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A Comparison of the Deposition Patterns of Different Nasal Spray Formulations Using a Nasal Cast
Abstract
For nasally delivered medications, it is quite a challenge in the formulation development to characterize the deposition pattern in vivo. An in vitro nose model has been developed recently and adopted in our study to compare the deposition pattern of different nasal solution formulations. One low-viscosity nasal solution and five other solutions containing either Avicel or hydroxypropyl methylcellulose (HPMC) as the viscosity enhancers were examined in this study. The viscosity, spray pattern, plume geometry, and droplet size were characterized. The in vitro deposition patterns were assessed using an anatomically correct silicone nasal cast combined with a color-based image-analysis method. The correlations between the formulation variables, the spray characteristics, and the deposition pattern were investigated. The addition of each viscosity enhancer resulted in increasing viscosity, larger droplet size, narrower plume angle, and lesser anterior deposition. However, it appears that the changes in spray characteristics and deposition pattern are influenced heavily by the identity of the viscosity enhancer, rather than merely by the formulation viscosity itself. Although the Avicel additions led to larger increases in the formulation viscosity, the HPMC additions had far greater impact on the spray characteristics and deposition pattern. The formulations with suboptimal deposition patterns, i.e., the formulations with ‘forward’ or ‘backward’ dripping, were successfully identified in this study. This in vitro method was able to discriminate between formulations, revealing differences in regional deposition and the tendency of formulations to drip. As such, the nasal cast method is recommended as a valuable tool for the development of nasal spray formulations.
... Reproduced with permission from [12]. publications [4,[12][13][14][15][16][17]. This cast has been described in some publications as 'anatomically correct' [13][14][15][16][17]. ...
... publications [4,[12][13][14][15][16][17]. This cast has been described in some publications as 'anatomically correct' [13][14][15][16][17]. However, no validation of the geometry and dimensions of this cast have been presented in publications to date. ...
... Based on these results, the validity of the Koken cast to model, inform, or compare drug delivery, including drug deposition profiles, of different nasally delivered products (as has been reported in multiple publications) must be called into question [13,[15][16][17]. ...
Background: Nasal casts may characterize intranasal drug deposition. Methodology: The Koken cast, described as 'anatomically correct', and the Optinose cast, derived from MRI of a healthy male during velum closure, were dimensionally compared and assessed for deposition assessment suitability.
... Ideally, nasal spray is limited to treatment areas with no leakage to the back of the throat, as 'drippage' of spray medication to the back of the throat can have a negative sensory impact, such as aftertaste (12,14,15) . ...
... Formulation factors include viscosity, thixotropic property, and surface tension (15) . Formulation viscosity differences can influence interaction with pump characteristics to affect size/shape of spray plume and therefore deposition patterns and the likelihood of dripping behaviour of formulations (14) . Spray droplet size significantly affects deposition, with larger droplets deposited at the anterior area of the nasal cavity, and smaller droplets depositing in the inner area of nasal cavity (15) . ...
... Nasal casts (biomimetic models of the human nasal passage) can be used to evaluate intranasal drug deposition (5,14,(17)(18)(19)(20) . Advantages of using nasal cast models include low cost and speed of in vitro evaluation as compared with testing in vivo (17) . ...
Background: Allergic rhinitis, rhinosinusitis, and upper respiratory tract infections, including the common cold, are caused by inflammation of nasal cavity areas. A key symptom is nasal congestion, which can be relieved with nasal spray medications. A key goal in developing a nasal spray medication delivery device for the relief of nasal congestion is delivering a fine mist to the inflamed areas while providing user comfort and convenience. Methodology: Using a Koken nasal cast model, we studied the deposition patterns of 2 xylometazoline and 1 oxymetazoline for- mulations with 2 different nasal pumps, the currently marketed Freepod and the investigational laterally actuated device. Effects of nasal tip orientation and breathing were investigated. Additionally, the degree of xylometazoline and oxymetazoline dripping down the back of the cast was assessed. Results: The largest coverage overall was observed with the xylometazoline formulation with the laterally actuated pump and without breath simulation. The laterally actuated pump used at a 30° angle resulted in deposition to the inferior, middle, and superior turbinates of the nasal cast, with less variability than the Freepod. Drippage at the back of the cast was observed with the Freepod device but not with the laterally actuated device. Conclusions: Using a nasal cast model, the laterally actuated pump used at a 30° angle produced a full mist covering areas inflamed with the common cold, allergic rhinitis, and rhinosinusitis with no dripping at the back of the cast, an improvement compared with the Freepod pump. In vivo studies are needed to confirm nasal cast results.
... Nasal spray pumps are popular due to their simplicity and ease of use, requiring no additional power or gas source [1,[5][6][7][8][9]. For these products, the delivery efficiency of a nasal pump system can be affected by several factors including device design, formulation characteristics, patient-related factors such as inhalation conditions, and nasal geometry [7,[10][11][12][13][14][15][16][17][18][19][20][21]. ...
... For evaluating generic nasal spray/aerosol systems that target local action, the U.S. Food and Drug Administration (FDA) Draft Guidance on Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action recommends in vitro spray testing and measurements of spray metrics, such as the single actuation content through container life, droplet size distribution, drug in small particles/droplet, spray pattern, plume geometry, and priming/repriming [38]. In vitro testing using realistic nasal airway geometries may also help to understand the geometrical factors influencing drug delivery to different regions of the nose [7,11,13,14,16,[18][19][20]22,[39][40][41][42][43]. In silico testing using computational fluid dynamics (CFD) simulations can provide detailed information on device performance and nasal deposition, and CFD models combined with pharmacokinetic models can provide additional information on systemic drug plasma concentration, while limiting time and cost associated with the testing [5,9,24,25,[44][45][46][47][48][49][50][51]. ...
... Pharmaceutics 2022,14, 956 ...
Nasal sprays, which produce relatively large pharmaceutical droplets and have high momentum, are primarily used to deliver locally acting drugs to the nasal mucosa. Depending on spray pump administration conditions and insertion angles, nasal sprays may interact with the nasal surface in ways that creates complex droplet–wall interactions followed by significant liquid motion after initial wall contact. Additionally, liquid motion can occur after deposition as the spray liquid moves in bulk along the nasal surface. It is difficult or impossible to capture these conditions with commonly used computational fluid dynamics (CFD) models of spray droplet transport that typically employ a deposit-on-touch boundary condition. Hence, an updated CFD framework with a new spray–wall interaction (SWI) model in tandem with a post-deposition liquid motion (PDLM) model was developed and applied to evaluate nasal spray delivery for Flonase and Flonase Sensimist products. For both nasal spray products, CFD revealed significant effects of the spray momentum on surface liquid motion, as well as motion of the surface film due to airflow generated shear stress and gravity. With Flonase, these factors substantially influenced the final resting place of the liquid. For Flonase Sensimist, anterior and posterior liquid movements were approximately balanced over time. As a result, comparisons with concurrent in vitro experimental results were substantially improved for Flonase compared with the traditional deposit-on-touch boundary condition. The new SWI-PDLM model highlights the dynamicenvironment that occurs when a nasal spray interacts with a nasal wall surface and can be used to better understand the delivery of current nasal spray products as well as to develop new nasal drug delivery strategies with improved regional targeting.
... Pu et al. studied in vitro spray deposition of nasal solution formulations with different viscosities by adding Avicel or HPMC as a viscosity enhancer [77]. Interestingly, the authors found that spray properties and subsequent deposition were not only influenced by the overall formulation viscosity, but also by the type of viscosity enhancer used, with HPMC having a much greater effect, although Avicel produced a higher formulation viscosity. ...
... However, Avicel-and HPMC-containing formulations showed significant differences. While Avicel eliminated 'forward' dripping (down the nostrils) without changing the total deposition footprint, HPMC substantially altered the deposition towards the nasopharynx with clear 'backward' drainage, mainly because of its moderate viscosity-enhancing effect [77]. ...
... Djupesland et al. compared a Koken silicon cast (Koken Co.), which is often reported in the literature for in vitro evaluation of nasal deposition [61,76,77,84], with an Optinose nasal model, which is designed to mimic the oropharyngeal geometries while using the EDS system where the soft palate is elevated, sealing the velum that separates nasal and oral cavities [106]. Geometry and shape assessments showed that the Koken cast had a significantly larger nasal volume and minimal cross-sectional areas compared to the Optinose model, as well as the typical in vivo ranges for both genders. ...
The nasal cavity is an attractive route for both local and systemic drug delivery and holds great potential for access to the brain via the olfactory region, an area where the blood–brain barrier (BBB) is effectively absent. However, the olfactory region is located at the roof of the nasal cavity and only represents ~5–7% of the epithelial surface area, presenting significant challenges for the deposition of drug molecules for nose to brain drug delivery (NTBDD). Aerosolized particles have the potential to be directed to the olfactory region, but their specific deposition within this area is confounded by a complex combination of factors, which include the properties of the formulation, the delivery device and how it is used, and differences in inter-patient physiology. In this review, an in-depth examination of these different factors is provided in relation to both in vitro and in vivo studies and how advances in the fabrication of nasal cast models and analysis of aerosol deposition can be utilized to predict in vivo outcomes more accurately. The challenges faced in assessing the nasal deposition of aerosolized particles within the paediatric population are specifically considered, representing an unmet need for nasal and NTBDD to treat CNS disorders.
... Those substances are coated inside the cast and change colouration when exposed to humidity. The colour intensity provides information about the amount of spray that is deposited across the cast [26,89,146,162]. Thus, it is necessary to have transparent materials and fine walls in contrast with block-like replicas. ...
... So, it is also adapted for optical measurements if the material used is transparent (Figure 12e). Another solution, used by Pu et al. is to work with a silicone transparent commercial cast made by Koken and intended for education ( Figure 12f) [89]. ...
... Finally, an educational cast, made by Koken, is also used for nasal spray deposition studies ( Figure 12f) [89,162,205]. However, a research team reported that the shape of this replica differs from the median adult [207]. ...
This review aims to cement three hot topics in drug delivery: (a) the pre-formulation of new products intended for nose-to-brain delivery ; (b) the development of nasal casts for studying the efficacy of potential new nose-to-brain delivery systems at the early of their development (pre-formulation); (c) the use of 3D printing based on a wide variety of materials (transparent, biocompatible, flexible) providing an unprecedented fabrication tool towards personalized medicine by printing nasal cast on-demand based on CT scans of patients.
This review intends to show the links between these three subjects. Indeed, the pathway selected to administrate the drug to the brain not only influence the formulation strategies to implement but also the design of the cast, to get the most convincing measures from it. Moreover, the design of the cast himself influences the choice of the 3D-printing technology, which, in its turn, bring more constraints to the nasal replica design. Consequently, the formulation of the drug, the cast preparation and its realisation should be thought of as a whole and not separately.
