The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

The global market of pharmaceutical biologics has expanded significantly during the last few decades. Currently, pharmaceutical biologic products constitute an indispensable part of the modern medicines. Most pharmaceutical biologic products are injections either in the forms of solutions or lyophilized powders because of their low oral bioavailability. There are certain pharmaceutical biologic entities formulated into particulate delivery systems for the administration via non-invasive routes or to achieve prolonged pharmaceutical actions to reduce the frequency of injections. It has been well documented that the design of nano- and microparticles via various particle engineering technologies could render pharmaceutical biologics with certain benefits including improved stability, enhanced intracellular uptake, prolonged pharmacological effect, enhanced bioavailability, reduced side effects, and improved patient compliance. Herein, we review the principles of the particle engineering technologies based on bottom-up approach and present the important formulation and process parameters that influence the critical quality attributes with some mathematical models. Subsequently, various nano- and microparticle engineering technologies used to formulate or process pharmaceutical biologic entities are reviewed. Lastly, an array of commercialized products of pharmaceutical biologics accomplished based on various particle engineering technologies are presented and the challenges in the development of particulate delivery systems for pharmaceutical biologics are discussed.

Direct compaction (DC) is the preferred method for tablet production. However, only a minority of the active pharmaceutical ingredients (APIs) can be truly manufactured into tablets by DC so far due to that most of APIs lack sufficient functional properties required for DC. Particle engineering with co-processing provides a promising way to obtain various composite API and/or excipient particles with markedly improved functional properties, which makes successful tableting of them by DC possible. This review, as an informative update and supplement, covers the improvement of functional properties of composite API and/or excipient particles via co-processing based on recent developments and researches in the area of particle engineering for DC. The improved functionality of co-processed particles and corresponding mechanisms were summarized and discussed from the perspective of structure characteristics (Crystal level and Particle level) as the properties of particles are markedly affected by their structure.

The pharmacokinetics of inhaled rapamycin (RAPA) is compared for amorphous versus crystalline dry powder formulations. The amorphous formulation of RAPA and lactose (RapaLac) was prepared by thin film freezing (TFF) using lactose as the stabilizing agent in the weight ratio 1:1. The crystalline formulation was prepared by wet ball milling RAPA and lactose and posteriorly blending the mixture with coarse lactose (micronized RAPA/micronized lactose/coarse lactose=0.5:0.5:19). While both powders presented good aerosolization performance for lung delivery, TFF formulation exhibited better in vitro aerodynamic properties than the crystalline physical mixture. Single-dose 24h pharmacokinetic studies were conducted in Sprague-Dawley rats following inhalation of the aerosol mist in a nose-only inhalation exposure system. Lung deposition was higher for the crystalline group than for the TFF group. Despite higher pulmonary levels of drug that were found for the crystalline group, the systemic circulation (AUC₀₋₂₄) was higher for the amorphous group (8.6 ngh/mL) than for crystalline group (2.4 ngh/mL) based on a five-compartmental analysis. Lung level profiles suggest that TTF powder stays in the lung for the same period of time as the crystalline powder but it presented higher in vivo systemic bioavailability due to its enhanced solubility, faster dissolution rate and increased FPF at a more distal part of the lungs.