T H E N A S A L S Y S T E M I C D R U G D E L I V E RY

AS AN ALTERNATIVE TO INJECTION

Back in the 1970s, a scientist and entrepreneur namedAlessandro Zaffaroni founded a company specialisingin drug delivery technology. One of its main platforms,

and most spectacular success stories, was the transdermalpatch: a new user-friendly route for administering drugs thatwould otherwise have to be given by injection.

Now it’s the turn of intranasal delivery, and this route canoffer similar prospects of commercial success to those whoinvest resources in developing it. This is the opinion ofProfessor Frans Merkus of the University of Leiden, who wasone of the participants at a unique workshop convened byValois, the French Drug Delivery Device expert specialising innasal delivery systems. The object of the workshop was toinvite discussion among experts on the intranasal route foradministration of drugs for systemic therapies.

A wide range of expertise – and an openagenda

The meeting represented a wide range of expertise in thedrug delivery field. The pharmaceutical industry was repre-sented by Greg Anderson and Margot Jones from GlaxoSmithKline; also Eric Chetaille from Servier. The medicoeco-nomic viewpoint was expressed by a managed care con-sultant, Gilles Bignolas; attitudes of the medical professionand the public towards nasal delivery were explored byAndy Fry, of Team Consulting. Apart from Prof Merkus, theviewpoint from academia was represented by Professor

Paolo Colombo,from the University ofParma.

The agendafor the workshopwas intentionallyopen, to encouragea free exchange ofopinions. Three gen-eral subject areaswere identified fordiscussion. First, what

therapies, now given by injection, are potential candidatesfor intranasal administration? Second, what are the limita-tions of the nasal route? And finally, participants were invitedto explore the future prospects and opportunities for nasaltherapies.

Opportunities

The meeting identified several types of drugs that areappropriate for intranasal administration; some are alreadybeing exploited, while others are potential opportunities.

VaccinesThere was general agreement that vaccines are ideal can-

didates for the nasal route. They can be self-administered,eliminating the need for injections given by health profes-sionals. For mass campaigns, vaccines could be supplied incheap, single-use nasal spray devices. A major advantage isthat accuracy of dose is not vital, as long as sufficient vac-cine is delivered to evoke an immune reaction.

Rapid route to the CNSThe workshop heard many examples of drugs which act on

the central nervous system and are good candidates forintranasal administration. They included anti-epilepsy agents,drugs for Parkinson’s disease; hypnotics, and drugs used inpain management, including migraine treatments andpatient-controlled analgesia for severe and/or chronic pain.An advantage of the nasal route for all of these indications isthat drugs given by this route can have a relatively rapidonset of action – usually within 30 minutes. The proximity ofthe olfactory bulb to the brain, with the possibility of directdiffusion of drug through the Blood Brain Barrier, was dis-cussed.

Prof Merkus gave the example of midazolam, when usedas “rescue” treatment in epilepsy. This provides immediatehelp to ward off an impending attack, but at present it mustbe given by injection, which requires the presence of ahealthcare professional. An intranasal formulation has beendeveloped which could offer an almost equally rapid-actingalternative; the patients could simply carry the devicearound in pocket or handbag, and a dose could be self-administered at the first signs of an attack.

Pulsatile deliveryEric Chetaille and Prof Colombo drew attention to the suit-

ability of the nasal route for pulsatile delivery of drugs.Sometimes, it is better to deliver a drug in timed pulses, ratherthan as an uninterrupted flow, as commonly occurs withtransdermal patches. HRT was mentioned as a specificinstance where pulsed delivery may be more effective andminimise side-effects.

Erectile dysfunction was cited as another condition appro-priate for nasal drug administration, possibly offering morerapid action than the oral route, and delivering a relativelyshort-acting bolus of drug when it is required.