... A later study by Pu et al. [70] using the Kundoor and Dalby methodology examined the effect of various viscosity enhancers in nasal sprays on spray properties (droplet size distribution and spray angle) and regional deposition. They found that, in general, a narrow spray angle gave a greater posterior deposition, but also that the type of viscosity enhancer (in this study Avicel and hydroxypropyl methylcellulose (HPMC)), more than the viscosity itself, had a significant impact on the deposition pattern. ...
... This difference could possibly be attributed to conclusions drawn from the lower extreme of the particle sizes simulated in the in silico CFD studies. Given the large MMADs of nasal spray droplets (commonly 30 to 70 µm) [25,70], it is expected that the vast majority of the dose will be concentrated in particles of large diameters, which would be insensitive to inspiratory flow, especially given the high injection velocities typical of nasal sprays, which in silico work has shown to have a detrimental effect on the probability of penetrating the nasal valve. These particles would then likely deposit via inertial impaction in the nasal vestibule regardless of the fluid flow rate, thus leading some in vitro researchers to conclude that regional deposition is insensitive to the presence of inspiratory flow. ...
... From a theoretical standpoint, it would be expected that a wide spray angle would cause a mismatch between the narrow dimensions of the nasal cavity and small surface area of the nasal valve, leading to lowered deposition beyond the nasal valve, an effect which is seen in the computational work utilizing an idealized nasal valve. In realistic geometries, the results are decidedly more mixed, with some in vitro and in silico studies reporting that narrow spray plumes result in more posterior deposition (consistent with previous in vivo work), while others report the opposite, and some report no statistically significant effect of spray angle [53,55,61,70,73,88]. It is likely that, as suggested in Foo et al. (2007) [55], the effect of the spray angle will depend on the administration angle and on the geometric characteristics of the patient's nose. ...
Background
Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways.
Objective
To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies.
Conclusion
The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.
... Because it is commercially available and readily accessible, it has been used for deposition studies in multiple peer-reviewed Reproduced with permission from [12]. publications [4,[12][13][14][15][16][17]. This cast has been described in some publications as 'anatomically correct' [13][14][15][16][17]. ...
... publications [4,[12][13][14][15][16][17]. This cast has been described in some publications as 'anatomically correct' [13][14][15][16][17]. However, no validation of the geometry and dimensions of this cast have been presented in publications to date. ...
... Based on these results, the validity of the Koken cast to model, inform, or compare drug delivery, including drug deposition profiles, of different nasally delivered products (as has been reported in multiple publications) must be called into question [13,[15][16][17]. ...
Background: Nasal casts may characterize intranasal drug deposition. Methodology: The Koken cast, described as ‘anatomically correct’, and the Optinose cast, derived from MRI of a healthy male during velum closure, were dimensionally compared and assessed for deposition assessment suitability. Results: Smallest vertical cross-sectional areas (valve region) for Koken and Optinose right/left: 2.55/2.75 and 1.18/1.18 cm ² , respectively, versus a ‘normative’ mean (range) of 0.85 cm ² (0.2–1.6 cm ² ). Intranasal volumes differed (computed tomography/water fill): Koken, 35.8/38.6 cm ³ and Optinose, 24.1/25.0 cm ³ , versus a ‘normative’ mean (range) of 26.4 cm ³ (20.9–31.1 cm ³ ). Conclusion: Koken cast dimensions are larger than the normal range and the Optinose cast. The validity of casts for regulatory drug deposition studies is suspect.
... 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). ...
... 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., 1988;Pu et al., 2014). ...
... 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 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 714-1422) 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.
... The particle size and plume geometry, consequently nasal drug delivery, is affected by device properties and formulation properties. 5,29,30 In this study, only one type of short and long nozzle nasal spray is used. We recommend further studies using other short and long nozzle nasal spray with different device properties. ...
... Compared to drug formulations, water has lower viscosity at 1.28 centipoise. 29 Increased viscosity of the liquid formulation resulted to larger droplet size, narrower plume angle, lower spray pattern and less vestibule, and nasal valve deposition. 25,29 Further studies using liquid with viscosity similar to nasal formulations are recommended. ...
... 29 Increased viscosity of the liquid formulation resulted to larger droplet size, narrower plume angle, lower spray pattern and less vestibule, and nasal valve deposition. 25,29 Further studies using liquid with viscosity similar to nasal formulations are recommended. ...
The aim of this study is to compare the delivery site of topical drugs using the short nozzle and the long nozzle. Fourteen fresh frozen cadaver heads were obtained. All cadaver specimens underwent bilateral endoscopic wide maxillary antrostomy, frontal sinusotomy, and complete sphenoethmoidectomy. The right nasal cavity of each cadaver was sprayed with radiolabeled saline using the short nozzle (short nozzle group), while the left nasal cavity was sprayed using the long nozzle (long nozzle group). The distribution of radioactive saline within the sinus cavities was determined using single-photon emission computed tomography/computed tomography. The distribution of the radiolabeled saline in reference with the maxillary line, vestibule, maxillary, ethmoid, sphenoid, and frontal sinus was compared between the 2 groups using Fisher exact test. The number of specimens that demonstrated radioactivity above the maxillary line is higher in the long nozzle group (14 cadavers, 100%) compared to short nozzle group (9 cadavers, 64.3%; p = .02). There are fewer specimens that demonstrated deposition of radioactive saline in the vestibule in the long nozzle group (6 cadavers, 42.86%) compared to short nozzle group (13 cadavers, 92.86%; P = .006). Compared to short nozzle group, there are more specimens demonstrating radioactivity in the maxillary, ethmoid, sphenoid, and frontal sinus in the long nozzle group, but the differences were not statistically significant (p = 0.241, 0.347, 0.126, 0.5). Compared to short nozzle, long nozzle more frequently delivers intranasal drugs beyond the maxillary line and less frequently in the vestibule. These findings support the hypothesis that the use of long and narrow nozzle, instead of the conventional short nozzle, can improve sinonasal drug delivery in post-endoscopic sinus surgery nose.
... The increase in C concentration resulted in a spray cone angle decrease and spray droplet size increase, both of which are related to increased solution viscosity [55,66,69]. Namely, the increased viscosity of the nasal spray led to the decrease in the velocity of the spray droplets as they exited the nozzle. ...
... Namely, the increased viscosity of the nasal spray led to the decrease in the velocity of the spray droplets as they exited the nozzle. Thereupon, the droplets of the spray spread out less and formed a narrower spray cone angle [69,70]. The increased viscosity resulted in the production of larger droplets in the aerosolisation process [56]. ...
Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer’s disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.
... According to the report, as the spray cone increased from 35 to 60 degree, it was difficult for the spray to penetrate through the nasal valve into the main nasal passage, leading to smaller deposition area (Newman et al. 1988). Meanwhile, the percentage of anterior deposition was reported to be linearly increased with the increment of the plume angle (Pu et al. 2014). However, not all the literature reported the same experimental phenomenon. ...
... It was reported that nasal formulations with low viscosity tend to deposite distal to the nares compared to viscous formulations (Guo et al. 2005;Sosnowski et al. 2020). Besides, it was found that the higher viscosity is associated with larger droplet size and narrower plume angle, leading to smaller spray area (Kundoor and Dalby 2011;Pu et al. 2014). Moreover, as shown in Fig. 2, for the nasal spray with carboxymethylcellulose (CMC) as viscosity modifier, the spray area decreased linearly and the droplet size (Dv 50 measured by Malvern's Spraytec®) increased linearly with viscosity increment of the formulation (Dayal et al. 2004). ...
Background
In nasal drug delivery system, nasal spray seems to be the most promising delivery method for both local and systemic diseases therapy. Nasal deposition behavior is the most basic and important process for nasal sprays, which is related to nasal mucociliary clearance, retention of a formulation in the nose therefore the therapeutic effect.Area coveredThe present paper systemically summarized and discussed the factors influencing drug deposition in the nasal cavity upon delivery via nasal sprays, including device, formulation and administration techniques. Emitted dose volume of the device, spray pattern and plume geometry, droplet size distribution and velocity of emitted droplets were important device factors influencing nasal deposition. Besides, viscosity, thixotropic property and surface tension were considered to be the formulation factors influencing nasal deposition of spray. In addition, administration technique influencing nasal deposition included head orientation, administration angle, insertion depth of spray nozzle and breathing profile. Meanwhile, the imaging methods used to predict and visualize the deposition of nasal formulation was illustrated.Expert opinionThe review provided important theoretical and experimental knowledge to control the deposition pattern of nasal sprays in order to achieve better therapeutic effect in the clinic.
... 67 pseudostratified columnar epithelium 69 along with a mucus layer. 70 This contributes to low systemic bioavailability (32%), significant "spillage" 71 along with inter-subject differences in self-administration, leading to suboptimal therapeutic effects, and rhinitis, which is a common adverse event (AE) (26%). 6 Drug deposition and coalescence in the vestibule region, from the cloud-like plume of the liquid spray in the lower nasal cavity, can lead to drug loss, 70,72,73 as it runs out onto the upper lip or down the back of the nasopharynx, leading to reports of disturbed taste 8% and abdominal pain (0.1-1.0%). ...
... 70 This contributes to low systemic bioavailability (32%), significant "spillage" 71 along with inter-subject differences in self-administration, leading to suboptimal therapeutic effects, and rhinitis, which is a common adverse event (AE) (26%). 6 Drug deposition and coalescence in the vestibule region, from the cloud-like plume of the liquid spray in the lower nasal cavity, can lead to drug loss, 70,72,73 as it runs out onto the upper lip or down the back of the nasopharynx, leading to reports of disturbed taste 8% and abdominal pain (0.1-1.0%). ...
Objective:
To provide a narrative review of clinical development programs for non-oral, non-injectable formulations of dihydroergotamine (DHE) for the treatment of migraine.
Background:
Dihydroergotamine was one of the first "synthetic drugs" developed in the 20th century for treating migraine. It is effective and recommended for acute migraine treatment. Since oral DHE is extensively metabolized, it must be given by a non-oral route. Intravenous DHE requires healthcare personnel to administer, subcutaneous/intramuscular injection is challenging to self-administer, and the approved nasal spray formulation exhibits low bioavailability and high variability that limits its efficacy. Currently there are several attempts underway to develop non-oral, non-injected formulations of DHE.
Method:
A systematic search of MEDLINE/PubMed and ClinicalTrials.gov databases, then narrative review of identified reports, focusing on those published in the last 10 years.
