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DRUGDELIVERY

NOVEMBER 2006

• Exubera: sparking a revolution

• New drug, new delivery system?

• Paediatric drug delivery: challenges and rewards

featuring the official preview of

Scrip Drug Delivery v16 22/11/06 1:56 PM

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Features 5 An industry evolving

2006 has seen many developments in the drugdelivery sector. Elizabeth Cairns gives us the highlights

6 Transforming potential for difficult drugsPeter Knight provides an update on drug delivery’slatest innovations

9 Paediatric regulation: reasons to beproactiveThe Regulation on Medicinal Products for PaediatricUse will create opportunities for drug deliverycompanies, says Jane Lamprill

12 A revolution in waitingHas Exubera opened up a world of possibilities forpulmonary drug delivery? Sylvia M Findlay reports

Head to Head15 “Should a new drug be launched in a new

delivery system?”In Scrip’s first Head to Head discussion, PaulColthorpe, William McVicar and James Stefely findsome answers to this difficult question

Official PreviewDrug Delivery Partnerships

23 Welcome to Drug Delivery Partnerships2007! Miriam Glick outlines the highlights of the world’slargest drug delivery and specialty pharmaceuticalevent

25 “Tremendous diversity in types of devices”Donna French talks up the potential for injectiondevices in the administration of biopharmaceuticals

26 “Companies wait too long to seek a Europeanpartner”Peter M Stein tells us the advantages of forgingtransatlantic drug delivery partnerships

27 “Push pricing research earlier indevelopment”We speak to Allen Downs about the challenges ofdealmaking in drug delivery technologies

28 Drug Delivery Partnerships in EuropeTahira Rashid tells us about DDP’s Europeancounterpart

CONTENTS

DRUG DELIVERYA supplement to Scrip World Pharmaceutical Newsin conjunction with Drug Delivery Partnerships & Target World Drug Delivery NewsEditorial: Jenefer Trevena – [email protected]

Pete Chan – [email protected] Charlish – [email protected]

Sales: Paul Thoroughgood – [email protected]: Lee Spencer – [email protected]

Head office: Informa Healthcare, Telephone House, 69-77 Paul Street, London, EC2A 4LQ, UKTel: +44 (0)20 7017 5000© Informa UK Ltd 2006All rights reserved. Full terms and conditions available on request. Printed by Burlington Press, Foxton, Cambridge, CB2 6SW

The views expressed in this supplement are those of the authors but notnecessarily those of Scrip. While information is compiled with all due care,Informa UK Ltd will not be liable for the consequences of anyone actingor refraining from acting in reliance on any information.

Supported by:

technologiesdbv

Industry focus30 Small-tech – big potential

Paul V Breen updates us on the benefitsnanotechnology gives to lifecycle managementstrategies

32 Coatings for protectionMicro-encapsulation technology offers manyadvantages over traditional techniques, says Dr Abdul Majid

35 Market trends: self-injection devicesIan Thompson explores the past, present and futureof self-injection technology

39 Product focus: The E-patchA guide to the properties and benefits of theseunique cutaneous drug delivery patches

41 COMPANY PROFILES

www.scripsupplements.com www.drugdeliverypartnerships.com www.drugdeliverynews.com


www.target-news.com CS5733


Drug Delivery 5

Introduction

2006 finds the drug delivery industry at a veryinteresting point in its evolution.Withextended-release drug formulations wellestablished in the market, and the first productsutilising nanotechnology beginning to makeinroads and prove profitable, the risk alwaysassociated with novel delivery techniques hasproved to be well worth taking.This year’sapproval of Pfizer’s Exubera sent shockwavesthrough not only the drug delivery sector butthe wider pharmaceutical arena, anddemonstrated that concepts long consideredunfeasible can indeed be realised.

Drug delivery is often thought to be focusedon convenience – where drug developmentcompanies create new drugs to cure fataldiseases, drug delivery simply means allowingrich, developed-world patients to take one pillper day rather than three.This is manifestlyfalse; innovative techniques allow solubilisationof erstwhile useless drugs, or successful deliveryof a molecule to its target tissue wherepreviously it had been eliminated by first-passmetabolism.

Patient benefitsDrug delivery also permits therapies to betailored to specific types of patient.As JaneLamprill points out in her article on page 9,taste-masking technology can be employed tocater to paediatric patients who must take theirdrugs orally but dislike its flavour (this alsomakes the job of administering the medicine,whether by a healthcare professional or aparent, much easier). Buccal delivery isparticularly appropriate for patients who areunable to swallow, and encapsulation ofbiologics can eliminate the need for longintravenous infusions, freeing up hospital bedsand saving money.

The success of the sector cannot beattributed to innovation in delivery alone.Themajority of 2006’s most noteworthy productsare the result of partnerships. Exubera is a casein point; Nektar Therapeutics invented the

inhaler and powder formulation, but theproduct would not have reached market nearlyso rapidly had it not been backed by the might– and the money – of Pfizer. However, theincreasing tendency of pharma and biotechfirms to merge, forming fewer, larger,companies, reduces the number of potentialpartners (see the article written by PeterKnight on page 6).The resulting giantcompanies are as likely to acquire a whole firmas they are to broker a licensing agreement fora single technology.

The mergers and acquisitions of recent yearshave changed the landscape considerably.Pfizer’s buyout of private companyPowderMed gave credence to the UK firm’stechnology – a needle-free DNA injectiondevice involving microscopic particles of puregold.This technique, though esoteric, has greatpotential, particularly for the delivery of DNAvaccines against pandemic influenza.

Vectura’s forthcoming acquisition ofInnovata in a deal worth nearly £130million(US$246million) is another example of thebenefits of consolidation.As both companiesspecialise in respiratory drugs, the merger notonly creates a broader pipeline of products inclinical development, and the cash resources toprogress their development, but also goes someway towards eliminating competition. It willalso allow only the best drugs in the extendedpipeline to reach market, further benefitingpatients.

Naturally, this trend towards consolidationought to mean that successive mergers reducethe number of firms involved in drug deliveryuntil one vast conglomerate dominates themarket. Clearly this has not happened, and it ishighly unlikely that it ever will.This is becauseof the ceaseless activity at the other end ofcorporate development: the formation of newcompanies.

Start-ups tend to begin life as a means ofdeveloping a novel technology. Often spun outof larger companies or universities where the

technique was developed, usually by only oneor two individuals, these firms must provetheir products’ efficacy before initiatingfunding rounds or partnerships. It’s a riskybusiness, but the sheer number of new drugdelivery start-ups appearing every year is atestament to the relative ease of entering thismarket.

Maximising profitsIndeed, drug delivery is, of its nature, rather lessrisky than drug development. Developing anew pharmaceutical is hugely expensive andthe risk of failure is high.A delivery orformulation technology, by comparison, ismuch cheaper to develop and enables theincreased use of already established drugs. Drugdelivery techniques have long been used forpharmaceutical lifecycle management,maximising profits from molecules developedat great expense. Now this innovation is beingused to benefit patients as well as shareholders,widening the uses to which established drugscan be put.The industry is evolving before oureyes; the only constant is the extraordinaryimagination and innovation demonstrated bydrug delivery professionals.

Elizabeth Cairns is editor of Target World Drug

Delivery News. She is based in London, UK.

An industry evolvingElizabeth Cairns casts an eye over 2006’s drug delivery

landscape and discovers there’s no such thing as the

norm in this innovative industry


www.scripsupplements.com6

New technologies

Getting a drug delivery form right is almost asimportant as the active ingredient itself. Studiessuggest that one in ten marketed drugs havesolubility problems and almost a third fail toreach profitability due to poor bioavailabilityor pharmacokinetics.Accordingly, it is notsurprising that drug delivery technologies havebeen widely adopted by the pharma industryas a powerful element of lifecycle managementstrategies, and by specialty pharmaceuticalcompanies to reinvigorate off-patentcompounds.

Many early drug delivery technologies, suchas controlled release products and transdermalpatches, are rapidly becoming commoditised.But the advent of hard-to-deliver biologics(peptides, proteins and DNA/RNA-baseddrugs), the discovery that many drugs showimproved efficacy with controlled releasecompared with conventional burst releasetechniques, and recognition of the benefits oftargeted delivery of certain drugs (for example,chemotherapeutics) is now driving theevolution of a new generation of drug deliverytechnologies.Advocates hope that by solvingthe delivery problems of new drug classes,these technologies will become an intrinsicpart of drug discovery and development, ratherthan a retrospective refit to increase the lifespanof old drugs.

NanoparticlesHyped in healthcare for the past decade,nanomedicines are finally reaching the marketin the form of nanotechnology-based drugdelivery products.The earliest of these addressthe fundamental issue of solubility byformulating the drug as nanocrystals, whoselarge surface area enhances solubility.

The leader in this area is Elan, whoseNanoCrystal technology employs a proprietarywet-milling technique in aqueous solution toproduce drug nanocrystals; crucially, the presence

of a stabiliser inhibits particle aggregation.Theresulting colloidal dispersion can be processedinto multiple dosage forms, solid or liquid.

There are already four approved drugproducts in the US that use the NanoCrystaltechnology:Wyeth’s Rapamune (sirolimus)tablets,Abbott’s TriCor (fenofibrate) tablets,Merck’s Emend (aprepitant) capsules and ParPharmaceutical’s Megace ES (megestrol) oralsuspension. Furthermore, both Johnson &Johnson and Roche have licensed thetechnology; the former is in Phase IIIdevelopment of a long-acting NanoCrystalreformulation of its schizophrenia therapy,paliperidone palmitate.

Competing methods for producingpharmaceutical nanocrystals includehomogenisation in aqueous solution(SkyePharma’s Insoluble Drug Delivery (IDD),Baxter’s NanoEdge platforms), andhomogenisation in non-aqueous solution(PharmaSol’s Nanopure platform); all of theserequire the presence of stabilisers to reduceparticle aggregation.

SkyePharma has launched an IDD-basedfenofibrate drug,Triglide, which competesdirectly with Abbott’s TriCor. Using a similartechnique,Abraxis BioScience’s technologycreates an albumin-stabilised nanoparticleformulation of the poorly soluble chemotherapydrug, paclitaxel, by homogenising crystals of thedrug in a solution of human serum albumin.The product, branded Abraxane, is approved inthe US as second-line therapy for breast cancer,and in Canada for metastatic breast cancer.Nanoparticle technology is particularly suitablefor use as part of a lifecycle managementstrategy, since it can be retrospectively applied toalready marketed drugs.

Lipid-based emulsionsMicellar nanoparticle technology takes thenanoparticle concept a step further, forming a

lipid-based colloidal emulsion in which thedrug is distributed in various forms: asnanocrystals/nanoparticles, in solution form inthe lipid phase, or associated with micelles.Micellar nanoparticles not only solubiliseinsoluble drugs, but the multi-phasic drugdistribution means the active ingredient ispresent in a readily available solution form aswell as a long-acting particulate depot form,useful for sustained drug release. In addition,the formulation is well suited for transdermaldrug delivery.

Novavax has applied the technology tohormone replacement therapy, with anoestrogen-containing micellar nanoparticleproduct, Estrasorb (estradiol), approved by theUS FDA.The company is also applying thetechnology to a range of other small moleculedrugs. Other companies are not far behind:NanoBio Corporation is developing its similarNanoStat micellar nanoparticle technology asan anti-infectives platform, with treatments forherpes virus, shingles and onchomyosis in theclinic, and plans to adapt the approach for thenasal delivery of vaccines.

DendrimersOther nano-scale drug delivery technologiesare at an earlier stage of development, andinclude pioneering concepts such as quantumdots and nanospheres.Among these, dendrimertechnology holds particular promise.Dendrimers are globular macromolecules,constructed in a step-wise fashion frommonomers radiating from a central core, toform a three-dimensional framework ofpredictable size and surface chemistry. Largedendrimers can encapsulate poorly solubledrugs, forming a depot for sustained release.Avariety of ligands can theoretically be attachedto each chain of the dendrimer, which opensup the possibility of targeted drug deliveryusing these macromolecules.

Transforming potentialfor difficult drugsAs the hype gives way to the first wave of marketed nanomedicines, Dr Peter Knight

reviews some of the hottest areas of innovation in drug delivery technology


Drug Delivery 7

New technologies

The Michigan NanotechnologyInstitute for Medicine andBiological Sciences (M-NIMBS) isa leading force in dendrimerresearch, and has already created acatalogue of dendrimers. However,its ultimate goal is thedevelopment of multi-functionaldendrimers that can recognisemalignant cells (via cancer-specificcell surface markers), deliver atoxic drug, and monitor and reportcell death via an attached imagingagent – a true ‘magic bullet’.

Other companies havedendrimers already in clinicaltrials. Starpharma and DendriticNanoTechnologies are developingVivaGel, a water-based topical gelcontaining a dendrimer modifiedto bind to and block the receptorsites for a variety of viruses.Thecandidate has shown promise inclinical trials aimed at preventingthe transmission of HIV andherpes viruses.

Dendrimers appear to haveenviable functional flexibility andconsiderable promise for drugdelivery, but remain some way from themarket.Aside from the technical barriers, twosignificant hurdles that remain are theestablishment of reproducible manufacturingprocesses, and the need for regulatory bodiessuch as the FDA and the European MedicinesAgency (EMEA) to develop approvalprocedures to deal with these novelnanodevices.

BiosiliconAn Australian company, pSivida, has developedBioSilicon as a platform for the controlledrelease of drugs for a wide range of clinicalapplications.The company nanoengineerselemental silicon to form a porous honeycombstructure that can be loaded with drugs,including proteins and nucleic acids. Byvarying properties such as particle and poresize, BioSilicon can be made biodegradable,and drug release rates can be tailored to aperiod varying from hours to months.Thislatter property makes BioSilicon valuable as along-term drug depot.As its first commercialproduct, pSivida is developing BrachySil, animplantable brachytherapy device composed ofBioSilicon loaded with radioactive elementsthat is injected directly into the tumour.BrachySil has successfully completed a Phase IItrial in patients with inoperable liver cancer.

Timed release technologiesFor orally-administered drugs, controlledrelease has several benefits over conventionalbatch release: reduction in drug blood levelfluctuation, reduction in local or systemic side-effects and better patient compliance. However,there is growing recognition that constant drugrelease is imperfect in many circumstances. Forexample, the symptoms of rheumatoid arthritisare often at their worst upon waking, butcommon anti-inflammatory medications suchas ibuprofen need 4-6 hours fromadministration to be maximally effective, andtheir effect tails off thereafter.This window ofactivity is sub-optimal from a dosingperspective – unless a time delay can be builtinto drug release.

