Journal: European Journal of Pharmaceutical Sciences, Volume 214, 2025

Abstract: Inhalable mRNA is an emerging field holding great potential for applications as mucosal vaccination, antiviral therapy or protein replacement therapies, but efficient delivery remains a bottleneck.

In this study, we explore the use of a Soft Mist Inhaler (SMI), based on Rayleigh-breakup, for pulmonary mRNA delivery. We found that the SMI successfully aerosolised GFP mRNA encapsulated in liposomes while maintaining colloidal stability, mRNA integrity and in vitro transfection efficiency in A549 cells. Furthermore, the device enabled simultaneous delivery of nucleic acids in various sizes using a model CRISPR/Cas13d system.

The formulation could be reproducibly aerosolised with a low geometric standard deviation (GSD) and optimal aerosol droplet size for lung delivery. Based on the aerosol data, lung deposition modeling was conducted, indicating high lung deposition with minimal exhaled fraction. In comparison, aerosolization by a conventional Vibrating Mesh Nebuliser led to significant loss of nanoparticles and transfection efficiency. Utilising SMIs may facilitate pulmonary delivery of mRNA nanoparticle formulations by lowering stability-associated hurdles while providing intrinsically high deposition in the lungs.

Reference

The post Soft mist inhaler nebulisation by Rayleigh-breakup largely preserves functional integrity of liposomal mRNA in respirable aerosols first appeared on Resyca.

Journal: International Journal of Pharmaceutics, Volume 683, 2025

Abstract: The COVID-19 pandemic has emphasised the need for innovative and efficient drug delivery systems, particularly for nucleic acid-based therapeutics.

Lipid nanoparticle (LNP)-based small interfering RNA (siRNA) technology provides a promising strategy for gene therapy, immune modulation, and targeted molecular medicine. Intranasal delivery of LNP-siRNA formulations offers advantages such as efficient gene silencing and non-invasive administration.

However, the nasal spray device plays a crucial role in determining the deposition patterns within the nasal cavity and can impact the physicochemical stability of LNP formulations during aerosolisation. In this study, the Rayleigh Jet Nasal Atomiser was evaluated for its performance in delivering three LNP-siRNA formulations designed based on the LNP structures of Moderna, Pfizer, and Alnylam (Onpattro) marketed formulations, respectively.

Key nanoparticle characteristics, including particle size distribution, polydispersity index (PDI), zeta potential, and encapsulation efficiency, as well as aerosol properties such as droplet size, were analyzed before and after aerosolisation. Deposition patterns were assessed using the Alberta Idealized Nasal Inlet (AINI) model to determine the distribution of aerosolized LNPs. The results demonstrate that the Rayleigh Jet Nasal Atomizer efficiently delivers all the three formulations to the nasal cavity, primarily targeting the nasopharynx, while minimizing deposition in the lower respiratory tract.

Additionally, the device maintained LNPs structural integrity, although a reduction in encapsulated siRNA concentration suggests partial LNP disruption during aerosolisation. These findings indicate that the Rayleigh Jet Nasal Atomiser is a suitable device for intranasal delivery of LNP-based siRNA therapeutics, offering a promising approach for nasal administration of RNA-based drug delivery.

Reference

The post Evaluation of Rayleigh jet atomiser for intranasal delivery of lipid nanoparticle – siRNA formulations: stability, deposition, and device performance first appeared on Resyca.

Journal: Journal of Drug Delivery Science and Technology, Volume 115, Part 1, 2026

Abstract: Pulmonary delivery of mRNA-lipid nanoparticles (mRNA-LNPs) offers a promising non-invasive route of administration for pulmonary gene therapy, vaccine applications, amongst others.

However, aerosolisation can compromise nanoparticle stability, affecting its payload and thus delivery efficiency. This study evaluates the impact of aerosolisation via Rayleigh breakup and Savart impinging jet-based SMIs and various mesh nebulisers in preserving mRNA-LNP integrity and thus optimising pulmonary deposition.

The PFSI (Resyca) and Respimat (Boehringer Ingelheim) SMIs, as well as the Innospire Go and Pari eFlow mesh nebulisers were assessed for their impact on LNP particle size, zeta potential, encapsulation efficiency, and mRNA stability.

The PFSI SMI maintained mRNA-LNP physicochemical properties with minimal aggregation and superior encapsulation efficiency, while the other devices induced significant particle alterations and mRNA degradation.

These findings highlight the potential of SMIs, particularly the PFSI device, for inhaled mRNA-LNP delivery. Its ability to maintain nanoparticle stability warrants clinical evaluation.

Reference

The post Rayleigh-based soft mist inhalers preserve mRNA-LNP integrity for pulmonary delivery first appeared on Resyca.

