Facile preparation of tetra-polyethylene glycol hydrogel microspheres for drug delivery by cross-flow membrane emulsification

The purpose of this work was to develop technology for facile, large-scale production of tetra-polyethylene glycol (PEG) hydrogel amino-microspheres to serve as intermediates for injectable microsphere-drug conjugates produced under cGMP guidelines. Here we developed equipment and procedures utilizing tubular cross-flow membrane emulsification to produce the amino-microspheres. The equipment comprised a polyether ether ketone tube containing 1000 evenly spaced pores encased in a cylindrical stainless steel jacket. The dispersed phase - an aqueous solution of two polymerizable tetra-PEG prepolymers - is delivered into the outer jacket of the assembly by a pulse dampened pump, and the continuous phase - decane and surfactant - is delivered into the bore of the microporous tube from a pressurized tank. As the dispersed phase is pressed through the pores, the continuous phase induces the detachment of small, uniform droplets of similar to 60 mu m diameter at the mouths of the pores. After collection of the emulsified droplets, they are allowed to self-polymerize and are then sieved to remove aberrantly small and large particles. The polymerized amino-microspheres - obtained in similar to 70% yield - are well within acceptance specifications, and show excellent injectability. Using this approach, we could prepare about 30 L of swollen amino-microspheres per day which could be forwarded to production of microsphere-drug substance under cGMP guidelines.

Automated summary

The study aimed to develop technology for the mass production of tetra-PEG hydrogel amino-microspheres as intermediates for injectable microsphere-drug conjugates under cGMP guidelines. Utilizing tubular cross-flow membrane emulsification, equipment and procedures were developed to successfully produce the amino-microspheres in accordance with specifications.