To meet this need, the Danish companyEgalet has developed an oral tablet that relieson erosion rather than diffusion to controldelivery. Egalet tablets consist of animpermeable shell enclosing a matrix.Thematrix contains the active drug, and is surface-erodible, hydrophobic and composed ofpolyethylene glycol (PEG)-stearate. Bychanging the properties of the matrix, Egalethas developed a constant release system, and aburst release system with a predetermineddelay. Burst release is achieved by closing the

ends of the tablet withbiodegradable plugs, whosecomposition and length thendetermine the time lag before theactive ingredient is exposed anddelivered.The formulation can beused for virtually any type of drugand, unlike water soluble diffusiontechnology, it is not affected bythe pH of the body fluid it comesin contact with. Egalet isemploying its eponymous tabletsto advance products in varioustherapy areas: two are enteringPhase III studies for hypertensionand pain management.

Delivery of biomoleculesPeptide, protein and DNAtherapeutics represent anincreasingly important group ofnew drug entities. But biologicsare far less robust than smallmolecule drugs when taken orally,being quickly digested in thestomach with most never reachingthe bloodstream. Consequently,most are delivered by injection orinfusion, neither of which is

popular with patients. New technologies areproviding alternative delivery routes, such aspulmonary, intranasal and transdermal, as wellas new approaches to oral delivery.

The challenges of delivering biomoleculesorally extend beyond survival of the drug inthe gastrointestinal (GI) tract, and encompasspassage through the intestinal wall. EmisphereTechnologies has developed its Eligentechnology to address this issue.The platformrelies on low molecular weight compounds,dubbed drug delivery agents or carriers, whichform a complex with a target protein,increasing its lipophilicity and thereby itsability to cross the gastrointestinal epitheliumusing the body’s natural passive transcellulartransport process.The company has establisheda library of delivery agents with varyingproperties, applicable to a wide range of drugs.Emisphere is applying its technology to theoral delivery of peptides including heparin,insulin, salmon calcitonin and human growthhormone. Its lead candidate, heparin, hassuccessfully completed Phase II trials.

Earlier patch-based transdermal deliverysystems deliver hydrophobic small moleculesacross the epithelium by passive diffusion, butare generally less suited to large moleculebiologics. Several companies are developingadvanced, active transdermal delivery systems

Technology

M

Selected novel drug delivery technologies



New technologies

PHARMACEUTICALINNOVATORS

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Person to contact Gerben Moolhuizen Chief Business Officer

OctoPlus N.V.Zernikedreef 12 2333 CL Leiden, the NetherlandsTelephone +31(0)71 524 40 44Fax +31(0)71 524 40 43www.octoplus.nl

Drug deliveryOctoPlus has developed proprietary drug delivery technologies that facilitate the parenteral controlled release of biologically active compounds:

OctoDEX™PolyActive™SynBiosys™

Contract pharmaceutical development and manufacturingOctoPlus offers pharmaceutical development of conventional and biotech- derived pharmaceuticals on a fee-for-service base. We are globally recognized as a center of excellence in formulation development, analytical services and small scale cGMP manufacturing.

which potentiate the delivery of largermolecules, including biologic drugs.AlteaTherapeutics’ skin microporation technologyuses a short electrical pulse to heat metallicfilaments that painlessly ablate the skin andfacilitate delivery of drugs into thebloodstream.TransPharma Medical’s ViaDermplatform uses radio-frequency current to openmicropores in the skin. Both technologiesrequire the use of small handheld devices toopen the pores, after which a patch-like drugreservoir is placed on the skin allowing largehydrophilic molecules, including proteins suchas insulin, to diffuse into the blood.

Changing business strategiesThe traditional ‘pure play’ drug deliverybusiness model follows a pattern common tomost biotech platform technologies: that ofselling improved productivity to big pharma,and signing non-exclusive licensing deals withmultiple companies to generate revenue. Butconsolidation in the pharma industry hasreduced the number of potential partners.Furthermore, increasing competition almost

inevitably results in the eventualcommoditisation of any technology platform, afact not lost on investors and shareholders.As aconsequence, many drug delivery companiesare now transitioning from technologylicensing towards product development andmarketing – they are becoming specialtypharmaceutical companies in their own right.

Attitudes to drug delivery vary widelywithin the pharma industry.While manycompanies have embraced the technology as akey aspect of their lifecycle managementstrategies, fewer have adopted it as an integralpart of the entire drug development process,starting as early as molecule discovery.Anotable exception to this is Johnson & Johnsonwith its landmark 2001 acquisition of Alza, adrug delivery expert.This has resulted in drugdelivery technology permeating many aspectsof Johnson & Johnson’s R&D operations. Butperhaps the biggest opportunity for novel drugdelivery technologies lies with the biotechindustry, the products of which are lessamenable to traditional delivery routesmeaning companies are inherently more

willing to experiment with non-validatedapproaches.

Drug delivery is a rapidly evolving and evermore competitive sector. Novel technologiesunder development or recently introduced tothe market are increasingly sophisticated, andare addressing many of the problems that candecimate early-stage discovery (solubility,permeability), reduce drug efficacy(timed/continuous release) or place pressure onmedical resources (injections/infusions).Andtechnologies are increasingly multifaceted,combining solutions to different deliveryproblems – witness the promise of dendrimers.A common goal is the development of self-administered, targeted, sustained-or-variablerelease methods with increased bioavailability, agold standard for future advances.Without thedevelopment of these new drug deliverytechnologies, new therapeutic advances maywell fail to fulfil their potential.

Dr Peter Knight is principal analyst and

biotechnology research manager at Wood

Mackenzie. He is based in Edinburgh, UK.


Drug Delivery 9

Drug delivery to children

The European Medicines Agency has beengiven considerable legal powers by theEuropean Commission to mandate and rewardcompanies for paediatric data. By beingproactive, the pharma industry can takeadvantage of this golden opportunity to berewarded for developing paediatric medicinesand contribute greatly to improved childhealth. However, companies that are notproactive and fail to comply with theregulation will be unable to submit theirMarketing Authorisation Applications for the adult drug and thus lose out tocompetitors.

Reasons for the regulationPublication of the proposed paediatricregulation in the EU’s Official Journal ispending at the time of writing, but objectivesare to:◆ Increase the development of medicines for

use in children.◆ Ensure that medicines used to treat children

are subject to high quality research.◆ Ensure that medicines used to treat children

are appropriately authorised for use in thesepatients.

◆ Improve the information available on the useof medicines in children.

◆ Achieve these objectives without subjectingchildren to unnecessary clinical trials and infull compliance with the EuropeanCommunity (EC) legislation on clinical

trials, namely Directive 2001/20/EC.◆ Not to delay the authorisation of the adult

drug.Sick children are very vulnerable. Most ofthem don’t like needles or bitter tastes, findtablets hard to swallow and young childrenmay need to be restrained for medicationdelivery.They may not understand the causeand effect of unpleasant medicine bringingbenefit. Hence babies and children needmedicines that are easy to administer and withminimal stress if current and future dosing is tobe effective.

There is an urgent need not only formedicines to be tested on children and licensedfor paediatric age groups at the optimum dosefor safety and efficacy, but for those drugs to bein suitable, stable formulations that are easy togive. Current efforts by hospital staff andparents to administer paediatric doses ofteninvolve the untested extemporaneous alterationof adult medicines, for example, crushing oftablets or cutting of suppositories in half in thehope of a 50% dose, although how much drugis in which ‘half ’ is unknown.

Children and babies given medicines in thisway could be under or overdosed, sometimeswith catastrophic consequences. Drug deliverycan also be problematic with decimal pointcalculation errors.A French boy died in 2004from a ten-fold overdose of morphine afterroutine surgery because the formulation wasdifficult to calculate for smaller doses.

The challenges of being proactiveEasier paediatric drug delivery is a tall orderand, interestingly, the challenges involved aresimilar to those faced by the veterinary sector –smaller market, high cost of developinginnovative technologies and the potentiallylong period before product profitability. It is ahigh-wire balancing act for shareholders andthe cost to member state healthcare providersmust be competitive to attract sales.

Tastes and cultural acceptability of differentformulations and routes of administration canvary around the world which makes designinga palatable global solution problematic. Mostimportantly, there are safety and ethicalchallenges involved in testing medicines onchildren. Recruitment usually takes longer andthe costs are higher than for adult trials.

On the plus side, the new PaediatricRegulation will soon be law and will reward

Paediatric regulation:reasons to be proactiveThe Regulation on Medicinal Products for Paediatric Use will

revolutionise the European drug development process and

increase the number of medicines available for children.

Why will companies have to take a proactive approach?

Jane Lamprill reports




companies for producing paediatric data.Therewill also be a substantial market of around 105million children in January 2007, whenRomania and Bulgaria join the EU. Spin-offproducts and further sales can be generated ifnew paediatric drug delivery mechanisms areadapted for the elderly and/or disabled patients.Novel technologies and better formulations foreasier drug delivery will improve child health,increase sales and can lengthen drug lifecycles inthe face of generic company competition.

Lessons from the veterinary sectorReducing drug delivery distress in animals andchildren involves giving drugs less often andwith less pain. For example, sustained releaseand needle-free technologies could work wellin both settings, especially as some companiesmake medicines for both.

In the sustained release field, the US companyPR Pharmaceuticals’TheraPhase technologydelivers livestock growth promoter using onesubcutaneous injection every five months.Thedelivered molecules of biodegradable polymerchange into active drug over time.This raises thequestion – could this system be adapted, withdifferent drugs, to reduce the frequency ofinjections in serious paediatric disease?

Bioject Medical Technologies, another USfirm, has a needle-free injection system,Vitaject, which has been modified for the

animal health company Merial to deliverinsulin to dogs and cats.A similar system couldspare children the more intense pain ofinjections, reduce fear of needles and abolishthe risk of needlestick injury.

Current therapeutic needThe European Medicines Agency (EMEA) hasestablished a paediatric expert group to drawup priority lists of medicines that need asuitable dosage, formulation or better methodof drug delivery in the neonatal and paediatricpopulations. In addition the UK medicinesregulator, the MHRA, initiated a voluntaryrequest for information from companies aboutpaediatric data already held.The agency haspublished a ‘top 20’ list of drugs that it thinksrequire a better paediatric formulation to avoidextemporaneous and untested usage.

There is also a lack of suitable medicationsfor terminally-ill children. Paediatricians haveto be creative in managing distressingsymptoms such as severe pain and nausea. Forexample, buprenorphine is available inpotentially child-friendly slow release dermalpatches for severe pain. However it requirescutting into 1/36th-size portions for babiesbecause a paediatric dose is not available. Drugdistribution may vary throughout the patch andlead to breakthrough pain.

Paediatric pharmacists were recently asked to

draw up a palliative care ‘wish list’ (see Figure1).As companies will now be compensated forthe financial outlay of developing specialistpaediatric medicines, the opportunity toaddress the pharmacological needs of the dyingor very sick child has never been greater.

US regulatory experienceOver in the US, legislation covering children isalready in place, particularly the US FDA BestPharmaceuticals for Children Act (2002) andthe Pediatric Research Equity Act (2003).These both mandate (by written request) andreward companies for the inclusion ofpaediatric data as part of new drug andbiological licence applications.To date, thepaediatric exclusivity reward, effectively a six-month patent extension, has been granted to126 products representing a significant increasein return on investment and benefit tocompanies’ shareholders. However, uncertaintimes are ahead as the incentive ‘sunsets’ in2007.This will mean a revision of thelegislation and the reward extension is notguaranteed.

However, results to date are impressive.TheFDA’s Dr Murray Lumpkin stated at the recentEuropean Forum for Good Clinical Practicemeeting in Brussels that there have beenpaediatric informational label changes on 114products, 22 dosing recommendations, 24

Severe pain MST continus 20mg, 30mg, 60mg, 5 mg, 10mg Oral Smaller doses are needed. Accuracysuspension 100mg, 200mg is not possible below 20mg because

granules; Oral it does not provide uniformity of suspension for fractionating to smallerdoses.

Nausea Cyclizine 50mg tablets, Liquid, e.g. Oral Currently, splitting tablets provides50mg/ml injection 25mgs in 5mls very inaccurate doses.

Nausea Levomepromazine 25mg tablets, Liquid, Oral Not available at present, so25mg/ml injection e.g. 5mg/5ml suspension pharmacies have to make up their

own despite minimal data on stabilityand no information on bioavailability. Short-dated preparation requiresextra trips to hospitals for parents topick up solution.

Excessive Hyoscine 1mg/72 hours; 0.25mg, 0.5mg Dermal patch Accuracy of dosing for bettersecretions hydrobromide Transdermal patch symptom management. Currently,

1mg patches are cut into quarters.

Intestinal Hyoscine 10 mg tablets, 10mg/5ml Oral solution Currently, injection solution is given colic butylbromide 20mgs/ml injection orally. Parents have to snap open

glass ampoules then strain through a filter straw to ensure no glass particles are administered.

Symptom Drug Current dose; route Desired dose Desired route Reasonof administration

Palliative care wish list

Source: Author request from Pharmacy Department, Royal Liverpool Children’s NHS Trust, UK

Figure 1: The inaccuracy of current drug delivery for serious symptom relief is a strong justification for companies to develop paediatric formulations of drugs for use

in very sick and terminally-ill children.


Drug Delivery 11


enhanced safety instructions, 63 age groupexpansions and ten new paediatricformulations. Interestingly safety and efficacywere not established in 21 products, which is ofcritical importance to paediatric prescribing.Asa result of 323 written requests, 732 paediatricclinical trials will be/are being performed,requiring an estimated 43,427 child researchparticipants.

The FDA and EMEA’s confidentialityagreement means that information on writtenrequests is shared, so presumably children willnot be exposed to a study drug by the samecompany in repeat clinical trials just to receivethe European reward.These are complex issues,which will be made clearer next year when theEMEA’s new Paediatric Committee (PC) is inplace.

Get proactive!The EMEA’s new Paediatric Committee willbe given extensive powers. It will give freescientific advice and review the timing andcontent of flexible Paediatric InvestigationPlans (PIPs) that outline planned paediatricresearch.They will also instigate and maintainan inventory of paediatric therapeutic need inconsultation with the EC, member states andother interested parties, such as patient groups.Companies will find this list a useful businessdevelopment tool.

The agreed PIP and results must be providedwith every new drug in order to obtain theMarketing Authorisation Application (MAA).Current timing of the plan (not the research) isthe end of Phase I to encourage early dialoguebetween industry and the PC and to preventpossible delay of the MAA. However, this maybe problematic if, for example, Phase I andPhase II trials overlap or if companies haveinsufficient data at the end of Phase I so adeferral may be necessary. If a drug is only foradults, such as for prostatic hypertrophy, then awaiver of paediatric data is appropriate.However this is flexible too if a paediatricindication is found at a later date.

The PC will scrutinise the PIPs not only forscientific integrity but for paediatric clinicalbenefit. If the PIP is purely for financial gain,for example if there is already a similarmarketed medicine, the committee will rejectthe PIP and the reward will not be given as itwould be unethical to duplicate paediatricclinical trials. Companies will therefore beincentivised to produce easy routes ofadministration, new palatable paediatricformulations or more suitable dosing to reducethe risk of medication errors.

