Aerogels are the lightest processed solid materials on Earth and with the largest empty volume fraction in their structure. Composition versatility, modularity, and feasibility of industrial scale manufacturing are behind the fast emergence of aerogels in the drug delivery field. Compared to other 3D materials, the high porosity (interconnected mesopores) and high specific surface area of aerogels may allow faster loading of small-molecule drugs, less constrained access to inner regions of the matrix, and more efficient interactions of the biological milieu with the polymer matrix. Processing in supercritical CO2 medium for both aerogel production (drying) and drug loading (impregnation) has remarkable advantages such as absence of an oxidizing environment, clean manufacture, and easiness for the scale-up under good manufacturing practices. The aerogel solid skeleton dictates the chemical affinity to the different drugs, which in turn determines the loading efficiency and the release pattern. Aerogels can be used to increase the solubility of BCS Class II and IV drugs because the drug can be deposited in amorphous state onto the large surface area of the skeleton, which facilitates a rapid contact with the body fluids, dissolution, and release. Conversely, tuning the aerogel structure by functionalization with drug-binding moieties or stimuli-responsive components, application of coatings and incorporation of drug-loaded aerogels into other matrices may enable site-specific, stimuli-responsive, or prolonged drug release. The present review deals with last decade advances in aerogels for drug delivery. An special focus is paid first on the loading efficiency of active ingredients and release kinetics under biorelevant conditions. Subsequent sections deal with aerogels intended to address specific therapeutic demands. In addition to oral delivery, the physical properties of the aerogels appear to be very advantageous for mucosal administration routes, such as pulmonary, nasal, or transdermal. A specific section devoted to recent achievements in gene therapy and theranostics is also included. In the last section, scale up strategies and life cycle assessment are comprehensively addressed.

Silica-gelatin hybrid aerogels of varying gelatin content (from 4 wt.% to 24 wt.%) can be conveniently impregnated with hydrophobic active agents (e.g. ibuprofen, ketoprofen) in supercritical CO₂ and used as drug delivery systems. Contrast variation neutron scattering (SANS) experiments show the molecular level hybridization of the silica and the gelatin components of the aerogel carriers. The active agents are amorphous, and homogeneously dispersed in these porous, hybrid matrices. Importantly, both fast and retarded drug release can be achieved with silica-gelatin hybrid aerogels, and the kinetics of drug release is governed by the gelatin content of the carrier. In this paper, for the first time, a molecular level explanation is given for the strong correlation between the composition and the functionality of a family of aerogel based drug delivery systems. Characterization of the wet aerogels by SANS and by NMR diffusiometry, cryoporometry and relaxometry revealed that the different hydration mechanisms of the aerogels are responsible for the broad spectrum of release kinetics. Low-gelatin (4-11 wt.%) aerogels retain their open-porous structure in water, thus rapid matrix erosion dictates fast drug release from these carriers. In contrast to this, wet aerogels of high gelatin content (18-24 wt.%) show well pronounced hydrogel-like characteristics, and a wide gradual transition zone forms in the solid-liquid interface. The extensive swelling of the high-gelatin hybrid backbone results in the collapse of the open porous structure, that limits mass transport towards the release medium, resulting in slower, diffusion controlled drug release. STATEMENT OF SIGNIFICANCE: Developing new drug delivery systems is a key aspect of pharmaceutical research. Supercritically dried mesoporous aerogels are ideal carriers for small molecular weight drugs due to their open porous structures and large specific surface areas. Hybrid silica-gelatin aerogels can display both fast and retarded drug release properties based on the gelatin contents of their backbones. The structural characterization of the aerogels by SANS and by NMR diffusiometry, cryoporometry and relaxometry revealed that the different hydration mechanisms of the hybrid backbones are responsible for the broad spectrum of release kinetics. The molecular level understanding of the functionality of these hybrid inorganic-biopolymer drug delivery systems facilitates the realization of quality-by-design in this research field.