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Nasal delivery is the primary option for the treatment of topical nasal disorders. However, there has been growing interest in using this route for systemic treatments. This is due to fast and direct drug absorption that circumvents pre-systemic gastrointestinal and hepatic first-pass metabolism, allowing quick onset of action and possible reduction of dose [1]. 24 June 2024 Inhalation Amorphous solid dispersions for nasal delivery Powder formulation and particle engineering considerations Patrícia Henriques, PhD a, b and Slavomíra Doktorovová, PhD b a University of Coimbra b Hovione FarmaCiencia Nasal delivery is the primary option for the treatment of topical nasal disorders. However, there has been growing interest in using this route for systemic treat- ments. is is due to fast and direct drug absorption that circumvents pre-systemic gastrointestinal and hepatic first-pass metabolism, allowing quick onset of action and possible reduction of dose [1]. erefore, systemic delivery through nasal administration is par- ticularly relevant for drugs that require fast onset of action in acute or emergency conditions [2]. Due to its large surface area and extensive vascu- larization, the respiratory region of the nasal cavity, where the turbinates are located, is the target for sys- temic drug delivery [3]. Additionally, the olfactory epithelium in the olfactory region of the nasal cavity allows unique contact between the external environ- ment and the central nervous system (CNS) and can enable an intranasal drug to directly target the brain. is strategy can circumvent the blood-brain barrier and it is commonly referred to as nose-to-brain deliv- ery. e targeted delivery through this pathway, with direct nose-to-brain drug transport, can reduce side effects related to systemic delivery and improve the efficacy of neurotherapeutics [4]. Powders for nasal delivery have been recognized as advantageous dosage forms compared to liquids, due to their increased stability and residence time on nasal mucosa as well as improved bioavailabil- ity. Nasal powders also represent an opportunity to administer poorly soluble drugs, which have been emerging in the drug discovery pipeline [5], namely through the development of amorphous solid disper- sions (ASD). is approach can improve drug disso- lution and, subsequently, systemic absorption [6, 7]. Nasal powders can be manufactured by utilizing diverse methodologies including lyophilization [8-13], spray drying [14-20], supercritical fluid- assisted spray drying [21], spray freeze drying [22- 24] and agglomeration of micronized powders [25-30]. Spray drying is one of the techniques used most often for nasal powder preparation, as it allows continuous processing and produces well-controlled particle characteristics such as size and shape [31], which may impact therapeutic outcomes [32]. A diverse range of particle sizes and morphologies can be designed, including microencapsulated particles and large porous particles with varying aerodynamic particle sizes. In addition, the technology is scalable and equipment sizes range from research-scale to commercial-scale. Despite these opportunities, nasal powder research and development is a new area compared to nasal sprays. Only two nasal powders for systemic action have been approved by the United States Food and Drug Administration (FDA), both within the last seven years: Onzetra ® Xsail ® , a sumatriptan product for migraine approved in 2016 [33] and Baqsimi ® , a glucagon powder for severe hypoglycemia approved in 2019 [34]. In fact, the scientific community still struggles with the existing gaps among formulation composition, particle engineering and nasal absorption. e com- plex interplay among particle deposition, muco- adhesion, drug release and permeation is generally difficult to mimic in vitro and strongly dependent on formulation and particle design. e aforementioned challenges and the opportunity for nasal powders to improve bioavailability are lever- aging research in developing formulation and process strategies, along with advanced performance char- acterization methodologies that can predict in vivo behavior in nasal powder early development. In the following sections, two case studies are presented, where different particle engineering and formulation strategies were evaluated, focusing on nasal delivery of poorly soluble drugs.