June 2007 Vol 7 No 6 www.drugdeliverytech.com IN THIS ISSUE

INTERVIEW WITH EURAND’S CHIEF COMMERCIAL OFFICER MR. JOHN FRAHER The eFlow® Nebulizer 30 Shabtai Bauer, PhD Markus Tservistas, PhD

Bioadhesive Microspheres 54 Jayvadan Patel, PhD

Transdermal Solutions 68 Gary W. Cleary, PhD

FEATURING

Imaging CROs 72 Richard Taranto

Autoimmune The science & business of specialty pharma, biotechnology, and drug delivery Diseases 80 Douglas Kerr, MD Adam Kaplin, MD JuliaJulia Rashba-Rashba- Shaukat Ali, Richard Step,Step, PhDPhD PhD Sitz, MBA EfEfficientficient PulmonaryPulmonary HMW Povidone Beyond Sticky Partnering With DeliveryDelivery ofof BiologicalBiological PolymerPolymer-Based-Based toto Sophisticated:Sophisticated: NovaQuest 84 MoleculesMolecules asas Films for The Many PROMAXXPROMAXX Fast-Dissolving Dimensions Ms. Cindy H. Dubin MicrMicrospheresospheres Drug Delivery of Adhesives

4 Drug Delivery Technology June 2007 Vol 7 No 6 $15.00, US,Canada,andMe 01923; pho Technology LLC for librariesandotherusersregistered withtheCopywriteClearance, 222RosewoodDrive, Danvers, MA items f Periodicals Postage Paid atMontville, NJ07045-9998andadditionalmailingoffices. Postmaster: Delivery T States, Canada,andMexico. AllsubscriptionsarepayableinUSfunds, drawnonUSbanks. Sendpayment to:Drug Subscription rates:$99.00f October (ISSN 1537-2898)ispublished10timesin2007,January, February, March,April,May, June, July/August, September, responsibility f o All editorialsubmissionsarehandledwithreasonable care, butthepublishersassumenoresponsibilityfor thesafety or inf be reproducedortransmitted inanyform orbyanymeans, electronicormechanical,includingbyphotocopy, recording, the U.S.,Internationaland P address changestoDrugDeliveryT f artwork, photographs ormation storageandretrieval system,withoutwrittenpermissionfromthepublisher or internalpersonaluse , and November/DecemberbyDrugDeliveryT echnology LL ne: (978)750-8400, f or theaccuracyo East &Midwest Mailing ListRental International W C est Coast subscription Department,219ChangebridgeRoad,Montville NJ07045.Singlecopies(prepaid) , or manuscripts or 1yearintheUnitedStates 219 Changebridge Road, Montville, NJ07045 an-American CopyrightConventions xico; $24.00inallothercountries ax: (978)750-4470. f EXECUTIVE EDITORIAL DIRECTOR inf [email protected] , echnology ormation suppliedhereinorfor anyopinionexpressed. Drug DeliveryTechnology or theinternalpersonal useof specificclients, isgrantedbyDrugDelivery Can Ralph Vitaro Warren DeGraff 103 Oronoco Street, Suite200 Cheryl S.Stratos -Account Executive Victoria Geis-Account Executive ADMINISTRA June 2007 TECHNICAL OPERATIONS CONTRIBUTING EDITORS PUBLISHER/PRESIDENT Corporate/Editorial Office . www.drugdeliverytech.com A d Every precautionistak EDITORIAL SUPPORT CREATIVE DIRECTOR dv y Fax: (973)299-7937 Shalamar Q.Eagel Nicholas D.Vitaro , T Dan Marino, MSc ertising SalesOffices Brecht 219 ChangebridgeRoad,MontvilleNJ07045.Allrights reservedunder Kathleen Kenny Jason McKinnie el: (973)299-1200 Debra Bingham Cindy H.Dubin Debbie Carrillo Mark Newland CONTROLLER Ralph Vitaro E-m Fax: (703)549-6057 Tel: (703)706-0383 E-mail: [email protected] Fax: (973)299-7937 Tel: (973)299-1200 Montville, NJ07045 219 Changebridge Road W E-mail: [email protected] E-mail: [email protected] Fax: (703)548-3733 Tel: (703)212-7735 Alexandria, VA 22314 E-mail: [email protected] Fax: (415)721-0665 Tel: (415)721-0644 San Rafael, CA94901 818 5thAvenue, Suite301 estern Regi echnology LL ail: cbr , TIVE SUPPORT Canada, andMexico. $153.00for 1yearoutsidetheUnited Vol 7No 6 [email protected] . en toensureaccuracy . All rightsreserved.Nopart of thispublicationmay on C, 219ChangebridgeRoad,MontvilleNJ07045. Add $5.00perorderfor shippingandhandling. al M an ag er , but publisherscannotaccept . A uthorization tophotocopy please send

26 Discussing Gastro Retentive Drug Delivery Systems Contributor Cindy H. Dubin interviews some experts on gastro retentive dosage forms, which may be one of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract.

44 Beyond Sticky to Sophisticated: The Many Dimensions of Adhesives Richard Sitz, MBA, presents two of his company’s recent innovations in adhesives, which are creating additional opportunities to advance the performance of transdermal drug delivery systems.

48 Efficient Pulmonary Delivery of Biological Molecules as PROMAXX Microspheres Julia Rashba-Step, PhD, explains how multiple biological molecules, including AAT, hGH, and insulin, have been successfully formulated using the PROMAXX microsphere delivery technology as viable products with excellent characteristics for pulmonary drug delivery using a simple dry powder inhaler.

54 Bioadhesive Microspheres & Their Pharmaceutical Applications “In this study, high molecular weight Jayvadan Patel, PhD, provides an introduction to and a comprehensive discussion on the advanced povidone (PVP), for example, Kollidon pharmaceutical applications of bioadhesive 90, was used as a carrier in fast- microspheres.

® 6 dissolving films, demonstrating strong 62 Eurand: Creation of AdvaTab - o N A New Technology for Orally 7 l

o hydrophilicity and compatibility with

V Disintegrating Tablets

7 Drug Delivery Executive: Mr. John Fraher, Chief 0

0 a wide array of polymers and 2 Commercial Officer of Eurand, discusses his e n u

J copolymers.” company’s successful strategy behind AdvaTab and y

g how Eurand views its co-development programs in o l o n

h light of its specialty pharma growth strategy. c e T y r e v i l e D g u r D p.36 6

68 Corium: New Dimensions in Transdermal Solutions Drug Delivery Executive: Dr. Gary W. Cleary, Co- Founder, President, and Chief Technology Officer of Corium, talks about the exciting opportunities on the forefront of novel drug delivery.

72 Imaging CROs & Their Impact on Clinical Trials Mr. Richard Taranto discusses several critical qualities to consider when choosing a central imaging CRO, including specific operational procedures, access to therapeutic and modality expertise, adherence to rigid quality control processes, use of technology that improves workflow, and the ability to provide regulatory support.

80 Revimmune: Delivering a Knockout Punch to Autoimmune Diseases Douglas Kerr, MD, PhD, and Adam Kaplin, MD, PhD, believe Revimmune, a patent-pending pharmaceutical treatment in late-stage development for a variety of autoimmune diseases, is a potential treatment option for severe, refractory, immune- mediated illnesses.

84 NovaQuest: Strategic Partnering to Optimize Portfolio Value, Growth & Profits Executive Summary: Mr. Ron Wooten, Executive Vice President of NovaQuest, shares his company’s partnership strengths, particularly in regard to product development and commercialization expertise from Quintiles and Innovex, and access to the healthcare industry and investment expertise of TPG-Axon Capital. 3 o 6 N o DEPARTMENTS N 7 l 7 o l V o “An imaging CRO can increase the overall efficiency Market News & Trends ...... 12 V

7 Attorney Review ...... 21 0 7 0 0

2 of the clinical trial program and decrease the costs 0 Who Needs Motivation? The New Obviousness h 2 c r e Standard in Patents a n associated with the overall development of a u M J Advanced Delivery Devices ...... 30 y y g g o

o compound by reducing the length of a clinical

l A Novel Electronic Nebulizer for AAT Patients l o o n n h h Excipient Update ...... 36 c c

e trial. With the appropriate expertise, an imaging e T T High Molecular Weight Povidone Polymer-Based Films for y y r r e e v v CRO will be able to assist in imaging trial design

i Fast-Dissolving Drug Delivery Applications i l l e e D D Technology Showcase ...... 66 g g and acquisition protocols that can potentially u u r r

D Facts & Figures ...... 78 D reduce the study’s size and duration.” External Delivery ...... 90 8 p.72 Resumes 101 9 Drug Delivery Technology April 2006 Vol 6 No 4 10 Drug Delivery Technology June 2007 Vol 7 No 6 Degussa Technical Service Manager Nasser Nyamweya,PhD Systems 3M DrugDelivery Division Vice President James Vaughan Dir Ronald L.Smith,PhD Research Institute Bristol-Myers Squibb Drug Delivery Bi P S Jack Aurora,PhD Schering-Plough Developm Delivery &LifeCycle Seni David Monteith,PhD,MBA Dir Philip Green,PhD Merck Research Laboratories Biologicals &Vaccines Pharm Associate Director, Marc J.Kirchmeier, PhD D M Vice President, Global Sarath Chandar, MBA S A Development BD enior Director, R&D errigo Company PI Pharma evelopm dvan opharm arketing &Commercial ector o Technology D Director Executive Editorial Dan Marino,MSc ector o or Director, Drug rug Delivery aceutical R&D ced DrugDelivery aceuti f ent e f nt nt Exploratory Busin cs & ess CIMA LABS,INC. New Technology Senior Manager, Beth A-S.Brown,PhD,MS Cardinal Health, PTS Process VP, Strategy &Business Cor Akina, Inc President Kinam Park,PhD B Associate Director PhD, MS Mahesh Chaubal, T President &CEO John A.Bermingham Pharm Associate Professor of Uday B.Kompella,PhD Development Pfizer GlobalResearch & Form Director, Research Keith Horspool,PhD Wilm Partner, FDA Department James N.Czaban,JD U M he Lang Companies axter Healthcare niversity o edi nell Stamoran cal Cen erH ulati aceuti ale on s ter f cs N ebr aska Glax S.R. One, Limited, Investment Manager Philip L.Smith,PhD Pharm Brookwood and Chief Scientific Officer Executive Vice President T at Austin University of Texas Pr James W Labor M Director Henry Y. Wu, PhD,MS Corium International President &CTO Phar Gary W. Cleary, PhD, P Investigator, Matthew D.Burke,PhD GlaxoSmithKline LifeT COO Ravi Kiron,PhD,MBA Eur President, North America John Fraher om Tice, PhD harmaceutical Development er ofessor of Pharmaceutics an ck Resear oSmithKlin ech Inn mD, MBA atories d aceuti . McGinity, PhD cals ovati ch e on s , LLC

