Soluble calcium lactate antibacterial complexes as non-irritating parenteral forms

Calcium lactate antibacterial complexes in parenteral dosage forms are provided that are relatively free from tissue irritation following injection, comprising a quinolone or naphthyridine.

FIELD OF THE INVENTION 
The present invention relates to calcium lactate antibacterial complexes of 
quinolone or naphthyridine in parenteral dosage forms that are compatible 
(i.e., free or relatively free from tissue irritation) following 
injection. 
BACKGROUND OF THE INVENTION 
The Journal of Parenteral Science and Technology, Vol. 40, No. 2, 1986, pp. 
70-72, describes a method of increasing solubility of anti-infective drugs 
enoxacin (a naphthyridine) and norfloxacin (a quinoline) by means of salt 
formation. The four salts found to be best were the aspartate, 
galacturonate, gluconate, and glutamate. 
German application 3635062 covers metal salts of 1-cyclopropylquinoline 
carboxylic acids used as antibacterials. 
European application 191,451 covers 1-cyclopropyl-5-substituted 
pyrrolidinyl-dihydro-oxonaphthyridines useful as antibacterials with good 
water solubility. 
U.S. Pat. No. 4,359,578 covers the compound enoxacin 
(1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3- 
carboxylic acid), methods of preparation, and the use thereof as an 
antibacterial agent. The patent is incorporated herein by reference. 
U.S. Pat. No. 4,795,751 covers the compound 
5-amino-1-cyclopropyl-6,8-difluoro-7-(3,5-methyl-1-piperazinyl)-1,4-dihydr 
o-4-oxoquinoline-3-carboxylic acid (Compound A) methods of preparation, and 
the use thereof as an antibacterial agent. The patent is incorporated 
herein by reference. 
U.S. Pat. No. 4,771,054 covers the compound 
7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o 
xo-3-quinoline carboxylic acid, its preparation and use as an 
antibacterial. The patent is incorporated herein by reference. 
U.S. Pat. No. 4,851,418 covers the compound 
[S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)amino]-1-pyrrolidinyl]-1-cyclopropy 
l-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 
hydrochloride, its preparation and use as an antibacterial. The patent is 
incorporated herein by reference. 
As a parenteral form, most quinolones and naphthyridines are used in the 
form of salts which provide acidic parenteral solutions. These 
formulations are associated with tissue irritation following injection, 
possibly because of the low pH of the solution. 
For parenteral administration, calcium salts are relatively nontoxic 
compared to other divalent and trivalent salts (e.g., Zn, Mg, Al). The 
latter salts can cause extreme systemic toxicity. Other di- and trivalent 
salts besides calcium may be useful for oral formulations of 
quinolones/naphthyridines. 
Concurrent administration of antacids has been implicated as a cause in the 
decrease in bioavailability of quinolones (Package Insert Cipro.RTM. 
Tablets: Miles, Inc. Pharmaceutical Division; 400 Morgan Lane; West Haven, 
Conn. 06516). 
Salts frequently contained in the antacids are calcium carbonate, magnesium 
hydroxide, and aluminum hydroxide. Interaction between quinolones, chiefly 
nalidixic acid, and metal ions have been reported. (Nakano, Masahiro; 
Yamamoto, Masakazu; and Arita, Takaichi; "Interactions of Aluminum, 
Magnesium, and Calcium Ions with Nalidixic Acid," Chem. Pharm. Bull., 26 
1505 (1978); Behrens, Barba Norah; and Diaz Guillermo Mendoza; "Metal 
Complexes of the Antibiotic Nalidixic Acid", Inorganica Chimica Acta, 125 
21 (1986); and Vincent, W. R.; Schulman, S. G.; Midgley, J. M., van Oort, 
W. J.; and Sorel, R. H. A.; "Prototropic and Metal Complexation Equilibria 
of Nalidixic Acid in the Physiological pH Region" International Journal of 
Pharmaceutics, 9 191 (1981). 
Japanese Application 63-188626 discloses aluminum, zinc, and magnesium 
compounds for solubilizing amphoteric pyridine carboxylic acids or their 
salts. These metals have been reported to be toxic, especially when 
administered parenterally. The reference mentions the addition of sodium, 
potassium, and calcium chloride to pyridine carboxylic acids. It does not 
disclose the preparation of sodium, calcium and potassium salts of 
pyridine carboxylic acid.

