Contrast medium for near infrared diagnosis

Abstract

This invention relates to colloidal systems charged with polymethine dyes and having suitable photophysical and pharmacological properties, their use as a contrast medium in fluorescence and transillumination diagnostics in the near infrared spectral range, as well as methods for their production.

1 . A contrast medium for near infrared diagnosis that contains colloidal systems charged with dye, characterized in that the colloidal particles have a size from 5 nm to 10 μm, and that they contain at least one dye absorbing and/or fluorescing in the wavelength range from 600 to 1200 nm.  
     
     
         2 . The contrast medium according to  claim 1 , characterized in that the colloids contain polyesters of α-, β-, γ-, or εe-hydroxycarboxylic acids, polyalkyl cyanoacrylate, polyamino acids, polyamides, polyacrylated saccharides, or poly(ortho)esters.  
     
     
         3 . The contrast medium according to  claim 1 , characterized in that the colloids contain proteins such as albumins, collagen, gelatin, haemoglobin or fibrinogen, or starches, dextranes, chitin or chitosan.  
     
     
         4 . The contrast medium according to  claim 1 , characterized in that the colloids contain phospholipids, fatty acids, fatty alcohols, cholesterol, esters of fatty alcohols and fatty acids, ethers of fatty alcohols, sugar derivatives with fatty acids or polyoxyethylene, esters or ethers of phospholipids, fatty acids, or fatty alcohols with polyoxyethylene, bile acids, derivatives of sorbitan with polyoxyethylene, fatty acids, or fatty alcohols, as well as combinations of said substances.  
     
     
         5 . A contrast medium according to at least one of  claims 1  to  4 , characterized in that it contains as its dye component a cyanine, styryl, merocyanine, squaraine, an oxonol dye, or a mixture of said dyes.  
     
     
         6 . A contrast medium according to at least one of  claims 1  to  4 , characterized in that it contains at least one dye from the class of cyanine dyes or squaraine dyes.  
     
     
         7 . The contrast medium according to  claim 6 , characterized in that said dye carries one or several additional unbranched, branched, cyclic or polycyclic alkyl, alkenyl, polyalkenyl, alkinyl, polyalkinyl, aryl, alkylaryl, or arylalkyl residues, each containing up to 60 carbon atoms which may optionally carry additional halogen atoms, hydroxy, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde, oxo, oxy, or alkoxy groups containing up to 20 carbon atoms and/or optionally interrupted and/or replaced by one or several additional heteroatoms from the O, N, S, or P series.  
     
     
         8 . The contrast medium according to  claim 7 , characterized in that it contains at least one dye of the general formula I, II, or III  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10  are same or different, each of which independently represents a —COOE 1 , —CONE 1 E 2 , —NHCOE 1 , —NHCONHE 1 , —NE 1 E 2 . —OE 1 , —SO 3 E 1 , —SO 2 E 1 , —SO 2 NE 1 E 2 , —E 1  residue, a fluorine, chlorine, bromine, or iodine atom or a nitro group, or where 5- to 6-member rings are anellated to each pair of adjacent residues R 1 , R 2 , R 3 , or R 4 , and R 7 , R 8 , R 9  or R 10  respectively, depending on the C atoms located in between, said rings being either saturated or unsaturated or aromatic and optionally carrying additional —COOE 1 , —CONE 1 E 2 , —NHCOE 1 , —NHCONHE 1 , —NE 1 E 2 , —OE 1 , —SO 3 E 1 , —SO 2 E 1 , —SO 2 NE 1 E 2  residues,  
 wherein 
 E 1  and E 2  are same or different, each of which independently represents a hydrogen atom, a saturated or unsaturated, branched or non-branched C 1 -C 50  alkyl chain, and said chain or parts thereof optionally form a cyclic C 5 -C 6 , or a bicyclic C 10  unit interrupted and/or replaced by oxygen atoms, sulfur atoms, nitrogen atoms, carboxylic acid ester, carboxylic acid amide, urea, thiourea, carbamate, ether groupings, or represent a hydroxypolyoxyethylene or methoxypolyoxyethylene chain or a branched or non-branched C 1 -C 10  alkyl chain substituted with 1 to 19 fluorine atoms,  
 
 R 5  and R 6  independently represent an —E 1  residue or a C 1 -C 4  sulfoalkyl chain, 
 where E1 is as defined above  
 
 Q represents a  
                     
 fragment  
 wherein  
 R 11  is a hydrogen, fluorine, chlorine, bromine, or iodine atom, a —NE 1 E 2 , —OE 1 , or —E 1  residue or a nitro group,  
 R 12  represents a hydrogen atom or an —E 1  residue,  
 b is one of the integers 0, 2 or 3, 
 where E 1  and E 2  are as defined above,  
 
 X and Y are same or different, each of which independently represents O, S, —CH═CH—, or a  
                     
 fragment,  
 wherein  
 R 13  and R 14  independently represent hydrogen, a saturated or unsaturated, branched or non-branched C 1 -C 15  alkyl chain, and where the residues R 13  and R 14  may be interconnected by forming a 5- or 6-member ring, said members being interrupted and/or replaced by oxygen atoms and/or hydroxy groups, alkoxy groups containing up to 6 carbon atoms, carboxylic acid ester and/or carboxylic acid amide units,  
 or their carboxylic acid and/or sulfonyl salts with physiologically tolerable inorganic or organic cations.  
 
     
     
         9 . Contrast medium according to at least one of  claims 1  to  8 , characterized in that it contains a minimum of two dyes with different photophysical and/or pharmacological properties.  
     
     
         10 . Contrast medium according to at least one of  claims 1  to  9 , together with the adjuvants, substrates, and diluents common in galenics.  
     
     
         11 . Use of contrast media according to at least one of  claims 1  to  10  for in vivo fluoroscopy and absorption diagnosis in the near infrared range.