Reconstitution medium for protein and peptide formulations

Abstract

Compositions useful for reconstitution of concentrated formulations containing protein/peptide pharmaceuticals are provided. The composition generally includes one or more lipids, as well as one or more alcohols that promote and stabilize the formation of (a) lipid molecular assemblies with greater protein encapsulation; (b) protein-lipid complexes and (c) protein and lipid solutions. The reconstitution medium improves the protein-lipid association that in turn alters the pharmaceutical properties.

1 ) A reconstitution medium for the reconstitution of dried protein comprising one or more alcohols, one or more lipids, and a buffer with a physiological pH, wherein the lipid content is in the range of from about 0.3 mM to about 40 mM, the buffer concentration is in the range of from about 0.5 mM to about 600 mM and the ethanol content is less than about 60% vol/vol.  
     
     
         2 ) A reconstitution medium as in  claim 1  wherein said one or more alcohols has a concentration which is less than about 20% vol/vol.  
     
     
         3 ) A reconstitution medium as in  claim 1  wherein said one or more alcohols has a concentration which is in the range of from about 5% vol/vol to about 10% vol/vol.  
     
     
         4 ) A reconstitution medium as in  claim 1  wherein said one or more alcohols includes ethanol, polyethylene glycol, or glycerol.  
     
     
         5 ) A reconstitution medium as in  claim 1  wherein said one or more lipids includes phosphatidyl serine or phosphatidyl choline.  
     
     
         6 ) A reconstitution medium as in  claim 1  wherein said reconstitution medium includes ethanol.  
     
     
         7 ) A reconstitution medium as in  claim 5  wherein said reconstitution medium includes ethanol.  
     
     
         8 ) A reconstitution medium as in  claim 7  containing phosphatidyl serine or phosphatidyl choline.  
     
     
         9 ) A method for forming a protein solution which comprises combining a medium comprising one or more alcohols, one or more lipids, and a buffer with a physiological pH, wherein the lipid content is in the range of from about 0.3 mM to about 40 mM, the buffer concentration is in the range of from about 0.5 mM to about 600 mM and the ethanol content is less than about 60% vol/vol. with a preparation comprised of a protein, wherein all of the circular dichroism spectral bands characteristic of the tertiary structure of the protein are present.  
     
     
         10 ) A method of  claim 9  wherein the alcohol content is less than about 20 vol/vol %, wherein all of the circular dichroism spectral bands due to tertiary structure of the protein are present.  
     
     
         11 ) A method of  claim 9  wherein the alcohol content is in the range of from about 5 vol/vol % to about 10 vol/vol %, wherein all of the circular dichroism spectral bands due to tertiary structure of the protein are present.  
     
     
         12 ) A method for the reconstitution of a protein preparation to produce a stabilized protein solution, said method comprising: 
 combining    a) said protein preparation, and    b) a reconstitution medium,    to form a reconstituted protein solution, said reconstitution medium comprising an alcohol and being buffered to a physiological pH, such that fewer than 30% of the dissolved protein forms aggregates as determined by size-exclusion chromatograph.    
     
     
         13 ) A method as in  claim 12  wherein the protein preparation contains one or more lipids.  
     
     
         14 ) A method as in  claim 12  wherein said reconstitution medium contains one or more lipids.  
     
     
         15 ) A method as in  claim 12  which further comprises adding one or more lipids to said reconstituted protein solution.  
     
     
         16 ) A method as in  claim 12  wherein said stabilized protein solution contains one or more lipids.  
     
     
         17 ) A method as in  claim 16  wherein said alcohol is ethanol, polyethylene glycol or glycerol.  
     
     
         18 ) A method as in  claim 17  wherein at least one of said lipids is phosphatidyl serine or phosphatidyl choline.  
     
     
         19 ) A method as in  claim 12  wherein said protein preparation is a dry protein preparation.  
     
     
         20 ) A method as in  claim 19  wherein said dry protein preparation contains one or more lipids which are associated with the protein as lipidic molecular assemblies or other protein-lipid complexes.