Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development.

Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug's behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on in vitro release methods, available biopharmaceutical models and reported in vitro/in vivo correlations (IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.

Molecularly Designed Interfacial Viscoelasticity by Dendronized Polymers: From Flexible Macromolecules to Colloidal Objects.

The thermodynamic and rheological properties of densely packed dendronized polymers (DPs) at water-air interfaces were studied here for first- and fourth-generation DPs (PG1, PG4) with both small (Pn ≈ 50) and large (Pn ≈ 500) backbone degrees of polymerization. The excellent control over the structural characteristics of these polymers enabled us to investigate how the interfacial properties change as we go from thin, flexible macromolecules toward thicker molecular objects that display colloidal features. The effects of the dendron generation, affecting the persistence length, as well as the degree of polymerization and surface pressure on the formation of DP layers at the water-air interface were studied. Surface pressure measurements and interfacial rheology suggest the existence of significant attractive interactions between the molecules of the higher generation DPs. While all DPs featured reproducible Π-A diagrams, successive compression-expansion cycles and surface pressure relaxation experiments revealed differences in the stability of the formed films, which are consistent with the variations in shape persistence and interactions between the studied DPs. Atomic force microscopy after Langmuir-Blodgett transfer of the films displayed a nanostructuring that can be attributed to the increase in attractive forces with increasing polymer generation and anisotropy. The importance of such structures on the surface properties was probed by interfacial shear rheology, which validated the existence of strong albeit brittle structures for fourth-generation DPs. Ultimately, we demonstrate how in particular rod-like DPs can be used as robust foam stabilizers.

Stress Contributions in Colloidal Suspensions: The Smooth, the Rough, and the Hairy.

The collective properties of colloidal suspensions, including their rheology, reflect an interplay between colloidal and hydrodynamic forces. The surface characteristics of the particles play a crucial role, in particular, for applications in which interparticle distances become small, i.e., at high concentrations or in aggregates. In this Letter, we directly investigate this interplay via the linear viscoelastic response of the suspensions in the high-frequency regime, using particles with controlled surface topographies, ranging from smooth to hairy and rough particles. We focus directly on the stresses at the particle level and reveal a strong impact of the surface topography on the short-range interactions, both dissipative and elastic. As the particle topography becomes more complex, the local stresses depend on how the topography is generated. The findings in this Letter, in particular, show how changes in topography can both screen or enhance the dissipation, which can be used to engineer the properties of dense or aggregated suspensions.

Quantifying the dispersion quality of partially aggregated colloidal dispersions by high frequency rheology.

An important parameter for the performance of nanomaterials is the degree by which the nanoparticles are dispersed in a matrix. Optical microscopy or scattering methods are useful to characterise the state of dispersion, but are not generally applicable to all materials. Electron microscopy methods are laborious in preparation and typically offer only quantitative information on a very local scale. In the present work we investigate how high frequency rheological measurements can be used for partially dispersed suspensions at intermediate to higher particle loadings, even for high viscous matrices. Although the contribution of the particles is particularly visible in the low frequency linear viscoelastic behaviour, a more direct relationship between rheological properties and degree of dispersion can be derived from the loss modulus in the high frequency limit. To this end, a home-built piezo shear rheometer is constructed to extend the frequency range typically accessible by commercial rotational rheometers. Measurements on spherical silica particles, with a varying degree of dispersion in low molecular weight PDMS, are used to demonstrate how high frequency rheometry can be used to quantify dispersion quality. The linear viscoelastic properties are compared to analytical scaling theories to demonstrate that a hydrodynamically dominated regime is reached. The dependence of the relative high frequency loss modulus on volume fraction is then compared to predictions of a hydrodynamic viscosity model for the derivation of a dispersion quality index. It is used to follow the evolution of the dispersion quality as a function of mixing time and consumed power.