Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT_1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.

This study aimed to optimise key parameters for maximising olfactory deposition (OD) of a valproic acid (VPA)-loaded nanostructured lipid carriers (NLC) formulation, with particular focus on nasal device selection. Three nasal devices (unidose liquid nasal spray system - UDSl, VP7 pump equipped with a nose-to-brain actuator - VP7N2B, and Preloaded) were tested using two distinct 3D-printed nasal casts and varying administration positions. Among the tested devices, the Preloaded exhibited a narrow spray pattern with consistent delivery, achieving over 50 % OD. This makes it the most promising for nose-to-brain transport, surpassing OD values typically reported in the literature for both powder and liquid formulations, which rarely reach 50 %. Maximising OD required positioning the Preloaded device at a high angle to the horizontal plane (53°), a low angle to the vertical plane (5°), and a deeper insertion depth (ID) (15 mm). While the Preloaded device showed consistent OD across both models, greater variability was observed with UDSl and VP7N2B, likely due to anatomical differences between the nasal casts. These findings highlight the crucial role of nasal device design, spray characteristics, user-independent administration, and positioning in optimising OD. Although this work does not establish a universal in vitro testing method, it lays important groundwork and introduces experimental strategies that could guide future optimisation of NLC-based nasal drug delivery systems.

Purpose: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the invivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device. Methods: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies. Results: APSD testing alone might not be able to explain differences reported elsewhere in invivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products. Conclusions: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing invitro tools that are able to provide a bridge between material attributes or process parameters and invivo performance.

Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-hydroxytryptamine/serotonin (5-HT)1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.

Background: Nose-to-brain delivery offers a noninvasive route to bypass the blood–brain barrier for the treatment of neurodegenerative diseases. AmyP53 is a first-in-class adaptive 12-mer peptide that prevents the formation of neurotoxic amyloid oligomers by competitively targeting lipid raft gangliosides on brain cell membranes, thereby blocking the shared pathological mechanism underlying both Alzheimer’s and Parkinson’s diseases. Objective: Here, we report the identification of optimal spray devices for the nose-to-brain delivery of AmyP53, ahead of a planned Phase 1 clinical trial. Method/Results: Among six devices evaluated (four commercial systems and two novel devices specifically engineered for nose-to-brain delivery), two systems were identified as optimal for further clinical development (narrower plume angles and significantly higher deposition in the olfactory region): the Neurospray™ and Neurospray™ Preservative-Free (PF). AmyP53 was quantitatively and reproducibly delivered by both Neurospray™ systems, retaining full recognition of its therapeutic target (gangliosides), as assessed by a surface pressure-based ganglioside-binding assay. In a rabbit preclinical model, intranasal administration of AmyP53 with the Neurospray™ resulted in rapid and sustained brain delivery, detectable at 10 min and persisting at 24 h post-administration, without significant systemic exposure. Conclusions: These results validate the Neurospray™ drug delivery systems as optimal drug delivery systems for the clinical development of AmyP53.

Introduction: The efficacy of nasal vaccination critically depends on the delivery method, which must ensure precise and reproducible deposition of the vaccine within the nasal cavity to effectively stimulate mucosal immune structures such as the nasal\x{2011}associated lymphoid tissue (NALT). Transitioning from pre\x{2011}clinical models to human applications is challenging because of anatomical and physiological differences in nasal structure and airflow dynamics. Methods: We developed a nasal\x{2011}spray device specifically designed for human nasal immunization. The device delivers a broad, homogeneous spray that is confined to the nasal cavity, thereby avoiding the lower respiratory tract and minimizing the risk of pulmonary exposure. It was engineered to be compatible with a wide range of vaccine formulations, preserving their physicochemical properties, stability, and delivery efficacy. To overcome the limitations of conventional rodent models, the device was validated using (i) in\x{2011}vitro human nasal cavity replicas (nasal casts) and (ii) an in\x{2011}vivo rabbit model, which is more appropriate for regulatory and translational studies. Results: The spray system achieved consistent, homogeneous deposition throughout the nasal cavity without spill\x{2011}over into the lower airways. Compatibility tests confirmed that the device does not alter the physicochemical characteristics or stability of a representative complex vaccine formulation. Validation in nasal casts and the rabbit model demonstrated reproducible delivery performance and supported the device\x{2019}s suitability for human use. Discussion: The presented transitory delivery platform offers a scalable, safe, and formulation\x{2011}compatible solution for intranasal vaccine administration. By ensuring targeted deposition and preserving vaccine integrity, the device reinforces the potential of mucosal immunization strategies across diverse indications and facilitates the translation of nasal vaccines from pre\x{2011}clinical research to clinical application.