Polyoxypropylene/polyoxyethylene copolymers with improved biological activity

Abstract

The present invention comprises novel preparations of polyoxypropylene/polyoxyethylene copolymers which retain the therapeutic activity of the commercial preparations, but are substantially free from the undesirable effects which are inherent in the prior art preparations. Because the preparations of polyoxypropylene/polyoxyethylene copolymers which comprise the present invention are a less polydisperse population of molecules than the prior art polyoxypropylene/polyoxyethylene copolymers, the biological activity of the copolymers is better defined and more predictable.

We claim:  
     
       1. A method of preparing a non-toxic surface-active copolymer composition including first condensing propylene oxide with a base compound containing a plurality of reactive hydrogen atoms to produce a first composition containing a plurality of polyoxypropylene polymer polymers and then condensing ethylene oxide with the plurality of polyoxypropylene polymer polymers to produce a polyoxypropylene/polyoxyethylene block copolymer composition, said block copolymer composition consisting essentially of block copolymers with each of the block copolymers having the following general formula: 
       
         
           HO(C 2 H 4 O) b (C 3 H 6 O) a (C 2 H 4 O) b H  
         
       
       wherein “a” is an integer such that the molecular weight represented by the polyoxypropylene portion of the respective block copolymer is between approximately 900 and 15000 daltons and “b” is an integer such that the molecular weight represented by the polyoxyethylene portion of the respective block copolymer constitutes between approximately 5% and 95% of the respective block copolymer,  
       the improvement being the purification of the polyoxypropylene polymer first composition before the step of condensing ethylene oxide with the plurality of polyoxypropylene polymer polymers so that the polydispersity value of the polyoxypropylene/polyoxyethylene block copolymer composition is less than approximately  1.07 and the block copolymer composition is substantially free of unsaturation as measured by nuclear magnetic resonance spectroscopy.    
     
     
       2. The method of  claim 1 , wherein the polydispersity value of the polyoxypropylene/polyoxyethylene copolymer is less than approximately 1.05. 
     
     
       3. The method of  claim 1 , wherein the polydispersity value of the polyoxypropylene/polyoxyethylene copolymer is less than approximately 1.03. 
     
     
       4. The method of  claim 1 , wherein the polyoxypropylene polymer first composition is purified by gel permeation chromatography. 
     
     
       5. The method of  claim 1 , wherein the copolymer is substantially unsaturated. 
     
     
       6. A method of preparing a non-toxic surface-active copolymer including first condensing propylene oxide with a base compound containing a plurality of reactive hydrogen atoms to produce polyoxypropylene polymer and then condensing ethylene oxide with the polyoxypropylene polymer to produce a polyoxypropylene/polyoxyethylene block copolymer with the following formula: 
       
         
           HO(C 2 H 4 O) b (C 3 H 6 O) a (C 2 H 4 O) b H  
         
       
       The method of  claim 1 , wherein “a” is an integer such that the molecular weight of the hydrophobe (C 3 H 6 O) represented by the polyoxypropylene portion of the respective block copolymer is approximately 1750 daltons and the total molecular weight of the compound respective block copolymer is approximately 8400 daltons, 
       the improvement being the purification of the polyoxypropylene polymer before the step of condensing ethylene oxide with the polyoxypropylene polymer thereby providing a polyoxypropylene/polyoxyethylene block copolymer preparation with a polydispersity value of less than approximately 1.07 .  
     
     
       7. The method of  claim 6 , wherein the polydispersity value of the polyoxypropylene/polyoxyethylene copolymer is less than approximately 1.05. 
     
     
       8. The method of  claim 6 , wherein the polydispersity value of the polyoxypropylene/polyoxyethylene copolymer is less than approximately 1.03. 
     
     
       9. The method of  claim 6 , wherein the polyoxypropylene polymer first composition is purified by gel permeation chromatography. 
     
     
       10. The method of  claim 6 , wherein the copolymer is substantially unsaturated. 
     
     
       11. A method of preparing a non-toxic surface-active copolymer polyoxypropylene/polyoxyethylene block copolymer composition including first condensing propylene oxide with a base compound containing a plurality of reactive hydrogen atoms to produce a first composition containing a plurality of polyoxypropylene polymer polymers and then condensing ethylene oxide with the plurality of polyoxypropylene polymer polymers to produce a polyoxypropylene/polyoxyethylene block copolymer composition, said block copolymer composition consisting essentially of block copolymers with each of the block copolymers having the following general formula: 
       
         
           HO(C 2 H 4 O) b (C 3 H 6 O)) a (C 2 H 4 O) b H  
         
       
       wherein the molecular weight of the hydrophobe (C 3 H 6 O) is approximately 1750 daltons and the average total molecular weight of the compound is approximately 8400 daltons ,  
       the improvement being the purification of the polyoxypropylene polymer first composition before the step of condensing ethylene oxide with the plurality of polyoxypropylene polymer polymers thereby providing a polyoxypropylene/polyoxyethylene block copolymer preparation composition wherein the polyoxypropylene portion of respective block the copolymer is between approximately 900 and 15000 daltons and the molecular weight represented by the polyoxyethylene portion of the respective block copolymer constitutes between approximately 5% and 95%.  
     
     
       12. The method of  claim 11 , wherein the respective block copolymer has a molecular weight range of between approximately 1,200 and 6500 daltons. 
     
     
       13. The method of  claim 11 , wherein polyoxyethylene portion of the respective block copolymer constitutes between approximately 10% and 90% of the respective block copolymer. 
     
     
       14. The method of  claim 11 , wherein the copolymer is substantially unsaturated free of unsaturation. 
     
     
       15. A method for preparing a surface active composition including first condensing propylene oxide with a base compound containing a plurality of reactive hydrogen atoms to produce a first composition containing a plurality of polyoxypropylene polymers and then condensing ethylene oxide with the plurality of polyoxypropylene polymers to produce a polyoxypropylene/polyoxyethylene block copolymer composition, said block copolymer composition comprising an impurity containing unsaturation and block copolymers with each of the block copolymers having the following general formula: 
       
         
             HO ( C   2   H   4   O ) b ( C   3   H   6   O ) a ( C   2   H   4   O ) b   H    
         
       
         wherein “a” is an integer such that the molecular weight represented by the polyoxypropylene portion of the respective block copolymer is between approximately  900  and  15000  daltons and “b” is an integer such that the molecular weight represented by the polyoxyethylene portion of the respective block copolymer constitutes between approximately  5   %  and  95   %  of the respective block copolymer,    
         the improvement being the purification of the block copolymer composition by fractionation so that the polydispersity value of the surface - active composition is less than approximately  1 . 07  and the surface - active composition is substantially free of unsaturation as measured by nuclear magnetic resonance spectroscopy.    
     
     
       16. The method of  claim 15 , wherein the fractionation is performed by gel permeation chromatography.  
     
     
       17. The method of  claim 15 , wherein the polydispersity value is less than approximately  1 . 05 .  
     
     
       18. The method of  claim 15 , wherein the polydispersity value is less than approximately  1 . 03 .