Supplement Article

Breath Powered Nasal Delivery: A New Route to RapidHeadache Relief

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 areaand 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 Poweredbi-directional delivery, a simple but novel nasal delivery mechanism, overcomes these barriers. This innovative mechanism hasnow been applied to the delivery of sumatriptan. Multiple studies of drug deposition, including comparisons of traditional nasalsprays to Breath Powered delivery, demonstrate significantly improved deposition to superior and posterior intranasal targetsites beyond the nasal valve. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposi-tion of sumatriptan translates into improved absorption and pharmacokinetics. Importantly, the absorption profile is shiftedtoward a more pronounced early peak, representing nasal absorption, with a reduced late peak, representing predominantlygastrointestinal (GI) absorption. The flattening and “spreading out” of the GI peak appears more pronounced in migrainesufferers 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 wasfaster than generally reported in previous trials with noninjectable triptans. Interestingly, Breath Powered delivery also allowsfor the potential of headache-targeted medications to be better delivered to the trigeminal nerve and the sphenopalatineganglion, potentially improving treatment of various types of headache. In brief, Breath Powered bi-directional intranasaldelivery offers a new and more efficient mechanism for nasal drug delivery, providing an attractive option for improvedtreatment of headaches by enabling or enhancing the benefits of current and future headache therapies.

Key words: migraine, nasal, sumatriptan, powder, drug delivery, absorption

(Headache 2013;53;S2:72-84)

Rapid relief in the treatment of headache is con-sidered very important by patients, and as a result,efforts toward identifying alternative formulationsand routes of delivery to improve on the speed ofrelief have been increasing in recent years.1,2

Although oral medications are generally preferred bymost patients with headache, it is not a route of admin-istration that is conducive to rapid action. Followingoral administration, dissolution and absorption areoften the rate limiting factors in determining the onset

From the R&D, OptiNose US Inc., Yardley, PA, USA (J.C.Messina and R.A. Mahmoud); R&D, OptiNose AS, Oslo,Norway (P.G. Djupesland).

Address all correspondence to P.G. Djupesland, CSO, c/o Opti-Nose US Inc, 1010 Stony Hill Road, Suite 375, Yardley, PA19067, USA, e-mail: pgd@optinose.com

Accepted for publication June 4, 2013.

This is an open access article under the terms of the CreativeCommons Attribution-NonCommercial-NoDerivs License,which permits use and distribution in any medium, providedthe original work is properly cited, the use is non-commercialand no modifications or adaptations are made.

OptiNose, Breath Powered and Bi-Directional, are trademarksof OptiNose AS.

Conflict of Interest:All three authors are employed by and holdoptions and/or shares in OptiNose.

ISSN 0017-8748doi: 10.1111/head.12186

Published by Wiley Periodicals, Inc.

Headache© 2013 The Authors. Headache: The Journal of Head and Face Pain publishedby Wiley Periodicals, Inc. on behalf of American Headache Society

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http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/

of effect. In addition, first-pass metabolism is acommon barrier to the achievement of rapid therapeu-tic concentrations. In the case of migraine, oral deliv-ery is often unsuitable or unattractive for manypatients because of the presence of nausea and vom-iting. Furthermore, migraine patients frequently haveautonomic dysfunction causing delayed gastric emp-tying during attacks which can both delay and reduceintestinal absorption.3-6 The consequence of a slowonset of action is that the severity of the headache isprolonged and often worsening which increases theduration of disability and disease burden, and thepotential to halt progression may be lost.3,6,7

The nose offers an attractive noninvasive alterna-tive route of drug delivery for many conditions.Because of its large mucosal surface area and highvascularity, it allows for rapid absorption of drugs intothe systemic circulation. In addition, this route ofdelivery may help address issues related to poor bio-availability, drug degradation in the gastrointestinal(GI) tract, and adverse events in the GI tract, andavoids the first-pass metabolism in the liver.8 In someinstances, structures directly related to disease patho-physiology also reside in the nasal cavity, and localdelivery may reduce the need for systemic exposureand improve the therapeutic index of medicaltreatment.9-11