Results:
Of 1881 references to DHE from a MEDLINE/PubMed search, 164 were from the last 10 years and were the focus of this review. Further cross reference was made to ClinicalTrials.gov for 19 clinical studies, of which some results have not yet been published, or are studies that are currently underway. Three nasal DHE products are in clinical development, reawakening interest in this route of delivery for migraine. Other routes of DHE administration have been, or are being, explored.
Conclusion:
There is renewed appreciation for DHE and the need for non-oral, non-injected delivery is now being addressed.
... First, this study was intended to replicate as closely as possible clinical practice situations. Thus, most of the tasks performed during our experimentations were performed manually, such as model positioning, unlike previous bench settings seen in adults [13,27]. These conditions could have created variability due to the human factor, despite having standardized all other stages. ...
Background: Nasal irrigation is widely practiced in infants, but its execution varies greatly. Although a consensus on how to perform this procedure has been published, supporting experimental evidence is lacking. In vitro investigations using anatomical models are a promising first step toward clinical research. Quantitative, exploratory data on pediatric nasal irrigation, obtained from a pragmatic irrigation setup, are needed.
Methods: A previously validated upper airway model of a 10-month-
old infant was used and filled with mucus-mimicking hydrogel at two different concentrations. The upper airway clearance efficacy (UAC%) of nasal irrigation (i.e., the extent of airway clearance) was tested by varying different parameters: head position and the nostril selected for irrigation (side-lying via the supra- or infra-lateral
nostril, or sitting), irrigation pattern (unilateral or bilateral irrigation), irrigation volume (5, 10, 15, or 20 mL), and hydrogel concentration (1 or 1.5%).
Results: Increasing nasal irrigation volume significantly improved UAC% with each 5 mL increment: mean (SD) UAC% was 75.10 (8.06), 84.00 (7.79), 89.94 (5.86), and 93.15 (4.63) % for 5, 10, 15, and 20 mL/nostril, respectively. Performing unilateral nasal irrigation through the supra-lateral nostril led to a greater UAC% compared to infra-lateral nostril irrigation (mean UAC% (SD) was 83.02 (7.32) and 75.30 (9.29) %, respectively; p < 0.001). The other parameters did not significantly impact the UAC%.
Conclusion: The irrigation volume and the nostril selected for unilateral nasal irrigation significantly impacted upper airway clearance during in vitro nasal irrigation. Future studies should investigate whether large irrigation volumes improve clinical outcomes in infants.
... The measurement of droplet size distribution of all in situ gelling AMT formulations (GG0.2 %, GG0.3 %, and GG0.4 %) was performed utilizing laser diffraction technique. This analysis was conducted with a Malvern Spraytec® system (Malvern Instruments Ltd., Malvern, UK), equipped with a 300 mm lens that capable of analyzing droplet sizes in a range of 0.1 − 900 µm (Dv 50: 0.5 − 600 µm) (Jullaphant et al., 2019;Kundoor and Dalby, 2011;Pu et al., 2014). The nasal spray device tip was aligned and positioned horizontally with the receiving lens, ensuring the laser beam precisely intersected with the center of the spray cone's expansion. ...
... In vitro studies have repeatedly shown negligible effect of inspiratory flow rate on regional deposition [39,43,44,47]. Given the large MMADs (mass median aerodynamic diameters) of particles used in nasal drug delivery [48,49], it is expected that the vast majority of the dose will be Nevertheless, there is no broad consensus on how various spray parameters (e.g. particle size, initial velocity, inspiration flow rate, administration angle, etc.) affect deposition behavior of nasal spray droplets and on their relative importance, even among studies that use the same geometry. ...
Introduction:
The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products.
Areas covered:
This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines.
Expert opinion:
As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.
... This behaviour is expected as the HPMC addition led to higher gel viscosity and, consequently, higher strength. Fig. 5 and Fig. 6 show a shear thinning behavior for the tested hydrogels before mixing with SNF, as the viscosity decreases with increasing shear rate, which facilitates the local spreading of the formulation (Manniello, 2021;Nižić, 2019;Deshkar et al., 2021;Kundoor and Dalby, 2011;Pu, 2014). The addition of SNF to the DZP-NLC, at 25.0 ± 0.1 • C (Fig. 4, supplementary data) and 34 ± 0.1 • C (Fig. 5), induced a significant increase in the viscosity, which is necessary to ensure a prolonged residence time of the formulation in the nasal cavity. ...
The nasal route has been investigated as a promising alternative for drug delivery to the central nervous system, avoiding passage through the blood-brain barrier and improving bioavailability. In this sense, it is necessary to develop and test the effectiveness of new formulations proposed for the management of neurological disorders. Thereby, the aim of this work was to develop and characterize an ion sensitive in situ hydrogel containing diazepam-loaded nanostructured lipid carriers (DZP-NLC) for nasal delivery in the treatment of epilepsy. Physical characterization of the developed formulations was performed and included the evaluation of rheological features, particle size, polydispersity index (PDI) and zeta potential (ZP) of an in situ hydrogel containing DZP-NLC. Afterwards, in vitro drug release, in vitro mucoadhesion and biocompatibility studies with RPMI 2650 nasal cells were performed. The in situ hydrogel containing DZP-NLC was aerosolized with a nasal spray device specifically designed for nose-to-brain delivery (VP7 multidose spray pump with a 232 N2B actuator) and characterized for droplet size distribution and spray cone angle. Finally, the deposition pattern of this hydrogel was evaluated in a 3D-printed human nasal cavity model. The developed in situ hydrogel containing DZP-NLC presented adequate characteristics for nasal administration, including good gelling ability, mucoadhesiveness and prolonged drug release. In addition, after inclusion in the hydrogel net, the particle size (81.79 ± 0.53 nm), PDI (0.21 ± 0.10) and ZP (-30.90 ± 0.10 mV), of the DZP-NLC remained appropriate for nose-to-brain delivery. Upon aerosolization in a nasal spray device, a suitable spray cone angle (22.5±0.2°) and adequate droplet size distribution (Dv (90) of 317.77±44.12 µm) were observed. Biocompatibility studies have shown that the developed formulation is safe towards RPMI 2650 cells in concentrations up to 100 μg/mL. Deposition studies on a 3D-printed human nasal cavity model revealed that the best nasal deposition profile was obtained upon formulation administration without airflow and at an angle from horizontal plane of 75°, resulting in 47% of administered dose deposited in the olfactory region and 89% recovery. The results of this study suggested that the intranasal administration of the developed in situ hydrogel containing DZP-NLC could be a promising alternative to the conventional treatments for epilepsy.
... Te marketed nasal DHE spray has low systemic bioavailability (32%) [41] and intersubject diferences in selfadministration, along with reported spillage [42] which can lead to drug loss, disturbed taste, and abdominal pain as it runs out of the upper lip or down the back of the nasopharynx, leading to suboptimal therapeutic efects [42][43][44], and rhinitis, which is a common adverse event [41]. ...
Objective. Dihydroergotamine (DHE) is used for acute migraine treatment. Oral DHE is extensively metabolized; therefore, it must be given by a nonoral route. The aim of this study was to investigate the potential use of chitosan nanoparticles as a system for improving the systemic absorption of dihydroergotamine (DHE) following nasal administration. Methods. DHE-loaded chitosan nanoparticles (CS-NPs) were prepared by a modified ionotropic gelation method with sodium tripolyphosphate. The resulting nanoparticles were evaluated for size, drug loading, and in vitro release. DHE was administered at a dose of 0.5 mg/kg to male Sprague–Dawley rats intravenously, as an intranasal solution, or intranasal nanoparticles (n = 3 in each group). A special surgical procedure was performed to ensure that the drug solution was held in the nasal cavity. Blood samples were collected at appropriate times for 90 min. An HPLC-fluorescence detection method was employed to determine DHE in the plasma. Results. DHE chitosan nanoparticles with 20% loading had 95 ± 13% encapsulation efficiency and a particle size of 395 ± 59 nm. In vitro DHE release studies showed an initial burst followed by a slow release of DHE. DHE intranasal nanoparticles demonstrated significantly increased absolute bioavailability (82.5 ± 12.3%) over intranasal DHE solution administration (53.2 ± 7.7%). Conclusion. Taking in consideration the limitations of delivering DHE, the results of the present study demonstrate that DHE CS-NPs have a great potential for nasal DHE administration (55% increase in bioavailability) compared to intranasal solution with effective systemic absorption.
... Nasal and inhalation drug delivery has become a common administration route in the last decades for local and even systemic therapies, and there is a growing interest in developing new formulations as well. For these drug delivery routes, the main challenge is to characterize the nasal and/or lung deposition pattern in vivo [77]. Although the recommended in vitro tests, for example, particle size distribution, spray pattern, or emitted dose, are useful to characterize or compare nasal dosage forms and ensure the required quality of the product, they provide limited information about nasal deposition, pharmacokinetics, or pharmacodynamics [78]. ...
Bioavailability assessment in the development phase of a drug product is vital to reveal the disadvantageous properties of the substance and the possible technological interventions. However, in vivo pharmacokinetic studies provide strong evidence for drug approval applications. Human and animal studies must be designed on the basis of preliminary biorelevant experiments in vitro and ex vivo. In this article, the authors have reviewed the recent methods and techniques from the last decade that are in use for assessing the bioavailability of drug molecules and the effects of technological modifications and drug delivery systems. Four main administration routes were selected: oral, transdermal, ocular, and nasal or inhalation. Three levels of methodologies were screened for each category: in vitro techniques with artificial membranes; cell culture, including monocultures and co-cultures; and finally, experiments where tissue or organ samples were used. Reproducibility, predictability, and level of acceptance by the regulatory organizations are summarized for the readers.
... Colorimeter gels were used to quantify the distribution of liquid spray. The material used to make the cast, therefore, had to be transparent to obtain the color intensity [37]. Casts are usually produced by milling, which is precise despite needing skilled staff and expensive equipment. ...
This interdisciplinary review focuses on how flexible three-dimensional printing (3DP) technology can aid patients with neurological diseases. It covers a wide variety of current and possible applications ranging from neurosurgery to customizable polypill along with a brief description of the various 3DP techniques. The article goes into detail about how 3DP technology can aid delicate neurosurgical planning and its consequent outcome for patients. It also covers areas such as how the 3DP model can be utilized in patient counseling along with designing specific implants involved in cranioplasty and customization of a specialized instrument such as 3DP optogenetic probes. Furthermore, the review includes how a 3DP nasal cast can contribute to the development of nose-to-brain drug delivery along with looking into how bioprinting could be used for regenerating nerves and how 3D-printed drugs could offer practical benefits to patients suffering from neurological diseases via polypill.
