Galenical formulations

Abstract

Abstract This invention describes galenical formulations that contain perfluoroalkyl-containing dye molecules and other perfluoroalkyl-containing substances. The new formulations are suitable as, i.a., contrast media for near-infrared diagnosis.

1 . Galenical formulation, characterized in that it contains perfluoroalkyl-containing dye molecules and other perfluoroalkyl-containing substances.  
     
     
         2 . Formulation according to  claim 1 , wherein the other perfluoroalkyl-containing substances are perfluoroalkyl-containing metal complexes.  
     
     
         3 . Formulation according to  claim 2 , wherein the formulations contain other perfluoroalkyl-containing substances in addition to the perfluoroalkyl-containing dye molecules and the perfluoroalkyl-containing metal complexes.  
     
     
         4 . Formulation according to  claim 1 , wherein the perfluoroalkyl-containing dye molecules and the other perfluoroalkyl-containing compounds are present dissolved in a solvent.  
     
     
         5 . Formulation according to  claim 4 , wherein the solvent is water.  
     
     
         6 . Formulation according to  claim 4 , wherein the proportion of the perfluoroalkyl-containing dye molecules is between 1 and 10 mol % relative to the total amount of perfluoroalkyl-containing substances.  
     
     
         7 . Formulation according to one of  claims 1  to  3 , wherein the perfluoroalkyl-containing dye molecules absorb and fluoresce in a spectral range of between 400 and 900 nm.  
     
     
         8 . Formulation according to  claim 1 , wherein the perfluoroalkyl-containing dye molecules are substances of general formula I: 
       R f -L-A  (I) 
       in which R f  represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, L stands for a linker, and A stands for a dye molecule.  
     
     
         9 . Formulation according to  claim 8 , whereby linker L represents a direct bond or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more —OH, —COOH, —SO 3  groups and/or optionally is interrupted by one or more —O—, —S—, —CO—, —CONH—, —NHCO—, —CONR—, —NRCO—, —SO 2 —, —NH—, —NR groups or a piperazine, whereby R stands for a C 1  to C 10  alkyl radical, which optionally is substituted with one or more OH groups and/or is interrupted by one or more oxygen atoms.  
     
     
         10 . Formulation according to  claim 8 , wherein dye molecule A is a dye from the class of polymethine dyes, xanthine dyes or the heteroaromatic, cationic dyes.  
     
     
         11 . Formulation according to  claim 8 , wherein dye molecule A is a cyanine dye, squarilium dye, coconium dye, oxonol dye, merocyanine dye, cryptocyanine dye, fluorescein, rhodamine, oxazine, phenoxazine, thiazine or phenothiazine.  
     
     
         12 . Formulation according to  claim 8 , wherein dye molecule A is a molecule according to Formula II:  
       
         
           
           
               
               
           
         
       
       in which 
 D stands for a fragment that corresponds to general formulas III to VI, whereby the position that is characterized with a star means the linkage with B:  
                     
 and in which B stands for a fragment that corresponds to general formulas VII to XII:  
                     
 whereby R 1  and R 2  represent a C 1 -C 4  sulfoalkyl chain, a saturated or unsaturated, branched or straight-chain C 1 -C 50  alkyl chain, whereby the chain or parts of this chain optionally can form one or more aromatic or saturated, cyclic C 5 -C 6  units or bicyclic C 10  units, and whereby the C 1 -C 50  alkyl chain optionally is interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or is substituted with 0 to 5 hydroxy groups,  
 R 3  stands for a radical —COOE 1 , —CONE 1 E 2 , —NHCOE 1 , —NHCONHE 1 , —NE 1 E 2 , —OE 1 , —OSO 3 E 1 , —SO 3 E 1 , —SO 2 NHE 1 , —E 1 ,  
 whereby E 1  and E 2 , independently of one another, represent a hydrogen atom, a C 1 -C 4  sulfoalkyl chain, a saturated or unsaturated, branched or straight-chain C 1 -C 50  alkyl chain, whereby the chain or parts of this chain optionally can form one or more aromatic or saturated cyclic C 5 -C 6  units or bicyclic C 10  units, and whereby the C 1 -C 50  alkyl chain optionally is interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups, and/or is substituted with 0 to 5 hydroxy groups,  
 and whereby R 4  stands for a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, or a branched or straight-chain C 1 -C 10  alkyl chain,  
 b means a number 2 or 3,  
 and X and Y, independently of one another, mean O, S, —CH═CH— or C(CH 3 ) 2 .  
 
