Intranasal delivery of thin-film freeze-dried monoclonal antibodies using a powder nasal spray system.

Monoclonal antibodies (mAbs) administered intranasally as dry powders can be potentially applied for the treatment or pre-exposure prevention of viral infections in the upper respiratory tract. However, a method to transform the mAbs from liquid to dry powders suitable for intranasal administration and a device that can spray the dry powders to the desired region of the nasal cavity are needed to fully realize the potentials of the mAbs. Herein, we report that thin-film freeze-dried mAb powders can be sprayed into the posterior nasal cavity using Aptar Pharma's Unidose (UDS) Powder Nasal Spray System. AUG-3387, a human-derived mAb that neutralizes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was used in the present study. First, we prepared thin-film freeze-dried AUG-3387 powders (i.e., TFF AUG-3387 powders) from liquid formulations containing different levels of mAbs. The TFF AUG-3387 powder with the highest solid content (i.e., TFF AUG-3387C) was then chosen for further characterization, including the evaluation of the plume geometry, spray pattern, and particle size distribution after the powder was sprayed using the UDS Powder Nasal Spray. Finally, the deposition patterns of the TFF AUG-3387C powder sprayed using the UDS Powder delivery system were studied using 3D-printed nasal replica casts based on the CT scans of an adult and a child. It is concluded that it is feasible to intranasally deliver mAbs as dry powders by transforming the mAbs into dry powders using thin-film freeze-drying and then spraying the powder using a powder nasal spray system.

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive vaccine powders.

Intranasal vaccination by directly applying a vaccine dry powder is appealing. However, a method that can be used to transform a vaccine from a liquid to a dry powder and a device that can be used to administer the powder to the desired region(s) of the nasal cavity are critical for successful intranasal vaccination. In the present study, using a model vaccine that contains liposomal monophosphoryl lipid A and QS-21 adjuvant (AdjLMQ) and ovalbumin (OVA) as a model antigen, it was shown that thin-film freeze-drying can be applied to convert the liquid vaccine containing sucrose at a sucrose to lipid ratio of 15:1 (w/w) into dry powders, in the presence or absence of carboxymethyl cellulose sodium salt (CMC) as a mucoadhesive agent. Ultimately, the thin-film freeze-dried AdjLMQ/OVA vaccine powder containing 1.9% (w/w) of CMC (i.e., TFF AdjLMQ/OVA/CMC1.9% powder) was selected for additional evaluation because the TFF AdjLMQ/OVA/CMC1.9% powder was mucoadhesive and maintained the integrity of the antigen and the physical properties of the vaccine. Compared to the TFF AdjLMQ/OVA powder that did not contain CMC, the TFF AdjLMQ/OVA/CMC1.9% powder had a lower moisture content and a higher glass transition temperature. In addition, the TFF AdjLMQ/OVA/CMC1.9% thin films were relatively thicker than the TFF AdjLMQ/OVA thin films without CMC. When sprayed with Aptar Pharma's Unidose Powder Nasal Spray System (UDSP), the TFF AdjLMQ/OVA powder and the TFF AdjLMQ/OVA/CMC1.9% powder generated similar particle size distribution curves, spray patterns, and plume geometries. Importantly, after the TFF AdjLMQ/OVA/CMC1.9% powder was sprayed with the UDSP nasal device, the integrity of the OVA antigen and the AdjLMQ liposomes did not change. Finally, a Taguchi L4 orthogonal array was applied to identify the optimal parameters for using the UDSP device to deliver the TFF AdjLMQ/OVA/CMC1.9% powder to the middle and lower turbinate and the nasopharynx regions in both adult and child nasal replica casts. Results from this study showed that it is feasible to apply the thin-film freeze-drying technology to transform a nasal vaccine candidate from liquid to a dry powder and then use the UDSP nasal device to deliver the vaccine powder to the desired regions in the nasal cavity for intranasal vaccination.

In Vitro Anatomical Models for Nasal Drug Delivery.

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.

A consensus research agenda for optimising nasal drug delivery.

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors.

Evaluation of Nasal Inlet Ports Having Simplified Geometry for the Pharmacopeial Assessment of Mass Fraction of Dose Likely to Penetrate Beyond the Nasopharynx: a Preliminary Investigation.

Nasal cavity breakthrough to the airways of the lungs is associated with nasally inhaled droplets whose size is smaller than ca. 10 µm aerodynamic diameter that behave as an aerosol rather than a spray in terms of their transport. The purpose of the present laboratory-based study was to evaluate a nasal product quality control procedure involving a new inlet for the quantification of mass of such droplets emitted by commercially available aqueous nasal spray pump products by cascade impactor. This inlet is more representative of the adult nasal vestibule in terms of entry angle for the spray as well as internal volume for plume expansion. Sampling was also undertaken via a spherical 1-L glass expansion vessel as inlet, previously established for quantification of these aerosol droplets. The selected solution- and suspension-formulated products containing azelastine and fluticasone propionate respectively were shown to contain < 1% of the total spray mass per actuation associated with droplets < 14.1 µm aerodynamic diameter. These measurements were consistent with laser diffraction-based measurements of the entire droplet size distribution. Comparable measures of aerosol droplet mass fraction were obtained when the spray was sampled by the cascade impactor method using either the 1-L glass expansion chamber or the new metal inlet as entry for the spray produced by either product evaluated. We conclude that the metal inlet has the potential to be adopted as a suitable induction port in the assessment of nasal product quality, where currently no standardized inlet exists.