Orthogonal Gelations to Synthesize Core-Shell Hydrogels Loaded with Nanoemulsion-Templated Drug Nanoparticles for Versatile Oral Drug Delivery

Hydrophobic active pharmaceutical ingredients (APIs) are ubiquitous in the drug development pipeline, but their poor bioavailability often prevents their translation into drug products. Industrial processes to formulate hydrophobic APIs are expensive, difficult to optimize, and not flexible enough to incorporate customizable drug release profiles into drug products. Here, a novel, dual-responsive gelation process that exploits orthogonal thermo-responsive and ion-responsive gelations is introduced. This one-step dual gelation synthesizes core-shell (methylcellulose-alginate) hydrogel particles and encapsulates drug-laden nanoemulsions in the hydrogel matrices. In situ crystallization templates drug nanocrystals inside the polymeric core, while a kinetically stable amorphous solid dispersion is templated in the shell. Drug release is explored as a function of particle geometry, and programmable release is demonstrated for various therapeutic applications including delayed pulsatile release and sequential release of a model fixed-dose combination drug product of ibuprofen and fenofibrate. Independent control over drug loading between the shell and the core is demonstrated. This formulation approach is shown to be a flexible process to develop drug products with biocompatible materials, facile synthesis, and precise drug release performance. This work suggests and applies a novel method to leverage orthogonal gel chemistries to generate functional core-shell hydrogel particles.

Automated summary

A novel dual-responsive gelation process that combines thermo-responsive and ion-responsive gelations is introduced in this study. This process synthesizes core-shell hydrogel particles and encapsulates drug-laden nanoemulsions, allowing in situ crystallization of drug nanocrystals in the polymeric core and templating of a kinetically stable amorphous solid dispersion in the shell. The study demonstrates programmable drug release for various therapeutic applications and independent control over drug loading between the shell and the core. This flexible formulation approach offers biocompatible materials, facile synthesis, and precise drug release performance.