     
     
         13 . Formulation according to  claim 2 , wherein the perfluoroalkyl-containing metal complexes are selected from the following groups of metal complexes: 
 the gadolinium complex of 10-[1-methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,    the gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,    1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-methyl-3,6-diaza-2,5,8-trioxooctane-1,8-diyl)-1,4,7,10-tetraazacyclododecane, Gd-complex}-10-(N-2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tridecanoyl)-1,4,7,10-tetraazacyclododecane,    1,4,7-tris{1,4,7-tris[(N-carboxylatomethyl)]-10-[N-1-methyl-3-aza-2,5-dioxopentam-1,5-diyl]-1,4,7,10-tetraazacyclododecane, Gd complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7,10-tetraazacyclododecane,    the gadolinium complex of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,    1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,3-dihydroxy-propyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex,    1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex,    1,4,7-tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-3,6,9,12,15-pentaoxa)-hexadexyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex,    and 1,4,7-tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(5-hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex.    
     
     
         14 . Formulation according to  claim 3 , wherein the additional perfluoroalkyl-containing substances are compounds of general formula XV: 
       R f -L 2 -G 1   (XXXII) in which R f  represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, L 2  stands for a linker, and G 1  stands for a hydrophilic group.    
     
     
         15 . Formulation according to  claim 14 , wherein linker L 2  is a direct bond, an —SO 2  group or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more —OH, —COO—, —SO 3  groups and/or optionally contains one or more —O—, —S—, —CO—, —CONH—, —NHCO—, —CONR—, —NRCO—, —SO 2 —, —PO 4 , —NH—, —NR groups, an aryl ring or a piperazine, whereby R stands for a C 1  to C 20  alkyl radical, which in turn can contain one or more O-atoms and/or can be substituted with —COO −  or SO 3  groups.  
     
     
         16 . Formulation according to  claim 14 , wherein hydrophilic group G 1  stands for a monosaccharide or disaccharide, one or more adjacent —COO −  or —SO 3  groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid, a quaternary ammonium ion, an aminopolycarboxylic acid, an aminodipolyethyleneglycolsulfonic acid, an aminopolyethylene glycol group, an SO 2 —(CH 2 ) 2 —OH group, a polyhydroxyalkyl chain with at least two hydroxyl groups or one or more polyethylene glycol chains with at least two glycol units, whereby the polyethylene glycol chains are terminated by an —OH or —OCH 3  group.  
     
     
         17 . Formulation according to  claim 1 , wherein the perfluoroalkyl chains of the perfluoroalkyl-containing dye molecules and the other perfluoroalkyl-containing compounds contain 6 to 12 carbon atoms.  
     
     
         18 . Formulation according to  claim 17 , wherein the perfluoroalkyl chains contain 8 carbon atoms in each case.  
     
     
         19 . Substances of general formula I 
       R f -L-A  (I) 
       in which R f  represents a straight-chain or branched perfluoroalkyl radical with 4 to 30 carbon atoms, L stands for a linker and A stands for a dye molecule from the class of polymethine dyes, xanthine dyes or the heteroaromatic, cationic dyes.  
     
     
         20 . Substances according to  claim 19 , wherein linker L represents a direct bond or a straight-chain or branched carbon chain with up to 20 carbon atoms, which can be substituted with one or more —OH, —COOH, —SO 3  groups and/or optionally is interrupted by one or more —O—, —S—, —CO—, —CONH—, —NHCO—, —CONR—, —NRCO—, —SO 2 —, —NH—, —NR groups or a piperazine, whereby R stands for a C 1  to C 10  alkyl radical, which optionally is substituted with one or more OH groups.  
     