A fact often ignored with nasal drug delivery isthat the site of deposition within the nasal cavity highlyinfluences the extent of systemic absorption from thenose. The anterior portions of the nose are lined withnonciliated squamous epithelium not well suited todrug absorption.However, the mucosal surface gradu-ally transitions, as one passes deeper into the nasalcavity, to ciliated respiratory epithelium.In the regionswith ciliated respiratory epithelium, branches of theophthalmic and maxillary arteries supply the mucosalmembranes covering the convoluted and complex slit-like nasal passages (Fig. 1). It is this richly vascularizedregion of the nasal cavity lined with respiratory epi-thelium which is conducive to the rapid absorption ofdrugs across the mucosa and into the systemic circula-tion from the nasal cavity and not the anterior regionslined with squamous epithelium.8

Beyond being a route of administration for sys-temic delivery, there are structures within the nasal

cavity that have a role in the pathophysiology of head-ache and may serve as therapeutic targets for head-ache. The trigeminal nerve, in particular the firstophthalmic branch (sensory) as well as the parasym-pathetic branches synapsing in the sphenopalatineganglion (SPG),is strongly involved in the pathophysi-ology of cluster headache and has been implicated inmigraine.12 Serotonin receptors (5HT1b and 5HT1d)have been found both at the terminal nerve endings inthe nasal mucosa and in the corresponding ganglia,which may offer a local target for nasally delivereddrugs, triptans being only one example.13 Furthermore,the parasympathetic part of the trigeminal nerve maybe responsible for mediating symptoms like increasedtearing and nasal secretion and congestion duringattacks, symptoms that are present in both cluster and

Fig 1.—The complex anatomy of the nasal airways showing theapproximate position of the olfactory and trigeminal nerves,the nasal valve, the regional segmentation (red dotted lines),and 3 different cross-sections vertical to the nasal floor at posi-tion (a), (b), and (c). The location of the nasal valve and thetrigeminal and olfactory nerves.

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migraine headache sufferers.14 Interestingly, levels ofmediators like vasoactive intestinal peptide and calci-tonin gene-related peptide (CGRP) are increased innasal secretions and saliva during attacks, suggestiveof a neurogenic inflammation in nasal vessels thatpotentially could enhance drug absorption across thenasal mucosa.15,16

Sinus headache, commonly associated withsinusitis, is often alleviated with the nasal administra-tion of locally active substances including topicalsteroids, antihistamines, and saline. Nasal delivery ofsmall amounts of CO2 for a short period of time has,in clinical trials, shown effects on migraine and on thesymptoms of allergic rhinitis.9,17,18 It is thought that theaddition of CO2 may induce therapeutic changes inintracellular pH, reduce CGRP release in nasal secre-tions, and/or produce other modifications of receptorsthat may mediate effects on trigeminal nerve trans-mission and neurogenic inflammation.9 Interestingly,in a recent paper, signs of nasal autonomic dysfunc-tion with significantly higher nasal pH and reducedmucociliary clearance time were observed in Parkin-son’s patients compared with controls.19 Both exhalednitric oxide (NO) levels and NO levels in nasal airhave been found to be significantly higher inmigraineurs compared with healthy volunteers.Several studies suggest a relationship between NOand neurogenic inflammation in the trigeminovascu-lar system, which is in agreement with the observedrelease of various vasoactive peptides like CGRP innasal secretions, indicating that NO may contributenegatively to the migraine disorder.20-22

