobionic acid and oxatic acid or in amino ac~ds from the group o~isting of L-Arginine, L-Aspartic, L-Cysteic, L-Glutamic, Glycine, L-Leucine, L-Lysine and L-Serine, if appropriate while warm-ing slightly, preferably to 20 - 80C.
An excess of acid is preferably used, for example in accordance with the doctrine of European Patent Applications 86 114 131.5 and 84 110 474.8. The acid solution is then adjusted to the physiological pH of 7 by addition of a physiologically tolerated alkaline solu-tion, for example of sodium hydroxide, potassium hydrox-ide or meglumine, the active compound being precipitated Le A 25 940 - 8 -out of the solution in finely divided form. On the other hand, there is also the possibility of dissolving the active compound of the quinolone/naphthyridone gyrase inhibitor type in an alkaline medium using one of the bases mentioned and then to precipitate it by one of the acicls mentionecl.
However, the acids and alkaline solutions can be combined without using pressure, but also with pressure~ in a range from 2 to 100 bar, optionally while gassing with nitrogen, it being possible to control the resulting particle size in the suspension via the preparation conditions defined. The actual precipitation operation can also be followed by additional homogenization using high-speed stirrers, rotor-stator homogenizers, high pressure homogenizers ~100-1000 bar~ and similar methods. If final sterilization is prohibited because of possible particle growth the suspension is to be prepared under aseptic corlditions by combining sterilized and sterile-filtered acid and basic part comp(?nents with one another under strictly aseptic conditions. If appropriate, one of the preservatives mentioned or a combination thereof can be employed in a suitable dosage in order to guarantee a germ-free preparation. Final sterilization in form of a ~?-ray sterilization may be applied too.
A presentation form which contains the active compound in a dry form without a liquid excipient can moreover be provided.
The separate liquid excipient is combined with the solids content of the recipe only shortly before administration, in which case homogeneous distribution of the solids particles in the liquid phase must be guaranteed by brief shaking.

1 3368~

Under the provisions set forth hereinabove and hereinbelow there are particularly preferred oil based intramuscular injection formulations which contain the active compound in water-soluble, crystalline or amorphous form, for instance in form of the hyclrochloride, lactate, mesilate, p-tol~l sulphorlate or other salts produced with physiologically well-tolerated acids as well as which contain interfacially active substances, as for instance lecithin in the form of soy bean lecithin, egg lecithin, brain lecithin or rape lecithin or other physiologically well-tolerated tensides in concentrations of 0.1 to 30 ~, particularly O.2 to 10 ~, above all O.5 to 5.0 % W/V as well as which contain, in addition to the water-soluble active compound in the form of their salts, an excess of ~ physiologically well-tolerated acids, as for instance lactic acid or citric acid in the range of 1 to 300 mmol/l, parti-cularly 5 to 50 mmol/l, preferably 10 to 30 mmol/l.

Oily suspensions of quinolone-type gyrase inhibitors contain the active compound either in the form of the betaine or in the form of water-soluble salts. Physiologically well-tolera-ted acids appropriate for formation of salts are set forth hereinabove.
Oily suspensions can contain, as non-aqueous excipients, for example almond oil, arachis oil, olive oil, poppyseed oil, sesame oil, cottonseed oil, soya bean oil, corn oil, castor oil, ethyl oleate, oleyl oleate, isopropyl myristate, isopropyl palmitate, medium-chain triglycerides and others. Ethanol, glycerol, propylene glycol, polyethylene glycol, 1,3-butane diol, benzyl alcohol, diethylene glycol and triethylene glycol of various origins, polyoxyethylene-polyoxypropylene copolymers of the Pluroni ~ type, polyoxysorbitan fatty acid esters, sorbitan fatty acid esters, monoolein, cremophor EL(R), Inwitor 742( ) and different types of lecithin such as soy bean lecithin, egg lecithin, brain lecithin and rape lecithin can be used as further auxiliaries which can be combined with the substances mentioned.

