- Email: [email protected]
Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model
Journal Pre-proofs Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model Tomasz R. Sosnowski, Piotr Rapiejko, Jarosław Sova, Katarzyna Dobrowolska PII: DOI: Reference:
S0378-5173(19)30956-1 https://doi.org/10.1016/j.ijpharm.2019.118911 IJP 118911
To appear in:
International Journal of Pharmaceutics
Received Date: Revised Date: Accepted Date:
10 July 2019 26 November 2019 27 November 2019
Please cite this article as: T.R. Sosnowski, P. Rapiejko, J. Sova, K. Dobrowolska, Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model, International Journal of Pharmaceutics (2019), doi: https://doi.org/10.1016/j.ijpharm.2019.118911
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier B.V.
Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model
Tomasz R. Sosnowski Conceptualization Methodology Resources Investigation Visualization Writing - Original draft preparation Writing - Reviewing and Editing Funding acquisition Project administrationa,*, [email protected], Piotr Rapiejko Conceptualization Methodology Resources Writing - Reviewing and Editingb, Jarosław Sova Methodology Resources c, Katarzyna Dobrowolska Investigation Visualizationa aFaculty
of Chemical and Process Engineering, Warsaw University of Technology, Waryńskiego 1,
00-645 Warsaw, Poland bDepartment
of Otolaryngology with Division of Cranio-Maxillo-Facial Surgery, Military Institute of
Medicine, Warsaw, Poland cDepartment
of Otolaryngology, 7th Navy Hospital in Gdansk, Poland
*Corresponding
author.
Graphical abstract
Highlights
Difference in properties of similar nasal drugs influences spraying and deposition
Inspiratory airflow spreads the deposited drug more distally into the nasal cavity
The secondary transport of nasal drugs depends on their rheological properties
Abstract The study is focused on the analysis of physicochemical properties of selected nasal sprays of mometasone furoate, and the influence of these properties on aerosol quality and penetration in the pediatric nose. After the determination of drugs surface tension and viscosity, spray geometry and size distribution of aerosol droplets, the topical delivery of each drug to different parts of the pediatric model of the nose with the flexible vestibule was evaluated by colorimetric visualization. All tested drugs are pseudo-plastic liquids, showing some differences in flow consistency constant k (range 7141422) and flow behavior index n (range 0.16-0.31). At no-flow conditions, all sprays are deposited mainly in the anterior of the nasal cavity and the septum (2-3 cm from the nostril), as a result of inertial impaction of large droplets. The deposition range is slightly influenced by the geometry of the aerosol cloud, which, in turn, depends both on drug properties and the type of the spraying nozzle. Deposition experiments accompanied by the airflow show an enhancement of drug transport to deeper parts of the nasal cavity (up 4-6 cm from the vestibule), and this effect can be attributed to the secondary effects of spreading of the deposited liquid layer along the narrow air passages in the nose. Plume geometry, dose volume and rheological properties of the drug were shown to be important factors in the spray penetration pattern in the pediatric nose. The deepest delivery can be expected for drugs of low viscosity and short aerosol plumes.
Keywords nasal sprays, mometasone, drug penetration, deposition, in vitro model
1.
Introduction Nasal glucocorticoids are the first-choice drugs for the treatment of allergic rhinitis and sinus
diseases (Roberts et al., 2013; Fokkens et al., 2012; Brożek et al., 2010). One of the basic symptoms of nasal and paranasal sinuses diseases is swelling of the mucosa, which contributes to the reduction in the patency of nasal cavities and a decrease in the penetration of the drug in the nose. Modern nasal glucocorticoids act locally on the nasal mucosa. The deposition of nasal drugs primarily in the front of the nasal cavity (in patients with reduced nasal patency) is one of the reasons for reducing the effectiveness of drugs and increasing the incidence of side effects (Jang & Kim, 2016). Even small differences in the properties of sprayed nasal preparations can significantly affect the contact of nasal drugs with the nasal mucosa and contribute to a change in their effectiveness (Rapiejko et al., 2015). There have been many studies carried out in the field of the deposition of aerosols administered inter-nasally in adults. Starting from the early work of Hallworth & Padfiled (1986), a number of papers focused on the nasal deposition of sprays, studied both experimentally in vivo/in vitro and by numerical modeling. For instance, Suman et al. (1999) demonstrated with
99Tc
radiolabelled saline
sprayed in adult volunteers that intensified aerosol deposition on the turbinates is due to inertial impacts of large droplets. These authors concluded that more efficient penetration to the nasal cavity obtained in the case of nebulized drugs was due to the smaller size of droplets and lower aerosol velocity. Cheng et al. (2001) pointed out the significance of the droplet diameter and the spray angle on the regional deposition of sprayed drugs in the reconstructed nasal cavity and showed that the
increase in both the droplet size and the spray angle results in the intensified deposition in the nostrils and the nasal valve. Consequently, at relatively high inhalation airflow rates (20 L/min), not more than 65% of the dose can be deposited in the turbinate region, and no penetration to the posterior part (nasopharynx) is detected. Foo et al. (2007) confirmed that regardless of the spray angle and droplet size, the deposition of the spray takes place exclusively in the first half of the turbinate region, i.e., at the maximum distance of 2.25 cm from the nasal valve, while 80% of the deposited mass is found at the first centimeter of this region. The airflow increase up to 60 L/min does not influence the deposition pattern. On the contrary, Kimbell et al. (2007) claimed that inspiratory airflow promotes deeper penetration of aerosol, however only for small droplets sprayed at low velocities. These authors also stressed the importance of the barrier-effect of the nasal valve which can notably restrict the penetration of the spray to the interior of the nasal cavity. The significance of spray characteristics was also studied by Inthavong et al. (2011) who demonstrated that small spray angles (less than 30) and swirling motion of the droplets released from the atomizer, improve aerosol penetration in the nose, however only for sufficiently small droplets (<15 m) and aerosol clouds formed as a hollow cone. Inthavong et al. (2011) also pointed out that the actual size and shape of the nasal cavity are of high importance for the deposition, and small changes in this geometry (even those caused by the nasal cycles) may result in a different deposition pattern. It was also proven that aerosol droplets in the free jet are formed at a distance of approximately 4 mm from the nozzle orifice due to the break-up of liquid ligaments. In an earlier paper by these authors (Inhtavong et al., 2006), the computational analysis showed a domination of inertia as the mechanism of anterior deposition of large droplets (>50 m), while the role of injection velocity, angle and airflow rate was found only for small droplets ( 20 m) which, in general, are not prevalent in aerosols delivered from nasal pumps. Kundoor & Dalby (2011) measured the effects of the orientation of the actuator tip inside the nostril and the patient’s head orientation on the deposition pattern, using the reconstructed nasal cavity. They also considered the influence of other factors, such as the volume of the dose, the viscosity of the sprayed liquid and the nozzle insertion depth. Their results showed that the orientation of the tip and the head is the
governing factor for the topical drug deposition. Liquid viscosity influences both the size distribution of the droplets and the shape of the aerosol plume, and both factors have some effects on the deposition pattern in the nasal cavity. The majority of published papers have been focused on the deposition of aerosol administered intra-nasally from spray pumps, and only some of them analyzed the fate of deposited liquid drugs. Pu et al. (2014) studied the spraying of drugs with different rheological properties and their dripping after intranasal administration. The authors indicated that viscosity enhancers influence the overall characteristics of the spray, and also influence the deposition and drainage regions (anterior vs. posterior). Particularly, an increase in the concentration of HPMC (hydroxypropyl methylcellulose) decreases the spray angle more than the addition of Avicel. At the same time, droplets obtained from HPMC solutions are smaller, so their deposition in the anterior regions of the nasal cavity decreases compared to sprayed Avicel solutions. In contrast to Avicel, HPMC solutions drain more easily towards the throat, and this effect can be explained by their shear-thinning rheological properties. Purely Newtonian, high viscosity Avicel solutions remain in the areas of their initial deposition for a longer time, and their dripping is minimal. Much less information is available regarding the deposition and fate of sprayed nasal drugs in children. Nasal air-passages are much smaller in this case, and the airflow is also different, so the conclusions from studies related to adults may not be valid. The recent theoretical analysis by Foo et al. (2018) indicates that the narrowing in the nasal valve area of a child makes the spray angle (cone) the decisive parameter in the penetration of the sprayed drug into the nasal cavity, and only cones narrower than 20 may be considered suitable, provided that the actuator tip is properly placed in the nostril. Using a pediatric (12-year-old) model of the nose covered with the artificial mucus Sawant & Donovan (2018) demonstrated that the deposition of the sprayed droplets was localized solely in the nasal vestibule and on the nasal valve, and no aerosol penetration to the turbinate region and nasopharynx was observed. The authors stressed the difference between this deposition pattern and the deposition in adults. Cast tilting after drug administration, which was applied to mimic the change in head positions, resulted in partial drainage of the deposited liquid to posterior regions of the nasal
cavity. A limitation of this study was that placing the actuator tip in a realistic way in the nostril was not possible because of the rigidity of the polymeric material (DurusTM) used to prepare the whole anatomical model. Many papers report the computational results of the nasal deposition of inhaled aerosol particles or droplets in children, especially in infants (Janssens et al., 2001; Minocchieri et al., 2008; StoreyBishoff et al., 2008). Such numerical analyses were often focused on the inhalation of “soft” aerosol clouds (such as those generated in nebulizers), so they neglected the dynamic effect of drug spraying in the nostril, i.e. the real conditions of the nasal drug administration from nasal pumps (Laube et al., 2010; Zhou et al. 2014; Carrigy et al., 2014). The realistic situation of drug spraying was considered by Laube et al. (2015). However, these authors studied the performance of the novel AccusprayTM aerosol delivery device with the pediatric nasal casts (2-, 5- and 12-year-old children). To better understand the differences between intranasal drug delivery in adults and children, the current paper analyses the processes of generation, deposition, and transport of sprayed drugs in the pediatric (7-year-old) model of the nasal cavity. The anatomical model used in this work has a flexible (elastic) vestibule, which allows the most realistic fit of the atomizer tip inside the nostril. The paper also analyzes the influence of the physicochemical properties of the sprayed liquid on the pump performance, aerosol characteristics and drug distribution in the nose.