NASAL DELIVERY OF HEADACHEMEDICATIONS

Intranasal administration of a variety of medica-tions for the treatment of headache has been utilizedfor some time. Intranasal formulations of dihydroer-gotamine mesylate (DHE), sumatriptan, zolmitrip-tan, butorphanol, civamide, and lidocaine have allbeen used/investigated for the treatment of migraineand/or cluster headache.23 Civamide and lidocainehave been administered via a nasal dropper to inter-rupt nerve transmission, and although there hasbeen some evidence of clinical efficacy, neither hasreceived US Food and Drug Administration approval

for the treatment of headache.24 Furthermore, nervestimulation of the SPG has shown promising results inaborting cluster headache, strongly supporting thepotential of local treatment to nerves that may beaccessed from the nasal cavity.12,25,26

DHE, sumatriptan, zolmitriptan, and butorphanolhave obtained regulatory approval for the treatmentmigraine and can be administered in the form of aconventional nasal spray by the patient. DHE is knownto be a highly effective medication when administeredintravenously. Unfortunately, it is less than 1% bio-available when given orally. However, when adminis-tered intranasally, it has a bioavailability of ª40%allowing for use of this medication in the outpatientsetting.23 In addition to the intranasal formulations,sumatriptan is available as a subcutaneous injection, anoral tablet, suppositories, and a rapid dissolving tablet(outside the United States). In addition to the intrana-sal formulation, zolmitriptan is available as an oraltablet and fast melt formulation. For both drugs, theintranasal formulations were introduced as alterna-tives to the oral formulations to overcome the issues ofslow onset, reduced GI absorption during headachefrom slowed motility, as well as the aversion of patientsto take oral medications in the presence of nausea.

Both intranasal sumatriptan and intranasalzolmitriptan have demonstrated superiority againstplacebo in providing relief of migraine symptoms, andintranasal zolmitriptan has been demonstrated toprovide earlier relief than the same dose of zolmitrip-tan oral tablets.27-29 Each provides a more rapidabsorption than the respective orally administeredtablet.30 However, neither has resulted in a markedincrease in total bioavailability relative to oral.30,31

These triptan conventional nasal sprays display abimodal absorption pattern with a fairly small earlypeak attributed predominantly to absorption acrossthe nasal mucosa, followed by a later more distinctpeak representing GI absorption of the significantamount of drug swallowed after bypassing thenose.30-33 For zolmitriptan, the nasal fraction has beenquantified in a study and found to account for approxi-mately 30% of the total absorption.32 A similar studyhas not been conducted with sumatriptan nasal spray,though sumatriptan liquid nasal spray pharmacokinet-ics have been studied.31,33 It is important to note that

74 September 2013

the approved dose of zolmitriptan delivered nasally isthe same as the highest dose for tablets (5 mg),whereas the range of approved conventionalsumatriptan nasal spray doses (5, 10, and 20 mg) isfivefold lower than the oral doses (25, 50, and 100 mg).Consequently, the systemic exposure is significantlylower for the range of sumatriptan nasal spray dosescompared with the oral formulation, whereas it issimilar or even slightly higher with nasal zolmitriptan.The opportunity to deliver a lower dose highlights apotential advantage of delivering sumatriptan nasally(vs zolmitriptan) as the risk for systemic andGI-related side effects relative to the oral formulationmay be reduced by lowering the systemic exposure.

Despite the theoretical advantages of intranasaldrug administration, there have been impediments tobroad adoption for the treatment of migraine head-ache. For patients, the consequences of the inad-equate deposition to the target mucosa achieved withtraditional nasal sprays is likely a key factor contrib-uting to a lack of perceived clinical benefits over oraltreatment. Prospective studies have demonstratedthat a key driver for patients preferring a nasal sprayis speed of onset. In addition, for obvious reasons,alternative formulations that offer the potential offaster absorption may be preferable over simplyincreasing the dose of an oral formulation.2,34

Enhanced tolerability or safety relative to oral formu-lations would simply add to patient preference shouldthey accompany a core efficacy benefit like improvedspeed of onset.