Le A 25 940 - 10 -Antioxidants ~hich are used are ~ -, y- and ~-tocopherol, ascorbyl palmitate, ascorbyl stearate, L-cysteine, thiodipropionic acid, thiolactic acid, thio-glycolic acid, monothioglycerol, propyl gallate, butyl-hydroxyan;sole, butylhydroxytoluene and others.
If appropriate, a desired viscosity can bebrought about by diluents such as ethanol or benzyl alcohol and by thickeners such as aluminum stearate.
Acids such as those mentioned hereinabove may be added as absorption enhancers. Viscosity values for oily suspensions are 5-500 mPa.s, preferably 10-150 mPa-s.
Oily suspensions are prepared by combining the oily excipient with the auxiliaries contained therein and the active compoun~, which has been comminuted to the desired particle size, using suitable apparatuses (see above) and homogenizing the mixture. The particle sizes of 90% of the particles are 0.5-150 ~m, preferably 4-12 ~m.
If final sterilization in the release vessel is prohibi-ted because of a Possible change in the particle size of the active compound, the suspension must again be pre-pared under aseptic conditions. Sterile filtration of the oily phase containing suitable auxiliaries in dissolved form is also indicated, such as antimicrobial pretreatment of the active compound, for example by heat treatment. Final sterilization in t~e fonmof a ~-ray sterili-zation may also be ~plie~.
In addition to a finished suspension, a formula-tion ~hich is to be freshly prepared shortly before administration can also be provided. In this case, the active compound must be homogeneously susPendable in the liquid excipient ~ithin a short time by shaking the vessel containing the formulation.
The invention also relates to suspension concen-trates ~hich are converted into the formulations accord-Le A 25 940 - 11 -ing to the invention shortly before administration.
These concentrates can have various compositions.
This invention relates to all the further combinations of concentrates and/or suspensions and solvents or solu-tions required for dilution which lead to the suspensionsaccording to the invention.
This invention also relates to other presentation forms or combinations of presentation forms which in the end lead to the injection solutions according to the invention - regardless of the procedure.
The containers filled with suspensions, active compound, solvents and other presentation forms, such as suspension concentrates, can be made of glass or of plastic. The container materials here can contain sub-stances which impart special protection to the contents,such as, for example, protection from light or protection from oxygen. In addition to small volume vessels, from which the suspension must be drawn into the injection syringe before administration, the vessels here can also be finished injection systems.
The injection formulations according to the invention are used in the therapeutic treatment of the human or animal body.
The formulations according to the invention have a low toxicity and exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative germs, in parti-cular against Enterobacteriaceae; above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cephalosporins, amino-glycosides, sulphonamides and tetracyclines.
The formulations according to the invention areactive against a very broad spectrum of microorganisms.
6ram-negative and Gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, alleviated and/or cured with the aid of these formulations.
Le A 25 940 The formulations according to the invention are particularly active against bacteria and bacteria-like microorganisms. They are therefore particularly suitable for the prophylaxis and chemotherapy, in human and veter-S inary medicine, of local and systemic infections causedby these pathogens.
For example, it is possible to treat and/or pre-vent local and/or systemic diseases caused by the follow-ing pathogens or by mixtures of the folloving pathogens:
Gram-positive cocci, for example Staphylococci (Staph.
aureus and Staph. epidermidis) and Streptococci ~Strept.
agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes); Gram-negative cocci (Neisseria gonor-rhoeae) and Gram-negative rod-shaped bacilli, such as Enterobacteriaceae, for example Escherichia coli, Haemo-philus influenzae, Citrobacter (Citrob. freundii and Citrob. divernis), Salmonella and Shigella; and further-more Klebsiellae (Klebs. pneumoniae, Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mira-bilis, Pr. rettgeri and Pr. vulgaris), Providencia and Yersinia, and the genus Acinetobacter. The antibacterial spectrum moreover includes the genus Pseudomonas (Ps.
aeruginosa and Ps. maltophilia) and strictly anaerobic bacteria, such as, for example, Bacteroides fragilis, representatives of the genus Peptococcus and Peptostrepto-coccus and the genus Clostridium; and furthermore Myko-plasma (M. pneumoniae, M. hominis and M. urealyticum) and Mycobacteria, for example Mycobacterium tuberculosis.
The above list of pathogens is to be interpreted merely by vay of example and in no vay as limiting.
Examples vhich may be mentioned of diseases vhich can be caused by the pathogens or mixed infections mentioned and can be prevented, alleviated or cured by the compounds according to the invention are: infection diseases in humans, such as, for example, otitis, pharyngitis, Le A 25 940 pneumonia, peritonitis, pyelonephritis, cystitis, endocar-ditis, systemic infections, bronchitis (acute and chronic), septic infections, diseases of the upper respiratory tract, diffuse panbronchiolitis, pulmonary emphysema, dysentery, enteritis, liver abscesses, urethritis, pros-tatitis, epididymitis, gastrointestinal infections, bone and joint infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses, phlegmons, ~ound infections, infected burns, burn ~ounds, infections in the oral region, infections following dental opera-tions, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, cholangitis, intraabdom-inal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelveoperitonitis and eye infections.
Bacterial infections can also be treated in other species as well as in humans. Examples ~hich may be mentioned are:
pigs: colidiarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis, mastitis-metritis agalactia syndrome and mastitis;
ruminants (cattle, sheep, goats): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, myco-plasmosis and genital infections;horses: bronchopneumonia, joint ill, puerperal and post-puerperal infections and salmonellosis;
dogs and cats: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections and prostatitis;
poultry (chickens, turkeys, quails, pigeons, ornamental birds and others): mycoplasmosis, E. coli infections, chronic diseases of the respiratory tract, salmonellosis, pasteurellosis and psittacosis.
~acterial diseases can also be treated in the rearing and keeping of stock and ornamental fish, the antibacterial spectrum extending beyond the abovementioned Le A 25 940 pathogens to further pathogens, such as, for example, Pasteurella, Brucella Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.
The auxiliaries mentioned in the examples are commercially available and are defined in part in H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete (Dictionary of Auxiliaries for Pharmacy, Cosmetics and Related Areas), Editio Cantor KG - Aulendorf i. Wurtt. 1971 (for example Tween ~ and l~iglyol ~ ).
The invention also extends to a commercial package containing a formulation according to the invention, together with instructions for its use for intramuscular injection.
The invention will be further described with reference to the accompanying drawings relating to comparison experiments which demorlstrate the good tolerability of a ciprofloxacin intramuscular suspension in contrast to ciprofloxacin intramuscular solutions.
Figure 1 shows the course of the creatinine kinase following intramuscular administration of ciprofloxacin intramuscular solutions, an intramuscular suspension and comparison solutions.
Figure 2 shows the local irritation following intramuscular administration of ciprofloxacin solutions and a ciprofloxacin intramuscular suspension and comparison solutions.
Figure 3 ~hows the blood plasma levels after application of an only ciprofloxacin-HCl suspension to rabbits.
The very fast absorption of ciprofloxacin-HCl from an 1 33682~

oily suspension into the blood is clearly evident.
Results:
1) The local irritations following intramuscular administration of 5 % wei~ht/volume ciprofloxacin suspensions are clearly less than those caused by intramuscular solutions (Rabbit test) 15a . .
, 2) In contrast to the intramuscular soLutions tested, administration of the ciprofloxacin suspension causes no increase in the serum creatinine kinase.
~ he formulations used for the experiments are described below (rabbit test).