     
         21 . Substances according to  claim 19 , wherein dye molecule A is a cyanine dye, squarilium dye, croconium dye, oxonol dye, merocyanine dye, cryptocyanine dye, fluorescein dye, rhodamine dye, oxazine dye, phenoxazine dye, thiazine dye or phenothiazine dye.  
     
     
         22 . Substances according to  claim 22 , wherein dye molecule A is a molecule according to formula II:  
       
         
           
           
               
               
           
         
       
       in which 
 D stands for a fragment that corresponds to general formulas III to VI, whereby the position that is characterized with a star means the linkage with B:  
                     
 and in which B stands for a fragment that corresponds to general formulas VII to XII:  
                     
 whereby R 1  and R 2  represent a C 1  -C 4  sulfoalkyl chain, a saturated or unsaturated, branched or straight-chain C 1 -C 50  alkyl chain, whereby the chain or parts of this chain optionally can form one or more aromatic or saturated, cyclic C 5 -C 6  units or bicyclic C 10  units, and whereby the C 1 -C 50  alkyl chain optionally is interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups and/or is substituted with 0 to 5 hydroxy groups,  
 R 3  stands for a radical —COOE 1 , —CONE 1 E 2 , —NHCOE 1 , —NHCONHE 1 , —NE 1 E 2 , —OE 1 , —OSO 3 E 1 , —SO 3 E 1 , —SO 2 NHE 1 , —E 1 ,  
 whereby E 1  and E 2 , independently of one another, represent a hydrogen atom, a C 1 -C 4  sulfoalkyl chain, a saturated or unsaturated, branched or straight-chain C 1 -C 50  alkyl chain, whereby the chain or parts of this chain optionally can form one or more aromatic or saturated cyclic C 5 -C 6  units or bicyclic C 10  units, and whereby the C 1 -C 50  alkyl chain optionally is interrupted by 0 to 15 oxygen atoms and/or by 0 to 3 carbonyl groups, and/or is substituted with 0 to 5 hydroxy groups,  
 and whereby R 4  stands for a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, or a branched or straight-chain C 1 -C 10  alkyl chain,  
 b means a number 2 or 3,  
 and X and Y, independently of one another, mean O, S, —CH═CH— or C(CH 3 ) 2 .  
 
     
     
         23 . Process for the production of galenical formulations according to  claim 1 , wherein the perfluoroalkyl-containing dye molecules and the other perfluoroalkyl-containing compounds are dissolved in a solvent while being stirred vigorously.  
     
     
         24 . Process for the production of galenical formulations according to  claim 1 , wherein the perfluoroalkyl-containing dye molecules and the other perfluoroalkyl-containing compounds are dissolved in a solvent while being treated simultaneously with ultrasound.  
     
     
         25 . Process for the production of galenical formulations according to  claim 1 , wherein the perfluoroalkyl-containing dye molecules and the other perfluoroalkyl-containing compounds are dissolved in a solvent while being treated simultaneously with microwaves.  
     
     
         26 . Process for the production of galenical formulations according to  claim 1 , wherein the perfluoroalkyl-containing dye molecules are dissolved in a solvent, the other perfluoroalkyl-containing compounds are dissolved in another solvent, the two solutions are combined, and one of the two solvents is distilled off.  
     
     
         27 . Solid formulation according to  claim 1 , wherein it is produced by freeze-drying a solution, which contains perfluoroalkyl-containing dye molecules and other perfluoroalkyl-containing substances.  
     
     
         28 . Use of galenical formulations according to  claim 1  for the production of contrast media for optical diagnosis, fluorescence diagnosis, near-infrared diagnosis, nuclear spin tomography, imaging with use of x-rays (x-ray or computer tomography) and for ultrasound imaging.  
     
     
         29 . Use of galenical formulations according to  claim 1  for the production of contrast media for visualizing lymph nodes or blood pools.  
     
     
         30 . Use of galenical formulations according to  claim 1  for the production of agents for intraoperative diagnosis.