LIMITATIONS OF NASALSPRAY DELIVERY

Traditional spray pumps used with nasal spraysresult in limited drug deposition to the target sitesbeyond the narrow triangular-shaped constrictioncalled the nasal valve, which is located approximately2 cm from the entrance of the nostril.35,36 The purposeof the narrow nasal valve, in concert with the complexconvoluted nasal passageways, is to filter and condi-tion the inspired air, enhance olfaction, and optimizegas exchange and fluid retention during exhalation.8

These important functional features of the noseimpose important limitations on efficient nasal drugdelivery that are too often ignored.

For example, the expanding convex spray plumeand high particle speed emitted from a spray bottlewill largely impact on the walls of the nasal vestibule.Increasing the propulsive force of the nasal deliverydoes not alter the fundamental anatomic constraints,as the plume impacts on the first surfaces it reaches,while “sniffing” exacerbates the problem as describedlater. The anterior segment of the nasal cavity, thenasal vestibule, is lined primarily with nonciliatedsquamous epithelium, which is less efficient for medi-cation absorption than the ciliated respiratory epithe-lium beyond the nasal valve8 (Fig. 1). Because of thismismatch between the geometry of the anteriorregion of the nose and the spray plume, only a smallfraction of the spray penetrates beyond the nasalvalve, and a large portion of the spray volumeremains in the vestibule.

The large volume of liquid in the vestibule of thenose may drip out or be wiped off. Sniffing duringdelivery further narrows the nasal valve, and reflexivesniffing after delivery to avoid drip-out will not onlyfurther narrow the nasal valve, which is already par-ticularly narrow superiorly (see Fig. 1a), but alsoshrink the already slit-like deeper nasal passages(Fig. 1b,c). This tends to impair both the intendedtargeting to a broad nasal surface area and any poten-tial benefits of higher deposition, and tends to directwhatever medication penetrates the nasal valve alongthe nasal floor to be swallowed. Taste buds sensingbitter taste located at the base of the tongue arequickly exposed to the concentrated liquid that con-tributes to the intense bitter taste often reported withthese nasal sprays. It is only the smaller proportion ofthe spray that reaches the highly vascularized respi-ratory mucosa that accounts for most of the earlynasal absorption. Such a significant portion of themedication delivered by conventional nasal sprays isswallowed, rather than being nasally absorbed, whichthe GI tract contributes more to the amount of drugabsorbed than does the nose.31,33 This phenomenon isclearly observed with sumatriptan where a bimodalabsorption profile is produced following conventionalnasal spray administration: a lower early peak, likelyrelated to intranasal absorption, is produced after 20minutes and is followed by a higher absorption peakconsistent with GI absorption around 90 minutes.31

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The predominance of oral absorption follow-ing conventional nasal spray delivery reduces theintended advantages of nasal delivery. Thus, the lackof significant differentiation from oral tablets resultsin only marginally faster onset of action in somepatients and likely contributes to the limited uptakein the market place observed with nasal sprays.

Notably, both the sensory and parasympatheticbranches of the trigeminal nerve involved in thepathophysiology of migraine and other headachesinnervate the mucosal surfaces beyond the nasalvalve, which is also where the SPG resides. To theextent that these structures are involved in headachepathophysiology, the posterior and superior portionof the nasal cavity would be an interesting target fortherapeutic intervention with current or future drugs;however, they cannot be effectively reached with astandard nasal spray (Fig. 1).

OPTINOSE BREATH POWEREDDELIVERY

Breath Powered Mechanism of Action andDevices.—A comprehensive review on depositionpatterns associated with nasal drops and spray pumpsconcluded that traditional delivery devices are subop-timal for delivery to the respiratory mucosa beyondthe nasal valve.8 Several approaches attempting toimprove the drug delivery of traditional spray pumpshave been suggested and tested over the years, but aregenerally either impractical, suboptimal, or have yetto be proven in replicated human intranasal deposi-tion studies. Efforts to optimize conventional nasalsprays by improving the method of use have beensimilarly unrewarding: a study tested 7 different headand body positions using traditional nasal sprays andconcluded that there is “no best method.”37