Ciprofloxacin intramuscular injection solution 5 ~ w/v A

Ciprof10xacin 50.0 9 Lactic acid saponified 20 % 131.0 9 Water for injection purposes 840.6 9 1021.6 9 c1ear yel1owish so1ution; pH 3.9, isotonic Ciprofloxacin intramuscular injection B
solution SZ weight/volume 2 ml 15 Ciprofloxacin SO.O g 100Z strength acetic acid 25.0 9 ~ater for injection purposes 943.7 9 1,018.7 9 (1 l) clear, yello~ solution; pH 4.2 Ciprofloxacin intramuscular injection solution C

SZ veight/volume 2 ml Ciprofloxacin SO.O g Methanesulphonic acid 14.5 9 Anhydrous glycerol 12.5 9 0.1 N NaOH solution to pH 4.~
~ater for injection purposes 945.5 9 1,022.5 9 (1 l) Clear, yellow solution; pH 4.2 Ciprofloxacin intramuscular suspension D
SZ ~cight/volume 2 ml Le A 25 940 - 16 -Ciprofloxacin 50.0 9 20Z ~eight/ueight NaOH solution55.2 9 Citric acid fine grit 17.9 9 Tylopur C 300 P 2.0 9 ~ater for injection purposes907.3 9 1,032.4 9 (1 l) Sedimenting, reshakable susPensions of pH 7; particle si~e of the crystals predominantly less than 10 ~m.

Ciprofloxacin suspension 5 ~ w/v E

Ciprofloxacin-HCl 58.2 9 Phospholipon l00 5.0 9 Benzyl alcohol destilled 20.0 9 Miglyol 812 ~ 883.8 9 967.0 9 white oily suspension;

Ciprofloxacin placebo . F
Lactic acid saponified 20 % 64.06 9 2 N NaOH - solution 38.4 9 Sodium chloride l.46 9 Water for injection purposes 900.08 9 1004.0 9 clear colorless solution isotonic; pH 3.9 Ciprofloxacin placebo Ciprofloxacin intramuscular injection solution placebo G
SX ~eight/volume 2 ml 100X strength acetic acid 50.0 9 1 N NaOH solution to pH 4.2 ~ater for injection purposes 956.7 9 1,006.7 9 Clear, colorless solution; pH about 4.2 Le A 25 940 - 17 -Ciprofloxacin placebo Ciprofloxacin intramuscular injection solution placebo H
5% weight/volume 2 ml Methanesulphonic acid 14.5 9 5 Anhydrous glycerol 12.5 9 1 N NaOH solution about 158.06 9 ~ater for injection purposes 825.54 9 1,010.6 9 Clear, almost colorless solution;
pH about 4.2 Osmolality about 425 m osmol Ciprofloxacin pLacebo Ciprofloxacin intramuscular injection solution placebo J
5~ weight/volume 2 ml 15 Citric acid fine grit 17.9 9 20% weight/weight NaOH solution 55.6 9 Tylopur C 300 P ~ 2.0 9 ~ater for injection purposes 940.3 9 1,015.8 9 (1 L) 20 Colorless, slightly opalescent solution; pH 6.8 Examples 1 .
Ciprofloxacin 50 9 20% weight/weight NaOH solution 55.2 9 preparation by precipitation Citric acid 17.9 9 Tylopur C 300 ~ ~ ~
~ater 909.3 9 pH = 6.5 30 2.
Ciprofloxacin 50 9 preparation by 20% weight/weight NaOH solution 55.2 9 precipitation Citric acid 17.9 9 Tylopur C 300 ~ 2.0 9 ~ater 907.3 9 pH = 6.7 Le A 25 940 - 18 -3.
Ciprofloxacin 50 9 20% weighttweight NaOH solution 55.2 9 preparation by precipitation 5 Citric acid 17.9 9 Tylopur C 300 ~ 5.0 9 ~ater 904.3 9 pH = 6.5 Ciprofloxacin 50 9 20Z ~eight/~eight NaOH solution 55.2 9 preparation by precipitation Citric acid 17.9 9 Tylopur C 300 P~ 7.5 9 ~ater 901.8 9 pH = 6.5 Ciprofloxacin50 9 preparation by 20% weight/~eight NaOH solution 55.2 9 precipitation Citric acid 17.9 9 Tylopur C 300 PQ 7.5 9 ~ater 899.5 9 pH = 6.5 6.
Ciprofloxacin 50 9 20~ ~eight/~eight NaOH solution 55.2 9 preparation by precipitation Citric acid 16.0 9 Tylopur C 300 P~ 2.0 9 ~ater 909.2 9 pH = 7.9 Le A 25 940 - 19 -Ciprofloxacin 50 9 20% weight/weight NaOH solution 55.2 9 preparation by precipitation 5 Citric acid 24.7 9 Tylopur C 300 P~ 2.0 9 ~ater 900.5 9 pH = 5.3 10 Ciprofloxacin 50 9 2û% weight/weight NaOH solution 55.2 9 Citric acid 17.9 9 preparation by precipitation Tylopur C 300 ~ 2.0 9 T~een 20 2.0 9 Water 900.5 9 pH = 6.9 Ciprofloxacin 5.0 9 20Z weight/weight NaOH solution 9.43 9 preparation by precipitation Lipoid E 80 0.2 9 Citric acid 1.8 9 Tylopur C 300 P~ 0.2 9 ~ater 77.17 9 10.
Ciprofloxacin 50.0 9 preparation by 20X ~eight/~eight NaOH solution 55.2 9 precipitation Methanesulphonic acid 16.15 9 30 10X ~eight/~eight NaOH solution 18.83 ml ~ater 400.8 9 pH = 7.0 Le A 25 940 - 20 -1 1 .
Ciprofloxacin S0.0 9 preparation by precipitation Methanesulphonic acid 16.15 9 S L-Arginine 6.113 9 ~ater 407.33 9 pH = 7.0 12.
Ciprofloxacin 50.0 9 Methanesulphonic acid 16.15 9 preparation by precipitation Trimethanol (tris) 4.41 9 ~ater 408.37 9 pH = 7.0 13.
Micronized ciprofloxacin hydrate (85.5%) 5.85 9 Suspension of Tylopur C 300 P ~ 0.2 9 micronized ciprofloxacin hydrate in the aqueous phase Anhydrous glycerol 2.5 9 ~ater to 100 ml 14.
Micronized ciprofloxacin hydrate (85.5~) 5.85 9 Suspension of Tylopur C 300 ~ 0.2 9 micronized ciprofloxacin hydrate in the aqueous phase Anhydrous glycerol 2.5 9 ~ater to 100 ml Le A 25 940 15.
Micronized ciprofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized Tylopur C 300 P~) 0.75 9 ciprofLoxacin hydrate in the aqueous phase T~een 80R 0.2 9 Anhydrous glycerol 2.5 9 ~ater to 100 ml pH 6.8 16.
Micronized ciprofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized Tylopur C 300 P~ 0.75 9 ciprofloxacin hydrate in the aqueous phase Lipoid E 80 0.2 9 Anhydrous glycerol 2.5 9 Water to 1,000 ml pH 6.8 17.
Micronized ciprofloxacin hydrate (85.5X) 5.85 9 Suspension of microni2ed Tylopur C 300 P~ O.Z g ciprofloxacin hydrate in the aqueous phase Tween 80~) 0.2 9 Anhydrous glycerol 2.5 9 ~ater to 100 ml pH 6.8 Le A 25 940 - 22 -18.
Micronized ciprofloxacin hydrate (85.5X) 5.85 9 Suspension of micronized Tylopur C 300 ~ 0.2 9 ciprofloxacin hydrate in the aqueous phase Lipoid E 80~ 0.2 9 10 Anhydrous glycerol 2.5 9 ~ater to 1,000 ml pH 6.8 19.
Ciprofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized ciprofloxacin hydrate in the aqueous phase Tylopur C 300 P~ 0.2 9 Lipoid E 80 0.2 9 20 ~ater 90.0 ml pH 7 20.
Ciprofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized ciprofloxacin hydrate in the aqueous phase Tylopur C 300 P~ 0.2 9 Citrate buffer solution pH 7 90.0 9 Lipoid E 80 0.2 9 pH 7 Le A 25 940 - 23 -21.
Ciprofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized ciprofloxacin hydrate in the Tylopur C 3ûû P~ 0.2 9 aqueous phase Phosphate buffer solution pH 7 90.0 9 Lipoid E 80 0.2 ml pH 7 22.
10 Ciprofloxacin 5.0 9 20% weight/weight NaOH solution 3.27 9 preparation by precipitation 85X strength H3P04 solution 1.07 9 Tylopur C 300 P~ 0.2 9 ~ater 93.14 9 23.
Ciprofloxacin 50.0 9 20X weight/weight NaOH solution 55.57 9 pH/
osmolality:
285 m osmol/kg Citric acid fine grit 17.9 9 ~ater 903.6 9 Particle size < 10 ~m Precipitation under aseptic conditions via a reaction jet 60/40 bar and high pressure homogenization under 400 bar.