12 Drug Delivery Technology June 2007 Vol 7 No 6 dr development teamwithaproven trackrecordinbiodegradable materials, combined strengthsofthetw Birmingham. inBirmingham. Aeon Biosciencewillbeheadquartered The Birmingham Technology Fund, managedby GreerCapital Advisors, LLCof medical device company. Series A fundingwas securedthroughthe company. Targeted Technology isaSan Antonio-based biotechnology and forBirmingham. industry development, jobcreation,andincreasedvisibilityinthemedicaldevice cardiovascular disease.” result inanimprovement inthequalityoflifeforpatientssuffering from coating inordertoimproveofDES. This willultimately thesafetyprofile result, Aeon willfocusonthedevelopment ofamoreeffective polymeric provides animmediateneedtodevelop asolutiontotheLSTproblem. As a Targeted Technology, who asCEOof willserve Aeon. "Thissafetyissue LST," safetyofDES, specifically term saidChristopherE.Banas,Principal, Barcelona, Spain,datawas over presentedidentifyingaconcern thelong- 2006 when, duringthe World ofCardiology Congress meetingheldin ofscartissue,knownto formation asrestenosis. or bloodatnearthesiteofstentandvessel closuredue clotformation eluting stenttoovercome oflatestentthrombosis(LST) concerns thecurrent Aeon Bioscience,Inc.,acompany thatwillwork todevelop anew drug- re K $150 Million KV B Company to Improve Aeon Bioscience Cardiac Stents Targeted Technology VenturesBrookwood Pharmaceuticals, Form New e e v sprayestradiol transdermal thatoffers anovel approachtothetreatmentof be paidiftheproductachie achieves $100millioninnetsalesa market year, andwill upto$20million tied tothenetsalesofproduct. appro an additionalpayment ofapproximately $140millionatthetimeoffinal the all-cashtransaction,KVag consistent withthose cur appro estrogen product. The company estimatesEvaMist's USmarket potential tobe appro 29, 2007,fromtheFD branded subsidiary, Ther-Rx Corporation. With aPDUFA action dateofJuly w April 1,2007. xclusi xpected tosignif asomotor symptomsassociatedwithmenopause.Uponappro hich ph gistrations. Brookw ug deli Brookwood Pharmaceuticals is a Birmingham-based drug deliveryBrookwood drug isaBirmingham-based Pharmaceuticals Mr. Banasaddedthatthecreationof Aeon willspureconomic stent(DES)market suffered“The drug-eluting asetbackinSeptember Ev The producttar recently announcedthecreationofacollaborative jointventure toform rookwood Inc.and Pharmaceuticals, Targeted Technology Ventures, LLC V previously announcedtransactionwith Vivus, Inc.forthesublicense of aMist, w v v ximately margins $125millioninpeak,annual netsaleswithgross al fromtheUSFDA. There arealsotwo, one-timemilestonepayments ed andlaunchedduringthesecondhalf ofitsf v Phar e hraetclCmltsAqiiino USRights to EvaMist for Completes Acquisition of Pharmaceutical v ysicians andpatientsareseekingan ef rights andpurchaseofassetsrelatedtoEvaMist. of Undertheterms er maceutical Compan y , hich hascompletedPhaseIIIclinicaltrials,isapatented v ascular stentengineering,clinicaltesting,andre icantl gets anannual$1.3-billionestrogen replacementmarket in ood and A, KVcur y rentl augment thew v es $200millioninnetsalesamarket year. o y Targeted Technology alsobringstrongskillsin parent companiesgi reed topa being achie y rently expects thattheproductmay be recentl T en millionwillbepaidiftheproduct omen’ y y repor v $10 millionatclosingandtomak ed b s fecti health of ted ithascompletedits y Ther-Rx Corporation. KV Ther-Rx Corporation. v v e e iscal 2008,w Aeon astrong and safe,low-dose ferings ofKV’s val, EvaMist is gulator hich be y gan e joint v strong commitmentandenthusiasmofeveryone involved withthisimportant launching ne and medicaldevice emphasison pharmaceutical, products,withaparticular collaboration uncommonexperience indeveloping arangeofdiagnostic, Principals ChristopherE.BanasandDr. Paul Castella,bringtothis technology resourcesresidinginBirmingham. The leadershipof TTV, prove tobethecatalyst forcapitalizingontheimmense,mostly untapped leadership, hasemerged asourtechnology crown jewel, andwillultimately working asateamtoward anambitiousgoal.Brookwood, underDr. Tipton's ofsuchtalentandexperience asBrookwoodassociated withgroups and TTV, as serve Aeon’s oftheBoardsaid, Chairman “Itisarareprivilege tobe synergy ofputtingtheseteamstogether.” appreciative of torecognizeAlan Dean(GreerCapital)who the was thefirst Greerandhisteam,we areparticularly addition tothefundingfromLarry of Brookwood who asPresidentof Pharmaceuticals, willalsoserve Aeon. "In on stentdeveloping andtesting,"saidDr. J.Arthur Tipton, PresidentandCEO Technology, who as willserve Aeon's ChiefBusinessOfficer. stents andcardiovascular implants,” saidDr. Paul Castella,Principal, Targeted tomeetthestringentdemandsofnext generationofcoronary necessary eluting polymers withthebiocompatibilityandbiological performance Aeon's technology make progress. platforms andmedicalleaders. Additional collaboratorswillbeaddedas scientific andaccesstorecognized portfolios management ofintellectualproperty belie cosmeticall that isamongthelowest available forthisindicationinamannerthat is also products. distinguished brandedandgeneric/non-brandedprescriptionphar company thatdevelops, andmarkets andacquirestechnology- manufactures, subsidiar with brandedproducts,and that compete anationalleaderinpharmaceuticals through Ethex Corporation, been completedforthetreatmentof obesity; and se commercialization ofne completed andanND Desire Disorder(HSDD);Ev Phase IIstudyhasbeencompletedfor thetreatmentofHypoactive Sexual The in underNDAIII clinicaltrials,andoneproductcurrently review by theFDA. on themark the treatmentoferectile dysfunction(ED).MUSEisappro symptoms; andavanafil, forwhich aPhaseIIstudyhasbeen completedfor Alan Dean,ManagingPartner, FundOperationsatGreerCapital,who will “We focus arethrilledtobeworking withsuchastrongteamspecific “Aeon Bioscienceisuniquely positionedintheracetodevelop new drug- KV Phar Vivus, company Inc.isapharmaceutical dedicatedtothedevelopment and v es Ev xual health. v enture. estigational pipelineincludesQnexa, forwhich aPhaseIIstudyhas y The compan . y aMist willof maceutical Compan et forthetreatment ofED w ” appealing forw inno V v i ati vus hasthreeproductsthatarepositionedtoenterPhase A y ve devices forcardiovascular diseases.Iappreciatethe mark xt-generation therapeuticproductsaddressingobesity submitted forthetreatmentofmenopausal fer therapeuticef Ther omen. aMist, forwhich a Phase IIIstudyhasbeen ets itstechnolo y -Rx Corporation, itsemerging brandeddrug -Rx Corporation, is afull . y fecti inte gy-distinguished products T v estosterone MDTS,forw g eness withestradioldosing rated specialtyphar ved and currently maceutical maceutical hich a

14 Drug Delivery Technology June 2007 Vol 7 No 6 Products Division, andaconsultant tothecompanies,commented, “Theresults Dr Food andDrug Administration, andadvance Indaflex intoregistration trials.” appropriate pi gained fromthisproof-of-conceptstudyhasprovided insightson important function forpatientssuffering oftheknee. fromosteoarthritis The knowledge with potentialforef of Indaflex well asavery toleratedandsafetopicalNSAID productcandidate, "Thedatapointtothepromise President andCEOofPropriusPharmaceuticals. comparing Indafle be to patientstreatedwitheitherplaceboorvehicle. Indaflex was demonstratedto at baselineshowed positive trendsinpatientstreatedwithIndaflex ascompared of patientswithmoderate-to-severe pain andmoreimpairedphysical function efficacy. analyses endpoints,subgroup While thetrialdidnotmeetitsprimary Index (WOMAC)Osteoarthritis score,andthesubject’s globalassessmentof to week 6intheglobal Western OntarioandMcMaster Universities the knee. endpointsusedinthetrialwereThe primary thechangefrombaseline included a6-week treatmentperiod, was conductedin233patients withOA of and was inCanada. performed 200). The proof-of-conceptstudy was initiatedinSeptember2005by AlphaRx (OA) PhaseIIclinicaltrialinosteoarthritis exploratory oftheknee(INDF- the works.” technology willhelpadvance thedevelopment in ofthetherapeuticcurrently production strainforits VGX-100 thatour protein,andwe areconfident collaboration with VGX quickly resultedinthedelivery Pfïnex robust ofavery economics,” saidNickHyde,GlobalBusinessDirector, Dowpharma. “Our looking foramoreextensive results,andbetter rangeofproteins,faster rapidly inthepastseveral months,driven by developers biopharmaceutical choice forthegrowingcandidatesthatrequirecomplex folding. numberofdrug overall costofgoods. This makes Pfïnex Expression Technology an obvious process,andavoids reducesthe arefold step thatsignificantly purification soluble proteinexpressed iseasiertohandle,enables aclearerpaththroughthe strain capable ofproducinghighyieldsproperly folded, active protein. The ofa able toscreenhundredsofexpression strains,enabling rapididentification increased yieldsofsoluble, foldedtherapeuticproteins.Dowpharma correctly is Pseudomonas fluorescens-basedPfïnex Expression Technology produces cancer therapy. will beusedtoproduceaproprietary VGX therapeuticproteinindicatedfor Underthisnon-exclusivePharmaceuticals. globallicense,Dow’s technology Expression Technology company toleadingbiopharmaceutical VGX and w expression systems. Viral toproduceinhighyields, proteinRhasbeendifficult Technology consistently othercommercially outperforms available microbial added, “We have toDowpharma turned becausethePfïnex Expression A I AnnounceAlphaRx Pharmaceuticals Top &Proprius Line Results From D Expression Pfïnex Licenses TechnologyDowpharma to VGX Pharmaceuticals ndaflex Phase IIStudy Phase inCanadandaflex ug Administration's Analgesic, Anti-Inflammatory, and Ophthalmic Drug Ophthalmic ug Administration's Analgesic,Anti-Inflammatory,and Dr. Lee S.Simon,aRheumatologist DirectoroftheFood andformer and “We trial humanefficacy areencouragedby theresultsofthisfirst The randomizeddouble-blind placeboandvehicle-controlled trial,which Dr “The adoptionofthePfïnex Expression Technology hasbeenaccelerating techniques,the Compared totraditionalmicrobialfermentation safe andwell tolerated. line resultsfromtheIndaflex 2.5% Topical IndomethacinCream lphaRx Inc.andPropriusPhar Chemical Company, recently announcedthatithaslicenseditsPfïnex unitof abusiness owpharma services, contractmanufacturing The Dow . e J. JosephKim,Co-Founder, President,andCEO, VGX Pharmaceuticals, w ere pleasedwiththeresultsobtainedPseudomonas votal trialdesign. We withthe areeagertodiscussourfindings x ficacy intreatingmoderate-to-severe painandimprovingficacy to bothplaceboandvehicle,” saidMichaelJ. Walsh, maceuticals, Inc.recently announcedtop commercialization. Propriusisaprivately held, venture-backed company. and diagnosticser autoimmune diseases. This novel pharmaceuticals combinationofproprietary develops andmarkets personalizedmedicinesolutionsinrheumatology and tuberculosis, ocularinfection,andinflammation, pneumonia,andsepsis. candidates addressvarious markets, including arthritis, pharmaceutical human bodywithanacceptab insoluble orpoorly soluble inwater orhave yet tobeadministrable tothe deliverydrug technology todevelop novel thatare ofdrugs formulations Indaflex (withtheexception of Asia andMexico) in April 2006. acquiredtheexclusivepreparations. PropriusPharmaceuticals globalrightsto incomparisontooraltreatmentsandothertopical tolerability profile companies believe Indaflex willhave an attractive efficacy, safety, and technology nanoparticle developedskin usingaproprietary by AlphaRx, the has along-standingandproven clinicaltreatmentrecord.Delivered throughthe 10% oftheworld's population. The active inIndaflex, indomethacin, ingredient the mostcommonchronicdiseaseinNorth America andafflicts anestimated reduction ofsignsandsymptomsassociatedwithOA oftheknee. is Arthritis associated withlocalizedpainandinflammation.” ofthe knee,aswellosteoarthritis asotherdiseasesanddisordersthatare selective NSAIDsorCOX-2 selective inhibitorsforthetreatmentof the needforaneffective, tolerable, andsaferalternative toeitheroralnon- safety ofIndaflex. This therapeuticproductcandidate hasthepotentialtofulfill of thisinitialclinicaltrialpro commercial launch. andscale-upfromfeasibilitythroughclinicaltrialsto manufacturing development, chiralcapabilities,andassociatedanalytical aswell services as delivery. Dowpharma offers processdevelopment, routeselection,methods ser industrieswithinnovativeand biopharmaceutical technologies, products,and cancer, diseases. andinflammatory and biologics productcandidatesforthetreatmentofinfectiousdiseases, additional, uniqueequipment. recovery,in traditionalfermentation, settingswithnoneedfor andpurification target proteinaccumulationand/orstability. The technology iseasily employed to identifyexpression strategy/host cellcombinationsthatresultinimproved expression hoststraindevelopment. Dozensofhoststrainsaretestedinparallel thanintraditionalmicrobial strain development andmoreefficient faster proteolytic andenhancedsolubility/activity, degradation, makingtheprocessof reduced bondformation, disulfide expressed inhighyieldswithcorrect productionstrainshavehigh-performance beendeveloped. Proteinsare infectious componentofthemicrobialflorasoil,water, andplants,many choice forus.” wesupport have received sofar fromDowpharma have madeitanexcellent underway. andknowledgeThe expertise thatcomewiththetechnology andthe Diosynth Biotechnology, processdevelopment andfurther andscale-upis toourcontractmanufacturer,and othercancers,hasalreadybeentransferred manufacturing VGX-100, ourleadproteintherapeuticcandidate forlymphoma fluorescens-based technology. The productionstrainandprocessfor Proprius Phar AlphaRx isaclinicalstagephar inclinicaldevelopmentIndaflex isatopicalNSAIDformulation forthe Dowpharma contract manufacturing services providesDowpharma services contractmanufacturing thepharmaceutical VGX company isabiopharmaceutical withsmallmolecules Pharmaceuticals andnon- Using anaturalisolateofPseudomonasfluorescens,anabundant vices for clients in drug discovery,vices forclientsindrug development, and manufacturing, maceuticals is a specialty pharmaceutical companymaceuticals isaspecialtypharmaceutical that vices provides a strategic anddifferentiated approachto vide supportive evidence and fortheefficacy le delivery method. The company's product maceutical company utilizingproprietary

