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THE NASAL SPRAYPUMP MARKET

Approximately 70% (worth $254billion) of drugs are administered orallyto patients, and 2% (worth $6 billion) areadministered via the nasal route (Figure1).1 Within this 2%, the treatment ofallergic rhinitis contributes to one-third,with a $2-billion market value in 20012

with a 10% annual growth.Decongestants and other treatments(including systemic therapies) completethe remaining $4 billion.

The nasal market can be dividedinto over-the-counter (OTC) andPrescription (Rx) medications. OTCnasal drugs mostly use non-meteringdevices (the delivery dose isapproximate, ie, squeeze bottle,droppers). In contrast, the Rx nasal drugsuse metering devices (the delivered doseis accurate). Using Nasal Metering DrugDelivery Devices, either Multidose orUnit-dose, the following two types ofactions can be achieved:

• Local delivery to target specificallythe nasal mucosa.

• Systemic delivery of the activedrugs as a non-invasive alternativeto injection and an alternative to oraltreatments to avoid the GI tract.

THE NASAL SPRAY

How Does It Work?The Nasal Metering Drug Delivery

Device (Multidose or Unit-dose)produces a spray of expelled formulation(most of the time liquid), which isdirected into the nasal cavity. For a localtreatment, the drug produces a localeffect within the nasal mucosa. For asystemic delivery, the active ingredient

goes through the nasal mucosa andreaches the general blood circulation vianumerous capillary vessels presentunderneath the mucosa. In this case, thenasal cavity (Figure 2) is used as a portalof entry into the blood stream.

Main AdvantagesThe nasal route for drug

administration has significant advantagesover the injection and the oral routes.

Exploring a Pharmaceutical Market Niche &Trends: Nasal Spray Drug Delivery

By: Gilles Devillers, PhD, MBA

F I G U R E 1

The nasal route of administration emerged decades ago as anefficient local delivery route to treat allergic rhinitis and nosecongestion, and as an attractive alternative to the oral andparenteral routes of administration. This niche market of deliveringdrugs via the nose has proven feasible and financially attractive for

the pharmaceutical market even though there are limits to thisroute of administration. Thus, Multidose and Unit-Dose nasal spraydevices are continually improving to enhance efficacy, safety, andcompliance of an increasing number of drugs.

I N T R O D U C T I O N

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For example, compared to an injection,nasal devices eliminate the pain and thefear associated with the needle.Delivering a drug via the nose also hasthe following benefits:

• Easier than giving an injection, thusit may enhance patient compliance.

• Decreases needle injuryoccurrences.

• Does not necessarily require trainedpersons for the administration, thusdecreasing the total cost of thetreatment.

When compared to the oral route,nasal devices have other advantages:

• Elimination of gastric and hepaticdrug degradation.

• Avoidance of vomiting afterswallowing the drug (eg, duringmigraine crisis).

• Fast onset of action.• Fewer side effects due to the

potential reduced dosage of thedrug.

Which Devices?Instead of the traditional injection

that avoids the oral route ofadministration with proteins andpeptides, two non-invasive drug delivery

systems for the nasal route are availableand already used: the Multidose andUnit-Dose Metering Spray Devices.

Multidose Metering Spray Pumpsare specially suited for repeatedadministrations and can providenumerous doses (typically 50 to 130mL). Typically, such devices are used totreat chronic diseases. Unit-DoseMetering Spray Devices are speciallysuited for single administration. Thesedevices are typically used for crisistreatments (ie, pain management) andsingle-dose delivery (ie, vaccination)and can accommodate liquidformulation, powder formulation, or amix of both.

Which Therapies?The nasal route of administration is

ideal for treating local diseases (Figure3a), such as allergic rhinitis and nosecongestion. In these cases, the commondrugs used include steroids,decongestants, saline solution, etc. Thenose is also the entry to systemicdelivery (Figure 3b) for numerous drugsand different therapies for a variety ofdiseases. Among these therapies anddiseases, hormone replacement therapy(Oestradiol), osteoporosis (Calcitonin),pain management (Butorphanol,Sumatriptan, and Zomitriptan), smokingcessation (Nicotine), enuresis(Desmopressin), and motion sickness(Metoclopramide) are already marketedwith a Metering Nasal Spray Device.

More drugs targeting othertherapies and diseases will soon join theincreasing list of marketed products forsystemic delivery using the nasal route,such as drugs to treat Central NervousSystem disorders (Parkinson andAlzheimer diseases). Another exampleis nasal vaccination. Mucosal vaccineselicit not only good local immuneprotection, but also a systemic responsesimilar to that of injection. A nasal flu

vaccination could be launched in timefor the next flu season.

Scientific & Cultural LimitsThe nasal route of administration

also has limitations. Both scientific andcultural limits can be attributed to thisroute. To avoid pain and discomfort, anasal formulation should be of relativelylow volume (approximately 70 to 100mL) and have a pH close to thephysiological one.3 The mucociliaryclearance, which is a natural andessential function of the nose, goesagainst extended drug diffusion fromthe surface to the nasal mucosa. Suchclearance sweeps any particles up(either dust, germs, or medicine) afterfew minutes.