... 47 A narrow plume angle seems to decrease the impaction in the nasal valve, increasing the postnasal-valve deposition. [84][85][86] For powder formulation, the plume angle is only affected by the administration device. 47 Indeed, the main factors influencing the plume of liquid sprays (viscosity, surface tension, and actuation force) 87 are fixed for dry sprays since the propellant gas is always the same (air in our case), and the actuation force set by the design of the device. ...
Introduction
This work aimed to develop chitosan-coated cubosomal nanoparticles intended for nose-to-brain delivery of paliperidone palmitate. They were compared with standard and cationic cubosomal nanoparticles. This comparison relies on numerous classical in vitro tests and powder deposition within a 3D-printed nasal cast.
Methods
Cubosomal nanoparticles were prepared by a Bottom-up method followed by a spray drying process. We evaluated their particle size, polydispersity index, zeta-potential, encapsulation efficiency, drug loading, mucoaffinity properties and morphology. The RPMI 2650 cell line was used to assess the cytotoxicity and cellular permeation. An in vitro deposition test within a nasal cast completed these measurements.
Results
The selected chitosan-coated cubosomal nanoparticles loaded with paliperidone palmitate had a size of 305.7 ± 22.54 nm, their polydispersity index was 0.166 ± 0.022 and their zeta potential was +42.4 ± 0.2 mV. This formulation had a drug loading of 70% and an encapsulation efficiency of 99.7 ± 0.1%. Its affinity with mucins was characterized by a ΔZP of 20.93 ± 0.31. Its apparent permeability coefficient thought the RPMI 2650 cell line was 3.00E-05 ± 0.24E-05 cm/s. After instillation in a 3D-printed nasal cast, the fraction of the injected powder deposited in the olfactory region reached 51.47 ± 9.30% in the right nostril and 41.20 ± 4.59% in the left nostril, respectively.
Conclusion
The chitosan coated cubosomal formulation seems to be the most promising formulation for nose-to-brain delivery. Indeed, it has a high mucoaffinity and a significantly higher apparent permeability coefficient than the two other formulations. Finally, it reaches well the olfactory region.
... Formulation viscosity can significantly affect spray generation and the subsequent dosimetry in the nose. Previous studies have demonstrated that a more viscous formulation would generate a spray with a narrower plume angle and large droplets, leading to a smaller spray area [34]. As a result, more doses would be deposited in the vestibule and anterior turbinate in comparison to formulations with lower viscosities [35,36]. ...
Delivering vaccines to the posterior nose has been proposed to induce mucosal immunization. However, conventional nasal devices often fail to deliver sufficient doses to the posterior nose. This study aimed to develop a new delivery protocol that can effectively deliver sprays to the caudal turbinate and nasopharynx. High-speed imaging was used to characterize the nasal spray plumes. Three-dimensional-printed transparent nasal casts were used to visualize the spray deposition within the nasal airway, as well as the subsequent liquid film formation and translocation. Influencing variables considered included the device type, delivery mode, release angle, flow rate, head position, and dose number. Apparent liquid film translocation was observed in the nasal cavity. To deliver sprays to the posterior nose, the optimal release angle was found to be 40° for unidirectional delivery and 30° for bidirectional delivery. The flow shear was the key factor that mobilized the liquid film. Both the flow shear and the head position were important in determining the translocation distance. A supine position and dual-dose application significantly improved delivery to the nasopharynx, i.e., 31% vs. 0% with an upright position and one-dose application. It is feasible to effectively deliver medications to the posterior nose by leveraging liquid film translocation for mucosal immunization.
... Several studies have investigated the correlation between the spray performance and dose deposition [20,21]. While spray pattern (SP) and administration angles are important factors influencing the nasal deposition efficiency, droplet size distribution (DSD) has shown relatively minor influences [22]. ...
PurposeThis study is the first vaccine candidate in vitro investigation with a focus on finding a correlation between the spray characteristics and the delivery efficiency of the local deposition in the nasal airways of infants under 24 months using various intranasal devices.Methods
In vitro tests were developed to measure the spray characteristics of four intranasal delivery devices and how they regionally deliver a candidate vaccine formulation matrix in five nasal airway replicas (3 to 24 months). The correlation between the spray performance, geometric parameters, and delivery efficiency were assessed.ResultsAll four devices performed consistently in terms of spray characteristics and were capable of delivering a high percentage of the candidate vaccine to the target areas, with a minimum delivery efficiency of 80%. Moreover, the delivery efficiency was affected by either the spray droplet size distribution or the distance between the nozzle tip and the internal nasal valve. Correlations between the spray performance and the in vitro local dose deposition were established.Conclusion
The infant nasal model tests can be complementary to device spray performance evaluation. In the absence of in vivo correlations, they can also facilitate the process of new product development by estimating delivery a priori.
... For nasal drug delivery, a representative geometry mimicking average in vivo regional spray deposition across a wide parameter space has not been definitively established, despite significant past research effort [14][15][16][17]. Recently, a new geometry was proposed based on extensive computational fluid dynamics (CFD) simulations performed in a set of realistic nasal geometries [18]. ...
Purpose
To compare in vitro regional nasal deposition measurements using an idealized nasal airway geometry, the Alberta Idealized Nasal Inlet (AINI), with in vivo regional deposition for nasal drug products.
Materials and Methods
One aqueous solution formulation (NasalCrom), one aqueous suspension formulation (Nasonex) and one nasal pressurized metered dose spray device (QNASL) were selected. Two spray orientation angles, 60° and 45° from the horizontal, were selected. A steady inhalation flow rate of 7.5 L/min was selected to simulate slow inhalation through a single nostril. After actuation, the AINI was disassembled. The mass of drug deposited in each region and a downstream filter, representing penetration of drug to the lungs, was determined using ultraviolet–visible (UV–Vis) spectrophotometry.
Results
No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11% for QNASL. For NasalCrom, 45% to 69% of the dose deposited in the AINI was deposited in the vestibule and 31% to 55% was deposited in the turbinates; for Nasonex, 66% to 74% (vestibule) and 26% to 34% (turbinates); for QNASL, 90% to 100% (vestibule) and 0% to 10% (turbinates). No statistically significant difference was observed between regional deposition in vivo and in vitro for any of the formulations, except that nasopharyngeal deposition with Nasonex differed by less than 1.56% from in vivo, which while statistically significant, is unlikely to be clinically significant.
Conclusions
The AINI was able to mimic regional in vivo deposition for nasal drug products, permitting differentiation between devices based on regional deposition.
... Up to thirty-eight different nasal anatomical models have recently been reported in the literature [2,[10][11][12][13][14][15]. They range in complexity from 'simple' geometries to 'sophisticated incomplete' geometries, 'sophisticated complete' geometries, and finally 'human like' geometry. ...
Nasal drug delivery has been utilized for locally acting diseases for decades. The nose is also a portal to the systemic circulation and central nervous system (CNS). In the age of SARS-CoV2, the development of nasal sprays for vaccination and prophylaxis of respiratory diseases is increasing. As the number of nasal drug delivery applications continue to grow, the role of targeted regional deposition in the nose has become a factor is nasal drug development. In vitro tools such as nasal casts help facilitate formulation and product development. Nasal deposition has been shown to be linked to pharmacokinetic outcomes. Developing an understanding of the complex nasal anatomy and intersubject variability can lead to a better understanding of where the drug will deposit. Nasal casts, which are replicas of the human nasal cavity, have evolved from models made from cadavers to complex 3D printed replicas. They can be segmented into regions of interest for quantification of deposition and different techniques have been utilized to quantify deposition. Incorporating a nasal cast program into development can help differentiate formulations or physical forms such as nasal powder versus a liquid. Nasal casts can also help develop instructions for patient use to ensure deposition in the target deposition site. However, regardless of the technique used, this in vitro tool should be validated to ensure the results reflect the in vivo situation. In silico, CFD simulation or other new developments may in future, with suitable validation, present additional approaches to current modelling, although the complexity and wide degree of variability in nasal anatomy will remain a challenge. Nonetheless, nasal anatomical models will serve as effective tools for improving the understanding of nasal drug delivery.
... It reaches 16.8 • ± 2.4 • and 3.9 • ± 0.3 • for the unidirectional device and the bidirectional device, respectively. As already described in the literature, a device that produces a smaller plume angle increases the deposition beyond the nasal valve due to the reduced impaction (35,54,55). Nevertheless, both devices are characterized by a narrow plume angle, which should allow targeting of the post-nasalvalve region. ...
Nose-to-brain delivery is a promising way to reach the central nervous system with therapeutic drugs. However, the location of the olfactory region at the top of the nasal cavity complexifies this route of administration. In this study, we used a 3D-printed replica of a nasal cavity (a so-called "nasal cast") to reproduce in vitro the deposition of a solid powder. We considered two different delivery devices: a unidirectional device generating a classical spray and a bidirectional device that relies on the user expiration. A new artificial mucus also coated the replica. Five parameters were varied to measure their influence on the powder deposition pattern in the olfactory region of the cast: the administration device, the instillation angle and side, the presence of a septum perforation, and the flow rate of possible concomitant inspiration. We found that the unidirectional powder device is more effective in targeting the olfactory zone than the bi-directional device. Also, aiming the spray nozzle directly at the olfactory area is more effective than targeting the center of the nasal valve. Moreover, the choice of the nostril and the presence of a perforation in the septum also significantly influence the olfactory deposition. On the contrary, the inspiratory flow has only a minor effect on the powder outcome. By selecting the more efficient administration device and parameters, 44% of the powder can reach the olfactory region of the nasal cast.
... We believe that the reason for the twofold lower P app value of azelastine from the suspension-based combination product Dymista ® is the complex network structure of the hydrogel limiting convection processes within it, thus extending the diffusion path of azelastine. The environment in the solutionbased sprays of azelastine that contain hydroxypropylmethylcellulose does not hinder the diffusion of the dissolved azelastine to the same extent, as it can be reflected through the viscosity of the nasal sprays, which can significantly differ based on the excipients used and their concentration (microcrystalline cellulose and sodium carboxymethylcellulose, or hydroxypropylmethylcellulose) [35]. However, further studies focused on such in-depth characterization of the nasal sprays in terms of reverse engineering, determination of the quantitative composition, and investigation of the viscosity of the formulations at different concentrations of the used excipients, and assessment of other important properties of the nasal formulations are needed, as this was beyond the scope of our current study. ...
The RPMI 2650 and Calu-3 cell lines have been previously evaluated as models of the nasal and airway epithelial barrier, and they have demonstrated the potential to be used in drug permeation studies. However, limited data exist on the utilization of these two cell models for the assessment of nasal formulations. In our study, we tested these cell lines for the evaluation of in vitro permeation of intranasally administered drugs having a local and systemic effect from different solution- and suspension-based formulations to observe how the effects of formulations reflect on the measured in vitro drug permeability. Both models were shown to be sufficiently discriminative and able to reveal the effect of formulation compositions on drug permeability, as they demonstrated differences in the in vitro drug permeation comparable to the in vivo bioavailability. Good correlation with the available bioavailability data was also established for a limited number of drugs formulated as intranasal solutions. The investigated cell lines can be applied to the evaluation of in vitro permeation of intranasally administered drugs with a local and systemic effect from solution- and suspension-based formulations.