24.
Ciprofloxacin 100.0 9 20~ weight/weight NaOH solution 62.0 9 Citric acid fine grit 19.8 9 ~ater 869.2 9 pH 7.0 Particle size < 2-5 ~m (90X less than 10 ~m) Precipitation under aseptic conditions via a reaction jet 60/40 bar and high pressure homogenization under 400 Le A 25 940 - 24 -bar.
25.
Ciprofloxacin 100.0 9 20% weight/~eight NaOH solution 62.0 9 5 Citric acid fine grit 19.8 9 Tween 80~ 0.1 9 Water 869.2 9 pH 7.0 26.
Ciprofloxacin 100.0 9 20% weight/~eight NaOH solution 62.0 9 Citric acid fine grit19.8 9 T~een 80~ 1.0 9 ~ater 868.2 9 pH 7.0 27.
Ciprofloxacin 100.0 9 20Z ~eight/~eight NaOH solution 62.0 9 Citric acid fine grit19.8 9 T~een 80~ 2.0 9 ~ater 867.1 9 pH 7.0 28.
Ciprofloxacin 100.0 9 20% ~eight/~eight NaOH solution 62.0 9 Citric acid fine grit19.8 9 Tueen 80~ 2.0 9 ~ater 867.1 9 pH 7.0 29.
Ciprofloxacin 40.0 9 preparation ~y prec;pitation 20Z ~eight/ueight NaOH solution 24.8 9 Citric acid fine grit 7.92 9 Lipoid E 75~ 4.0 9 ~ater 343.6 9 pH 7.0 Le A 25 94û - 25 -30.
Ciprofloxacin 200.0 9 preparation by precipitation 20% weight/~eight NaOH solution 62.8 9 S Citric acid fine grit 41.88 9 ~ater 738.27 9 pH 7.05 31.
Ciprofloxacin 20.0 9 preparation by precipitation 20Z weight/~eight NaOH solution 12.4 9 15% ~eight/weight H3P04 solution 21.38 ml ~ater to 100 ml pH 7.05 32.
15 Ciprofloxacin 15.0 9 preparation by precipitation 20% ~eight/~eight NaOH solution 9.3 9 15% ~eight/weight H3PO4 solution 16.05 ml ~ater to 100 ml 20 33.
Ciprofloxacin 25.0 9 20X ~eight/~eight NaOH solution 11.25 9 preparation by precipitation 20% ~eight/~eight lactic acid 25 solution 3.72 9 15Z ~eight/~eight H3PO4 solution 21.5 ml ~ater to 100 ml pH 7.0 34.
30 Ciprofloxacin 20.0 9 20Z ~eight/~eight NaOH solution 10.0 9 preparation by precipitation Le A 25 940 - 26 -20X weight/weight lactic acid solution 7.44 9 15% weight/weight H3P04 solution 12.0 ml 5 ~ater to 100 ml pH 7.0 35.
Ciprofloxacin 20.0 9 20% weight/weight NaOH solution 8.75 9 preparation by precipitation 10 20X weight/weight lactic acid solution 11.16 9 15% weight/weight H3P04 solution 6.7 ml ~ater to 100 ml pH 7.0 15 36.
Ciprofloxacin 20.0 9 20% weight/weight NaOH solution 12.4 9 preparation by precipitation 15% weight/weight H3PO4 20 solution 21.1 ml Tylopur C 300 P~ 0.05 9 ~ater to 100 ml pH 7.0 37.
Ciprofloxacin 20.0 9 Z0Z weight/weight NaOH solution 12.4 9 preparation by precipitation 15% weight/weight H3PO4 solution 21.1 ml HPC 0.05 9 ~ater to 100 ml pH 7.0 38.
Ciprofloxacin 20.0 9 20~ weight/weight NaOH solution 12.4 9 preparation by precipitation Le A 25 940 - 27 -15Z weight/~eight H3P04 solution 21.1 ml T~een 80~ .S g Water to 100 ml pH 7.0 5 39.
Ciprofloxacin 20.0 9 20Z ~eight/~eight NaOH solution 12.4 9 preparation by precipitation 15Z ~eight/weight H3P04 10 solution 21.1 ml T~een 80~ 1.0 9 ~ater to 100 ml pH 7.0 40.
Ciprofloxacin hydrochloride 5 9 Suspension of ciprofloxacin hydrochloride Ethyl oleate 50 9 41.
Ciprofloxacin hydrochloride 10 9 20 Ethyl oleate 50 9 42.
Ciprofloxacin hydrochloride 30 9 Ethyl oleate 50 9 43.
25 Ciprofloxacin hydrochloride 25 9 Ethyl oleate 50 9 44.
Ciprofloxacin hydrochloride 5 9 Miglyol 812~ 50 9 Le A 25 940 - 28 -1 33682~

