Peer Reviewed Journal Publications
2010: Impact of baseline nasal polyp size and previous surgery on efficacy of fluticasone delivered with a novel device: A subgroup analysis
Per G. Djupesland, M.D., Ph.D.,1 Ingrid Vlckova, M.D., Ph.D.,2 and Graeme Hewson, Ph.D.3
Am J Rhinology Allergy 24, 1-5, 2010; doi: 10.2500/ajra.2010.24.3516
ABSTRACT
Background
Little information exists on the impact of baseline polyp size and previous nasal surgery on the efficacy of intranasal steroids. This study was designed to investigate whether baseline polyp size and previous nasal surgery influence the efficacy of an intranasal steroid delivered with a novel device.
Methods
A post hoc analysis of recently published results with intranasal administration using the OptiNose bi-directional delivery device containing fluticasone propionate (Opt-FP) was performed in 109 patients with mild-to-moderate bilateral polyposis. Patients were allocated to subgroups based on summed polyp score at baseline (2, 3, or 4) and on their history of previous sinus surgery.
Results
A highly significant and progressive reduction in summed polyp size was observed for Opt-FP versus placebo in all three polyp size subgroups (p < 0.001). A greater relative reduction in polyp size (p < 0.05) and an increase in peak nasal inspiratory flow (p < 0.001) were observed for Opt-FP at 12 weeks in the 28 patients with a baseline summed score of 3 and 4 compared with the 27 with a summed score of 2. Nevertheless, in patients with small polyps at baseline, the polyps were completely resolved on both sides in 7 of 27 patients. Previous sinus surgery had no impact on efficacy.
Conclusion
The highly significant progressive treatment effect of Opt-FP was observed regardless of baseline polyps score. Coupled with the complete removal of polyps in many patients with small polyps, this suggests that improved deposition to target sites achieved with the bi-directional delivery device may translate into true clinical benefits and reduced need for surgery.
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September, 2010: Preliminary Efficacy of Fluticasone Delivered By a Novel Device in Recalcitrant Chronic Rhinosinusitis.
F.S. Hansen, PG Djupesland, W.J. Fokkens
Rhinology, 48, 000, 2010
ABSTRACT
Objective
To assess whether delivery of fluticasone propionate using a novel bi-directional delivery device (Opt-FP) offers therapeutic benefits in patients with chronic rhinosinusitis (CRS).
Methods
A prospective, single centre, randomized, double-blind, placebo (PBO)-controlled, parallel group study was conducted in adult subjects (n = 20) with CRS without nasal polyps or only cobble stoned mucosa. Subjects received Opt-FP 400 μg or placebo twice daily for 12 weeks (n = 10/group). Outcome measures included symptom scores, RSOM-31, CRS VAS, nasendoscopy, peak nasal inspiratory flow (PNIF) and magnetic resonance imaging (MRI).
Results
Endoscopy score for oedema showed a highly significant and progressive improvement (12 weeks (median scores): Opt-FP -4.0, PBO -1.0, p = 0.015). PNIF increased significantly during Opt-FP treatment compared to placebo (4 weeks: p = 0.006; 8 weeks: p = 0.03). After 12 weeks MRI scores in the Opt-FP group improved against baseline (p = 0.039) and a non significant trend was seen versus placebo. The nasal RSOM-31 subscale was significantly improved with Opt-FP treatment (4 weeks: p = 0.009, 8 weeks: p = 0.016, 12 weeks: NS). Sense of smell, nasal discomfort and combined score were all significantly improved (p < 0.05). The Opt-FP was well tolerated.
Conclusions
The OptiNose breath-actuated bi-directional delivery device administering fluticasone propionate (400 μg b.i.d.) is an effective and well tolerated treatment for recalcitrant CRS.
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December, 2009: Intranasal Sumatriptan Powder Delivered by a Novel Breath Actuated Bi-Directional Device for the Acute Treatment of Migraine: A Randomised, Placebo-Controlled Study.
PG Djupesland, P Docˇekal and the Czech Migraine Investigators Group
Cephalalgia OnlineFirst, published on March 17, 2010 as doi:10.1177/0333102409359314
ABSTRACT
Introduction
Intranasal sumatriptan is an option for the treatment of migraine; however, nasal delivery using conventional spray pumps is suboptimal.