The rewards of taking action include:

◆ A six-month extension to the supplementaryprotection certificate (SPC) for new drugswhen all the required criteria for paediatricdata, authorisation and labelling have beenmet.There will be a transition phase andsome drugs, such as those for HIV, may nothave SPCs and this is currently under review.

◆ Companies will receive the reward for“significant” studies even if the outcome isnegative for paediatric therapeutic benefit incertain age groups.

◆ A new optional Paediatric Use MarketingAuthorisation (PUMA) for off-patentmedicines will enjoy a reduced authorisationfee, ten years of data protection andpermission to continue brand namerecognition.This will be useful for lineextensions for drugs nearing the end of theirpatent and for the generics industry.

◆ Orphan drugs, when tested for a paediatricindication, will receive 10+2 years’ marketexclusivity.

Pharmaceutical innovationsIn the Autumn/Winter 2005 Drug DeliveryReport from PharmaVentures, Dr CatherineTuleu, a paediatric formulation expert at theSchool of Pharmacy, University of London,maintains that the ideal medicines for childrenshould be efficacious, tailored, tolerable,convenient to give and dispense, good qualityand safe, as should their routes ofadministration.They should be easy to give forincreased compliance and excipients should bechosen with care, she says. Extemporaneousmethodology should also be tested forbioavailability, stability, safety and efficacy.

Innovative drug delivery approaches in thepaediatric sector include:◆ “Sip” technology, developed by Grünenthal

of Germany, uses the drinking straw principleenabling a liquid permeable ‘controller’,which draws up tiny dissolvable drug granulescontained in the straw and indicates when alldrug is taken. It comes predosed and isneutral tasting so the drug can be sucked upwith the child’s favourite drink.

◆ Captopril liquid, which can be used toreduce hypertension and therefore kidneydamage in children awaiting renal transplant,has been formulated by the UK’s SpecialProducts Ltd with a long half-life to enableonce-daily dosing and a raspberry flavour toincrease compliance.

◆ Epistat, also made by Special Products, isspecial order unlicensed midazolam,administered buccally while a child is fitting.It is fast-acting, can be given when teeth areclenched, and avoids the complexity and

indignity of the rectal route of delivery.◆ Chewing gum is proven to be acceptable to

older children. It hides bitter tastes, can betaken anywhere without water and isconvenient and discrete. Drugs impregnatedinto gum can be hydrophilic or lipophilic andhave included fluoride against tooth decay anddymenhydrenate to prevent travel sickness.Interestingly, the MHRA announced inDecember 2005 an initiative to help preventthe morbidity and mortality associated withearly addiction to cigarette smoking. Nicotinereplacement therapy can now be given tochildren aged 12 years and above for up to 12weeks, in a counselling context.

◆ The EMEA’s reflection paper on paediatricformulations mentions some current non-invasive drug delivery techniques: paediatricanaesthesia uses S-ketamine and patient-controlled intranasal analgesia is beinginvestigated. Intranasal diamorphine is usedfor pain relief following trauma anddesmopressin and some vaccines can also begiven via this route.

◆ Other products under development includemelts, lyophilised wafers, oral strips, minitablets, beads, granules and minimicrospheres.

Europe’s new paediatric regulation willrevolutionise not only medicines for childrenbut the whole European drug developmentprocess. Companies will need supportiveshareholders as it will be an expensive andprecarious challenge, fraught with ethical andpractical difficulties. It remains to be seen howthis will work in practice.Those companies thatare proactive and seek to meet the clinicalneeds of children with innovative and easy togive drug delivery will surely be rewarded.

Jane Lamprill is a paediatric research consultant

based near Oxford, UK. She advises companies on

the practical, ethical and management aspects of

paediatric clinical trials.



Pulmonary delivery

Venturing into an era of advanced pulmonarydelivery, the healthcare community is awaitinga revolution in drug delivery technology.Thetrigger has been the approvals in early 2006, inboth the US and Europe, of Pfizer’s inhaledinsulin Exubera.This represents an importantmilestone in the treatment of systemic diseasesthrough pulmonary delivery and has openedup a whole world of possibilities for thedelivery of drugs to the deep lung.As such, itis all set to revolutionise the drug deliverymarket.

Other key factors driving drug developersto move towards pulmonary delivery, and tomaximise the potential for this market, includemounting pressure on the pharma industry tocut R&D costs, technological advancements,increasing unmet medical needs, dissatisfactionwith current therapies and the need forpharma companies to stay ahead of theircompetitors. In the case of insulin in diabetesmanagement, the end-users have also becomepart of the equation in the sense that morechallenging customer requirements areshaping the trajectory of this market growthcurve.

It is estimated that 15-20% of therapeuticsare administered through the lungs andpulmonary drug delivery is one of the fastestgrowing markets. In fact, the market is likely togrow from US$13billion today up toUS$20billion by 2012. In parallel, increasedattention is being showered on systemic drugs.

The playersThe economic benefits offered by thepulmonary mechanism of delivery includelower R&D costs and higher return oninvestment as the development of a pulmonarydrug delivery product consumes onlyUS$50million compared with aroundUS$900million in the case of researching anew chemical entity. So going forward, thismarket is set to attract a large number ofpartnership deals. In addition, the constantinflux of new protein and peptide drugs fromthe biotech industry is creating a demand fornovel devices that can deliver thesetherapeutics through the pulmonary route.Thisis opening up avenues for major alliances andM&As between pharma and biotechcompanies and device manufacturers.

Pfizer and Nektar Therapeutics, the UScompany that developed the dry powderformulation in Exubera and the device used todeliver the drug, may be the first movers in theinhaled insulin segment, but interest in thisfield has been such that a host of other pharmaand biotech companies have teamed up toexplore this new arena.

Some of the companies in pursuit of insulininhalation devices follow.◆ Novo Nordisk collaborated with Aradigm

in 1998 on the development andcommercialisation of the AERx inhaledinsulin system, currently in Phase III trials.

◆ Lilly and Alkermes are partnered in thedevelopment of AIR insulin, which enteredPhase III trials in 2005.

◆ Mannkind is developing Technosphere, a drypowder formulation also in Phase III trials.

◆ Kos Pharmaceuticals (Abbott) is developinga line of inhalation devices for the deliveryof large and small molecules. It is alsoworking on inhaled insulin.

◆ BioSante Pharmaceuticals is developingBioAir.

◆ Epic Therapeutics, a subsidiary of BaxterHealthcare, is working on ProMaxxmicrospheres for the pulmonary delivery ofproteins.

The approval of an inhalable

formulation of insulin has

helped remove some of the

convenience and compliance

hurdles in the treatment

regimen of insulin-dependent

diabetics. So is the market

about to be flooded by other

drugs delivered via the

pulmonary route?

Sylvia M Findlay reports

A revolution in waiting

◆ Long-term safety concerns◆ Premium pricing◆ Reimbursement issues◆ Lack of regulatory

guidelines/standardisation fordevice performance

◆ Consistent dosing performance isstill an issue

Industry challenges in pulmonary drug delivery


Although most pipelines at present featuredrug candidates born out of licensing deals orstrategic alliances, the future is more in favourof companies licensing novel drug deliverytechnologies. Going forward, the primary aimof such activity will be to create in-housecapabilities in a range of technologies, not justpulmonary delivery. Elan, for instance,transformed from a drug delivery companyinto a specialty pharma firm mainly throughvarious M&A activities. Such licensing andM&A between pharma and drug deliverycompanies offers them with key productdifferentiation and the competitive edge thatthey yearn for.

Safety concernsInitial demand for pulmonary drug deliverywas primarily driven by the respiratory diseasesmarket.The environmental safety concerns thatled to the withdrawal of CFC propellants fromthe market by 2000, in accordance with theMontreal Protocol, and the successful launch ofdry powder hydrofluoroalkane (HFA) inhalersto replace CFC inhalers, have changed themarket. Pressurised metered dose inhalers(pMDI) have played a part in drugreformulation and the market for suchpulmonary drug delivery devices is likely toexpand. However, only those devices that scorehigh in terms of safety and efficacy, and thatare easy on the purse, will be a sure-fire hitamong patients.

The diagnosis, treatment and managementof diabetes are still major concerns for thediabetic community, with convenience andcompliance in treatment regimen proving tobe major hurdles. Hence the introduction of anovel alternative in delivering insulin throughsystemic pulmonary delivery, such as Exubera,is likely to remove some of the hurdles in thistherapeutic area. Even so, long-term safety andefficacy remain major challenges and Exuberais still viewed with scepticism. For example,occurrences of pulmonary fibrosis duringclinical trials on the drug have causedconcerns over its safety.The occurrence ofside-effects such as coughing tends to deterthe patients from using the inhaled insulin. Inaddition, there are a number of industrychallenges that plague pulmonary drugdelivery (see table opposite).

Beyond diabetes management, therapeuticareas where there remains unmet medicalneed, and that could benefit from systemicpulmonary drug delivery, include multiplesclerosis, anti-infectives, pain management,osteoporosis, migraine, male sexualdysfunction, immunosuppression, smoking

cessation, premature ejaculation, growthhormone deficiency, neurological problems andeven certain cancers.The cost factor involvedin treating chronic diseases is crucial here –some illnesses warrant higher expenditures,frequent dosing and constant visits to thephysician. Lilly and Alkermes’ venture toproduce an inhaled formulation of theparathyroid hormone Forteo (teriparatide), forexample, is intended to ensure bettercompliance and improve the lifestyle ofpatients suffering from osteoporosis.

The concept of pulmonary vaccines,meanwhile, has triggered immense interestfrom pharmaceutical developers. Suchtechnology would facilitate administration andempower greater compliance to thecommunity.Although there are very few suchvaccines under development, one being Aktiv-Dry’s inhalable vaccine for measles, the futureholds great promise for this drug category. Inaddition to measles, diseases like pneumoniaand influenza are promising indications forinhaled pulmonary vaccines.The globalvaccines market was valued at US$10billion in2005. However, the needle-free delivery ofvaccines, especially pulmonary delivery, willlikely double this market value by 2012.

Pulmonary delivery: the outlookPulmonary drug delivery has generatedimmense interest and the very concept of non-invasive drug delivery is welcomed by the

healthcare community.This has been a majordriving force for this market, which is boundto experience explosive growth rates. Frost &Sullivan estimates the market to grow in thenext 5-6 years thanks to the influx of manybiotechnological products onto the market.

As the market expands, the focus will likelybe on new indications and also the delivery ofnew macromolecules. In terms of pulmonarydrug delivery, current pipelines house variousmolecules including interferons for thetreatment of multiple sclerosis and hepatitis Band C, alpha 1 antitrypsin for emphysema andcystic fibrosis, heparin for blood clotting,interleukin-1 receptor for asthma, andcalcitonin and other peptides for the treatmentof osteoporosis.

Even so, drug developers are also trying toovercome the various disadvantages associatedwith pulmonary delivery by focusing on otherinnovative technologies. Nanotechnology andgene therapy are two research areas beingstudied for the efficient and painless delivery ofvarious therapeutic macromolecules like insulinand other hormones.While they are still intheir infant stages, these technologies arebound to garner significant attention andexpand the drug delivery market in future.

Sylvia M Findlay is an industry analyst for Europe,

the Middle East and Africa in Frost & Sullivan’s

Pharmaceutical and Biotechnology Healthcare

practice. She is based in Chennai, India.

Drug Delivery 13

Pulmonary delivery


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Head to Head

Global pharma giant Pfizerundisputedly stole the headlines inJanuary 2006 when it receivedback-to-back approvals from theEuropean Commission and theFDA allowing it to sell Exubera,its powdered, inhalableformulation of insulin, to thelucrative European and USmarkets.At the same time, theproduct registrations delivered atide of good fortune to a smallerplayer, Nektar Therapeutics, theUS company that partnered withPfizer and that developed boththe dry powder formulation and the inhaler used to deliver the drug.

Nektar revised its 2006guidance from US$60-80millionto US$70-90million, most ofwhich it expected to come frommanufacturing sales to Pfizer and

the company is also in line toreceive additional royalties onsales. In mid-September, Pfizerand Nektar’s product was thrustinto the spotlight once againwhen it topped the biotech-medical category of The WallStreet Journal’s 2006 TechnologyInnovation Awards beforepocketing the third place prize forinnovation overall.

The Exubera story is a goodexample of a successful drugdelivery partnership. But this isn’tto say that the drug enjoyed astraightforward route to market.Development work took over 15years and involved input fromdiverse scientific disciplinesspanning biology, chemistry,mechanics, manufacturing, fluidengineering and physics. Evenaeronautical engineers had theirpart to play.Then came concernsover the safety of inhaling insulininto the lungs – Exubera is thefirst drug to be approved for thismode of delivery. Even now,Pfizer is being dragged into thecourts by Novo Nordisk’s lawyers

who claim that Exubera infringespatents the Danish company ownscovering inhaled insulin.

All of which highlights theconsiderable risks involved atevery stage of the drugdevelopment process, not only forpharma companies, but alsoinnovator biotechs and firmsfocused on developing novel waysof administering drugs to patients.Over several years’ worth ofdevelopment work, partners couldquite feasibly clear all theanticipated hurdles and pull out allthe stops to almost get a productto market, only to come acrosssome stumbling block they hadn’tforeseen at the start of theirrelationship. In this increasinglytricky development environment,it pays to consider from the outsetall the issues that are likely to cropup – that way companies canreduce the risk of an unexpectedfactor throwing a spanner into theworks at the last minute.

Risk management couldinvolve verifying the ownership of intellectual property in the

Facing risk – head-onScrip’s Pete Chan

explains why we

have partnered

with 3M to ask:

“Should a new drug

be launched in a new

delivery system?”

“It’s well worth their while getting to grips with

what partner firms think about risk in order to be able

to offer them the best possible service”

Head to head Q4 22/11/06 2:02 PM

www.3M.com/DDS50years16

Head to Head

technologies being used to avoidbecoming embroiled in lawsuitsfurther down the line. But it alsomeans dealing with relativelysimple elements such as ensuringthat suppliers have the rightmaterials and a robust supplychain in place. As for companiestrying to compete in theirrespective markets, it’s wellworth their while getting togrips with what partner firmsthink about risk in order to beable to offer them the bestpossible service.

The value of this type ofinformation is the reason Scrip hasteamed up with 3M DrugDelivery Systems, a global leaderin the drug delivery field, toproduce this opinion piece underthe broad heading: ‘Should a newdrug be launched in a newdelivery system?’

Unlike in typical businessenvironments, where partnercompanies need to take a sensitiveapproach to dealing with theirworking relationships, thisScrip/3M ‘Head to Head’ hasposed a number of key questionsand created an open and frankforum for industry experts tohonestly air their views andconcerns. Seemingly basicquestions such as what isconsidered to be a new drug

delivery system are open toconsiderable differences ininterpretation.As are differentcompanies’ views on the risksinvolved in launching new drugsin novel delivery systems, whatactions are needed to keep risk toa minimum, and how these risksshould be prioritised.Thisdiscussion aims to get the views of the market’s key players andidentify the factors that underpinthe launch of new drugs,new delivery systems or, in some cases, both.

