Fluoroquinolone compositions

Abstract

The invention relates to pharmaceutical compositions comprising (i) a fluoroquinolone, (ii) a salt formed between a carboxylate anion and a divalent metal cation, (iii) a liquid comprising an organic solvent selected from the group consisting of glycerol, propylene glycol, glycerol formal, and (iv) optionally water. The invention further relates to methods of treating or preventing a condition in an animal comprising administering to the animal in need thereof a pharmaceutical composition of the invention.

1 . A pharmaceutical composition comprising: 
 (i) a fluoroquinolone;    (ii) a salt formed between a carboxylate anion and a divalent metal cation; and    (iii) a liquid comprising (a) an organic solvent selected from the group consisting of glycerol, propylene glycol, glycerol formal, and mixtures thereof.    
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein the fluoroquinolone is selected from the group consisting of ciprofloxacin, enrofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, difloxacin, cinofloxacin, pefloxacin, tosufloxacin, temafloxacin, fleroxacin, amifloxacin, binfloxacin, danofloxacin, marbofloxacin, ruflocaxin, and sarafloxacin.  
   
   
       3 . The pharmaceutical composition of  claim 1 , wherein the divalent metal cation is selected from the group consisting of Be +2 , Mg +2 , Ca +2 , Sr +2 , Ba +2 , Ra +2 , Cu +2 , Fe +2 , and Zn +2 .  
   
   
       4 . The pharmaceutical composition of  claim 3 , wherein the divalent metal cation is Zn +2  or Mg +2 .  
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein the carboxylate anion is a C 1  to C 6  saturated or unsaturated, straight chain or branched alkyl group optionally substituted with —N(R 1 ) 2 , SR 1 , —COOR 2 , —Cl, —Br, —I, —F, —OR 1 , wherein each R 1  is independently a H or a C 1  to C 6  saturated or unsaturated, straight chain or branched alkyl group and each R 2  is a C 1  to C 6  saturated or unsaturated, straight chain or branched alkyl group.  
   
   
       6 . The pharmaceutical composition of  claim 1 , wherein the salt formed between a carboxylate anion and a divalent metal cation is zinc acetate.  
   
   
       7 . The pharmaceutical composition of  claim 1 , wherein the salt formed between a carboxylate anion and a divalent metal cation is magnesium acetate.  
   
   
       8 . The pharmaceutical composition of  claim 1 , wherein the liquid comprises glycerol.  
   
   
       9 . The pharmaceutical composition of  claim 1 , wherein the liquid comprises propylene glycol.  
   
   
       10 . The pharmaceutical composition of  claim 1 , wherein the liquid comprises glycerol formal.  
   
   
       11 . The pharmaceutical composition of  claim 1 , wherein the liquid further comprises water.  
   
   
       12 . The pharmaceutical composition of  claim 1 , wherein the water is present in an amount of up to about 75 percent by volume of the liquid.  
   
   
       13 . The pharmaceutical composition of  claim 1 , wherein the liquid comprises glycerol, propylene glycol, glycerol formal, or a mixture thereof in an amount ranging from about 25 percent to 100 percent by volume of the liquid and water in an amount ranging from about 75 percent to 0 percent by volume of the liquid.  
   
   
       14 . The pharmaceutical composition of  claim 1 , wherein the liquid comprises glycerol, propylene glycol, glycerol formal, or a mixture thereof in an amount ranging from about 50 percent to 90 percent by volume of the liquid and water in an amount ranging from about 50 percent to 10 percent by volume of the liquid.  
   
   
       15 . The pharmaceutical composition of  claim 1 , wherein the fluoroquinolone is present in an amount ranging from about 2 percent to 20 percent by weight of the pharmaceutical composition.  
   
   
       16 . The pharmaceutical composition of  claim 15 , wherein the fluoroquinolone is present in an amount ranging from about 10 percent to 20 percent by weight of the pharmaceutical composition.  
   
   
       17 . The pharmaceutical composition of  claim 1 , wherein the ratio of the fluoroquinolone to the salt formed between a carboxylate anion and a divalent metal cation ranges from about 3 to 0.5.  
   
   
       18 . The pharmaceutical composition of  claim 1 , wherein the ratio of the fluoroquinolone to the salt formed between a carboxylate anion and a divalent metal cation ranges from about 2.5 to 0.8.  
   
   
       19 . The pharmaceutical composition of  claim 11 , wherein the salt formed between a carboxylate anion and a divalent metal cation is zinc acetate, the liquid comprises glycerol in an amount of about 75 percent by volume of the liquid and water in an amount of about 25 percent water by volume of the liquid, and the ratio of fluoroquinolone to zinc acetate is about 2 to 1.  
   
   
       20 . The pharmaceutical composition of  claim 19 , wherein the fluoroquinolone is selected from the group consisting of enrofloxacin, ciprofloxacin, and marbofloxacin.  
   
