Excipients for Stabilising Viral Particles, Polypeptides or Biological Material

Abstract

A sterile pharmaceutically acceptable aqueous solution, which solution is provided in a sealed container and comprises: a pharmaceutically acceptable aqueous solvent; viral particles or a physiologically active polypeptide; an excipient selected from a polyethyleneimine; a compound of formula (I) or a physiologically acceptable salt or ester thereof; or a compound of formula (II) or a physiologically acceptable salt or ester thereof; and optionally, one or more sugars.

1 . A solution, which solution is provided in a sealed container and comprises:
 an aqueous solvent;   viral particles or a physiologically active polypeptide;   an excipient selected from a polyethyleneimine; a compound of formula (I) or a physiologically acceptable salt or ester thereof   
       
         
           
           
               
               
           
         
         
           wherein: 
           R 1  represents hydrogen or C 1-6  alkyl; and 
           R 4  represents hydrogen; or 
           R 1  and R 4  together with the atoms to which they are attached form a pyrrolidine ring; 
           R 2  represents hydrogen, C 1-6  alkyl or —(CH 2 ) 2-5 NHC(O)(CH 2 ) 5-15 CH 3 ; and 
           R 3  represents C 1-6  alkyl; or 
         
         a compound of formula (II) or a physiologically acceptable salt or ester thereof 
       
       
         
           
           
               
               
           
         
         wherein:
 X represents —S(O) 2 — or —S + (R c )—; 
 R a  and R b  independently represent C 1-6  alkyl; and 
 R c  represents C 1-6  alkyl substituted with a carboxylate anion and with an amine (—NH 2 ) moiety; and 
 
         optionally, one or more sugars; and 
         wherein (a) said solution is a sterile pharmaceutically acceptable aqueous solution and said solvent is a pharmaceutically acceptable solvent, or (b) said solution is a ready-to-use, storage-stable aqueous solution. 
       
     
     
         2 . A solution according to  claim 1  which comprises viral particles. 
     
     
         3 . A solution according to  claim 2  wherein (a) the viral particles are composed of a live virus or killed virus, or (b) the viral particles are composed of a live virus or killed virus and the live virus is whole virus or live attenuated virus, or (c) the solution comprises a virus selected from Adenoviridae, Orthomyxoviridae, Paramyxoviridae, Parvoviridae, Picornoviridae and Poxviridae, or (d) the solution comprises a virus selected from Adenoviridae, Orthomyxoviridae, Paramyxoviridae, Parvoviridae, Picornoviridae and Poxviridae which is selected from an adenovirus, vaccinia virus, influenza virus or measles virus. 
     
     
         4 . (canceled) 
     
     
         5 . A solution according to  claim 1  which comprises a physiologically active polypeptide. 
     
     
         6 . A solution according to  claim 5  wherein the polypeptide is:
 (a) a hormone, growth factor, peptide or cytokine; 
 (b) an antibody or antigen- or ligand-binding fragment thereof; 
 (c) an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase or a ligase; 
 (d) a vaccine immunogen; 
 (e) a tachykinin peptide, a vasoactive intestinal peptide, a pancreatic polypeptide-related peptide, an opioid peptide or a calcintonin peptide; 
 (f) a monoclonal antibody or fragment thereof; 
 (g) a chimeric, humanized or human antibody, or fragment thereof; 
 (h) an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase or a ligase; or 
 (i) a full-length viral or bacterial protein, glycoprotein or lipoprotein; or a fragment thereof. 
 
     
     
         7 . (canceled) 
     
     
         8 . A solution according to  claim 1 , wherein the excipient is:
 a polyethyleneimine having a number-average molar mass (M n ) between 20 and 1000 kDa or between 1 and 10000 Da;   (b) an N,N-di(C 1-6  alkyl)-, N,N,N-tri(C 1-6  alkyl)-, or N—C 1-6  alkyl-glycine or a physiologically acceptable salt or ester thereof;   (c) N,N-dimethylglycine, N,N,N-trimethylglycine, or N-methylglycine or a physiologically acceptable salt or ester thereof; or   (d) N-methylglycine, N,N-dimethyglycine or N,N,N-trimethylglycine or a hydrochloride salt thereof;   (e) N,N-dimethylglycine or a physiologically acceptable salt or ester thereof;   (f) a compound of formula (IA) or a physiologically acceptable salt or ester thereof   
       
         
           
           
               
               
           
         
       
       wherein R 5  and R 6  independently represent C 1-4  alkyl and R 7  represents C 1-4  alkyl or —(CH 2 ) 2-5 NHC(O)(CH 2 ) 5-15 CH 3 ;
 (g) a compound of formula (IB) or a physiologically acceptable salt or ester thereof: 
 