The importance of new drugdelivery systems to the pharmaand biotech sectors hardly needsstating – technological advancesoffer considerable advantages interms of lifecycle management,market positioning and productdifferentiation, for instance, andbusinesses are well aware of this.

Companies detected by theScrip drug delivery radar in 2006range from the UK’s Vectura,which has spun out its oral anddermal technology division,Pharmakodex, in order to focuson its pulmonary drug deliverytechnologies; through to GileadSciences, which in Augustacquired the drug delivery firmCorus Pharma for a sum of$US365million.Aradigm hasdivested its Intraject needle-freedrug delivery system to a newfirm, Zogenix, allowing it to focuson its AERx pulmonary deliveryplatform. MerrionPharmaceuticals, meanwhile, hasboth in-house and partneredprogrammes in which it isdeveloping oral formulations oftherapies that can only bedelivered by injection at present.

As for 3M Drug DeliverySystems, 2006 is a milestone in thecompany’s history for acompletely different reason.Thisyear marks the 50th anniversary of

the launch of the first pressurisedmetered dose inhaler (pMDI),which 3M subsidiary RikerLaboratories originally developedfor asthma in response to patientdissatisfaction with existing aerosoldelivery technologies. Fast forward50 years and the patient of the21st century is infinitely moreclued up on the variousformulations of medicinesavailable to them.What better time for marketleading companies to discuss the way ahead?

Dr Paul Colthorpe is head ofInhalation and Device

Development at NovartisPharma. He serves on theboard of the International

Pharmaceutical AerosolConsortium on Regulation &Science (IPAC-RS) and waspreviously a board member

of the Academy ofPharmaceutical Sciences

(APS). He also co-founded theAPS’ Inhalation Focus Group.

Dr William K McVicar is aprogram director and

vice-president ofDevelopment Operations –

Respiratory at Sepracor. Heoversees all developmentteams in the respiratory

field and is responsible for amultidisciplinary team that

helps manage thecompany’s respiratory

portfolio and assesscandidates for in-licensing.

THE HEADS

“Seemingly basic questions such as what is

considered to be a new drug delivery system are open

to considerable differences in interpretation”Dr James Stefely is a

manager in the EarlyPharmaceutics and New

Technology department in3M’s Drug Delivery Systems

division where he hasserved since 2002. He hasalso worked for 3M’s LifeSciences Materials Sector

lab, the company’sBiomaterials Technology

Center and 3MPharmaceuticals.



Head to Head

There are many reasons formarketing a drug in a noveldelivery system.They may berelated to the clinical usefulness ofthe drug, to assist with productdifferentiation, or part of thelifecycle management process. Byand large, novel delivery systemstend to be used with drugs thatare already on the market, eitherin different formulations or indifferent presentations. But is itpossible to make a case forlaunching a new chemical entity(NCE) using novel deliverytechnology?

The case for...William McVicar certainly

thinks so.A program director atMarlborough, Massachusetts-basedSepracor, with responsibility for alldevelopment projects in therespiratory field, McVicaridentifies three good reasons tolaunch a new drug in a newdelivery system.“The first is toimprove the therapeutic index ofthe drug, either by reducing side-effects or increasing efficacy,” hesays.“Because drugs can causeunwanted effects in non-targettissues, a better therapeutic indexcan sometimes be achieved bydelivering the drug selectively tothe target tissue. Examples of thisinclude topical formulations totreat skin diseases or the injection

of chemotherapeutics directly intotumours. Such techniques allowfor higher local concentrations ofa drug in the target tissue andperhaps better efficacy whileavoiding the side-effects thatmight accompany systemicexposure to the drug.”

The second good reason, inMcVicar’s view, is to improvepatients’ quality of life. Examplesof this include developing acontrolled-release formulation sothat dosing can be less frequentand compliance perhapsimproved, or delivering anantimigraine medication viainhalation, so the patient benefitsfrom a faster onset of action thanwith oral or subcutaneousadministration.“Finally”, McVicarsays,“a certain measure ofcompetitive protection can beobtained by developing a uniquedrug product with a superiordelivery system that is patent-protected.This adds to thecomposition of matter protectionan NCE is likely to have.”

James Stefely, a manager in theEarly Pharmaceutics andTechnology Department in 3M’sDelivery Systems Division in StPaul, Minnesota, is anotherbeliever in the new drug/newdelivery system model.“It is amisconception that there are moreinherent barriers to launching an

NCE in a new drug deliverysystem,” he says.After all, anyonelaunching a new drug product isfaced with the same questions,regardless of the novelty of thedrug, the delivery platform or of acomponent within the system. Isthe product safe? Is it efficacious?Is the formulation sufficientlyrobust? Can it be manufacturedreproducibly?

Recognising riskPaul Colthorpe, head of the

Inhalation and DeviceDevelopment Department atNovartis Pharma in Basel,Switzerland agrees with theupsides but points out a numberof risks associated with developinga new drug in a new deliverysystem.They include anything thatcould affect the safety of patients

using the device as well aspotential problems duringdevelopment and registration.“Each of these areas can lead tolengthy delays to approval, andhence to the introduction of thenew system to patients,” he says.“But if we can successfullyidentify risks as we go through

the development, scale-up andmanufacture of a new device, wecan work to mitigate them as wedevelop the new technology.”

McVicar agrees there are risks.“All significantly complex deliverysystems add cost, time and risk tothe drug product’s development,”he says.“If the activepharmaceutical ingredient is atherapeutic advance when givenin an old-fashioned, tried and truedelivery system, this is probablythe best way to develop theoriginal product.An improveddelivery system can then be usedto introduce a differentiated,improved line extension whileenjoying revenues and brandawareness from the originalproduct.” But, he says, if thedelivery system is required for atruly differentiated product, the

decision to develop must includeconsideration of the greater risk,cost and time that comes with anovel delivery system.

Defining designAccording to Stefely, the belief

that launching an NCE in a newdelivery system is inevitably

Should a new drugbe launched in a newdelivery system?Novartis’s Paul Colthorpe, Sepracor’s William McVicar and 3M’s James Stefely discuss the pros and cons of this approach. Scrip’s Peter Charlish reports

“It is a misconception that there are more inherent barriers

to launching an NCE in a new drug delivery system”



Head to Head

associated with unexpectedbarriers and costs arises because,in the past, many delivery systemswere developed alongside thedrug, which meant that thedelivery system did not have itsown defined design space. Delaysand unexpected costs are bestavoided by accurately defining thecritical factors at the outset anddesigning a research ordevelopment programme toaddress them early on. In that way,the delivery system does notbecome rate-limiting to the NCEdevelopment programme.

All three agree that a robust andreliable supply chain is vital.“Supply chain considerationsbecome particularly importantwhen the product cost is high orwhen the medical need is great,”says McVicar. Colthorpe adds thatit is critical to work in partnershipwith the regulatory agencies toensure delivery of devices thatexceed the latest standards andhence have a high chance ofapproval. He predicts that cost willremain an important factor in thisarea, and that the burden onpharmaceutical companies todemonstrate a positive impact ofnew delivery systems on theoverall cost of treatment willincrease.

So when should a new drug belaunched in a new deliverysystem? What criteria need to betaken into account? And what arethe anticipated benefits?

Finding balanceA major consideration is the

balance of risks between thetechnical development and theclinical development, McVicarsays.“It would not make sense todevelop a high-risk drug in ahigh-risk delivery system.Thereare too many ways to fail.A betterbalance is a high-risk drug in asimple delivery system unless thedelivery system is critical to thedrug’s ability to improve oncurrent products. Likewise, acomplex delivery system makesmore sense with a less risky drug– or a series of drugs, so the cost

of the delivery systemdevelopment can be amortisedover more products.”

“Delivery systems are initiallychosen in the belief that theyprovide the greatest probability ofsafely obtaining the desiredclinical outcome in a patient-preferred manner,” says Stefely.The ideal delivery system shouldprovide the desired dose, at thetarget location, with the optimalrelease profile and at the correcttime, in a manner that improvespatient freedom and compliance.Every new drug delivery platformintroduced over the past half-century has improved at least oneof these elements:“When 3MRiker introduced the metereddose inhaler (MDI) 50 years ago,it addressed several of thoseissues,” Stefely explains.“TheMDI’s development was market-driven, by providing patientsfreedom from the bulky powerednebulisers of the 1950s. Itimproved the compliance ofasthmatics, delivered the drugsmore efficiently, and providedportability in a very cost-effective,stable system.”

In more recent times broaderquestions such as environmentalimpact and the effect of thedelivery system on developmenttimelines have also becomeimportant considerations whenselecting a new delivery system.For example, the replacement ofchlorofluorocarbons (CFCs) aspropellants in MDIs withhydrofluoroalkanes (HFAs) wasinitially driven by concerns aboutthe environmental impact ofCFCs.

With numerous inhalationdelivery-related patents andpublications to his name, Stefelyclearly speaks as someone withconsiderable experience ofdeveloping new vehicles forclients’ molecules. From thepharma perspective, Colthorpesays that the criteria for putting anew drug molecule in a newdelivery system include whetherthe development schedule for thedrug product has sufficientflexibility to allow for theintroduction of a new deliverysystem as well, and the degree oftechnical and regulatory riskassociated with the new system,

although he points out that thelatter concern may be mitigatedby co-developing a backup systemusing established technology.

Colthorpe also makes the pointthat a new delivery system mayoffer advantages in terms ofincreased compliance and/or userconvenience, performance, costand so on, which would beparticularly important for ‘me too’drugs to provide a further degreeof differentiation and competitiveadvantage.There may also betechnical reasons why a newdelivery system is required for anew drug – for instance if thecompany’s current dry powderinhaler provides insufficientmoisture protection for amoisture-sensitive NCE.AtNovartis, the potential benefits areevaluated on a case-by-case basis,and technical considerations areweighed against marketing drivers.Colthorpe says that to make thesedecisions effectively it is critical tobring together cross-functionalteams comprising representativesfrom the relevant functions –marketing, regulatory, clinical,operations, and technical R&D.

No launch is without its risks…



Head to Head

Stefely echoes the latter point.“Early involvement ofmultifunctional teams is vital tokeeping a new platformdevelopment project on target,”he says.“A partner who has anestablished organisation to managecomplex supply chains, or who isvertically integrated, significantlyreduces the risk associated withlaunching a new deliveryplatform, especially if that partnerhas experience with developingand manufacturing multiple drugdelivery platforms.”

Of course, all these differentelements are interdependent. Forexample, says Stefely, if thedelivery system is capable of localdelivery, thereby reducing boththe systemic dose required and theincidence of side-effects, it canimpact both safety andcompliance. Or if an extended-release profile enhances efficacy(technical benefit), it also reducesthe dosing schedule (whichconfers a market/compliancebenefit). Improved compliancetypically improves patientoutcomes, which in turn mayenable the drug to obtain apremium price while still beingconsidered a more cost-effectivetreatment than a cheaperalternative product.

New or different?At this point it is perhaps

germane to ask, when is ‘new’really new? As Colthorpe says,there are plenty of ‘different’delivery systems, but genuinelynew, innovative systems are rare.Stefely agrees:“There is really acontinuum in the definition anddegree of risk associated with‘new’,” he says.“At one extreme isa new delivery system targeting anentirely new delivery route, suchas when nebulisers were first usedto deliver drugs to the lung. Lessrisky is a new delivery systemthrough a known route: forexample when MDIs were firstintroduced, they were a radicallynew delivery system that filled asignificant patient need, butinhalation was an established

delivery route. Since then therehave been continual minorchanges to the MDI, whichtypically present less risk becauseyou are building on the existingdelivery platform’s knowledgebase.”

On the other hand, thetransition from CFCs to HFAswas a substantial change because itaffected every aspect of thedelivery system, from theformulation approach and doseconsistency to the containerstability and valve function. Evenso, the transition was not as riskyas developing an entirely newdelivery system and actuallyenabled a large number of minorimprovements to the MDI.Theseimprovements have resulted in asignificantly better MDI deliverysystem, but cumulatively they arestill not large enough for themodern MDI to be considered a‘new’ system.

Colthorpe takes a regulatoryviewpoint.“A ‘different’ system isanything that could potentiallyaffect performance, functionality,user handling, safety and so on,”he says. So although it wouldcommonly be a lifecyclemanagement activity, Colthorpeconsiders the change from astandard press-and-breathe MDIto a breath-activated MDI torepresent a different deliverysystem.“Changing from one DPIto another, for example from aSingle Dose Dry Powder Inhaler(SDDPI) to a Multi Dose DryPowder Inhaler (MDDPI), or onetype of MDDPI to another,would also constitute a differentsystem,” he says.

McVicar defines a delivery‘system’ as anything in the drugproduct except the activepharmaceutical ingredient, forexample tablet excipients for acontrolled-release tablet, canistersand valves for MDIs, or materialsin active or passive transdermalpatches.A new system is one thatprovides the same (i.e.,bioequivalent) delivery cheaper,with better shelf life, or with alower manufacturing scrap rate

(i.e., offers economic advantages),or one that truly improves thetherapeutic performance of a newor existing drug, such as a targetedmono-dispersed aerosol. So likeColthorpe, McVicar views thetransition from pMDI to DPI, orfrom a press-and-breath pMDI toa breath-actuated pMDI, aschanges to ‘new’ systems. In short,for a delivery system to be ‘new’ itmust confer an advantage to thepatient (therapeutic or quality oflife) or the drug company(economic).

For a system to be consideredgenuinely ‘new’ Colthorpe saysthere would need to be aninnovative change involved ratherthan a stepwise evolution ofcurrent technology.This could forinstance be diagnostic/self-titrating systems, delivery via anew route of administration, orthe use of active, electronicallydriven DPI systems to generateaerosol without the requirementfor inspiratory effort by thepatient.The need for new deliverysystems could be driven by adesire to better meet the needs ofpatients or to keep pace with, orstay ahead of, the competition,changes in legislation, and thedelivery demands associated withnew therapies and formulations.

The case against...Are there any occasions when it

would definitely not beappropriate to put a new drug ina new delivery system? Thatdepends on what type of ‘new’system you mean, says Colthorpe.“Delivery systems that are alreadyavailable and used by others, butwhich are ‘new’ for a particularcompany so that no internalexperience is available yet,represent one category.This is a‘reduced risk’ scenario for acombination with an NCE,” hesays. But delivery systems new forthe entire pharmaceutical arenarepresent a substantial risk.“Hereyou add the risk of developing anew technology to the intrinsicdevelopment risk of an NCE.Whilst this can often lead to a

breakthrough new therapy forpatients, it does mean thatpharmaceutical companies have totake on a very large amount offinancial and technical risk toachieve their goal.”

