Large scale process for preparing poly (glutamyl-glutamate) conjugates

摘要

Described herein are processes of making biocompatible water-soluble polymers conjugates. In particular, large scale processes of making poly(L-γ-glutamyl-glutamate) conjugates that can be useful for a variety of drug delivery applications are described herein.

主权项

1. A process of manufacture for preparing batches of a poly(L-γ-glutamyl-glutamate)-anticancer drug conjugate comprising:
polymerizing a compound of Formula (A) to form a polymer having recurring units of Formula (I), wherein R1 is selected from the group consisting of C1-6 alkyl, an optionally substituted phenyl and an optionally substituted benzyl; forming the alkali metal salt of the recurring unit of Formula (I); reacting the alkali metal salt of the recurring unit of Formula (I) with a compound of Formula (B) to form a polymer having recurring units of Formula (II), wherein each R2 is independently selected from the group consisting of C1-6 alkyl, an optionally substituted phenyl and an optionally substituted benzyl; removing the R2 groups from the recurring units of Formula (II) to form a polymer having recurring units of Formula (III); and reacting an anticancer drug with a portion of the recurring units of Formula (III) to form the poly(L-γ-glutamyl-glutamate)-anticancer drug conjugate, wherein the poly(L-γ-glutamyl-glutamate)-anticancer drug conjugate comprises recurring units of Formula (IV) and recurring units of Formula (V):wherein:
each R3 is independently hydrogen or an alkali metal; and each R4 is independently hydrogen, an alkali metal or the anticancer drug, provided that at least one R4 is the anticancer drug; wherein at least 3 batches of poly(L-γ-glutamyl-glutamate)-anticancer drug conjugate are prepared; wherein each batch provides an amount of the poly(L-γ-glutamyl-glutamate)-anticancer drug conjugate greater than or equal to about 300 grams; and wherein each batch of poly(L-γ-glutamyl-glutamate)-anticancer drug conjugate has one or more characteristics selected from a weight average molecular weight within ±10 kDa from each other batch, a polydispersity in the range of 1.0 to 2.0 and an endotoxin content <0.25 EU/mg.