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.

Design and Use of a Thermogelling Methylcellulose Nanoemulsion to Formulate Nanocrystalline Oral Dosage Forms.

Oral drug products have become indispensable in modern medicine because of their exceptional patient compliance. However, poor bioavailability of ubiquitous low-water-soluble active pharmaceutical ingredients (APIs) and lack of efficient oral drug formulations remain as significant challenges. Nanocrystalline formulations are an attractive route to increase API solubility, but typically require abrasive mechanical milling and several processing steps to create an oral dosage form. Using the dual amphiphilic and thermoresponsive properties of methylcellulose (MC), a new thermogelling nanoemulsion and a facile thermal dripping method are developed for efficient formulation of composite particles with the MC matrix embedded with precisely controlled API nanocrystals. Moreover, a fast and tunable release performance is achieved with the combination of a fast-eroding MC matrix and fast-dissolving API nanocrystals. Using the versatile thermal processing approach, the thermogelling nanoemulsion is easily formulated into a wide variety of dosage forms (nanoparticle suspension, drug tablet, and oral thin film) in a manner that avoids nanomilling. Overall, the proposed thermogelling nanoemulsion platform not only broadens the applications of thermoresponsive nanoemulsions but also shows great promise for more efficient formulation of oral drug products with high quality and tunable fast release.

Nanoemulsion-Loaded Capsules for Controlled Delivery of Lipophilic Active Ingredients.

Nanoemulsions have become ideal candidates for loading hydrophobic active ingredients and enhancing their bioavailability in the pharmaceutical, food, and cosmetic industries. However, the lack of versatile carrier platforms for nanoemulsions hinders advanced control over their release behavior. In this work, a method is developed to encapsulate nanoemulsions in alginate capsules for the controlled delivery of lipophilic active ingredients. Functional nanoemulsions loaded with active ingredients and calcium ions are first prepared, followed by encapsulation inside alginate shells. The intrinsically high viscosity of the nanoemulsions ensures the formation of spherical capsules and high encapsulation efficiency during the synthesis. Moreover, a facile approach is developed to measure the nanoemulsion release profile from capsules through UV-vis measurement without an additional extraction step. A quantitative analysis of the release profiles shows that the capsule systems possess a tunable, delayed-burst release. The encapsulation methodology is generalized to other active ingredients, oil phases, nanodroplet sizes, and chemically crosslinked inner hydrogel cores. Overall, the capsule systems provide promising platforms for various functional nanoemulsion formulations.