The air conditioning in the nose of mammals depends on their mass and on their maximal running speed.

The nose of the mammals is responsible for filtering, humidifying, and heating the air before entering the lower respiratory tract. This conditioning avoids, notably, dehydration of the bronchial and alveolar mucosa. However, since this conditioning is not perfect, exercising in cold air can induce lung inflammation, both for human and non-human mammals. This work aims to compare the air conditioning in the noses of various mammals during inspiration. We build our study on computational fluid dynamics simulations of the heat exchanges in the lumen of the upper respiratory tract of these mammals. These simulations show that the efficiency of the air conditioning in the nose during inspiration does not relate only to the mass m of the mammal but also to its maximal running speed v. More precisely, the results allow establishing a scaling law relating the efficiency of air conditioning in the nose of mammals to the ratio v / log 10 ( m ) . The simulations also correlate the resistance to the flow in the nose to the efficiency of this air conditioning. The obtained scaling law allows predicting the air temperature at the top of the trachea during inspiration for nasal-breathing mammals, and thus notably for humans of various ages.

What Are the Key Anatomical Features for the Success of Nose-to-Brain Delivery? A Study of Powder Deposition in 3D-Printed Nasal Casts.

Nose-to-brain delivery is a promising way to improve the treatment of central nervous system disorders, as it allows the bypassing of the blood-brain barrier. However, it is still largely unknown how the anatomy of the nose can influence the treatment outcome. In this work, we used 3D printing to produce nasal replicas based on 11 different CT scans presenting various anatomical features. Then, for each anatomy and using the Design of Experiments methodology, we characterised the amount of a powder deposited in the olfactory region of the replica as a function of multiple parameters (choice of the nostril, device, orientation angle, and the presence or not of a concomitant inspiration flow). We found that, for each anatomy, the maximum amount of powder that can be deposited in the olfactory region is directly proportional to the total area of this region. More precisely, the results show that, whatever the instillation strategy, if the total area of the olfactory region is below 1500 mm2, no more than 25% of an instilled powder can reach this region. On the other hand, if the total area of the olfactory region is above 3000 mm2, the deposition efficiency reaches 50% with the optimal choice of parameters, whatever the other anatomical characteristics of the nasal cavity. Finally, if the relative difference between the areas of the two sides of the internal nasal valve is larger than 20%, it becomes important to carefully choose the side of instillation. This work, by predicting the amount of powder reaching the olfactory region, provides a tool to evaluate the adequacy of nose-to-brain treatment for a given patient. While the conclusions should be confirmed via in vivo studies, it is a first step towards personalised treatment of neurological pathologies.

In vitro Evaluation of Paliperidone Palmitate Loaded Cubosomes Effective for Nasal-to-Brain Delivery.

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.

Validation and Sensitivity analysis for a nasal spray deposition computational model.

Validating numerical models against experimental models of nasal spray deposition is challenging since many aspects must be considered. That being said, it is a critical step in the product development process of nasal spray devices. This work presents the validation process of a nasal deposition model, which demonstrates a high degree of consistency of the numerical model with experimental data when the nasal cavity is segmented into two regions but not into three. Furthermore, by modelling the flow as stationary, the computational cost is drastically reduced while maintaining quality of particle deposition results. Thanks to this reduction, a sensitivity analysis of the numerical model could be performed, consisting of 96 simulations. The objective was to quantify the impact of four inputs: the spray half cone angle, mean spray exit velocity, breakup length from the nozzle exit and the diameter of the nozzle spray device, on the three quantities of interest: the percentage of the accumulated number of particles deposited on the anterior, middle and posterior sections of the nasal cavity. The results of the sensitivity analysis demonstrated that the deposition on anterior and middle sections are sensitive to injection angle and breakup length, and the deposition on posterior section is only, but highly, sensitive to the injection velocity.

Instillation of a Dry Powder in Nasal Casts: Parameters Influencing the Olfactory Deposition With Uni- and Bi-Directional Devices.

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.

The importance of pre-formulation studies and of 3D-printed nasal casts in the success of a pharmaceutical product intended for nose-to-brain delivery.

This review aims to cement three hot topics in drug delivery: (a) the pre-formulation of new products intended for nose-to-brain delivery; (b) the development of nasal casts for studying the efficacy of potential new nose-to-brain delivery systems at the early of their development (pre-formulation); (c) the use of 3D printing based on a wide variety of materials (transparent, biocompatible, flexible) providing an unprecedented fabrication tool towards personalized medicine by printing nasal cast on-demand based on CT scans of patients. This review intends to show the links between these three subjects. Indeed, the pathway selected to administrate the drug to the brain not only influence the formulation strategies to implement but also the design of the cast, to get the most convincing measures from it. Moreover, the design of the cast himself influences the choice of the 3D-printing technology, which, in its turn, bring more constraints to the nasal replica design. Consequently, the formulation of the drug, the cast preparation and its realisation should be thought of as a whole and not separately.

Comprehensive Analysis of Heat and Water Exchanges in the Human Lungs.

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.