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|Title:||Method for purifying a branched water-soluble polymer|
|Abstract:||Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure ##STR00001## wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms poly.sub.a and poly.sub.b, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure ##STR00002## where mPEG.sub.a and mPEG.sub.b have the structure CH.sub.3O--(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2-- wherein n may be the same or different for poly.sub.a- and poly.sub.b- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.|
|Inventor(s):||Harris; J. Milton (Huntsville, AL), Veronese; Francesco Maria (Padua, IT), Caliceti; Paola (Padua, IT), Schiavon; Oddone (Padua, IT)|
|Assignee:||Nektar Therapeutics AL, Corporation (Huntsville, AL)|
|Filing Date:||Aug 05, 2003|
|Claims:||1. A method for preparing a purified polymer, said method comprising the steps of: providing an impure polymer composition comprising (i) a branched water-soluble polymer having the structure: ##STR00040## where R is a non-reactive moiety, Z is a moiety comprising a site suitable for interacting with ion exchange chromatography media, PEG.sub.a and PEG.sub.b are each independently an end-capped polyethylene glycol (PEG), and P and Q each comprise a non-reactive linker absent an aromatic ring or ester group, and (ii) one or more polymeric impurities selected from the group consisting of PEG diol, end-canned PEG-OH, and activated end-capped PEG, and purifying said impure polymer composition by ion exchange chromatography under conditions effective to essentially remove said polymeric impurities and thereby provide said branched water-soluble polymer in essentially pure form. |
2. The method of claim 1, wherein PEG.sub.a and PEG.sub.b are each end-capped with a methyl group, said end-capped PEG-OH is methoxy-PEG-OH, and said activated end-capped PEG is activated methoxy-PEG.
3. The method of claim 1, wherein prior to said providing, said method comprises identifying said one or more polymeric impurities in said composition.
4. The method of claim 1, wherein said site suitable for interacting with ion exchange chromatography media is selected from the group consisting of carboxyl, hydroxyl, and amino.
5. The method of claim 4, wherein said site suitable for interacting with ion exchange chromatography media is carboxyl.
6. The method of claim 1, wherein said purifying further comprises: loading the impure polymer composition onto an ion exchange chromatography medium to provide a loaded medium, washing the polymeric impurities from said loaded medium using an aqueous eluent under conditions effective to elute said impurities from said medium, adjusting the conditions of the aqueous eluent to effect elution of said branched water-soluble polymer from the medium, and eluting said branched water-soluble polymer from said medium to provide an aqueous solution comprising said branched water-soluble polymer in essentially pure form.
7. The method of claim 6, further comprising recovering said purified branched water-soluble polymer from said aqueous solution.
8. The method of claim 1, wherein said branched water soluble polymer has a molecular weight ranging from about 10,000 daltons to about 50,000 daltons.
9. The method of claim 6, wherein PEG.sub.a and PEG.sub.b are each end-capped with a methyl group, said end-capped PEG-OH is methoxy-PEG-OH, and said activated end-capped PEG is activated methoxy-PEG.
10. The method of claim 9, wherein said branched water-soluble polymer has a molecular weight ranging from about 100 to about 100,000 daltons.
11. The method of claim 9, wherein said activated methoxy-PEG comprises an electrophilic activating group.
12. The method of claim 11, wherein said electrophilic activating group is an active ester activating group.
13. The method of claim 9, wherein said adjusting step comprises adjusting the pH of the aqueous eluent.
14. The method of claim 9, wherein said adjusting step comprises adjusting the salt concentration of the eluent.
15. The method of claim 9, wherein said branched water-soluble polymer has the structure: ##STR00041## and mPEG.sub.a and mPEG.sub.b are each independently a monomethoxy polyethylene glycol.
16. The method of claim 1, wherein said polymeric impurities further comprise a mono-substituted PEG intermediate.
17. The method of claim 1, wherein P and Q are the same or different.
18. The method of claim 1, wherein Z comprises a single site suitable for interacting with ion exchange chromatography media.
19. The method of claim 15, wherein said polymeric impurities further comprise monomethoxy polyethylene glycol mono-substituted lysine.
20. A branched water-soluble polymer purified by the method of claim 1.
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