Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment

D S Quintana, L T Westlye, O G Rustan, N Tesli, C L Poppy, H Smevik, M Tesli, M Roine, R A Mahmoud, K T Smerud, P G Djupesland and O A Andreassen.  Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment.  Translational Psychiatry. 2015. 93.

 

Abstract

 

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8IU (international units) or 24IU OT, 1IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8IU OT in comparison to both placebo and 24IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

 

 

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AVP-825 Breath-Powered Intranasal Delivery System Containing 22 mg Sumatriptan Powder vs 100 mg Oral Sumatriptan in the Acute Treatment of Migraines (The COMPASS Study): A Comparative Randomized Clinical Trial Across Multiple Attacks

Tepper SJ, Cady RK, Silberstein S, et al. AVP-825 Breath-Powered Intranasal Delivery System Containing 22 mg Sumatriptan Powder vs 100 mg Oral Sumatriptan in the Acute Treatment of Migraines (The COMPASS Study): A Comparative Randomized Clinical Trial Across Multiple Attacks. Headache. 2015. May;55(5):621-35.

Objective:

The objective of this study was to compare the efficacy, tolerability, and safety of AVP-825, an investigational bi-directional breath-powered intranasal delivery system containing low-dose (22 mg) sumatriptan powder, vs 100 mg oral sumatriptan for acute treatment of migraine in a double-dummy, randomized comparative efficacy clinical trial allowing treatment across multiple migraine attacks.

Background:

In phases 2 and 3, randomized, placebo-controlled trials, AVP-825 provided early and sustained relief of moderate or severe migraine headache in adults, with a low incidence of triptan-related adverse effects.

Methods:

This was a randomized, active-comparator, double-dummy, cross-over, multi-attack study (COMPASS; with two <12-week double-blind periods.  Subjects experiencing 2-8 migraines/month in the past year were randomized 1:1 using computer-generated sequences to AVP-825 plus oral placebo tablet or an identical placebo delivery system plus 100 mg oral sumatriptan tablet for the first period; patients switched treatment for the second period in this controlled comparative design.  Subjects treated <5 qualifying migraines per period within 1 hour of onset, even if pain was mild.

The primary end-point was the mean value of the summed pain intensity differences through 30 minutes post-dose (SPID-30) using Headache Severity scores. Secondary outcomes included pain relief, pain freedom, pain reduction, consistency of response across multiple migraines, migraine-associated symptoms, and atypical sensations. Safety was also assessed.

Results:

A total of 275 adults were randomized, 174 (63.3%) completed the study (ie, completed the second treatment period), and 185 (67.3%) treated at least one migraine in both periods (1531 migraines assessed). There was significantly greater reduction in migraine pain intensity with AVP-825 vs oral sumatriptan in the first 30 minutes post-dose (least squares mean SPID-30 = 10.80 vs 7.41, adjusted mean difference 3.39 [95% confidence interval 1.76, 5.01]; P < .001). At each time point measured between 15 and 90 minutes, significantly greater rates of pain relief and pain freedom occurred with AVP-825 treatment compared with oral sumatriptan. At 2 hours, rates of pain relief and pain freedom became comparable; rates of sustained pain relief and sustained pain freedom from 2 to 48 hours remained comparable. Nasal discomfort and abnormal taste were more common with AVP-825 vs oral sumatriptan (16% vs 1% and 26% vs 4%, respectively), but ~90% were mild, leading to only one discontinuation. Atypical sensation rates were significantly lower with AVP-825 than with conventional higher dose 100 mg oral sumatriptan.

Conclusions:

AVP-825 (containing 22 mg sumatriptan nasal powder) provided statistically significantly greater reduction of migraine pain intensity over the first 30 minutes following treatment, and greater rates of pain relief and pain freedom within 15 minutes, compared with 100 mg oral sumatriptan. Sustained pain relief and pain freedom through 24 and 48 hours was achieved in a similar percentage of attacks for both treatments, despite substantially lower total systemic drug exposure with AVP-825. Treatment was well tolerated, with statistically significantly fewer atypical sensations with AVP-825.

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A Randomized, Double-Blind, Placebo-Controlled Study of Breath Powered Nasal Delivery of Sumatriptan Powder (AVP-825) in the Treatment of Acute Migraine (The TARGET Study)

Cady RK, McAllister PJ, Spierings ELH, Messina JC, Carothers J, Djupesland PG, Mahmoud RA. A Randomized, Double-Blind, Placebo-Controlled Study of Breath Powered Nasal Delivery of Sumatriptan Powder (AVP-825) in the Treatment of Acute Migraine (The TARGET Study). Headache. 2015;55:88-100.