45.
Ciprofloxacin hydrochloride 10 9 Miglyol 812~ 50 9 46.
5 Ciprofloxacin hydrochloride 15 9 Miglyol 812~ 50 9 47.
Ciprofloxacin hydrochloride 5 9 Peanut oil 50 9 10 48.
Ciprofloxacin hydrochloride 5 9 Ethyl oleate/Phospholipon 100~
= 99.5/0.5 50 9 49.
15 Ciprofloxacin hydrochloride 30 9 Ethyl oleate/Phospholipon 100~ = 99.5/0-5 50 9 50.
Ciprofloxacin hydrochloride 10 9 20 Miglyol 81 ~/Phospholipon 100~ = 99.5/0-5 50 9 51.
Ciprofloxacin hydrochloride 15 9 Miglyol 812~/Phospholipon 100~ = 99.5/O.S 50 9 52.
Ciprofloxacin 30 9 Ethyl olea ~ S0 9 Le A 25 940 - 29 -53.
Ciprofloxacin 10 9 Miglyol 81 ~ 50 9 54.
5 Ciprofloxacin 2.5 9 Peanut oil 50 9 55.
Ciprofloxacin hydrochloride30 9 Ethyl oleate 50 9 10 Ascorbyl palmitate 0.1 9 Lecithin (Phospholipon 100)~ 0.5 9 56.
Ciprofloxacin hydrochloride25 9 Miglyol 812 ~ 50 9 15 Ascorbyl palmitate 0.1 9 Lecithin (Phospholipon 100)~ 0.5 9 57.
Ciprofloxacin hydrochloride30 9 Ethyl oleate 50 9 20 Ascorbyl palmitate 0.1 g Lecithin (Phospholipon 100)~ 0.5 9 Benzyl alcohol 3 9 58.
Ciprofloxacip~hydrochloride25 9 Miglyol 812 ~ 50 9 Benzyl alcohol 3 9 Lecithin (Phospholipon 100)~ 0.5 9 Ascorbyl palmitate 0.1 9 59.