Stefely takes a similar view.“Ifexisting delivery technologies canprovide a safe, efficacious product,which is likely to have a strongcompetitive position in themarket through the majority of itslife, there is less reason to utilise anew delivery system,” he says.“However, you have to look atthe prospect of having acompetitive drug product utilisethe novel delivery system indeciding if you will have a strongcompetitive position throughoutthe product’s lifecycle.You shouldalso consider the impact of thenovel delivery system on theability of generic competitors tocopy your product.When you aremaking this decision it isimportant to be able to assessaccurately the true costs andbenefits of the new deliverysystem during the product’slifecycle.”

McVicar identifies threesituations when a novel deliverysystem is inappropriate for anNCE.The first is whenintroducing a new therapeuticapproach in an area of greatmedical need, when the patients’need for the new therapy in anyform outweighs the benefit of thenew delivery system. In this case,he says, the ‘simpler’ product canbe introduced much earlier aspossible, with a more sophisticateddelivery system to follow.Thesecond situation is when there is ahigh probability of ‘biological’failure that does not justify theextra cost, time and risk of a newdelivery system.The third is whenthe cost of the delivery systemcannot be supported by themarketplace.

Clearly, using a new deliverysystem is not appropriate for everynew drug. But provided theappropriate checks and balancesare in place, there are times whenit is a very attractive proposition.



Head to Head

Our viewpoints on launching new drugs in novel delivery systems are substantially in agreement. Do it when it makes sense.

We agree that a holistic, lifecycle view of the risks to the product have to be taken into consideration as well as the potential

benefits to patients. True novelty clearly means we are in unexplored territory, which implies we have increased the range of

possible risky and rewarding outcomes. It is important to remember that increasing the number of negative possibilities, in other

words risk, is different from saying that the probability of having a negative event has increased. The negative possibilities are

balanced by mitigation strategies and by the positive possibilities that encouraged us to choose a novel approach. We accept

increased risk because we believe the probability of having a breakthrough new therapy has increased.

We agree a risk mitigation strategy can be to utilise experienced teams or companies that have demonstrated the ability to

navigate new territories and who have greater capabilities to address the unexpected events in a timely manner. Experienced

innovators have frequently been rewarded for their risk-taking.

We also agree that the increased risk associated with utilising a new delivery system has to be balanced by an increased

probability of success in another aspect, for example patient compliance or competitive advantage. Additionally the risk to one

programme may be further balanced by the increased probability of success on future programmes – in other words, developing

new delivery capabilities pays future dividends. The more holistic your viewpoint, the greater the acceptability of the risk

associated with a new delivery system.

Dr James Stefely

I think we are in agreement that a careful risk/benefit analysis must be conducted for each opportunity to combine a new drug

and delivery system. Whilst concern for patient safety is a given, perhaps the weighting applied to some of the other variables

in this analysis may differ based upon whether the commentator is working for a CRO drug delivery company or in pharma.

Another factor which should be considered is that much of this discussion has focused on delivery systems for inhalation.

However, these systems tend towards the more complex end of the spectrum and carry with them more technical risk in

development. The tipping point in the risk/benefit analysis will be markedly different for other routes of delivery.

Another relevant question is whether companies should try to rationalise the number of new delivery systems they present to

patients. For instance, in asthma and COPD many patients need multiple drugs, and hence multiple inhalers, to manage their

condition effectively. It is therefore critical to balance the need for better inhalation devices against the need for simplicity and

consistency for the patient. This implies that it may be more effective to develop technically robust and versatile platforms with

a range of medicines rather than innovating for each new molecule or combination.

Dr Paul Colthorpe

Reactions

Competition for new, innovative drug products is greater now than ever. The high burden of healthcare cost on businesses

and governments will make it harder each year to justify the value of new products that don’t offer a significant

advantage to the patient and/or payor. The consolidation of multinationals has created a pool of ‘mega-customers’ looking

for ‘mega-products’ they desperately need to feed their infrastructures and maintain growth despite the relative success

for their internal discovery efforts. So while the development of a new drug in the simplest form is a dauntingly complex

and risky task, the extra advantage that may be conferred via a more complex delivery system may just create the benefit

for patients and the resulting marketing differentiation. The strategic decision to couple the biological uncertainty of an

NCE and that of a novel, complex delivery system must be carefully considered as discussed, but can no longer be

ignored as a viable option.

Dr William K McVicar

Scrip went back to the ‘Heads’, for their comments and conclusions



Head to Head

There is broad agreement that yes; launching a new drug in a new delivery system is a viableoption in the right circumstances.The reasons why industry would follow this path areprimarily patient-driven.As our industry experts point out, from the patient’s perspective anew delivery system should be considered if it would improve the effectiveness or safety oftheir medicines.

A new delivery system would also be beneficial if using it was easy, or meant less restrictionon patients’ life styles, thereby leading to better compliance. So, really understanding the needsof patients is core to understanding the benefits that a new delivery system should convey andwhere industry should be focusing its innovation efforts.

The secondary driver for launching a new drug in a new delivery system is to gainadditional competitive advantage.The costs and complexity of pharmaceutical R&D continueto rise and the remaining patent protection on a new chemical entity at the time of launchhas decreased over the years, hence the ever-increasing importance of having other forms ofprotection against generic competition to maximise payback.The additional advantage thatcan be gained by using a new delivery system, which can confer that protection, is animportant consideration in the overall life cycle management for a new product.Understanding the patent landscape and maximising patent coverage for new delivery systemsare critical success factors.

Perhaps ‘should’ and ‘why would’ a new delivery system be used are not the real questions;it is really more a question of ‘when’ and ‘how’ should one be used.All three participants haveraised the classic dilemma of risk versus benefit, risk management being at the heart ofeveryone’s thinking. Early identification of the risks and consideration of possible mitigationstrategies will increase the likelihood of success. For example, understanding and managingthe complexity and security of the supply chain is fundamentally important to avoiding delaysand unexpected costs.

One of the key mitigation strategies to the inherent risks is to leverage experience. So withmore than 50 years’ experience in bringing new delivery systems from concept successfully tomarket, including the first pressurised metered dose inhaler, the first breath-actuated inhalerand the first non-CFC inhaler, 3M is well placed as a drug delivery company with that depthof experience and understanding of the challenges involved, underpinned by financialsecurity.

Other strategies that have been highlighted include involving the relevant multifunctionaldisciplines early in any development programme and working in partnership with theregulators.The need to evolve continuously to meet the changing needs of the regulators andthe market place is undoubtedly important. Finally, in the case of a high risk/high potentialgain programme, co-development of a back-up established system may also be warranted.

At the end of the runway, being able to demonstrate the positive value of a new deliverysystem in the overall costs of patient care is of increasing importance. Returning to theExubera story, despite regulatory approval to market in the UK, Pfizer failed to gain approvalearlier this year from the National Institute for Health and Clinical Excellence (NICE) as itcould not convince the Institute of the product’s cost-effectiveness.The visibility of likelycosts of a new delivery system as well as the advantages it will confer are likely to be keydecision factors for any company deciding to use it for its new drug.

In summary, the key take-away message is that there are times when the potentialadvantages to launching new drugs in new delivery systems outweigh the risks – good newsfor patients whose needs are not being met today.

The final word...Nola Bowles, 3M’s product development manager, sums up what we have learned by

answering the question: “Should a new drug be launched in a new delivery system?”

“Perhaps ‘should’ and ‘why

would’ a new delivery system

be used are not the real

questions; it is really more

a question of ‘when’ and

‘how’ should one be used”


Enabling your success

3M Drug Delivery Systems

1956 was the year we

invented the world’s first

metered dose inhaler,

making medical history

and improving the lives

of many millions of asthma

sufferers worldwide.

In 2006 put our experience to work for you.In 50 years we’ve taken MDI technology from pioneering invention to worldwide recognition

with over 60 million metered dose inhalers produced by 3M annually. Our global regulatory

experience, time-tested processes and flexible business models help take your molecules from

discovery to commercialisation. And we’re continually exploring future technologies and

formulations, to meet the changing needs of the marketplace.

When you need drug delivery results, experience matters.

www.3M.com/DDS50years

© 3M 2006


www.drugdeliverypartnerships.com 23

Drug Delivery Partnerships

We are pleased to introduce you to the 11thannual Drug Delivery Partnerships (DDP)event, which will take place next January 22-24 at the Red Rock Casino, Resort andSpa, in Las Vegas, Nevada, US.

DDP is the world’s largest internationaldrug delivery and specialty pharmaceuticalevent. Its purpose is to drive and enhancepharmaceutical and drug delivery alliances.DDP’s sessions tackle industry challenges,providing solutions towards more transparentcompetitive intelligence, strategic businesstransactions, innovative product development,and informative lifecycle managementstrategies – to ultimately improve businesssustainability and growth.

DDP 2007 is the only event of its kind tocombine a top-notch programme, a premiumline-up of speakers, and optimal networkingopportunities with more than 500 of theindustry’s key decision-makers.

Programme highlights Senior Executive Keynote Panel: How Are We

Creating Sustainable Business Models Out of

Evolving Technology Companies?

Bioworld Columnist Cynthia Robbins-Roth,CEO of Norgine, Peter Stein, Senior VicePresident, corporate development of Santarus,Michael Step, Executive Vice President ofMedicis, Joseph P Cooper, and ManagingPartner of Sanders Morris Harris, James Galewill examine the driving forces behind themove away from ‘pure play’ business modelstowards ‘products, products, products’.

Growth Opportunities for Drug Delivery

Systems: Development Trends for New Drugs

in the Pipeline

Renowned director of economic analysis at the prestigious Tufts Center for the Study ofDrug Development, Dr Joseph Dimasi willevaluate the economics of new drugdevelopment, and the implications for drugdelivery systems. Dr Dimasi will review crucial factors like time, risks and costs,and will examine pipeline and in-licensingtrends.

Wall Street Address: Stock Updates, Market

Trends and Key Technologies to Watch

David M Steinberg, Managing Director, equityresearch, specialty pharmaceuticals and drugdelivery for Deutsche Bank delivers his annualWall Street perspective and offers both anassessment of the 2006 environment as well asthe outlook for the remainder of the decade.

Drug Delivery Partnerships Trend Report 2007

– What’s Fuelling Market Changes?

Roger Longman, Managing Partner ofWindhover information, reports on the dealsthat have fuelled market changes, explores thestrengths and the pitfalls of various dealstructures, and examines the mergers andacquisitions that have had an impact on thedrug delivery industry.

How the End-User Can Inspire New

Opportunities: Bridging the Patient, Physician

and Payer

Hamilton Jordan,White House Chief of Staffunder President Carter, best-selling author of‘No Such Thing As a Bad Day’, and four-timecancer survivor moderates this patientcompliance panel.As a man who has alwaysbeen in tune with the pulse of the nation andwho has tackled not only political challengesbut personal obstacles, Hamilton Jordan willshare his extraordinary strength and vision togive the end-user’s view on the importance ofpatient-friendly treatments.

The following pages – Scrip’s official previewto DDP 2007 – will give you a taste of whatyou can expect from our expert speakers.Thisseries of interviews provide indispensableopinion and advice on how to improve yourdrug delivery partnerships.To meet theseindustry experts face-to-face and hear theirinsights first-hand, be sure to join us in Vegas!

I look forward to seeing you there.

Miriam GlickProgramme Director – Drug DeliveryPartnerships 2007

Welcome to Drug DeliveryPartnerships 2007! DDP, the world’s largest drug

delivery and speciality

pharma event takes place in

January. Here, we give you a

taste of this prestigious event




QWhy do biotech and pharmacompanies choose to develop

injection devices for biopharmaceuticalsas opposed to non-invasive technologiessuch as inhalers or transdermal patches?

“Non-invasive technologies arepresumably the most appealing drug

delivery system to a patient, but thephysicochemical properties of biologics makethem difficult or impossible to administer bynon-invasive routes. Extensive research anddevelopment would be required, costs wouldbe significant, the timelines tocommercialisation would be long, and there’ssignificant risk that the system will not becommercially viable. Device technologies aredoable and pose less risk. Injection devicesprovide convenience, improve ease of use andmay reduce the anxiety of an injection – thesefeatures make injections more tolerable thanthe conventional methods of administration.These benefits drive patient preference and canlead to increased market share.The downside Isee is that although a company can use devicesto improve the market share of their products,their competitors have access to similartechnologies, so these systems may not providea long-term competitive advantage.

QAre injection devices valueddifferently in self-administration

vs clinical settings?

“In self-administering markets, the valueis patient convenience and ease of

administration. Devices can ease and/or enableself-injection for patients who have dexteritylimitations, needle phobia or that lackexperience with injections.The increasedconvenience of a device can be particularlyvaluable in markets in which injections arefrequent or chronic. In my opinion,convenience and ease of use factors aren’t asrelevant in the clinical setting. Healthcareprofessionals are comfortable with needles.Safety, prevention against needle stick injuries,and enabling the clinic or hospital to complywith needle stick prevention laws or guidelines

is a key requirement and success factor in thesesettings.This is particularly true for the US, asfederal legislation requires that healthcareprofessionals take appropriate actions toprevent accidental needle sticks.

QHow do you think the market forinjection devices has evolved over

the past decade?

“In the last decade, the tremendousgrowth of the biopharmaceutical market

and increased competition in the industry hasspurred the development and commercialisationof devices for injectables worldwide. I haveseveral observations that I think demonstratethe growth of devices in the marketplace.Tenyears ago, injection devices were primarily usedfor insulin, human growth hormone and someemergency antidote products.Within the lastten years, pre-filled syringes have entered themarket and become a common dosage form forinjectable products. In the last five years,numerous injection devices and user aids havebeen launched in at least ten newbiopharmaceutical markets. Companies arelaunching second and third generation systems,and there is also a trend from reusable towardspre-filled disposable systems. Needle stickprevention devices are now marketed withclinically administered products – these deviceswere not on the market ten years ago.Another

observation is that a wider variety of devicetypes are being developed and commercialised– ‘hybrids’ and variations of the conventionaldevice types are being developed and have beencommercialised. For the first time, there havebeen some new product launches in which thedrug is available only in combination with adevice and not in other more commonconventional dosage forms such as vials. Lastly,there are more companies in the injectiondevice and user aid business developing andmarketing technologies to thebiopharmaceutical industry than ever before.

QHow do you see the market fordevices evolving over the next

5-10 years?

“I think that the insulin and humangrowth hormone markets today may be

representative of the future for devices inbiopharmaceutical markets.These markets haveadvanced drug delivery technologies and along-standing history with devices in a highlycompetitive environment. Some companiesoffer as many as four devices for a singleproduct and many companies do not providethe product in less convenient dosage formssuch as vials. Eventually, I believe injectiondevices will become commonplace, and thatthere will be tremendous diversity inthe types of devices on the market.

“Tremendous diversity in types of devices”

Dr Donna French is executive director,

drug delivery engineering at Amgen. She

is responsible for the development and

commercialisation of injection devices

and aids with external partners. She has

over 12 years’ experience in various

aspects of injectable drug delivery and

novel formulations for proteins.

”




QHow does the US differ fromEurope when it comes to

developing a novel delivery systemapplied to a well established activeingredient?

