Stabilised protein compositions based on semifluorinated alkanes

Abstract

The invention provides novel compositions of bioactive polypeptides and proteins with improved stability and shelf-life. The compositions are based on liquid vehicles selected from semifluorinated alkanes. These vehicles are remarkably effective in protecting polypeptides and proteins from degradation and/or aggregation. The compositions are useful for topical administration, e.g. into an eye, or by parenteral injection, e.g. via the subcutaneous or intramuscular route.

The invention claimed is: 
     
       1. Composition A liquid suspension composition comprising a bioactive compound and a liquid vehicle, wherein the liquid vehicle comprises a semifluorinated alkane of the formula RFRH wherein RF is a linear perfluorinated hydrocarbon segment with 4 to 12 carbon atoms, and wherein RH is a linear alkyl group with 4 to 8 carbon atoms selected from the group consisting of F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10; and wherein the bioactive compound is a therapeutic or diagnostic agent or vaccine selected from polypeptides and proteins having a molecular mass of at least 1,500 Da, dispersed or suspended in the liquid vehicle; wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10. 
     
     
       2. The composition of  claim 1 , wherein the bioactive compound is sensitive to degradation and/or aggregation. 
     
     
       3. The composition of  claim 1 , wherein the bioactive compound is a single-domain protein or a two-domain protein prone to hydrolysis. 
     
     
       4. The composition of  claim 1 , wherein the bioactive compound is an insulin. 
     
     
       5. The composition of  claim 1 , wherein the semifluorinated alkane is selected from F4H5 and F6H8. 
     
     
       6. The composition of  claim 1 , wherein the composition is substantially free of water. 
     
     
       7. Method A method of preparing a liquid suspension composition comprising a bioactive therapeutic or diagnostic agent or vaccine selected from a polypeptide or protein compound and a liquid vehicle, comprising the step of incorporating suspending solid particles of the bioactive polypeptide or protein within a compound in the liquid vehicle which comprises a semifluorinated alkane of the formula RFRH wherein RF is a linear perfluorinated hydrocarbon segment with 4 to 12 carbon atoms, and wherein RH is a linear alkyl group with 4 to 8 carbon atoms selected from the group consisting of F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10 such as to form a dispersion or suspension; wherein the bioactive compound is a therapeutic or diagnostic agent or vaccine selected from polypeptides and proteins having a molecular mass of at least 1,500 Da, dispersed or suspended in the liquid vehicle; and wherein the semifluorinated alkane is selected from F4H5, F4H6, F4H8, F6H4, F6H6, F6H8, and F6H10. 
     
     
       8. The method of  claim 7 , wherein the bioactive polypeptide or protein is sensitive to degradation and/or aggregation. 
     
     
       9. The method of  claim 7 , wherein the composition is chemically and/or physically stabilised. 
     
     
       10. The composition of  claim 4 , wherein the semifluorinated alkane is selected from the group consisting of F4H5 and F6H8. 
     
     
       11. The composition of  claim 10 , wherein the composition is substantially free of water. 
     
     
       12. The composition of  claim 1 , wherein the polypeptide or protein has a molecular mass of at least about 2,000 Da comprises from 25 to 500 amino acids. 
     
     
       13. The method of  claim 7 , wherein the polypeptide or protein has a molecular mass of at least about 2,000 Da comprises from 25 to 500 amino acids. 
     
     
       14. The composition of  claim 1 , wherein the semifluorinated alkane is F6H8. 
     
     
       15. The composition of  claim 4 , wherein the semifluorinated alkane is F6H8. 
     
     
       16. The composition of  claim 1 , wherein the bioactive compound is sensitive to degradation and/or aggregation, and wherein the bioactive compound is easily re-dispersed by gentle shaking after flotation or sedimentation. 
     
     
       17. The composition of claim 1, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H6 and F6H8. 
     
     
       18. The method of claim 7, wherein the semifluorinated alkane is selected from the group consisting of F4H5, F4H6, F6H6 and F6H8. 
     
     
       19. The composition of claim 1, wherein the semifluorinated alkane is F6H10. 
     
     
       20. The method of claim 7, wherein the semifluorinated alkane is F6H10. 
     
     
       21. The composition of claim 1, wherein the protein is an enzyme, hormone, growth factor or a structural protein. 
     
     
       22. The composition of claim 1, wherein the protein is a recombinant protein. 
     
     
       23. The composition of claim 1, wherein the protein is a naturally derived protein. 
     
     
       24. The composition of claim 1, wherein the protein is a synthetic protein. 
     
     
       25. The composition of claim 1, wherein the protein is an analog of a natural or endogenous protein. 
     
     
       26. The composition of claim 1, wherein the protein is a recombinant human insulin. 
     
     
       27. The method of claim 7, wherein semifluorinated alkane is F6H8. 
     
     
       28. The composition of claim 1, wherein the composition is a pharmaceutical composition formulated for dermal, subcutaneous, intramuscular, or locoregional injection. 
     
     
       29. The composition of claim 1, wherein the composition is a pharmaceutical composition formulated for topical administration to the eye, ear, nose, or lung. 
     
     
       30. The composition of claim 29, wherein the semifluorinated alkane is selected from F4H5 and F6H8. 
     
     
       31. A liquid suspension composition for topical administration to the eye, the composition comprising solid particles of a bioactive compound suspended in a liquid vehicle, wherein the liquid vehicle comprises a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F4H8, F6H4, F6H6, F6H8 and F6H10, and wherein the bioactive compound is a therapeutic agent selected from polypeptides and proteins having a molecular mass of at least 1,500 Da. 
     
     
       32. The composition of claim 31, wherein the bioactive compound is a protein having a molecular mass of between 2,000 to 60,000 Da. 
     
     
       33. The composition according to claim 31, wherein the composition is preservative-free and microbiologically stable. 
     
     
       34. The composition according to claim 31, consisting of the bioactive polypeptide or protein and one or more semifluorinated alkanes. 
     
     
       35. A liquid suspension composition for topical administration to the eye, ear, nose, or lung, of a patient, the composition comprising solid particles of a bioactive compound suspended in a liquid vehicle, wherein the liquid vehicle comprises a semifluorinated alkane selected from the group consisting of F4H5, F4H6, F4H8, F6H4, F6H6, F6H8 and F6H10, and wherein the bioactive compound is a therapeutic agent selected from polypeptides and proteins having a molecular mass of at least 1,500 Da.