2. Materials and methods 2.1 Atomizing devices and drugs Experimental studies were conducted for five products delivering the same dose (50 g) of mometasone furoate in the form of spray delivered from a nasal pump. The products were denoted as A, B, C, D, and E (see the detailed specification in the Appendix). As shown in Fig. 1, the shape of atomizing nozzles of these products is not identical. 2.2 The scope and methodology of experimental studies
The following experimental studies were conducted for each product A, B, C, D, and E: a)
visual determination of spray geometry – obtained from digital video sequences (Casio Exilim EX-F1; Japan, frame rate: 60 fps);
b)
optical determination of droplet size distribution during the stable (fully developed) phase of spray emission (FDA, 2003). Measurements were done with Spraytec (Malvern Instruments, UK) in the open-spray configuration without the hood, using the distance of 50 mm between the actuator and the laser beam. The particle size was measured in the range of 0.1-900 m;
c)
gravimetric determination of the mass output of each product after 5, 10 and 15 successive actuations (Radwag analytical balance, Poland);
d)
determination of complex rheological properties of drug formulations (MCR302 cone-plate rheometer - Anton Paar, Austria);
e)
determination of the surface tension of the drugs (PAT-1M drop shape tensiometer - Sinterface, Germany);
f)
visual determination of the deposition of aerosols sprayed to the nose model. This part of the study was conducted with a 3D anatomical model of the right half of the nasal cavity of a 7-yearold girl. The model was reconstructed by rapid prototyping using CT-scans (Siemens Emotion VI scanner, layer thickness: 0.63 mm). The model was assembled from two parts: the nasal cavity containing the side-wall, and the plate containing the left side of the septum. The model was manufactured by a rapid prototyping method from the rigid acrylic polymer RGD720. However, the vestibule with the nostrils was made of the elastic acrylic polymer FLX930to allow the realistic fit of the atomizing nozzle in the nostril (both polymers were purchased from Stratasys, USA). The drugs were sprayed into the assembled air-tight model after insertion of the atomizer tip into the nostril (insertion depth 0.7 cm at 30 angle to the vertical direction – Fig. 2c), with the tip oriented to the eye corner. The method of deposition assessment is described in section 2.3.
The measurements (a), (d), (e), and (f) were done in two independent repetitions for each drug, while experiments (b) and (c) were done in triplicate. The general statistical methods were applied to calculate the mean values and the standard deviation of the measured parameters. Canisters with drugs were manually shaken and primed before each experiment. The nasal pumps were activated manually to mimic the realistic conditions of using these atomizers. All measurements were taken at room temperature (23 ± 1 C) and the relative air humidity of 50 ± 10%.
2.3. Spray deposition in the model of the pediatric nasal cavity The details of the anatomical model used in the experiments are shown in Figs 2 and 3. Before each deposition experiment, the inner surfaces of the nasal cast: both of the side-wall and the septum, were covered with a very thin layer of water-sensitive gel (Water Finding Paste M; Merck, Germany). The gel changes the color from gray to purple after contact with water, allowing fast and straightforward determination of the deposition areas. The method was adapted according to the paper by Kundoor & Dalby (2010, 2011) and after the validation in studies done with the adult nasal replica (Rapiejko et al., 2015).
After each deposition experiment, the model was disassembled, and both the nasal side-wall and the septum were photographed (Casio Exilim, Japan). All photographs were taken from a distance of 40 cm under the same lighting conditions. The reference pictures for both surfaces were obtained in two cases (Fig. 3): 1. without the deposited material (it corresponds to 0% deposition), and 2. for the surfaces fully covered by aqueous spray (100% deposition). The simple conversion of colors was done with FIJI open-source software (imagej.net) to visualize the deposition areas more clearly.
Aerosol deposition studies were conducted in two types of experiments: 1. spraying of drugs through the nostril without the simultaneous airflow (breath-hold), 2. spraying of drugs through the nostril with a simultaneous airflow (8 L/min).
Airflow rate of 8 L/min modeled
inspiratory flow easily achieved by 7-year-old children,
considering that such a value is significantly below the reported maximum inspired flow rate obtained at this age during nasal breathing (Pickering & Beardsmore, 1999). In the experiments, the airflow was switched on two seconds before spraying and was maintained for two more seconds after aerosol release.
3. Results and discussion 3.1. Spray geometry The photographs of the studied nasal drugs spray geometry are presented in Fig. 4.In all cases, the free jets of droplets extend above 30 cm from the nozzle orifice, i.e., to the distance significantly longer than the distance between the nozzle tip and the ceiling of the pediatric nasal cavity (approximately 5 cm). Spray geometry differs between the products and the properties of all jets are listed in Table 1.
Spraying pumps A and C produce almost identical aerosol jets, whereas device E releases longer plume, however, with a similar cone angle. Aerosol jet obtained from pump D is the narrowest and the
longest (almost 50 cm). Two zones of droplets can be observed in the spray obtained from device B: the first dense zone of droplets has the length similar to the plume obtained in drugs A and C (37 cm), but the additional jet of large droplets can be seen a few centimeters above. Despite some differences in the plume geometry, the results show that aerosol droplets sprayed from each device always have high kinetic energy, which should result in a considerable inertial deposition of the drug on the nasal surfaces near the spray inlet (i.e., near the nostril).As reported by Liu et al. (2010) and Inthavong et al. (2014), the linear velocity of drops in the central part of the plume produced by nasal pumps, is in the range of 12-20 m/s. This suggests that the time needed for these drops to reach the wall of the nose interior a few centimeters above the atomizing nozzle s shorter than 5 milliseconds. Moreover, the expanding shape of the aerosol cone released from the nozzle is non-compatible with the constricted geometry of the nostril (Fig. 5). As a result, only droplets from the central part of the aerosol jet are expected to penetrate beyond the nasal valve and reach deeper regions of the nasal cavity. However, even these droplets will hit the surface of the nasal cavity in the proximity of the nasal valve because they have a very high momentum. The exact spot of their deposition may depend on the insertion depth of the nozzle tip and the tip orientation (e.g., Kundoor & Dalby, 2011), however, both factors should be of less importance in children due to large dimensions of the atomizer tip in relation to the size of the nostril (low freedom of movement of the tip in the nostril). 3.2. Droplet size distribution Table 2 contains the numerical parameters of the size distribution of the droplets released from tested spraying pumps. The average value of droplet volume median diameter, Dv50, is in the same range of 60-70 m for all studied sprays. However, the complete droplet size distributions are not identical. The distribution width can be characterized by Span parameter defined as:
𝑆𝑝𝑎𝑛 =
𝐷𝑣90 ― 𝐷𝑣10 𝐷𝑣50
(1).
The Span determined for the tested sprays is in the range of 0.59 ± 0.12 (spray B) to 0.79 ± 0.06 (spray C), and these data show that droplets released from device B are the most homogenous. The data shown in Table 2 suggest that droplets obtained from all atomizers have a low chance to be carried beyond the nasal cavity, which matches the typically expected penetration depth of nasal aerosols. Droplet size distributions in the aerosol cloud produced by all drugs A-E are characterized by good reproducibility, especially in the view of their hand-actuated operation. 3.3. Aerosol mass output Comparison of the mass output of tested nasal drugs during a release of 5, 10, and 15 successive doses is shown in Fig. 6,while the average values and the variability of the mass output are summarized in Table 3. It is found that all products spray a comparable mass of the liquid during each actuation, although the scatter between consecutive doses is higher in some products (e.g., drug B). Interestingly, some spraying devices show a decrease in the aerosol output during the successive actuations, which may be attributed to the individual features of the operation of dosing pumps in these products. The best performance was found in devices A and D, which were also characterized by the lowest overall scatter of the emitted mass of drug (CV < 1.5 %). 3.4. Rheological properties of the drugs Fig 7. shows an example of rheometric characteristics of one drug (A), i.e. the relationship between the dynamic viscosity [mPas] and the strain rate 𝛾 [s-1].Results for other products can be found in the Supplementary Material, and they are qualitatively the same. These graphs show that the drugs are pseudo-plastic (shear-thinning) liquids. This property of the formulation is intentional because it allows the drug to be less viscous during atomization and to recover to the gel-like substance when the drug is deposited on the nasal surface. The gelling of drugs reduces their gravitational drainage (Pennington et al., 1998; Pu et al., 2014). Rheological properties of such liquids can be described by the power-law (Ostwald-de Waele equation):
𝜏 = 𝑘𝛾𝑛
(2)
where denotes the shear stress, k is the so-called flow consistency index and n – the flow behavior index. The apparent viscosity at the given strain rate can be expressed as: 𝜏
𝜇𝑎𝑝𝑝 ≡ 𝛾 = 𝑘𝛾𝑛 - 1
(3)
Parameters of this rheological model evaluated from the experimental results for all drugs A, B, C, D, and E are listed in Table 3. The data show that drug D has the highest viscosity at rest and remains thick (viscous) even at high rates of strain. On the contrary, drug B is the least viscous at rest and becomes even thinner at increased rates of strain. Rheological properties of drugs A and B are comparable while drugs C and E show the intermediate viscosity at rest, and their viscosity is also less dependent on the rate of liquid deformation (i.e., the strain rate). Differences in the rheological properties of drugs help to understand their different behavior during spraying, i.e., during the process which generates high strain rates (Broniarz-Press et al., 2015). The rheological characteristics also provide information on the behavior of the drugs on the nasal surfaces, especially regarding their drainage rate.
3.5. Surface tension Fig. 8. shows that the surface tension of drugs A, B, C, and E is in the range of 32-33 (mN)/m, but the surface tension of drug D is lower, near 28 (mN)/m. This physicochemical property of drug D may explain why it is sprayed to the plume with a more narrow geometry (Fig. 4).
