a better way to make core-shell hydrogel particles

This project, the first in my PhD, focused on figuring out a clever way to engineer core-shell hydrogel drug carrier particles. Core-shell particles are extremely useful in oral drug delivery. They can unlock sustained and delayed release profiles, which is important for instestinal and colonic targeting applications. They can also formulate fixed dosage combination (FDC) products, structuring different active ingredients in the core and the shell. Despite these useful applications, conventional methods for engineering core-shell carriers for pharmaceutical applications are limited, relying on organic solvents, high processing temperatures, and are often unable to structure drugs in the shell (see below).

Different ways to make core-shell particles

With this project, we invented a clever way to circumvent these challenges by making two different types of hydrogels in a single core-shell structure. We rely on methylcellulose and alginate-based hydrogels to do this. Methylcellulose gels thermally (gels when heated, opposite of gelatin), while alginate gels from salt crosslinking. By dripping a salty methylcellulose solution (loaded with whatever cargo you want to encapsulate) into a syringe and dripping droplets into a heated alginate bath, we can trigger the methylcellulose thermal gelation of a droplet into a ‘core,’ encapsulating the cargo. Simultaneously salt diffuses out of the core into the bath and crosslinks alginate, generating a gel ‘shell’ layer. In one stop, we have generated an all-aqeuous core-shell particle. The process is simple, avoids the use of an organic solvent, is gentle (methylcellulose can gel in temperatures as low as 33 C), and provides is an opportuntity to encapsulate different cargo in each layer, with no overlap. Plus, the particles end up looking beautiful!

Digital microscopy image of a core-shell hydrogel particle.

References

2023

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

Lucas Attia, Liang-Hsun Chen, and Patrick S Doyle

Adv. Healthc. Mater., Jul 2023

Abs PDF

Hydrophobic active pharmaceutical ingredients 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. This article is protected by copyright. All rights reserved.