Objective

To evaluate the efficacy and safety of AVP-825, a drug–device combination of low-dose sumatriptan powder (22 mg loaded dose) delivered intranasally through a targeted Breath Powered device vs an identical device containing lactose powder (placebo device) in the treatment of migraine headache.

Background

Early treatment of migraine headaches is associated with improved outcome, but medication absorption after oral delivery may be delayed in migraineurs because of reduced gastric motility. Sumatriptan powder administered with an innovative, closed-palate, Bi-Directional, Breath Powered intranasal delivery mechanism is efficiently absorbed across the nasal mucosa and produces fast absorption into the circulation. Results from a previously conducted placebo-controlled study of AVP-825 showed a high degree of headache relief with an early onset of action (eg, 74% AVP-825 vs 38% placebo device at 1 hour, P < .01).

Methods

In this double-blind, placebo-controlled, parallel-group study in adults with a history of migraine with or without aura, participants were randomized via computer-generated lists to AVP-825 or placebo device to treat a single migraine headache of moderate or severe intensity.The primary endpoint was headache relief (defined as reduction of headache pain intensity from severe or moderate migraine headache to mild or none) at 2 hours post-dose.

Results

Two hundred and thirty patients (116 AVP-825 and 114 placebo device) were randomized, of whom 223 (112 and 111, respectively) experienced a qualifying migraine headache (their next migraine headache that reached moderate or severe intensity).  A significantly greater proportion of AVP-825 patients reported headache relief at 2 hours post-dose compared with those using the placebo device (68% vs 45%, P = .002, odds ratio 2.53, 95% confidence interval [1.45, 4.42]). Between-group differences in headache relief were evident as early as 15 minutes, reached statistical significance at 30 minutes post-dose (42% vs 27%, P = .03), and were sustained at 24 hours (44% vs 24%, P = .002) and 48 hours (34% vs 20%, P = .01). Thirty-four percent of patients treated with AVP-825 were pain-free at 2 hours compared with 17% using the placebo device (P = .008). More AVP-825 patients reported meaningful pain relief (patient interpretation) of migraine within 2 hours of treatment vs placebo device (70% vs 45%, P < .001), and fewer required rescue medications (37% vs 52%, P = .02). Total migraine freedom (patients with no headache, nausea, phonophobia, photophobia, or vomiting) reached significance following treatment with AVP-825 at 1 hour (19% vs 9%, P = .04). There were no serious adverse events (AEs), and no systemic AEs occurred in more than one patient. Chest pain or pressure was not reported, and only one patient taking AVP-825 reported mild paresthesia. No other triptan sensations were reported.

Conclusions

Targeted delivery of a low-dose of sumatriptan powder via a novel, closed-palate, Breath Powered, intranasal device (AVP-825) provided fast relief of moderate or severe migraine headache in adults that reached statistical significance over placebo by 30 minutes. The treatment was well tolerated with a low incidence of systemic AEs.

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The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview

Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: anatomic, physiologic and delivery technology overview. Therapeutic Delivery. 2014 5(6), 709–733.

 

Introduction

The intricate pathophysiology of brain disorders, difficult access to the brain, and the complexity and high risks and costs of drug development represent major hurdles for improving therapies. Nose-to-brain drug transport offers an attractive alternative or addition to formulation-only strategies attempting to enhance drug penetration into the CNS. Although still a matter of controversy, many studies in animals claim direct nose-to-brain transport along the olfactory and trigeminal nerves, circumventing the traditional barriers to CNS entry. Some clinical trials in man also suggest nose-to-brain drug delivery, although definitive proof in man is lacking. This review focuses on new nasal delivery technologies designed to overcome inherent anatomical and physiological challenges and facilitate more efficient and targeted drug delivery for CNS disorders.

Conclusion

N2B transport is a promising emerging field that may be one of the solutions for the significant difficulties in getting emerging brain therapies into the CNS where they can achieve the desired activity. The barriers to CNS entry of drugs include both the BBB and the BCSFB, and these challenge research into N2B transport. The evidence for N2B transport that has already been developed in animals and the mechanisms for such transport and the issues that surround translating animal research into human implications have been discussed. We have reviewed core concepts in human nasal anatomy and physiology, how they influence nasal drug deposition patterns and the potential for achieving N2B drug transport in man. We have also discussed the limitations of in vitro models and CFD simulations and the important need for human studies of drug deposition. Lastly, we have provided a scan of available technologies for delivering drugs in a manner that may produce N2B transport and a review of the available data to suggest successful N2B type deposition and transport.

 

 

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Improved Pharmacokinetics of Sumatriptan With Breath Powered™ Nasal Delivery of Sumatriptan Powder

Mohammad Obaidi, PhD; Elliot Offman, BSc, Pharm MSc; John Messina, PharmD; Jennifer Carothers, ScD; Per G. Djupesland, MD, PhD; Ramy A. Mahmoud, MD, MPH

Introduction

A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels.

