AU613238B2

AU613238B2 - Ph-neutral aqueous solutions of quinolone-carboxylic acids

Info

Publication number: AU613238B2
Application number: AU41395/89A
Authority: AU
Inventors: Arundev Haribhai Naik; Herbert Voege
Original assignee: Bayer AG
Current assignee: Bayer Animal Health GmbH
Priority date: 1988-09-16
Filing date: 1989-09-14
Publication date: 1991-07-25
Anticipated expiration: 2009-09-14
Also published as: AU4139589A; CA1340487C; EP0359076B1; DE58906552D1; EP0359076A3; DE3831514A1; ZA897044B; EP0359076A2; JPH02121971A; JP2728516B2

Description

Our Ref: 288076 61323

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: o oo 00 0 000 0 00 00 00 0 oo0 0 0 0 0 0 00 oo 0 0000 0 0000 0 0 S o0 o 0 O 0 00 0 a o 000 O a Priority: Related Art: Applicant(s): Address for Service: BAYER AKTIENGESELLSCHAFT D-5090 Leverkusen, Bayerwerk, Germany ARTHUR S. CAVE CO.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 Complete specification for the invention entitled 00 00 0 C e ea a a "PH-Neutral aqueous solutions of quinolone-carboxylic acids".

The following statement is a full description of best method of performing it known to me:this invention, including the 1 The present invention relates to pH-neutral aqueous solutions of quinolonecarboxylic acids, their preparation and their use as bactericides.

Eggs for hatching are treated with bactericides in order to prevent losses by bacterial infections. For this purpose, the solution of a bactericide is injected into the eggs, for example by means of a syringe. The method has the advantage that each egg receives a defined amount of active compound. However, the method is labourintensive.

0 6

U

°o It is simpler to treat the eggs by dipping. In order to facilitate penetration of the active compound through the o protective layer of the eggs, the eggs are either initially warmed (the air bubble in the egg expands) and then dipped into a cold active compound solution, or the eggs are dipped into an active compound solution, and the oo latter, together with the eggs, are placed in a vacuum.

0 In both methods, a small amount of active compound 0 solution is sucked through the egg shell. However, the S, 20 amount of active substance which is taken up varies widely, depending on the constitution of the shell.

oo oSuch treatments of eggs for hatching with bactericides S o and antibiotics, such as, for example, gentamycin, S°tetracyclin and chloramphenicol were already known. The effect of these active compounds, in particular against resistant strains of bacteria and against mycoplasma, were not fully satisfactory in practice. Therefore, it was desirable to treat eggs for hatching with active compounds of the type of the quinolonecarboxylic acids.

Quinolonecarboxylic acids are only sparingly soluble in Le A 26 360 la neutral water. Due to their betain character, they can be dissolved in acid or alkaline aqueous solutions by salt formation. However, such solutions are very sensitive against variations in the pH range.

Acid solutions cannot be employed for the treatment of eggs since they attack the egg shell too severely. Alkaline solutions are, in principle, suitable for the treatment of eggs, but have the disadvantage that they dissolve small amounts of magnesium and calcium ions out of the egg shell (no damage to the egg). Due to the very poor solubility of the magnesium salt of the quinoloneo oo carboxylic acids, a precipitate is formed in the treat- 000 0 c.o ment solution. As more eggs are treated, more of the 0 0 0 active compound is depleted. It is then necessary to So 1 5 replace not only the solution which has been used up, 0 0o but also to add the active compound which has fallen out o of solution in order to maintain the concentration of the dissolved active compound in the treatment solution (replenishment).

o 20 Similar problems can occur wherever aqueous 00 0 0 o solutions of quinolonecarboxylic acids are employed. It 0 0 was therefore desirable that pH-neutral, stable aqueous 1 solutions of quinolonecarboxylic acids are available in which the active compound does not precipitate in the form of sparingly-soluble salts.

S The invention relates to pH-neutral aqueous solutions of quinolonecarboxylic acids, which are obtained when quinolonecarboxylic acids are treated with water-soluble calcium salts in at least an equimolar ratio, and the pH of the solution is subsequently adjusted to a value of between 6.5 and The invention furthermore relates to a process for the Le A 26 360

L

I~W~Bslra~&~ cc~as~~~nnrraaas~ ~a~ preparation of pH-neutral aqueous solutions of quinolonecarboxylic acids, which is characterized in that quinolonecarboxylic acids are reacted in water with water-soluble calcium salts in at least an equimolar ratio, and the pH or he solution is subsequently adjusted to a value of between 6.5 and The invention furthermore relates to the use of the prepared solutions, for example for the treatment of eggs, as drinking water formulations, infusions, and in all those cases where ph-neutral aqueous solutions of quinolonecarboxylic acids are required.

0 0 o It was surprising that stable, pH-neutral o..o aqueous solutions of quinolonecarboxylic acids could be prepared in this manner. The magnesium salts of quinolonecarboxylic acids are very sparingly soluble in water.