Methods
Adult subjects (n¼117) with migraine were enrolled in a multicentre, randomised, double blind, parallel group, placebo-controlled study. A single migraine attack was treated in-clinic with sumatriptan 10 mg, sumatriptan 20 mg or placebo administered intranasally by a novel bi-directional powder delivery device when migraine was moderate or severe.
Results
A greater proportion of subjects who received sumatriptan were pain-free at 120 minutes compared with those who received placebo (10 mg/20 mg sumatriptan vs. placebo¼54%/57% vs. 25%, P<.05). Significant benefits were also observed for pain relief at 120 minutes (84%/80% vs. 44%, P<.001/.01) and as early as 60 minutes (73%/74% vs. 38%, P<.01) and for 48 hours sustained pain-free (P<.05). Treatment-related adverse events were rare, with a metallic taste being the most commonly reported (10%/13%).
Conclusions
Sumatriptan nasal powder administered using the new device during a migraine attack was effective and well tolerated.
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October, 2009: Effective treatment of mild-to-moderate nasal polyposis with fluticasone delivered by a novel device.
Ingrid Vlckova, Pavel Navrátil, Radim Kaňa, Pavel Pavlicek, Pavel Chrbolka, Per G. Djupesland
Rhinology, 47, 419-426, 2009.
ABSTRACT
Objective
To assess the efficacy and safety of fluticasone propionate administered using OptiNose’s novel delivery device (Opt-FP) in subjects with bilateral mild-to-moderate nasal polyposis.
Methods
A prospective, multicentre, randomized, double blind, placebo-controlled, parallel group study was conducted in adult subjects (n = 109) with mild-to-moderate bilateral nasal polyposis. Subjects received Opt-FP 400 μg or placebo twice daily for 12 weeks. Endpoints included endoscopic assessment of polyp size using Lildholdt’s Scale, peak nasal inspiratory flow (PNIF), symptom scores and use of rescue medication.
Results
The proportion of subjects with improvement in summed polyp score ≥ 1 (Lildholdt’s Scale) was significantly higher with Opt-FP compared with placebo at 4, 8 and 12 weeks (22% vs 7%, p = 0.011, 43% vs 7%, p < 0.001, 57% vs 9%, p < 0.001). After 12 weeks the summed polyp score was reduced by 35% (-0.98 vs +0.23, p < 0.001). PNIF increased progressively during Opt-FP treatment (p < 0.05). Combined symptom score, nasal blockage, discomfort, rhinitis symptoms and sense of smell were all significantly improved. Rescue medication use was lower (3.1% vs 22.4%, p < 0.001). Opt-FP was well tolerated.
Conclusions
Fluticasone propionate (400 μg b.i.d.) administered using OptiNose’s breath actuated bi-directional delivery device was an effective and well tolerated treatment for mild-to moderate bilateral nasal polyposis.
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September, 2009: Rapid Absorption of Sumatriptan Powder and Effects on Glyceryltrinitrate Model of Headache Following Intranasal Delivery using a Novel Bi-Directional Device.
Luthringer R, Djupesland PG, Sheldrake CD, Flint A, Boeijinga P, Danjou P, Demazières A, Hewson G.
Journal of Pharmacy and Pharmacology, 61: 1–10.
Abstract
Objectives
The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared.
Methods
The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design.
Key findings
Following intranasal delivery, median tmax was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean ± SD values for Cmax were 96 ± 25, 11 ± 7 and 16 ± 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure.
Conclusions
Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.
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August, 2009: A new method for scintigraphic quantification of deposition and clearance in anatomical regions of the human nose.
Skretting A, Djupesland PG.
Nuclear Medicine Communications; 30(8):629-38.
Abstract
Objectives
To develop methods for absolute quantification of the deposition of 99mTc-labeled aerosols and powders in well-defined anatomical regions of the nose, and to enable accurate comparisons of different nasal administration techniques in the same individual.
Methods
The volunteer was seated and positioned relative to the scintillation camera field of view by means of a fixation frame. After nasal administration, a dynamic series of images was acquired for 32 min with a lateral direction of view. The images were corrected for photon attenuation by the use of a lateral transmission image acquired before the delivery of aerosols or powders. Marker images, obtained with a line source fixed to a balloon and kept for a short while against the palate as well as with a point source held on anatomical landmarks, were used to co-register the scintigraphic images to sagital sections through a three-dimensional magnetic resonance (MR)-image series. The MR set was used to define the inner nose contour and the nasal regions used for quantification.