... Generally, significant changes in the area of deposition have also been reported as a function of plume angle [63]. As the plume angle decreases (narrower plume), an increased deposition in the turbinate region has been reported, but it was also dependent on the droplet size and velocity [62,64]. Indeed, high-speed droplets are mostly deposited in the anterior part of the nose [62]. ...
The extract of Cardiospermum halicacabum L. (C. halicacabum) obtained from flower, leaf and vine was loaded into modified phospholipid vesicles aiming at obtaining sprayable, biocompatible and effective nasal spray formulations for the treatment of nasopharyngeal diseases. Penetration enhancer-containing vesicles (PEVs) and hyalurosomes were formulated, and stabilized by adding a commercial gelatin from fish (20 mg/mL) or chondroitin sulfate from catshark cartilages (Scyliorhinus canicula, 20 mg/mL). Cryo-TEM images confirmed the formation of spherical vesicles, while photon correlation spectroscopy analysis disclosed the formation of small and negatively-charged vesicles. PEVs were the smaller vesicles (~100 nm) along with gelatin-hyalurosomes (~120 nm), while chondroitin-PEVs and chondroitin-hyalurosomes were larger (~160 nm). Dispersions prepared with chondroitin sulfate were more homogeneous, as the polydispersity index was ~0.15. The in vitro analysis of the droplet size distribution, average velocity module and spray cone angle suggested a good spray-ability and deposition of formulations in the nasal cavity, as the mean diameter of the droplets was in the range recommended by the Food and Drug Administration for nasal targets. The spray plume analysis confirmed the ability of PEVs, gelatin-PEVs, hyalurosomes and gelatin-hyalurosomes to be atomized in fine droplets homogenously distributed in a full cone plume, with an angle ranging from 25 to 30°. Moreover, vesicles were highly biocompatible and capable of protecting the epithelial cells against oxidative damage, thus preventing the inflammatory state.
... However, as all nasal casts, silicone casts do not replicate the entire complexity of the nasal cavity, such as nasal valve dynamics or mucociliary clearance. Notwithstanding, the 3D nasal casts allow the visualization of the influence of breathing patterns (with and without airflow), consistency of formulations (liquid, powder or gels), variables of the nasal device (e.g., spray angle and plume characteristics) and the formulation deposition location [68,82,84,[87][88][89]. Nizic et al. [68] used a commercial silicone cast to study the deposition profile of melatonin-loaded pectin/hypromellose microspheres. ...
The nasal route has been used for many years for the local treatment of nasal diseases. More recently, this route has been gaining momentum, due to the possibility of targeting the central nervous system (CNS) from the nasal cavity, avoiding the blood−brain barrier (BBB). In this area, the use of lipid nanoparticles, such as nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN), in nasal formulations has shown promising outcomes on a wide array of indications such as brain diseases, including epilepsy, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and gliomas. Herein, the state of the art of the most recent literature available on in vitro studies with nasal formulations of lipid nanoparticles is discussed. Specific in vitro cell culture models are needed to assess the cytotoxicity of nasal formulations and to explore the underlying mechanism(s) of drug transport and absorption across the nasal mucosa. In addition, different studies with 3D nasal casts are reported, showing their ability to predict the drug deposition in the nasal cavity and evaluating the factors that interfere in this process, such as nasal cavity area, type of administration device and angle of application, inspiratory flow, presence of mucoadhesive agents, among others. Notwithstanding, they do not preclude the use of confirmatory in vivo studies, a significant impact on the 3R (replacement, reduction and refinement) principle within the scope of animal experiments is expected. The use of 3D nasal casts to test nasal formulations of lipid nanoparticles is still totally unexplored, to the authors best knowledge, thus constituting a wide open field of research.
... The angle of plume generated by glycerosomes and glyhyalurosomes was narrower than that of liposomes and hyalurosomes, probably due to the presence of glycerol, which led to the formation of a more viscous system. A narrow plume with an angle < 30 • is not the most effective for the deposition of the formulation in the anterior part of the nose and can favour the deposition in the turbinate region as a function of the droplet size and velocity [65,[68][69][70]. Indeed, droplets with high-speed are deposited in the anterior part of the nose [70]. ...
A total green nanotechnological nasal spray has been manufactured and proposed as an alternative treatment of rhinitis and rhinosinusitis. It was obtained by combining the strengthening effect of liposomes on barrier function, the hydrating and lubricating properties of sodium hyaluronan and the anti-inflammatory and antioxidant activities of the extract of Zingiber officinalis. To this purpose, the extract was loaded in special phospholipid vesicles immobilized with hyaluronic acid (hyalurosomes), which were further enriched with glycerol in the water phase. Liposomes and glycerosomes were prepared as well and used as reference. Vesicles were oligolamellar and multicompartment, as confirmed by cryogenic transmission electron microscopy (cryo-TEM) observation, small in size (~140 nm) and negatively charged (~−23 mV). Spray characteristics were evaluated by using the Spraytec® and instant images, from which the plume angle was measured. The range of the droplet size distribution and the narrow spray angle obtained suggest a good nebulization and a possible local deposition in the nasal cavity. In vitro studies performed by using human keratinocytes confirmed the high biocompatibility of vesicles and their ability to effectively counteract oxidative damage on cells induced by hydrogen peroxide. The overall collected data suggest that our vesicles are suitable as nasal spray.
... Understanding the device performance and quantifying the delivery efficiency are important for improving drug delivery to the intended site of action, assisting in developing generic products and may be helpful for the evaluation of those generic products for bioequivalence (Kolanjiyil, Strickler, et al., 2020;Kundoor & Dalby, 2010;Longest, Rygg, & Hindle, 2016;Manniello et al., 2020;Suman et al., 2006). Experimental visualization and in vitro testing using nasal casts together with plume measurements can provide insights into device performance, plume characteristics and drug delivery (Chen, Kiaee, Martin, & Finlay, 2020;Pu, Goodey, Fang, & Jacob, 2014;Suman, Laube, Lin, Brouet, & Dalby, 2002;Xi et al., 2016). At the same time, in silico studies of spray droplet transport and deposition in nasal airway models using Computational Fluid Dynamics (CFD) simulations can provide detailed information on device performance and nasal deposition (Basu, Frank-Ito, & Kimbell, 2018;Basu et al., 2020;Inthavong, Das, Singh, & Sznitman, 2019;Inthavong, Ge, Se, Yang, & Tu, 2011;Inthavong et al., 2006;Kimbell et al., 2007;. ...
Nasal sprays, which produce relatively large pharmaceutical droplets with sizes mostly higher than 10 μm, are primarily used to deliver locally acting drugs to the nasal mucosa. Due to the large spray droplet size and high spray velocity, these droplets carry significant momentum, which can influence the surrounding gas field (i.e., two-way coupling) and strongly influence the transport mechanics and droplet deposition profile. The objective of this study was to determine if two-way momentum coupling leading to cloud motion is an important factor in simulating pharmaceutical nasal sprays, and if so, to develop a computationally efficient method to capture this effect. In this study, the effects of two-way momentum exchange between the nasal spray droplets and the surrounding air were analyzed using Computational Fluid Dynamics (CFD) simulations of sprays from two pharmaceutical nasal spray pumps. The computational spray transport was modeled using different modeling approaches including one-way coupled and two-way coupled Euler-Lagrange framework and Euler-Euler framework. Detailed comparisons of the computational simulation results and in vitro spray transport measurements were performed to establish which approach is more accurate for predicting the nasal spray transport. The simulation results indicated that the coupling effect of the spray momentum exchange with the air molecules created an air-jet velocity profile, which in turn led to a cloud-like motion of the smaller droplets. The airflow created by the cloud of droplets as a whole imparts significant momentum on the smaller droplets and transports them further into the flow field. The comparison study of simulation results and the in vitro measurements demonstrated that the two-way coupled Euler-Lagrange approach is more effective in accurately capturing the nasal spray transport. The spray modeling results indicated that the effects of two-way momentum exchange between the nasal spray droplets and the surrounding air was significant and influenced the spray droplet transport. Calculating the two-way coupling effects was computational resource intensive and time-consuming. Hence, reduced-time and resource modeling approaches including a quasi two-way coupled approach and momentum transfer approach were introduced to simplify the calculation.
... Several researchers have created three-dimensional nose models from polypropylene using MRI scans (Xi et al., 2016) or from CT data (Pu et al., 2014;Shah et al., 2014). In one study, an anatomical model (S.I.M.O.N.T) was used to study saline irrigation (Wawginiak et al., 2017). ...
Nasal saline irrigation is frequently utilised in allergic rhinitis and rhinosinusitis management, and after nasal and sinus surgery. Anatomical modelling, clinical and computational studies guide treatment optimisation. This review offers a comprehensive summary of the modelling methodologies used in previous nasal irrigation studies by undertaking a systematic analysis of anatomical, clinical and computational investigations that assessed nasal saline irrigation using Medline, EMBASE, and Cochrane Review databases. Both procedural and assessment methods were reviewed. It was found that all twenty-four publications reviewed did not discuss the influence of the nasal cycle on internasal geometry and nasal resistance. Cadaver studies misrepresent in vivo nasal geometry. Irrigation pressure and shear forces, which could influence mucociliary transport and postoperative cleaning, were not evaluated. Previous studies focus on irrigation coverage and have not considered the nasal cycle which influences unilateral nasal resistance and thus pressure/ flow relationships and may also increase nasal air-locking. New computational fluid dynamic models could better inform nasal irrigation clinical practice.
... Other experimental studies include [9] that found greater anterior deposition in children (12 year old model) leading to decreased effectiveness; Pu et al. [10] investigated the effect of spray formulation (e.g. viscosity) on deposition patterns in a nasal cavity cast; Warken et al. [11] found the optimum administration angle for nasal sprays applied to ten 3D-printed nasal cavity replicas, and showed that it could increase deposition in the main nasal passage. ...
