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

Deruyver, Laura; Rigaut, Clément; Lambert, Pierre; Haut, Benoı̂t; Goole, Jonathan

doi:10.1016/j.addr.2021.113826

Cited by 29 publications

(42 citation statements)

References 190 publications

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“…Then, the drug diffuses through the olfactory mucosa ( Figure 1.4 ) and subsequently follows the olfactory nerves through the cribriform plate to reach the brain ( Figure 1.5 ). The main advantage of this route is to bypass the blood-brain barrier (BBB), which allows a decrease in the therapeutic dose and thus the side effects as well ( 6 , 7 ). Moreover, the trigeminal nerve allows reaching the brain without targeting a particular zone of the nasal cavity because this nerve spans over the cavity ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

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

Rigaut

Deruyver

Goole

et al. 2022

Front. Med. Technol.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Rigaut

Deruyver

Goole

et al. 2022

Front. Med. Technol.

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“…The regions beyond the nasopharynx located at the back of the nasal casts can allow for the estimation of small inhalable particles, <10 µm, that may pass inadvertently to the lungs. Further improvements to these sophisticated anatomical models in order to more closely mimic human nasal cavities have resulted in the use of artificial mucus or coatings, humidification and flexible nose segments [20]. The addition of coatings mimics the presence of a mucus layer and can more accurately represent the entrapment of droplets or Further improvements to these sophisticated anatomical models in order to more closely mimic human nasal cavities have resulted in the use of artificial mucus or coatings, humidification and flexible nose segments [20].…”

Section: Evolution Of Nasal Castsmentioning

confidence: 99%

“…Further improvements to these sophisticated anatomical models in order to more closely mimic human nasal cavities have resulted in the use of artificial mucus or coatings, humidification and flexible nose segments [20]. The addition of coatings mimics the presence of a mucus layer and can more accurately represent the entrapment of droplets or Further improvements to these sophisticated anatomical models in order to more closely mimic human nasal cavities have resulted in the use of artificial mucus or coatings, humidification and flexible nose segments [20]. The addition of coatings mimics the presence of a mucus layer and can more accurately represent the entrapment of droplets or particles in a humid nasal cavity [18,23].…”

Section: Evolution Of Nasal Castsmentioning

confidence: 99%

In Vitro Anatomical Models for Nasal Drug Delivery

Williams

Suman

2022

Pharmaceutics

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Nasal drug delivery has been utilized for locally acting diseases for decades. The nose is also a portal to the systemic circulation and central nervous system (CNS). In the age of SARS-CoV2, the development of nasal sprays for vaccination and prophylaxis of respiratory diseases is increasing. As the number of nasal drug delivery applications continue to grow, the role of targeted regional deposition in the nose has become a factor is nasal drug development. In vitro tools such as nasal casts help facilitate formulation and product development. Nasal deposition has been shown to be linked to pharmacokinetic outcomes. Developing an understanding of the complex nasal anatomy and intersubject variability can lead to a better understanding of where the drug will deposit. Nasal casts, which are replicas of the human nasal cavity, have evolved from models made from cadavers to complex 3D printed replicas. They can be segmented into regions of interest for quantification of deposition and different techniques have been utilized to quantify deposition. Incorporating a nasal cast program into development can help differentiate formulations or physical forms such as nasal powder versus a liquid. Nasal casts can also help develop instructions for patient use to ensure deposition in the target deposition site. However, regardless of the technique used, this in vitro tool should be validated to ensure the results reflect the in vivo situation. In silico, CFD simulation or other new developments may in future, with suitable validation, present additional approaches to current modelling, although the complexity and wide degree of variability in nasal anatomy will remain a challenge. Nonetheless, nasal anatomical models will serve as effective tools for improving the understanding of nasal drug delivery.

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“…Nasal spray pumps are commonly used to deliver locally acting formulations to treat diseases and disorders such as allergic rhinitis, sinusitis, nasal polyposis and migraines [ 1 , 2 , 3 , 4 ]. Nasal spray pumps are popular due to their simplicity and ease of use, requiring no additional power or gas source [ 1 , 5 , 6 , 7 , 8 , 9 ]. For these products, the delivery efficiency of a nasal pump system can be affected by several factors including device design, formulation characteristics, patient-related factors such as inhalation conditions, and nasal geometry [ 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…In vitro deposition measurements are typically performed using nasal airway models made of rapid prototyped plastics, or molded with silicone, glass, or metal [ 8 , 13 , 18 , 28 , 42 , 52 , 53 , 54 ]. A primary focus of these in vitro investigations is often estimating the amount of drug delivered to the nasal regions past the nasal valve, which is the intended site of action for most nasal sprays.…”

Section: Introductionmentioning

confidence: 99%

Importance of Spray–Wall Interaction and Post-Deposition Liquid Motion in the Transport and Delivery of Pharmaceutical Nasal Sprays

et al. 2022

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Nasal sprays, which produce relatively large pharmaceutical droplets and have high momentum, are primarily used to deliver locally acting drugs to the nasal mucosa. Depending on spray pump administration conditions and insertion angles, nasal sprays may interact with the nasal surface in ways that creates complex droplet–wall interactions followed by significant liquid motion after initial wall contact. Additionally, liquid motion can occur after deposition as the spray liquid moves in bulk along the nasal surface. It is difficult or impossible to capture these conditions with commonly used computational fluid dynamics (CFD) models of spray droplet transport that typically employ a deposit-on-touch boundary condition. Hence, an updated CFD framework with a new spray–wall interaction (SWI) model in tandem with a post-deposition liquid motion (PDLM) model was developed and applied to evaluate nasal spray delivery for Flonase and Flonase Sensimist products. For both nasal spray products, CFD revealed significant effects of the spray momentum on surface liquid motion, as well as motion of the surface film due to airflow generated shear stress and gravity. With Flonase, these factors substantially influenced the final resting place of the liquid. For Flonase Sensimist, anterior and posterior liquid movements were approximately balanced over time. As a result, comparisons with concurrent in vitro experimental results were substantially improved for Flonase compared with the traditional deposit-on-touch boundary condition. The new SWI-PDLM model highlights the dynamicenvironment that occurs when a nasal spray interacts with a nasal wall surface and can be used to better understand the delivery of current nasal spray products as well as to develop new nasal drug delivery strategies with improved regional targeting.

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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

Cited by 29 publications

References 190 publications

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

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

In Vitro Anatomical Models for Nasal Drug Delivery

Importance of Spray–Wall Interaction and Post-Deposition Liquid Motion in the Transport and Delivery of Pharmaceutical Nasal Sprays

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