The Breath Powered Bi-Directional deliverymechanism can be implemented in simple deviceswithout electromechanical cost or complexity, andovercomes many deficiencies of traditional nasaldelivery. Both liquid and powder drugs can be deliv-ered using such devices, and implementations of eachare in active development. This novel nasal deliveryconcept consists of devices with a flexible mouthpieceand a shaped, sealing nosepiece. It is designed toexploit unique aspects of the nasal anatomy and physi-

ology to improve the extent and reproducibility ofdrug delivery to target sites in the nose beyond thenasal valve while avoiding the risk of lung inhalation.38

The user slides the shaped nosepiece into onenostril to create a seal with the nasal tissue, insertsthe mouthpiece between the open lips, takes a deepbreath, closes the lips around the mouthpiece, andthen exhales forcefully into the mouthpiece. The oralexhalation into the device creates a positive pressurein the oropharynx, naturally elevating and sealing thesoft palate and completely separating the nasal andoral cavities. Because of the sealing nosepiece, theairflow and dynamic positive pressure is transferredby the device into the nasal cavity where it expandsthe nasal valve and narrow slit-like passages. Theintranasal pressure, which is slightly reduced com-pared with the intraoral driving pressure due to theresistance of the device and the nasal passage, auto-matically balances the pressure across the soft palateto avoid overelevation of the soft palate.This is essen-tial as it maintains patency of the important commu-nication pathway between the two nostrils that islocated deep in the nasal cavity posterior to the nasalseptum, permitting the exhaled breath to escape fromthe contralateral nostril while relieving the nasalcavity of excess pressure.

A dedicated multiuse Breath Powered powderdevice with a reusable device body and a disposablenosepiece was developed for use in patients withmigraine headache (Fig. 2). An 11-mg dose ofsumatriptan powder is filled into a standard respira-tory capsule and provided to the patient in a capsulechamber of a disposable nosepiece. There is a smallentrance for airflow at the bottom of the chamber anda larger opening at the top. Prior to use of the device,a fresh nosepiece is snapped into the top of thedevice, and the capsule is pierced by depressing abutton on the device body. Upon exhalation into thedevice, the pierced capsule vibrates and rotates withthe exhaled breath, releasing the powder into theairflow. Drug particles are carried posteriorly by theexpanding flow of physiologically warmed air intoone nostril, beyond the nasal valve, and depositedbroadly throughout the deep nasal cavity before theair reverses course and escapes anteriorly through theother nostril (Bi-directional delivery) (Fig. 3).

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Multiple studies evaluating anthropometric dif-ferences between individuals were conducted inorder to develop the appropriate design of the devicein order to accommodate differences in individualnostril size and distances and angles between themouth and nose.The current design has been found inusability testing as well as clinical trials to be wellaccepted in terms of comfort and ease of use.

Drug Deposition With Breath Powered Devices.—The scintigraphic techniques used in the last decadesto study in vivo nasal deposition of liquid and powder

formulations are relatively crude and did not allowfor reliable absolute or relative quantification ofregional nasal deposition and clearance patterns.An improved system allowing reliable quantificationof the regional nasal deposition of radiolabeled par-ticles in human subjects has been introduced and usedin clinical deposition trials comparing conventionalnasal spray devices to Breath Powered devices forboth liquid and powder drugs.39

In the most recent study, Tc99m-labeled lactosepowder was delivered with the Breath Powered

Fig 2.—The Breath Powered powder device for sumatriptan delivery.

Fig 3.—Illustration of the Breath Powered nasal delivery.

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powder device.35 A capsule fill and particle size profilesimilar to sumatriptan powder was used. For measur-ing differences in deposition, the nose was dividedinto 3 horizontal segments, and a vertical dividing linewas positioned at the head of the inferior turbinate(Fig. 4), and radiation counts within each segmentwere quantified after administration.