Deposition of polydisperse particles representing nasal spray application in a human nasal cavity was performed under transient breathing profiles of sniffing, constant flow, and breath hold. The LES turbulence model was used to describe the fluid phase. Particles were introduced into the flow field with initial spray conditions, including spray cone angle, insertion angle, and initial velocity. Since nasal spray atomizer design determines the particle conditions, fifteen particle size distributions were used, each defined by a log-normal distribution with a different volume mean diameter (Dv50). Particle deposition in the anterior region was approximately 80% when Dv50 > 50μm, and this decreased to 45% as Dv50 decreased to 10μ m for constant and sniff breathing conditions. The decrease in anterior deposition was countered with increased deposition in the middle and posterior regions. The significance of increased deposition in the middle region for drug delivery shows there is potential for nasal delivered drugs to reach the highly vascularised mucosal walls in the main nasal passages. For multiple targeted deposition sites, an optimisation equation was introduced where deposition results of any two targeted sites could be combined and a weighting between 0 to 1 was applied to each targeted site, representing the relative importance of each deposition site.
The nasal administration of therapeutic fluids and vaccines is used to treat allergic rhinitis, sinusitis, congestion, coronaviruses and even Alzheimer's disease. In the latter, the drug must reach the olfactory region, so it finds its way into the central nervous system. Effective administration techniques able to reach the olfactory region are challenging due to the tortuous anatomy of the nasal cavity, and are frequently evaluated in vitro using transparent anatomical models. Here, the liquid distribution inside a 3D printed human nasal cavity is quantified for model fluids resulting from the discharge of a 1-mL syringe with either a spray-generating nozzle, and a straight tip emitting a collimated fluid stream. Experiments using two model fluids with different viscosities suggest that a simple, correctly positioned straight tip attached to a syringe is able to efficiently deliver most of a therapeutic fluid in the human olfactory region in the side-laying position, avoiding the adoption of head-back and head-down positions that can be difficult for patients in the age range typical of Alzheimer's disease. Furthermore, we demonstrate by computer simulations that the conclusion is valid within a wide range of parameters.
Introduction:
Although the landscape of migraine symptomatic treatment has been enriched by novel effective drugs, it is mandatory to critically reappraise older molecules to ascertain whether they could still represent reliable alternatives in specific endophenotypes of patients or migraine attacks. Among these, dihydroergotamine (DHE) nasal spray has been shown to be effective and is characterized by greater tolerability and manageability than the parenteral DHE formulation.
Areas covered:
In this narrative review, the authors describe the pharmacodynamic and pharmacokinetic properties of DHE nasal spray and explore the results of the trials which explored its efficacy, safety and tolerability as migraine symptomatic treatment. They also discuss the limitations of the classically used device and the attempts that several companies are carrying out to generate devices warranting a more reproducible drug absorption.
Expert opinion:
DHE nasal spray could be considered as rescue treatment in patients who have failed other symptomatic therapeutic strategies. Nevertheless, in the perspective of tailored therapy, the intranasal route of administration and the consequent rapid onset of action may represent benefits putatively making DHE a treatment of choice for challenging migraine attacks such as those with nocturnal onset or quickly reaching the climax of both headache and neurovegetative associated symptoms.
Many respiratory infections have epidemic and pandemic potential, as evidenced by influenza and the recent COVID-19 pandemic. Vaccination is an established and effective strategy to contain the spread of communicable diseases. Most vaccines are injectables that induce potent systemic immunity. However, they are less efficient in eliciting immune responses at the respiratory mucosa, the site where many respiratory pathogens invade and replicate. This therapeutic inadequacy may be addressed by intranasal and inhaled vaccines which can trigger mucosal immunity. Only limited intranasal and inhaled vaccines are clinically available, including a live-attenuated influenza vaccine and two recently marketed viral vector vaccines targeting SARS-CoV-2. Nevertheless, the immunological advantages of mucosal vaccines should not be undermined, which include the activation of tissue-specific mucosal immune response and common mucosal immune system, while they also induce systemic immunity as injectable vaccines do. In this chapter, the mechanisms of intranasal and inhaled vaccines are introduced and their advantages over injectable vaccines are discussed. Other social and economic benefits of intranasal and inhaled vaccines are also presented, followed by an overview of associated challenges and limitations that must be overcome and addressed before their therapeutic potential can be better utilised.
Objective:
Sprayable hydrogel formulations are promising topical treatments for skin wounds due to their ability to reduce application pain, prolong drug release, and provide moisture to promote skin healing. These viscoelastic materials, however, present challenges in sprayability which can be overcome using a thermoreversible hydrogels sprayed as lower viscosity liquids at cooler temperatures. The purpose of this research was to evaluate the impact of thermoreversible hydrogel formulation and device characteristics on topical spray patterns and to develop metrics to accurately describe surface coverage.
Methods:
Cold solutions of Pluronic F127 were prepared at 15, 17, and 20% (w/w) and tested to determine their rheological properties. Formulations were sprayed from hand-held atomizing pump dispersers under cold conditions and two distinct areas of their spray patterns analyzed: the concentrated core and the full spray pattern. Traditional analysis of spray patterns was conducted to determine major and minor axes, ovality, and total area. In addition, new scripts were developed to evaluate the concentrated core.
Results:
The full spray pattern analysis quantified the total area over which the spray would extend a flat surface, while the concentrated core analysis quantified the continuous region where a drug dose would be concentrated. The combination of formulation viscosity, sprayer nozzle, and spray distance produced spray patterns from highly concentrated to highly dispersed. These parameters can be controlled to generate desired hydrogel spray patterns for application on skin surfaces.
Conclusion:
The developed metrics provide a basis for topical spray analysis that can inform future product performance.
Nasal sprays are typically characterized using in vitro spray metrics such as spray cone angle and droplet size distribution. It is currently not clear how these in vitro metrics correlate with regional nasal deposition, and these relationships could help understand the impact of product differences. In this study, the effects of changes in spray cone angle, spray velocity, spray ovality and droplet size distribution on regional nasal deposition were analyzed using a validated computational fluid dynamics model in recently developed adult characteristic nasal airway anatomies. The impact of the spray on the surrounding air phase was included. Results indicated that changes in spray cone angle largely influenced the posterior deposition (PD) of the drug. Changes in the plume ovality and characteristic droplet size moderately influenced PD, but the results were dependent on the insertion conditions and nasal geometry. Changes in spray velocity and uniformity constant of the droplet size distribution had only minimal influence on PD. The rank order of metrics having the greatest to least impact on PD was cone angle ≫ plume ovality ≫ characteristic droplet size ≫ velocity ≫ size distribution uniformity constant. Overall, results from this study established quantitative relationships for predicting expected changes in PD.
To improve the relationships between commonly conducted in vitro studies for locally-acting nasal spray drug products with in vivo regional deposition, this study developed a set of in vitro adult nasal geometries that captured the range of nasal drug delivery to the region posterior to internal nasal valve (INV), also known as posterior delivery (PD), and evaluated their performance with existing in vivo data. The PD of fluticasone propionate (FP) and fluticasone furoate (FF) in 40 nasal cavities was statistically analyzed to identify three airway models representing the low, mean, and high PD in adults. The models were also externally validated by comparing the in vitro nasal deposition from a different drug product (mometasone furoate (MF)) with the relevant in vivo data. The three selected geometries represented the low, mean, and high PD with multiple nasal sprays. They were verified in terms of reproducibility of in vitro data and validated by showing a reasonable agreement with preexisting in vivo MF PD despite differences in administration and defining the regions. The three models are envisioned to potentially facilitate the development of locally-acting nasal sprays and provide a better understanding of how in vitro metrics relate to in vivo regional nasal deposition.
In this work we present the development of in situ gelling nanosuspension as advanced form for fluticasone propionate nasal delivery. Drug nanocrystals were prepared by wet milling technique. Incorporation of drug nanocrystals into polymeric in situ gelling system with pectin and sodium hyaluronate as constitutive polymers was fine-tuned attaining appropriate formulation surface tension, viscosity and gelling ability. Drug nanonisation improved the release profile and enhanced formulation mucoadhesive properties. QbD approach combining formulation and administration parameters resulted in optimised nasal deposition profile, with 51.8% of the dose deposited in the middle meatus, the critical region in the treatment of rhinosinusitis and nasal polyposis. Results obtained in biocompatibility and physico-chemical stability studies confirmed the leading formulation potential for safe and efficient nasal corticosteroid delivery.
Momentum transfer from nasal spray droplets to the surrounding gas may create droplet cloud motion and influence nasal deposition patterns. The objective of this study was to develop a validated computational fluid dynamics (CFD) model of nasal spray deposition for two different spray-pump designs that includes cloud motion effects (i.e. two-way coupling) in a computationally efficient manner. Spray droplet transport and deposition were simulated in an average adult nasal airway model (that captures average drug delivery) using both two-way coupled and one-way coupled Euler-Lagrange frameworks. CFD model accuracy was established by comparing predictions of the two-way and one-way modeling frameworks with in vitro measurements. The two-way coupled simulation showed that momentum from the spray cloud resulted in displacement of surrounding gas, leading to an upward air velocity in the direction of the spray, which significantly increased the travel distance of smaller droplets with diameters equal to a median diameter of ∼70 µm and below. For the Flonase Sensimist spray pump, two-way coupling produced <10% relative error in posterior deposition fraction compared with the in vitro data, versus 47% relative error using one-way coupling. For the Flonase spray pump, two-way coupling did not improve posterior deposition agreement with both methods having a relative error of ∼30%; however, two-way coupling showed substantial increase in posterior deposition. As a result, two-way coupling is likely needed for the simulation of most nasal spray pumps and additional factors may be important to better capture final formulation distribution of the Flonase product, like post-deposition liquid motion.
Copyright © 2021 American Association for Aerosol Research
Quantifying drug delivery to the site of action using locally-acting nasal suspension sprays is a challenging but important step toward understanding bioequivalence (BE) between test and reference products. The main objective of this study was to investigate the in vitro deposition pattern of two common but different locally-acting nasal suspension sprays using multiple nasal cavities. Twenty anatomically accurate nasal replicas were developed from high-resolution sinonasal computed tomography scans of adults with healthy nasal airways. The airways were segmented into two regions of anterior and posterior to the internal nasal valve. Both sides of the septum were considered separately; hence, 40 nasal cavities were studied. The positioning of the spray nozzle in all 40 cavities was characterized by the head angle, coronal angle, and the insertion depth. Despite using a controlled protocol to minimize the anterior losses, a wide range of variability in posterior drug delivery was observed. The observed intersubject variability using this in vitro method may have important implications for understanding BE of locally-acting nasal suspension sprays.
