Preparations and processes for stabilizing biological materials by means of drying processes without freezing

Abstract

The present invention concerns processes for the production of dry, partially amorphous products containing biologically active and in particular therapeutically active material which are macroscopically homogeneous substance mixtures, the substance mixtures being selected from at least one substance of each of the groups (i) carbohydrate or zwitterion with a polar residue and derivatives thereof, and (ii) zwitterion with an apolar residue and derivatives thereof, wherein a solution is prepared of the biologically or therapeutically active material and of substances (i) and (ii) and the solution is dried at a product temperature above the freezing point of the solution. In addition the invention concerns new substance mixtures which are obtained by the said process as well as the use thereof in diagnostic or therapeutic methods.

1 . Process for the production of dry, partially amorphous products which, in addition to biologically active and in particular therapeutically active material, contain substance mixtures, the substance mixtures being selected from at least one substance from each of the groups 
 (i) carbohydrate or zwitterion with polar residues and derivatives thereof, and    (ii) zwitterion with apolar residues and derivatives thereof,    wherein a solution is prepared of the biologically or therapeutically active material and of the substances (i) and (ii) and the solution is dried at a product temperature above the freezing point of the solution.    
     
     
         2 . Process as claimed in  claim 1 , wherein the zwitterion with an apolar residue is an aminocarboxylic acid or a derivative thereof.  
     
     
         3 . Process as claimed in one of the claims  1  or  2  , whereinthe zwitterion with a polar residue is an aminocarboxylic acid or a derivative thereof.  
     
     
         4 . Process as claimed in  claim 1 , wherein substance mixtures are selected from one or several substances of the respective group, 
 monosaccharides, disaccharides, arginine, aspartic acid, citrulline, glutamic acid, ornithine, histidine, lysine and derivatives thereof and    acetylphenylalanine ethyl ester, alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, tryptophan, valine, sarcosine and derivatives thereof.    
     
     
         5 . Process as claimed in one of the claims  1 - 4  , whereinthe biological material can be selected from one or several substances of the groups proteins, peptides, glycoproteins, lipoproteins, enzymes, coenzymes, antibodies, antibody fragments, viruses, viral components, cells and cell components, vaccines, DNA, RNA, PNA, biological therapeutic agents and diagnostic agents and derivatives thereof.  
     
     
         6 . Process as claimed in one of the claims  1 - 5  , whereinthe solution additionally contains common auxiliary substances from the groups buffers, surfactants, antioxidants, isotonic agents and preservatives.  
     
     
         7 . Process as claimed in one of the claims  1 - 6  , whereinthe drying is carried out by means of vacuum drying.  
     
     
         8 . Process as claimed in one of the claims  1 - 7  , whereinthe vacuum drying is carried out as a continuous drying process.  
     
     
         9 . Process as claimed in one of the claims  1 - 6  , whereinthe drying is carried out by means of spray drying.  
     
     
         10 . Process as claimed in one of the claims  1 - 6  , whereinthe drying is carried out by means of drum drying.  
     
     
         11 . Process as claimed in one of the claims  1 - 6 , whereinthe drying is carried out by means of infrared rays, microwaves or other methods of radiation drying.  
     
     
         12 . Process as claimed in one of the claims  1 - 11  , whereina zwitterion with an apolar residue is selected in such a way that the dried substance mixture has an increased glass point compared to a substance mixture without a corresponding addition.  
     
     
         13 . Process as claimed in one of the claims  1 - 8  , whereinthe drying is carried out in a freeze-drying apparatus without previous freezing.  
     
     
         14 . Process as claimed in one of the claims  1 - 8 ,  12  or  13 , wherein the substance mixture is dried in single dose containers.  
     
     
         15 . Process as claimed in one of the claims  1 - 13  , whereinthe substance mixture obtained is subsequently ground to form a powder.  
     
     
         16 . Substance mixtures containing in addition to a biologically active and in particular a therapeutically active material, substances selected from one or several substances of the following groups 
 (i) carbohydrate or zwitterion with polar residues and derivatives thereof    (ii) zwitterions with apolar residues and derivatives thereof,    wherein the substance mixtures due to the addition of one or several substances of group (ii) have an increased glass transition temperature compared to substances of group (i) without the corresponding addition, with the exception of lyophilisates.    
     
     
         17 . Substance mixtures obtainable by a process in which a solution containing in addition to a biologically active and in particular a therapeutically active material at least one substance selected from each of the groups 
 (i) a carbohydrate or zwitterion with polar residues and derivatives thereof    (ii) zwitteriohs with apolar residues and derivatives thereof,    is dried at a product temperature above the freezing point of the solution.    
     
     
         18 . Substance mixtures as claimed in  claim 16  or  17 , whereinit is partially amorphous.  
     
     
         19 . Substance mixtures as claimed in one of the claims  16 - 18 , wherein the glass transition temperature is above 4° C. preferably above 20° C. and the residual moisture content is less than 6% (g/g) preferably less than 4% (g/g).  
     
     
         20 . Substance mixtures as claimed in one of the claims  16 - 19  , wherein they have an at least 10% higher apparent density than lyophilisates.  
     
     
         21 . Substance mixtures as claimed in one of the claims  16 - 20  , wherein they have a brittle, partially amorphous, glass-like, compact structure.  
     
     
         22 . Substance mixtures as claimed in one of the claims  16 - 21 , wherein they retain the partially amorphous structure over storage periods of at least 2 weeks.  
     
     
         23 . Substance mixtures as claimed in one of the claims  16 - 22 , wherein their drying periods are at least halved compared to substances of group (i).  
     
     
         24 . Diagnostic agents, wherein they contain substance mixtures as claimed in one of the claims  16 - 23 .  
     
     
         25 . Use of substance mixtures as claimed in one of the claims  16 - 23  for the production of diagnostic agents.  
     
     
         26 . Therapeutic preparations, wherein they contain substance mixtures as claimed in one of the claims  16 - 23 .  
     
     
         27 . Use of substance mixtures as claimed in one of the claims  16 - 23  in addition to common auxiliary substances and additives for the production of therapeutic agents.  
     
     
         28 . Process for stabilizing biologically or therapeutically active material, wherein a solution is prepared from this material together with common stabilizing agents and a further substance, which when dried above the freezing point of the resulting solution results in a partially amorphous homogeneous substance mixture whose glass transition temperature is increased by at least 10K by the further substance.