Journal: International Journal of Pharmaceutics, Volume 672, 2025

Abstract: The nasal delivery of mRNA vaccines attracts great interests in both academia and industry. While the lipid nanoparticle (LNP)-mRNA complexes are vulnerable and need a subtle process for aerosolisation. In this study, a new nasal atomiser, based on the working rationale of Rayleigh breakup, was employed to aerosolise LNP-mRNAs.

The data revealed no statistical differences in physiochemical properties before and after aerosolisation, strongly suggesting LNP-mRNAs be well preserved upon aerosolisation by Rayleigh breakup technology.

Additionally, these Rayleigh breakup droplets showed a physical size of ∼25 µm in mean with a narrow size distribution (Span: 1.24) and demonstrated a large portion (70–80 % w/w) greater than 10 µm in aerodynamic diameter, strongly suggesting a predominate deposition in the upper airway and designating a great appropriateness for nasal drug delivery.

Furthermore, the recently developed Alberta Idealized Nasal Inlet (AINI) was utilized to evaluate the regional nasal deposition of LNP-mRNA aerosols.

It was demonstrated that, at the administration angle of 45°, the major deposition of mRNAs (>50 % w/w) was in the target region of turbinates.

The inhalation airflow at 7.5 L/min can maximize the targeted delivery of mRNA (∼64 % w/w) and minimise the undesirable depositions in other segments.

This study provides a new approach to aerosolise LNP-mRNAs with undisturbed stabilities for targeted nasal vaccine delivery.

Reference

The post Targeted nasal delivery of LNP-mRNAs aerosolised by Rayleigh breakup technology first appeared on Resyca.

Journal: Pharmaceutics, Volume 16(2), 2024

Abstract: Currently, nasal administration of active pharmaceutical ingredients is most commonly performed using swirl-nozzle-based pump devices or pressurised syringes.

However, they lead to limited deposition in the more active regions of the nasal cavity, especially the olfactory region, which is crucial for nose-to-brain drug delivery. This research proposes to improve deposition in the olfactory region by replacing the swirl nozzle with a nanoengineered nozzle chip containing micrometer-sized holes, which generates smaller droplets of 10–50 μm travelling at a lower plume velocity.

Two nanotech nozzle chips with different hole sizes were tested at different inhalation flow rates to examine the deposition patterns of theophylline, a hyposmia treatment formulation, using a nasal cavity model. A user study was also conducted and showed that the patient instructions influenced the inhalation flow rate characteristics. Targeted flow rates of between 0 and 25 L/min were used for the in vitro deposition study, yielding 21.5–31.5% olfactory coverage. In contrast, the traditional swirl nozzle provided only 10.8% coverage at a similar flow rate. This work highlights the potential of the nanotech soft mist nozzle for improved intranasal drug delivery, particularly to the olfactory region.

Reference

The post Improved olfactory deposition of theophylline using a nanotech soft mist nozzle chip first appeared on Resyca.

Journal: Expert Opinion on Drug Delivery , Volume 20(8), 2023

Abstract: Soft mist inhalers (SMIs) are propellant-free inhalers that utilise mechanical power to deliver single or multiple doses of inhalable drug aerosols in the form of a slow mist to patients.

Compared to traditional inhalers, SMIs allow for a longer and slower release of aerosol with a smaller ballistic effect, leading to a limited loss in the oropharyngeal area, whilst requiring little coordination of actuation and inhalation by patients.

Currently, the Respimat® is the only commercially available SMI, with several others in different stages of preclinical and clinical development.

Areas covered: The primary purpose of this review is to critically assess recent advances in SMIs for the delivery of inhaled therapeutics. Expert opinion: Advanced particle formulations, such as nanoparticles which target specific areas of the lung, biologics, such as vaccines, proteins and antibodies (which are sensitive to aerosolisation), are expected to be generally delivered by SMIs.

Furthermore, repurposed drugs are expected to constitute a large share of future formulations to be delivered by SMIs. SMIs can also be employed for the delivery of formulations that target systemic diseases.

Finally, digitalising SMIs would improve patient adherence and provide clinicians with fundamental insights into patients’ treatment progress.

Reference

The post Advances in soft mist inhalers first appeared on Resyca.

Journal: Nature Scientific Report, Volume 13(1), 2023

Abstract: Nebulisation of mRNA therapeutics can be used to directly target the respiratory tract.

A promising prospect is that mucosal administration of lipid nanoparticle (LNP)-based mRNA vaccines may lead to a more efficient protection against respiratory viruses.

However, the nebulisation process can rupture the LNP vehicles and degrade the mRNA molecules inside. Here we present a novel nebulisation method able to preserve substantially the integrity of vaccines, as tested with two SARS-CoV-2 mRNA vaccines.

We compare the new method with well-known nebulisation methods used for medical respiratory applications. We find that a lower energy level in generating LNP droplets using the new nebulisation method helps safeguard the integrity of the LNP and vaccine.

By comparing nebulisation techniques with different energy dissipation levels we find that LNPs and mRNAs can be kept largely intact if the energy dissipation remains below a threshold value, for LNP integrity 5–10 J/g and for mRNA integrity 10–20 J/g for both vaccines.