How prevalent are peptide therapeutic products? How innovative are the formulations used to deliver peptides? This review provides a critical analysis of therapeutic peptide products and the formulations approved by the United States Food and Drug administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). This review also provides an in-depth analysis of dosage forms and administration routes for delivering peptide therapeutics, including injectables, oral dosage forms, and other routes of administration. We discuss the function of excipients in parenteral formulations in detail, since most peptide therapeutics are parenterally administered. We provide case studies of alternate delivery routes and dosage forms. Based on our analysis, therapeutic peptides administered as injectables remain the most commonly used dosage forms, particularly in the form of subcutaneous, intravenous, or intramuscular injections. In addition, therapeutic peptides are formulated to achieve prolonged release, often through the use of polymer carriers. The limited number of oral therapeutic peptide products and their poor absorption and subsequent low bioavailability indicate a need for new technologies to broaden the formulation design space. Therapeutic peptide products may also be delivered through other administration routes, including intranasal, implant, and sublingual routes. Therefore, an in-depth understanding of how therapeutic peptides are now formulated and administered is essential to improve peptide delivery, improve patient compliance, and reduce the healthcare burden for these crucial therapeutic agents.
Background:
A spray pattern (SP) test is one of the most challenging in vitro tests for nasal spray products (NSPs) associated with a high degree of variation. The total results variation observed in such studies should be in major part representative of product performance to assure high confidence when making conclusions based on obtained results. Analytical methods should be developed in a way to minimize variation contribution of random factors. A systematic statistical assessment of sources of variation is encouraged to be performed during any method development.
Methods:
This study includes the development of a product-shaking procedure, definition of in vivo relevant actuation parameters, and the development of a robust SP method considering NSP behavior. The final SP method is tested on different days and in different laboratories to evaluate the contribution of individual factors and interactions to the observed variance in SP using a gauge repeatability and reproducibility (GRR) model.
Results:
It was found that the time lag between consecutive actuations significantly influences the variability of the SP area, suggesting the importance of determining a recovery period. Factor analyst was not found to be important. Factor day was found to have the potential to impact results, mostly through interactions with other factors, suggesting that one should pay attention when performing any comparative studies within the same laboratory on different days. Significant differences were observed when the same product was tested in different laboratories.
Conclusion:
Key random factors, which significantly contribute to total variation, were identified using a GRR approach. By applying an appropriate control strategy over these factors, one can assure that assessed total variation can be representative of product performance. The same general approach is not only applicable to development of SP method for NSP but to all types of analytical testing as well.
Effective nasal drug delivery is highly dependent on the delivery of drug from the nasal spray device. Atomisation of liquid spray occurs through the internal atomizer that can produce many forms of spray patterns and two of these, hollow-cone and full-cone sprays, are evaluated in this study to determine which spray pattern produced greater deposition in the middle regions of the nasal cavity. Past studies of spray particle deposition have ignored the device within the nasal cavity. Using computational fluid dynamics (CFD), two computational models of human nasal cavity model were reconstructed from CT-scans, where the difference between the two models was the presence of the nasal spray device accounting for the airway blockage at one of the nostrils. Experimental measurements from Particle Droplet Image Analyser (PDIA) were taken in order to gain confidence in determining the initial particle conditions for the computational models. An airflow field is induced through a negative pressure flow condition applied at the pharynx instead of constant flow rates at the left and the right nasal cavities. Subsequent airflow patterns and its effects on particle deposition, with and without a spray device, are compared. Contours and streamlines of the flow field revealed that the presence of a spray device in the nasal vestibule produced higher levels of disturbed flow, which helped the dispersion of the sprayed particles. Particle deposition was found to be high in the anterior regions of the nasal cavity caused by its inertia. Evaluation of the two spray types found that hollow spray cones produced more deposition in the middle regions of the nasal cavity. This paper also demonstrates the CFD methodology used, which can help in better understanding the design of future atomizers for nasal spray use.
Deposition patterns are described of a nasal spray formulation for a novel rhinovirus protease inhibitor. These patterns, which were generated from different nasal spray pumps, were characterized using a multisectional nasal airway model. A human nasal replica was made from an in vivo magnetic resonance imaging (MRI) scan of an adult male human. The nasal replica consisted of 77 acrylic plastic sections, 1.5-mm thick. Our data showed that the aerosols were deposited mainly in the anterior and turbinate regions with little passing beyond the nasopharyngeal region. Detailed deposition information from the turbinate region indicated that deposition was high toward the anterior portion where most deposition was concentrated on the inferior meatus. Spray droplets were also deposited in spots of the middle and posterior portions of the turbinate region, and this nonuniform deposition pattern may be correlated with the flow pattern. The spray angle and droplet size of the nasal spray were found to be important in influencing the deposition pattern in the nasal airway. The droplet size was determined by a laser-diffraction technique and the spray angle by high-speed photography. Larger droplets and a wider spray angle increased deposition in the anterior region of the nasal airway, which prevented more material from depositing in the turbinate region.
Drugs are given intranasally for both local and systemic applications, and the use of the intranasal route is predicted to rise dramatically in the next 10 years. Nasal drug delivery may be assessed by a variety of means, but high reliance is often placed upon in vitro testing methodology (emitted dose, droplet or particle size distribution, spray pattern, and plume geometry). Spray pattern and plume geometry define the shape of the expanding aerosol cloud, while droplet size determines the likelihood of deposition within the nasal cavity by inertial impaction. Current FDA guidance recommends these methods as a means of documenting bioavailability (BA) and bioequivalence (BE) for topically acting solution formulations, because they can be performed reproducibly and are more discriminating among products. Nasal drug delivery in vivo may be determined by several radionuclide imaging methods: the two-dimensional imaging technique of gamma scintigraphy has been used most widely, but the three-dimensional method of positron emission tomography (PET) is being used increasingly often. In some situations a good in vitro/in vivo correlation (IVIVC) exists; for instance, negligible penetration into the lungs has been demonstrated in the case of nasal pump sprays delivering large droplets, while a clear difference may be shown in intranasal deposition between two aerosols with markedly different size distributions. However, recent studies have shown a poorer IVIVC for two similar nasal pump sprays, where significant differences in in vitro parameters were not reflected in differences in nasal deposition in vivo. It is suggested that radionuclide imaging data may have an important role to play as an adjunct to in vitro testing in BA and BE assessments and may provide a clearer understanding of the changes in in vitro parameters that are important for predicting differences in in vivo performance.
Many studies suggest limited effectiveness of spray devices for nasal drug delivery due primarily to high deposition and clearance at the front of the nose. Here, nasal spray behavior was studied using experimental measurements and a computational fluid dynamics model of the human nasal passages constructed from magnetic resonance imaging scans of a healthy adult male. Eighteen commercially available nasal sprays were analyzed for spray characteristics using laser diffraction, high-speed video, and high-speed spark photography. Steadystate, inspiratory airflow (15 L/min) and particle transport were simulated under measured spray conditions. Simulated deposition efficiency and spray behavior were consistent with previous experimental studies, two of which used nasal replica molds based on this nasal geometry. Deposition fractions (numbers of deposited particles divided by the number released) of 20- and 50-microm particles exceeded 90% in the anterior part of the nose for most simulated conditions. Predicted particle penetration past the nasal valve improved when (1) the smaller of two particle sizes or the lower of two spray velocities was used, (2) the simulated nozzle was positioned 1.0 rather than 0.5 or 1.5 cm into the nostril, and (3) inspiratory airflow was present rather than absent. Simulations also predicted that delaying the appearance of normal inspiratory airflow more than 1 sec after the release of particles produced results equivalent to cases in which no inspiratory airflow was present. These predictions contribute to more effective design of drug delivery devices through a better understanding of the effects of nasal airflow and spray characteristics on particle transport in the nose.
While numerous devices, formulations, and spray characteristics have been shown to influence nasal deposition efficiency, few studies have attempted to identify which of these interacting factors plays the greatest role in nasal spray deposition. The deposition patterns of solutions with a wide range of surface tensions and viscosities were measured using an MRI-derived nasal cavity replica. The resulting spray plumes had angles between 29° and 80° and contained droplet sizes (Dv50) from 37-157 μm. Each formulation contained rhodamine 590 as a fluorescent marker for detection. Administration angles of 30°, 40°, or 50° above horizontal were tested to investigate the role of user technique on nasal deposition. The amount of spray deposited within specific regions of the nasal cavity was determined by disassembling the replica and measuring the amount of rhodamine retained in each section. Most of the spray droplets were deposited onto the anterior region of the model, but sprays with small plume angles were capable of reaching the turbinate region with deposition efficiencies approaching 90%. Minimal dependence on droplet size, viscosity, or device was observed. Changes in inspiratory flow rate (0-60 L/min) had no significant effect on turbinate deposition efficiency. Both plume angle and administration angle were found to be important factors in determing deposition efficiency. For administration angles of 40° or 50°, maximal turbinate deposition efficiency (30-50%) occurred with plume angles of 55-65°, whereas a 30° administration angle gave an ∼75% deposition efficiency for similar plume angles. Deposition efficiencies of ∼90% could be achieved with plume angles <30° using 30° administration angles. Both the plume angle and administration angle are critical factors in determining deposition efficiency, while many other spray parameters, including particle size, have relatively minor influences on deposition within the nasal cavity.
Background:
Previous studies showed nasal spray in vitro tests cannot predict in vivo deposition, pharmacokinetics, or pharmacodynamics. This challenge makes it difficult to assess deposition achieved with new technologies delivering to the therapeutically beneficial posterior nasal cavity. In this study, we determined best parameters for using a regionally divided nasal cast to predict deposition. Our study used a model suspension and a design of experiments to produce repeatable deposition results that mimic nasal deposition patterns of nasal suspensions from the literature.
Methods:
The seven-section (the nozzle locator, nasal vestibule, front turbinate, rear turbinate, olfactory region, nasopharynx, and throat filter) nylon nasal cast was based on computed tomography images of healthy humans. It was coated with a glycerol/Brij-35 solution to mimic mucus. After assembling and orienting, airflow was applied and nasal spray containing a model suspension was sprayed. After disassembling the cast, drug depositing in each section was assayed by HPLC. The success criteria for optimal settings were based on nine in vivo studies in the literature. The design of experiments included exploratory and half factorial screening experiments to identify variables affecting deposition (angles, airflow, and airflow time), optimization experiments, and then repeatability and reproducibility experiments.
Results:
We found tilt angle and airflow time after actuation affected deposition the most. The optimized settings were flow rate of 16 L/min, postactuation flow time of 12 sec, a tilt angle of 23°, nozzle angles of 0°, and actuation speed of 5 cm/sec. Neither cast nor operator caused significant variation of results.
Conclusion:
We determined cast parameters to produce results resembling suspension nasal sprays in the literature. The results were repeatable and unaffected by operator or cast. These nasal spray parameters could be used to assess deposition from new devices or formulations. For human deposition studies using radiolabeled formulations, this cast could show that radiolabel deposition represents drug deposition. Our methods could also be used to optimize settings for other casts.