Quinolonecarboxylic acids also form sparingly soluble salts with stoichiometric amounts of calcium salt. It is only with equimolar amounts of o0 0 calcium salt and quinolonecarboxylic acid that a stable S 0 8 0 o0 aqueous solution is obtained.

Suitable quinolonecarboxylic acids are the quinolonecarboxylic acids of the general formula I 0 R1

COOH

a«00K0 2 j I 3 4 in which

R

1 represents halogen, C 1 4-alkyl, C 2 .4-alkenyl,

R

2 and R 3 represent hydrogen, C 1 4-alkyl, or together with the adjacent nitrogen atom form an optionally substituted morpholine or piperazine ring.

Le A 26 360 3

L:

R

4

X

R

4 and R 5 Substituents which may be mentioned are C 1 i 4 alkyl, C 1 -4-hydroxyalkyl.

represents C 1 4 -alkyl or C 3 6 -cycloalkyl, which are optionally substituted.

represents or -CR represents hydrogen, halogen, OH or C 1 4 -alkyl, together with the C and N atoms positioned between them, can form a saturated 5- or 6-ring which can contain other hetero atoms and which is optionally substituted.

0CC CC C S 15 13 00 3 CCC Compounds of the formula I which are preferably used are those in which

R

1 represents fluorine, chlorine, bromine,

R

2 and R 3 together with the adjacent nitrogen atom form a morpholine or piperazine ring, which are optionally substituted by C 1 4 -alkyl, C 1 4 hydroxyalkyl,

R

4 represents C 1 4 -alkyl or cyclopropyl, X represents or -CR

R

5 represents hydrogen, fluorine, chlorine or bromine,

R

4 and R 5 together with the atoms positioned between them, can therefore form a saturated 6-ring which optionally contains 0 as further hetero atom and which is optionally substituted by

C

1 -4-alkyl.

0 3 33 n a Compounds ably used

R

1

R

2 and R 3 of the formula I which are particularly preferare those in which represents fluorine, together with the adjacent nitrogen atom form a piperazine ring which is optionally substituted by C 1 4 -alkyl, C 1 -4-hydroxyalkyl, represents ethyl or cyclopropyl, represents N= or m- c- Le A 26 360 ICa R represents hydrogen or fluorine,

R

4 and R 5 together with the atoms positioned between them, can therefore form a saturated 6-ring which is optionally substituted by inethyl or ethyl.

The following may be mentioned in particular: l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(1-piperazinyl-)quinoline-3-carboxylic acid (cyprofloxacin), l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(4-ethyl-lpiperazinyl-)quinoline-3-carboxylic acid (enrofloxacin), 0 o° l-Ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)- .o.oo quinoline-3-carboxylic acid, 0o o oo 0o 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)-1,8o o naphthydrine-3-carboxylic acid, .15 9-Fluoro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2,3ooo odihydro-7,4-pyrido[l,2,3-de]1,4-benzoxazine-6-carboxylic acid.

Water-soluble calcium salts which are suitable are: oooo 0oo0 calcium acetate, calcium chloride, calcium bromide, 0o 20 calcium nitrate, calcium phosphates and the hydrates thereof. Calcium chloride and the hydrates thereof may 0 be mentioned in particular.

The calcium salts can also be formed using calcium S.hydroxide or calcium oxide.

Water is used as the solvent for the preparations according to the invention. If appropriate, it is also possible to use mixtures of water with other solvents. The solvents include: alcohols, such as monohydric or polyhydric primary, secondary or tertiary alkanols, such as, for example, ethanol, butanol, benzyl alcohol, glycol, glycerol, propylene glycol, and also N-methylpyrrolidone.

Le A 26 360 XP~aarrrrrp-r~i~Ur~I=PUI CI~CI~--- The concentration of the solvents employed in the preparations according to the invention, in addition to water, is 1 to 30 preferably between 1 to 10 very particularly preferably between 1 to 3 Customary additives can be added to the preparations according to the invention. Non-toxic pharmaceutical substances, such as diluents, absorption accelerators, absorption inhibitors, substances which delay crystallization, sequestering agents, antioxidants, preservatives, protonization agents come as such. The following may be mentioned particularly preferably: preservatives, such as, for example, p-hydroxy-benzoic acid esters, benzyl alcohol or phenols, antioxidants, such as, for example, sodium meta-bisulphite or sodium sulphite, 0015 sequestering agents, such as sodium salts of ethylene- °,00 diaminetetraacetic acid, substances which delay crystal- 0000 lization, such as polyvinyl pyrrolidone.

The concentration of the auxiliaries in the preparations a according to the invention is 0.1 to 10 preferably 1 ,0 20 to 2 SThe compounds of the formula I lie in the preparations according to the invention in concentrations of 0.1 to preferably 0.5 to 10 or 0.2 to 2 or 10 to 30 Sdepending on the type of application. Solutions containing 0.5 to 10 of compound of the formula I are particularly preferred. For this purpose, the calcium salts are employed in the 1- to 5-fold equimolar amount.