Result
Attenuation correction factors ranged from 1.1 to 1.7 in different parts of the nasal cavity. Alignment of the markers on the teeth and palate with the sagital MR images could be reproduced with accuracies of 1.2 and 1.7 mm, respectively.
Conclusion
The new method provides reliable quantification of the deposition in anatomic regions that can be defined in MR images. Accurate co-registration and quantification are essential when comparing distribution and clearance patterns for different administration techniques.
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October, 2006: Intranasal midazolam: A comparison of two delivery devices in human volunteers.
Ola Dale, Turid Nilsen, Thorsteinn Loftsson, Hanne Hjorth Tønnesen, Pål Klepstad, Stein Kaasa, Trond Holand, Per G. Djupesland
Journal of Pharmacy and Pharmacology 58: 1311-18.
Abstract
Bi-directional nasal drug delivery is a new administration principle with improved deposition pattern that may increase nasal drug uptake. Twelve healthy subjects were included in this open, non-randomized 3-way crossover study: midazolam (3.4 mg) intravenously (1 mg mL−1), or nasally by bi-directional or traditional spray (2 × 100 μL of a 17 mg mL−1 nasal midazolam formulation). The primary outcome was bioavailability. Blood samples were drawn for 6 h for determination (gas-chromatography-mass-spectrometry) of midazolam and 1-OH-midazolam. Pharmacokinetic calculations were based on non-compartmental modelling, sedation assessed by a subjective 0–10 NRS-scale, and nasal dimensions by non-invasive acoustic rhinometry. Mean bio-availabilities were 0.68-0.71, and Tmax 15 min for the sprays, which also were bioequivalent (ratio geometric means (90%) CI: 97.6% (90% CI 83.5; 113.9)). Sedation after bi-directional spray followed intravenous sedation closely, while sedation after the traditional spray was less pronounced. A negative correlation between Cmax and smallest cross-sectional area was seen. Adverse effects such as local irritation did not differ significantly between the sprays. Apparently bi-directional delivery did not increase systemic bio-availability of midazolam. We cannot disregard that only the traditional spray caused less sedation than intravenous administration. This finding needs to be confirmed in trials designed for this purpose.
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March, 2006: Oral spray immunization may be an alternative to intranasal vaccine delivery to induce systemic antibodies but not nasal mucosal or cellular immunity.
Hilde Bakke, Helvi Holm Samdal, Johan Holst, Fredrik Oftunga, Inger Lise Haugen, Anne-Cathrine Kristoffersen, Anita Haugan, Libuse Janakova, Gro-Ellen Korsvold, Grethe Krogh, Ellen Anette S. Andersen, Per Djupesland, Trond Holand, Rino Rappuolid, Bjørn Haneberg
Scan J of Immunol. 63, 233-31.
Abstract
Sixty-five healthy adult volunteers were immunized four times at 1-week intervals with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1) without adjuvant. The vaccine was administered as nasal spray with a newly developed device to secure intranasal delivery (OptiMist™, OptiNose AS, Oslo, Norway), as regular nasal spray, nasal drops or as an oral spray. Significant IgA-antibody responses in nasal secretions were induced in volunteers immunized intranasally but not after oral spray immunization. In saliva, IgA antibodies were only marginally amplified even after oral spray immunizations. At least 73% of the volunteers belonging to any group of vaccine delivery reached serum haemagglutination inhibition titres of 40 or higher, considered protective against influenza, after only two vaccine doses. Those who had the vaccine delivered intranasally also showed evidence from in vitro secretion of granzyme B that cytotoxic T cells had been stimulated. Although immunization with the breath-actuated OptiMist™ device and nasal drops were superior with respect to both mucosal and systemic immune responses, oral spray immunization might still be considered for studies of mucosal adjuvants that are not yet acceptable for intranasal use.
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March, 2006: Breath actuated device improves delivery to target sites beyond the nasal valve.
Djupesland PG, Skretting A, Windern M, Holand T.
Laryngoscope. 116(3): 466-472.
Abstract
Objectives
The objective was to compare nasal deposition patterns achieved with a conventional hand actuated spray pump and a novel breath actuated bi-directional prototype device housing the same spray pump (OptiMist™, OptiNose AS, Oslo, Norway).