       
         
           
           
               
               
           
         
       
       wherein R 8  and R 9  independently represent C 1-4  alkyl;
 (h) a compound of formula (IIA) or a physiologically acceptable salt or ester thereof: 
 
       
         
           
           
               
               
           
         
       
       wherein R c  and R d  independently represent C 1-4  alkyl;
 (i) a compound of formula (IIB) or a physiologically acceptable salt or ester thereof: 
 
       
         
           
           
               
               
           
         
       
       wherein R e  and R f  independently represent C 1-4 ; and R g  represents C 1-4  alkyl substituted with a carboxylate anion and with an amine moiety; or
 (j) dimethylsulfone, N-methyl-glycine, N,N-dimethyl-glycine, N,N,N-trimethylglycine, cocamidopropyl betaine, proline betaine or S-methyl-L-methionine. 
 
     
     
         9 - 13 . (canceled) 
     
     
         14 . A solution according to  claim 1  in which (a) sucrose is present, or (b) sucrose is present and raffinose is also present. 
     
     
         15 . A solution according to claim which is suitable for parenteral administration. 
     
     
         16 . A solution which comprises:
 an aqueous solvent;   viral particles;   an N—(C 1-6  alkyl)-, N-N-di(C 1-6  alkyl)- or N,N,N-tri(C 1-6  alkyl)-glycine or a physiologically acceptable salt or ester thereof; and   a sulfone compound of formula (IIC):   
       
         
           
           
               
               
           
         
         wherein R a  and R b  independently represent C 1-6  alkyl; and 
         optionally, one or more sugars; and 
         wherein (a) said solution is a sterile pharmaceutically acceptable aqueous solution and the solvent is a pharmaceutically acceptable aqueous solvent; or (b) said solution is a ready-to-use, storage-stable aqueous solution and is provided in a sealed container. 
       
     
     
         17 . The solution according to  claim 16 (a), wherein (i) the concentration of the N—C 1-6  alkyl-, N,N-di(C 1-6  alkyl)- or N,N,N-tri(C 1-6  alkyl)-glycine or salt or ester thereof is from 0.1 to 1.5M, and/or (ii) the sulfone compound of formula (IIC) is methylsulfonylmethane, and/or (iii) the concentration of the sulfone compound of formula (I) is from 0.1 to 1.5M, and/or (iv) the aqueous solution comprises a non-reducing sugar or sugar alcohol, and/or (v) the aqueous solution comprises sucrose or mannitol, and/or (vi) the sugar concentration of the aqueous solution is from 0.05 to 1M, and/or (vii) the solution is provided in a sealed container. 
     
     
         18 . A solution according to  claim 1 , which further comprises:
 an adjuvant;   a physiologically acceptable buffer; and/or   a tonicity adjustment agent; and/or   a preservative.   
     
     
         19 . A solution according to  claim 1 , which is (a) isotonic, and/or (b) is provided in a sealed container under nitrogen. 
     
     
         20 . A solution according to  claim 1  wherein (a) the solution is provided in a sealed vial, ampoule, syringe, cartridge, flexible bag or glass bottle, and/or (b) a unit dosage amount of the viral particles or polypeptide is present. 
     
     
         21 - 39 . (canceled) 
     
     
         40 . The solution according to  claim 16 (b), wherein (i) the concentration of the N—C 1-6  alkyl-, N,N-di(C 1-6  alkyl)- or N,N,N-tri(C 1-6  alkyl)-glycine or salt or ester thereof in said solution is from 0.1 to 1.5M, and/or (ii) the concentration of the sulfone compound of formula (IIC) in said solution is from 0.1 to 1.5M, and/or (iii) the said solution comprises a non-reducing sugar or sugar alcohol, and/or (iv) the solution comprises sucrose or mannitol, and/or (v) the sugar concentration in said solution is from 0.05 to 1M. 
     
     
         41 . The solution according to  claim 16 (b), wherein (i) the said solution further comprises an adjuvant; a physiologically acceptable buffer; and/or a tonicity adjustment agent; and/or a preservative, and/or (ii) the said solution is isotonic, and/or (iii) said sealed container is a sealed vial, ampoule, syringe, cartridge, flexible bag or glass bottle, and/or (iv) the said solution is provided under nitrogen, and/or (v) a unit dosage amount of the viral particles is present in said solution. 
     
     
         42 - 48 . (canceled) 
     
     
         49 . An aqueous solution which comprises (i) a sample taken from a human or animal, (ii) an excipient as defined in  claim 1 , and (iii) optionally one or more sugars. 
     
     
         50 . An aqueous solution according to  claim 49  which is sealed in a container and optionally stored in a refrigerator or freezer. 
     
     
         51 - 52 . (canceled)