SUMMARY AND DETAILED DESCRIPTION 
In one aspect, the invention concerns a soluble calcium lactate 
antibacterial complex in parenteral dosage form, comprising lactic acid, 
calcium hydroxide, and an antibacterial compound. The antibacterial 
compound is selected from 1) a quinolone of formula 
##STR1## 
where A is aminomethyl, ethylaminomethyl or amino; 2) a naphthyridine of 
formula 
##STR2## 
or an optical isomer thereof, where B is 2-amino-1-oxopropylamino, 
aminoacetylamino, (2-amino-1-oxo-3-phenylpropyl)amino, 
(2,5-diamino-1,5-dioxopentyl)amino, (2-amino-4-carboxy-1-oxobutyl)amino, 
(2,6-diamino-1-oxohexyl) amino, or (aminopheylacetyl)amino; or 3) a 
naphthyridine of formula 
##STR3## 
or an optical isomer thereof, where C' is 
[(2-amino-1-oxo-3-phenylpropyl)amino]methyl, 
[(2-amino-1-oxopropyl)amino]methyl, [(aminoacetyl)amino]methyl, 
[(aminophenylacetyl)amino]methyl, 
[(2-amino-4-carboxy-1-oxobutyl)amino]methyl, 
[(2,6-diamino-1-oxohexyl)amino]methyl, or 
[(2,5-diamino-1,5-dioxopentyl)amino]methyl. 
In one preferred embodiment, the antibacterial compound is 
7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o 
xo-3quinolinecarboxylic acid. In another preferred embodiment, the 
antibacterial compound is 
[S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)amino]-1-pyrrolidinyl]-1-cyclopropy 
l-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 
The complex in a preferred embodiment is produced by dissolving an 
antibacterially effective quantity of the antibacterial compound in an 
aqueous lactic acid solution, preferably L-(+)-lactic acid solution, 
neutralizing the resulting solution with calcium hydroxide in a quantity 
that is selected so that any precipitation of the antibacterial compound 
from the solution is avoided and yet on intravenous injection, venous 
irritation by the neutralized solution is either absent or is minimized. 
The quantity of lactic acid preferably is from 1 to 3 moles and more 
preferably about 1.6 moles per mole of the carboxylic acid. The amount of 
calcium hydroxide is that amount sufficient to raise the pH of the 
injectable solution between about 4.0 to about 5.5. The resulting 
neutralized solution is then processed by sterile filtration to provide a 
sterile solution. The sterile solution is preferably lyophilized 
(freeze-dried) to provide a dry product that is stable for extended 
periods. 
For use as an intravenous infusion, a liquid product is obtained by 
reconstitution of the dry product in an intravenous infusion fluid such as 
saline (0.9% NaCl), 5% dextrose solution, Ringer's solution, lactated 
Ringer's solution, and the like. Upon reconstitution, the product 
preferably has a pH in the range from about 4 to about 5.5, more 
preferably about 4.8. 
A formula for preparation of a dry product suitable for reconstitution in 
an infusion fluid is the following: 
______________________________________ 
Ingredients Amount 
______________________________________ 
1. Antibacterial 30.0 g* 
2. L-(+)-lactic acid 12.0 g 
3. Calcium hydroxide, USP 
1.9 g 
4. Water for injection, USP 
1000 ml 
5. Nitrogen gas high purity 
q.s. 
______________________________________ 
*Amount used should be corrected to 100% based on purity and moisture. 
Procedure: Dissolve 2 in approximately 900 ml of 4 in a suitable container 
and mix well. Add 1 with mixing until all the drug particles are 
dissolved. Add 3 with mixing. Check pH (ca. 4.6-4.9); adjust pH with 
calcium hydroxide or lactic acid if necessary. Sterilize the solution by 
filtering through a previously sterilized 0.22 .mu.m membrane or 
equivalent (Millipore 293 mm assembly or Millipack 100) using 5 for 
positive pressure. Discard 100 ml of solution to flush the system. 
Aseptically fill 10.05-10.1 ml of the solution into previously sterilized 
and depyrogenated vials. Stopper loosely with slotted closures and 
lyophilize. Stopper and cap the lyophilized vials. 
The above product was prepared in 20 c.c. Type I, amber tubing vials with 
20 mm neck. When reconstituted with 10 ml of sterile water for injection, 
the resultant solution contains 30 mg/ml of free base equivalent. The 
solution typically is greenish yellow with a pH of 4.8. The product 
prepared as above by aseptic filtration followed by lyophilization 
provides a suitable dissolution rate for reconstitution. The product can 
be redissolved in 0.9% NaCl, 5% Dextrose solution, Ringer's solution and 
lactated Ringer's solution for use in the hospital.