16 Drug Delivery Technology June 2007 Vol 7 No 6 Administration,” continuedDr. “Thetrialwillbe conductedby CMAXat Ogru. In glucose, insulinandc-peptidelevels.” President atPhosphagenics.“ bloodstream without any adverse reactions,” saidDr. Executive EsraOgru, Vice of TPM-02/Insulin gelrapidly delivered insulinacrosstheskinand into the attracti insulin, provides appropriatelevels ofinsulininhumans,andiscommercially of long-actinginsulin,w Phosphagenics’ oflong-actinginsulin.Recentadvancementsassess anoptimizedformulation in completion ofaPhaseIastudyutilizingshor administering insulintopatientswithdiabetes.F quar containing long-actinginsulin. improved insulinproduct, ofitstransdermal formulation TPM-02/Insulin, P Trial Quarter inSecond P and isalsosubjecttotheapproval ofIOMEDshareholders. closingconditions customary ofcertain Directors, issubjecttothesatisfaction acquisition, which hasbeenunanimously approved by IOMED'sBoardof medical device company markets. intherehabilitationandorthopedics The for themanagementofpain.ReAble Therapeutics isaprivately held, leading price over thelast30tradingdays. merger representsapremiumofapproximately 38%over theaverage closing transaction considerationwillbeapproximately $22million. The all-cash in anall-cashmerger for$2.75pershare,subjecttoadjustment. The total wherebyagreement ReAble willacquirealltheoutstandingsharesofIOMED I IOMED Agrees toAcquired be byReAble for $22Million Therapeutics par manuf ReAble, operatingunderReAble's Empidivision. Empiisaleading network ofindependentsalesagentsandspecialtydistributors. continue todistrib f andproductdevelopmentcustomer support, functionsatitsSaltLake City W and technologies, network. distribution anexcellent andhasbuilt third-party “IOMED hasde strategy.” stepforwardacquisition representsanimportant inReAble’s overall growth assets. IOMED’s productsandextensive network distribution strategic asimportant its excellent productdevelopment capabilitiesintoourEmpidivision. We view acility v e Medical Corporation) recently announcedthesigningofadefinitive Medical Corporation) OMED, Inc.andReAble Therapeutics, Inc.(formerly known asEncore “The PhaseIbstudyisintendedtoprovide dataforan additionalsupporting “In TPM-02/Insulin gelisbeingdeveloped asanovel “needle-free”way of F delivery ofdrug devicesIOMED isaleadingmanufacturer usedprimarily Commenting onthetransaction,K Rober hosphag estig t initiate aPhaseIbclinicaltrialtodemonstratetheef hosphagenics Limitedrecentl are v ollo ter of2007. of theEmpidi acturer andmark August 2006,ourPhaseIastudydemonstrated thatasingleapplication ve. . W wing theacquisition,IOMEDwillbeaw ational Ne In addition,IOMEDwillmaintainitsf er t e J y belie . Lollini, IOMED’ pleased toincor v patented TPM-02 delivery system have enabled theformulation veloped anoutstandinglineofinnovative delivery drug devices e w ute itscoreiontophoresisproductlinesthroughe IOMED is an excellent strategic fit withEmpi,andthatthis IOMED isanexcellent strategic fit vision, IOMEDisexpected tocontinueitsmanufacturing, enics Limited Transdermal Ib to Commence Phase enics Insulin Clinical Drug applicationtotheUSFoodDrug andDrug eter ofpainmanagementandrehabilitationde hich issignif porate IOMED’ s Additionall CEO, commented, “Empiisaworld-class pain The trialise y announced thatthecompan enneth icantl y , it signif y xpected tocommenceinthesecond s W t-acting insulin,thistrialwill less e strong portfolio of productsand strong portfolio . ield-sales suppor Da ollowing thesuccessful holly owned of subsidiary xpensi vidson, ReAb icantly lowered blood f ve thanshort-acting icac y y and safetyofthe t, andwill le's CEO, said, intends to vices. xisting As nutraceutical products. the bioa company focused onthediscovery ofnew andcost-effective ways toenhance ef “This technology hasthepotentialtoprovide diabeticswithanon-invasive and TPM-02/Insulin, Phase IItrialthatislikely to includeuptoseveral hundredpatients.” v the Ro safety ofe phosphate g aprocessinwhichscience andapplicationofphosphorylation, theaddition ofa the-counter mark York (PPGNY)forUSinvestors totradeinPhosphagenics'stockontheover- ADR -Level 1program hasbeen established intheUSwithBankofNew and theLondonStockExchange’ deliveryproduction ofdrug platforms. de advisor toIOMEDinthistransaction. close inJuly 2007.Seven LLCactedasexclusive HillsPartners financial announced. Pending suchshareholderapproval, thetransactionisexpected to including approval by IOMEDshareholdersinaspecialmeetingyet tobe fortransactionsofthistype, andconditionscustomary terms to certain strategicmakes senseforbothcompanies.” great and developing delivery category, theiontophoresisdrug andthiscombination commercialized broadly. IOMEDandEmpishareastrategic visionofgrowing our products,andtechnologies willcontinuetobeutilizedeffectively and continue tooffer world-class productsandtoknow thatourcorecapabilities, management company. We pleasedtojointogether arevery withEmpito Exchange underthesymbolIOX. both locally andsystemically. IOMEDispublicly tradedonthe American Stock and propelthemthroughtheskin.Iontophoresisisusedtodeli molecules toionizedrug transdermally usingelectriccurrent pharmaceuticals focused primarily oniontophoresis.Iontophoresisisatechnology thatdelivers inagoprivatethe private transactioninNovember equityfirm, 2006. reconstr ReAb rehabilitation, physical therapy, enhancement. performance andsport fitness, and otheror Rehabilitation Di traumatic events, injuries. andsports-related Through itsOrthopedic musculosk sur medical devices usedby physicians, therapists,athletictrainers,orthopedic olunteers, andise fective treatment,andwe lookforward toitscontinueddevelopment.” v Phosphagenics isaMelbour “This isanimpor hshgnc’shares arelistedonthe Australian StockExchange(POH) Phosphagenics’ ReAble is a diversified rehabilitation and orthopedic device rehabilitationandorthopedic ReAble company isadiversified that andtheclosingoftransactionissubject merger agreement The definitive IOMED isadi geons, andotherhealthcareprofessionalstotreatpatientswith elops, manuf le's Sur yal vailability, activity, safety, anddelivery ofproven and pharmaceutical uctive jointproducts.ReAble was acquiredby The BlackstoneGroup, Adelaide Hospital,South Australia, willincludeupto45healthy xisting phar eletal conditionsresultingfromde roup hasbeenfoundtoenhancethe bioavailability, activity, and thopedic productsusedforpainmanagement,or gical ImplantDi actures, and distributes acomprehensiveactures, anddistributes rangeofhigh-quality ” et. vision, ReAb v said Har ersif xpected toleaddirectl tant stepforthede maceuticals andnutraceuticals,asw The compan ied dr r y ug deli vision of Rosen, PresidentandCEOofPhosphagenics. le isaleadingdistrib ne-based s Alter y's coretechnolo very productandtechnologyvery company fers acomprehensi velopment andcommercializationof , nati globall y into thestar ve Investment Market (PSG). An generative diseases,deformities, y dri utor ofelectricalstimulation gy isb v en biotechnology t of alar ve suiteof ell astoassistinthe uilt aroundthe thopedic v ge multi-site er medication CyDex Licenses Captisol to Sunesis Pharmaceuticals for Oncology Drug Candidate

yDex, Inc., a specialty pharmaceutical company developing improved important advance for CyDex,” said John M. Siebert, PhD, Chief Executive Cproducts through innovative drug delivery, recently announced an Officer of CyDex. “We are pleased to be participating in the process of agreement licensing its Captisol enabling technology to Sunesis developing SNS-314 and potentially creating a significant new therapeutic Pharmaceuticals, Inc. for formulation of a selective Aurora kinase inhibitor alternative for oncology. Including SNS-314, our partners have a total of 23 with potent anti-tumor activity across a number of nonclinical human cancer licensed Captisol formulations involved in clinical trials around the world. We models. look forward to further expanding CyDex’s technology licensing activity in the CyDex’s patented Captisol technology improves water solubility, months and years ahead. At the same time, we expect to continue making bioavailability, and complexation characteristics of insoluble and/or unstable progress on our proprietary products strategy. Our current proprietary pipeline drugs. The CyDex pipeline of licensed and proprietary Captisol-enabled includes eight hospital acute care and four other Captisol-enabled drugs that formulations targets a range of market segments, including injectables, oral have the potential to provide unique therapeutic benefits and satisfy unmet solutions and capsules, ophthalmic solutions, oral solids, and inhalation. medical needs.” CyDex granted Sunesis global rights to Captisol for a formulation of SNS- CyDex is a specialty pharmaceutical company developing proprietary 314 – a selective small molecule inhibitor of Aurora kinases that potently products and licensing its Captisol enabling technology. CyDex is bringing 6

inhibits proliferation of a wide panel of human cancer cell lines. Aurora kinases important new medications to patients by developing its own pipeline of o are over-expressed in several types of cancer, including colon, breast, ovarian, proprietary products with advanced drug delivery solutions, and by partnering N 7 l

bladder, esophageal, gastric, and pancreatic. with the world’s leading pharmaceutical and biotechnology companies. Four o As demonstrated in multiple nonclinical models, the combination of potency, Captisol-enabled drugs are currently being commercially marketed. These V 7 selectivity and robust in vivo activity, coupled with tumor growth inhibition include Bristol Myers Squibb’s Abilify IM, Pfizer Animal Health’s Cerenia and 0 0 through intermittent dosing, suggests that SNS-314 may be a best-in-class Geodon for Injection and Vfend IV, both marketed globally by Pfizer Inc. 2 e n

Aurora kinase inhibitor for the treatment of diverse human malignancies. An In addition, CyDex has development agreements with Allergan, Inc.; Bristol- u Investigational New Drug Application has been submitted for SNS-314, and a Myers Squibb; Daiichi Asubio Pharma Co., Ltd., of Japan; Merck & Co., Inc.; J y g

Phase I clinical trial for the treatment of patients with solid tumors is planned Kanisa Pharmaceuticals; Mitsubishi Corporation; OSI Pharmaceuticals, Inc.; o l o to begin in the second quarter of 2007. Sunesis Pharmaceuticals is a clinical- PTC Pharma AG; TargeGen, Inc.; Taisho Pharmaceuticals; and Teva n h c stage biopharmaceutical company focused on the discovery, development, and Pharmaceutical Industries Ltd. CyDex also has clinical use agreements with e T y commercialization of novel small molecule therapeutics for oncology and other major pharma and biotech companies. CyDex is a privately held company r e v i

serious diseases. located in suburban Kansas City. l e

“Adding Sunesis to our roster of technology licensing partners is an D g u r D

17 BioProgress Announces Rocgel Acquisition & Out-Licensing of Two Products

ioProgress plc, the specialty pharma and healthcare company, recently delighted by the addition of Rocgel to our portfolio of products in Dexo S.A. Bannounced the acquisition of Rocgel, an antacid used in the treatment of Rocgel is a highly recognized brand that brings the potential of both line pain associated with gastro-intestinal conditions. The product will add to the extensions using our drug delivery technologies and of launching the brand in portfolio of the company’s sales and marketing division in France, Dexo S.A. the over-the-counter market. “The company expects to announce further Rocgel is a growth brand and will be distributed by the company in France accretive organic product acquisitions during the course of 2007 as we and in French-speaking African countries. The product is currently execute our strategy of marketing high-growth, differentiated and XGEL- prescription-only but has the potential, and registration approvals, for sales enhanced products in both the prescription-only and OTC markets.” into the over-the-counter healthcare market. The Rocgel brand has high BioProgress plc is an innovative specialty pharmaceutical and healthcare recognition in French-speaking markets, making it suitable for line extensions business based around its platform technologies in polymer and film systems. through the company’s suite of enabling drug delivery technologies, in Listed on London’s AIM in May 2003 and on US NASDAQ in October 2004, particular Solupol. the company has over 80 patents granted or in application within 24 patent As the result of a regular review of its product portfolio to ensure that the families and has product development agreements and strategic alliances with company’s resources are focussed on growth opportunities, the company has several global companies. As a virtually integrated business, BioProgress has out-licensed two low-growth brands in the Dexo S.A. portfolio, Dimegan and acquired sales and marketing resources within Europe and the US as a launch Mucipulgite. These brands were unlikely to benefit from enhancement via the mechanism for its own pharmaceutical products. The business continues to company’s drug delivery technologies, one of the key elements in the develop innovative delivery mechanisms using its XGEL polymer technology, company’s growth strategy. replacing the need to use animal-derived gelatine in pharmaceutical and Richard Trevillion, Chief Executive Officer, BioProgress, said “We are healthcare products.

Cipher Pharmaceuticals Receives Approvable Letter From the FDA for CIP-TRAMADOL ER ipher Pharmaceuticals Inc. recently announced it has received an Cipher Pharmaceuticals is a drug development company focused on Capprovable letter from the US Food and Drug Administration (FDA) commercializing novel formulations of successful, currently marketed pertaining to its New Drug Application (NDA) for CIP-TRAMADOL ER, the molecules using advanced drug delivery technologies. Cipher's strategy is to company’s once-daily formulation of tramadol. in-license products that incorporate proven drug delivery technologies and In its letter, the FDA indicated that Cipher's application is approvable advance them through the clinical development and regulatory approval subject to the resolution of certain issues, including chemistry, stages, after which the products are out-licensed to international partners. manufacturing, and controls (CMC) and a request for an additional adequate Because Cipher’s products are based on proven technology platforms applied clinical trial to provide further efficacy data. While Cipher believes its to currently marketed drugs, they are expected to have lower approval risk, submission includes sufficient data to support regulatory approval, the shorter development timelines, and significantly lower development costs. company requires clarification from the FDA on the issues raised in the Cipher currently has three late-stage drugs in its pipeline. The company's action letter before determining the path forward. Cipher anticipates meeting lead compound, CIP-FENOFIBRATE, received final approval from the US with the FDA shortly to discuss these matters. Food and Drug Administration and Health Canada in the first quarter of Cipher submitted its NDA for CIP-TRAMADOL ER in June 2006, and the 2006. In addition, Cipher is developing formulations of the pain reliever NDA was accepted for review during the third quarter of 2006. The NDA tramadol (currently under regulatory review by the FDA) and the acne contains data from six pharmacokinetic studies and five Phase III studies treatment isotretinoin (currently under regulatory review by the FDA). Cipher (three of these providing pivotal efficacy data and two providing long-term is listed on the Toronto Stock Exchange under the symbol DND and has safety data). approximately 24 million shares outstanding. Azopharma Broadens Contract Product Development Services With Additional Acquisitions 6

o S based Azopharma recently announce newly established relationships compounds; Aniclin Preclinical Services – Preclinical services in support of N with iQ Synthesis and Cyanta Drug Development. Phil Meeks, CEO of early product development; and Cyanta Drug Development – Analytical

7 U l

o the Azopharma Product Development Group of companies, said, “These two chemistry services from development to QC testing, and AvivoClin Clinical V additions, combined with our four current companies, will round out our Services – Human clinical pharmacology services for Phase I clinical trials. 7

