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In Vitro Regional Deposition of Nasal Sprays in an Idealized Nasal Inlet: Comparison with In Vivo Gamma Scintigraphy

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John Chen at Access to Advanced Health Institute
John Chen
  • Access to Advanced Health Institute
Warren H Finlay at University of Alberta
Warren H Finlay
Andrew R Martin at University of Alberta
Andrew R Martin
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Abstract and Figures

Purpose To compare in vitro regional nasal deposition measurements using an idealized nasal airway geometry, the Alberta Idealized Nasal Inlet (AINI), with in vivo regional deposition for nasal drug products. Materials and Methods One aqueous solution formulation (NasalCrom), one aqueous suspension formulation (Nasonex) and one nasal pressurized metered dose spray device (QNASL) were selected. Two spray orientation angles, 60° and 45° from the horizontal, were selected. A steady inhalation flow rate of 7.5 L/min was selected to simulate slow inhalation through a single nostril. After actuation, the AINI was disassembled. The mass of drug deposited in each region and a downstream filter, representing penetration of drug to the lungs, was determined using ultraviolet–visible (UV–Vis) spectrophotometry. Results No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11% for QNASL. For NasalCrom, 45% to 69% of the dose deposited in the AINI was deposited in the vestibule and 31% to 55% was deposited in the turbinates; for Nasonex, 66% to 74% (vestibule) and 26% to 34% (turbinates); for QNASL, 90% to 100% (vestibule) and 0% to 10% (turbinates). No statistically significant difference was observed between regional deposition in vivo and in vitro for any of the formulations, except that nasopharyngeal deposition with Nasonex differed by less than 1.56% from in vivo, which while statistically significant, is unlikely to be clinically significant. Conclusions The AINI was able to mimic regional in vivo deposition for nasal drug products, permitting differentiation between devices based on regional deposition.
Schematic of experimental setup.
Schematic of experimental setup.
… 
Comparison of regional deposition of NasalCrom in realistic vs. idealized geometries (n = 3 repeats for plastic idealized, n = 3 repeats for AINI, n = 9 nostrils for realistics). Error bars indicate one standard deviation (measured across geometries for realistics and across repeats for idealized).
Comparison of regional deposition of NasalCrom in realistic vs. idealized geometries (n = 3 repeats for plastic idealized, n = 3 repeats for AINI, n = 9 nostrils for realistics). Error bars indicate one standard deviation (measured across geometries for realistics and across repeats for idealized).
… 
Comparison of regional deposition of NasalCrom in AINI vs. in vivo (60° and 45°, n = 3 repeats for AINI, n = 9 nostrils for realistics). In vivo data taken from Al-Ghananeem et al. [20]. Note that administration angles in vivo were not reported. Error bars indicate one standard deviation (measured across repeats for AINI and across subjects for in vivo).
Comparison of regional deposition of NasalCrom in AINI vs. in vivo (60° and 45°, n = 3 repeats for AINI, n = 9 nostrils for realistics). In vivo data taken from Al-Ghananeem et al. [20]. Note that administration angles in vivo were not reported. Error bars indicate one standard deviation (measured across repeats for AINI and across subjects for in vivo).
… 
Comparison of regional deposition of Nasonex in AINI vs. in vivo data as fraction of dose deposited in the nasal cavity (i.e. excluding filter deposition; 45° and 60°, n = 3 repeats for AINI, n = 9 subjects for in vivo). In vivo data taken from Leach et al. [21]. Note that administration angles in vivo were not reported. Ve = Vestibule; Tu = Turbinates; Ol = Olfactory; Na = Nasopharynx. Error bars indicate one standard deviation (measured across repeats for AINI and across subjects for in vivo).
Comparison of regional deposition of Nasonex in AINI vs. in vivo data as fraction of dose deposited in the nasal cavity (i.e. excluding filter deposition; 45° and 60°, n = 3 repeats for AINI, n = 9 subjects for in vivo). In vivo data taken from Leach et al. [21]. Note that administration angles in vivo were not reported. Ve = Vestibule; Tu = Turbinates; Ol = Olfactory; Na = Nasopharynx. Error bars indicate one standard deviation (measured across repeats for AINI and across subjects for in vivo).
… 
Regional deposition of QNASL in AINI as fraction of emitted dose (i.e. including filter deposition and fraction dripping from the vestibule; 45° and 60°, n = 3 repeats for AINI). Error bars indicate one standard deviation (measured across repeats for AINI).