3.6. Drug deposition in the nasal cavity
The photographs of deposition areas after drug spraying to the nostril without using any additional airflow are shown in Fig.9. It is seen that sprayed droplets hit solely the anterior parts of the nasal cavity and the septum. The numerical data of drug penetration along the nasal surface, which are compared in Table 4, show that for all drugs, the penetration length is only 2-3 cm from the nasal valve. As expected from the schematic picture drawn in Fig. 5, droplets that obtain high kinetic energy during spraying are not expected to penetrate far through the narrow air channels of the nasal cavity. The differences observed in the aerosol jet geometry shown earlier in Fig. 4 have only a minor effect on the spatial distribution of droplet deposition. One may notice, however, that a less dynamic, shorter jets (as those obtained from drugs A and E) may allow a slightly (up to a few millimeters) deeper penetration of the drug along the middle and bottom air channels of the nasal cavity. It is interesting to compare the data of Fig. 9 obtained without the airflow to the results obtained when the additional airflow was applied during and following the application of the sprays (Fig. 10). The deposition patterns obtained in this case show that the auxiliary airflow enhances the penetration of drug in the nasal cavity. From Table 4, one may find that the horizontal penetration of drugs increases by another 2-3 cm toward the nasopharynx. Therefore, the airflow provides an additional mechanism of drug transport in the nose. It may be speculated, however, that deeper penetration of drugs is not caused by the improved transport of aerosol droplets with the airflow, since such transport is minimal because of the high inertia of droplets (e.g., Foo et al., 2007; Inhtavong et al., 2006). A more plausible explanation is that the presence of drugs in deeper parts of the nose is caused by the dynamic displacement of the already deposited liquid film along the nasal surface (Fig. 11), resulting from the aerodynamic shear stresses transferred from the flowing air. Such dislocation of films and droplets on solid supports is the wellknown phenomenon, often encountered in numerous non-biological systems (e.g., Dimitrakopoulos & Higdon, 2007; Carroll & Hidrovo, 2013; Fan et al., 2011). It is also possible that extremely narrow air channels of the pediatric nose may be incidentally plugged by liquid bridges formed by the deposited
drug layers. Such liquid structures may be ruptured by the airflow during the intense inspiration or sniffing, which will result in the secondary aerosolization (splashing) of the drug, and this process should provide another way of transferring the deposited drug along the nasal side-wall and the septum. High viscosity (at rest) of deposited liquid drugs reduce the rate of gravitational drainage which helps the liquid to remain in the spot of deposition. However, it also makes it more stable (rigid) when airflow tries to push it along the air passages. Based on the previous findings (Rapiejko et al., 2015), it may also be claimed that higher volumes of sprayed drugs are more advantageous for drug displacement since they will form deeper liquid layers on the nasal surface. All tested products A-E deliver the same volume in a single dose (100 L – also confirmed by the mass output data presented in Table 3). Therefore, small differences in the drug penetration observed in this study should be explained rather by different rheological properties of the drugs and – to a less extent - to some differences in the primary deposition. Pictures in Fig. 10 and data in Table 5 suggest that the drug which more easily penetrates to distal regions of the nasal cavity (drug A) has the following properties: (i)
relatively deep initial deposition (Fig. 9A),
(ii)
low viscosity even at low strain rates(k = 714, as shown in Table 4).
In contrast, drug B, although characterized by similar rheological properties, is transported weaker with the airflow, and this can be attributed to the more anterior initial aerosol deposition of this drug (Fig. 9B, Table 5). Drugs C and E, which show a comparable primary deposition and almost identical apparent viscosity at low strain rates (k value close to 1000), are spread similarly by the airflow (Fig. 10, Table 5). Finally, drug D sprayed mostly to the upper parts of the nasal cavity anterior (Fig. 9D), is dislocated along these upper regions (Fig 10D), and does not drain quickly because of the high viscosity at rest (k = 1422, Table 4). Our results show that none of the tested products were detected in the throat region. It means that the effects of sensing the taste of drugs sprayed to the nose are probably not associated with direct delivery of the aerosol to the nasopharynx but rather to the slow dripping of drugs of low viscosity.
4. Conclusions The study discussed several aspects of the deposition of drugs administered as nasal sprays to the nose of children. Experiments conducted on the anatomical model with a flexible nasal vestibule region allowed testing the use of nasal sprays in the most realistic way. The qualitative relationships between drug properties and the deposition pattern were investigated for five popular nasal spray products of mometasone furoate (50 g per dose). Tested drugs, in spite of the identical nominal dose of the active compound, had slightly different physicochemical characteristics, probably due to different contents of the additives. All drugs are pseudo-plastic fluids. However, some differences were found regarding the numerical values of their rheological parameters. These dissimilarities, together with the variability in the surface tension and pump design, are responsible for differences in the geometry of sprayed clouds and aerosol droplet size distribution. As a consequence, some variability in the drug deposition pattern in the 3D pediatric model of the nasal cavity is observed for these virtually identical drugs. The primary deposition of each sprayed drug in the nose is governed by the impaction of droplets which are ejected as a high-velocity, wide, conical plume from the nozzle of the atomizing pump. The droplets are relatively large (Dv50 in the range of 60-70 m), so they are immediately captured by the inertial mechanism in the vestibule and anterior region of the nasal cavity. However, it was shown that the deposited drugs could be displaced along the nasal surface bythe dynamic force of the inspired air which acts on the liquid layer of the drug that covers the nasal surface. The proposed mechanism of drug translocation should be of greater importance when nasal airways are narrower, such as in the studied case of the pediatric nose. The results indicate that drugs with low viscosity at low strain rates are pushed more efficiently to deeper regions of the nasal cavity than more viscous drugs. On the other hand, increased viscosity retards the gravitational drug drainage after deposition on the nasal surfaces (Pu et al., 2014), although the effect of dripping may be not less important at short, a few-second periods after drug administration.
The results of the study allow concluding that the complete analysis of deposition and penetration of aerosolized drugs delivered to the nose from atomizers (nasal pumps) should consider the following steps: (i)
liquid atomization in the spraying nozzle and aerosol formation,
(ii)
primary deposition of the released drug droplets - mainly by impaction because of their large diameter and high velocity,
(iii)
spreading of the deposited liquid drug along the nasal surfaces due to the aerodynamic interactions with the airflow during inspiration or sniffing.
Each process is influenced by physicochemical properties of the drug, design of the atomizer, but also on the exact way of drug application. These factors must be optimized to obtain the required topical delivery of drugs applied intra-nasally in the form of the spray. It may also be stated that small differences in the physicochemical properties of nasal formulations may cause variable clinical efficacy of these drugs, despite the similarity in the nominal dose of the active substance. The results of this study indicate that liquid atomization using nasal pumps does not assure homogeneous deposition of drugs in the pediatric nasal cavity, although it surely presents a more convenient drug delivery to the nasal mucosa than dropping. However, due to the demonstrated secondary spreading of the deposited liquid by inhaled air, the distribution of the drug in the nasal cavity can be more homogeneous. Small dimensions of the nasal geometry in children may be beneficial because, after the plugging of air passages by the deposited drug, it can be pushed more distally when inhaled air re-opens the ducts. Such a mechanism of improved drug penetration should remain valid also in obstructed nasal passages of adults. If so, this can explain why using the nasal sprays provide the clinically proven efficient treatment of the nasal and sinuses diseases despite a very limited direct deposition of sprayed aerosols in deeper regions of the nasal cavity.
Author contribution Tomasz R. Sosnowski was involved in paper conceptualization, development of methodology, data analysis and manuscript preparation. Piotr Rapiejko was involved in paper conceptualization, development of methodology and reviewing of the manuscript. Jaroslav Sova was responsible for gathering anatomical data and preparation of 3D model. Katarzyna Dobrowolska was responsible for experiments and data analysis.
Acknowledgments The research co-funded by NCN project No. 2018/29/B/ST8/00273. The authors acknowledge Adamed for providing drugs for the studies.
Appendix 1 Specification of studied nasal products is given in Table A1
References
Broniarz-Press, L., Sosnowski, T.R., Matuszak, M., Ochowiak, M., Jabłczyńska, K. (2015). The effect of shear and extensional viscosities on atomization of Newtonian and non-Newtonian fluids in ultrasonic inhaler. Int J Pharm. 485, 41-9. 10.1016/j.ijpharm.2015.02.065. Brożek, J.L., Bousquet, J., Baena-Cagnani, C.E. et al. (2010). Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 126, 466–476. 10.1016/ j.jaci.2010.06.047. Carrigy, N.B., Ruzycki, C.A., Golshahi, L., & Finlay, W.H. (2014). Pediatric in vitro and in silico models of deposition via oral and nasal inhalation. J Aerosol Med Pulm Drug Deliv. 27, 149-169. 10.1089/jamp.2013.1075. Carroll, B. & Hidrovo, C. (2013). Droplet detachment mechanism in a high-speed gaseous microflow. J Fluids Eng. 135(7), 071206. 10.1115/1.4024057. Cheng, Y.S., Holmes, T.D., Gao, J., Guilmette, R.A., Li. S, Surakitbanharn, Y. & Rowlings, C. (2001). Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway. J Aerosol Med. 14, 267–280. 10.1089/08942680152484199. Dimitrakopoulos, P.& Higdon, J. J. L. (2007). Displacement of fluid droplets from solid surfaces in low-Reynolds-number shear flows. J Fluid Mech. 336, 351-378. 10.1017/ S0022112096004788. Fan, J., Wilson, M.C.T. & Kapur, N. (2011). Displacement of liquid droplets on a surface by a shearing air flow. J Coll Interface Sci. 356, 286–292. 10.1016/j.jcis.2010.12.087. FDA. (2003). Guidance for industry: bioavailability and bioequivalence studies for nasal aerosol and nasal sprays for local action (Draft Guidance). Available at: https://www.fda.gov/ regulatoryinformation/search-fda-guidance-documents/bioavailability-and-bioequivalence-studies-nasalaerosols-and-nasal-sprays-local-action. Fokkens, W.J., Lund, V.J., Mullol J., et al. (2012). EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50, 1–12. 10.4193/Rhino50E2.