“All too often we are offered theEuropean rights for products originally

developed in the US and find that thedevelopment strategy was not optimised forthe European market.This leads to delay and aloss of potential profits. Commercial andpricing strategies must be determined muchearlier in Europe than in the US.

Europe is a single market with respect to theregistration process and, consequently, aproduct will emerge with a single Europeanlabel. However, that product will still need tocompete in 25 national markets. Medicalpractice and competitors will be different and,for historic reasons, a single competitor mayeven have a different label across Europe.Thesenational characteristics must be consideredbefore beginning a development programme.

Europe has also always been a heavily priceregulated market for pharmaceuticals.While thedetails of the systems are in constant flux andvary from country to country, the movement isall towards further decreasing prices. Europeancompanies need to build a robust pricing andreimbursement strategy and conduct clinicalstudies to generate the outcomes data necessaryto implement that strategy.This is particularlytrue for products that combine novel deliverysystems with well established pharmaceuticalactives.

We frequently see companies developproducts for the US marketplace on theassumption that the data will be adequate forEuropean registration. In fact, these studies arerarely sufficient for the commercially successfullaunch of the product due to differences in thenature of Phase III trials, differences in thetarget label and the added hurdle of thereimbursement systems.

QHow has the European environmentchanged in the past few years?

“Perhaps the most significant change isthat, despite the remaining national

differences, there is an inexorable drive towards

a single European market. One registration andone label inevitably also leads to the need toexecute one strategy across Europe.This isparticularly true in the specialty pharmaceuticalsector where so many of the scientific forumsare now multinational.This means that a USdrug delivery company must, more than ever,seek a single European partner for its product.

QWhat should a US-based drugdelivery company look for in a

European partner?

“Developing a product for Europe will becomplex and will take time and therefore,

first and foremost, you must find a partner thatyou can work with for the long haul. Is theircorporate culture compatible with your own?Does the company have the long-term strategicinterest in your product? Does the topmanagement of the company have the necessary,long-term, commitment to the project?

Once the cultural fit is there, look forcompanies with a proven track record acrossEurope in your specialty area.All too often, wesee companies ask the wrong questions abouttheir European partners. For example, manyEuropean companies have affiliates acrossmultiple countries, which sell differentproducts to different medical specialities.Theywill lack the integrated and consistent structurethat you will need to develop and launch yourproduct. Don’t just ask about where they havean office or a company. Go one step further tolook at the real structure of the business.Arethe sales force targets consistent across Europe?Do they have experience in launching and

selling a product across Europe? Do they havethe strong central management team to driveimplementation across Europe and maximisethe sales of your product?

Finally, look at the specialist knowledge. Isyour partner able to manage the clinical studiesthat will be necessary across multiple markets?Are you confident that these trials will be doneto the quality necessary for Europeanregistration? Will they support your regulatorysubmissions elsewhere? Will they be able tomanage pharmacovigilance reporting across 25countries and a similar number of languages inorder to allow you to comply with bothEuropean and US reporting requirements?Choosing the best European partner shouldinvolve detailed due diligence about thecompany’s operations and not just a simplecomparison of the draft term sheets.

QWhen should you look for aEuropean partner for your product?

“As a rule, companies wait too long toseek a European partner. It is tempting

to wait until the next Phase II or Phase III dataare available and, of course, positive data willhelp to attract a partner. However, waiting forthe ‘best time’ often involves delaying theEuropean launch of the product and losingdownstream value.This is particularly truewhen additional clinical or pharmacoeconomicstudies will be required to support theEuropean launch. If in doubt, find a partnernow so that you can be sure that the projectwill advance in Europe in parallelwith the US.

“Companies wait too long toseek a European partner”

Peter M Stein is the CEO and principal

shareholder of Norgine, an independent

specialty pharmaceutical company with

operations throughout Europe. Stein

previously co-founded and was

vice-president of Invitron, a spin-off

from the Monsanto Company.

”




QWhat are major challenges toopportunity valuation and

dealmaking in new drug deliverytechnologies?

“There’s often a cultural divide betweentechnology-driven and market-driven

companies.The former may choose aconvenient proof-of-principle demonstrationof their drug delivery technology, using a wellworn path to show their technology’spotential, unaware that other companies aredoing the same thing.This puts the end-product in a competitive space with similarly-fashioned formulations of the same molecule.On the other hand, products may be muchmore competitive if companies considered adifferent molecule, so that their product is notcompared with other formulations of the samemolecule.

This technology-driven culture can be atodds with that of a market-driven company,which will view opportunities from competitiveand market needs perspectives.The twoperspectives need to come together in asuccessful opportunity. From a technology-driven perspective, companies need to educatemarket-driven firms on the value of theirtechnology and how it can be applied. Market-driven companies need to understand the visionof the technology and then translate it intowhere the best market opportunity is. It maymean adjusting expectations on both sides. Drugdelivery technology companies will do well tomeet early with prospective partners to obtainmarket insights for future potential products.

QWhat challenges and opportunitiesdoes the current market present to

globally-focused organisations?

“The market preference for compoundsmay vary by global region, a result of

the history of those compounds and how theywere developed. If a compound was discoveredin Europe and initially introduced there, it maynot have made its way to the US or Japan,meaning there might be no history of thatcompound in these other markets.

A challenge with global deals is then notonly establishing the right drug deliveryplatform from a technology point of view, but

also identifying the right compound, one thatwill be broadly accepted across all the majormarkets.

One approach is to select a compound thatis well known in one country, but less familiarin other regions.That way, when it’sintroduced into these other markets, it’s a newchemical entity that can be positioned in itsown right. But that also creates a challengebecause different regulatory hurdles have to beovercome.Additionally, introducing a productde novo means setting up the whole marketeducation process so that the compound andtechnology are both appreciated.This is aconundrum to sort out for each market toidentify the optimal choice.

There are many products in Japan that havenot been introduced in the US or Europebecause the companies that own them haven’tlicensed them to western firms and havechosen not to introduce the drugs themselvesoutside Japan or the Asia region.There’s a classof companies, in the US at least, that scour theworld for these regional compounds andidentify opportunities to market them in otherregions.

QAre drug developers pushing aheadwith innovation without considering

how well their technologies would bereimbursed?

“Drug delivery-based improvements towell established therapies are not always

well appreciated by payers such that there maynot be a sufficient price premium available toprovide an adequate return on the investmentrequired to bring the innovation to market.

For example, Japan has historically beenone of the most attractive markets in theworld. However, Japan’s reference pricingsystem now caps the price the governmentwill pay for drugs by a comparison with othercountry prices, irrespective of what might bea comparative price within the Japanesemarket. So even though there may be aprecedent within Japan of higher prices, newproducts can be introduced at a much lowerprice level given the competitive nature ofother markets.

We can’t assume that we can price newproducts at a premium to their predecessors.Pricing will in fact be more what certain keypayers will bear.Those payers have a growinginfluence over what will become successfulinnovations and what kind of price premiumsthey’ll be able to support.

Drug developers should push pricingresearch earlier in the development cycle of anopportunity and evaluate what prices payerswill accept before they invest significant sumsinto a technology. It also means looking atmarket segments where there is lesscompetitive pricing, where there are fewerproducts and where there remain significantunmet medical needs that novelformulations could address.

Allen Downs is senior

executive director of licensing

and business development at

Purdue Pharma. He has led

teams that completed a

biotech acquisition, a product

co-development alliance,

and several in-bound and

out-bound licences.

“Push pricing researchearlier in development”

”




Drug DeliveryPartnerships in Europe

Dear colleagues,

I would like to introduce you to the 6thannual European Drug Delivery Partnerships2007, which will take place on May 15-16 in Germany.

This practical and strategic networking andpartnering event for pharma, biotech andinnovative drug delivery companies will, nextyear, bring together the leaders of the mostinnovative drug delivery companies from allover Europe in order to help you decidewhich strategic business transactions will profityou the most.

The event will enable you to:◆ Examine the opportunities and challenges

faced by the European drug delivery industry ◆ Better understand the business aspects of

partnering with big pharma, in order to stayahead of your competitors

◆ Understand what factors make partnershipssuccessful, and build robust relationships thatwork

◆ Find out how pharma companies choosetheir technology partners and be the first ontheir list

◆ Be aware of the legal and regulatory aspectsof drug delivery partnering in Europe andcomply with industry standards

◆ Enhance your product lifecycle with thelatest improved drug delivery systems

This year’s highlights ◆ NEW dedicated networking space for

one-on-one business meetings. Forge newbusiness alliances on site!

◆ Our NEW Evening Working Dinner on May 14, which will showcase the latest advances in protein and peptide delivery

◆ Speed networking breaks and extensiveroundtable sessions to promote in-depthdiscussion on technologies and partnering

More networking opportunitiesAs a registered delegate of European DrugDelivery Partnerships, you will have theopportunity to meet and do business withdelegates from the Scrip’s co-located events:Developing and Managing Strategic Alliancesand Licensing and Alliances in the GenericsIndustry.

I look forward to meeting you in May.

Tahira Rashid, PhDProgramme Director – European DrugDelivery Partnerships 2007

Now you know what you can

expect from the US-based


2007, read on to find out

about its European

counterpart

Poster title, abstract (max. 200 words), principal author, organisation, mailing address, email, telephone, fax, additional authors. Last date for submission is Friday May 4 2007.

Share your researchwith your peers andindustry leaders bypresenting a posterat the conference. Please sendthe following information in English to Dr Tahira Rashid at: [email protected].

PRESENT

POSTERa



Lifecycle management

The US National Nanotechnology Initiative(NNI) defines nanotechnology as “research andtechnology development at the atomic,molecular or macromolecular scale leading tothe controlled creation and use of structures,devices and systems with a length scale ofapproximately 1 to 100nm”.

Nanotechnology has gained recognition inmany disciplines, including the pharmaceuticaland drug delivery sectors.This recognition isillustrated by the fact that, in February 2006,US President George W Bush dedicated,through the NNI, US$1.28billion of fundingfor nanotechnology for Fiscal 2007 – bringingthe cumulative total invested since the NNI’sinception in 2001 to over US$6.5billion.1

Optimising drug deliveryIn the pharmaceutical industry,nanotechnology is being embraced particularlyas a means of improving or enhancing thedelivery of drugs.At present, approximatelyUS$65billion in annual drug revenues areaccounted for by pharmaceuticals with poorbioavailability, which far too often results ininefficient treatment but also, moreimportantly, in increased risk of toxicity.Reducing drugs to nanoscale has theimmediate impact of making otherwise poorlysoluble drugs much more bioavailable, solubleand safer. Unsurprisingly, industry analystspredict that the drug market fornanotechnology products could be worth asmuch as US$200billion by 2015.2

The poor bioavailability of pharmaceuticals isoften caused by poor water solubility.Combinatorial screening programmes suggestthat more than 40% of all active substances areaffected.3 The result is that these compounds arenot effectively formulated, which leads to avariety of problems.As well as having poor andhighly-variable bioavailability, drugs with poorwater solubility are more easily influenced bythe patient fed/fasted state, can have a sloweronset of action, and can cause the undesirable side-effects associated with co-solvents in

Figure 1: FDA approvals 2003-2005

NCE’s New forms/combinations2003 21 48

2004 31 70

2005 19 30

(Source: FDA approval lists, www.fda.gov)

parenterals.Any or all of these issues can lead tosub-optimal dosing and poor clinicalperformance. Nanotechnology has the potentialto address these deficiencies and thereforeprovide significant value to pharmaceuticalportfolios. Indeed, in accepting that 40% of anycompany’s product portfolio may be poorlywater-soluble, and that nanoparticulatetechnology can reduce or eliminate theproblem, we find significant reason to becomeexcited by the potential for nanotechnology inthe lifecycle management (LCM) arena.

An industry under pressure In 2005, despite pharmaceutical research spendbeing at an all-time high, the number of newchemical entity (NCE) approvals was downfrom previous years.4 For the period 2003 to2005, NCEs accounted for only one in fourproducts approved by the US Food and Drug

Administration (FDA) (see Figure 1). Indeed, in2005, several major pharmaceutical companiesfailed to win approval for an in-house NCE.

These figures illustrate why LCM strategieshave become key to maximising a brandeddrug’s profitability. Employed properly andproviding real patient benefits, they can enablea company to sustain revenue streams and fillgaps in its pipeline. So, for those products in aportfolio that have poor water solubility,application of a nanoparticulate technology tooptimise the drug can be a worthwhile strategyto pursue.

The value of reformulationsAs well as sustaining revenue streams andboosting pipelines, LCM strategies can be seento save money.The cost of a reformulation isminimal compared to the cost of developing a‘next generation’ product.The typical cost of anext generation product is, on average,US$330million.A new formulation costsapproximately US$40million – and takes only4-5 years to develop.This lesser cost can be seenas a saving if we consider that, according to arecent study, the overall perceived effectivenessof a next-generation is equal to that of a

Figure 2: Reformulations deliver excellent return

in terms of investment and perceived effectiveness

Small-tech – big potential

Elan’s Paul V Breen

explains why we should be

excited by the potential for

nanotechnology in the

lifecycle management arena


Drug Delivery 31

Lifecycle management

reformulation (see Figure 2).The study,which surveyed many of the world’s biggestpharma companies, compares the average costsand perceived effectiveness of each LCMapproach.5

Unsurprisingly, this NCE/reformulation‘imbalance’ is expected to continue. By 2008,sales of reformulated products (soluble andinsoluble) are expected to account for 80% oftotal pharmaceutical sales in the US market(see Figure 3).6

Where are we now? While the future seems bright fornanotechnology in the pharmaceuticalindustry, what of the present? Although manypharmaceutical products utilisingnanotechnology remain in development,significant achievements have been made sincethe first nanoparticulate product, Rapamune,which was launched in the US in July 2001.This product, marketed by Wyeth, wasdeveloped using Elan’s NanoCrystalTechnology.The tablet formulation of thisimmunosuppressant (sirolimus) was previouslyavailable only as an oral solution, available in bottles or sachets. It required refrigerationand reconstitution in water or orange juice.The new tablet, developed with

NanoCrystal Technology, provides patients withmore convenient administration and storage.

Since the launch of Rapamune, a number ofnanoparticulate products have been launched,many of which are LCM plays.These include:◆ Three additional products, all of which are

delivered orally, using Elan’s NanoCrystaltechnology: Emend by Merck in 2003,TriCor by Abbott in 2004 and Megace ESby Par in 2005.

◆ The first topical product, Estrasorbdeveloped by Novavax, in 2004.

◆ Abraxane, an injectable formulation ofpaclitaxel, in 2005, by Abraxis Biosciences.

◆ Triglide, incorporating Skyepharma’s IDDsolubilisation technology.

