Core-Shell Hydrogel Particles for the Formulation of Hydrophobic Small-Molecule APIs

Lucas Attia, Massachusetts Institute of Technology

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Hydrophobic active pharmaceutical ingredients (APIs) are becomingly increasingly relevant to drug discovery. It is estimated that 40% of commercialized therapeutic molecules and 90% of drug candidates in the pharmaceutical development pipeline are hydrophobic1. However, most hydrophobic API candidates fail in clinical trials, often due to poor oral bioavailability. Additionally, clinicians have increasingly prescribed fixed dose combinations (FDCs) for their benefits in therapeutic applications including hypertension, HIV, microbial infections, hepatitis C, and others2. The pharmaceutical industry has developed some solutions to formulate hydrophobic APIs, namely the preparation of nanocrystalline API through milling and amorphous solid dispersions through hot melt extrusion or spray drying3,4. However, these processes are energy-intensive, over-fitted to specific APIs, and often rely on empirical correlations and tedious optimization experiments. These processes also lack the flexibility to formulate FDCs comprised of APIs with different pharmacokinetic requirements. Innovations aimed at overcoming these 5-8. Here, we show a dual gelation dripping technique that uses two simultaneous gelations to synthesize core-shell particles in a single processing step. Through encapsulating a drug-loaded nanoemulsion in a hydrogel matrix, we show that this technique enables the preparation of drug nanocrystals without milling. We highlight flexible controlled drug release profiles from these particles that are tunable to therapeutic needs, including delayed burst-release, sustained-release, and a fixed dose combination product. We hypothesize a potential formulation parameter as a potential control for inducing specific drug crystal structures, propose mechanistically exploring drug-excipient interactions using molecular dynamics (MD) simulations.

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4Bhujbal. Acta Pharm Sin B 11, 2505–2536 (2021).
5Gupta. Soft Matter 12, 2826-2841 (2016).
6Li. Nat Dev Mater 1, (2016).
7Chen. Adv. Sci. 7, 2001677 (2020).
8Chen. Adv. Mater. 33, e2008618 (2021).

Abstract Author(s): Lucas Attia*, Dr. Liang-Hsun Chen*, Professor Patrick S. Doyle and *Massachusetts Institute of Technology, Department of Chemical Engineering