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Nose-to-brain delivery is a promising way to reach the central nervous system with therapeutic drugs. However, the location of the olfactory region at the top of the nasal cavity complexifies this route of administration. In this study, we used a 3D-printed replica of a nasal cavity (a so-called “nasal cast”) to reproduce in vitro the deposition of a solid powder. We considered two different delivery devices: a unidirectional device generating a classical spray and a bidirectional device that relies on the user expiration. A new artificial mucus also coated the replica. Five parameters were varied to measure their influence on the powder deposition pattern in the olfactory region of the cast: the administration device, the instillation angle and side, the presence of a septum perforation, and the flow rate of possible concomitant inspiration. We found that the unidirectional powder device is more effective in targeting the olfactory zone than the bi-directional device. Also, aiming the spray nozzle directly at the olfactory area is more effective than targeting the center of the nasal valve. Moreover, the choice of the nostril and the presence of a perforation in the septum also significantly influence the olfactory deposition. On the contrary, the inspiratory flow has only a minor effect on the powder outcome. By selecting the more efficient administration device and parameters, 44% of the powder can reach the olfactory region of the nasal cast.

This work presents a new mathematical model of the heat and water exchanges in the human lungs (newborn to adult). This model is based on a local description of the water and energy transports in both the lumen and the surrounding tissues, and is presented in a comprehensive, dimensionless framework with explicitly stated assumptions and a strong physiological background. The model is first used to analyze and quantify the key phenomena and dimensionless numbers governing these heat and water exchanges and then it is applied to an adult in various situations (varying atmospheric conditions, exercising…). The results highlight several interesting physiological elements. They show that the bronchial region of the lungs is able to condition the air in all the considered situations even if, sometimes, for instance when exercising, distal generations have to be involved. The model also shows that these distal generations are super-conditioners. Moreover, the results quantify the key role of the submucosal glands in mucus hydration. They also show that, during expiration, a significant cooling of the air and condensation of water occur along the respiratory tract as the vascularization of the tissues surrounding the airways is not able to maintain these tissues at body temperature during inspiration. Due to the interaction between several phenomena, it appears that the ratio of the amount of water returned to the mucosa during expiration to the amount extracted during inspiration is almost independent of the breathing conditions (around 33%). The results also show that, in acute situations, such as suffering from a pathology with airway dysfunction, when being intubated or when exercising above an intensity threshold, the heat and water exchanges in the lungs may be critical regarding mucus hydration. In proximal generations, the evaporation may overwhelm the ability of the submucosal glands to replenish the airway surface liquid with water. In some situations, the cooling of the mucosa may be very important; it can even become colder than the inspired air, due to evaporative cooling. Finally, the results show that breathing cold air can significantly increase the exchanges between the lungs and the environment, which can be critical regarding disease transmission.

Introduction This work aimed to develop chitosan-coated cubosomal nanoparticles intended for nose-to-brain delivery of paliperidone palmitate. They were compared with standard and cationic cubosomal nanoparticles. This comparison relies on numerous classical in vitro tests and powder deposition within a 3D-printed nasal cast. Methods Cubosomal nanoparticles were prepared by a Bottom-up method followed by a spray drying process. We evaluated their particle size, polydispersity index, zeta-potential, encapsulation efficiency, drug loading, mucoaffinity properties and morphology. The RPMI 2650 cell line was used to assess the cytotoxicity and cellular permeation. An in vitro deposition test within a nasal cast completed these measurements. Results The selected chitosan-coated cubosomal nanoparticles loaded with paliperidone palmitate had a size of 305.7 ± 22.54 nm, their polydispersity index was 0.166 ± 0.022 and their zeta potential was +42.4 ± 0.2 mV. This formulation had a drug loading of 70% and an encapsulation efficiency of 99.7 ± 0.1%. Its affinity with mucins was characterized by a ΔZP of 20.93 ± 0.31. Its apparent permeability coefficient thought the RPMI 2650 cell line was 3.00E-05 ± 0.24E-05 cm/s. After instillation in a 3D-printed nasal cast, the fraction of the injected powder deposited in the olfactory region reached 51.47 ± 9.30% in the right nostril and 41.20 ± 4.59% in the left nostril, respectively. Conclusion The chitosan coated cubosomal formulation seems to be the most promising formulation for nose-to-brain delivery. Indeed, it has a high mucoaffinity and a significantly higher apparent permeability coefficient than the two other formulations. Finally, it reaches well the olfactory region.

h i g h l i g h t s Development and validation by MD simulations of an analytical model able to predict the dynamic contact angles in a capillary liquid bridge confined between two parallel plates in relative motion with different wettabilities. Detailed description of the pinning/ depinning process of a contact line on a chemical heterogeneity at the nanoscale. Development and validation by MD simulations of a geometrical model able to predict the pinning time on a chemical heterogeneity. The pinning time depends not only on substrate/heterogeneity wettability contrast and relative plate velocity, but also on the separation distance between the plates confining the capillary bridge.