0 service offering portfolio and enhance our position as a major resource in the “Some of our clients prefer one company managing their entire pipeline 0 2 global contract product development arena. We are now poised to capitalize across several scientific disciplines and prefer a service provider, such as e n

u on the emerging trends transforming the pharmaceutical industry. Our entire Azopharma Contract Services, while others prefer to outsource a single J network now consists of a family of six companies with capabilities ranging aspect of their developmental program. The latter can now turn to our other y

g from preclinical to manufacturing. Working either individually or in five companies depending upon their scientific needs.” o l o

n conjunction, these companies offer tailored choices to the pharmaceutical and All companies in the Azopharma product development group of companies h c

e medical device industries of North America, Europe, and Asia.” are wholly owned subsidiaries of Azopharma Contract Services, Inc. The T y

r He added, “Clients seeking contract research services and support can turn group collectively consists of over 200 scientists providing contract research e v

i to the Azopharma Product Development Group of companies for complete services both domestically and internationally. All companies are owned by a l e

D solutions. This unique group of companies includes Azopharma Contract holding company, Chemir, Inc., based in St. Louis, Missouri. Chemir, Inc. is g u

r Services – Integrated product development and CTM manufacturing; IQ owned by Dr. Shri Thanedar, who serves as Chairman of all of the companies D Synthesis – Synthetic chemistry services from discovery to clinical materials; in the Azopharma product development group of companies. ApiCross Drug Delivery – Proprietary drug delivery platforms for insoluble 18 Endo Pharmaceuticals & Project Sunshine Partner to Brighten the Day of Pediatric Patients ndo Pharmaceuticals Inc. and Project Sunshine Erecetly announced a Project Sunshine Patches Day program partnership designed to help brighten the day of pediatric patients at children's hospitals in select cities nationwide. Endo Pharmaceuticals will sponsor 10 Project Sunshine events with pediatric hospital patients to facilitate quality playtime and craft activities, and distribute stuffed animals to all participants. Despite increasing efforts to assuage fear in hospitalized children, healthcare providers continue to face challenges managing procedure-related pain and the anxiety that can be associated with it. In a recent survey of 200 pediatric healthcare professionals conducted by Roper Public Affairs & Media in partnership with Endo Pharmaceuticals, 75% of respondents said their patients demonstrated anxiety prior to venous access and other superficial procedures. Children who experience pain or anxiety- related discomfort are at risk for developing subsequent, long-term aversions to treatment experiences. “For pediatric patients, hospital stays can be frightening and even traumatic, which is why we feel it is so important to try to improve the quality of life for these children,” said Amy Saperstein, Executive Director, Project Sunshine. “We are delighted to bring our volunteers and arts and crafts activities to hospitals around the country, and thank Endo Pharmaceuticals for their generous support to make these events possible.” “Endo Pharmaceuticals is committed to improving the lives of patients and meeting the needs of 6 healthcare professionals,” said Peter A. Lankau, Chief Executive Officer of Endo Pharmaceuticals. “We are pleased to partner with Project o N

Sunshine in an effort to brighten the day of pediatric patients and raise awareness about issues essential to their care.” 7 l o Endo Pharmaceuticals and Project Sunshine will conduct the Project Sunshine Patches Day events at 10 hospitals across the country during the V 7

summer of 2007. Project Sunshine is a nondenominational, nonprofit organization that provides free programs and services to children and 0 0 families who are affected by serious medical challenges. Project Sunshine sends volunteers to visit hospitalized children and their families to 2 e n u

provide arts and crafts, tutoring, entertainment, and special events. Project Sunshine volunteers are corporate executives, lawyers, artists, students, J

and people of all ages and backgrounds who donate their time and resources to improving the lives of children and families in need. Project y g o l

Sunshine has 180 chapters throughout the United States, Canada, and in Kenya. In the past year, 10,000 volunteers served 100,000 children o n h c

and families. e T y Endo Pharmaceuticals Holdings Inc. is a fully integrated specialty pharmaceutical company with market leadership in pain management r e v i l products. Through its wholly owned Endo Pharmaceuticals Inc. subsidiary, the company researches, develops, produces, and markets a broad e D g

product offering of both branded and generic pharmaceuticals, meeting the needs of healthcare professionals and consumers alike. u r D

19 Watson Pharmaceuticals Agrees to Permit Sandoz Pharmaceuticals to Launch Metoprolol Succinate Extended-Release 50-mg Tablets

atson Pharmaceuticals, Inc., a leading specialty current US Food and Drug Administration (FDA) policy, applicants Wpharmaceutical company, recently announced that pursuant to that do not obtain final approval before AstraZeneca's pediatric study an agreement with Sandoz, a subsidiary of Novartis AG, Watson has market exclusivity commences would be barred from obtaining final relinquished its rights to a 180-day period of marketing exclusivity approval until March 18, 2008, when AstraZeneca's pediatric study for its 50-mg strength of metoprolol succinate extended-release market exclusivity expires. tablets (the generic equivalent to AstraZeneca PLC’s Toprol XL 50- Watson Pharmaceuticals, Inc. is a leading specialty pharmaceutical mg product). Watson was awarded market exclusivity as the first company that uses innovative science and market insight to develop generic applicant to submit an Abbreviated New Drug Application responsive products for a changing world. Since its founding in

6 (ANDA) for metoprolol succinate extended-release 50-mg tablets. 1984, Watson has pursued a growth strategy combining internal o N As a result of Watson's agreement to relinquish its marketing product development, strategic alliances and collaborations, and 7 l

o exclusivity, Sandoz has obtained final approval of its ANDA for synergistic acquisitions of products and businesses. Watson is V

7 metoprolol succinate extended-release 50-mg tablets. Watson will be uniquely positioned with its infrastructure and internal research and 0 0

2 entitled to a share of Sandoz’s profits on the sale of the product. development capabilities to support its three divisions: U.S. Generic, e n

u Other terms of the agreement were not disclosed. According to IMS Brand, and Anda Distribution. J

y Sales data, Toprol XL extended-release 50 mg had 2006 US brand Watson has adhered to a three-pronged strategy for growth: g o l

o sales in excess of $600 million. internal product development, strategic alliances, and select product n h c

e Watson continues to pursue approval of its own pending ANDA acquisitions. The company will continue to grow through the T y r

e for metoprolol succinate extended-release tablets, but does not understanding and capitalization of key market trends. As it expands v i l e

D anticipate obtaining final approval before AstraZeneca's pediatric its branded and generic businesses, successful business development g u

r study market exclusivity commences. Watson believes that under deals will continue to be a key component of its success and strategy. D

20

Who Needs Motivation? The New Obviousness Standard in Patents By: Clifford M. Davidson, Esq. (Davidson, Davidson & Kappel, LLC)

ost individuals reading this publication are based on “a lack of motivation to combine the teachings of well-versed in at least the basic concepts of these references” is found quite often in the file histories of MMthe standard for patentability in the US. Very US patents. The argument follows that without such basically, in order to obtain a patent, the claimed invention motivation to combine the teachings of those references, a must be considered new, useful, and unobvious. The person having ordinary skill in the art would simply not consideration as to whether something is new (novelty) recognize the benefits of combining such teachings. For involves, eg, whether there is one piece of prior art, be it example, if the prior art references that are to be combined an earlier patent, earlier publication, or earlier use that are directed at solving different problems, it is often argued discloses all of the claimed features of the invention in that one of ordinary skill in the art seeking to solve the question. This article addresses the standards for problem addressed by the claimed invention would not be determining obviousness, and how those standards may motivated to prior art directed at solving a different have been affected by a recent Supreme Court decision. problem. Or, if each reference solves the problem addressed in the claimed invention in a different way, there THE BASICS might be no motivation to combine such disparate work to Obviousness is a legal conclusion based on the factual solve the problem. As another example, it is often argued inquiries set forth in Graham v. John Deere Co., 383 US 1, that the two references that the examiner seeks to combine 15 L. Ed. 2d 545, 86 S. Ct. 684 (1966): (1) the scope and are in entirely different scientific fields; and so there would content of the prior art; (2) the differences between the be a lack of motivation for the person having ordinary skill claims and the prior art; (3) the level of ordinary skill in in the art to look outside that art for a solution to the the pertinent art; and (4) secondary considerations, if any, problem. of nonobviousness. See McNeil-PPC, Inc., v. L. Perrigo Until now, the law was reasonably clear: “[i]t is Company, 337 F.3d 1362 (Fed. Cir. 2003). A court must insufficient to establish obviousness that the separate also consider any secondary indicators of non-obviousness elements of the invention existed in the prior art, absent that are asserted by the applicants, including (1) some teaching or suggestion in the prior art, to combine commercial success; (2) unexpected results; (3) long felt the elements.” See Ruiz v. AB Chance Co., 234 F.3d 654 but unsolved need; and (4) failure of others. See Graham (Fed. Cir. 2000) quoting Arkie Lures, Inc. v. Gene Larew v. John Deere Co. of Kansas City, 303 US 1, 17-18 (1966). Tackle, Inc., 119 F.3d 953 (Fed. Cir. 1997). This rule has 6

Typically, a determination of obviousness by a patent sometimes been referred to as the “TSM” test (teaching, o N examiner or a court is not based on one piece of prior art. suggestion, or motivation). The suggestion or motivation 7 l o Rather, such a determination is based on a combination of could be explicit or implicit. See Brown & Williamson V 7 0 0

prior art (eg, two or more earlier patents/publications). One Tobacco Corp. v. Philip Morris, Inc., 229 F.3d 1120 (Fed. 2 e n

of the classic arguments that patent practitioners have used Cir. 2000) “the suggestion to combine need not be express, u J

to argue in favor of patentability when faced with a and may come from the prior art, as filtered through the y g o l o

combination of two or more prior art references concerns a knowledge of one skilled in the art.” In other words, the n h c e lack of motivation to combine: that is, a patent claim is suggestion to combine the disclosures of two or more prior T y r e v only proved obvious if the prior art, the problem’s nature, art references in order to establish prima facie obviousness i l e D

or the knowledge of a person having ordinary skill in the required some suggestion for doing so, either in the g u r art reveals some motivation or suggestion to combine the references themselves or in the knowledge generally D prior art teachings. Thus, an argument for patentability available to one of ordinary skill in the art. In re Jones, 958 21 F.2d 347, 351 (Fed., Cir. 1992). describe placement of sensors on adjustable pedals. Have these seemingly well-settled rules for determinations The District Court granted summary judgment in KSR’s of obviousness/nonobviousness now been eliminated by the favor. Following Graham’s direction, the Court found that the Supreme Court? In its recent decision in KSR International v. Asano patent taught everything contained in Claim 4 except the Teleflex Inc., 127 S. Ct. 1727 (April 30, 2007), the Supreme use of a sensor to detect the pedal’s position, which the Court Court sent shockwaves throughout the patent community, and recognized was taught in patents describing self-contained indeed throughout the scientific community with its holding that modular sensors. The District Court determined that the level of the Federal Circuit (which hears all appeals from patent ordinary skill in pedal design was an undergraduate degree in litigations) had been applying a flawed analysis with respect to mechanical engineering or equivalent experience. The District the obviousness inquiry. The Supreme Court, in reversing a Court then applied the TSM test and reasoned that the state of Federal Circuit decision which employed the TSM test to uphold the industry would lead inevitably to combinations of electronic a patent, held that the Federal Circuit “addressed the sensors and adjustable pedals; that the prior art patents obviousness question in a narrow, rigid manner that is regarding the placement of sensors on adjustable pedals inconsistent with §103 and this Court’s precedents.” provided the basis for such developments; and finally that the Smith patent taught locating the sensors on the fixed structure THE KSR DECISION of the pedal. The District Court was further swayed by the fact that the USPTO had not had the opportunity to consider the In KSR, Teleflex sued KSR for infringement of its US Asano patent in its patentability determination. Patent No. 6,236,565 entitled “Adjustable Pedal Assembly With Relying mainly on the TSM test, the Federal Circuit Electronic Throttle Control.” The patent litigation involved an reversed the District Court’s decision. It held that unless the adjustable mechanical pedal that KSR developed for Ford, for “prior art references address[ed] the precise problem that the which KSR added a modular sensor. Teleflex, a rival to KSR in patentee was trying to solve” the problem would not motivate an the design and manufacture of adjustable pedals, asserted the inventor to look at these other references (119 Fed. Appx. at ‘565 patent against KSR. Claim 4 of the ‘565 patent, which was 288). The Federal Circuit found that the Asano pedal was at issue, claimed a vehicle-controlled pedal apparatus. It designed to solve a “constant ratio problem” whereas the includes a pivot for pivotally supporting an adjustable pedal asserted ‘565 patent sought to provide a simpler adjustable assembly, and an electronic sensor responsive to the pivot for electronic pedal. In similar fashion, the Federal Circuit found providing a signal that corresponds to pedal arm position. The that the other prior art patents did not necessarily go to the issue position of the pivot remains constant. The electronic sensor of motivation to attach electronic control on the support bracket transmits the position of the pedal to a computer that controls of a pedal assembly. When viewed in this manner, the Federal the engine throttle. Circuit determined that such prior art would not have led a There was a robust amount of prior art involved in the person of ordinary skill to put a sensor on the sort of pedal obviousness consideration. The prior art included an accelerator described in Asano, and therefore did not render the ‘565 patent pedal that interacts with the throttle via a mechanical link; obvious. computer-controlled throttles that open and close valves in The case was appealed to the Supreme Court, which began response to electronic signals rather than through movement of by rejecting the “rigid” approach of the Federal Circuit. The the pedal; pedals that could be adjusted to change their location Decision addressed the Supreme Court’s prior decisions in the footwell (for different-size drivers); a patent (Asano) that concerning obviousness, including Graham: described a support structure that housed the pedal such that 6

o N

even when the pedal is adjusted relative to the driver, one of the “The principles underlying these cases are instructive when