The Breath Powered powder device demon-strated a broader deposition on the regions wherenasal mucosa is lined by ciliated respiratory epithe-lium (especially upper and middle posterior regions,but also the upper anterior and middle anteriorregions) with less deposition in the nonciliated nasalvestibule and significantly greater initial deposition tothe upper posterior regions beyond the nasal valvecompared with the conventional spray delivery (ª54%vs 16%) (Figs. 4 and 5a).35 In contrast, liquid spraysdeposited most of the dose (ª60% vs ª17%) in limitedregions in the lower parts of the nose (Fig. 5).35

Pharmacokinetics (PK) of Breath PoweredSumatriptan Nasal Powder.—The regional analysesof deposition and clearance clearly demonstrate thatthe Breath Powered powder device provides broaderexposure to the highly vascularized respiratorymucosa beyond the nasal valve, and particularlyimproves delivery to the middle and upper regions ofthe nasal cavity.35 This should reasonably be expectedto translate into more rapid and more extensive drug

absorption of suitable medications than is achievedwith standard nasal spray delivery. This differenceshould be possible to measure objectively, as it shouldbe reflected in improved PK and ultimately inimproved efficacy. Such studies have now been per-formed assessing the consequences of deliveringsumatriptan in this fashion.40,41

Two studies have evaluated the PK of sumatrip-tan delivered with the OptiNose Breath Powereddevice. One was a crossover study in 12 migrainepatients pretreated with either subcutaneous (SC)injection sumatriptan, or sumatriptan powder deliv-ered with a Breath Powered device, prior to a chal-lenge with nitroglycerine known to induce migraine(GTN-challenge).40 The larger second study was a4-way crossover study in healthy volunteers compar-ing sumatriptan powder delivered with a BreathPowered device (15 mg delivered dose split betweennostrils) to 20 mg sumatriptan nasal spray (1 nostril),100 mg sumatriptan tablet, and 6 mg sumatriptan SCinjection.41 In both studies, there was a bimodalabsorption pattern representing an initial nasalabsorption followed by a GI absorption with BreathPowered delivery (Fig. 6).40,41 The initial peakobserved in both studies was more pronounced thanthe peak observed with the standard nasal spray (asmeasured in the second study),41 indicative along withother PK parameters of a more efficient and faster

Fig 4.—Gamma camera images 2 minutes after delivery using a traditional liquid spray (a) and powder with OptiNose BreathPowered Device (b) shown with a logarithmic hot iron intensity scale. Initial gamma images from one of the subjects aresuperimposed on a lateral magnetic resonance (MR) image. The red dotted lines indicate the segmentation used for regionalquantification.

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systemic absorption with the Breath Powered device(Fig. 6). Absorption also occurred earlier than withtablet delivery but with a significantly lower peak andtotal systemic exposure than either the oral tablet orsubcutaneous injection.41

The nasal peak for sumatriptan powder is verysimilar in the two PK studies, one in migraineurs andone in healthy volunteers, occurring early in bothpopulations.40,41 However, the later peak, assumed torepresent predominantly GI absorption, is substan-tially smaller in the study performed in migraineursduring GTN-challenge40 (Fig. 6). This likely reflectsthe delayed and decreased GI absorption because ofautonomic dysfunction observed in migraineurs thatis further accentuated during an attack.3-6

It should be noted that sumatriptan powder wassplit between the two nostrils while the nasal spraywas administered to a single nostril.40,41 The impact onthe PK profile of dividing the liquid spray dosebetween nostrils has been previously investigated andfound not to improve either the rate or extent ofabsorption over administration to a single nostril.42

Therefore, it seems unlikely that this difference inadministration procedure explains the findings in thePK study in healthy subjects.