Foo, M.Y., Cheng, Y.S., Su, W.C. & Donovan, M.D. (2007). The influence of spray properties on intranasal deposition. J Aerosol Med. 20, 495-508. 10.1089/jam.2007.0638 Foo, M.Y., Sawant, N., Overholtzer, E. & Donovan, M.D. (2018). A simplified geometric model to predict nasal spray deposition in children and adults. AAPS PharmSciTech. 19, 2767-2777. 10.1208/s12249-018-1031-2. Golshahi, L., Finlay, W. H., Olfert, J. S., Thompson, R.B., & Noga M. L. (2010). Deposition of inhaled ultrafine aerosols in replicas of nasal airways of infants. Aerosol Sci Tech. 44, 741-752. 10.1080/02786826.2010.488256 Hallworth, G.W. & Padfield, J.M. (1986). A comparison of the regional deposition in a model nose of a drug discharged from metered aerosol and metered pump nasal delivery systems. J Allergy Clin Immunol. 77, 348–353. Inthavong, K., Qinjiang, G.,Se, C.M.K., Yang, W. & Tu J.Y. (2011). Simulation of sprayed particle deposition in a human nasal cavity including a nasal spray device. J Aerosol Sci. 42, 100–113. 10.1016/j.jaerosci.2010.11.008. Inthavong, K., Fung, M.C., Tong, X, Yang, W. & Tu J. (2014). High resolution visualization and analysis of nasal spray drug delivery. Pharm Res. 31, 1930–1937. 10.1007/s11095-013-1294-y. Jang, T.Y. & Kim, Y.H. (2016). Recent updates on the systemic and local safety of intranasal steroids. Curr Drug Metab. 17, 992-996. 10.2174/1389200218666161123123516. Janssens, H.M, de Jongste, J.C., Fokkens, W.J., Robben, S.G.F., Wouters, K., & Tiddens, H.A.W.M. (2001). The Sophia anatomical infant nose-throat (Saint) model: a valuable tool to study aerosol deposition in infants. J Aerosol Med. 14, 433-441. 10.1089/08942680152744640 Kimbell, J.S., Segal, R.A., Asgharian, B., Wong, B.A., Schroeter, J.D., Southall, J.P., Dickens, C.J., Brace, G. & Miller, F.J. (2007). Characterization of deposition from nasal spray devices using a computational fluid dynamics model of the human nasal passages. J Aerosol Med. 20, 59-74. 10.1089/jam.2007.0578.
Kundoor, V. & Dalby, R.N. (2010). Assessment of nasal spray deposition in a silicone human nose model using a color based method. Pharm Res. 27, 30–36. 10.1007/s11095-009-0002-4. Kundoor, V. & Dalby, R.N. (2011). Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast. Pharm Res. 28, 1895–1904. 10.1007/s11095-011-0417-6. Laube, B.L., Sharpless, G.J., Shermer, C., & Powell, K.G. (2010). Deposition of albuterol aerosol generated by pneumatic nebulizer in the Sophia Anatomical Infant Nose-Throat (SAINT) model. Pharm Res. 27, 1722–1729. 10.1007/s11095-010-0171-1. Laube, B.L., Sharpless, G., Vikani, A.R., Harrand, V., Zinreich, S.J., Sedberry, K., Knaus, D., Barry, J., & Papania M. (2015). Intranasal deposition of Accuspray™ aerosol in anatomically correct models of 2-, 5-, and 12-year-old children. J Aerosol Med Pulm Drug Deliv. 28, 320-33. 10.1089/jamp.2014.1174. Liu, X., Doub, W.H. & Guo, C. (2010). Evaluation of droplet velocity and size from nasal spray devices using phase Doppler anemometry (PDA). Int J Pharm. 388, 82–87. 10.1208/ s12249-0119594-1. Minocchieri, S., Burren, J. M., Bachmann, M. A., Stern, G., Wildhaber, J., Buob, S., Schindel, R., Kraemer, R., Frey, U. P., & Nelle, M. (2008). Development of the premature neonate for the study of aerosol delivery. Pediatr Res., 64, 141–146. 10.1203/PDR.0b013e318175dcfa Pennington, A.K., Ratcliffe, J.H., Wilson, C.G. & Hardy J.G. (1988). The influence of solution viscosity on nasal spray deposition and clearance. Int J Pharm. 43, 221-224. 10.1016/03785173(88)90277-3. Pickering, D.N. & Beardsmore, C.S. (1999). Nasal flow limitation in children. Pediatr Pulmonol. 27, 32–36.
Pu, Y., Goodey, A.P., Fang, X. & Jacob, K. (2014). A comparison of the deposition patterns of different nasal spray formulations using a nasal cast. Aerosol Sci Technol. 48, 930–938. 10.1080/02786826.2014.931566. Rapiejko, P., Sosnowski, T.R., Sova, J. & Jurkiewicz, D. (2015). Deposition of intranasal glucocorticoids – preliminary study. Otolaryngol Pol. 69, 30-38. 10.5604/00306657. 1184545. Roberts, G., Xatzipsalti, M., Borrego, L.M. et al. (2013). Paediatric rhinitis: position paper of the European Academy of Allergy and Clinical Immunology. Allergy
68, 1102–1116. 10.1111/
all.12235. Sawant, N. & Donovan, M.D. (2018). In vitro assessment of spray deposition patterns in a pediatric (12 year-old) nasal cavity model. Pharm Res. 35, 108. 10.1007/s11095-018-2385-6. Suman, J.D., Laube, B.L., & Dalby R. (1999). Comparison of nasal deposition and clearance of aerosol generated by nebulizer and an aqueous spray pump. Pharm Res. 16, 1648–1652. Storey-Bishoff, J., Noga, M., & Finlay, W.H. (2008). Deposition of micrometer-sized aerosol particles in infant nasal airway replicas. J Aerosol Sci. 39, 1055-1065. 10.1016/ j.jaerosci. 2008.07.011 Zhou, Y., Guo, M., Xi, J. Irshad, H., & Cheng Y.S. (2014). Nasal deposition in infants and children. J Aerosol Med Pulm Drug Deliv. 27, 110-116. 10.1089/jamp.2013.1039.
Fig. 1. Shapes of atomizer tips in tested nasal drugs.
Fig. 2. (a) Schematic of the experimental set-up used in deposition experiments: 1 – nasal spray, 2 – anatomical pediatric model of the nose, 3 – airflow meter (removed during deposition
measurements), 4 – valve, 5 - vacuum pump; (b) position of the actuator tip in the nostril during measurements.
Fig. 3. Side-wall of the nasal cavity (a) and the covering plate with the nasal septum (b): before aerosol deposition (upper panels) and at the maximum coverage by deposited droplets (lower panels). The scale is in centimeters.
Fig. 4. Aerosol jet geometry of aerosol released from different atomizers.
Fig. 5. The schematic operation of the nasal spray: 1 – the cone of the freely released aerosol plume, 2 – regions of initial droplets deposition in the nostril, 3 - jet penetrating beyond the nasal valve, 4 – the nasal cavity.
Fig. 6. Mass output during the release of 15 successive doses of tested drugs.
Fig. 7. The viscosity of nasal drug A as a function of strain rate (graphs for other drugs are available in the Supplementary Material).
Fig. 8. The surface tension of tested drugs.
Fig. 9. Drug penetration and deposition in the experiments without additional airflow. Gray dashed line shows the maximum horizontal position of detected drugs.
Fig. 10. Drug penetration and deposition in the experiments with additional airflow (8 L/min). Gray dashed line shows the maximum horizontal position of detected drugs.
Fig. 11. Proposed mechanisms of drug penetration during the simultaneous air inspiration: a – droplet entrainment by air during spray application (probably less important for large droplets), b – spreading of already deposited drug along the nasal surface due to the interactions with the air stream.
Table 1. Numerical values of the range and angle of aerosol jets.
*
Product designation
Maximum jet range (mm)
Spray angle
A
371
29
B
353/420*
27
C
364
27
D
507
20
E
398
29
the second zone of the jet – Fig. 4B
Table 2. Parameters of particle (droplet) size distribution: mean values ± SD (n=3). A
B
C
D
E
Dv10 [m]
42.6 ± 2.6
52.2 ± 5.3
43.9 ± 3.2
44.6 ± 1.7
47.4 ± 5.9
Dv50 [m]
61.3 ± 6.2
69.8 ± 3.8
65.3 ± 6.5
60.5 ± 4.8
64.4 ± 5.1
Dv90 [m]
88.3 ± 13.0
93.5 ± 4.2
95.8±12.2
84.4 ± 7.0
87.5 ± 4.8
Span [-]
0.74 ± 0.12
0.59 ± 0.12
0.79± 0.06
0.65 ± 0.07
0.63 ± 0.09
Table 3. The mass output of tested nasal drugs and rheological parameters of the Ostwald-de Waele model (eq. 2)
Product
Average output
designation
[mg/actuation]
Standard
Coefficient
deviation
of variation
of the
of the
flow
flow
output
output
consistency
behavior
(SD) [mg]
(CV) [%]
index, k
index, n
A
103.6
1.29
1.2
714.1
0.288
B
100.3
7.94
7.9
657.6
0.311
C
97.2
4.16
4.3
1013.2
0.194
D
99.0
0.88
0.9
1421.7
0.160
E
95.6
3.17
3.3
1006.6
0.232
Table 4. Horizontal distance of drug penetrating along the nasal surface - the average values measured on the side-wall and on the septum (Figs. 9 and 10). Product designation
No airflow
Airflow 8 L/min
A
3.0 ± 0.1
5.9 ± 0.9
B
2.1 ± 0.1
3.9 ± 0.3
C
2.1 ± 0.0
5.2 ± 0.3
D
2.2 ± 0.1
5.2 ± 0.2
E
2.3 ± 0.0
4.6 ± 0.5
Table A1. Mometasone furoate nasal sprays studied in this work.
Product
Product brand name
Serial no.