7

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o pedal’s pivot point stays fixed; a patent (Redding) that describes the question is whether a patent claiming the combination of V

7 a different, sliding mechanism where both the pedal and the elements of prior art is obvious. When a work is available in one 0 0 2 pivot point are adjusted; a patent that taught that it was field of endeavor, design incentives and other market forces can e n u

J preferable to detect the pedal’s position in the pedal assembly, prompt variations of it, either in the same field or a different

y

g not in the engine (and described a pedal with an electronic

o one. If a person of ordinary skill can implement a predictable l o n

h sensor on a pivot point in the electronic assembly); and finally a variation, §103 likely bars its patentability. For the same reason, c e T

y patent (Smith) that taught that the sensor should be put on a

r if a technique has been used to improve one device, and a e v i l fixed part of the pedal assembly. In addition, the prior art e person of ordinary skill in the art would recognize that it would D

g

u included patents for self-contained modular sensors to be taken improve similar devices in the same way, using the technique is r D off the shelf and attached to mechanical pedals, and patents that obvious unless its actual application is beyond his or her 22 found thatmoti “common knowledge andcommonsense”inthe TSM test,and Court’s earlierprecedents. Those casesrequiredtheuseof decisions thatappearedtobe more consistentwiththeSupreme decisioninKSR,theFederalincorrect Circuit hadmadefurther was notalways correct. deter aware oftheimproperusehindsight,SupremeCourt shouldbe under §103. Thus, while notingthatthefact-finders combination was obvious might show totry thatitwas obvious thata skill andcommonsense.Inthatinstance,thefact success, itislikely theproductnotofinnovation ofordinary but his orhertechnicalg ordinar numberofidentified, predictable solutions,apersonof finite elements w pro Federal Circuitfound, inerror, thatapatentclaimcannotbe F designed tosolve thesame problem. solve aproblem willbeledonly tothoseelementsofpriorart Circuit’ elements inthemannerclaimed. addressed by thepatentcanprovide areasonforcombiningthe ofendeavorknown atthetimeofinvention inthefield and moti was whether tosolve inordertodetermine therewas trying patent examiners should lookonly totheproblem thepatentee that theFederal by and Circuitwas holdingthatcourts inerror nonob inthe errors a fairly scathingopinionconcerning inconsistent withtheGrahamanalysis, wrote theSupremeCourt that aperson ofordinary skillintheartwould employ. for acourtcantakeaccountoftheinferences andcreative steps directed subjectmatterofthechallenged claim, tothespecific clear, however, theanalysis neednotseekoutprecise teachings fashion claimed bythepatentatissue…Asourprecedents make was anapparent reason tocombinetheknown elementsinthe ordinary skillintheart,allorder todeterminewhether there and thebackground knowledge possessedbyaperson having known tothedesigncommunityorpresent inthemarketplace; i skill…Often, itwillbenecessaryfor acourttolook nterrelated teachings ofmultiplepatents;theeffects ofdemands ederal Circuit’ ved obvious by merely showing thatthecombinationof vation to combine. Under the correct analysis,vation any tocombine.Underthecorrect problem F withrespecttothe thenfounderror The SupremeCourt Second, intheFederal founderror theSupremeCourt While notingthatthe TSM testisnotnecessarily mined thatthe“obvious standard nonobviousness totry” inall viousness analysis madeby theFederal Circuit.Itstated y skillhasgoodreasontopursuekno s assumptionthatapersonofordinar y , theSupremeCour as “ob s hindsightanal v ation couldbefoundimplicitl vious totry.” Itreasonedthatwhen therearea rasp. Ifthisleadstotheanticipated t notedthatafterithadmadeits ysis. Itdeter mined thatthe wn optionswithin y skillattemptingto y inthepriorar ” t. have beenobvious where otherswould not.See skilled inthear deter for quoted theKSRmantraofalackrigidformula least speaktothepresent. Already, theFederal Circuithas w also what their commonknowledge is?How doesonedetermine oftheinventioneducation/experience oneskilledintheart is,but no inthemechanical arts? Will thanhiscounterpart litigants fields Can thathigher-educated personapply solutionsfrommore haveformulator “more”commonknowledge orcommonsense? belo skill ofthepersonordinar world aremuchlesspredictable. ofpharma Likewise, thelevel of KSR, arepredictab opposed tophar differences between theinventiveness consideredinKSRas common sense. ordinar indeed permissibleaslongitwould beobvious tooneof standard. Itnow appears thattheobvious standardis totry Supreme Cour field, albeitforovercoming different problems. common senseanalysis ofcombiningelementsusedinthesame application arigidtestthatwould nottake intoaccounta sense.” wasThe SupremeCourt clearly annoyed atthe invocation “commonknowledge” ofterms and“common by ofa“rigid” patent claimsgranted virtue TSM consideration. Nevertheless, theKSRDecisiondoesindeedmake suspectall throw intothemarketplace. ahugeamountofuncertainty Certainly, given thepopularityof TSM test,thatwould combine thereferences)shouldnow beconsideredinvalid? thattherewasargument/determination alackofmotivation (to wascombination ofpriorart overcome by an mean thatallpreviously patentsinwhich the granted how thisdecisionwillaffect thefuture.DoesKSRDecision S (F Enterprises, Inc.v. Fisher-Price, Inc.andMattel, Inc. upreme Court’s decisioninKSR.Itisimpossible topredict hat thele ed. Cir w ha w thattypically Butdoesahigher-educated foundinpharma. While the long-term effectsWhile thelong-term arenotyet known, we canat How doesthiseffect pharma? There areimportant Another disturbingfeatureofKSRtofuturecasesisthe The underlying themethroughouttheKSRDecisionis There aremany messagesthatmightbetaken fromthe mining ob v y skill in the art usingtheircommonknowledgey skillintheart or e toprovide evidence notonly directedatwhat level of . 2007). vel of common sense in the art is? vel ofcommonsenseintheart WHERE DOWEGOFROMHERE? t’ viousness, andtheuseofcommonsensethose t todemonstratew s statementsconcer ma. F N le. Itisoftenthecasethatin irst, mechanicalinventions, suchasthatin y skill in the art inKSRiswelly skillintheart h ning the“obvious totry” y somecombinationsw v , eg, entions inthe Leapfrog , ---F.3d--- ould 23 Drug Delivery Technology June 2007 Vol 7 No 6

26 Drug Delivery Technology June 2007 Vol 7 No 6 y id .Dbn Contributor Dubin, CindyH. By: Systems Delivery Drug Retentive Gastro Discussing novo se absorbed toadifferent extent invarious oftheGItractonly portion orare particular areabsorbed ina (GI) tract.Somedrugs uniformly throughoutthegastrointestinal candidatesareabsorbed that notalldrug increased bioavailability (BA) ofdrugs. aimed atachie delivery system(DDS)shouldbeprimarily D predictable, andcontrolledrate. The pro deliveryrelease drug systems(CRDDS) control o systemic circulationwithoutof concentrationin drug provide aspecific College, conventional oraldosageforms at Pharmaceutics, Anand Pharmacy Julan U. Desai,Lecturer, of Department According toresearchconductedby Ms. ischallenging. administered drugs the issueofbioavailability oforally leads tohighlevels ofpatientcompliance, therapy andeaseofadministrationthat therapeutic agentsbecauseoflo prefer effects ofonce-a-daybeneficial medication. after beingswallowed, negating the areabsorbedratherquicklythese drugs oftheintestines. in theupperpart That is, that ha release ofawidevariety ofmedications toobtaincontrolled persists intrying one ofthemostfeasible approachesfor development of gastric retention. of thedelivery system. This hasledtothe for dr decreasesthetimeavailablesignificantly with negligible which ornoabsorption, window, goestowaste thereleaseddrug absorption. After crossingtheabsorption absor preceding andinclosevicinitytothe onl said tohave window,” an “absorption thus, D gments oftheGItract.Suchdr y thedr vide drug releaseatapredetermined,vide drug A majorconstraintinoralCRDDis Although oraldeli In herresearch,Ms. Desaiwritesthat design ofanoralcontrolleddrug ption windo ug absor red routeofadministration ve only window anarrow absorption in recentyears, aproblem still delivery drug technologies espite advances madeinsustained v er drug delivery.er drug Controlled- ug releasedinthere ption andlimitsthesuccess ving morepredictab w isavailable for v er y remainsthe fering an gion w costof ugs are le and de y floating systems, and modified systems. floating systems,andmodified expanding systems,high-density Floating Drug Delivery Systems Delivery Drug Floating bioadhesi inthestomach. form These include increase theretentionofanoraldosage Various approacheshave beenpursuedto remo hasbeenserved,purpose itshouldbe premature gastric emptying,andoncethe mechanisms.Itmustresist churning and stomach andconstantgrinding forces causedby peristalticwaves inthe dosage for absor controlled deliverythathave ofdrugs an systems (GRDDS)andmay improve the deliverydrug gastroretentive called the stomachare can beretainedin that Dosage forms therapy.drug better optionfor of (GRDFs), w dosage forms gastroretentive (GRT) using residence time control theg the GItractisto in delivery profile predictable drug prolonged and achieving a emptying ratefor aprolongedperiodof stomach without affecting thegastric- gastric fluidsandsoremain buoyant inthe (FDDS) have densitylessthan abulk thus ensuringitsoptimalbioa site, time beforeitreachesitsabsorption releasing thedr fer ane APPROACHES TO GRDDS v Floating dr To achieve gastro retention,the ption windo ed fromthestomachwithease. v w and m mustbeable towithstandthe e systems,swelling and hich astric ug foraprolongedperiodof ug deli w b y continuousl v ery systems ery Cutaway ofEurand'sDiffucaps Cutaway vailability. y FIGURE 1 at thedesiredrate. isreleasedslowlygastric contents,thedrug time. While thesystemisfloatingon inte administration andmaintainsarelative contact withg a gel-for involvesforms with intimatemixingofdrug noneffervescent floating dosage formulation following criteria: stomach. FDDSmustcompl the residualsystemisemptiedfrom Desai. the outergelatinous barrier, explains Ms. g rity ofshapeand ab One oftheapproachesto • • a • toform Have structure asufficient • Maintain an overallgravity specific The airtrappedb ® effervescent systems. FDDS: noneffervescent and been utilizedinthede buoyancy, two technologies have Based onthemechanismof reservoir.a drug Dissolve slowly as enoughtoserve cohesi lo Technology ming hydrocolloid, which swells in w er thanthatofg v astric fluidafteroral e gelbar After releaseofdr rier y theswollen ulk densitywithin astric contents. . y withthe v elopment of ug,

polymer confers buoyancy to these dosage marketed by partners throughout forms. In addition, the gel structure acts as a the world as a decongestant and in FIGURE 2 reservoir for sustained drug release because the combination with various drug is slowly released by a controlled antihistamines, including in Intec Pharma's Accordion Pill diffusion through the gelatinous barrier. UCB’s Cirrus® in combination Effervescent FDDS utilize matrices with Citrizine and in Almirall’s prepared with swellable polymers, such as Rinoebastel® in combination with Methocel® or polysaccharides (eg, Chitosan) Ebastine. and effervescent components (eg, sodium bicarbonate and citric or tartaric acid), or Polymeric Systems matrices containing chambers of liquid that According to Dr. Michel gasify at body temperature. The matrices are Afargan, Chief Scientific Officer at fabricated so that upon arrival in the stomach, IntecPharma, the main challenges carbon dioxide is liberated by the acidity of with GR (Gastric Retention) are the gastric contents and is entrapped in the related to the following: gellified hydrocolloid. This produces an upward motion of the dosage form to float on • The extent of gastric the chyme. retention. An effective GR FDDS require a sufficiently high level of system should exhibit a fluids in the stomach for the drug delivery retention of at least 6 hours buoyancy, to float and to work efficiently. in the stomach. This Floating systems are not feasible for those system must be able to drugs that have solubility or stability problems overcome the physiological in gastric fluid. Also, there are limitations to gastric emptying of the the applicability of FDDS for drugs that stomach. irritate the gastric mucosa. • Food effects. Obtaining the Drug Layering aforementioned GR profile • Elimination. The dosage form should Eurand’s Diffucaps® technology is a even with or after low calorie meal. be eliminated following its retention in multiparticulate system that provides optimum One should remember that food the stomach, ie, biodegradability in the release profiles for single or combination increases gastric retention while under intestines. drugs. Drug-release profiles are created by fast conditions, the GR is poor due to layering active drug onto a neutral core, such the “housekeeping wave.” Safety issues • The incorporated API. Because the as sugar spheres, crystals, or granules are a concern. The GR dosage form drug should be stable under acidic pH, followed by a rate-controlling, functional should not interfere with the some modifications of the drug are membrane. The Diffucaps system allow for physiological gastric emptying of food. sometimes required. The GR should the combination of different types of release enable a significant increase in profiles into one dosage form. According to • GR control. The duration of GR (the absolute bioavailability of narrow Troy Harmon, Vice President of Business aforementioned 6 hours) should be absorption drugs. The prolonged drug Development at Eurand, his company can controlled in an optimized manner, for release should be well controlled in customize any combination of sustained- each drug, in order to obtain order to prevent possible dose release, pulsatile-release, and immediate- synchronized drug release during GR. dumping. A combination of release profiles, depending on the specific Some specific challenges, all related to immediate- and slow-release profiles needs of the product. Mr. Harmon points out the GR control, include the following:

6 may be sometimes crucial, especially

o that Diffucaps is not a true GRDDS, but it N for most CNS drugs. Drugs that may

7 does accomplish what such delivery systems • Gastric pH. A GR dosage form affect gastric emptying, such as l o

V set out to do: address the issue of solubility by should be robust (intact and prokinetics, may reduce the GR of the

7 allowing the drug to be absorbed in the lower stable) to pH fluctuations. The dosage form. 0 0

2 GI tract. gastric pH under fast condition is

e

n Eurand recently developed a sustained- about 1 to 2, while under fed

u Dr. Afargan says that the company’s J

release formulation of the decongestant conditions, is about 3 to 4

Accordion Pill addresses all of the y

g Pseudoephedrine using Diffucaps. The (following the meal). o aforementioned. For instance, the Pill exhibits l o

n sustained-release profile used in this product (using different imaging methods in humans) h c

e allows for 12-hour decongestant relief, which • Physical properties. The T gastric retention of more than 6 hours. It has

y r eliminates the need for multiple doses mechanical properties and e exhibited prolonged GR even with a low v i l throughout the day. Additionally, this product integrity of the dosage form e calorie meal, and Intec has demonstrated that D

g can be combined with once-a-day should enable prolonged stability following a single dose of the Accordion Pill u r D antihistamine products for more complete in the stomach during GR. under fed conditions, there was no treatment of allergy symptoms. Eurand’s interference with the physiological gastric 28 Diffucaps Pseudoephedrine is currently being emptying of food. The Accordion Pill action/deployment in of action, and decrease its therapeutic benefit. According to Intec’s Zeev Weiss, the stomach is not affected by pH. The planar These problems can result in patients being Executive Vice President, Commercial geometry and mechanical properties of the given higher and more frequent drug doses, Operations, the GR market is going to face a Accordion Pill enable its stability under which can result in increased therapy costs, significant progression within the next years. stomach conditions, and the Pill undergoes a greater likelihood of side effects, and “We have to remember that GR, under a low complete biodegradation in the intestine complicated dosing regimens. calorie meal, was considered as an unmet following its gastric emptying. Customized drug release profiles are need, which many pharma and drug delivery Finally, the Accordion Pill enables a created by first layering active drug onto a companies have tried to address, for many significant increase of absolute bioavailability. neutral core (such as cellulose spheres) years. Yet, those many failures with this The company has conducted a trial with followed by the application of one or more respect have blocked a wide use of GR, and healthy volunteers, demonstrating that the rate-controlling, functional membranes. The pharma companies were forced to find other Accordion Pill doubled the absolute drug-layering process can be conducted either solutions that were not always sufficient. Now bioavailability of Riboflavin, a known marker from aqueous- or solvent-based drug solutions. that GR under a low calorie meal is possible, for narrow absorption window. To date, Intec Eurand has also developed formulation we witness, through our wide interactions with has developed a combined-release profile of technology that combines the customized drug pharma companies, that GR is considered not IR followed by SR with a CNS drug – an release offered by Diffucaps with technologies only for the traditional drugs known to suffer ongoing clinical development project. that enhance the solubility of insoluble drugs from a narrow absorption window, but for The Accordion Pill is a polymeric system in the GI tract. Eurand is using this technology completely new directions. I truly believe that composed of pharmaceutical synthetic and to provide a degree of delivery control that within a few years, GR will be heavily used as biodegradable polymers. The polymeric goes beyond that of single technology systems. an enhancement technology for the treatment system possesses a unique planar geometry Diffucaps beads are small in size, of various GI disorders, such as obesity, IBS, that unfolds like an “accordion” into a approximately 1mm in diameter, and are filled and GERD. Moreover, GR will be widely used standard capsule. When the capsule reaches into a capsule to create the final dosage form. to overcome ADR of current drugs and as an the stomach, it dissolves, and the Accordion Beads of differing drug release profiles can be enablement technology to obtain new Pill then deploys. The drug is then released in easily combined in a single capsule providing indications for existing drugs.” N a controlled manner from its reservoir, ie, an high levels of control over release profiles. inner membrane of the Accordion Pill. Diffucaps beads of different drugs can be Following the gastric retention period combined to make convenient single dose BIOGRAPHY (that may be controlled), the system undergoes units for combination therapies. a complete biodegradation that mainly occurs Thus, the Diffucaps system offers Ms. Cindy H. throughout the intestines. significant flexibility by enabling the Dr. Afargan says, “The Accordion Pill is combination of different types of release Dubin has been a the only known GR system based on a planar profiles into one dosage form. As a result, professional and not spherical geometry. Other dosage Eurand can combine sustained release, journalist since forms are mainly spherical and are positioned pulsatile release and immediate release 1988. She is most of the time near the antrum pylori (the profiles depending on the specific needs of the gastric-intestinal sphincter). By using gamma product. Also, different dose-proportional currently a imaging and MRI, it was demonstrated that strengths of a product can be easily Contributing Editor the Accordion Pill moves within the stomach manufactured by filling capsules with varying to Drug Delivery and does not sit in a specific location. amounts of the Diffucaps beads. Technology as well as Editor of its Specialty Moreover, the unique mechanical Pharma section. Prior to these positions, she properties of the Accordion Pill enable its 6

spent several years focusing her writing on elasticity to overcome the contraction stress SUMMARY o N

pharmaceutical formulation and imposed by the stomach.” 7

l o

Dosage forms with a prolonged GRT will development. She has been recognized by V

Multiparticulate Dosing bring about new and important therapeutic the American Society of Business Press 7 0

Eurand’s proprietary Diffucaps options, says Ms. Desai. They will 0 2 Editors for an article she wrote on e

technology can be applied to enable significantly extend the period of time over n u

nanotechnology, and her writing has been J

formulation of insoluble drugs and to improve which drugs may be released and thus prolong

y the rate and extent of absorption of drugs from dosing intervals and increase patient awarded by the prestigious Neal Award g o l o oral dosage forms. compliance beyond the level of existing Committee for Journalistic Excellence. Ms. n h c

Drug insolubility poses significant controlled-release dosage forms. “Many of the e T

Dubin earned her BA in Journalism from y challenges throughout drug development “once-a-day” formulations will be replaced by r e

Temple University in Philadelphia and her v i owing to its impact on the extent and rate of products with release and absorption phases of l e D drug absorption into the body, says Mr. approximately 24 hours,” says Ms. Desai. certificate in Business Logistics from g u r

Harmon. It can prevent the absorption of “GRDFs will be used as carriers of drugs with Pennsylvania State University. D therapeutic levels of drug, delay a drug’s onset the “absorption window.” 29

30 Drug Delivery Technology June 2007 Vol 7 No 6 y hba ae,PD n aksTevsa,PhD andMarkus PhD, Tservistas, ShabtaiBauer, By: A hereditar I route onaweekly basis. beingtreatedbycurrently theintravenous patients with AAT who are deficiency friendly therapeuticalternative fortreating a activity maintained, inhalationmay become tissue canbeensuredandbiological As sufficient AAT tothelung permeation dose. times andthepotentialtoreducedrug treatment shorter result insignificantly hyperinflation ofthelungs.Emphysema trapped intheair sacs,leadingto exhaled breath. This causesairtobecome with the tonormal the lungsdonotreturn because eachbreathinflatesthelungs, b tobreathe becomes moredifficult cannot functionproperly. Eventually, it larger,and form sacsthat inefficient airsacslosetheirelasticity destruction, small airsacs(alveoli). With this by ofthedelicatewalls thedestruction of individuals have beenidentified. Currently, only about6,000ofthese homozygote individuals intheUS. that thereareatleast100,000Zallele frequency oftheZallele, itisestimated so-called Zallele.Basedonthegene caused by inheritanceoftwo pairsofthe expectancy. AAT ismostly deficiency impact everyday qualityoflifeand of lungfunctionthatcansignificantly progressivefrom theseindicationsface loss bronchitis. (COPD), mainl of chronicobstr I new, cost-effective, efficient, andpatient- the eFlow of using anoptimizedconfiguration (AAT) nhaling Alpha-1Antitrypsin Novel Nebulizer Electronic for AAT Patients Alpha-1 Emphysema isalungdiseasecaused ALPHA-1 ANTITRYPSIN y condition thatincreasestherisk AAT adultssuffering deficient DEFICIENCY Antitr ® y ucti Electronic Nebulizer mayElectronic Nebulizer emph v ypsin def e pulmonar ysema andchronic icienc y disease y is a ut PARI’s eFlow T ransportable, blood functionisto cells,anditsprimary Neutrophil elastaseisreleasedb enzyme calledneutrophilelastase. inhibiting thedestr protects thedelicatetissuesoflungsb COPD orasthma. diseases,suchas other chronicpulmonary AAT isoftenmisdiagnosedas deficiency ofbreatharecommonsymptoms, shortness and cough.Becausewheezing and ofbreathonexertion,shortness wheezing, cases, death. function, hospitalization,andinsome deteriorationinthepatient’sin sharp lung leading tofrequentexacerbations resulting aggravatesfurther theirconditionby from chronicbronchialinflammationthat patients with AAT alsosuffer deficiency bloodstream. Recentstudiesindicate that oxygen andcarbondioxide withthe until thelungscannolongerexchange disease. The destructive actioncontinues caused by AAT isa progressive deficiency Alpha-1 antitr Symptoms of AAT include deficiency ® nEetoi,Easily anElectronic, , Batter y-P ucti ypsin isaproteinthat owered Nebulizer v e action ofan y white FIGURE 1 y diaphragm isflattenedduetothe the destr h lung surf de f patient, thelo the lungswhile inthe AAT deficient damage usually affects of theupperportion emphysema causedby smoking,the smoking ("acquired"emphysema). In different fromemphysema causedby "genetic" or"inherited"emphysema) is (alsoknown as deficiency Antitrypsin disease ifnottreated. emphysema severity, which progresses the healthy lungtissueby neutrophilelastaseis tissue. The eventual resultofthedamage ofhealthyleading todestruction lung the lungscontinuesactingwithoutcontrol, infection, theneutrophilelastasereleasedin of AAT orcontractsalung inhalesirritants the lungs. When apersonwho isdeficient digest bacteriaandotherforeignobjectsin irst af yperinflated duetoairtrappingcausedb velops eventually throughouttheentire Emphysema causedby Alpha-1 fected. Nonetheless,emph uction ofthelungtissue,and ace. Ineithercase,thelungsare w er re gions ofthelungsare ysema y

hyperinflation of the lungs. Emphysema caused by AAT deficiency FIGURE 2 usually causes symptoms in people while they eFlow® Components (Nebulizer Handset) are in their 30s or 40s. As discussed, many of these patients also have chronic bronchitis. With this, the lung lining becomes swollen and congested with mucus, restricting air flow. The bronchi often go into bronchospasm in which muscles contract, further reducing air flow. This often results in a chronic cough.

TESTING FOR AAT DEFICIENCY

The guidelines of the American Thoracic Society and the European Respiratory Society strongly recommend testing for AAT deficiency in individuals with chronic airway obstruction. They also recommend testing of family members of AAT-deficient individuals. Although it is simple and painless to detect alpha-1 deficiency, it is unfortunate to say that testing for AAT deficiency is rarely DELIVERING AAT VIA eFLOW® This past January, PARI’s eFlow was performed, despite the fact that it is a major awarded the 2006 Good Design Award for known genetic risk factor and the fourth AAT is currently used for replacement medical equipment by The Chicago leading cause of death in the US, and therapy in the form of weekly intravenous Athenaeum: Museum of Architecture and intervention may substantially improve the infusion that distributes the medication Design. This was the second design award lives of many patients and families. This is throughout the bloodstream in order to supply eFlow has won to date, following the Medical due to healthcare providers not following AAT to the lungs. An inhaled treatment Design Excellence Award granted in April testing guidelines for this common genetic would offer a more targeted therapy by 2006. condition. delivering medication directly to the lungs and One reason for this may be the fact that avert patient discomfort by avoiding the ADAPTING THE eFLOW® recommendations that advocate Z allele weekly and time-consuming intravenous NEBULIZER identification over AAT concentration assays infusion of the drug. have been slow in forthcoming. There are eFlow, an electronic, easily transportable, Emphysema patients show a specific likely more general reasons for not following breathing pattern characterized by a relatively

6 battery-powered nebulizer weighing less than

o the recommendation of these societies, N 300 g (9.3 oz), enables extremely efficient short inhalation cycle followed by a prolonged

7 including the lack of training in genetic l aerosolization of liquid medications via a exhalation. A typical breathing pattern consists o V diseases, leading to lack of disease awareness. vibrating, perforated membrane. Compared to of, for example, a tidal volume of 450 ml, 17 7

0 These deficiencies in training are breaths/min, and an inspiration/expiration ratio

0 other nebulizer systems, eFlow can produce 2 currently being addressed by training oversight e aerosols with a very high density of active of 1:2.5. n u J committees. Additionally, new online drug, a precisely defined droplet size, and a Current augmentation therapy uses

y resources, such as GeneReviews funded by the g high proportion of respirable droplets intravenous AAT application in doses of about o l

o NIH, are now available to healthcare n delivered in the shortest possible period of 60 to 90 mg/kg body weight (about 4 to 7 g h c

e providers. As these tools find their way into T time. Combined with its silent mode of total dose) given once weekly. This treatment y r medical practice, there should be a more rapid e regime is burdensome, lasts for a long time,

v operation, small size (it fits in the palm of i l

e incorporation of genetics in general clinical and only about 2% of the dose is estimated to D your hand), light weight, and battery use,

g 1

u medicine. reach the target tissue of the lungs. Because r eFlow helps reduce the burden of daily D inhalation treatments. availability of AAT derived from pooled 32

purposes, and reduced fees to the FDA and the FIGURE 3 EMEA. Phases II to III of clinical development of the inhaled API with PARI's eFlow are planned to start during 2008. N

REFERENCES

1. Hubbard RC, Crystal RG. Strategies for aerosol therapy of alpha-1 antitrypsin deficiency by the aerosol route. Lung. 1990;168(Suppl):565-578. 2. Keller M, Tservistas M, Bitterle E, Bauer S. Aerosol characterization of alpha-1 antitrypsin after nebulization with the eFlow, a novel vibrating perforated membrane nebulizer. Proceedings Respiratory Drug Delivery X, Boca Raton, Florida;2006:729-732.