It is important to recall when reviewing the phar-macokinetic data that the total delivered sumatriptandose with the Breath Powered delivery device is20-25% lower than the sumatriptan 20 mg liquidspray. A shift to greater nasal absorption with Breath

Regional initial deposition (0– 2 minutes)

Segment

Percentage of inital delivered dose (%)

Relative initial deposion in upper, middleand lower third of the nasal cavity

Traditional liquid spray pump

a

b

Breath powered powder device

P < .02

P < .02 P < .02

P < .02

P < .04

NS (P = .3)

70

70 80 90

60

60

50

50

Frac

tio

n d

epo

site

d (

%)

40

40

30

30

23.8

2.9Sum Upper Third

Sum Middle Third

Sum Lower Third

Traditional liquid sprayBreath powered powder device

57.1

23.2

17.4

59.8

20

20

10

10

0

0

Upperanterior

Middleanterior

Middleposterior

Loweranterior

Lowerposterior

Upperposterior

P < .02

P < .02

P < .04

Fig 5.—(a) Initial Regional nasal deposition (0-2 minutes) for Breath Powered powder delivery device and delivery with atraditional nasal spray pump. (b) Initial horizontal nasal distribution (0-2 minutes) for the Breath Powered powder delivery deviceand delivery with a conventional nasal spray pump.

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Powered delivery reduces the fraction of sumatriptanbypassing the nose compared with sumatriptan spray,and the dose is split between the two nostrils (Fig. 6).The lower dose, broader nasal distribution, and sig-nificantly altered clearance pattern (NB, the softpalate is closed at the time of delivery) followingBreath Powered delivery further reduce the amountand concentration of drug reaching the taste buds atthe base of the tongue, which is likely to mitigate theintensity of the bitter taste sensation.The results showthat the enhanced nasal deposition produced by theBreath Powered device is indeed associated withpharmacokinetic advantages.

Clinical Trials in Migraine.—It is reasonable tohypothesize that the increased early absorption mayoffer advantages in terms of improved efficacy and inparticular more rapid onset of pain relief, and thatthe low dose may enhance tolerability or safety. Theability to prevent migraine attacks in the study withGTN-challenge combined with the similar electroen-cephalography findings following SC and BreathPowered powder delivery, despite much lower bloodlevels, also suggest potential clinically relevant advan-

tages.40 These findings provided the rationale toproceed to a randomized placebo-controlled trialwith a Breath Powered sumatriptan delivery device.

In the first placebo-controlled, parallel group,3-arm trial in acute migraine (117 total patients), twodoses of sumatriptan powder were delivered withthe Breath Powered device and compared with a“placebo” control group using dummy devices.43 Fastonset of pain relief was observed for both active doseswith early pain relief rates similar to historical datafor SC injection despite much lower systemic expo-sure. Significant benefits were also observed for painrelief at 120 minutes for both doses, and the higherdose was selected for further development. Thehigher dose produced a response of 80% vs 44% withplacebo (P < .01) at 2 hours, and high early responserates at 60 minutes (74% vs 38%, P < .01) and at 30minutes (54% vs 31%; NS).43

A phase III, placebo-controlled, parallel group,2-arm study in 212 patients was recently conductedwith sumatriptan powder being delivered with theBreath Powered device.44 At 2 hours postdose, a sig-nificant proportion of patients experienced pain relief

Fig 6.—Pharmacokinetics (PK) profiles for nasal sumatriptan from two crossover studies performed with the Breath Poweredpowder device and the marketed Imitrex sumatriptan nasal spray. The one study was done in migraine patients during GTN-challenge, whereas the other study was performed in healthy volunteers.

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compared with placebo (68% vs 45%, P < .01), a highvalue for triptan therapy. However, again, the moststriking result was the fast onset of pain relief, with aremarkably high response rate at 30 minutes (42% vs27%, P < .05). This is particularly notable in light ofthe extremely low dose of a triptan medication. Thereported adverse events were primarily mild andtransient and generally limited to the site of adminis-tration. It was concluded that Breath Powered deliv-ery of intranasal sumatriptan powder is effective, safe,and well tolerated and can offer fast onset of painrelief in adults with acute migraine headache.