30 Norfloxacin 50 9 Le A 25 940 20% weight/weight NaOH solution 55.2 9 preparation by precipitation 60.
Norfloxacin 50 9 preparation by precipitation 20% weight/weight NaOH solution 55.2 9 Citric acid 17.9 9 Tylopur C 300 P~ 2.0 9 ~ater 907.3 9 pH = 6.7 10 61.
Norfloxacin 50 9 20% weight/weight NaOH solution 55.2 9 preparation by precipitation Citric acid 17.9 9 Tylopur C 300 P~ 5.0 9 Water 904.3 9 pH = 6.5 62.
Ofloxacin 50 9 20% weight/weight NaOH solution 55.2 9 preparation by precipitation Citric acid 17.9 9 Tylopur C 300 P~ 7.5 9 ~ater 901.8 9 pH = 6.5 63.
25 Ofloxacin 50 9 preparation by precipitation 20X ~e;ght/~e;ght NaOH solution 55.2 9 Citric acid 17.9 9 Tylopur C 300 ~ 7.5 9 ~ater 899.5 9 pH = 6.5 Le A Z5 940 - 31 -64.
Ofloxacin 50 9 20X weight/weight NaOH solution 55.2 9 preparation by precipitation 5 Citric acid 16.0 9 Tylopur C 300 P~ 2.0 9 ~ater 909.2 9 pH = 7.8 65.
Ofloxacin 50 9 20% weight/weight NaOH solution 55.2 9 preparation by precipitation Citric acid 24.7 9 Tylopur C 300 P~ 2.0 9 ~ater 900.5 9 pH = 5.3 66.
Norfloxacin 50 9 20% weight/weight NaOH solution 55.2 9 Citric acid 17.9 9 preparation by precipitation Tylopur C 300 P~ 2.0 9 Tween 20~ 2.0 9 ~ater 900.5 9 pH = 6.9 67.
Ofloxacin 5.0 9 20% weight/weight NaOH solution 9.43 9 preparation by precipitation Lipoid E 80 ~ 0.2 9 Citric acid 1.8 9 Tylopur C 300 ~ 0.2 9 ~ater 77.17 9 Le A 25 940 - 32 -68.
Pefloxacin 50.0 9 preparation by precipitation Methanesulphonic acid 16.15 9 10Z ~eight/~eight NaOH solution 10.83 ml ~ater 400.8 9 pH = 7.0 69.
Norfloxacin 50.0 9 preparation by precipitation Methanesulphonic acid 16.15 9 ~-Arginine 6.11 9 ~ater 407-33 9 70.
Norfloxacin 50.0 9 Methanesulphonic acid 16.15 9 preparation by precipitation Trimethanol (tris) 4.41 9 ~ater 408.3 9 pH = 7.0 71.
20 Micronized norfloxacin hydrate (85.5~) 5.85 9 Tylopur C 300 ~ 0.2 9 Suspension of micronized norfloxacin hydrate in the aqueous phase Anhydrous glycerol 2.5 9 ~ater to 100 ml 72.
Micronized ofloxacin hydrate (85.5Z) 5.85 9 Tylopur C 300 ~ 0.75 9 Suspension of Le A 2S 940 micronized norfloxacin hydrate in the aqueous phase 5 Anhydrous glycerol 2.5 9 ~ater to 100 ml 73.
Micronized amifloxacin hydrate (85.5~) 5.85 9 Tylopur C 300 P~ 0.75 9 Suspension of micronized norfloxacin hydrate in the aqueous phase T~een 80R 0.2 g Anhydrous glycerol 2.5 9 ~ater to 100 ml pH 6.8 74.
Micronized pefloxacin hydrate (85.5%) 5.85 9 Tylopur C 300 P~ 0.75 9 Suspension of micronized norfloxacin hydrate in the aqueous phase Lipoid E 80~ 0.2 9 Anhydrous glycerol 2.5 9 ~ater to 100 ml pH 6.8 Le A 25 940 _ 34 _ 75.
Micronized enrofloxacin hydrate (85.5%) 5.85 9 Tylopur C 300 ~ 0.2 9 Suspension of micronized enrofloxacin hydrate in the aqueous phase T~een 8 ~ 0.2 9 10 Anhydrous glycerol 2.5 9 ~ater to 100 ml pH 6.8 76.
Microni2ed enrofloxacin hydrate (85.5%) 5.85 9 Tylopur C 300 ~ 0.2 9 Suspension of micronized enrofloxacin hydrate in the aqueous phase Lipoid 80~ 0.2 9 Anhydrous glycerol 2.5 9 ~ater to 100 ml pH 6.8 77.
Enrofloxacin hydrate (85.5X) 5.85 9 Suspension of micronized enrofloxacin hydrate in the aqueous phase Tylopur C 300 ~ 0.2 9 Lipoid E 80~ 0.2 9 ~ater 90.0 ml pH 7 Le A 25 940 35 78.
Enrofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized enrofloxacin hydrate in the aqueous phase Tylopur C 300 P~ 0.2 9 Citrate buffer solution pH 7 90.0 9 Lipoid E 8 ~ 0.2 9 pH 7 79.
Enrofloxacin hydrate (85.5%) 5.85 9 Suspension of micronized enrofloxacin hydrate in the aqueous phase Tylopur C 300 ~ 0.2 9 Phosphate buffer solution pH 7 90.0 9 Lipoid E 80~ 0.2 ml pH 7 80.
Active compound A 5.0 9 20% ~eight/~eight NaOH solution 2.27 9 preparation by precipitation 85Z H3PO solution 1.07 9 Tylopur C 300 ~ 0.2 9 ~ater 93.14 9 81.
Active compound B 50.0 9 20Z ~eight/weight NaOH solution 55.5 9 pH 7 osmolality:
285 m osmol/kg 30 Citric acid fine grit 17.9 9 ~ater 903.6 9 Particle size ~10 ym Le A 25 940 Precipitation under aseptic conditions via a reaction jet 60/40 bar and high pressure homogenization under 400 bar.

82.
Active compound C 100.0 9 20% weight/weight NaOH solution 62.0 9 Citric acid fine grit 19.8 9 ~ater 869.2 9 Particle size 2-5 lm (90% under 10 ~m) Precipitation under aseptic conditions via a reaction jet 60/40 bar and high pressure homogenization under 400 bar.

