Abstract:
N,N,N-trimethyl-2-hydroxyethyl-ammonium-[1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-quinolizine-3-carboxylate] of the formula I ##STR1## as a norfloxacin antimicrobial salt capable of enteral administration.

Description:
FIELD OF THE INVENTION 
     The present invention relates to the new salts of 1-ethyl-4-oxo-6-fluoro-7-(1-piperazinyl)-1, 4-dihydro-quinoline-3-carboxylic acid (norfloxacin) formed with N,N,N-trimethyl-2-hydroxy-ethyl-ammonium hydroxide, ##STR2## to the preparation thereof and compositions containing same. Norfloxacin (Belgian Pat. No. 863,429) is the first of the nalidixic acid analogs of generation III, which has good activity in the therapy of urethral infections caused by Pseudomonas aeruginosa and gram positive and gram negative bacteria. (Antimicrobial Agents and Chemotherapy 1980, 17, 103-108). 
     BACKGROUND OF THE INVENTION 
     It is known that norfloxacin is not absorbed well by the organism due to its low watersolubility (0.20 mg/ml) (J. Antimicr. Chemother. 1984, 13, suppl. B 1 , 66); therefore the therapeutic blood level develops slowly. Going through the intestines only about 40% of the material is absorbed because of the low solubility. 
     DESCRIPTION OF THE INVENTION 
     It has been found that the solution necessary for absorption forms quickly when the N,N,N-trimethyl-2-hydroxymethylammonium hydroxide salt is formed according to the invention, thereby resulting in better absorption. The watersolubility of the new compound of the Formula I according to the invention, i.e. N,N,N-trimethyl-2-hydroxyl-ethyl-ammonium [-1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-quinoline-carboxylate] is more than 1 g/ml. The quick absorption and the good biological utilization enable reduction of the dosage needed for the therapeutic effect, and hence to a reduction of side effects. While--because of the slow and bad absorption and the quick evacuation no sustained release form for norfloxacin was previously developed, the excellent absorption of the compound according to the invention makes even this dosage form possible. 
     In case of a body weight of 70 kg. the composition according to the invention can be administered in a dose ranging from 70 mg. to 15 g., preferably from 200 mg. to 5 g., per day in divided dosages. The compound of the formula I is suitable for human therapy in the form of tablets, capsules, dragees, enterosoluble dragees, suppositories, solutions, syrups, or in a sustained release form of any of these. The pharmaceutical compositions can be prepared by methods known per se in the pharmacological industry. 
     In veterinary therapy the active ingredient of the Formula I can be applied, in addition to the forms used in human therapy, also as the free active ingredient admixed with the food of the animals in any form or as food additive. 
     The compound of the Formula I can be readily prepared by reacting 1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-quinoline-3-carboxylic acid with N,N,N-trimethyl-2-hydroxyethyl-ammonium hydroxide in an aqueous or alcoholic or aqueous-alcoholic medium. As alcohols C 1-4  straight or branched chained aliphatic alcohols, preferably methylalcohol, ethylalcohol, isopropanol can be used. The compound of the Formula I can be isolated by usual methods, e.g. optionally by evaporation at low pressure or lyophilization. Optionally the obtained compound of the Formula I can be crystallized. 
     Further details of the invention are shown in the following examples. 
    
