Core–Shell Composite Hydrogels for Controlled Nanocrystal Formation and Release of Hydrophobic Active Pharmaceutical Ingredients

Abstract

Although roughly 40% of pharmaceuticals being developed are poorly water soluble, this class of drugs lacks a formulation strategy capable of producing high loads, fast dissolution kinetics, and low energy input. In this work, a novel bottom-up approach is developed for producing and formulating nanocrystals of poorly water-soluble active pharmaceutical ingredients (APIs) using core-shell composite hydrogel beads. Organic phase nanoemulsion droplets stabilized by polyvinyl alcohol (PVA) and containing a model hydrophobic API (fenofibrate) are embedded in the alginate hydrogel matrix and subsequently act as crystallization reactors. Controlled evaporation of this composite material produces core-shell structured alginate-PVA hydrogels with drug nanocrystals (500-650 nm) embedded within the core. Adjustable loading of API nanocrystals up to 83% by weight is achieved with dissolution (of 80% of the drug) occurring in as little as 30 min. A quantitative model is also developed and experimentally validated that the drug release patterns of the fenofibrate nanocrystals can be modulated by controlling the thickness of the PVA shell and drug loading. Thus, these composite materials offer a "designer" drug delivery system. Overall, our approach enables a novel means of simultaneous controlled crystallization and formulation of hydrophobic drugs that circumvents energy intensive top-down processes in traditional manufacturing.

High drug-loading nanomedicines: progress, current status, and prospects

“…Basically, such nanomedicines consist of DNCs dispersed in liquid medium, and are stabilized by surface-active agents, such as the poloxamer family, [169][170][171][172][173] Tween, [174][175][176] and polymers. [177][178][179][180] For oral administration, the high surface:volume ratios of DNCs significantly increase dissolution velocity, thereby leading to an improvement in the gastrointestinal tract absorption based on the Noyes-Whitney equation. 181 For intravenous administration, the smallness of this nanomedicine enables it to enter blood circulation and achieve targeted delivery through further surface modification.…”

Composite double network hydrogels with thermoresponsive colloidal nanoemulsions

“…Other possibilities include studying the effects on mechanical strength when nanoemulsions are loaded with nanoparticles, such as nanodiamonds . Mechanically optimized DN nanoemulsion hydrogels may be used to produce wound dressings or drug delivery devices, and are particularly attractive due to the potential to load lipophilic drugs into the hydrophobic nanoemulsion domains, where diffusion profiles of hydrophobic drug release may be controlled . Since the DN nanoemulsion gels possess enhanced mechanical properties, they could also be suitable for applications such as 3D printing and scaffolds for bone or tissue engineering …”

Nanoemulsion‐Loaded Capsules for Controlled Delivery of Lipophilic Active Ingredients

“…[27] Recently, our group encapsulated nanoemulsions inside alginate beads for confined crystallization. [3,[28][29][30] After solvent evaporation, nanocrystals of a lipophilic active pharmaceutical ingredient (API) were formed with the crystal size dictated by the oil droplet size. In addition, nanoemulsion-loaded alginate beads have also been applied for delivering a lipophilic bioactive ingredient in the liquid form.…”

“…To the best of our knowledge, nanoemulsion encapsulation techniques are limited to monolithic dosage forms. [3,[28][29][30][31][32] Here, we report a new method to encapsulate nanoemulsions in alginate capsules for the controlled delivery of lipophilic active ingredients. After the addition of CaCl 2 into nanoemulsions, a simple one-batch inverse gelation technique [33] is applied by dripping the calcium-laden nanoemulsions into an alginate bath.…”