83.
Active co0pound A 100.0 9 20% weight/weight NaOH solution 62.0 9 Citric acid fine grit19.8 9 Tween 80@ 0.1 9 ~ater 869.2 9 pH 7.0 84.
Active compound B 100.0 9 20% weight/weight NaOH solution 62.0 9 Citric acid fine grit19.8 9 Tween 8 ~ 1.0 9 ~ater 868.2 9 pH 7.0 85.
Active compound B 100.0 9 20X we;ght/weight NaOH solution 62.0 9 Citric acid fine grit 19.8 9 Tween 80~ 2.0 9 ~ater 867.1 9 pH 7.0 Le A 25 940 37 _ 86.
Active compound A 100.0 9 20% ~eight/~eight NaOH solution 62.0 9 Citric acid fine grit 19.8 9 Tween 80~ 2.0 9 Water 867.1 9 pH 7.0 87.
Active compound B 40.0 9 preparation by precipitation 20% ~eight/~eight NaOH solution 24.8 9 Citric acid fine grit 7.92 9 Lipoid E 7 ~ 4,0 9 Water 343.6 9 pH 7.0 88.
Active compound El 200.0 9 preparation by precipitation 20% ~eight/~eight NaOH solution 62.8 9 Citric acid fine grit 41.88 9 Water 738.27 9 pH 7.05 20 89.
Active compound C 20.0 9 preparation by precipitation 20% ~eight/~eight NaOH solution 12.4 9 15X ~eight/~eight H3PO solution 21.38 ml Water to 100 ml pH 7.05 90.
Active compound B 15.0 9 preparation by precipitation 20X weight/weight NaOH solution 12.4 9 15X ~eight/~eight H3PO solution 16.05 ml Water to 100 ml Le A 25 940 - 38 -91.
Active compound A 20.0 9 20% weight/~eight NaOH solution 11.25 9 preparation by precipitation 5 20X weight/~eight lactic acid solution 3.72 9 15% ~eight/weight H3PO4 solution 21.5 ml ~ater to 100 ml pH 7.0 10 92.
Active compound B 20.0 9 20% weight/weight NaOH solution 10.0 9 preparation by precipitation 20% weight/weight lactic acid 15 solution 7.44 9 15Z weight/weight H3PO4 solution 12.0 ml ~ater to 100 ml pH 7.0 93.
20 Active compound B 20.0 9 20X weight/weight NaOH solution 8.75 9 preparation by precipitation 20% weight/~eight lactic acid solution 11.16 9 25 15X veight/~eight H3PO4 solution 6.7 ml ~ater to 100 ml pH 7.0 94.
Active compound C 20.0 9 20% ~eight/veight NaOH solution 12.4 9 preparation by precipitation 20X weight/weight lactic acid solution 21.1 ml Tylopur C 300 P~ 0.05 9 Le A 25 940 ~ater to 100 ml pH 7.0 Active compound C 20.0 9 20% weight/weight NaOH solution 12.4 9 preparation by S precipitation 15X ~eight/~eight H3P04 solution 21.1 ml HPC O.OS g ~ater to 100 ml pH 7.0 10 96.
Active compound B 20 9 20% ~eight/~eight NaOH solution 12.4 9 preparation by precipitation 15% weight/weight H3P04 15 solution 21.1 ml T~een 80~ 0.05 9 ~ater to 100 ml pH 7.0 Active compound C 20.0 9 20% weight/weight NaOH solution 12.4 9 preparation by precipitation 15% weight/~eight H3P04 solution 21.1 ml T~een 80~ 1.0 9 ~ater to 100 ml pH 7.0 Norfloxacin 5 9 suspension of norfloxacin in oily excipient Ofloxacin 10 9 Le A 25 940 1 33682~

Ethyl oleate 50 9 100.
Norfloxacin 30 9 Ethyl oleate 50 9 101.
Norfloxacin 25 9 Ethyl oleate 50 9 102.
Ofloxacin 5 9 Miglyol 812~ 50 9 103.
Pefloxacin 10 9 Miglyol 812~ 50 9 104.
15 Active compound A 15 9 Miglyol 812~ 50 9 105.
Active compound 5 9 Peanut oil 50 9 106.
Active compound B 5 9 Ethyl oleate/phospholipon 10 ~ = 99.5/0.5 50 9 107.
25 Active compound C 30 9 Ethyl oleate/phospholipon 10 ~ = 99.5/0.5 50 9 Le A 25 940 108.
Active compound B 10 9 Miglyol 81 ~/phospholipon 10 ~ = 99.5/0.5 50 9 5 109.
Active compound A 15 9 Miglyol 812~/Phospholipon 100R = 99.5/0.5 50 9 110.
10 Active compound C 30 9 Ethyl oleate 50 9 1 1 1 .
Active compound A 10 9 Miglyol 812~ 50 9 112.
Active compound B 2.5 9 Peanut oil 50 9 113.
Active compound B 30 9 15 Ethyl oleate 50 9 Ascorbyl palmitate 0.1 9 Lecithin (Phospholipon 10 ~ 0.5 9 114.
Active compo~d C 25 9 Miglyol 812 ~ 50 9 Ascorbyl palmitate 0.1 9 Lecithin (Phospholipon 10 ~ 0.5 9 Le A 25 940 - 42 -115.
Active compound B 30 9 Ethyl oleate 50 9 Ascorbyl palmitate 0.1 9 5 Lecithin (Phospholipon 10 ~) 0.5 9 eenzyl alcohol 3 9 116.
Active compound C 25 9 Miglyol 812 ~ 50 9 10 r~enzyl alcohol 3 9 Lecithin (Phospholipon 10 ~) 0.5 9 Ascorbyl palmitate 0.1 9 117.
Ciprofloxacin hydrochloride5.8 9 15 Benzyl alcohol 2.0 9 Soy bean lecithin purified0.5 9 Medium chain triglycerides DAB9 ad 100.0 ml 118.
Ciprofloxacin hydrochloride 11.6 9 Benzyl alcohol 2.0 9 Egg lecithin purified 0.5 9 Medium chain triglycerides DAB9 ad 100.0 ml 119 .
Ciprofloxacin hydrochloride11 . 6 9 25 Benzyl alcohol 2.0 9 Soy bean lecithin purified5.0 9 Miglyol 812 ~ ad 100.0 ml 120.
Ciprofloxacin hydrochloride11. 6 9 30 Ethanol absolute 5.0 9 Egg lecithin purified 5.0 9 Medium chain triglycerides DAB9 ad 100.0 ml Le A 25 940 - 43 -121.
Ciprofloxacin hydrochloride 11.6 9 Ethanol absolute 5.0 9 Soy bean lecithin purified 5.0 9 Lactic acid concentrated 0.05 -1.0 9 Miglyol 812 ~3 ad 100 ml 122.
Ciprofloxacin lactate 12.7 9 Benzyl alcohol 2.0 9 10 Soy bean lecithin purified5.0 9 Medium chain triglyceridesad 100.0 ml 123.
Ciprofloxacin mesilate13.42 9 Ethanol 10.0 9 15 Egg lecithin purified 10.0 9 Ethyl oleate ad 100.0 ml 124.
Ciprofloxacin lactate 12.7 9 Ethanol 5.0 9 20 Soy bean lecithin purified5.0 9 Lactic acid concentrate0.05 - 1.0 9 Miglyol 812 ~ ad100.0 ml 125.
Ciprofloxacin hydrochloride 11.6 9 25 Ethanol 10.0 9 Soy bean lecithin purified 5.0 9 Methane sulphonic acid0.05 - 1.0 9 Miglyol 812 ~ ad100.0 ml 126.
30 Ciprofloxacin hydrochloride 11.6 9 Ethanol 5.0 9 Soy bean lecithin purified 5.0 9 Citric acid anhydrous micronized 0.05 - 2.0 9 Miglyol 812 ~ ad 100.0 ml Le A 25 940 44 It will be appreciated that the instant specification and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.