+1
Regional deposition of QNASL in AINI as fraction of emitted dose (i.e. including filter deposition and fraction dripping from the vestibule; 45° and 60°, n = 3 repeats for AINI). Error bars indicate one standard deviation (measured across repeats for AINI).
… 
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https://doi.org/10.1007/s11095-022-03388-7
ORIGINAL RESEARCH ARTICLE
In Vitro Regional Deposition ofNasal Sprays inanIdealized Nasal Inlet:
Comparison withIn Vivo Gamma Scintigraphy
JohnZ.Chen1· WarrenH.Finlay1· AndrewMartin1
Received: 24 June 2022 / Accepted: 30 August 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Purpose To compare in vitro regional nasal deposition measurements using an idealized nasal airway geometry, the Alberta
Idealized Nasal Inlet (AINI), with in vivo regional deposition for nasal drug products.
Materials and Methods One aqueous solution formulation (NasalCrom), one aqueous suspension formulation (Nasonex) and
one nasal pressurized metered dose spray device (QNASL) were selected. Two spray orientation angles, 60° and 45° from
the horizontal, were selected. A steady inhalation flow rate of 7.5 L/min was selected to simulate slow inhalation through
a single nostril. After actuation, the AINI was disassembled. The mass of drug deposited in each region and a downstream
filter, representing penetration of drug to the lungs, was determined using ultraviolet–visible (UV–Vis) spectrophotometry.
Results No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11% for
QNASL. For NasalCrom, 45% to 69% of the dose deposited in the AINI was deposited in the vestibule and 31% to 55% was
deposited in the turbinates; for Nasonex, 66% to 74% (vestibule) and 26% to 34% (turbinates); for QNASL, 90% to 100%
(vestibule) and 0% to 10% (turbinates). No statistically significant difference was observed between regional deposition in
vivo and in vitro for any of the formulations, except that nasopharyngeal deposition with Nasonex differed by less than 1.56%
from in vivo, which while statistically significant, is unlikely to be clinically significant.
Conclusions The AINI was able to mimic regional in vivo deposition for nasal drug products, permitting differentiation
between devices based on regional deposition.
Keywords aerosols· in vitro-in vivo correlations· nasal sprays· regional deposition
Introduction
Benchtop in vitro test methods are vital to researchers and
drug developers seeking to understand or characterize the
performance of medical aerosols and nasal sprays. For
example, the United States Pharmacopeia General Chap-
ter < 601 > contains standardized in vitro procedures for the
measurement of properties of medical aerosol and nasal
spray products, such as delivered dose uniformity, aerody-
namic size distribution and fine particle fraction, that facili-
tate comparisons between different products and give some
indication of the possible behavior of the product in vivo [1].
For nasal spray drug products, FDA guidance recommends
additional in vitro tests, including characterization of spray
pattern and plume geometry [2]. Knowledge of the spray
characteristics of a test formulation can be particularly
valuable in the early stages of product development, where
parameter refinement based on early feedback from in vitro
experiments can save time later in the development process
when testing moves to an in vivo setting. Measured in vitro
parameters are also intended to provide a convenient way
to support assessment of bioavailability and bioequivalence
of different nasal spray products, and should ideally be
highly discriminating between products [2–4]. However, the
strength of correlation between in vitro measurement param-
eters for nasal spray products and relevant in vivo responses
remains uncertain and is a topic of frequent debate.
In the related field of aerosol drug delivery to the lungs,
researchers have described in vitro methods using idealized
or selected realistic airway geometries that mimic average
deposition measured in in vivo studies [5–13]. These geom-
etries can function as a reference for in vitro experiments
* Andrew Martin
andrew.martin@ualberta.ca
1 Department ofMechanical Engineering, Faculty
ofEngineering, University ofAlberta, 10-265 Donadeo
Innovation Centre for Engineering, Edmonton, Canada
/ Published online: 15 September 2022
Pharmaceutical Research (2022) 39:3021–3028
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Nasal deposition using human idealized geometry and in vivo pharmacokinetic studies with a rat model were then conducted with the selected formulations. Performance methodologies were chosen based on their frequent use in the literature and biomimetic potential (similar conditions to the nasal cavity) (Wadell et al. 2003;Jug et al. 2018;Jurišić Dukovski et al. 2019;Chen et al. 2022;Trenkel and Scherließ 2023). The second aim of this study was to establish IVIVCs of the results obtained, in order to investigate the potential of the methodologies used as predictive tools for nasal powder development. ...