Limitations and challenges

The main potential limitation for nasal delivery, identified byseveral speakers, is the chemical and physical nature of thedrug. Delivery of large molecules across the nasal mucosacan be problematical. Eric Chetaille pointed out that for anydrug with a molecular weight of more than 500 daltons, someform of active transport is likely to be required. Absorptionenhancers (for example, substances which temporarily“open” the mucosal barrier to the passage of large mole-cules) are one possible answer to this problem. However,those which have already been investigated tend to have

T IM E T O TA K E T HE NOSE SER IOUSLY

problems such as unaccaptable toxicity. There is amplescope here for research into better-tolerated absorptionenhancers.

For a drug which is not efficiently absorbed across thenasal mucosa (perhaps because of molecular size), there islikely to be wide variability in the proportion of a dose thatreaches the bloodstream. Prof Merkus gave the instance ofintranasal calcitonin,where amountsabsorbed can rangefrom 1% to 3% of theadministered dose.However, for a drugwhich is efficientlyabsorbed by this route,there is not likely to besignificant inter-individ-ual variation in the doseabsorbed.

Margot Jones high-lighted two other poten-tial drawbacks related to the nature of the drug: irritancy tothe nose, and unpleasant taste. Again, these depend on thecharacteristics of the individual drug; for some chemicalsthere is no taste or irritancy problem at all. And in some cir-cumstances, if the patient experiences a taste after a nasaladministration, it provides sensory confirmation that the dosehas been delivered.

Image and perceptionApart from problems which may arise because of the

physicochemical nature of the drug, another main chal-lenge identified by the meeting was the perception of nasaldelivery among the public and even the medical profession..Greg Anderson pointed out that the tablet is the “ultimatedelivery device”; people prefer taking tablets to puttingsomething up their noses. Nasal delivery is commonly associ-ated with administration of (illegal) recreational drugs, suchas snorting cocaine. This negative image is particularly impor-tant when considering the nasal route for administration ofdrugs in dry powder form – although a powder may be moreeffective than a liquid mist for reaching the olfactory bulb, asProf Colombo suggested.

Regulatory hurdlesOne of the challenges facing companies developing nasal

delivery formulations and devices is the regulatory process.Products for nasal delivery face more stringent regulatoryhurdles than, for example, simple injections, and this tends tohold back new developments in the nasal area, because itmakes the product development process longer and moreexpensive. Also, there is at present a lack of adequate models to testintranasal absorption before a formulation/device is devel-oped for clinical testing. Animal noses are too unlike human

noses to be useful as experimental models. There is a needfor fundamental research into the development of a “nasalmodel” that would give a realistic preview of the behaviourof a new nasal formulation in the human nose.

Profit and cost factors

Prof. Merkus described his own early experience inattempting to find a pharmaceutical company interested in

commercialising anintranasal form of VitaminB12 which he had devel-oped. A leading multina-tional company was notinterested because thepotential market (perni-cious anaemia) was notlarge enough. Smallercompanies were unableto afford the costsinvolved in clinical devel-opment and productionscale-up. The sameproblem was encoun-

tered when the anti-epileptic “rescue therapy” using mida-zolam was being developed. This illustrates a fundamentalbarrier to be overcome: even if the drug is appropriate fornasal delivery, economic factors may deter both large andsmall companies.

Future prospects and opportunities

Throughout the morning’s discussions, workshop partici-pants offered positive recommendations as a counterbal-ance to the problems and challenges which they identified,and they were positive, in some cases even enthusiastic,about future prospects for the nasal delivery route. Thesewere some of the specific points made:

• There are opportunities for improvement in the design ofnasal delivery devices. The device must deliver ade-quate quantities of drug deep into the nasal passages.Devices should be easy to use correctly.

• Device design should also communicate an image of“serious medicine”. Current devices often resemble thoseused to deliver locally-acting decongestants for coldsand rhinitis.Others are more like cosmetic delivery vehicles – oftenstreamlined and produced in bright or pastel colours. Adevice which aims to deliver a drug systemically for a seri-ous medical purpose should reflect this in its aestheticdesign.

• Planning for the device design should begin at an earlystage in product development; it should not be an “after-thought”. The drug, the formulation and the device are

all equally important parts of the whole.