Abstract Physiological conditions and pathophysiological changes in the lungs may affect many applications in aerosol medicine and pulmonary drug delivery. In the diseased lung, spatial heterogeneity in function and structure may cause substantial changes in aerosol transport and local deposition among different lung regions. Non-uniform aerosol deposition affects airway or tissue pharmacological dosing, which could reduce the therapeutic effectiveness of inhalation therapy. This review article presents examples of pulmonary imaging using PET and PET-CT in lung physiology with an emphasis on their implications for aerosol medicine. Measurements of regional ventilation, perfusion, and ventilation/perfusion ratio, by imaging local kinetics of intravenously injected Nitrogen-13 in saline solution, and of pulmonary inflammation, by assessing the regional uptake of the radiotracer (18)F-FDG, are presented. These examples demonstrate that it is possible to access both preexisting conditions, such as heterogeneity of ventilation, perfusion, and/or inflammatory stimuli, which may affect inhalation therapy, and the functional effects of inhaled medications or inflammatory agents on lung regional function. The imaging techniques described could be efficient tools to evaluate quantitatively and noninvasively these processes in vivo. Furthermore, it can be expected that imaging of respiratory structure and function will yield sensitive biomarkers of disease, which will help and speed drug discovery, and the evaluation of novel inhalation therapies.
To systematically evaluate the effect of formulation- and administration-related variables on nasal spray deposition using a nasal cast.
Deposition pattern was assessed by uniformly coating a transparent nose model with Sar-Gel®, which changes from white to purple on contact with water. Sprays were subsequently discharged into the cast, which was then digitally photographed. Images were quantified using Adobe® Photoshop. The effects of formulation viscosity (which influences droplet size), simulated administration techniques (head orientation, spray administration angle, spray nozzle insertion depth), spray pump design and metering volume on nasal deposition pattern were investigated.
There was a significant decrease in the deposition area associated with sprays of increasing viscosity. This appeared to be mediated by an increase in droplet size and a narrowing of the spray plume. Administration techniques and nasal spray pump design also had a significant effect on the deposition pattern.
This simple color-based method provides quantitative estimates of the effects that different formulation and administration variables may have on the nasal deposition area, and provides a rational basis on which manufacturers of nasal sprays can base their patient instructions or post approval changes when it is impractical to optimize these using a clinical study.
To develop a simple and inexpensive method to visualize and quantify droplet deposition patterns.
Deposition pattern was determined by uniformly coating the nose model with Sar-Gel (a paste that changes from white to purple on contact with water) and subsequently discharging sprays into the nose model. The color change was captured using a digital camera and analyzed using Adobe Photoshop. Several tests were conducted to validate the method. Deposition patterns of different nasal sprays (Ayr, Afrin, and Zicam) and different nasal drug delivery devices (Afrin nasal spray and PARI Sinustar nasal nebulizer) were compared. We also used the method to evaluate the effect of inhaled flow rate on nasal spray deposition.
There was a significant difference in the deposition area for Ayr, Afrin, and Zicam. The deposition areas of Afrin nasal spray and PARI Sinustar nasal nebulizer (2 min and 5 min) were significantly different. Inhaled flow rate did not have a significant effect on the deposition pattern.
Lower viscosity formulations (Ayr, Afrin) provided greater coverage than the higher viscosity formulation (Zicam). The nebulizer covered a greater surface area than the spray pump we evaluated. Aerosol deposition in the nose model was not affected by air flow conditions.
The morphology and airflow behavior in the nose are considered briefly in relationship to the various ways that are often used to evaluate the spray or aerosol discharged from inhalation delivery systems. A glass-model nose of a design based on published anatomic measurements is described. Its use is described for examining the major sites of drug deposition from nasal delivery systems. That no significant differences are detected between the regional deposition from a metered aerosol and a metered-pump product confirm what might be expected from the nasal anatomy. Most of the drug in each case is deposited in the anterior region of the nose by inertial impaction, and there is little nasal penetration of the drug. Inhaled airflow at 10 L/min through one side of the nose has little effect on regional deposition. The anteriorly deposited drug can be spread backward by mucociliary flow and general surface flow, factors that are essentially independent of the presentation used.
This study used positron emission tomography (PET) to investigate the deposition and disposition of zanamivir administered as a nasal spray.
This was an open-label single-dose study in healthy volunteers.
Six healthy male volunteers, aged 19 to 33 years (mean age 25 years) with a bodyweight of 65 to 94 kg (mean bodyweight 76 kg), took part in the study.
Each participant received by nasal spray zanamivir 6.4 mg mixed with, on average, 2.5 MBq of [11C]zanamivir. The amount of radioactivity was recorded sequentially in 5 different sectors of the body, starting with a short dynamic sequence over the nasal passage. Each of the regions was examined 1 to 4 times at different times after inhalation. The duration of the examination was 90 minutes. During this time, multiple blood samples were taken for analysis of radioactivity in whole blood. Serum samples for pharmacokinetic determinations were collected for 8 hours after administration.
Immediately after administration, about 90% of the drug was deposited in the nasal passage, decreasing to 48% at 90 minutes after administration. Less than 2% was detected in the lower respiratory tract. The major elimination route was via the oesophagus to the stomach. Approximately 2% of the dose was absorbed; the median maximum drug concentration in serum was 15 micrograms/L, and occurred around 1.75 hours after inhalation.
The major deposition site for zanamivir administered by nasal inhalation is the nasal passage; half of the drug remains there for at least 1.5 hours after administration. PET seems to be an excellent tool for this type of kinetic study, allowing imaging and measurements of inhaled drugs with high quantitative accuracy and good spacial resolution.
To determine whether deposition pattern is related to in vitro measurements of droplet size, plume geometry, and spray pattern between two different nasal spray pumps believed to have different performance characteristics.
Ten healthy volunteers inhaled radiolabeled saline from two different spray pumps (pump A and pump B). Deposition pattern was quantified from lateral views of the nose by gamma scintigraphy, expressed as the ratio of anterior to posterior (I:O) and superior to inferior (U:L) deposition. Droplet size was determined by Malvern Mastersizer S. Spray patterns were determined at 2.5 and 5 cm from the tip of the spray nozzle. Two-dimensional images of the emitted plume were captured by high-speed still photography.
There were no significant differences in I:O or U:L ratios for pump A compared to pump B, indicating no significant differences in deposition pattern. The volume diameters, Dv10 and Dv50, were not statistically different for pump A compared to pump B. There was a significant difference in Dv90 between pump A and pump B, (86.9 +/- 5.8 microm and 77.4 +/- 2.4 microm. respectively; P < 0.001). The ratio of the longest to shortest diameter for the spray pattern with pump A was 1.26 +/- 0.06 at 2.5 cm and 1.44 +/- 0.08 at 5 cm. The ratio for pump B was 1.13 +/- 0.03 at 2.5 cm and 1.19 +/- 0.05 at 5 cm. Ratios at both heights were statistically different for pump A compared to pump B (P < 0.00002 and P < 0.000001, respectively) Plume geometry analysis indicated statistical differences in both the width (17.0 +/- 0.97 vs. 18.5 +/- 0.56 cm, respectively: p<0.001) and the maximum length of the plumes (46.0 +/- 1.83 vs. 53.1 +/- 4.88 cm, respectively; p < .002). The differences in velocity of the plume and spray angle between the two pumps were not statistically different. CONCLUSIONS. Certain in vitro tests detected performance differences between the two pumps. However, these differences did not translate into different deposition patterns in vivo.
This study was conducted to evaluate the effect of formulation variables and breathing patterns on aerosol distribution in the nasal cavity.
Placebo nasal spray formulations containing 0.25% w/v Avicel CL611 (viscosity = 4 cP) and 2% w/v methylcellulose (MC; viscosity = 18.2 cP) were radiolabeled with (99m)Technicium. Following spraying into a silicone nose model, through which air was drawn at one of three constant rates (0, 10, and 20 L/min) or one of two breathing profiles (representing fast and slow inhalations), aerosol deposition in the model was quantified by gamma scintigraphy. Regional deposition was expressed as horizontal[inner, middle (h), outer] and vertical distribution [upper, middle (v), lower] in the nose model.
Compared to 2% MC, Avicel CL611 significantly increased aerosol deposition in the middle (h) region of the nasal cavity under all breathing conditions, and in the inner region at 0 and 20 L/min and with a slow inhalation. The different breathing rates showed no effect on deposition of 2% MC. However, 10 L/min significantly increased the upper deposition of Avicel compared to 0 and 20 L/min.
Nasal sprays with a low viscosity provided greater surface coverage of the nasal mucosa than higher viscosity formulations. Changes in breathing profiles did not affect aerosol deposition in this nose model.
This research investigated the impact of the full range of in vitro spray characterization tests described in the FDA Draft Bioequivalence Guidance on nasal deposition pattern, pharmacokinetics, and biological response to nicotine administered by two aqueous nasal spray pumps in human volunteers. Nicotine was selected as a model drug (even though it is not locally acting) based on its ability to alter cardiac function and available plasma assay. Significant differences in pump performance-including mean volume diameters, spray angle, spray width, and ovality ratios-were observed between the two pumps. There were no significant differences in deposition pattern, or pharmacokinetic or pharmacodynamic response to the nasally administered nicotine. Although there were statistical differences in the in vitro tests between the two pumps, these differences did not result in significant alterations in the site of droplet deposition within the nose, the rate and extent of nicotine absorption, or the physiologic response it induced. These results suggest that current measures of in vitro performance, particularly spray angle and spray pattern (ovality), may not be clinically relevant. Additional research is needed to define what spray pump characteristics are likely to produce differences in deposition pattern and drug response.
The present work was carried out to study the deposition patterns and clearance of technetium-99m (99mTc) DTPA labeled cromolyn sodium (CS) solutions when administered from two different CS nasal products using gamma scintigraphy. Five healthy volunteers received a single dose with complete crossover design involving treatment A (test formulation) and treatment B (reference formulation). The deposition patterns as well as the changes in distribution of the radiolabeled CS solutions due to the mucociliary transport were monitored by gamma scintigraphy. Primary deposition of the aforementioned nasal solutions occurred in the anterior portion of the nose. After migration into the posterior nasal cavity, the solutions were rapidly cleared by ciliary action into the nasopharynx where it was swallowed. The test product of cromolyn sodium was shown to be equivalent to the reference product with regard to nasal deposition and clearance. The results from this study indicate that external gamma scintigraphy can be used to demonstrate the equivalence of nasal sprays that are intended for local therapeutic action where the drug is not systemically absorbed into the blood circulation. Furthermore, a non-invasive imaging method such as rhinoscintigraphy may prove to be a useful technique to be utilized during the regulatory approval process for local-acting nasal products, and may facilitate the early introduction of these products to the market.
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FDA Draft Guidance for Industry. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action
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FDA. (2003). FDA Draft Guidance for Industry. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm070111.pdf