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 . A process for producing a dry, biologically or therapeutically active compound as an at least partially amorphous composition, which comprises: 
 (a) forming a solution of said biologically or therapeutically active compound which contains at least one sugar or a polar amino acid selected from the group consisting of arginine, aspartic acid, glutamic acid, histidine, citrulline, lysine and ornithine; and an apolar amino acid selected from the group consisting of phenylalanine, tryptophan, leucine, methionine, valine, alanine, glycine, acetylphenylalanine ethyl ester, cysteine, sarcosine and isoleucine; and    (b) vacuum drying said solution without freezing to produce said dry biologically or therapeutically active compound in an at least partially amorphous composition.    
   
   
       2 . The process of  claim 1  wherein said biologically or therapeutically active compound is selected from the group consisting of a protein, a cell, a virus, DNA, RNA and PNA.  
   
   
       3 . The process of  claim 1  which further comprises grinding said at least partially amorphous composition to form a powder.  
   
   
       4 . The process of  claim 1  wherein said solution further comprises an additional ingredient selected from the group consisting of one or more of a buffer, a surfactant, an antioxidant, an isotonic agent and a preservative.  
   
   
       5 . The process of  claim 1  wherein said biologically or therapeutically active compound is a protein.  
   
   
       6 . The process of  claim 5  wherein said protein is a human protein.  
   
   
       7 . The process of  claim 5  wherein said protein is a viral protein.  
   
   
       8 . The process of  claim 5  wherein said protein is selected from the group consisting of an antibody and an enzyme.  
   
   
       9 . The process of  claim 5  wherein said protein is selected from the group consisting of a glycoprotein and a lipoprotein.  
   
   
       10 . The process of  claim 5  wherein said protein is selected from the group consisting of recombinant granulocyte colony stimulating factor, recombinant plasminogen activator, nerve growth factor, lactate dehydrogenase and parathyroid hormone.  
   
   
       11 . The process of  claim 1  wherein said sugar is selected from the group consisting of a monosaccharide and a disaccharide.  
   
   
       12 . The process of  claim 1  wherein said sugar is sucrose.  
   
   
       13 . The process of  claim 1  wherein said sugar is maltose.  
   
   
       14 . The process of  claim 1  wherein said vacuum drying is continuous vacuum drying.  
   
   
       15 . The process of  claim 1  wherein said vacuum drying is carried out in a freeze-drying apparatus, without freezing.  
   
   
       16 . The process of  claim 1  wherein said drying is performed in single dose containers.  
   
   
       17 . The process of  claim 1  wherein said at least partially amorphous composition has a glass transition temperature which is increased compared to the same composition produced without an apolar amino acid.  
   
   
       18 . The process of  claim 17  wherein said at least partially amorphous composition has a glass transition temperature above 4° C. and a residual moisture content of less than 6% (g/g).  
   
   
       19 . The process of  claim 17  wherein said glass transition temperature is above 20° C.  
   
   
       20 . The process of  claim 17  wherein said residual moisture content is less than 4% (g/g).  
   
   
       21 . The process of  claim 1  wherein said at least partially amorphous composition has at least 10% higher apparent density than a corresponding lyophilized composition.  
   
   
       22 . The process of  claim 1  wherein said at least partially amorphous composition remains in at least partially amorphous form upon storage for a period of at least two weeks.  
   
   
       23 . The process of  claim 1  wherein said at least partially amorphous composition remains in at least partially amorphous form upon storage for a period of at least twenty-six weeks.  
   
   
       24 . The process of  claim 1  wherein said drying requires at most half of the time necessary to dry the same composition produced without said apolar amino acid to an equivalent moisture level.  
   
   
       25 . A dry composition produced by the process of  claim 1 .  
   
   
       26 . A dry, at least partially amorphous composition of a biologically or therapeutically active compound, which comprises said biologically or therapeutically active compound; at least one sugar or a polar amino acid selected from the group consisting of arginine, aspartic acid, glutamic acid, histidine, citrulline, lysine and ornithine; and an apolar amino acid selected from the group consisting of phenylalanine, tryptophan, leucine, methionine, valine, alanine, glycine, acetylphenylalanine ethyl ester, cysteine, sarcosine and isoleucine wherein said composition is vacuum-dried.  
   
   
       27 . The composition of  claim 26  which is ground to form a powder.  
   
   
       28 . The composition of  claim 26  wherein said dry, at least partially amorphous composition further comprises an additional ingredient selected from the group consisting of one or more of a buffer, a surfactant, an antioxidant, an isotonic agent and a preservative.  
   
   
       29 . The composition of  claim 26  wherein said dry, at least partially amorphous composition further comprises a pharmaceutically acceptable excipient.  
   
   
       30 . The composition of  claim 26  wherein said biologically or therapeutically active compound is selected from the group consisting of a protein, a cell, a virus, DNA, RNA and PNA.  
   
   
       31 . The composition of  claim 26  wherein said biologically or therapeutically active compound is a protein.  
   
   
       32 . The composition of  claim 31  wherein said protein is a human protein.  
   
   
       33 . The composition of  claim 31  wherein said protein is a viral protein.  
   
   
       34 . The composition of  claim 31  wherein said protein is selected from the group consisting of an antibody and an enzyme.  
   
   
       35 . The composition of  claim 31  wherein said protein is a selected from the group consisting of a glycoprotein and a lipoprotein.  
   
   
       36 . The composition of  claim 31  wherein said protein is selected from the group consisting of recombinant granulocyte colony stimulating factor, recombinant plasminogen activator, nerve growth factor, lactate dehydrogenase and parathyroid hormone.  
   
   
       37 . The composition of  claim 26  wherein said sugar is selected from the group consisting of a monosaccharide and a disaccharide.  
   
   
       38 . The composition of  claim 26  wherein said sugar is sucrose.  
   
   
       39 . The composition of  claim 26  wherein said sugar is maltose.  
   
   
       40 . The composition of  claim 26  which is vacuum dried by continuous vacuum drying.  
   
   
       41 . The composition of  claim 26  which is vacuum dried in a freeze-drying apparatus, without freezing.  
   
   
       42 . The composition of  claim 26  which is vacuum dried in single dose containers.  
   
   
       43 . The composition of  claim 26  which has a glass transition temperature which is increased compared to the same composition produced without an apolar amino acid.  
   
   
       44 . The composition of  claim 43  which has a glass transition temperature above 4° C. and a residual moisture content of less than 6% (g/g).  
   
   
       45 . The composition of  claim 43  wherein said glass transition temperature is above 20° C.  
   
   
       46 . The composition of  claim 42  wherein said residual moisture content is less than 4% (g/g).  
   
   
       47 . The composition of  claim 26  which has at least 10% higher apparent density than a corresponding lyophililzate.  
   
   
       48 . The composition of  claim 26  which remains in at least partially amorphous form upon storage for a period of at least two weeks.  
   
   
       49 . The composition of  claim 26  which remains in at least partially amorphous form upon storage for a period of at least twenty-six weeks.  
   
   
       50 . The composition of  claim 26  wherein said drying requires at most half of the time necessary to dry the same composition produced without said apolar amino acid to an equivalent moisture level.