BIOGRAPHIES

Dr. Shabtai Bauer earned Kamada’s AAT IV Drug his MSc in Biochemistry and his PhD in Enzymology from the Hebrew University of human serum is limited and purification is nebulization of the contents of the medication Jerusalem. He was a Senior Researcher in the Department expensive, resulting in high drug costs, cup. of Biological Chemistry, and administration via inhalation using a nebulizer The drug remaining in the eFlow device Chief of the Biotechnology Unit, both at the is regarded as a more economic and less- is reflected by the Drug Residue. The in vitro Hebrew University of Jerusalem. In addition, he burdensome alternative. Delivered Dose (DD) and Aerosol Losses was a visiting scientist in the Department of correspond to the drug collected on and Biology of the Brookhaven National Laboratory, MATERIALS & METHODS assayed from inhalation and exhalation filters, New York. He has been with Kamada, formerly respectively. The in vitro Respirable Dose RAD Chemicals, since 1985. Dr. Bauer’s activities An eFlow electronic nebulizer in different (RD) was calculated by multiplying DD with encompass over 35 years of professional research and consultancy activities, and he configurations (PARI Pharma GmbH, Munich, the Respirable Fraction (% mass in droplets < authored more than 40 publications in Israel Germany) was used to nebulize a highly 5 µm) obtained from LD data. The in vitro and abroad. purified 2% human, liquid, ready-to-use AAT data shows high delivered doses, even when preparation (Kamada Ltd, Ness Ziona, Israel). breathing patterns of patients with impaired Dr. Markus Tservistas Geometric aerosol droplet size distribution breathing capabilities are mimicked.1 studied chemistry at the was determined by laser diffraction (LD) In a previous study, it has been shown University of Hanover, utilizing a Malvern MasterSizerX device that no degradation of the AAT occurs, and Germany, where he also (Malvern, Herrenberg, Germany). activity is retained at higher than 90% using completed his PhD on the

6 subject of enzymatic reactions 2

o Aerosol delivery efficiency was the eFlow vibrating membrane technology.

N in supercritical fluids. From

7 determined by breath simulation using the The inhaled AAT was designated, both in

l 1997 to 2000, he worked as a Post-doctoral o V emphysema breathing pattern (tidal volume Europe and in the US, as an orphan drug for Research Fellow at the University College in 7

0 450 ml, 17 breaths/min, and an the treatment of congenital emphysema and London, UK, on a project studying the 0 2 inhalation/exhalation ratio of 1:2.5) generated cystic fibrosis. Therefore, should PARI and application of supercritical fluids for the e

n TM u by a PARI Compas breath simulator. As a Kamada be the first to successfully complete production of drug powders for inhalation. J Following this, he took up an R&D position at

y reference, a standardized regular breathing the clinical trials and obtain the regulatory g

o Vectura Ltd. in Bath, developing powder l

o pattern (tidal volume 500 ml, 15 breaths/min, authorities’ approval, they will be entitled to n formulations for pulmonary drug delivery by dry h c

e inhalation/exhalation ratio of 1:1) was also the rights and enjoy the benefits ancillary to

T powder inhalers. He returned to Germany in y

r investigated. Samples were analyzed for the orphan drug status, including exclusive

e 2003, where he is now working with PARI v i l

e protein content by UV analysis at 280 nm. marketing rights (7 years in the US and 10 Pharma, Munich, in the field of nebulization of D

g Nebulization time was determined by an years in Europe, as the case may be), research liquid formulations for inhalation. u r D electronic shut-off of the eFlow upon funds support, tax benefits for research 34

36 Drug Delivery Technology June 2007 Vol 7 No 6 y hua l,PD n nslQai,PD MBA PhD, Quadir, andAnisul PhD, ShaukatAli, By: Applications Delivery Drug Fast-Dissolving High Molecular WeightPovidone Polymer-Based Films for with taste-masking effects. Fast- to deli systems, becausethey have theability such assublingual fast-dissolving continued focusfordelivery devices, drugs. poorl attention foref technology hasgained dissolving film v for patientsandcompliantwith delivery systemsthatareconvenient new andinnovativeto find drug companiesendeavorpharmaceutical a subjectofcontinuedinterestas vitamins. deli suitable for films fast-dissolving flexible,its abilitytoform elongated, Kollicoat MAE100Pcopolymer for copolymer, andacrylate-based polyethylene-grafted Kollicoat SR polymer, polyvinyl alcohol 30), polyvinyl acetate-basedKollidon po Copo was evaluated incombinationwith deliveryintraoral drug system.K-90 development ofafast-dissolved excipient foruseinthe forming (Kollidon T T arious re vidone K-30pol v Intraoral films have beena Intraoral films Life-c er y w vidone (K 4 v y ofhighly and potentdrugs er potentdr weight povidone K-90 to examine highmolecular ofthisstudywas he purpose ater-soluble andpermeable ® INTRODUCTION gulations. ycle managementhasbeen 90F) polymer asafilm- f ollidon icient deli ymer (K ugs ef 1-3 As aresult,f V A64), fecti very of very ollidon vely, and ® IR ast- Model Strips polymers usedinfilmdevelopment. The structureofthe FIGURE 2 FIGURE 1

dissolving strips of Listerine®, obtained from Gardco, Inc. (Pompano Chloraseptic®, Triaminic®, and several Beach, FL). A Propeller IKA mixer METHODS other drugs have been launched to (VWR Scientific; Bridgeport, NJ) and alleviate or avoid the dosage-related SRT1 roller mixer (Jenkins; Bridgeville, The drawdowns of the wet films compliances. PA) were used to prepare the were made by casting on the release Vitamins and multivitamins have formulations. liner, Scotchpak® 1022 (3M, St. Paul, been a subject of recent interest in the MN). The wet films with 10-, 20-, 30-, development of intraoral strips for children. A number of the multivitamins TABLE 1 strips have been launched recently in ® ® ® ® multiple flavors, including Barbie®, (A) Kollidon 90F & Kollidon SR (B) Kollidon 90F & Kollicoat IR ® Formulation A Formulation B Arthur , and other brand name flavored Composition I II III Composition I II III % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) strips. Thus, a continued interest in Kollidon® 90F 13.8 12.5 10.8 Kollidon® 90F 13.8 12.6 10.8 multivitamin and other kinds of strips Kollidon® SR 0.8 1.7 2.8 Kollicoat® IR 0.9 1.6 2.8 Ethanol 82.5 80.4 77.6 Ethanol 80.0 76.7 69.1 DI Water 2.4 5.0 8.5 DI Water 4.8 8.7 17.0 has extended opportunities to find ® Lutrol® E400 0.5 0.4 0.4 Lutrol E400 0.5 0.4 0.4 carriers for safe and effective delivery of FD&C Red #40 q.s. q.s. q.s. FD&C Red #40 q.s. q.s. q.s. Total 100 100 100 Total 100 100 100 the actives. Cellulose-based polymers have often been used as the carriers in the (C) Kollidon® 90F & Kollicoat® MAE 100P (D) Kollidon® 90F & Kollidon® VA64 films. In this paper, we demonstrate that Formulation C Formulation D Composition I II III Composition I II III high molecular weight povidone (PVP), % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) Kollidon® 90F 13.6 12.6 10.7 Kollidon® 90F 13.6 12.5 14.4 for example, Kollidon 90, can be used as Kollicoat® MAE 100P 0.9 1.6 2.9 Kollidon® VA64 0.9 1.7 4.2 Ethanol 82.3 80.5 77.5 Ethanol 85.0 85.4 81.0 a carrier in fast-dissolving films because DI Water 2.7 4.9 8.6 DI Water 0 0 0 Lutrol® E400 0.5 0.4 0.4 Lutrol® E400 0.5 0.4 0.5 of its strong hydrophilicity and FD&C Red #40 q.s. q.s. q.s. FD&C Red #40 q.s. q.s. q.s. Total 100 100 100 Total 100 100 100 compatibility with a wide array of polymers and copolymers. Kollidon

VA64 in K-90 has been evaluated to (E) Kollidon® 90F & Kollidon® 30 Formulation E demonstrate that the copovidone can be I II III Composition % (w/w) % (w/w) % (w/w) used as an auxiliary excipient in the ® Kollidon 90F 13.6 12.5 14.4 development of fast-dissolving Kollidon® 30 0.9 1.7 4.2 Ethanol 85.0 85.4 80.9 multivitamin strips. DI Water 0 0 0 Formulations (A-E) con- Lutrol® E400 0.5 0.4 0.5 taining K-90 and other FD&C Red #40 q.s. q.s. q.s. Total 100 100 100 auxiliary polymers. MATERIALS FIGURE 3 Water-soluble and fat-soluble vitamins were obtained from BASF’s Human Nutrition business. Kollidon 90F, Kollidon VA64, Kollidon SR, Kollicoat 6

IR, and Kollicoat MAE 100P polymers, o N

® and Cremophor RH 40 are products of 7

l o V

BASF Pharma Solutions business.

7

0 Sucralose was obtained from McNeil 0 2

e Nutrinals (McIntosh, AL). Absolute n u J

ethanol (technical grade) and

y g o

l diphenhydramine hydrochloride were o n h

c obtained from Sigma Aldrich (St. Louis, e T

y r MO). Viscosity measurements were e v i l

e made at room temperature with a D

g u

r Brookfield DV-II viscometer D (Middleboro, MA). The applicator edged Elongation as a function of polymer composition. 38 with 5 to 50 ml for casting the films was TABLE 2 40-, and 50-ml thickness were dried in Blue M (Bluefield, IL) oven at 50°C for Target % 10, 15, 20, 25, and 30 mins, respectively. Vitamin Amount Amount Per Daily (wt%) Serving The dried films were cut with the help of Value Vitamin A 0.9 1 50 IU a die board prepared by Bomar Die Co. Vitamin K 0.6 15 12 g (Millville, NJ) on a Carver Press Vitamin E 5.6 2 0.5 IU (Wabash, IN) to yield strips. The Ascorbic acid (Vit. C) 28.5 10 6 mg thickness was measured on a Mitutoyo Thiamine HCl (Vit. B1) 3.7 40 0.6 mg Riboflavin 100 (Vit. B2) 2.9 35 0.6 mg digitmatic indicator (Kawasaki, Japan). Niacinamide (Vit. B3) 38.0 40 8 mg The disintegration was carried out in Calcium Pantothenate (Vit. B5) 15.8 30 3 mg 100-ml aqueous media (DI water) at Pyridoxine HCl (Vit. B6) 3.5 30 0.6 mg Cyanocobalamin (Vit. B12) 0.6 20 1.2 g 25°C to 30°C with a stirring rate of 100 Total 100.0 23 mg rpm at room temperature. The physical Blend of multivitamins prepared based on target % daily dose and required amount per serving. characteristics of the strips such as weight, flexibility, elongation, thickness, FIGURE 4 and dissolution properties were evaluated as described previously.5

FORMULATION PREPARATIONS

Kollidon 90 is a brittle polymer, and to assess the suitability of the excipients in film development, a series of binary formulations were prepared. Each binary formulation (Table 1) contained the high molecular weight povidone (K-90) with approximately 5%, 10%, and 20% (w/w) of an auxiliary polymer component. Lutrol® E 400 was used as plasticizing agent, at 3% (wt/wt) in all formulations. The formulations (A-E) in Table 1 were Film dissolution as a function of binary polymer composition. prepared in ethanol, and unless stated otherwise, the amount of water was kept T ABLE 3 at the minimum required to dissolve the polymers. Material Amount Total Amount Solid % Solid A typical composition of the blend (g) (g) is shown in Table 2. To prepare the blend ® Kollidon 90F 13.7 15.1 67.5 of 100 g of multivitamins stock, each of ® Kollidon VA64 3.6 4 17.9 the vitamins weighed in at the 6

Ethanol 76.6 0 0 o N

appropriate amount as required by the

DI Water 3.2 0 0 7

l

target % daily value and were then o V

Multivitamin 2.1 2.3 10.4

Lutrol E 400 0.5 0.5 2.3 mixed thoroughly. 7 0 0 2

Sucralose 0.2 0.2 0.9 The multivitamin formulation was e

® n

Cremophor RH40 0.2 0.2 0.9 u prepared in an 80:20 ratio of K-90 and J

FD&C Yellow #5 0.02 0.02 0.1 y Kollidon VA64 (Table 3). The g o l

FD&C Blue #1 0.02 0.02 0.1 o n

multivitamin content was about 10% of h c

Total 100 22.4 100 e T the formulation. In addition, the y r

Formulation of multivitamins for strips. e v i

formulation also contained sucralose as a l e D

sweetening agent, Cremophor RH40 as a g u r D

39 taste-masking agent, and Lutrol E400 as FIGURE 5 a plasticizing agent. Table 4 exhibits the viscosity measurement of the placebo (A-E) and the multivitamin formulations.