Comparison of these results with published datasuggest that the speed of onset of pain relief is muchfaster than oral treatment and approaches thatachieved with SC injection, but with substantiallylower systemic exposure and therefore the attendantrisk of adverse events.44

Potential Therapeutic Effects of the BreathPowered Device.—In each clinical trial with BreathPowered delivery, an interestingly high placeboresponse rate has been observed.43,44 In these trials,control patients did not receive “no treatment” butused identical Breath Powered delivery devices toactive patients. Although the high response amongthese “placebo” patients may be due to chance,secular trends, or other factors, it is interesting to notethat there are also potential explanations directlyrelating to the use of the Breath Powered device.

During normal respiration, there is minimalexchange of air in the upper narrow part of the nose.The particular aerodynamics of the Breath Powereddelivery device blowing a large amount of exhaled airwith 5-6% CO2 at a flow rate of 30 L/minute or morelasting for 2-3 seconds, which penetrates the uppernarrow segments of the nose, could provide therapeu-tic effects, in part similar to those reported with thedelivery of 100% CO2, albeit that this CO2 deliverywas done for short duration and done at low flow(10 mL/s) and low volume.17,18 In the present BreathPowered device, it is postulated that the oscillatingcapsule and airflow may significantly enhanceexchange of air in upper narrow parts of the nose, asin part observed in response to humming and pulsat-ing nebulizers.45,46 In addition, there are reasons tohypothesize that potential positive effects mediated

by the positive air pressure, rapid vibrations producedby the rattling capsule, and the removal of NO may allplay a role in alleviating migraine headache.46,47 Oneor more of these, or other, device-related mechanismsmay contribute to the high response rate in theplacebo groups in the trials with Breath Poweredpowder delivery in migraine patients.

Potential Headache Treatments With BreathPowered Bi-Directional Delivery.—The deep nasalcavity deposition associated with Breath Powereddelivery enables the potential for medications to bedelivered more broadly to the trigeminal nerve inner-vated tissue and to the SPG, which may prove to bebeneficial in the treatment of a range of headachedisorders. The aerodynamic properties of the deviceitself may offer alternative mechanisms of actionand/or synergetic effects.

In addition to possibilities in preemption or pre-vention of migraine, cluster headache and trigeminalneuralgia represent target indications for possibledelivery of numerous new or current drugs alone or incombination, including for example triptans, DHE,lidocaine, nonsteroidal anti-inflammatory drugs(NSAIDs), locally acting corticosteroids, and poten-tially CGRP-antagonists. There is great unmet need,and it is possible to modify the current device tooptimize delivery for treatments intended to particu-larly target the region closest to the SPG for optimalefficacy. Other potential indications include chronicmigraine, where delivery of a very small daily dose ofa triptan or other drugs in this manner may offersufficient receptor blockage to reduce the number ofacute attacks. Even topical steroids may prove valu-able alone or as an adjuvant therapy in cluster head-ache or in sinus headache.

CONCLUSIONSNasal drug delivery has long been a route of

administration known to be useful in the treatment ofheadache and other disorders. However, the typicalmethods of intranasal delivery are relatively ineffec-tive in their delivery of medication broadly and to theposterior/superior areas of the nasal cavity whererapid and efficient drug absorption and other benefitscan effectively accrue. Therefore, the promise ofintranasal drug delivery has not been fully realized.

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Human gamma-deposition studies in vivo withBreath Powered devices have proven that this noveldevice mechanism is capable of producing a signifi-cantly improved nasal drug deposition pattern. Phar-macokinetic studies to assess the consequences of thisimproved deposition were performed following thedelivery of a low dose of sumatriptan powder, andshow that this improved delivery is associated withenhanced speed and efficiency of absorption acrossthe nasal mucosa with a reduced proportion of GIabsorption relative to standard nasal spray. In repli-cated clinical trials, Breath Powered delivery of low-dose sumatriptan has now been shown to producesubstantial response rates, with early pain relief moresimilar to SC injection than to other forms of delivery,but with much lower exposure than with oral or SCtreatment. This new form of nasal delivery may offera number of interesting therapeutic options for thetreatment of a range of headache disorders in thefuture.

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