... Samples from the receptor compartment (400 µL) were collected at 0.17 (10 min), 0.33 (20 min), 0.5 (30 min), 1, 1.5, 2, 3, 4, 6 and Scientific, Nottingham, United Kingdom) coupled with Next Generation Impactor (NGI) (Copley Scientific, Nottingham, United Kingdom). This idealized nasal airway geometry in aluminum was developed according to computational fluid dynamics simulations performed in a set of realistic nasal geometries, in order to mimic human nasal deposition (Chen et al. 2020(Chen et al. , 2022. The drug was quantified in the four regions of interest: vestibule (nostril), the turbinates, the olfactory region and the nasopharynx. ...
... To mitigate particle bounce, the AINI and NGI stages were coated with Brij solution (0.15 g/ml Brij in ethanol) in glycerol (1mL Brij solution for 5 g glycerol) (Murphy et al. 2022). The device was actuated at a 45º angle between the inlet plane of the vestibule and the device tip (Chen et al. 2022), with an inhalation flow rate of 15 L/min (Kiaee et al. 2019), in 3 actuations of 2 s each, based on previous experience using this device. Piroxicam quantification was performed by HPLC analysis in the AINI regions, NGI stages and device after washing with fixed volumes of methanol. ...
Amorphous nasal powder advanced performance: in vitro/ex vivo studies and correlation with in vivo pharmacokinetics
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Purpose Amorphous solid dispersions (ASD) for nasal delivery offer the opportunity to increase drug release performance, while using polymers with mucoadhesive properties. The aim of the present study was to apply this solubility enhancement technique to a poorly soluble drug for nasal delivery, while comparing two particle engineering strategies, namely spray dried microparticles and chimeral agglomerates, with the corresponding physical blends with crystalline drug. Methods Formulations of piroxicam were manufactured using varied polymer and particle engineering strategies and evaluated through in vitro drug release and ex vivo permeation studies, as well as nasal deposition and in vivo pharmacokinetic studies. Results ASD with hydroxypropyl methylcellulose (HPMC) showed enhanced drug release and permeation, compared to polyvinylpyrrolidone/vinyl acetate formulations and blends. Nasal deposition of HPMC chimeral agglomerates suggested off-target deposition. In vivo pharmacokinetic studies revealed that spray-dried HPMC-containing microparticles exhibited the highest maximum plasma concentration (C max ) and the lowest time to attain it (t max ). In vitro release rate and in vivo absorption rate were correlated as well as t max and in vitro performance. When excluding the formulation with least nasal targeted deposition, in vitro release and ex vivo permeation performance were also correlated with C max and area under the drug concentration-time curve (AUC) from 0 to 1 h, with R ² > 0.89. Conclusion ASD for nasal delivery provide fast drug absorption, which depends on the supersaturation ability of the polymer employed. In vitro-in vivo correlations suggested that in vitro release and ex vivo permeation studies are predictive tools regarding nasal absorption.
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... Regional deposition measured in the idealized geometry was found to consistently match average regional deposition measured in a set of realistic geometries. In a further set of in vitro experiments, Chen et al. demonstrated that regional depositions of three types of nasal drug products in a commercially available aluminum version of the aforementioned idealized geometry, the Alberta Idealized Nasal Inlet, or AINI (Copley Scientific) were in good agreement with previously published in vivo data [58]. ...
... Murphy et al. [119] conducted an in vitro study of regional deposition of a liquid amebiasis vaccine candidate in the AINI and in realistic infant nasal airway geometries. The vaccine candidate, LecA + GLA-3 M − 052 liposomes, was delivered using a syringe-based liquid atomization device, the Teleflex MAD Nasal ™ , using a methodology similar to what was [13,58]. Most deposition occurred in the turbinates, with relatively little dripping from nostrils. ...
Characterizing regional drug delivery within the nasal airways
Article
Introduction: The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products. Areas covered: This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines. Expert opinion: As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.
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... The KNI was designed specifically for testing nasal sprays and additional evaluation will be required if it is to be applied for testing other dosage forms such as nasal aerosols or nasal powders. An idealized nasal inlet, the Alberta Idealized Nasal Inlet (AINI), has been developed to mimic in vivo deposition by the group led by Finlay (Fig. 6) [40]. The AINI consists of four anatomical regions: vestibule, turbinates, olfactory, and nasopharynx. ...