    
     EXAMPLE 1 
     Preparation of N,N,N-trimethyl-2-hydroxyethyl-ammonium-[1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-quinoline-3-carboxylate]. 
     In a round-bottomed 1000 ml. flask 20 g. of 1-ethyl-4-oxo-6-fluoro-7-(piperazinyl)-1,4-dihydro-quinoline-3-carboxylic acid are suspended in a mixture of 150 ml. methanol and 50 ml. distilled water. From a dropping funnel 18 ml. of N,N,N-trimethyl-2-hydroxyethyl-ammonium hydroxide (choline base) dissolved in 50% methanol are added dropvise to the suspension under constant stirring at room temperature. A clear, light yellow solution is obtained. The aqueous-methanolic solution is evaporated above 40% water bath in vacuo. The yellow, adhesive solution thus obtained is suspended in 200 ml of acetone and heated to boiling, then isopropanol (36 ml.) is added dropwise under boiling until total dissolution. The solution is cooled slowly. The precipitated material is filtered under vacuo on a glass filter G-4 and washed. Wet-weight after filtration: 27.4 g. 
     The wet material is dried for 20 hours above P 2  O 5  in a vacuum desiccator. 
     Dry-weight: 24.6 
     Meltingpoint: 102°-104° C. 
     The remaining isopropanol is removed by drying for 3 hours at 70° C. in a desiccator. 
     Obtained material: 23.9 g (90.4%). 
     Melting point: 130°-132° C. 
     Analysis for the formula C 21  H 32  N 4  O 4  F: Calculated: C 59.56%, H 7.62%, N 13.23%, F 4.49%, Found: C 59.72%, H 7.54%, N 13.36%, F 4.61%. 
     
                       TABLE I______________________________________Comparison of the solubility of norfloxacin complex withguanidine carbonate 2:1 and N,N,N--trimethyl-2-hydroxyethylammonium-[1-ethyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylate]in distilled water of a temperature of 5° C.                  Solubility calculated       Solubility on NorfloxacinCompound      mg/ml   μMol/ml                          mg/ml  μMol/ml______________________________________Norfloxacin   0.20    0.63     0.20   0.63Complex of guanidin         12.5    15.3     9.8    30.6carbonateCompound of the         &gt;1000   &gt;2360    &gt;753   &gt;2360Formula I______________________________________ I = EP PS 84011 
    
     EXAMPLE 2 
     In in vitro tests with agar-diffusion technique the minimal inhibiting concentration was determined (MIC) by series diluting method against the strains in the Table. Norfloxacin was dissolved in dimethyl-sulphoxide and the norfloxacin-THA salt was dissolved in water. 
     
                       TABLE______________________________________MIC value (μg/ml)                Pseudomonas StaphylococcusCompound    E. Coli  Aeruginosa  aureus______________________________________Norfloxacin 0.25-0.5  0.5-0.75   0.25-0.5Norfloxacin-THA-       0.05-0.25                0.25-0.5    0.25salt______________________________________ 
    
     EXAMPLE 3 
     Formulating examples 
     a. Composition of the tablets with an active ingredient content of 100-400 mg. 
     
         ______________________________________(calculated on 100 tablets)Compound of the Formula I              10.0-40.0    g.Lactose            2.0          g.Saccharose         0.3          g.Amylum solani      5.2          g.Mucilago ad gran.  q.sMagn. stearat      0.1          g.Talcum             0.2          g.Amylum solani ad   60.0         g.Composition of granulating solutionGelatin alba        5.0%Amylum solani       5.0%Aqua dest. ad      100.0%______________________________________ 
    
     b. Intestinosolvent dragees: 
     The dragees of the above composition are coated with Eurdragit L by methods known per se. 
     c. Composition of tablets with prolonged effect with an active ingredient content of 400 mg. 
     
         ______________________________________ (calculated on 100 tablets)______________________________________Compound of the Formula I               40.0       g.CMC Na (Carboxy-methyl-               4.5        g.cellulose-Na)Lactose             5.0        g.Gypsum              48.5       g.Acid Stearinic      5.0        g.Aqua dest           q.sMagn. stearinic     0.7        g.Talcum              1.4        g.______________________________________ 
    
     d. Suppositories for children with an active ingredient content of 25-50 mg. 
     
         ______________________________________ (calculated on 100 suppositories)______________________________________Compound of the Formula I               2.5-5.0    g.Tagat R 1           7.5        g.Softisan 378        7.5        g.Witopsol H 32 ad    150.0      g.______________________________________ 
    
     e. Suppositories for adults with an active ingredient content of 100-400 mg. 
     
         ______________________________________ (calculated on 100 suppositories)______________________________________Compound of the Formula I               10.0-40.0   g.Tagat R 1           15.0        g.Softisan 378        15.0        g.Witopsol H 32 ad    300.0       g.______________________________________