Study Design and Methods
The bi-directional delivery device exploits the posterior connection between the nasal passages persisting when the velum automatically closes during oral exhalation. The deposition and clearance patterns achieved with the two devices were compared in nine healthy subjects by scintigraphy after administration of 99mTc-aerosols.
Results
Compared with traditional spray pump delivery, the OptiMist device provided significantly (P < .004) larger initial and cumulative deposition (area under the deposition vs. time curve) in the upper posterior segment of the nasal passage, housing the sinus ostia and the olfactory region, and significantly lower deposition (P < .004) in the anterior segment, lined by nonciliated squamous epithelium. Furthermore, intersubject reproducibility of the initial and cumulative deposition was higher for the OptiMist™ device both in the upper posterior segment and the entire nose.
Conclusions
Compared with a spray pump, the novel breath actuated bi-directional device provides significantly larger deposition in the clinically important regions beyond the nasal valve and reduced anterior deposition. These striking differences provide new opportunities for improved therapy of chronic rhinosinusitis and polyposis as well as extended use of the nose for delivery of drugs from the nose into the brain.
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June, 2005: Using computational fluid dynamics (CFD) to improve the bi-directional nasal drug delivery concept.
Kleven M, Melaaen M, Reimers M, Rotnes JS, Aurdal L, Djupesland PG.
Trans IChemE, Part C, Food and Bioproducts Processing., 83(C2): 107-117.
Abstract
Nasal delivery is considered for an increasing number of existing and new drugs and vaccines, but current nasal delivery devices have major disadvantages. The Norwegian company OptiNose AS is developing a novel concept that challenges traditional delivery systems. The patented bi-directional delivery system improves drug and vaccine distribution to the nasal mucous membrane while at the same time preventing lung deposition. It takes advantage of the posterior connection between the nasal passages persisting when the velum automatically closes during oral exhalation. It is the exhalation into the delivery device that triggers the release of particles into an airflow, which enters one nostril via a sealing nozzle and exits through the other nostril. This paper describes how OptiNose is using Computational Fluid Dynamics (CFD) during the development process for their drug delivery concept. The simulations are used to visualize and demonstrate the basic features of the bi-directional technique and discuss how its design and function could be further optimized. CFD computations thus increase the efficiency of device development and reduce the need for expensive and time consuming laboratory experiments. To perform successful CFD calculations on the nose, construction of a proper surface grid of the nasal cavity is important. The process of building the surface grid is presented in the paper. The final surface grid was next imported into Tgrid, a volume grid generator, and finally the simulations were carried out by use of the commercial CFD code FLUENT. These steps are described in the paper. Testing of the cell quality, both during surface grid and volume grid generation, is mandatory. The testing procedures are briefly presented in the paper. Finally, to be able to rely on the CFD computations done, one needs thorough validation. This article presents some comparison of the CFD computation results against physical experiments. The comparison analysis shows promising results.
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September, 2004: Bi-Directional Nasal Delivery of Aerosols Can Prevent Lung Deposition
Djupesland PG, Skretting A, Windern M, Holand T.
Journal of Aerosol Medicine. 17(3): 249-59.
Abstract
Nasal delivery of drugs and vaccines has important advantages compared to injection and oral administration, and is being considered for a widening range of vaccines and substances with topical and systemic action. Traditional nasal delivery technologies are, however, trapped in the dilemma between achieving improved nasal distribution and limiting deposition in the lower airways. The novel bi-directional nasal delivery concept takes advantage of the posterior connection between the nasal passages persisting when the soft palate automatically closes during oral exhalation. Exhalation into the delivery device triggers release of liquid or powder particles into an airflow, which enters one nostril via a sealing nozzle and exits through the other nostril. In a study of 16 healthy subjects using 99mTc labeled nebulized particles with a mean particle size of 3.5 µm, delivery with this novel concept showed no or minimal lung deposition (0.8 ± 2.0% (range –4.1% to 5.6%) for bi-directional delivery, whereas significant fractions were deposited in the lungs in all 16 subjects (mean 22.3 ± 8.1%, range 12.2–39.3%) following conventional nasal inhalation (p < 0.0005). In the latter case, the fraction deposited in the lungs correlated significantly (r2 = 0.47, p < 0.004) with the volume of the nasal passages. The bi-directional nasal delivery concept minimizes the risks and problems related to lung deposition occurring during conventional nasal inhalation from a nebulizer and opens up a new range of opportunities for nasal delivery of drugs and vaccine.
