key: cord-0909603-syysgz1w authors: Basu, S.; Akash, M. M. H.; Lao, Y.; Balivada, P. A.; Ato, P.; Ka, N. K.; Mituniewicz, A.; Silfen, Z.; Suman, J.; Chakravarty, A.; Joseph-McCarthy, D. title: A model-based approach to improve intranasal sprays for respiratory viral infections date: 2022-01-28 journal: nan DOI: 10.1101/2022.01.26.22269854 sha: ace55249280759b86dac69ed7be78dddacb2414c doc_id: 909603 cord_uid: syysgz1w Drug delivery for viral respiratory infections, such as SARS-CoV-2, can be enhanced significantly by targeting the nasopharynx, which is the dominant initial infection site in the upper airway, for example by nasal sprays. However, under the standard recommended spray usage protocol ("Current Use", or CU), the nozzle enters the nose almost vertically, resulting in sub-optimal deposition of drug droplets at the nasopharynx. Using computational fluid dynamics simulations in two anatomic nasal geometries, along with experimental validation of the generic findings in a different third subject, we have identified a new "Improved Use" (or, IU) spray protocol. It entails pointing the spray bottle at a shallower angle (almost horizontally), aiming slightly toward the cheeks. We have simulated the performance of this protocol for conically injected spray droplet sizes of 1 - 24 microns, at two breathing rates: 15 and 30 L/min. The lower flowrate corresponds to resting breathing and follows a viscous-laminar model; the higher rate, standing in for moderate breathing conditions, is turbulent and is tracked via Large Eddy Simulation. The results show that (a) droplets sized between ~ 6 - 14 microns are most efficient at direct landing over the nasopharyngeal viral infection hot-spot; and (b) targeted drug delivery via IU outperforms CU by approximately 2 orders-of-magnitude, under the two tested inhalation conditions. Also quite importantly, the improved delivery strategy, facilitated by the IU protocol, is found to be robust to small perturbations in spray direction, underlining the practical utility of this simple change in nasal spray administration protocol. established mesh-refinement protocols 13, 14 were followed such that each computational 100 grid contained more than 4 million unstructured, graded, tetrahedral elements. To en-101 able accurate tracking near tissue surfaces, further mesh refinement involved adding 102 three prism layers at the cavity walls, with 0.1-mm thickness and a height ratio of 1. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 28, 2022. for small particulates, e.g., the Saffman lift force, and by implementing a no-slip trap 127 boundary condition on the cavity walls. Note that Brownian effects were neglected in 128 view of the tracked droplet sizes. The drug formulation density was set to 1.5 g/ml. All 129 simulations released monodispersed inert drug droplets ranging in diameters from 1 -24 130 µm, with 3000 monodispersed inert droplets being released during each iteration. The 131 droplets were injected into the airspace from a single source point where the spray nozzle 132 is located, streaming out in a hollow-cone shape, mimicking the action of a nasal spray; 133 this method of release is referred to as a cone injection. The Valois VP7, an affordable 134 mass-produced pharmaceutical nasal spray pump, with its accompanying dimension 135 properties, such as plume angle and initial spray velocity, was used as an initial point 136 of reference for the cone injections. 29 The droplets were given an initial velocity of 10 137 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 28, 2022. While the CU protocol would provide the acceptable state-of-art for targeted drug 158 delivery with nasal sprayers, the key focus of this study was to perturb that spray 159 direction to test alternate protocols that bear the promise to improve delivery of drugs CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 28, 2022. ; https://doi.org/10.1101/2022.01.26.22269854 doi: medRxiv preprint Once the IU for an airway reconstruction was determined (following guidelines described 178 in Section 2.3), a tolerance sensitivity study was performed to assess how far the user 179 could deviate from the determined IU spray direction and still get similar regional drug (1) Here the mass median diameters (alternatively, the geometric mean diameter 32 ) for 212 Flonase TM and Nasacort TM were respectively, x 50 = 37.16 µm and 43.81 µm; the 213 corresponding geometric standard deviations were respectively, σ g = 2.080 and 1.994. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 28, 2022. ; https://doi.org/10.1101/2022.01.26.22269854 doi: medRxiv preprint The latter quantifies the span of the droplet size data. Note that the measurements were 215 also collected with and without a saline additive in the sprayer, with the tests returning 216 similar droplet size distributions. The reader is referred to our previous publications 15, 18 217 for additional details. higher deposition at the nasopharynx in comparison to the CU protocol over a defined 248 range of particle sizes (see Fig. 6 ). For instance: if we examine the deposition trends 249 for spray administration through the right nostril of Subject 2 for the laminar regime 250 inhalation (i.e. at 15 L/min), the peak nasopharyngeal deposition for IU is 46.5% for 251 13 µm drug droplets ( Fig. 6(b) ), while the peak deposition for CU is only 0.53% for 252 14 µm drug droplets (see again Fig. 6(b) and the corresponding zoomed-in for the CU 253 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 28, 2022. delivery trends visual in Fig. 6(k) ). In general, the droplet size range of ∼ 6 -14 µm is 254 found conducive to targeted nasopharyngeal delivery with the IU protocol, considering 255 a 2% cut-off for deposition efficiency of the tracked monodispersed droplet cluster of 256 each size . The nearly hundred-fold increase in targeted deposition is remarkable and is 257 achievable simply by re-orienting the spray axis from CU to IU. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 28, 2022. Hence, the computational predictions differ from the in vitro data by less than 5%, 311 thereby lending robust support to the implemented in silico framework. Table 1 : Statistical testing on the correlation between the regional deposition trends (for different drug droplet sizes) at the nasopharynx for the perturbed spray directions (i.e. PD 1 -5), when compared to the nasopharyngeal deposition with the IU protocol. Pearson's Correlation Coefficient (r) p-value associated with correlation PD 1 PD 2 PD 3 PD 4 PD 5 PD 1 PD 2 PD 3 PD 4 PD 5 Left Nostril Administration . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 28, 2022. • On inputs for effective spray usage strategies -The significant 2 orders-of-magnitude 322 improvement (see Fig. 9 ) in nasopharyngeal delivery of intranasally sprayed drugs with 323 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 28, 2022. • On toxicity evaluation -Any new formulation or drug delivery device that might 359 attempt to replicate the improved targeted deposition at intranasal sites, based on 360 the current findings, will essentially form a surface contacting mechanism with limited 361 † (i) Extended spray axis for the IU protocol intersects the nasopharynx; (ii) as a condition for clinical safety (based on recommendation from attending rhinologists 15, 37 ), the axis must not cut through the septum; (iii) the spray axis should intersect the lateral wall of the nasal cavity as posteriorly as feasible. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 28, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 28, 2022. 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