... The AINI consists of four anatomical regions: vestibule, turbinates, olfactory, and nasopharynx. Chen et al. recently evaluated a commercially available nasal spray solution, suspension, and HFA-based nasal aerosol, comparing in vitro deposition with the AINI, over a range of actuation angles, to in vivo deposition by gamma scintigraphy [40,41]. Their outcomes indicated that the AINI represented well the average in vivo deposition across this range of drug products (see Table III). ...
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Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets produced by the various nasal devices are large, and for suspension products, individual droplets may contain multiple drug particles or none at all. Assessment of suspension products is further complicated by the presence of solid excipient particles. These complications make it imperative that the limitations of the instruments used for characterization as well as the underlying assumptions that govern the interpretation of data produced by these instruments are understood. In this paper, we describe various methodologies used to assess APSD for nasal inhalation products and discuss proper use, limitations, and new methodologies on the horizon.
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... Another anatomical model of the human nasal airway is the Alberta Idealised Nasal Inlet (Copely, UK) with separable sections, including the vestibule, conchae, olfactory region, and nasopharynx. Contrary to the transparent nasal cavity model, the detachable sections of the Alberta Idealised Nasal Inlet enable quantitative evaluations of the regional IN drugs' deposition [105]. ...
Challenges in the Development and Application of Organ-on-Chips for Intranasal Drug Delivery Studies
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With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that they can be delivered promptly to the market is critically acknowledged. There have been attempts to manufacture anatomically relevant 3D replicas of the human nasal cavity for in vitro IN drug tests, and a couple of organ-on-chip (OoC) models, which mimic some key features of the nasal mucosa, have been proposed. However, these models are still in their infancy, and have not completely recapitulated the critical characteristics of the human nasal mucosa, including its biological interactions with other organs, to provide a reliable platform for preclinical IN drug tests. While the promising potential of OoCs for drug testing and development is being extensively investigated in recent research, the applicability of this technology for IN drug tests has barely been explored. This review aims to highlight the importance of using OoC models for in vitro IN drug tests and their potential applications in IN drug development by covering the background information on the wide usage of IN drugs and their common side effects where some classical examples of each area are pointed out. Specifically, this review focuses on the major challenges of developing advanced OoC technology and discusses the need to mimic the physiological and anatomical features of the nasal cavity and nasal mucosa, the performance of relevant drug safety assays, as well as the fabrication and operational aspects, with the ultimate goal to highlight the much-needed consensus, to converge the effort of the research community in this area of work.
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... Such printed in vitro 3D models are already available for humans and have been recently validated for the study of aerosol deposition in the upper airways [10,[17][18][19]. Furthermore, it is undeniable that, preclinical experimentation on animals is facing a re-evaluation, given the increasing of restrictions and demanding procedures required to justify the use of animals. ...
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Article
  • Feb 2018
Effective targeting of nasal spray deposition could improve local, systemic, and CNS drug delivery, however, this has proven to be difficult due anatomical features of the nasal cavity including the nasal valve and turbinate structures. Furthermore, nasal cavity geometries and dimensions vary between individuals based on differences in their age, gender and ethnicity. The effect of patient-specific administration parameters was evaluated for their ability to overcome the barriers to targeted nasal drug delivery. The nasal spray deposition was evaluated in ten 3D printed nasal cavity replicas developed based on the CT-scans of five pediatric and five adult subjects. Cromolyn sodium nasal solution, USP modified with varying concentrations of hypromellose was utilized as a model nasal spray to evaluate the deposition pattern from formulations producing a variety of plume angles. A central composite design of experiments was implemented using the formulation with the narrowest plume angle to determine the patient-specific angle for targeting the turbinate region in each individual. The use of the patient-specific angle with this formulation significantly increased the turbinate deposition efficiency compared to that found for all subjects using an administration angle of 30°, around 90% compared to about 73%. Generally, we found turbinate deposition increased with decreases in the administration angle. Deposition to the upper regions of the replica was poor with any formulation or administration angle tested. Effective turbinate targeting of nasal sprays can be accomplished with the use of patient-specific administration parameters in individuals. Further research is required to see if these parameters can be device-controlled for patients and if other regions can be effectively targeted with other nasal devices.
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