Spray Freeze Drying of Biologics: A Review and Applications for Inhalation Delivery.

Biopharmaceuticals have established an indisputable presence in the pharmaceutical pipeline, enabling highly specific new therapies. However, manufacturing, isolating, and delivering these highly complex molecules to patients present multiple challenges, including the short shelf-life of biologically derived products. Administration of biopharmaceuticals through inhalation has been gaining attention as an alternative to overcome the burdens associated with intravenous administration. Although most of the inhaled biopharmaceuticals in clinical trials are being administered through nebulization, dry powder inhalers (DPIs) are considered a viable alternative to liquid solutions due to enhanced stability. While freeze drying (FD) and spray drying (SD) are currently seen as the most viable solutions for drying biopharmaceuticals, spray freeze drying (SFD) has recently started gaining attention as an alternative to these technologies as it enables unique powder properties which favor this family of drug products. The present review focus on the application of SFD to produce dry powders of biopharmaceuticals, with special focus on inhalation delivery. Thus, it provides an overview of the critical quality attributes (CQAs) of these dry powders. Then, a detailed explanation of the SFD fundamental principles as well as the different existing variants is presented, together with a discussion regarding the opportunities and challenges of SFD as an enabling technology for inhalation-based biopharmaceuticals. Finally, a review of the main formulation strategies and their impact on the stability and performance of inhalable biopharmaceuticals produced via SDF is performed. Overall, this review presents a comprehensive assessment of the current and future applications of SFD in biopharmaceuticals for inhalation delivery.

Production of Lysozyme-PLGA-Loaded Microparticles for Controlled Release Using Hot-Melt Extrusion.

Biopharmaceuticals are usually administered intravenously with frequent dosing regimens which may decrease patient compliance. Controlled-release formulations allow to reduce the frequency of injections while providing a constant dosing of the biopharmaceutical over extended periods. These formulations are typically produced by emulsions, requiring high amounts of organic solvents and have limited productivity. Hot-melt extrusion (HME) is an alternative technology to produce controlled drug delivery systems. It is a continuous solvent-free process, leading to a small ecological footprint and higher productivity. However, it may induce thermolabile compounds' degradation. In this work, the impact of the formulation and extrusion temperature on lysozyme's bioactivity and release profile of poly(lactic-co-glycolic acid) (PLGA)-based extended release formulations were evaluated using a design-of-experiments (DoE) approach. The lysozyme-loaded PLGA microparticles were produced by HME followed by milling. It was observed that the in vitro release (IVR) profile was mainly affected by the drug load; higher drug load led to higher burst and total lysozyme release after 14 days. HME temperature seemed to decrease lysozyme's activity although this correlation was not statistically significant (p value = 0.0490). Adding polyethylene glycol 400 (PEG 400) as a plasticizer to the formulation had no significant impact on the lysozyme release profile. The burst release was effectively mitigated with the inclusion of a washing step. Washing the microparticles with water reduced the burst release by 80% whereas washing them with a poly(vinyl alcohol) (PVA) aqueous solution eliminated it. In conclusion, HME is demonstrated to be suitable in producing controlled-release microparticles of small biopharmaceuticals. Graphical abstract.