A
Metmin 50 g
223
B
Momester 50 g
191
C
Nasometin 50 g
GH9969
D
Nasonex 50 g
6KTLDEY001
E
Pronasal 50 g
3A606022
designation in this study
S0378-5173(19)30956-1 https://doi.org/10.1016/j.ijpharm.2019.118911 IJP 118911
To appear in:
International Journal of Pharmaceutics
Received Date: Revised Date: Accepted Date:
10 July 2019 26 November 2019 27 November 2019
Please cite this article as: T.R. Sosnowski, P. Rapiejko, J. Sova, K. Dobrowolska, Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model, International Journal of Pharmaceutics (2019), doi: https://doi.org/10.1016/j.ijpharm.2019.118911
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier B.V.
Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model
Tomasz R. Sosnowski Conceptualization Methodology Resources Investigation Visualization Writing - Original draft preparation Writing - Reviewing and Editing Funding acquisition Project administrationa,*, [email protected], Piotr Rapiejko Conceptualization Methodology Resources Writing - Reviewing and Editingb, Jarosław Sova Methodology Resources c, Katarzyna Dobrowolska Investigation Visualizationa aFaculty
of Chemical and Process Engineering, Warsaw University of Technology, Waryńskiego 1,
00-645 Warsaw, Poland bDepartment
of Otolaryngology with Division of Cranio-Maxillo-Facial Surgery, Military Institute of
Medicine, Warsaw, Poland cDepartment
of Otolaryngology, 7th Navy Hospital in Gdansk, Poland
*Corresponding
author.
Graphical abstract
Highlights
Difference in properties of similar nasal drugs influences spraying and deposition
Inspiratory airflow spreads the deposited drug more distally into the nasal cavity
The secondary transport of nasal drugs depends on their rheological properties
Abstract The study is focused on the analysis of physicochemical properties of selected nasal sprays of mometasone furoate, and the influence of these properties on aerosol quality and penetration in the pediatric nose. After the determination of drugs surface tension and viscosity, spray geometry and size distribution of aerosol droplets, the topical delivery of each drug to different parts of the pediatric model of the nose with the flexible vestibule was evaluated by colorimetric visualization. All tested drugs are pseudo-plastic liquids, showing some differences in flow consistency constant k (range 7141422) and flow behavior index n (range 0.16-0.31). At no-flow conditions, all sprays are deposited mainly in the anterior of the nasal cavity and the septum (2-3 cm from the nostril), as a result of inertial impaction of large droplets. The deposition range is slightly influenced by the geometry of the aerosol cloud, which, in turn, depends both on drug properties and the type of the spraying nozzle. Deposition experiments accompanied by the airflow show an enhancement of drug transport to deeper parts of the nasal cavity (up 4-6 cm from the vestibule), and this effect can be attributed to the secondary effects of spreading of the deposited liquid layer along the narrow air passages in the nose. Plume geometry, dose volume and rheological properties of the drug were shown to be important factors in the spray penetration pattern in the pediatric nose. The deepest delivery can be expected for drugs of low viscosity and short aerosol plumes.
Keywords nasal sprays, mometasone, drug penetration, deposition, in vitro model
1.
Introduction Nasal glucocorticoids are the first-choice drugs for the treatment of allergic rhinitis and sinus
diseases (Roberts et al., 2013; Fokkens et al., 2012; Brożek et al., 2010). One of the basic symptoms of nasal and paranasal sinuses diseases is swelling of the mucosa, which contributes to the reduction in the patency of nasal cavities and a decrease in the penetration of the drug in the nose. Modern nasal glucocorticoids act locally on the nasal mucosa. The deposition of nasal drugs primarily in the front of the nasal cavity (in patients with reduced nasal patency) is one of the reasons for reducing the effectiveness of drugs and increasing the incidence of side effects (Jang & Kim, 2016). Even small differences in the properties of sprayed nasal preparations can significantly affect the contact of nasal drugs with the nasal mucosa and contribute to a change in their effectiveness (Rapiejko et al., 2015). There have been many studies carried out in the field of the deposition of aerosols administered inter-nasally in adults. Starting from the early work of Hallworth & Padfiled (1986), a number of papers focused on the nasal deposition of sprays, studied both experimentally in vivo/in vitro and by numerical modeling. For instance, Suman et al. (1999) demonstrated with
99Tc
radiolabelled saline
sprayed in adult volunteers that intensified aerosol deposition on the turbinates is due to inertial impacts of large droplets. These authors concluded that more efficient penetration to the nasal cavity obtained in the case of nebulized drugs was due to the smaller size of droplets and lower aerosol velocity. Cheng et al. (2001) pointed out the significance of the droplet diameter and the spray angle on the regional deposition of sprayed drugs in the reconstructed nasal cavity and showed that the
increase in both the droplet size and the spray angle results in the intensified deposition in the nostrils and the nasal valve. Consequently, at relatively high inhalation airflow rates (20 L/min), not more than 65% of the dose can be deposited in the turbinate region, and no penetration to the posterior part (nasopharynx) is detected. Foo et al. (2007) confirmed that regardless of the spray angle and droplet size, the deposition of the spray takes place exclusively in the first half of the turbinate region, i.e., at the maximum distance of 2.25 cm from the nasal valve, while 80% of the deposited mass is found at the first centimeter of this region. The airflow increase up to 60 L/min does not influence the deposition pattern. On the contrary, Kimbell et al. (2007) claimed that inspiratory airflow promotes deeper penetration of aerosol, however only for small droplets sprayed at low velocities. These authors also stressed the importance of the barrier-effect of the nasal valve which can notably restrict the penetration of the spray to the interior of the nasal cavity. The significance of spray characteristics was also studied by Inthavong et al. (2011) who demonstrated that small spray angles (less than 30) and swirling motion of the droplets released from the atomizer, improve aerosol penetration in the nose, however only for sufficiently small droplets (<15 m) and aerosol clouds formed as a hollow cone. Inthavong et al. (2011) also pointed out that the actual size and shape of the nasal cavity are of high importance for the deposition, and small changes in this geometry (even those caused by the nasal cycles) may result in a different deposition pattern. It was also proven that aerosol droplets in the free jet are formed at a distance of approximately 4 mm from the nozzle orifice due to the break-up of liquid ligaments. In an earlier paper by these authors (Inhtavong et al., 2006), the computational analysis showed a domination of inertia as the mechanism of anterior deposition of large droplets (>50 m), while the role of injection velocity, angle and airflow rate was found only for small droplets ( 20 m) which, in general, are not prevalent in aerosols delivered from nasal pumps. Kundoor & Dalby (2011) measured the effects of the orientation of the actuator tip inside the nostril and the patient’s head orientation on the deposition pattern, using the reconstructed nasal cavity. They also considered the influence of other factors, such as the volume of the dose, the viscosity of the sprayed liquid and the nozzle insertion depth. Their results showed that the orientation of the tip and the head is the
governing factor for the topical drug deposition. Liquid viscosity influences both the size distribution of the droplets and the shape of the aerosol plume, and both factors have some effects on the deposition pattern in the nasal cavity. The majority of published papers have been focused on the deposition of aerosol administered intra-nasally from spray pumps, and only some of them analyzed the fate of deposited liquid drugs. Pu et al. (2014) studied the spraying of drugs with different rheological properties and their dripping after intranasal administration. The authors indicated that viscosity enhancers influence the overall characteristics of the spray, and also influence the deposition and drainage regions (anterior vs. posterior). Particularly, an increase in the concentration of HPMC (hydroxypropyl methylcellulose) decreases the spray angle more than the addition of Avicel. At the same time, droplets obtained from HPMC solutions are smaller, so their deposition in the anterior regions of the nasal cavity decreases compared to sprayed Avicel solutions. In contrast to Avicel, HPMC solutions drain more easily towards the throat, and this effect can be explained by their shear-thinning rheological properties. Purely Newtonian, high viscosity Avicel solutions remain in the areas of their initial deposition for a longer time, and their dripping is minimal. Much less information is available regarding the deposition and fate of sprayed nasal drugs in children. Nasal air-passages are much smaller in this case, and the airflow is also different, so the conclusions from studies related to adults may not be valid. The recent theoretical analysis by Foo et al. (2018) indicates that the narrowing in the nasal valve area of a child makes the spray angle (cone) the decisive parameter in the penetration of the sprayed drug into the nasal cavity, and only cones narrower than 20 may be considered suitable, provided that the actuator tip is properly placed in the nostril. Using a pediatric (12-year-old) model of the nose covered with the artificial mucus Sawant & Donovan (2018) demonstrated that the deposition of the sprayed droplets was localized solely in the nasal vestibule and on the nasal valve, and no aerosol penetration to the turbinate region and nasopharynx was observed. The authors stressed the difference between this deposition pattern and the deposition in adults. Cast tilting after drug administration, which was applied to mimic the change in head positions, resulted in partial drainage of the deposited liquid to posterior regions of the nasal
cavity. A limitation of this study was that placing the actuator tip in a realistic way in the nostril was not possible because of the rigidity of the polymeric material (DurusTM) used to prepare the whole anatomical model. Many papers report the computational results of the nasal deposition of inhaled aerosol particles or droplets in children, especially in infants (Janssens et al., 2001; Minocchieri et al., 2008; StoreyBishoff et al., 2008). Such numerical analyses were often focused on the inhalation of “soft” aerosol clouds (such as those generated in nebulizers), so they neglected the dynamic effect of drug spraying in the nostril, i.e. the real conditions of the nasal drug administration from nasal pumps (Laube et al., 2010; Zhou et al. 2014; Carrigy et al., 2014). The realistic situation of drug spraying was considered by Laube et al. (2015). However, these authors studied the performance of the novel AccusprayTM aerosol delivery device with the pediatric nasal casts (2-, 5- and 12-year-old children). To better understand the differences between intranasal drug delivery in adults and children, the current paper analyses the processes of generation, deposition, and transport of sprayed drugs in the pediatric (7-year-old) model of the nasal cavity. The anatomical model used in this work has a flexible (elastic) vestibule, which allows the most realistic fit of the atomizer tip inside the nostril. The paper also analyzes the influence of the physicochemical properties of the sprayed liquid on the pump performance, aerosol characteristics and drug distribution in the nose.