• Formulation development will need to take the physicalcharacteristics of the device into account; factors suchas particle size and delivery vehicle will have a profoundeffect on the way the formulation behaves in the device.

• The physical design of the device itself will need to beadapted to its intended function. This should include suchconsiderations as whether the device is for use in an “ondemand” situation, or in a regular dosage schedule –which may be once or more times per day, or once aweek, or even once a month.

• Doctors, patients andpayers are also importantcontributors to theprocess of new productdevelopment, and theyshould have a role in theevolution of new nasaldelivery modalities. Infact the customers (doc-tor and patient) and pay-ers (health service, insurer,managed care provider)should be involved at anearly stage of new prod-uct design, so that theirexpectations can berecorded before the drugand formulation scientistsand device engineers arebriefed on the project.

• There is important educational, even missionary, work tobe done towards creating a positive image for nasaldelivery. The development of user friendly nasal devicescan be seen as a step towards greater patient empow-erment, and this is in line with current trends international-ly.

• One of the important aspects of nasal delivery, for theuser, is nomenclature. The word “device” should beavoided; it is too cold and mechanical. Similarly a phrasesuch as “dry powder inhaler” gives a negative impressionto an asthmatic patient, with its connotation that themedication will irritate his over-sensitive airways.Speakers suggested that the focus should be on thenose, or nasal delivery; or more radically on a new way ofgiving medical treatment.

• The cost factor must be confronted in communication

with payers. A nasal delivery product will cost more thana simple injection or tablet, partly because of the need todevelop a specific formulation, and partly because ofthe development and production of a delivery device.However, the increased cost of the product is usually off-set by the saving in professional time and in avoiding theneed to provide for safe disposal, as with an injectionsyringe. Any cost comparison must paint the full picture,not just a part of it.

• Major opportunities for nasal delivery include vaccines,especially influenza vaccine; migraine prophylaxis andtreatment; management of severe and/or chronic pain;

rescue treatment for epilep-sy; on-demand treatment oferectile dysfunction; themanagement of Parkinson’sdisease, and anticoagula-tion (LMW heparins).

• Companies focusing onnasal delivery should selectdrugs which are good candi-dates for this technology; thisis the best way to introducethe benefits of intranasaldelivery and generateacceptance among payersand customers. At present,molecular size and lipophilic-ity are limiting factors. Amajor opportunity is offeredby protein and peptidedelivery, but this will involve

fundamental work towards achieving delivery of large-molecule drugs.

• Here is no “one size fits all” in the field of nasal devices.Individual drugs each have their own physical and chem-ical characteristics; the needs of therapy are also specif-ic in terms of dosing schedules, speed and duration ofeffect, and so on. The sophisticated devices that hold thekey to the future of systemic delivery by the nasal routewill each be individually designed with specific goals inmind.

The right time …Greg Anderson pointed out that this was absolutely the

right time to be having the workshop. Prof Merkus agreed; hesaid the prospects for nasal delivery were extremely bright,and needed only the kind of commitment that AlessandroZaffaroni brought to the transdermal field thirty years ago.

www.valois.com

Founded in 1947, Valois SAS is a world leader in the design and manufacture of spray and delivery systems for the Pharmaceutical, Perfumery andCosmetics markets. Since 1993, Valois SAS has been part of the Aptar group, headquartered in Chicago (USA). Aptar is listed on the New York StockExchange.

Left to right : G. Anderson (GSK), G. Bignolas (Consultant - ManagedCare), P. Evers (Journalist), M. Jones (GSK), M. Baschet - Vernet(Pharmpack), D. Davoust (Valois), M.N. Bas (Parole & Cie),M. Lenegaret (Valois), G. Brouet (Valois), P. Carlotti (Valois),Pr. P. Colombo (University of Parma), A. Théodorakis (Valois), A. Fry(Team - Consulting), Pr. F. Merkus (University of Leiden), J.M. Pardonge(Valois), E. Chetaille (Servier), G. Devillers (Valois).