Methods

  • A randomized open-label, cross-over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA
  • Following randomization, fasted subjects received a single dose of each of the following treatments AVP-825 (OptiNose device delivering sumatriptan powder), Imitrex® 20 mg liquid nasal spray, Imitrex® 100 mg oral tablet and Imitrex® 6 mg subcutaneous injection, each separated by a 7-day washout.
  • Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis.

Results

  • Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8 ± 0.9 mg (mean ± standard deviation) of sumatriptan powder in each nostril (total dose 16 mg)
  • Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16-mg sumatriptan powder and 20-mg liquid nasal spray (area under the curve [AUC 0-∞ ] 64.9 ng*hour/mL vs. 61.1 ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8 ng/mL vs. 16.4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC 0-30 minutes 5.8 ng*hour/mL vs. 3.6 ng*hour/mL)
  • On a dose adjusted (per-milligram of drug delivered to the patient) basis this represents a 59% higher peak exposure and 100% higher early exposure.
  • The absorption profile of standard nasal spray showed bimodal peaks, consistent with lower early followed by higher later absorption
  • In contrast, the profile following Breath Powered delivery showed higher early and lower late absorption peaks
  • The peak and overall drug exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower than the 100-mg oral tablet (Cmax 70.2 ng/mL,AUC0-∞,308.8 ng*hour/mL) and 6-mg injection (Cmax 111.6 ng/mL,AUC 0-∞ 128.2 ng*hour/mL)

Conclusions

Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray, and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection.

Clinical Data

Data was published in the September 2013 issue of Headache ISSN 0017-8748, the official journal of the American Headache Society

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Breath Powered™ Nasal Delivery: A New Route to Rapid Headache Relief

Introduction

Per G. Djupesland, MD, PhD; John C. Messina, PharmD; Ramy A. Mahmoud, MD, MPH

The nose offers an attractive noninvasive alternative for drug delivery. Nasal anatomy, with a large mucosal surface area and high vascularity, allows for rapid systemic absorption and other potential benefits. However, the complex nasal geometry, including the narrow anterior valve, poses a serious challenge to efficient drug delivery. This barrier, plus the inherent limitationsof traditional nasal delivery mechanisms, has precluded achievement of the full potential of nasal delivery. Breath Powered bi-directional delivery, a simple but novel nasal delivery mechanism, overcomes these barriers. This innovative mechanism has now been applied to the delivery of sumatriptan. Multiple studies of drug deposition, including comparisons of traditional nasal sprays to Breath Powered delivery, demonstrate significantly improved deposition to superior and posterior intranasal target sites beyond the nasal valve. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposition of sumatriptan translates into improved absorption and pharmacokinetics. Importantly, the absorption profile is shifted toward a more pronounced early peak, representing nasal absorption, with a reduced late peak, representing predominantly gastrointestinal (GI) absorption. The flattening and “spreading out” of the GI peak appears more pronounced in migraine sufferers than healthy volunteers, likely reflecting impaired GI absorption described in migraineurs. In replicated clinical trials, Breath Powered delivery of low-dose sumatriptan was well accepted and well tolerated by patients, and onset of pain relief was faster than generally reported in previous trials with noninjectable triptans. Interestingly, Breath Powered delivery also allows for the potential of headache-targeted medications to be better delivered to the trigeminal nerve and the sphenopalatine ganglion, potentially improving treatment of various types of headache. In brief, Breath Powered bi-directional intranasal delivery offers a new and more efficient mechanism for nasal drug delivery, providing an attractive option for improved treatment of headaches by enabling or enhancing the benefits of current and future headache therapies.

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Clinical Implications for Breath-Powered™ Powder Sumatriptan Intranasal Treatment

Stewart J. Tepper, MD

Introduction

The acute treatment of migraine requires matching patient need to drug and formulation. In particular, nausea and vomiting, quick time to peak intensity, and the common astroparesis of migraineurs, all call for a variety of non-oral formulations for treatment of attacks. A novel breath-powered powder sumatriptan intranasal treatment offers an improvement, at least in pharmacokinetics, over conventional liquid nasal sumatriptan spray. The device for delivery in this breath-powered nasal sumatriptan uses natural nose anatomy to close the soft palate and propel the sumatriptan high up in the nasal cavity on one side with bidirectional airflow coming out the other side. This approach has the potential to reduce adverse events and improve efficacy. Phase 3 data on this system are in press at the time of this writing and results appear promising. The clinical role for a fast acting non-oral nasal formulation will be in those for whom tablets are bound to fail, that is, in the setting of nausea and vomiting or when the time to central sensitization, allodynia, and disabling migraine is too short for the patient to respond to a tablet. This review provides a clinical perspective on the breath-powered powder sumatriptan intranasal treatment.