Le A 25 940

Claims

1. An intramuscular injection formulation of a gyrase inhibitor carprising about 0. 05 to 70% by weight of a gyrase inhibitor of the formula (I) in which R1 stands for methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-di-fluorophenyl, R2 stands for hydrogen, alkyl having 1 to 4 carbon atoms or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, R3 stands for methyl or a cyclic amino group of the formula , , , , , , , , , or wherein R4 stands for hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl,

2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFCL2-S-, CFCL2-SO2-, CH3O-CO-S-, benzyl, 4-aminobenzyl or , R5 stands for hydrogen or methyl, R6 stands for hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyloxymethyl, R7 stands for hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl or hydroxymethyl and R8 stands for hydrogen, methyl, ethyl or chlorine, X stands for fluorine, chlorine or nitro and A stands for N or C-R6, wherein R6 stands for hydrogen, halogen, methyl or nitro or, together with R1, forms a bridge having the structure , or , or a salt thereof with an acid or base or as a pro-drug, in aqueous or oily suspension.
2. An intramuscular injection formulation according to Claim 1, wherein the particle size of the gyrase inhibitor is about 0.05-150 µm.

3. An intramuscular injection formulation according to claim 1, wherein the particle size of the gyrase inhibitor is about 4 to 40 µm.

4. An aqueous intramuscular injection formulation according to claim 1, wherein the osmolality is about 200 to 900 µm osmol/kg.

5. An aqueous intramuscular injection formulation according to claim 1, wherein the osmolality is about 260 to 390 µm osmol/kg.

6. An intramuscular injection formulation according to claim 1, containing about 2.5 to 50% by weight of the gyrase inhibitor.

7. A formulation according to claim 1, 2, 3, 4, 5 or 6, wherein the gyrase inhibitor is ciprofloxacin, norfloxacin, pefloxacin, amifloxacin, pirfloxacin, ofloxacin, fleroxacin, lomefloxacin or enoxacin.

8. A process for the preparation of an intramuscular injection formulation according to claim 1, which process comprises:
(a) incorporating an active compound of the formula I in micronized form into an aqueous excipient medium; or (b) dissolving an active compound of the formula I in a base or acid or in an aqueous solution of a base or acid and precipitating the active compound therefrom by means of an acid or base; or (c) incorporating an active compound of the formula I
into an oil which is initially introduced into the vessel.

9. A process according to claim 8(b) which is carried out under a pressure of about 2 to about 100 bar.

10. A process according to claim 8(b) or 9, wherein the obtained formulation is subjected to additional homogenization.

11. A process according to claim 8(c), wherein the active compound is incorporated into the oil while gassing with nitrogen.

12. A process according to claim 8(c), wherein there is present in the oil into which the active compound is incorporated an antioxidant, stabilizer or surface active agent.

13. A process according to claim 8(c), 11 or 12, wherein the obtained formulation is subjected to additional homogenization.

14. An intramuscular injection formulation according to claim 1, comprising an oily suspension and containing the active compound in water-soluble, crystalline or amorphous form as a salt of physiologically well-tolerated acid.

15. An intramuscular injection formulation according to claim 14, wherein the salt is a hydrochloride, lactate, mesylate or p-tolyl sulphonate salt.

16. An intramuscular injection formulation according to claim 1, comprising an oily suspension and containing a well-tolerated tenside selected from the group consisting of soy bean lecithin, egg lecithin, brain lecithin or rape lecithin in a concentration of about 0.1 to 30% W/V.

17. An intramuscular injection formulation according to claim 1, comprising an oily suspension and containing a well-tolerated tenside selected from the group consisting of soy bean lecithin, egg lecithin, brain lecithin or rape lecithin in a concentration of about 0.2 to 10% W/V.

18. An intramuscular injection formulation according to claim 1, comprising an oily suspension and containing a well-tolerated tenside selected from the group consisting of soy bean lecithin, egg lecithin, brain lecithin or rape lecithin in a concentration of about 0.5 to 5% W/V.

19. An intramuscular injection formulation according to claim 14, containing 1 to 300 mmol/1 of physiologically well-tolerated acid in excess of the amount required to form the salt.

20. An intramuscular injection formulation according to claim 14, containing 5 to 50 mmol/1 of physiologically well-tolerated acid in excess of the amount required to form the salt.

21. An intramuscular injection formulation according to claim 14, containing 10 to 30 mmol/1 of physiologically well-tolerated acid in excess of the amount required to form the salt.

22. An intramuscular injection formulation according to claim 19, wherein the acid is lactic acid or citric acid.

23. An intramuscular injection formulation according to any one of claims 1 to 6 and 14 to 22, wherein the gyrase inhibitor is enrofloxacin.

24. Use of a formulation according to any one of claims 1 to 6 and 14 to 22 for intramuscular administration to a patient.

25. A commercial package containing as active pharmaceutical ingredient, a formulation as claimed in any one of claims 1 to 6 and 14 to 22, together with instructions for its use for intramuscular injection.