These products are enjoying considerablesuccess.Their annual combined sales areestimated to be in excess of US$1.4billion. 7

For nanotechnology to have a significantimpact on poorly water-soluble molecules thetechnology must be:◆ Capable of being rapidly utilised in

discovery at the milligram scale, using astandardised cost-effective approach;

◆ Up-scalable to commercial production, anduse excipients generally regarded as safe(GRAS);

◆ Capable of being formulated intoconventionally acceptable dosage forms, suchas tablets, using conventional secondaryprocessing equipment;

◆ Capable of being combined with other drugdelivery technologies including oralcontrolled release, delayed release andpulsatile release; and

◆ Provide proprietary protection.In the past, companies may have been able tosucceed without capitalising on rigorousportfolio management. But in today’s marketand regulatory climate, portfolio optimisationstrategies will become essential if a product is to achieve its true potential. Over the next

decade the benefits of enhancing the dissolution rate of poorly water-solublecompounds through nanoparticulatetechnologies will be more greatly appreciated as a prudent LCM strategy.

TrademarksNanoCrystal Technology is a registeredtrademark of Elan Pharma InternationalLimited, Ireland.TriCor is a registered trademark owned byAbbott Laboratories Corporation.Megace is a registered trademark of Bristol-Myers Squibb Company licensed to ParPharmaceutical, Inc.Rapamune is a registered trademark owned byWyeth Pharmaceuticals.Estrasorb is a registered trademark of Novavax IncAbraxane is a registered trademark ofAmerican Pharmaceuticals Inc

References1 National NanoTechnology Initiative,

http://www.nano.gov/, September 20062 Griffin Securities Inc, Nanotechnology

Industry Review, December 2005 3 Lipinski C,“Avoiding investment in doomed

drugs”, Current Drug Discovery, 20014 “Drugs in '05: Much promise, little payoff;

just 20 new products are approved, despitebiotechnology’s hope” NY Times, 11thJanuary 2006 and http://www.recap.com/

5 Cutting Edge Information, Defending BrandRevenue – Pharmaceutical Lifecycle ManagementPlanning, 2005

6 BCC Research, US ethical drug market,Strategies for Sustained Growth, 2004

7 IMS Health, Situation Analysis (US SalesDatabase), IMS Portal,August 2006

Paul V Breen is executive vice-president and head

of Elan Drug Technologies.

Elan Drug Technologies’ (EDT’s) keybusiness is focused around productdevelopment and optimisation. Their leadtechnology, NanoCrystal Technology,which has been incorporated into commondosage forms, has the potential forsubstantial improvements to the drugperformance of poorly water-solublecompounds. Now successfully used tolaunch four products in the US, theNanoCrystal Technology has contributedto more than US$1.3billion in annual in-market sales of these drugs. For moreinformation on EDT’s range of technologysolutions go to www.elan.com/EDT.

Figure 3: % share by type of total US drug revenue – 2003 and 2008 (expected)



Micro-encapsulation

Micro-encapsulation is a process by whichsmall particles or droplets are coated in orderto produce capsules that shield the activeingredient from the surrounding environment.Such products are common in thepharmaceutical industry, especially since theyallow the slow release of medicines.They canalso perform a number of other functions,including controlled and targeted drug deliveryof active pharmaceutical ingredients (APIs),with the coating material varying according towhere in the gastrointestinal tract the drug isdesigned to be released.

Coatings are also used to mask the bitter orunpleasant tastes and/or odours of many APIs(the hot-melt coating process may be appliedto taste-mask granules for the development oftablet formulations) and to protect APIs frommoisture.APIs sensitive to the gastricenvironment, such as omeprazole,esomeprazole and pentaprozole, can beformulated as coated pellets, ready to fill intocapsules.The technology likewise enables toxicmaterials to be handled safely.

The preparation of a micro-encapsulatedproduct requires, first of all, the recognition ofa need for micro-encapsulation, whether inorder to improve an existing product, or todevelop a new one. Next, a shell material thatprovides the desired release characteristics mustbe identified. Finally, a process to prepare themicrocapsules must be selected.

The substance that is encapsulated may becalled the core material, active ingredient,agent, fill, payload, nucleus or internal phase.The material encapsulating the core is referredto as the coating, membrane, shell or wallmaterial. Microcapsules may have one wall, ormultiple shells arranged in varying thicknessesaround the core. Many hydrophilic andlipophilic shell materials are available and meetfood and drug regulatory requirements, such asproteins, hydrocolloids, gums, waxes, fats,organic polymers and resins.

The micro-encapsulation technique chosenwill depend on purpose. Substances may bemicro-encapsulated with the intention that

the core material be confined within capsulewalls for a specific period of time.Alternatively, core materials may beencapsulated so that they will be releasedgradually through the capsule walls – with thewall dissolving or melting, or with thematerial being diffused through the wall – ormore abruptly, when the wall is ruptured. Lesscommon release mechanisms include ablation(slow erosion of the shell) andbiodegradation.

Micro-encapsulation processes are usuallycategorised under one of two headings:chemical and mechanical/physical.These labelscan be misleading, as some processes classifiedas mechanical may involve or even rely upon achemical reaction, while some chemicaltechniques depend entirely on physical events.It may be useful to consider whether thecapsules are produced via chemical processes ina tank or reactor containing liquid, or bymechanical or physical processes, whichemploy a gas phase as part of the encapsulationand rely chiefly on commercially availabledevices and equipment to generatemicrocapsules. Some commonly employedprocesses are briefly discussed below.

Spray dryingSpray drying is a mechanical micro-encapsulation method developed in the 1930s.An emulsion is prepared by dispersing thecore material (usually an oil or materialimmiscible with water), into a concentratedsolution of wall material until droplets of adesired size are attained.The resultantemulsion is pumped through a rotating discinto the heated compartment of a spray drier.There, the water portion of the emulsion isevaporated, yielding dried capsules of variableshape that contain scattered drops of corematerial.The capsules are collected throughcontinuous discharge from the spray-dryingchamber.This method can also be used to drysmall micro-encapsulated materials fromaqueous slurry, which are produced bychemical methods.

Micro-encapsulation

technology is becoming

increasingly popular in the

pharma industry worldwide

owing to its many applications

and the advantages it offers

over traditional techniques,

says Nabiqasim’s

Dr Abdul Majid

Coatings forprotection


Drug Delivery 33

Micro-encapsulation

Fluid bed coatingFluid bed coating technology, anothermechanical encapsulation method, is restrictedto encapsulation of solid core materials,including liquids absorbed into porous solids.This technique is used extensively toencapsulate pharmaceuticals. Solid particles tobe encapsulated are suspended on a jet of airand sprayed from below with a liquid coatingmaterial.The capsules are then moved to anarea where their shells are solidified by coolingor solvent vaporisation.The process ofsuspending, spraying, and cooling is repeateduntil the capsule walls are of the desiredthickness.

Pan coatingIn pan coating, solid particles are mixed with adry coating material.The temperature is raisedso that the coating material melts and enclosesthe core particles; it is then cooled so the

material solidifies.The coating material can begradually applied to core particles tumbling ina vessel, rather than being mixed with the coreparticles from the beginning of the process.The temperature of the inlet air can beadjusted within a range of 25°C to 80°C,depending on the requirement andtemperature sensitivity of the material to becoated.Temperature-sensitive materials arecoated at between 25°C and 35°C.A three-component nozzle emits a very fine spray of

solution, applying a thin coating to eachgranule, so they are of homogeneous size andboth evenly and thoroughly coated.Amicroclimate feature within the nozzle helpsproduce a good spray cone while keeping thefront part of the nozzle clean and ensuring acontinuous flow. Dynamic filters enablerecirculation of the coating product.

Micro-encapsulation is now coming intoplay in nearly all pharmacological groups.These techniques have become common inEurope and US, and are also gaining popularityand market share in Asia.

Dr Abdul Majid is chairman of Pakistan’s Nabiqasim

Group. His knowledge and experience of the API

and formulations market, as well as of the pharma

industry as a whole, have helped establish

Nabiqasim as a leader in the manufacture and

marketing of pharmaceutical and healthcare

products for Asia, the Middle East and Africa.

Surge Laboratories, based in Pakistan anda member of the Nabiqasim Group,performs micro-encapsulation of variousmolecules, employing the latesttechnologies and equipment. Thecompany also has its own developmentfacilities and offers contract/tollmanufacturing/development services to its customers worldwide.

Coatings can also be used to mask unpleasant tastes


Drug Delivery 35

Self-injection technology

The market for self-injection devices – pensand auto-injectors – continues to show above-average growth as a result of several factors. Forone thing, the surge in biotech-based researchmeans that many more protein therapeutics arereaching the market, driving demand forinjectable products as a whole.Also, theincreased incidence of diseases such as diabetesand the availability of therapies for previouslyuntreatable conditions are expanding theinjectables market.The advanced features ofmodern self-injection devices are making themmuch more acceptable to patients. If patientscan self-administer their own medications, thennot only is it more convenient for them, it alsosaves on healthcare resources and costs –making self-injection much more cost-effective.

Pens and auto-injectorsPen injectors are essentially sophisticated‘cartridge-based’ syringes.The first pens wereintroduced for insulin in 1984 and weredeveloped for the reliable and accurate self-administration of the first wave of biotechmolecules, mainly insulin and human growthhormone (hGH).Today, insulin still dominatesthe market for self-injection devices, followedby hGH and newer therapies such as fertilitytreatment (FSH) and osteoporosis (PTH).During the 1990s, the insulin pen marketbecame segmented with the introduction ofdisposable pens and reusable pensincorporating improved handling functions andelectronics.

These therapies require frequent, often daily,manual injection with weight-based dosing ordose titration, and injections are repeated untilthe cartridge is empty – usually after one totwo weeks.The drugs in the multiple-dosecartridges require the use of preservatives,while individual dose volumes are typically0.5 ml or lower. Pen injector patients are

accustomed to injecting themselves manuallywith 29-31G pen needles and their desire fordiscreet and easy-to-use devices hastraditionally overshadowed the need forautomated needle insertion or injection.

Auto-injectors have been on the market aslong as pen injectors but, until the 1990s, theiruse was restricted to emergency situations suchas epinephrine for treating anaphylactic shockand sumatriptan for treating migraine.Reusable auto-injectors have been used sincethe 1990s for syringe-based hormonereplacement therapies, and are increasinglybeing used for newer waves of biotechmolecules as prefilled formulations becameavailable for example, interferon for treatingmultiple sclerosis (MS).The first disposableauto-injector for a therapeutic protein waslaunched in 2005 by Amgen for its EPOproduct,Aranesp.

Auto-injectors, as their name implies,automatically insert the needle and perform theinjection – typically spring driven – and areusually designed for use with fillable or prefilledsyringes.A key requirement for auto-injectionis the need for liquid-stable formulations in aprefilled syringe or cartridge-based drugreservoir. Some of these drugs are injecteddaily, but many long-acting therapeutics arenow injected weekly or even less frequently,

particularly those for treating autoimmunediseases such as rheumatoid arthritis (RA) andpsoriasis. Most of these newer drugs do notcontain preservative (mono-dose formulations)and have comparatively large injection volumesof 0.5 to 1.0ml.

Factors influencing developmentThere are a range of patient and technologicalfactors influencing the further development ofpens and auto-injectors which are blurring thelines between the two types of devices.

Firstly, the fear of injections (needle-phobia)has spawned the development of needle hidersand automated needle insertion systems forpens, and auto-injectors for prefilled syringes.Studies performed with needle-naïve patientsconfirm that up to half of patients areunwilling or reluctant to inject themselves.Aspatients gain experience giving injections theproportion with needle phobia falls to 10-15%.Among insulin-dependent diabetics who injectthemselves very frequently the proportion ofneedle phobic patients is less than 10%.

Secondly, whether a prefilled syringe orcartridge-based injection is being performedthe need for needle safety is essential forinjections performed in the clinic or at home.This has led to the development of safety penneedles for pen injectors, safety syringes for use

Market trends: self-injection devicesYpsomed’s Ian Thompson reviews the development of self-injection technology and examines

the key features incorporated into modern-day devices, as well as future developments

Pens to cover a range of dosing needs and cartridge types



Self-injection technology

with prefilled syringes and disposable auto-injectors.

Thirdly, finer needles for pen cartridges andprefilled syringes are reducing the pain ofinjection.The introduction of 31G pen needleshas however increased the force required topush the drug through the fine cannula – thismeans that for larger volume pen injectionssome form of energy assisted injectionmechanism can help the patient to perform theinjection more easily. Prefilled syringes arebeing equipped with finer thin-wall 29Gneedles, which have the same flow-characteristics as traditional 27G needles.

Fourthly, many new biotech drugs are in afreeze-dried state and not available as a liquid ina prefilled syringe.The dual-chamber cartridgeprovides a convenient means of self-injectingthese drugs. In the case of multidoseformulations such as hGH, pens have beenavailable for many years. But many of these newlyophilised drugs are mono-dose formulations,injected immediately after reconstitution. If thedose needs to be varied, a pen-like dosingdevice used with a safety pen needle is ideal.

Cartridge-based systemsPatient needs for a broad range of pentherapies require pens with a range offunctionality.The pen systems can be brokendown into the following categories.

Reusable and disposable insulin pensincorporating all the functionality expected bydiabetics, such as easy dose-setting and clearlast-dose indication when the cartridge isnearly empty. For reusable devices simplecartridge exchange is essential.Above all thedose display must be large and easy to read,while the device itself needs to suit the targetpatient group. Insulin pens are today verymuch a consumer product where design, lookand feel are very important.Accessories andoptions offered to diabetics, such as needle-hiders, auto-inserters and electronic displays,are also available for pens in other therapeuticareas. Safety pen needles developed for insulininjections performed in care-giving situationscan also be used for other pen therapies.

Pens are also available to deal with dosingrequirements for non-insulin therapies. Manytherapies require weight-based dosing, butonce this dose is defined, the patient does nothave to change the dose. Dose-memory penssimplify handling so that the patient only needsto set the required dose once. For allsubsequent injections the patient only needs topull and push the dosing knob until thecartridge is empty. Other therapies require verysmall doses and the pen must incorporate

mechanisms to clearly communicate that thedose has been set and injected.

The use of dual-chamber cartridges putsspecial demands on the pen system in terms ofintuitive reconstitution, priming and dose-setting steps. It is very important for the patientthat these steps are therefore easy to learn andalways performed in the correct order.

Which pen device is ultimately selecteddepends on the dosing demands and patientpreferences.

Scale of convenience In conjunction with efforts to move mono-dose formulations from the vial into theprefilled syringe, pharma partners are lookingfor easier ways of giving injections.A simpleprefilled syringe alone can bring muchconvenience to a self-injection therapy.Whenused with a passive safety syringe the clinicianor patient is provided with needle safety, andan injection aid, making it easier to performthe injection.The passive safety syringe devices– with their low activation forces – can also beused in conjunction with new generationreusable auto-injectors.This has the advantagethat the same safety syringe (single SKU –stock-keeping unit) can be used in both theclinic and home environment with the simpleaddition of an auto-injector for home carewithout the cost and risk of packaging everysyringe in a disposable auto-injector.