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Nasal Deposition and Clearance in Man: Comparison of a Bidirectional Powder Device and a Traditional Liquid Spray Pump

Per Gisle Djupesland, M.D., Ph.D.,1 and Arne Skretting, M.Sc.
Journal of Aerosol Medicine and Pulmonary Drug Delivery
Volume 25, Number 0, 2012

ABSTRACT

Background

Delivery of powder formulations to the nose is an attractive alternative for many drugs and vaccines. This study compared the regional nasal deposition and clearance patterns of lactose powder delivered by the OptiNose powder device (Opt-Powder; OptiNose US Inc., Yardley, PA, USA) to that of liquid aerosol administered via a traditional hand-actuated liquid spray pump (Rexam SP270, Rexam Pharma, France).

Methods

The study was an open-label, crossover design in seven healthy subjects (five females, two males). The regional nasal deposition and clearance patterns of the Opt-Powder device were compared to a traditional liquid spray pump by dynamic gamma camera imaging after administration of either 99mTc-labeled lactose powder or liquid 99mTc- diethelyne triamine pentaacetic acid-aerosol. The gamma camera images were scaled and aligned with sagittal magnetic resonance images to identify nasal regions. Possible deposition of radiolabeled material in the lungs following both methods of delivery was also evaluated.

Results

Both powder and spray were distributed to all of the nasal regions. The Opt-Powder device, however, achieved significantly larger initial deposition in the upper and middle posterior regions of the nose than spray (upper posterior region; Opt-Powder 18.3% ± 11.5 vs. Spray 2.4% ± 1.8, p < 0.02; sum of upper and middle posterior regions; Opt-Powder 53.5% ± 18.5 vs. Spray 15.7% ± 13.8, p < 0.02). The summed initial deposition to the lower anterior and posterior regions for spray was three times higher compared to Opt-Powder (Opt-Powder 17.4% ± 24.5 vs. Spray 59.4% ± 18.2, p < 0.04). OptiNose powder delivery resulted in more rapid overall nasal clearance. No lung deposition was observed.

Conclusion

The initial deposition following powder delivery was significantly larger in the ciliated mucosa of the upper and posterior nasal regions, whereas less was deposited in the lower regions. Overall nasal clearance of powder was slower initially, but due to retention in anterior nonciliated regions the overall nasal clearance after spray was slower.

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Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review

Per Gisle Djupesland, M.D.
Drug Deliv. and Transl. Res.
DOI 10.1007/s13346-012-0108-9

Introduction

Intuitively, the nose offers easy access to a large mucosal surface well suited for drug- and vaccine delivery. However, factors related to the nasal anatomy, physiology and aerodynamics that can severely limit this potential, have historically been challenging to address. The most recent FDA guidance for nasal devices provides detailed guidelines for in vitro testing of the physical properties such as in vitro reproducibility and accuracy of plume characteristics and dose uniformity of mechanical liquid spray pumps and pressurized metered-dose inhalers (pMDIs) for nasal use [1]. The guidance primarily addresses in vitro testing of nasal sprays and pressurized aerosols for local action. The reference to in vivo performance is limited to the recommendation of minimizing the fraction of respirable particles below 9 μm in order to avoid lung inhalation of drugs intended for nasal delivery. Thus, although important as measures of the quality and reliability of the spray pump and pMDI mechanics, these in vitro tests do not necessarily predict the in vivo particle deposition, absorption, and clinical response [2]. Furthermore, the guidance offers no or limited guidance on nasal products for systemic absorption and for alternative dispensing methods like drops, liquid jets, nebulized aerosol, vapors, and powder formulations. Finally, it does not address aspects and challenges related to the nasal anatomy and physiology that are highly relevant for the device performance in the clinical setting like body position, need for coordination, and impact of airflow and breathing patterns at delivery.
The mechanical properties of different modes of aerosol generation are already well described in depth in a previous publication [3]. The anatomy and physiology of the nasal airway has also recently been summarized in an excellent recent review [4]. The aim of this paper is to take a step further by reviewing the characteristics of existing and emerging nasal delivery devices and concepts of aerosol generation from the perspective of achieving the clinical promise of nasal drug and vaccine delivery. Focus is put on describing how the nasal anatomy and physiology present substantial obstacles to efficient delivery, but also on how it may be possible to overcome these hurdles by innovative approaches that permit realization of the therapeutic potential of nasal drug delivery. Specific attention is given to the particular challenge of targeted delivery of drugs to the upper narrow parts of the complex nasal passages housing the middle meatus where the sinuses openings are located, as well as the regions innervated by the olfactory nerve and branches of the trigeminal nerve considered essential for efficient “nose-to-brain” (N2B) transport.

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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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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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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 (n=117) 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. placebo 54%/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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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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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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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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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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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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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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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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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.

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