Reference

The post Low energy nebulisation preserves integrity of SARS-CoV-2 mRNA vaccines for respiratory delivery first appeared on Resyca.

Journal: Pharmaceutics, Volume 14(11), 2022

Abstract: Favipiravir displays a rapid viral clearance, a high recovery rate and broad therapeutic safety; however, its oral administration was associated with systemic side effects in susceptible patients.

Considering that the pulmonary route could provide a high drug concentration, and a safer application with less absorption into systemic circulation, it was aimed to elucidate whether favipiravir delivered via soft-mist inhaler has any deleterious effects on lung, liver and kidney tissues of healthy rats. Wistar albino rats of both sexes (n = 72) were placed in restrainers, and were given either saline or favipiravir (1, 2.5, 5 or 10 mg/kg in 1 mL saline) by inhalation within 2 min for 5 consecutive days.

On the 6th day, electrocardiographic recording was obtained, and cardiac blood and lung tissues were collected. Favipiravir did not alter cardiac rhythm, blood cell counts, serum levels of alanine transaminase, aspartate transaminase, blood urea nitrogen, creatinine, urea or uric acid, and did not cause any significant changes in the pulmonary malondialdehyde, myeloperoxidase activity or antioxidant glutathione levels. Our data revealed that pulmonary use of favipiravir via soft-mist inhaler enables a high local concentration compared to plasma without oxidative lung injury or cardiac or hepatorenal dysfunction.

Reference

The post Pulmonary delivery of favipiravir in rats reaches high local concentrations without causing oxidative lung injury or systemic side effects first appeared on Resyca.

Journal: Drug Delivery, Volume 29(1), 2022

Abstract: Favipiravir, an RNA-dependent RNA polymerase (RdRp) inhibitor, is used to treat patients infected with influenza virus and most recently with SARS-CoV-2.

However, poor accumulation of favipiravir in lung tissue following oral administration has required an alternative method of administration that directly targets the lungs. In this study, an inhalation solution of favipiravir at a concentration of 2 mg mL⁻¹ was developed and characterized for the first time. The chemical stability of inhaled favipiravir solution in two different media, phosphate buffer saline (PBS) and normal saline (NS), was investigated under different conditions: 5 ± 3 °C, 25 ± 2 °C/60% RH ± 5% RH, and 40 ± 2 °C/75% RH ± 5% RH; in addition to constant light exposure. As a result, favipiravir solution in PBS revealed superior stability over 12 months at 5 ± 3 °C. Antiviral activity of favipiravir was assessed at the concentrations between 0.25 and 3 mg mL⁻¹ with real time cell analyzer on Vero-E6 that were infected with SARS-CoV-2/B.1.36.

The optimum concentration was found to be 2 mg mL⁻¹, where minimum toxicity and sufficient antiviral activity was observed. Furthermore, cell viability assay against Calu-3 lung epithelial cells confirmed the biocompatibility of favipiravir at concentrations up to 50 μM (7.855 mg mL⁻¹). The in vitro aerodynamic profiles of the developed inhaled favipiravir formulation, when delivered with soft-mist inhaler indicated good lung targeting properties. These results suggest that favipiravir solution prepared with PBS could be considered as a suitable and promising inhalation formulation for pulmonary delivery in the treatment of patients with COVID-19.

Reference

The post Pulmonary delivery of favipiravir inhalation solution for COVID-19 treatment: in vitro characterisation, stability, in vitro cytotoxicity, and antiviral activity using real time cell analysis first appeared on Resyca.

Journal: Journal of Advanced Research, Volume 44, 2023

Abstract: This publication covers the evaluation of nasal deposition and deposition patterns of an innovative nasal spray nozzles generating slow velocity soft mists.

The methods involved studying the deposition pattern of a fluorescent liquid formulation in a transparent nasal cast under simulated inhalation flow conditions.

Image and fluorescence analysis were employed to assess the extent of deposition, while particle size distribution and initial droplet velocity were determined using laser diffractometry and high-speed camera techniques. The results demonstrated that uniform intranasal coverage was achieved with droplets of volume median particle size (Dv50) between 15 and 25 µm at airflow rates of 10-30 L/min.

Aerosol formulations could be uniformly deposited in nasal vestibule and turbinate cavity regions, with less than 10% passing beyond the nasopharyngeal region. In conclusion, the method allowed for determining nasal cast coverage across different regions using image and fluorometric analyses.

Droplet velocity emerged as a critical parameter for nasal cavity deposition. Standard swirl nozzles tended to deposit many droplets on the surface of the nasal vestibule, while soft mist nozzles produced smaller droplets at lower velocities, resulting in more uniform coverage.

The post Fluorescence-enabled evaluation of nasal tract deposition and coverage of pharmaceutical formulations in a silicone nasal cast using an innovative spray device first appeared on Resyca.