Finally, the biggest scientific limitto achieve systemic delivery most likelyconsists of the molecule size. The nasalmucosa can only accept relatively smallmolecules across its membrane.Absorption decreases significantly withmolecular weights higher than 1000Daltons.3 Above 3000 Daltons andwithout absorption enhancers, thebioavailibility is rather low for thisroute to be of great interest. Culturallimits can also be a barrier to the use ofthe nasal route. Certain people can bereluctant to introduce a device andspray into their nostrils. Others can havedoubts about the real efficacy of suchnasal drugs.

NEW TRENDS &UNMET NEEDS

ErgonomyThese days, medication and health

not only go with therapeuticallyeffective and safe molecules, but alsowith the comfort of their dispensingsystems. Not only should a deliverysystem help a patient accept itstreatment, but it should also facilitate

F I G U R E 2

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the compliance with it. Hence,ergonomy should be applied to nasaldevice design to make them attractiveand user friendly. For example, a side-actuation triggering mechanism(Figures 4 and 5) decreases theactuation force and allows thefollowing:

• A better grip, reducing risks ofhurting oneself during instillation.

• Discreet usage while in public.• Intuitive handling.• More accurate delivery due to a

better orientation.• A wider population use of nasal

devices (ie, children and elderlyfriendly).

Ergonomy can also include specificdesign and customization toaccommodate the labeling and productdifferentiation.

Preservative-Free SystemsPreservatives are commonly used in

drug formulations. Their advantages are

obvious, and they are generally welltolerated. However, when theformulation is delivered directly to thenasal mucosa, some adverse effects mayoccur due to the preservative,particularly for chronic use. In this case,preservatives can irritate the mucosa,causing some unpleasant itching, butmore seriously, they can slow down oreven stop the mucociliary clearance,which is essential for the protection ofthe upper airways. To reduce theinherent preservative risks, regulatorybodies have started to identify and bansuch preservatives. This past summer,the German Regulatory Authorities(BfArM) launched a ban onBenzalkonium Chloride (the standardpreservative for nasal formulation) in allmedications in Germany. Thisrepresents more than 300pharmaceutical products, including 98nasal products. Preservatives can alsomake the work of the chemist moredifficult by generating some instabilitiesor by modifying the smell and taste ofthe formulation, which is not desirable.To help formulation experts reduce oreliminate the preservatives from nasalspray formulations, some drug deliverydevice manufacturers have successfullydeveloped specific multidose sprayingdevices, which provide protection, thusmaking the use of preservativesunnecessary. These devices are basedupon the following two main principles:

• Metering Spray Pump working as aclosed system: (Aerodiol® fromServier, Nezeril® from AstraZeneca, and Otrivin® fromNovartis). Unlike conventionalMetering Nasal Spray Pumps, theclosed system does not allow air toenter into the container, thuspreventing contamination fromairborne germs.

• Metering Spray Pump workingwith a filter: In this system, theventing air is sucked through afilter assembled inside the pump,which eliminates the airbornegerms and keeps them out of thecontainer.

To provide a complete protection ofthe formulation, specific nozzles aredesigned to prevent contamination ofthe formulation trapped in the deadvolume of the actuator. Basically, thefollowing two principles can be used:

• A mechanical protection of thedead volume of the nozzle, whichopens only when the internalpressure of the liquid increases.When the dose is delivered, thenozzle seals back.

• A chemical protection of the deadvolume using a bacteriostaticmaterial (generally silverderivatives or ions) either includedor coating parts of the actuator.

F I G U R E 3 a F I G U R E 3 b

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Unit-Dose Spray Devices deliverone or two sprays (one per nostril) usinga syringe principle: the formulation ispushed out via a plunger from thedevice. For injections, Unit-Doses canbe produced and filled in an asepticenvironment or sustain terminalsterilization. Therefore, Unit-Doses canalso deliver preservative-freeformulations.

Micro-Electronics & TelemedicineWe have seen that Metering Nasal

Spray Devices can be user friendly andcontribute to better patient compliance.Time is ticking until such devices alsotake advantages of micro-electronics toallow for effective telemedicine.Electronic prototypes (Figure 6) arealready featuring new possibilities, suchas data transmission, lock-out systems,treatment monitoring, etc.

SUMMARY

The nasal route is an already provenalternative method of administration forboth local and systemic treatments.Metering Nasal Spray devices areconstantly evolving to provide evenbetter solutions to comply with thehealthcare and ergonomic needs of thepatient.

REFERENCES

1. Arthur D Little 20002. DataMonitor 2001.3. Aurora J. Development of nasal

delivery systems: a review. DrugDelivery Technology. 2002;2(7):70-73

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F I G U R E 6

Dr. Gilles Devillers isa pharmacist with anMBA. He has held variouspositions in R&D atSmithKline Beecham(now GSK) and at thedrug delivery companyQuadrant Healthcare (nowElan Drug Delivery),where he moved to abusiness developmentrole. Dr. Devillerscurrently serves asAssociate Director,Business Development,Pump in thepharmaceutical divisionof Valois, where hisresponsibilities includebusiness developmentand marketing for theMultidose spray pumprange.

B I O G R A P H Y