Autoclave sterilization of tetra-polyethylene glycol hydrogel biomaterials with β-eliminative crosslinks

Sterilization of degradable polymeric biomaterials intended for injection presents a formidable challenge. Often, either the polymer backbone or labile crosslinks controlling degradation are adversely affected by commonly used sterilization methods. The purpose of this work was to develop an approach to sterilize tetra-polyethylene glycol hydrogel microspheres (MSs) with beta -eliminative crosslinks that are destined to be carriers for drug delivery. The approach taken was to acidify the medium to compensate for the base-catalyzed cleavage of linkers at high temperatures. We determined that rates of linker cleavage at pH 4 or below were sufficiently slow as to allow autoclaving and showed that precursor amine-derivatized MSs could withstand autoclaving at pH 4 for at least four cycles of 20minutes each at 121 degrees C. Thus, amine-MSs need not be prepared aseptically, but instead can be prepared in a low bioburden environment, and then sterilized by autoclaving before drug attachment.