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 polyoxypropylene/polyoxyethylene block copolymer .Iadd.composition, said composition consisting essentially of block copolymers .Iaddend.with .Iadd.each of the block copolymers having .Iaddend.the following general formula:   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein a is an integer such that the molecular weight represented by the polyoxypropylene portion of the .Iadd.respective block .Iaddend.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 .Iadd.respective block .Iaddend.copolymer constitutes between approximately 5% and .[.90.]. .Iadd.95.Iaddend.% of the .Iadd.respective block .Iaddend.copolymer and the polydispersity value .Iadd.of the composition .Iaddend.is less than approximately 1.07 .Iadd.and the composition is substantially free of unsaturation as measured by nuclear magnetic resonance spectroscopy.Iaddend..   
     
     
       2. The .[.block copolymer.]. .Iadd.composition .Iaddend.of claim 1, wherein the polydispersity value is less than approximately 1.05. 
     
     
       3. The .[.block copolymer.]. .Iadd.composition .Iaddend.of claim 1, wherein the polydispersity value is less than approximately 1.03. .[.4. The block copolymer of claim 1, wherein the copolymer is substantially free of 
     
     
        unsaturation..].5. The .[.block copolymer.]. .Iadd.composition .Iaddend.of claim 1, wherein the .Iadd.respective block .Iaddend.copolymer has a molecular weight range of between approximately 1,200 and 6500 daltons. 
     
     
           The .[.block copolymer.]. .Iadd.composition .Iaddend.of claim 5, wherein the polyoxyethylene portion of the .Iadd.respective block .Iaddend.copolymer constitutes between approximately 10% and 90% of the 
     
     
        .Iadd.respective block .Iaddend.copolymer. 7. A surface-active copolymer .[.comprising a.]. .Iadd.composition consisting essentially of .Iaddend.polyoxypropylene/polyoxyethylene block .[.copolymer.]. .Iadd.copolymers .Iaddend.with .Iadd.each of the block copolymers having .Iaddend.the following general formula:   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein a is an integer such that the molecular weight of the hydrophobe (C 3  H 6  O) .Iadd.of the respective block copolymer .Iaddend.is approximately 1750 daltons and b is an integer such that the average total molecular weight of the .[.compound.]. .Iadd.block copolymers in the composition .Iaddend.is approximately 8400 daltons and the polydispersity value .Iadd.of the composition .Iaddend.is less than approximately 1.07.   
     
     
           The surface-active copolymer .Iadd.composition .Iaddend.of claim 7, 
     
     
        wherein the polydispersity value is less than approximately 1.05. 9. The surface-active copolymer .Iadd.composition .Iaddend.of claim 7, wherein 
     
     
        the polydispersity value is less than approximately 1.03. 10. The surface-active copolymer .Iadd.composition .Iaddend.of claim 7, wherein the .[.copolymer.]. .Iadd.composition .Iaddend.is substantially free of unsaturation .Iadd.as measured by nuclear magnetic resonance 
     
     
        spectroscopy.Iaddend.. 11. A surface-active copolymer .[.comprising a.]. .Iadd.composition consisting essentially of .Iaddend.polyoxypropylene/polyoxyethylene block .[.copolymer.]. .Iadd.copolymers .Iaddend.with .Iadd.each of the block copolymers having .Iaddend.the following general formula:   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein the total molecular weight of the .Iadd.respective block .Iaddend.copolymer is between approximately 5,000 and 15,000 daltons and b is an integer such that the molecular weight represented by the polyoxyethylene portion of the .Iadd.respective block .Iaddend.copolymer constitutes between approximately 75% and 85% of the .Iadd.respective   
     
     
        block .Iaddend.copolymer. 12. The surface-active copolymer .Iadd.composition .Iaddend.of claim 11, wherein the total molecular weight of the .Iadd.respective block .Iaddend.copolymer is between approximately 
     
     
        7,000 and 12,000 daltons. 13. The surface-active copolymer .Iadd.composition .Iaddend.of claim .Iadd.11, .Iaddend.wherein the .[.copolymer.]. .Iadd.composition .Iaddend.is substantially free of unsaturation .Iadd.as measured by nuclear magnetic resonance 
     
     
        spectroscopy.Iaddend.. 14. A surface-active copolymer .[.comprising a.]. .Iadd.composition consisting essentially of .Iaddend.polyoxypropylene/polyoxyethylene block .[.copolymer.]. .Iadd.copolymers .Iaddend.with .Iadd.each of the block copolymers having .Iaddend.the following general formula:   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein a is an integer such that the molecular weight of the hydrophobe (C 3  H 6  O) .Iadd.of the respective block copolymer .Iaddend.is approximately 9,700 daltons and the average total molecular weight of the .[.compound.]. .Iadd.block copolymers in the composition .Iaddend.is approximately 10,000 daltons and the polydispersity value .Iadd.of the   
     