In terms of convenience, the fully disposableauto-injector device is the obvious goldstandard for self-injection. Here, the prefilledsyringe is already packaged in the auto-injector,providing both ease of use and convenience forthe patient.All the patient needs to do isremove the device cap, press the device againstthe skin and start the injection process.Thedevice automatically performs the insertion ofthe needle and the injection.After injection, theneedle is automatically covered and made safe,as the device is removed from the injection site.With disposable auto-injectors a clearindication of the device status before, duringand after injection is important; the handlingshould be intuitive and the device should givevisual and audible notification that the injectionhas been successful.

Ultimately, which device is selected from theprefilled ‘scale of convenience’ (see Figure 1)depends on the competitive environment, theproportion of patients self-injecting, and theirspecific needs.

Patient-driven developmentIt is the patient who drives the continueddevelopment of new self-injection devices and

this is why device companies are developingstandardised device platforms that have beentried and tested with patients to cover theirbasic needs of ease of use, safety and reliability.The diverse range of therapies and needs ofpharma partners mean that the devicemanufacturers must be in a position to providetested and standardised devices at short noticewhich can then be customised to the needs ofeach drug, therapeutic area and patientsegment as needed.

Beyond the patients’ basic needs there are arange of special needs depending on their ageand clinical condition. For example patientswith visual impairment (such as diabetics orthe elderly) have special requirements, as dothose with age-related or motor disabilities(multiple sclerosis, rheumatoid arthritis,cancer). Care about needles is an issue withAIDS and HCV (hepatitis C virus), while 10-15% of the population can be expected to haveneedle phobia.

In summary, the market for self-injectiondevices – pens and auto-injectors – continuesto grow at above-average rates, based onpatent-protected technical designs customisedto patient and pharma companies’ specificneeds. Novel technical features to provide safeand reliable use have by no means beenexhausted, and the choice of the correct devicerequires careful selection and closecollaboration between the patient, the devicecompany and the drug manufacturer.

Ian Thompson is manager business development at

Ypsomed AG.

Figure 1: ‘Scale of convenience’


The first dry patch using electrostatic technology, E-patch®, a cost-effective deli-very system, opens up new pharmaceutical markets:• non invasive Diagnosis of airway, skin and food allergy• specific immunotherapy applied to highly sensitized patients• Preventive Vaccination, suitable for Biodefence• Transcutaneous Administration of Peptides

DVB TechnologiesContact : Jean-François BIRY - 88, avenue du Général Leclerc - 92100 Boulogne Billancourt - FranceTel: +33 (0)1 55 38 92 70 - Fax: +33 (0)1 41 31 28 82www.dbv-technologies.com - [email protected]

E-patch technology, an innovativepharmaceutical vector for diagnosis and treatment

100% non invasive

Diallertest® diagnosis portfolio: milk, wheat, dust mite allergyNON INVASIVE, FIRST READY-TO-USE AND MARKETED PRODUCT

Epicutaneous Specific Immunotherapy applied to highlysensitized patientsMAKING TREATMENT SHORTER, NO SYSTEMIC SHOCK

Preventive Vaccination, Suitable for BiodefenceE-patch® is a delivery system making the industrial developmentof epicutaneous vaccination possible:MASS VACCINATION, NO NEEDLE, NO COLD CHAIN REQUIREMENT

Transcutaneous Administration of PeptidesE-patch® makes Transcutaneous Administration of Peptides possibleHIGHER BIOAVAILABILITY, NO PEPTIDE DENATURATION

Cré

atio

n :

Sam

oa

- V

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aill

es


Drug Delivery 39

Product focus

Quite simply, the E-patch is a ‘dry patch’electrostatic technology that stores, on thecutaneous device, active ingredients in powderform.The ingredients are delivered when thepatch is stuck to the skin.The E-patch consistsof a non-adhesive polymeric support (backing)stuck on the skin by a peripheral adhesivecrown.The backing is a biocompatiblepolymer film with cutaneous tolerance.Although the technology is simple to describeit is a significant advancement to existingcutaneous systems!

Creating an E-patchFirst, the active ingredient must be in a powderform, with a controlled particle-sizedistribution. It is ‘powdered’ (sprayed) onto thesupport using a proprietary process. Duringthis powdering step, the powder particlesbecome, and remain, electrically charged.Theactive ingredient is therefore absorbed and heldin place on the backing by electrostaticattraction forces.

The amount of powder required will varyfrom one compound to another.Typically, from600 µg to 1000 µg of powder can be adsorbedon a 1cm2 backing. Indeed, the powder mustbe perfectly matched to the backing.Thismatching process may require the applicationof special treatments to the backing – forexample, employing an electret (see Figure 1).Application of electrets and other special

treatments (such as grinding) have no impacton the active ingredient.

Delivering the drugOnce the patch has been applied, its backingforms an airtight chamber with the skin, whichcollects natural water loss. Occlusion results inrapid hydration of the powder whichconsequently loses all adhesion to the plasticsupport.When the substance has dissolved, theactive ingredient comes into contact with theskin. Diffusion is usually very quick.Thisoriginal kinetic is nevertheless dependent onthe size of the molecules and the way in whichthey travel through the cells of the skin.

It is also possible (and often necessary) topurposely alter the characteristics of an E-patch – its occlusive volume, the size of thegap between the backing and skin, the powdergrading, its permeability etc.Altering theseelements will affect the solubilisation time ofthe powder, the amount of powder adsorbedon the backing and the acceptance of thepatch by the skin.

For instance, Diallertest Milk, a diagnosispatch-test for milk allergy (and the first E-patch application, now sold in Frenchdrugstores as well in Mexico the Middle Eastand Australia) is designed to stay in contactwith children or babies’ skin for 48 hours.Theocclusive room, therefore, is not too tight – toprevent the backing being in direct contact

Product focus: The E-patchBertrand Dupont, directeur

industriel of DBV

Technologies, describes the

properties and benefits of

DBV’s unique cutaneous drug

delivery patches, which

combine powder and

electrostatic technologies

for epicutaneous or

transcutaneous delivery

PolymericFilm

Heating

VHV Generator

Cooling

Electret

An electret is a plastic film that is completely and permanently polarised. To transform it into an electret,

the plastic support, generally a thermoplastic, is brought to a temperature higher than its glass transition

temperature, and then subjected to an intense electrical field before being cooled rapidly so as to freeze

the electrical charges.

Figure 1: The electret



Product focus

with the skin for too long, and causingirritation. In addition, the backing is water-permeable enough to prevent soaking asmoisture builds over the application period.

On the other hand, for applications whichdo not require a long application period, thebacking of the patch is almost in direct contactwith the skin – provoking very quickdissolution and absorption of the activeingredient by the skin (see Figure 3).

Why use the E-patch?As well as the flexibility of its design, the E-patch has many characteristics that mean ithas a variety of applications.◆ Long-lasting and stable: the active

ingredient is a dry powder without adhesiveor solvent; therefore it is perfectly suitable tofragile molecules such as proteins andpeptides. It is deposited in a dry atmosphereand packaged in a dry and waterproof bag. Itis easy to preserve, whatever the storageconditions – even if of organic nature orparticularly fragile. It can be kept at roomtemperature and does not require a coldchain.Typically, the shelf life of an E-patch istwo years.

◆ Economical: unlike reservoir or matrixpatches which require a large amount of theactive ingredient, E-patches retain only avery small amount of the active ingredientafter use.The quantity of active ingredientdeposited on a dry patch is the doserequired, no more no less.

◆ Safe: the patch cannot be re-used and doesnot cause pollution.

◆ Efficient: unlike most of the patches on themarket which deliver a more-or-lessconstant flow of active ingredient, the E-Patch can be used as a one-dose-releasepatch.

When to use the E-patchAllergy diagnosis: E-Patch is a perfecttechnology for the Atopy Patch Test (APT) –indeed, this was its first diagnostic application.Every food-allergen or pneumo-allergenpowder can be properly spread on an E-patch. Specificity and sensitivity of ‘E-patch-tests’ are at least as high as otherpatch-tests.

Epicutaneous immunisation: E-patchtechnology provides ideal access to the skinimmune system (SIS). Dominated by denselydistributed and potent antigen presenting cells,it can be stimulated to cause immune systemresponses. Practical advantages of epicutaneousimmunisation using a patch include:◆ Needle-free systems improve patient

compliance,◆ Avoidance of transmission of disease,◆ Stabilisation of antigens, avoiding the cold

chain.

Transcutaneous deliveryThe traditional patch technique has somedrawbacks:◆ The use of adhesive as a solvent may denature

some active ingredients which, consequently,cannot be administered transdermally,

◆ The absorbed dose depends on the length ofthe application period,

◆ A significant quantity of active ingredientremains after use.As discussed above, E-patch technology, can

overcome these problems.With an E-patch:◆ There is very little of the active ingredient

left on the patch after use,◆ There is no risk of overdose,◆ ‘Peak’ action kinetics are possible with ‘fast

transdermal passage’ molecules, using a lowquantity of active ingredient,

◆ Fragile active ingredients can be used intheir native state, without risk ofmodification by any interaction with asolvent or an adhesive (peptides),

◆ There is little waste and environmentaldamage,

◆ Large scale production is economical.For more information on DBV Technologies and theE-patch see our company profile opposite.

Figure 2: The E-patch – delivering the active ingredient

Figure 3: Altering the characteristics of an E-patch changes its effects


Drug Delivery 41

Company profile

DBV TechnologiesSpecialising in epicutaneous vaccination: desensitisation, biodefence, mass vaccination

Established in 2002, DBV Technologies is a private limited company. In January 2006, DBV raised€12.3m, with Sofinnova (leading investor) and Apax.

MANAGEMENT TEAMJean-François Biry, Chairman and CEO (former CEO of CIDER Santé)Bertrand Dupont, CTO, Ingeneer (founder)Dr Jorge Ronco, CSO (former Corporate Responsible at Pasteur Mérieux Connaught)Dr Pierre-Henri Benhamou, Paediatrician – gastroenterology, nutrition (founder)

SCIENTIFIC BOARDProf. Christophe Dupont, Chairman, Professor of Paediatrics, Head of Neonatology andNutrition Department, Hospital Saint Vincent de Paul, Paris (founder)

PRODUCTS/SERVICESDBV is working towards painless delivery of many other drugs and vaccines via the skin. Inparticular, DBV aims to successfully cross the protective outer layer of skin and to deliver fragilemolecules (peptides and proteins) in their native form, without excipients.

The E-patch • E-patch technology devices are innovative, cost-effective and easy to use• E-patches deliver larger and fragile molecules on (epicutaneous) or into (transcutaneous) the

skin, for controlled, pain-free delivery of drugs or vaccines.• Patch technique is particularly adapted to epicutaneous treatment, taking advantage of the

huge immunological potential of the skin.

MAIN AREAS OF ACTIVITY• Diagnostics: (non-invasive kits for testing for milk, dust-mite and wheat allergies):

Diallertest milk is DBV’s first product – launched in France in June 2004• Epicutaneous vaccination: biodefence, oncology• Cosmetic: skin treatment patches• Desensitisation treatment for food allergy (under development)• Biochemical research in allergy, immunology and drug delivery• Industrial development (manufacturing process, machines and production)

Competitive advantages of E-patch technology:In allergy diagnosis and desensitisation:• Allergen applied without excipients• Easy to use, apply and read• Standardised and reliable• Safe, no risk of systemic shockIn epicutaneous administration of active ingredients:• Administration of fragile molecules• Storage at ambient temperature• Very low amount of active ingredient remaining on the patch after use

CONTACT INFORMATIONDBV TechnologiesContact person Jean-François Biry – CEOTel +33 155 389 270Email [email protected] address www.dbv-technologies.comtechnologies

dbv



Company profile

Baxter Healthcare Corporation

1 µm1 µm

Baxter Healthcare Corporation’s award-winning BioPharma Solutions business is dedicated topharma and biopharma customers, offering contract services and proprietary technologiesfocused on parenteral (injectable or pulmonary) delivery. Contract services include:development, form/fill/finish into syringes, vials, and cartridges, lyophilisation and cytotoxicsmanufacturing. Proprietary technologies include NANOEDGE dispersion and PROMAXXmicrosphere formulation technologies and enhanced packaging.

CONTRACT SERVICESRecipient of the 2006 pharmaceutical Facility of the Year Award, Baxter’s Bloomington facilityhas expanded capacities for syringe and vial filling/finishing, making Baxter the global SCFleader in prefilled syringes. We have added new capability in cartridge filling/finishing, as wellas a fully automated kitting line. Our newest lyophilisation and vial-filling lines are specificallydesigned for biologics; lyophilisation capacity has increased along with the advancement of theLyophilisation Center of Excellence. Baxter can also provide analytical and microbiologicalservices as well as validation and regulatory assistance.

In our German facilities, we can take you from scale-up to commercial production for dedicatedcytotoxic contract services. Our state-of-the-art facility features advanced aseptic processingusing barrier isolator technology. Our technologies include lyophilisation, aseptic liquid vialfilling, dry powder vial filling and sterile cystallization. Other services include stability storage,validation and documentation, and analytical services.

Baxter is a proven CMO provider offering best-in-class parenteral outsourcing solutionsincluding:

• Reliable supply – complete contract manufacturing resources.

• Expertise – highly skilled solutions for a streamlined path to market.

• Bottom-line results – lower expenses and increased revenue.

PROPRIETARY FORMULATION TECHNOLOGIESNANOEDGE dispersion technology offers innovative formulations for your solubility challengesand is applicable for multiple routes of administration. It reduces the particle size of most drugsto nanometer size, which can enhance a drug’s saturation solubility and dissolution rate andeliminates the need for undesirable cosolvents.

The PROMAXX microsphere technology is a unique, elegant and cost effective formulationplatform, tailored to fit your specific requirements. It is applicable to a broad range ofmolecules – from small molecules and nucleic acids to peptides and proteins. PROMAXXtechnology can offer high drug loading and precise particle size control and enable dosingflexibility across various administration routes.

CONTACT INFORMATIONBaxter Healthcare CorporationIn US: +1 800 422 9837Direct: +1-847 948 4770Fax: +1 847 948 3642Email: [email protected] addresswww.baxterbiopharmasolutions.com


The power of pulmonary delivery with PROMAXX microsphere technology.

By giving you precise control over microsphere sizeand uniformity, PROMAXX facilitates development ofpulmonary formulations. This versatile platform workswith a wide range of compounds, from proteins andpeptides to small molecules.

Plus, you can trust the experienced Baxter team to workwith you to solve your unique formulation challenge.

Add powerful new potential to your drug pipeline with PROMAXX. To learn more, visit www.baxterbiopharmasolutions.com. For specific requests, send an e-mail [email protected], or call 1-800-422-9837.

Now open for business.Now open for business.

Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 920302 4/05Baxter and PROMAXX are trademarks of Baxter International Inc., its subsidiaries or affiliates.

1 µm1 µm

PROMAXX microspheretechnology delivers uniqueparticle size control ideal forinhalation therapies.

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