2. Materials and methods 2.1 Atomizing devices and drugs Experimental studies were conducted for five products delivering the same dose (50 g) of mometasone furoate in the form of spray delivered from a nasal pump. The products were denoted as A, B, C, D, and E (see the detailed specification in the Appendix). As shown in Fig. 1, the shape of atomizing nozzles of these products is not identical. 2.2 The scope and methodology of experimental studies
The following experimental studies were conducted for each product A, B, C, D, and E: a)
visual determination of spray geometry – obtained from digital video sequences (Casio Exilim EX-F1; Japan, frame rate: 60 fps);
b)
optical determination of droplet size distribution during the stable (fully developed) phase of spray emission (FDA, 2003). Measurements were done with Spraytec (Malvern Instruments, UK) in the open-spray configuration without the hood, using the distance of 50 mm between the actuator and the laser beam. The particle size was measured in the range of 0.1-900 m;
c)
gravimetric determination of the mass output of each product after 5, 10 and 15 successive actuations (Radwag analytical balance, Poland);
d)
determination of complex rheological properties of drug formulations (MCR302 cone-plate rheometer - Anton Paar, Austria);
e)
determination of the surface tension of the drugs (PAT-1M drop shape tensiometer - Sinterface, Germany);
f)
visual determination of the deposition of aerosols sprayed to the nose model. This part of the study was conducted with a 3D anatomical model of the right half of the nasal cavity of a 7-yearold girl. The model was reconstructed by rapid prototyping using CT-scans (Siemens Emotion VI scanner, layer thickness: 0.63 mm). The model was assembled from two parts: the nasal cavity containing the side-wall, and the plate containing the left side of the septum. The model was manufactured by a rapid prototyping method from the rigid acrylic polymer RGD720. However, the vestibule with the nostrils was made of the elastic acrylic polymer FLX930to allow the realistic fit of the atomizing nozzle in the nostril (both polymers were purchased from Stratasys, USA). The drugs were sprayed into the assembled air-tight model after insertion of the atomizer tip into the nostril (insertion depth 0.7 cm at 30 angle to the vertical direction – Fig. 2c), with the tip oriented to the eye corner. The method of deposition assessment is described in section 2.3.
The measurements (a), (d), (e), and (f) were done in two independent repetitions for each drug, while experiments (b) and (c) were done in triplicate. The general statistical methods were applied to calculate the mean values and the standard deviation of the measured parameters. Canisters with drugs were manually shaken and primed before each experiment. The nasal pumps were activated manually to mimic the realistic conditions of using these atomizers. All measurements were taken at room temperature (23 ± 1 C) and the relative air humidity of 50 ± 10%.
2.3. Spray deposition in the model of the pediatric nasal cavity The details of the anatomical model used in the experiments are shown in Figs 2 and 3. Before each deposition experiment, the inner surfaces of the nasal cast: both of the side-wall and the septum, were covered with a very thin layer of water-sensitive gel (Water Finding Paste M; Merck, Germany). The gel changes the color from gray to purple after contact with water, allowing fast and straightforward determination of the deposition areas. The method was adapted according to the paper by Kundoor & Dalby (2010, 2011) and after the validation in studies done with the adult nasal replica (Rapiejko et al., 2015).
After each deposition experiment, the model was disassembled, and both the nasal side-wall and the septum were photographed (Casio Exilim, Japan). All photographs were taken from a distance of 40 cm under the same lighting conditions. The reference pictures for both surfaces were obtained in two cases (Fig. 3): 1. without the deposited material (it corresponds to 0% deposition), and 2. for the surfaces fully covered by aqueous spray (100% deposition). The simple conversion of colors was done with FIJI open-source software (imagej.net) to visualize the deposition areas more clearly.
Aerosol deposition studies were conducted in two types of experiments: 1. spraying of drugs through the nostril without the simultaneous airflow (breath-hold), 2. spraying of drugs through the nostril with a simultaneous airflow (8 L/min).
Airflow rate of 8 L/min modeled
inspiratory flow easily achieved by 7-year-old children,
considering that such a value is significantly below the reported maximum inspired flow rate obtained at this age during nasal breathing (Pickering & Beardsmore, 1999). In the experiments, the airflow was switched on two seconds before spraying and was maintained for two more seconds after aerosol release.
3. Results and discussion 3.1. Spray geometry The photographs of the studied nasal drugs spray geometry are presented in Fig. 4.In all cases, the free jets of droplets extend above 30 cm from the nozzle orifice, i.e., to the distance significantly longer than the distance between the nozzle tip and the ceiling of the pediatric nasal cavity (approximately 5 cm). Spray geometry differs between the products and the properties of all jets are listed in Table 1.
Spraying pumps A and C produce almost identical aerosol jets, whereas device E releases longer plume, however, with a similar cone angle. Aerosol jet obtained from pump D is the narrowest and the
longest (almost 50 cm). Two zones of droplets can be observed in the spray obtained from device B: the first dense zone of droplets has the length similar to the plume obtained in drugs A and C (37 cm), but the additional jet of large droplets can be seen a few centimeters above. Despite some differences in the plume geometry, the results show that aerosol droplets sprayed from each device always have high kinetic energy, which should result in a considerable inertial deposition of the drug on the nasal surfaces near the spray inlet (i.e., near the nostril).As reported by Liu et al. (2010) and Inthavong et al. (2014), the linear velocity of drops in the central part of the plume produced by nasal pumps, is in the range of 12-20 m/s. This suggests that the time needed for these drops to reach the wall of the nose interior a few centimeters above the atomizing nozzle s shorter than 5 milliseconds. Moreover, the expanding shape of the aerosol cone released from the nozzle is non-compatible with the constricted geometry of the nostril (Fig. 5). As a result, only droplets from the central part of the aerosol jet are expected to penetrate beyond the nasal valve and reach deeper regions of the nasal cavity. However, even these droplets will hit the surface of the nasal cavity in the proximity of the nasal valve because they have a very high momentum. The exact spot of their deposition may depend on the insertion depth of the nozzle tip and the tip orientation (e.g., Kundoor & Dalby, 2011), however, both factors should be of less importance in children due to large dimensions of the atomizer tip in relation to the size of the nostril (low freedom of movement of the tip in the nostril). 3.2. Droplet size distribution Table 2 contains the numerical parameters of the size distribution of the droplets released from tested spraying pumps. The average value of droplet volume median diameter, Dv50, is in the same range of 60-70 m for all studied sprays. However, the complete droplet size distributions are not identical. The distribution width can be characterized by Span parameter defined as:
𝑆𝑝𝑎𝑛 =
𝐷𝑣90 ― 𝐷𝑣10 𝐷𝑣50
(1).
The Span determined for the tested sprays is in the range of 0.59 ± 0.12 (spray B) to 0.79 ± 0.06 (spray C), and these data show that droplets released from device B are the most homogenous. The data shown in Table 2 suggest that droplets obtained from all atomizers have a low chance to be carried beyond the nasal cavity, which matches the typically expected penetration depth of nasal aerosols. Droplet size distributions in the aerosol cloud produced by all drugs A-E are characterized by good reproducibility, especially in the view of their hand-actuated operation. 3.3. Aerosol mass output Comparison of the mass output of tested nasal drugs during a release of 5, 10, and 15 successive doses is shown in Fig. 6,while the average values and the variability of the mass output are summarized in Table 3. It is found that all products spray a comparable mass of the liquid during each actuation, although the scatter between consecutive doses is higher in some products (e.g., drug B). Interestingly, some spraying devices show a decrease in the aerosol output during the successive actuations, which may be attributed to the individual features of the operation of dosing pumps in these products. The best performance was found in devices A and D, which were also characterized by the lowest overall scatter of the emitted mass of drug (CV < 1.5 %). 3.4. Rheological properties of the drugs Fig 7. shows an example of rheometric characteristics of one drug (A), i.e. the relationship between the dynamic viscosity [mPas] and the strain rate 𝛾 [s-1].Results for other products can be found in the Supplementary Material, and they are qualitatively the same. These graphs show that the drugs are pseudo-plastic (shear-thinning) liquids. This property of the formulation is intentional because it allows the drug to be less viscous during atomization and to recover to the gel-like substance when the drug is deposited on the nasal surface. The gelling of drugs reduces their gravitational drainage (Pennington et al., 1998; Pu et al., 2014). Rheological properties of such liquids can be described by the power-law (Ostwald-de Waele equation):
𝜏 = 𝑘𝛾𝑛
(2)
where denotes the shear stress, k is the so-called flow consistency index and n – the flow behavior index. The apparent viscosity at the given strain rate can be expressed as: 𝜏
𝜇𝑎𝑝𝑝 ≡ 𝛾 = 𝑘𝛾𝑛 - 1
(3)
Parameters of this rheological model evaluated from the experimental results for all drugs A, B, C, D, and E are listed in Table 3. The data show that drug D has the highest viscosity at rest and remains thick (viscous) even at high rates of strain. On the contrary, drug B is the least viscous at rest and becomes even thinner at increased rates of strain. Rheological properties of drugs A and B are comparable while drugs C and E show the intermediate viscosity at rest, and their viscosity is also less dependent on the rate of liquid deformation (i.e., the strain rate). Differences in the rheological properties of drugs help to understand their different behavior during spraying, i.e., during the process which generates high strain rates (Broniarz-Press et al., 2015). The rheological characteristics also provide information on the behavior of the drugs on the nasal surfaces, especially regarding their drainage rate.
3.5. Surface tension Fig. 8. shows that the surface tension of drugs A, B, C, and E is in the range of 32-33 (mN)/m, but the surface tension of drug D is lower, near 28 (mN)/m. This physicochemical property of drug D may explain why it is sprayed to the plume with a more narrow geometry (Fig. 4).