Preferably in the approximately equimolar amount.

The pH of the preparations according to the invention is between 6.5 and 7.5, preferably 7.

In order to prepare the preparations according to the Le A 26 360 L invention, the compounds of the formula I can be dissolved in water, and the required amount of calcium salt as such or in the form of its aqueous solution can be incorporated in this solution. The solution obtained is subsequently neutralized with acid. In this manner, ready-for-use solutions of the active substance, packaged in suitable containers, for example in ampoules, injection bottles or infusion bottles, but also those unfinished products which are suitable for solutions, for example concentrates, can be prepared.

°n The solutions according to the invention and also the compounds of the formula on which they are based are to be used as drugs for the control of bacterial infections.

o The solutions are particularly suitable for the treatment a15 of eggs, for example against infections by bacteria or t mycoplasms.

Example 1 0o 0 10% strength composition 0 0 0 00 Enrofloxacin 10.00 g 02 20 Potassium hydroxide, 85.3 strength 1.80 g Calcium chloride, 6HzO 27.30 g IN Hydrochloric acid to pH 7.0 approx. 1.00 g 0 Benzyl alcohol 1.00 g Water to 100.00 ml Potassium hydroxide was dissolved in water, the active compound enrofloxazin was subsequently added with stirring and dissolved, and calcium chloride was then stirred in. In this process, a precipitate formed. Hydrochloric acid was added with stirring until a clear solution of pH 7 was formed. The mixture was subsequently made up to 100 ml with water.

Le A 26 360 J. i

S*

Some of this solution was diluted with 99 parts of WHO Standard Water, and no precipitates were observed over 25 days.

Example 2 10 strength enrofloxacin solution in aqueous potassium hydroxide solution of pH11 plus 1 of benzyl alcohol 50 ml strength aqueous calcium chloride x 6H20 solution 25 ml 10 strength acetic acid solution approx. 6.2 8.0 g Water to 100 ml Calcium chloride solution was added to the stirred enrofloxacin solution. The precipitate which formed was dissolved by the addition of acetic acid while stirring was continued. The pH was controlled by the addition of acetic acid. Three formulations were prepared with the pH set to 6.7; 7.0; and 7.2 respectively.

Stability of the formulations The three formulations (pH 6.7; 7.0; 7.2) had remained stable while stored for two months at 4 0 C and 50 0

C.

Stability of the dilution The formulation (pH 7.0) was diluted 1+ 49 1000 ppm) in demineralized water, 20, 40, 60, 80 and 100 ppm of Mg were added, and the mixture was observed over 26 days without precipitates being noticed.

Le A 26 360 8 L bL

Claims

1. Ph-neutral aqueous solutions of quinolonecarboxylic acids of the general formula I 0 O R 1 C OOH 2 R 3 R R 4 in which R 1 represents halogen, C 1 4 -alkyl, C 2 4 -alkenyl, R 2 and R 3 represent hydrogen, CI. 4 -alkyl, or together with the adjacent nitrogen atom form an optionally o0i o substituted morpholine or piperazine ring. o 0 Substituents which may be mentioned are Ci- 4 .ol0 alkyl, C,-_-hydroxyalkyl. 0ooo R 4 represents C 1 _4-alkyl or C 3 ,_-cycloalkyl, which o.o are optionally substituted. oooo X represents or -CR 5 R 5 represents hydrogen, halogen, OH or C 1 _.-alkyl, R 4 and R 5 together with the C and N atoms positioned ,c between them, can form a saturated 5- or 6-ring which can contain other hetero atoms and which is optionally substituted, characterized in that the quinolonecarboxylic acids are reacted in water with water-soluble calcium compounds in at least an equimolar ratio and the pH of the solution is subsequently adjusted to a value of between 6.5 and

2. Process for the preparation of pH-neutral aqueous solutions of quinolonecarboxylic acids of the formula I S 25 according to Claim 1, characterized in that the quino- lonecarboxylic acids are reacted in water with water- soluble calcium compounds in at least an equimolar ratio and the pH of the solution is subsequently adjusted to a value of between 6.5 and Le A 26 360 4019F:AB

3. A method for the treatment of eggs wherein eggs are treated with a solution as claimed in claim 1.

4. A method for the treatment of drinking water wherein water, for drinking, is treated with a solution as claimed in claim 1. pH-Neutral aqueous solutions according to claim 1, characterized in that they contain enrofloxacin.

6. pH-Neutral aqueous solutions according to claim characterized in that they contain 1 to 5 moles of water- soluble calcium salts per mole of enrofloxacin. DATED this 26th day of April, 1991. o 00 00 0 0000 0 o 00 0 0 0 00 0 0 0 0C0 00 0 0 0 0 0 0 0 0000 0 o o 0 000oo 0 0o 0 0o 00 BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys ARTHUR S. CAVE CO. 'O i i 1- 2 ,6. c 10