     
        composition .Iaddend.is less than approximately 1.07. 15. The surface-active copolymer .Iadd.composition .Iaddend.of claim 14, wherein 
     
     
        the polydispersity value is less than approximately 1.05. 16. The surface-active copolymer .Iadd.composition .Iaddend.of claim 14, wherein 
     
     
        the polydispersity value is less than approximately 1.03. 17. The surface-active copolymer .Iadd.composition .Iaddend.of claim 14, wherein the .[.copolymer.]. .Iadd.composition .Iaddend.is substantially free of unsaturation .Iadd.as measured by nuclear magnetic resonance 
     
     
        spectroscopy.Iaddend.. 18. A surface-active copolymer .[.comprising a.]. .Iadd.composition consisting essentially of .Iaddend.polyoxypropylene/polyoxyethylene block .[.copolymer.]. .Iadd.copolymers .Iaddend.with .Iadd.each of the block copolymers having .Iaddend.the following general formula:   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein a is an integer such that the molecular weight of the hydrophobe (C 3  H 6  O) .Iadd.of the respective block copolymer .Iaddend.is approximately 3400 daltons and the average total molecular weight of the .[.compound.]. .Iadd.block copolymers in the composition .Iaddend.is approximately 4000 daltons and the polydispersity value .Iadd.of the   
     
     
        composition .Iaddend.is less than approximately 1.07. 19. The surface-active copolymer .Iadd.composition .Iaddend.of claim 18, wherein 
     
     
        the polydispersity value is less than approximately 1.05. 20. The surface-active copolymer .Iadd.composition .Iaddend.of claim 18, wherein 
     
     
        the polydispersity value is less than approximately 1.03. 21. The surface-active copolymer .Iadd.composition .Iaddend.of claim 18, wherein the .[.copolymer.]. .Iadd.composition .Iaddend.is substantially free of .[.unsaturated.]. .Iadd.unsaturation as measured by nuclear magnetic 
     
     
        resonance spectroscopy.Iaddend.. 22. Substantially pure block copolymer .Iadd.composition consisting essentially of block copolymers with each of the block copolymers .Iaddend.having the formula.Iadd.:.Iaddend.   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein a is an integer such that the molecular weight of the hydrophobe (C 3  H 6  O) .Iadd.of the respective block copolymer .Iaddend.is approximately 1750 Daltons and b is an integer such that the average molecular weight of the .[.compound.]. .Iadd.block copolymers in the composition .Iaddend.is approximately 8400 Daltons, the .[.block copolymer.]. .Iadd.composition .Iaddend.having a polydispersity value of   
     
     
        less than approximately 1.07. 23. The block copolymer .Iadd.composition .Iaddend.of claim 22, wherein the polydispersity value is less than 
     
     
        approximately 1.05. 24. The block copolymer .Iadd.composition .Iaddend.of claim 22, wherein the polydispersity value is less than approximately 
     
     
        1.03. 25. The block copolymer .Iadd.composition .Iaddend.of claim 22, wherein the .[.copolymer.]. .Iadd.composition .Iaddend.is substantially free of unsaturation .Iadd.as measured by nuclear magnetic resonance 
     
     
        spectroscopy.Iaddend.. 26. Substantially pure block copolymer .Iadd.composition consisting essentially of block copolymers with each of the block copolymers .Iaddend.having the formula.Iadd.:.Iaddend.   HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H     wherein a is an integer such that the molecular weight of the hydrophobe (C 3  H 6  O) .Iadd.of the respective block copolymer .Iaddend.is approximately 1750 Daltons and the average .Iadd.total .Iaddend.molecular weight of the .[.compound.]. .Iadd.block copolymers in the composition .Iaddend.is approximately 8400 Daltons, and wherein the .[.block copolymer.]. .Iadd.composition .Iaddend.comprises .[.at least.]. .Iadd.greater than .Iaddend.92.2 percent by weight of a middle molecular weight fraction.[., not more than 2.1 percent by weight of an early molecular weight fraction, and not more than 5.7 percent by weight of a late molecular weight fraction.]. when fractionated by gel permeation   
     
     
        chromatography. 27. The .[.block copolymer.]. .Iadd.composition .Iaddend.of claim 26, wherein the .[.copolymer.]. .Iadd.composition .Iaddend.is substantially free of unsaturation .Iadd.as measured by 
     
     
        nuclear magnetic resonance spectroscopy.Iaddend.. 28. The .[.block copolymer.]. .Iadd.composition .Iaddend.of claim 26, wherein the .[.copolymer.]. .Iadd.composition .Iaddend.comprises essentially 100 percent of the middle molecular weight fraction.