3.6. Drug deposition in the nasal cavity
The photographs of deposition areas after drug spraying to the nostril without using any additional airflow are shown in Fig.9. It is seen that sprayed droplets hit solely the anterior parts of the nasal cavity and the septum. The numerical data of drug penetration along the nasal surface, which are compared in Table 4, show that for all drugs, the penetration length is only 2-3 cm from the nasal valve. As expected from the schematic picture drawn in Fig. 5, droplets that obtain high kinetic energy during spraying are not expected to penetrate far through the narrow air channels of the nasal cavity. The differences observed in the aerosol jet geometry shown earlier in Fig. 4 have only a minor effect on the spatial distribution of droplet deposition. One may notice, however, that a less dynamic, shorter jets (as those obtained from drugs A and E) may allow a slightly (up to a few millimeters) deeper penetration of the drug along the middle and bottom air channels of the nasal cavity. It is interesting to compare the data of Fig. 9 obtained without the airflow to the results obtained when the additional airflow was applied during and following the application of the sprays (Fig. 10). The deposition patterns obtained in this case show that the auxiliary airflow enhances the penetration of drug in the nasal cavity. From Table 4, one may find that the horizontal penetration of drugs increases by another 2-3 cm toward the nasopharynx. Therefore, the airflow provides an additional mechanism of drug transport in the nose. It may be speculated, however, that deeper penetration of drugs is not caused by the improved transport of aerosol droplets with the airflow, since such transport is minimal because of the high inertia of droplets (e.g., Foo et al., 2007; Inhtavong et al., 2006). A more plausible explanation is that the presence of drugs in deeper parts of the nose is caused by the dynamic displacement of the already deposited liquid film along the nasal surface (Fig. 11), resulting from the aerodynamic shear stresses transferred from the flowing air. Such dislocation of films and droplets on solid supports is the wellknown phenomenon, often encountered in numerous non-biological systems (e.g., Dimitrakopoulos & Higdon, 2007; Carroll & Hidrovo, 2013; Fan et al., 2011). It is also possible that extremely narrow air channels of the pediatric nose may be incidentally plugged by liquid bridges formed by the deposited
drug layers. Such liquid structures may be ruptured by the airflow during the intense inspiration or sniffing, which will result in the secondary aerosolization (splashing) of the drug, and this process should provide another way of transferring the deposited drug along the nasal side-wall and the septum. High viscosity (at rest) of deposited liquid drugs reduce the rate of gravitational drainage which helps the liquid to remain in the spot of deposition. However, it also makes it more stable (rigid) when airflow tries to push it along the air passages. Based on the previous findings (Rapiejko et al., 2015), it may also be claimed that higher volumes of sprayed drugs are more advantageous for drug displacement since they will form deeper liquid layers on the nasal surface. All tested products A-E deliver the same volume in a single dose (100 L – also confirmed by the mass output data presented in Table 3). Therefore, small differences in the drug penetration observed in this study should be explained rather by different rheological properties of the drugs and – to a less extent - to some differences in the primary deposition. Pictures in Fig. 10 and data in Table 5 suggest that the drug which more easily penetrates to distal regions of the nasal cavity (drug A) has the following properties: (i)
relatively deep initial deposition (Fig. 9A),
(ii)
low viscosity even at low strain rates(k = 714, as shown in Table 4).
In contrast, drug B, although characterized by similar rheological properties, is transported weaker with the airflow, and this can be attributed to the more anterior initial aerosol deposition of this drug (Fig. 9B, Table 5). Drugs C and E, which show a comparable primary deposition and almost identical apparent viscosity at low strain rates (k value close to 1000), are spread similarly by the airflow (Fig. 10, Table 5). Finally, drug D sprayed mostly to the upper parts of the nasal cavity anterior (Fig. 9D), is dislocated along these upper regions (Fig 10D), and does not drain quickly because of the high viscosity at rest (k = 1422, Table 4). Our results show that none of the tested products were detected in the throat region. It means that the effects of sensing the taste of drugs sprayed to the nose are probably not associated with direct delivery of the aerosol to the nasopharynx but rather to the slow dripping of drugs of low viscosity.
4. Conclusions The study discussed several aspects of the deposition of drugs administered as nasal sprays to the nose of children. Experiments conducted on the anatomical model with a flexible nasal vestibule region allowed testing the use of nasal sprays in the most realistic way. The qualitative relationships between drug properties and the deposition pattern were investigated for five popular nasal spray products of mometasone furoate (50 g per dose). Tested drugs, in spite of the identical nominal dose of the active compound, had slightly different physicochemical characteristics, probably due to different contents of the additives. All drugs are pseudo-plastic fluids. However, some differences were found regarding the numerical values of their rheological parameters. These dissimilarities, together with the variability in the surface tension and pump design, are responsible for differences in the geometry of sprayed clouds and aerosol droplet size distribution. As a consequence, some variability in the drug deposition pattern in the 3D pediatric model of the nasal cavity is observed for these virtually identical drugs. The primary deposition of each sprayed drug in the nose is governed by the impaction of droplets which are ejected as a high-velocity, wide, conical plume from the nozzle of the atomizing pump. The droplets are relatively large (Dv50 in the range of 60-70 m), so they are immediately captured by the inertial mechanism in the vestibule and anterior region of the nasal cavity. However, it was shown that the deposited drugs could be displaced along the nasal surface bythe dynamic force of the inspired air which acts on the liquid layer of the drug that covers the nasal surface. The proposed mechanism of drug translocation should be of greater importance when nasal airways are narrower, such as in the studied case of the pediatric nose. The results indicate that drugs with low viscosity at low strain rates are pushed more efficiently to deeper regions of the nasal cavity than more viscous drugs. On the other hand, increased viscosity retards the gravitational drug drainage after deposition on the nasal surfaces (Pu et al., 2014), although the effect of dripping may be not less important at short, a few-second periods after drug administration.
The results of the study allow concluding that the complete analysis of deposition and penetration of aerosolized drugs delivered to the nose from atomizers (nasal pumps) should consider the following steps: (i)
liquid atomization in the spraying nozzle and aerosol formation,
(ii)
primary deposition of the released drug droplets - mainly by impaction because of their large diameter and high velocity,
(iii)
spreading of the deposited liquid drug along the nasal surfaces due to the aerodynamic interactions with the airflow during inspiration or sniffing.
Each process is influenced by physicochemical properties of the drug, design of the atomizer, but also on the exact way of drug application. These factors must be optimized to obtain the required topical delivery of drugs applied intra-nasally in the form of the spray. It may also be stated that small differences in the physicochemical properties of nasal formulations may cause variable clinical efficacy of these drugs, despite the similarity in the nominal dose of the active substance. The results of this study indicate that liquid atomization using nasal pumps does not assure homogeneous deposition of drugs in the pediatric nasal cavity, although it surely presents a more convenient drug delivery to the nasal mucosa than dropping. However, due to the demonstrated secondary spreading of the deposited liquid by inhaled air, the distribution of the drug in the nasal cavity can be more homogeneous. Small dimensions of the nasal geometry in children may be beneficial because, after the plugging of air passages by the deposited drug, it can be pushed more distally when inhaled air re-opens the ducts. Such a mechanism of improved drug penetration should remain valid also in obstructed nasal passages of adults. If so, this can explain why using the nasal sprays provide the clinically proven efficient treatment of the nasal and sinuses diseases despite a very limited direct deposition of sprayed aerosols in deeper regions of the nasal cavity.
Author contribution Tomasz R. Sosnowski was involved in paper conceptualization, development of methodology, data analysis and manuscript preparation. Piotr Rapiejko was involved in paper conceptualization, development of methodology and reviewing of the manuscript. Jaroslav Sova was responsible for gathering anatomical data and preparation of 3D model. Katarzyna Dobrowolska was responsible for experiments and data analysis.
Acknowledgments The research co-funded by NCN project No. 2018/29/B/ST8/00273. The authors acknowledge Adamed for providing drugs for the studies.
Appendix 1 Specification of studied nasal products is given in Table A1
References
Broniarz-Press, L., Sosnowski, T.R., Matuszak, M., Ochowiak, M., Jabłczyńska, K. (2015). The effect of shear and extensional viscosities on atomization of Newtonian and non-Newtonian fluids in ultrasonic inhaler. Int J Pharm. 485, 41-9. 10.1016/j.ijpharm.2015.02.065. Brożek, J.L., Bousquet, J., Baena-Cagnani, C.E. et al. (2010). Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 126, 466–476. 10.1016/ j.jaci.2010.06.047. Carrigy, N.B., Ruzycki, C.A., Golshahi, L., & Finlay, W.H. (2014). Pediatric in vitro and in silico models of deposition via oral and nasal inhalation. J Aerosol Med Pulm Drug Deliv. 27, 149-169. 10.1089/jamp.2013.1075. Carroll, B. & Hidrovo, C. (2013). Droplet detachment mechanism in a high-speed gaseous microflow. J Fluids Eng. 135(7), 071206. 10.1115/1.4024057. Cheng, Y.S., Holmes, T.D., Gao, J., Guilmette, R.A., Li. S, Surakitbanharn, Y. & Rowlings, C. (2001). Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway. J Aerosol Med. 14, 267–280. 10.1089/08942680152484199. Dimitrakopoulos, P.& Higdon, J. J. L. (2007). Displacement of fluid droplets from solid surfaces in low-Reynolds-number shear flows. J Fluid Mech. 336, 351-378. 10.1017/ S0022112096004788. Fan, J., Wilson, M.C.T. & Kapur, N. (2011). Displacement of liquid droplets on a surface by a shearing air flow. J Coll Interface Sci. 356, 286–292. 10.1016/j.jcis.2010.12.087. FDA. (2003). Guidance for industry: bioavailability and bioequivalence studies for nasal aerosol and nasal sprays for local action (Draft Guidance). Available at: https://www.fda.gov/ regulatoryinformation/search-fda-guidance-documents/bioavailability-and-bioequivalence-studies-nasalaerosols-and-nasal-sprays-local-action. Fokkens, W.J., Lund, V.J., Mullol J., et al. (2012). EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50, 1–12. 10.4193/Rhino50E2.