   
       21 . The pharmaceutical composition of  claim 11 , wherein the salt formed between a carboxylate anion and a divalent metal cation is magnesium acetate, the liquid comprises glycerol in an amount of about 75 percent by volume of the liquid and water in an amount of about 25 percent water by volume of the liquid, and the ratio of fluoroquinolone to magnesium acetate is about 2 to 1.  
   
   
       22 . The pharmaceutical composition of  claim 21 , wherein the fluoroquinolone is selected from the group consisting of enrofloxacin, ciprofloxacin, and marbofloxacin.  
   
   
       23 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is a solution.  
   
   
       24 . The pharmaceutical composition of  claim 1 , wherein the composition is injectable.  
   
   
       25 . The pharmaceutical composition of  claim 11 , wherein the pharmaceutical composition is a solution.  
   
   
       26 . The pharmaceutical composition of  claim 11 , wherein the composition is injectable.  
   
   
       27 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is prepared by adding the fluoroquinolone and the salt formed between a carboxylate anion and a divalent metal cation to glycerol, propylene glycol, glycerol formal, or a mixture thereof.  
   
   
       28 . The pharmaceutical composition of  claim 11 , wherein the pharmaceutical composition is prepared by adding the fluoroquinolone and the salt formed between a carboxylate anion and a divalent metal cation to glycerol, propylene glycol, glycerol formal, water, or any combination thereof.  
   
   
       29 . The pharmaceutical composition of  claim 1 , further comprising a cyclodextrin.  
   
   
       30 . A pharmaceutical composition comprising a complex of formula:  
       M +2 (GLY)(FQ), M +2 (PG)(FQ − ), or M +2  (GF)(FQ),  
     wherein: 
 FQ is a fluoroquinolone or an anion of a fluoroquinolone,  
 M +2  is a divalent metal cation,  
 GLY is glycerol or an anion of glycerol,  
 PG is propylene glycol or an anion of propylene glycol; and  
 GF is glycerol formal or an anion of glycerol formal.  
 
   
   
       31 . The pharmaceutical composition of  claim 30 , wherein the complex can be detected by mass spectral analysis.  
   
   
       32 . The pharmaceutical composition of  claim 30 , further comprising a cyclodextrin.  
   
   
       33 . A pharmaceutical composition comprising: 
 (i) a fluoroquinolone;    (ii) a salt formed between a carboxylate anion and a divalent metal cation; and    (iii) a liquid comprising an organic solvent and water,    wherein the pharmaceutical composition is a solution of the fluoroquinolone in the liquid and the concentration of the fluoroquinolone in the solution is higher than can be obtained in the absence of the organic solvent.    
   
   
       34 . The pharmaceutical composition of  claim 33 , wherein the organic solvent is selected from the group consisting of glycerol, propylene glycol, glycerol formal, and mixtures thereof.  
   
   
       35 . The pharmaceutical composition of  claim 33 , further comprising a cyclodextrin.  
   
   
       36 . A method of treating or preventing a condition in an animal comprising orally administering to the animal in need thereof, the pharmaceutical composition of  claim 1 .  
   
   
       37 . The method of  claim 36 , wherein the condition is a bacterial infection.  
   
   
       38 . The method of  claim 37 , wherein the bacterial infection as a bacterial infection caused by an organism selected from the group consisting of  Staphylococcus aureus, Streptococcus pneumoniae, coagulese - negative staphylococci, Streptococcus pyogenes, Staphylococcus epidermis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Haemophilus influenzae , or  Neisseria gonorrhea.    
   
   
       39 . The method of  claim 36 , wherein the condition is a respiratory tract infection, a urinary tract infection, a postoperative-wound infection, a bone or joint infection, a skin infection, an ear infection, or a sexually transmitted disease.  
   
   
       40 . The method of  claim 36 , wherein the animal is selected from the group consisting of a canine, a feline, an equine, a bovine, an ovine, or a porcine.  
   
   
       41 . The method of  claim 40 , wherein the animal is a cat.  
   
   
       42 . The method of  claim 40 , wherein the animal is a dog.  
   
   
       43 . The method of  claim 36 , wherein the composition is administered in an amount to provide a dose of the fluoroquinolone that ranges from about 0.1 mg/kg of body weight to 50 mg/kg of body weight.  
   
   
       44 . The method of  claim 43 , wherein the pharmaceutical composition is administered daily or twice daily until 2-3 days after cessation of the condition.  
   
   
       45 . The method of  claim 43 , wherein the pharmaceutical composition is administered for about 7 days.  
   
   
       46 . The method of  claim 43 , wherein the pharmaceutical composition is administered for about 14 days.  
   
   
       47 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition show less than a 5 percent decrease in the amount of the fluoroquinolone after being stored at 70° C., for 10 days.