Zwitterion solution for low-volume therapeutic delivery

Abstract

A formulation is provided that includes a volume of an aqueous multivalent physiological ion solution compatible with cerebrospinal fluid containing at least one divalent cation of magnesium or calcium, and at least one anion of carbonate or phosphate, and having a pH between 6.5 and 8.0. A zwitterionic therapeutic agent other than baclofen is dissolved the solution to achieve higher concentration or ease of solution and/or storage relative to therapeutic saline solutions of the same agent. A process of delivering a zwitterionic therapeutic agent into a subject is provided that includes dissolving a therapeutic amount of the zwitterionic therapeutic agent in a volume of artificial cerebrospinal fluid to form a stable formulation. The solution is then administered to the subject using an intrathecal pump.

1 . A formulation comprising:
 a volume of an aqueous multivalent physiological ion solution compatible with cerebrospinal fluid comprising at least one divalent cation of magnesium or calcium, and at least one anion of carbonate or phosphate, and having a pH between 6.5 and 8.0; and   a zwitterionic therapeutic agent in said aqueous solution with the proviso that said zwitterionic therapeutic agent is not baclofen.   
   
   
       2 . The formulation of  claim 1  wherein said compound is selected from the group consisting of: salicylates, fexofenadine, ofloxacin, cefepine, (4-{2-[2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethylamino]-propyl}-phenoxy)-acetic acid, 7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2,3-dihydro-1H-5-isoind-olyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate (bis-quinolone), (Z)-4-[(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy}ethyl)amino]-4-oxo-2-butenoic acid, cis,endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, cephalosporin, cefdinir, cefixime, cefpodoxime, ceftriaxone, 2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, spiro-2-aza-alkane-3-carbonitriles, heterocylic selenates of the formulae 
     
       
         
         
             
             
         
       
     
     where R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently hydrogen, C 1 -C 6  alkyl, a C 0 -C 6  alkyl having a substituent of amine or hydroxyl, and a C 0 -C 16  selenol with the proviso that one and only one of R 1 -R 6  contains a selenol moiety. 
   
   
       3 . The formulation of  claim 1  wherein said zwitterionic therapeutic agent is a polymer. 
   
   
       4 . The formulation of  claim 1  wherein said aqueous solution contains 130-160 mM NaCl, 2.7-3.9 mM KCl, 1-3 mM CaCl 2 .2H 2 O, 0.5-2.5 mM MgCl 2 .6H 2 O, 0.5-1.0 mM Na 2 HPO 4 .7H 2 O, 0.1-0.5 mM NaH 2 PO 4 .H 2 O. 
   
   
       5 . The formulation of  claim 1  wherein said aqueous solution contains 148 mM NaCl, 3 mM KCl, 1.4 mM CaCl 2 .2H 2 O, 0.8 mM MgCl 2 .6H 2 O, 0.8 mM Na 2 HPO 4 .7H 2 O, and 0.2 mM NaH 2 PO 4 .H 2 O. 
   
   
       6 . The formulation of  claim 1  wherein said aqueous solution contains 124 mM NaCl, 5 mM KCl, 1.3 mM MgCl 2 , 2 mM CaCl 2 , 26 mM NaHCO 3 , and 10 mM D-glucose. 
   
   
       7 . The formulation of  claim 1  wherein said aqueous solution is artificial cerebrospinal fluid. 
   
   
       8 . The formulation of  claim 7  further comprising an oncotic agent. 
   
   
       9 . The formulation of  claim 1  further comprising a pain regulating agent. 
   
   
       10 . The formulation of  claim 9  wherein said pain regulating agent is selected from the group consisting of: morphine, clondine, hydromorphine, hydrocodone, merperidine, celeroxib, tramadol, oxycodone, acetometaphen, ketaprofen, ibuprofen, naproxen sodium, and aspirin. 
   
   
       11 . A formulation comprising:
 a volume of an aqueous multivalent physiological ion solution compatible with cerebrospinal fluid containing 130-160 mM NaCl, 2.7-3.9 mM KCl, 1-3 mM CaCl 2 .2H 2 O, 0.5-2.5 mM MgCl 2 .6H 2 O, 0.5-1.0 mM Na 2 HPO 4 .7H 2 O, 0.1-0.5 mM NaH 2 PO 4 .H 2 O, and having a pH between 6.5 and 8.0; and   a zwitterionic therapeutic agent dissolved in said aqueous solution and selected from the group consisting of: salicylates, fexofenadine, ofloxacin, cefepine, (4-{2-[2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethylamino]-propyl}-phenoxy)-acetic acid, 7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2,3-dihydro-1H-5-isoind-olyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate (bis-quinolone), (Z)-4-[(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy}ethyl)amino]-4-oxo-2-butenoic acid, cis,endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, cephalosporin, cefdinir, cefixime, cefpodoxime, ceftriaxone, 2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, spiro-2-aza-alkane-3-carbonitriles, heterocylic selenates of the formulae   
     
       
         
         
             
             
         
       
     
     where R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently hydrogen, C 1 -C 6  alkyl, a C 0 -C 6  alkyl having a substituent of amine or hydroxyl, and a C 0 -C 16  selenol with the proviso that one and only one of R 1 -R 6  contains a selenol moiety. 
   
   
       12 . The formulation of  claim 11  wherein said aqueous solution contains 148 mM NaCl, 3 mM KCl, 1.4 mM CaCl 2 .2H 2 O, 0.8 mM MgCl 2 .6H 2 O, 0.8 mM Na 2 HPO 4 .7H 2 O, and 0.2 mM NaH 2 PO 4 .H 2 O. 
   
   
       13 . The formulation of  claim 11  wherein said aqueous solution contains 124 mM NaCl, 5 mM KCl, 1.3 mM MgCl 2 , 2 mM CaCl 2 , 26 mM NaHCO 3 , and 10 mM D-glucose. 
   
   
       14 . The formulation of  claim 11  wherein said zwitterionic therapeutic agent is a polymer. 
   
   
       15 . The formulation of  claim 11  further comprising an oncotic agent. 
   
   
       16 . The formulation of  claim 11  further comprising a pain regulating agent. 
   
   
       17 . A process of delivering a zwitterionic therapeutic agent into a subject comprising:
 dissolving a zwitterionic therapeutic agent in a volume of artificial cerebrospinal fluid to form a stable formulation; and   administering the formulation into the subject using an intrathecal pump.   
   
   
       18 . The process of  claim 17  wherein said compound is selected from the group consisting of: salicylates, fexofenadine, ofloxacin, cefepine, (4-{2-[2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethylamino]-propyl}-phenoxy)-acetic acid, 7-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2,3-dihydro-1H-5-isoind-olyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate (bis-quinolone), (Z)-4-[(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy}ethyl)amino]-4-oxo-2-butenoic acid, cis,endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, cephalosporin, cefdinir, cefixime, cefpodoxime, ceftriaxone, 2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, spiro-2-aza-alkane-3-carbonitriles, heterocylic selenates of the formulae 
     
       
         
         
             
             
         
       
     
     where R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently hydrogen, C 1 -C 6  alkyl, a C 0 -C 6  alkyl having a substituent of amine or hydroxyl, and a C 0 -C 16  selenol with the proviso that one and only one of R 1 -R 6  contains a selenol moiety. 
   
   
       19 . The process of  claim 17  further comprising a pain regulating agent. 
   
   
       20 . A medical package comprising a formulation according to  claim 1  as active ingredient together with instructions for the use thereof as a therapeutic treatment.