Foo, M.Y., Cheng, Y.S., Su, W.C. & Donovan, M.D. (2007). The influence of spray properties on intranasal deposition. J Aerosol Med. 20, 495-508. 10.1089/jam.2007.0638 Foo, M.Y., Sawant, N., Overholtzer, E. & Donovan, M.D. (2018). A simplified geometric model to predict nasal spray deposition in children and adults. AAPS PharmSciTech. 19, 2767-2777. 10.1208/s12249-018-1031-2. Golshahi, L., Finlay, W. H., Olfert, J. S., Thompson, R.B., & Noga M. L. (2010). Deposition of inhaled ultrafine aerosols in replicas of nasal airways of infants. Aerosol Sci Tech. 44, 741-752. 10.1080/02786826.2010.488256 Hallworth, G.W. & Padfield, J.M. (1986). A comparison of the regional deposition in a model nose of a drug discharged from metered aerosol and metered pump nasal delivery systems. J Allergy Clin Immunol. 77, 348–353. Inthavong, K., Qinjiang, G.,Se, C.M.K., Yang, W. & Tu J.Y. (2011). Simulation of sprayed particle deposition in a human nasal cavity including a nasal spray device. J Aerosol Sci. 42, 100–113. 10.1016/j.jaerosci.2010.11.008. Inthavong, K., Fung, M.C., Tong, X, Yang, W. & Tu J. (2014). High resolution visualization and analysis of nasal spray drug delivery. Pharm Res. 31, 1930–1937. 10.1007/s11095-013-1294-y. Jang, T.Y. & Kim, Y.H. (2016). Recent updates on the systemic and local safety of intranasal steroids. Curr Drug Metab. 17, 992-996. 10.2174/1389200218666161123123516. Janssens, H.M, de Jongste, J.C., Fokkens, W.J., Robben, S.G.F., Wouters, K., & Tiddens, H.A.W.M. (2001). The Sophia anatomical infant nose-throat (Saint) model: a valuable tool to study aerosol deposition in infants. J Aerosol Med. 14, 433-441. 10.1089/08942680152744640 Kimbell, J.S., Segal, R.A., Asgharian, B., Wong, B.A., Schroeter, J.D., Southall, J.P., Dickens, C.J., Brace, G. & Miller, F.J. (2007). Characterization of deposition from nasal spray devices using a computational fluid dynamics model of the human nasal passages. J Aerosol Med. 20, 59-74. 10.1089/jam.2007.0578.
Kundoor, V. & Dalby, R.N. (2010). Assessment of nasal spray deposition in a silicone human nose model using a color based method. Pharm Res. 27, 30–36. 10.1007/s11095-009-0002-4. Kundoor, V. & Dalby, R.N. (2011). Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast. Pharm Res. 28, 1895–1904. 10.1007/s11095-011-0417-6. Laube, B.L., Sharpless, G.J., Shermer, C., & Powell, K.G. (2010). Deposition of albuterol aerosol generated by pneumatic nebulizer in the Sophia Anatomical Infant Nose-Throat (SAINT) model. Pharm Res. 27, 1722–1729. 10.1007/s11095-010-0171-1. Laube, B.L., Sharpless, G., Vikani, A.R., Harrand, V., Zinreich, S.J., Sedberry, K., Knaus, D., Barry, J., & Papania M. (2015). Intranasal deposition of Accuspray™ aerosol in anatomically correct models of 2-, 5-, and 12-year-old children. J Aerosol Med Pulm Drug Deliv. 28, 320-33. 10.1089/jamp.2014.1174. Liu, X., Doub, W.H. & Guo, C. (2010). Evaluation of droplet velocity and size from nasal spray devices using phase Doppler anemometry (PDA). Int J Pharm. 388, 82–87. 10.1208/ s12249-0119594-1. Minocchieri, S., Burren, J. M., Bachmann, M. A., Stern, G., Wildhaber, J., Buob, S., Schindel, R., Kraemer, R., Frey, U. P., & Nelle, M. (2008). Development of the premature neonate for the study of aerosol delivery. Pediatr Res., 64, 141–146. 10.1203/PDR.0b013e318175dcfa Pennington, A.K., Ratcliffe, J.H., Wilson, C.G. & Hardy J.G. (1988). The influence of solution viscosity on nasal spray deposition and clearance. Int J Pharm. 43, 221-224. 10.1016/03785173(88)90277-3. Pickering, D.N. & Beardsmore, C.S. (1999). Nasal flow limitation in children. Pediatr Pulmonol. 27, 32–36.
Pu, Y., Goodey, A.P., Fang, X. & Jacob, K. (2014). A comparison of the deposition patterns of different nasal spray formulations using a nasal cast. Aerosol Sci Technol. 48, 930–938. 10.1080/02786826.2014.931566. Rapiejko, P., Sosnowski, T.R., Sova, J. & Jurkiewicz, D. (2015). Deposition of intranasal glucocorticoids – preliminary study. Otolaryngol Pol. 69, 30-38. 10.5604/00306657. 1184545. Roberts, G., Xatzipsalti, M., Borrego, L.M. et al. (2013). Paediatric rhinitis: position paper of the European Academy of Allergy and Clinical Immunology. Allergy
68, 1102–1116. 10.1111/
all.12235. Sawant, N. & Donovan, M.D. (2018). In vitro assessment of spray deposition patterns in a pediatric (12 year-old) nasal cavity model. Pharm Res. 35, 108. 10.1007/s11095-018-2385-6. Suman, J.D., Laube, B.L., & Dalby R. (1999). Comparison of nasal deposition and clearance of aerosol generated by nebulizer and an aqueous spray pump. Pharm Res. 16, 1648–1652. Storey-Bishoff, J., Noga, M., & Finlay, W.H. (2008). Deposition of micrometer-sized aerosol particles in infant nasal airway replicas. J Aerosol Sci. 39, 1055-1065. 10.1016/ j.jaerosci. 2008.07.011 Zhou, Y., Guo, M., Xi, J. Irshad, H., & Cheng Y.S. (2014). Nasal deposition in infants and children. J Aerosol Med Pulm Drug Deliv. 27, 110-116. 10.1089/jamp.2013.1039.
Fig. 1. Shapes of atomizer tips in tested nasal drugs.
Fig. 2. (a) Schematic of the experimental set-up used in deposition experiments: 1 – nasal spray, 2 – anatomical pediatric model of the nose, 3 – airflow meter (removed during deposition
measurements), 4 – valve, 5 - vacuum pump; (b) position of the actuator tip in the nostril during measurements.
Fig. 3. Side-wall of the nasal cavity (a) and the covering plate with the nasal septum (b): before aerosol deposition (upper panels) and at the maximum coverage by deposited droplets (lower panels). The scale is in centimeters.
Fig. 4. Aerosol jet geometry of aerosol released from different atomizers.
Fig. 5. The schematic operation of the nasal spray: 1 – the cone of the freely released aerosol plume, 2 – regions of initial droplets deposition in the nostril, 3 - jet penetrating beyond the nasal valve, 4 – the nasal cavity.
Fig. 6. Mass output during the release of 15 successive doses of tested drugs.
Fig. 7. The viscosity of nasal drug A as a function of strain rate (graphs for other drugs are available in the Supplementary Material).
Fig. 8. The surface tension of tested drugs.
Fig. 9. Drug penetration and deposition in the experiments without additional airflow. Gray dashed line shows the maximum horizontal position of detected drugs.
Fig. 10. Drug penetration and deposition in the experiments with additional airflow (8 L/min). Gray dashed line shows the maximum horizontal position of detected drugs.
Fig. 11. Proposed mechanisms of drug penetration during the simultaneous air inspiration: a – droplet entrainment by air during spray application (probably less important for large droplets), b – spreading of already deposited drug along the nasal surface due to the interactions with the air stream.
Table 1. Numerical values of the range and angle of aerosol jets.
*
Product designation
Maximum jet range (mm)
Spray angle
A
371
29
B
353/420*
27
C
364
27
D
507
20
E
398
29
the second zone of the jet – Fig. 4B
Table 2. Parameters of particle (droplet) size distribution: mean values ± SD (n=3). A
B
C
D
E
Dv10 [m]
42.6 ± 2.6
52.2 ± 5.3
43.9 ± 3.2
44.6 ± 1.7
47.4 ± 5.9
Dv50 [m]
61.3 ± 6.2
69.8 ± 3.8
65.3 ± 6.5
60.5 ± 4.8
64.4 ± 5.1
Dv90 [m]
88.3 ± 13.0
93.5 ± 4.2
95.8±12.2
84.4 ± 7.0
87.5 ± 4.8
Span [-]
0.74 ± 0.12
0.59 ± 0.12
0.79± 0.06
0.65 ± 0.07
0.63 ± 0.09
Table 3. The mass output of tested nasal drugs and rheological parameters of the Ostwald-de Waele model (eq. 2)
Product
Average output
designation
[mg/actuation]
Standard
Coefficient
deviation
of variation
of the
of the
flow
flow
output
output
consistency
behavior
(SD) [mg]
(CV) [%]
index, k
index, n
A
103.6
1.29
1.2
714.1
0.288
B
100.3
7.94
7.9
657.6
0.311
C
97.2
4.16
4.3
1013.2
0.194
D
99.0
0.88
0.9
1421.7
0.160
E
95.6
3.17
3.3
1006.6
0.232
Table 4. Horizontal distance of drug penetrating along the nasal surface - the average values measured on the side-wall and on the septum (Figs. 9 and 10). Product designation
No airflow
Airflow 8 L/min
A
3.0 ± 0.1
5.9 ± 0.9
B
2.1 ± 0.1
3.9 ± 0.3
C
2.1 ± 0.0
5.2 ± 0.3
D
2.2 ± 0.1
5.2 ± 0.2
E
2.3 ± 0.0
4.6 ± 0.5
Table A1. Mometasone furoate nasal sprays studied in this work.
Product
Product brand name
Serial no.
A
Metmin 50 g
223
B
Momester 50 g
191
C
Nasometin 50 g
GH9969
D
Nasonex 50 g
6KTLDEY001
E
Pronasal 50 g
3A606022
designation in this study