Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration

Abstract

The present invention relates in general to the field of modulators of the innate immune system, particularly to pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof, preferably suitable for local administration, such as, intravesical administration. In addition, the present invention concerns the use of imidazoquinolin(amines) and derivatives thereof for intravesical treatment of bladder diseases, such as, for example, bladder cancer and cystitis. The present invention furthermore comprises methods of treatment for these diseases as well as methods of administration of the inventive pharmaceutical compositions.

1 .- 43 . (canceled) 
     
     
         44 . A method, comprising:
 obtaining a pharmaceutical composition comprising imidazoquinolin(amine) and lactic acid,   wherein the imidazoquinolin(amine) in the pharmaceutical composition is selected from a compound defined by one of the following groups (a), (b) and (c):   a) 1H-imidazo[4,5-c]quinolin-4-amine;   b) an imidazoquinolin(amine) compound selected from following formula (I):   
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , and R 3  are each independently selected from hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; fluoro or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkyl group does not have a fully carbon substituted carbon atom bonded directly to the nitrogen atom; benzyl; (phenyl)ethyl; and phenyl; the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, wherein the benzene ring is substituted by two of the moieties, then the moieties together contain no more than six carbon atoms; 
         —CHR x R y , wherein R y  is hydrogen or a carbon-carbon bond, wherein when the R y  is hydrogen R x  is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and wherein when the R y  is a carbon-carbon bond R y  and R x  together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy or hydroxyalkyl of one to four carbon atoms; 
         straight chain or branched chain alkyl containing one to eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to six carbon atoms, morpholinomethyl, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, or halogen; 
         —C(R S )(R T )(X) wherein R S  and R T  are independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; 
         X is alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms, or morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; 
         R 4  is hydrogen, C 1-8  alkyl, C 1-8  alkoxy, or halo; 
         n is 1, 2, 3, or 4; 
         R a  and R b  are each independently hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 ) alkyl, amino(C 1 -C 6 )alkyl, aminosulfonyl, (C 1 -C 6 )alkanoyl, aryl, or benzyl, all of them being optionally substituted by one or more amino groups; or 
         R a  and R b  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino group; the dashed lines in the five membered ring of formula (I) 
         above denote an optional bond that connects a nitrogen of the five membered ring to the carbon that is between the two nitrogens of the five membered ring, and when the bond is present, either R 1  or R 3  is absent; provided, that R a  and R b  together allow formation of a quaternary ammonium ion either at the nitrogen of the central structural element N(R a )(R b ) or by any quaternary ammonium ion being provided by R a  and/or R b ; 
         or a pharmaceutically acceptable salt thereof; and 
         c) imiquimod, having the specific formula 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, selected from following formula (X): 
       
       
         
           
           
               
               
           
         
         administering a sufficient amount of the pharmaceutical composition by bladder instillation to a patient in need thereof for a sufficient period of time so as to treat the patient in need thereof, wherein the patient in need thereof has a bladder disease. 
       
     
     
         45 . The method of  claim 44 , wherein the pharmaceutical composition further comprises at least one thermo-sensitive agent selected from chitosan, or a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) copolymer (also termed PEO-PPO-PEO or poloxamer). 
     
     
         46 . The method of  claim 44 , wherein the pharmaceutical composition comprises lactic acid in a concentration of 0.025 M to 0.200 M. 
     
     
         47 . The method of  claim 44 , wherein the pharmaceutical composition comprises imidazoquinolin(amine) in an amount of 0.005% (w/v) to 5% (w/v). 
     
     
         48 . The method of  claim 45 ,
 i) wherein the pharmaceutical composition further comprises one or more cyclodextrin(s), selected from α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, δ-cyclodextrins and ε-cyclodextrins in an amount of 0.1% (w/v) to 30% (w/v), and/or   ii) wherein the at least one thermo-sensitive agent is selected from chitosan or a poly(ethylene oxide)-poly(propylene oxide)-poly (ethylene oxide) copolymer (also termed PEO-PPO-PEO or poloxamer) and exhibits a specific “lower critical solution temperature” (LCST) measured at ambient pressure in a range of 15° C. to 35° C.   
     
     
         49 . The method of  claim 45 , wherein the at least one thermo-sensitive agent is in an amount of 0.1% (w/v) to 40% (w/v). 
     
     
         50 . The method of  claim 45 , wherein the pharmaceutical composition comprises a first thermo-sensitive agent and a second thermo-sensitive agent. 
     
     
         51 . The method of  claim 50 , wherein the first thermo-sensitive agent and the second thermo-sensitive agent are contained in the pharmaceutical composition as a mixture in a ratio of 1:20 to 20:1. 
     
     
         52 . The method of  claim 45 , wherein the at least one thermo-sensitive agent is Poloxamer 407 and/or Poloxamer 188 or a mixture of Poloxamer 407 and Poloxamer 188. 
     
     
         53 . The method of  claim 52 ,
 i) wherein the at least one thermo-sensitive agent is Poloxamer 407 in an amount of 10% (w/v) to 25% (w/v), or   ii) wherein the at least one thermo-sensitive agent is a mixture of Poloxamer 407 and Poloxamer 188 in an (overall) amount of 22.5% (w/v)/(w/w) to 27.5% (w/v)/(w/w).   
     
     
         54 . The method of  claim 44 , wherein the pharmaceutical composition comprises lactic acid in a concentration of 0.025 to 0.2 M. 
     
     
         55 . The method of  claim 45 , wherein the cyclodextrin(s) is in an amount of 2% (w/v) to 6% (w/v). 
     
     
         56 . The method of  claim 45 , wherein the Poloxamer 407 is in an amount of 10% (w/v) to 40% (w/v). 
     
     
         57 . The method of  claim 45 , wherein the Poloxamer 407 is in an amount of 15% (w/v) to 40% (w/v). 
     
     
         58 . The method of  claim 45 , wherein the Poloxamer 407 is in an amount of 20% (w/v) to 40% (w/v). 
     
     
         59 . The method of  claim 45 , wherein the Poloxamer 407 is in an amount of 30% (w/v) to 40% (w/v). 
     
     
         60 . The method of  claim 44 , wherein the bladder diseases are selected from bladder cancer, cystitis, and urothelial cell carcinoma. 
     
     
         61 . The method of  claim 44 , wherein the administering comprises intravesical administration.