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US 2003/0224971 A1Published application
Manufacture of polyglutamate-therapeutic agent conjugates
AssigneeCell Therapeutics, Inc.
InventorsAnil M. Kumar, J. Peter Klein, Rama Bhatt, Edward Vawter
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Abstract
The invention provides new processes for preparing polyglutamic acid-therapeutic agent conjugates for clinical development and pharmaceutical use, and polyglutamic acid-therapeutic agent conjugates prepared by these processes.
Claims23
A process for preparing a conjugate of polyglutamic acid and a therapeutic agent, comprising:
- (a) providing the protonated form of a polyglutamic acid polymer and a therapeutic agent for conjugation thereto;
- (b) covalently linking said agent to said polyglutamic acid polymer in an inert organic solvent to form a polyglutamic acid-therapeutic agent conjugate;
- (c)) precipitating said polyglutamic acid-therapeutic agent conjugate from solution by addition of an excess volume of aqueous salt solution;
- and
- (d) collecting said conjugate as a protonated solid.
2 more elements
A process of preparing a conjugate of polyglutamic acid and a therapeutic agent, comprising:
- (a) suspending a salt of a polyglutamic acid polymer in an inert organic solvent;
- (d) protonating said polymer by the addition of an anhydrous acid to said suspension to form a soluble salt of the conjugate base;
- (e) providing a therapeutic agent and covalently linking said agent to said polyglutamic acid polymer to form a polyglutamic acid-therapeutic agent conjugate;
- (d) precipitating said polyglutamic acid-therapeutic agent conjugate from solution by the addition of an excess volume of aqueous salt solution;
- and
- (e) collecting said conjugate as a protonated solid.
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A process of preparing a poly-L-glutamic acid-2′-paclitaxel conjugate from the sodium salt of poly-L-glutamic acid and paclitaxel, said process comprising the steps of:
- (a) providing an aqueous solution of the sodium salt of poly-L-glutamic acid;
- (b) acidifying the solution to a pH of about 2 to 4, thereby converting the sodium salt of poly-L-glutamic acid to the protonated form and precipitating it from solution;
- (c) collecting the poly-L-glutamic acid precipitate and washing with water;
- (d) drying said poly-L-glutamic acid to a water content of between 7% and 21% by weight;
- (e) contacting said poly-L-glutamic acid with paclitaxel under standard coupling conditions for sufficient time to conjugate said paclitaxel to said polyglutamic acid polymer via an ester linkage formed between the 2′-OH group of paclitaxel and a carboxy group of poly-L-glutamic acid,
- (f) cooling said reaction mixture from between 0° C. to 10° C. while slowly adding aqueous salt solution to the reaction mixture;
- (h) acidifying the resulting suspension;
- (i) collecting the conjugate as a protonated solid;
- and
- (j) extracting impurities from said protonated solid.
7 more elements
Dependencies are inferred from the claim text.