RESULTS

Formulation Assessment The elongation property of the films composed of K-90 and auxiliary polymers in the approximate ratios of 15:1, 8:1, and 4:1 (A-E) was assessed by stretching the films from both ends as described previously.5 The elongation was estimated (in percentage) from the original distance marked on the films. Weight gain as a function of multivitamin and placebo films thickness. Figure 3 illustrates the elongation of the films. The data suggests that the films T ABLE 4 were elongated to approximately 200% with about 5 wt% (15:1) and 10 wt% (8:1) of Kollidon SR in K-90, and were Formulation Viscosity (mPas)* less elongated (around 100%) with about 20 wt% (4:1). This change in I II III elongation was due, in part, to the nature A 1250 1130 950 of Kollidon SR, which presumably had a B 1900 2150 2090 stronger interaction with K-90 at higher composition (4:1). The elongation was C >5000 >5000 >5000 significant with Kollicoat IR and D 1310 1000 1490 Kollicoat MAE 100P, but was not as E 1290 1010 1660 pronounced as Kollidon SR, and was less pronounced with Kollidon 30 or Multivitamin 2082 with Kollidon VA64 at all ratios (Table 3) examined. The K-90 films containing Kollidon VA64 showed relatively less * Spindle SV4, speed 100 RPM and temp. 23°C elongation than Kollidon 30 at all Viscosity Measurement compositions investigated. Figure 4 shows the dissolution polymer. It further suggests that lack of prototype formulation, 18 wt% 6

o

N profile of the films composed of K-90 pH > 5.5 required for dissolution of copovidone was used as an auxiliary

7

l methacrylic acid:ethylacrylate carrier with K-90 for the delivery of a o and auxiliary polymers. The data V

copolymer contributed to longer multivitamin. Figure 5 shows the plot of 7 suggests that the K-90 film containing 0 0

2 dissolution time. In contrast, K-90 films loading of the multivitamin as a function Kollicoat MAE 100P showed the e n

u with Kollicoat IR, Kollidon SR, of thickness. Increasing the weight of J maximum dissolution time compared to

y

g those containing Kollicoat IR, Kollidon Kollidon 30, or Kollidon VA64, the film increased the multivitamin o l o

n SR, Kollidon 30, or Kollidon VA64. By dissolved in 60 seconds or less at all weight gain per strip from the h c e T

increasing the amount of Kollicoat ratios under the similar conditions. formulation containing 10 wt% of y r e v

i Kollidon VA64 was selected for its multivitamin. l MAE100 to 20% (4:1), the dissolution e D

g time increased significantly to ability to form flexible and elegant films Figure 6 illustrates that the increase u r D approximately 6 to 7 mins, presumably with limited elongation and fast in weight gain was nearly linear with 40 attributed due to the acrylic nature of the dissolution characteristics. For a increasing the thickness of the films. For

a weight gain of about 12 mg of the DISCUSSION The work described in this article multivitamin per strip, the thickness was demonstrates that high molecular weight 50 wet mils (112 microns) from the The use of polyvinylpyrrolidone, povidone can be used in combination formulation that contained 10 wt% of hydroxyethyl cellulose, and carrageenan with other auxiliary polymers to form multivitamin. as a an auxiliary polymer in fast-dissolving films. The results Dissolution properties of the combination with microcrystalline demonstrate that K-90 films with Kollidon 90/Kollidon VA64 films of cellulose for fast-dissolving consumable increasing amounts of polyvinyl acetate varied thickness were evaluated, and the films has been reported.6 Laruelle et al and acrylic acid based Kollidon SR and results are shown in Figure 7. It is also reported the use of combination of Kollicoat MAE 100P, respectively, obvious that increasing the film polyvinylpyrrolidone (PVP) and showed significant flexibility and thickness increased the dissolution time. polyvinyl acetate (PVAc) polymers in elongation. On the other hand, Interestingly, the films dissolved within the development of fast-disintegrating increasing amounts of K-30 or Kollidon 60 seconds, suggesting the suitability of galenic formulations.7 Other studies also VA64 showed good flexibility but the two hydrophilic excipients suggest the use of PVP in combination limited elongation. This was more significantly contributes to the quick with Eudragit, ethyl cellulose, and/or pronounced with Kollidon VA64 than K- dissolution of the multivitamin strips. cellulose acetate in transdermal 30. Furthermore, the elongation of K-90 applications.8-10 film was nearly two-fold greater with Kollicoat IR than Kollidon VA64 or K- FIGURE 6 30 at all compositions (Figure 3). Interestingly, all the films were highly hydrophilic and dissolved relatively quickly in 60 seconds or less with the exception of K-90/Kollicoat MAE 100P, which dissolved in 6 to 7 mins (Figure 4). This suggests that an acrylic-based polymer could require a much longer time to dissolve than a hydrophilic polymer. Multivitamin strips weighing approximately 23 to 113 mg based on a formulation carrier comprising K-90 and Kollidon VA64 (80 wt% to 20 wt%) were flexible, non-tacky, and fast- Loading of multivitamin per strip as a function of film thickness. dissolving. The strips with lower weight dissolved relatively faster than those FIGURE 7 with heavier weight under the same conditions. But irrespective of the weight and thickness, all the strips 6

dissolved within 60 seconds. (Figure 7). o N

2

7 For a strip 6.9 cm , the maximum dose

l o V

limit was about 20 mg/strip at 50-ml and

7

0 2.5 mg/strip at 10 ml of thickness. In 0 2

e both the cases, the strips were flexible n u J

and non-tacky. The loading of the

y g o

l multivitamin was dependent on the film o n h

c thickness (Figure 6); however, higher e T

y r loading may result in tacky films. e v i l

e Hydrogenated polyoxyl castor oil 40 D

g u

r (Cremophor RH 40) can be used as a D Dissolution of strips as a function of thickness. taste-masking agent.11 The mechanism is 42 11. Stier RE,ZanoneJ. Oralhygiene sensationandtheastringency compositionswhich ofeucalyptol masktheburn 8. C.Edible7. Laruelle coatingcomposition.USPatent No.6669957(2001). 10. Cilurzo F. Polymethacrylates inhibitorsinmonolayer ascrystallization patchescontainingIbuprofen. transdermal 9. Mukherjee B, MahapatraS,GuptaR, Patra B, Tiwari A, Arora P. A comparisonbetween povidone-ethylcellulose 6. 5. Ali S,Quadir A. BASFdevelopment polymers technology delivery infilm fordrug application.Paper presented at 4. 3. S,JanzonL.Prevalence2. Lindgren ofswallowing among50-to79-year oldmen complaintsandclinicalfindings 1. Slowson M,Slowson S. What todowhen patientscan’t swallow theirmedications.Pharmacy Times. the bittertasteofactives. such asCremophors(CremophorRH40)and/orpolo 100P canbeusedforactives requiringlongerdissolutiontime. The solubilizers, K-90incombinationwithKollicoatmultivitamin MAE instrips.Furthermore, mixturefordelivery of tackiness, andmightbesuitablecarrier asabinary low withlimitedelongation andsignificantly elegantformed andflexible films suggeststhatKollidonThe studyfurther dissolution ofthefilms. VA64 andK-90 The hydrophilicfilms. natureofthepolymers provides addedadvantage tofast polymercombination withK-90asanauxiliary forproviding thestrengthto Kollicoat IR,Kollidon VA64, Kollicoat MAE100P, orKollidon SR,canbeusedin vitamins andmultivitamins. Otherpolymers andcopolymers, suchasKollidon 30, masking effect. multivitamins (datanotshown). work Further isneededtofully evaluate thetaste- s available datasuggeststhatthesestripswere Barbiebrandstrips.Preliminary V receptors anddelays theresponsetime. The multivitamin stripsofK-90/Kollidon n weet andthattheCremophorRH40hadhelpedmasked tothebittertasteof ot clear, itisspeculatedthatthesolubilizerworks but by coatingthetastebud A64 were evaluated forthetaste-maskingeffect andcomparedtocommercially Rao PR,Diw Biopharm. 2005;59:475-483. Biopharm. and povidone-eudragit EurJPharm dexamethasone matrixpatchesbasedoninvitroskinpermeation. transdermal Sci.1996;58:246-250. administration. IndianJPharm P (a) the CRC Annual Meeting,MiamiBeach,FL,2005,Poster #501. Delivery Drug Tech. 2006;6(2):68-71. Delivery Tech. CM.Quick-dissolve strips:fromconcepttocommercialization. 2003;3(3):63-66.(b)Corniello, -anovel(a) BorsadiaS,O’HalloranD, delivery. JL.Quick-dissolvingfilms approachtodrug Osborne Drug Doheny K. You really expect metoswallow thosehorsepills? 1993;208:34-35. Am Druggist. and women inanurbanpopulation.Dysphagia.1991;6:187-192. 1985(Aug):90-96. and zinc.USPatent No. 6306372B1(2001). Eur JPhar atent No.42443000. Higher molecularweight fordelivery of K-90canbeusedasacarrier Augello Metal.USP m Biophar an PV . Dr m. 2005;60:61-66. ug dif atent No.6723342.(b)LeungS,S-hS,Leon,RS,K fusion fromcelluloseacetate-pol N CONCLUSIONS REFERENCES yvin yl pyrrolidone free films fortransdermal yl pyrrolidonefreefilms xamers, canbeusedtomask umar LD, Kulkarni N, Sorg AF. US solubilization technology. d pharmaceutical industry. The group provide technical supporttothe pharmaceutical excipients and to gr Solutions, North America development positi University atNew Jersey. Inhiscurrent Rhode Island and hisMBA from Rutgers in Pharm reviewed journals and holds 5patents. authored 7publications inpeer- hi d development technology, floating drug b used indiffer and drug solubilization, which canbe gelatin coating, floating technology, taste- m Pharm American Cyanamid and Catalytica Bef FD Scientist. He hasbeeninvitedbythe in Ch the CityUniversity of New York, allin University (Canada), and hisPhDfrom (India), hisMSc from Laurentian earned hisBScfrom Gorakhpur University drug development applications. Dr. Ali products toinnovative pharmaceutical supplements bypositioning the BASF excipients, actives, and dietary companies inNAFTA topromote and hasworked since withthe Pharma Solutions teamover3yearsago patents tohiscredit. He joined the peer-reviewed journals and 12US drug delivery, and has25publications in areas of drug design, formulations, and elivery system eveloped vari iotech industries. He hasworked inthe clu gh fun oup f emistry. Hiscurrent research interest A tospeakaboutth ore joining BASF, he worked at des the polymer evaluation for film on, he leadsthe BASF Pharma aceuti BIOGRAPHIES or new applications of asking, intraoral film,soft cti aceuti on cal asaDevelopment en ality e ous techn s cs from the University of , coatin t d rug d pharmaceutical and experience inthe has over13yearsof P Manager atBASF Development is the Product Dr. Shaukat Ali Quadir Dr H Ro Corporation in Manager of BASF Development Technical x harma Solutions and cipi e earned hisPhD xbury . Anisul e d gs, and elivery system ologi en evelopment of ts , New Jersey. . H is the es, such as e has s . 43 Drug Delivery Technology June 2007 Vol 7 No 6

AADHESIDHESIVVESES

Beyond Sticky to Sophisticated: The Many Dimensions of Adhesives By: Richard Sitz, MBA

INTRODUCTION 3M’s long history with adhesive materials has made its name virtually synonymous with things that stick (sometimes tenaciously) to bond the heaviest of metal parts; other times gently, so that objects can easily be repositioned or removed without leaving a trace. Seemingly mundane in purpose to join materials, adhesives actually comprise one of 3M’s broadest and most sophisticated technology platforms. This platform has generated thousands of innovative products that span the full spectrum of adhesive properties, with applications in countless markets. In each of the diverse markets 3M serves, the company’s in-house development of adhesives has been a key advantage, allowing it to develop solutions that address unique market issues. Today, 3M combines its adhesives with dozens of other technologies to attach, hold, seal, protect, communicate (think Post-it® Notes, telecommunications) and of course, to deliver drugs.

AN ENABLING TECHNOLOGY or channels when combined with a compartmentalized, channeled, or FOR TRANSDERMAL DELIVERY cap layer. Performance properties overlapped to suit applications. of TDD systems can be tailored by Channels, for example, can create 3M's long-standing expertise independently varying the unrestricted or less-restricted in adhesives brought to market the rheological properties of the movement of the substances within world's first stand-alone, 7-day adhesive and the structures formed the adhesive layer. transdermal system, leveraging its in the adhesive layer. Combinations of shapes, sizes, proprietary drug-in-adhesive The shapes and structures and orientations allow highly technology. Two of its recent formed in the adhesive can be regulated placements of innovations (discussed further) in adhesives are creating FIGURE 1 additional opportunities to advance the performance of 6

o transdermal drug delivery N 7

l (TDD) systems. o V 7 0 0

2 Microstructured Adhesives e n u

J for Greater Control in Drug y g

o Delivery l o n

h 3M's patented c e T y

r microstructured adhesives e v i l

e involve manipulating pressure- D g u r sensitive adhesives (PSAs) to Microstructured PSA D create patterns of micro-wells, 44 which form discrete reservoirs

ADHEADHESIVESIVESS

reservoirs/channels for greater amount of functional monomers that companies address vexing issues of control in drug delivery. can be incorporated typically is patch creep or excessive tackiness. Furthermore, additional medicinal limited because excessive Furthermore, a higher excipient ingredients can be introduced in a reinforcement will cause a loss of loading can enable potentially higher second adhesive layer or matrix to the soft, tacky properties necessary drug loading and corresponding

enable even more sophisticated drug in a PSA. increases in delivery rate and delivery performance. Using functional monomers with duration. Creating defined void volumes specific chemical structures, 3M has These aforementioned within a TDD device has a number developed adhesives with an optimal technologies represent promising of benefits. Among these is the level of functional monomers, new advances in adhesive ability to contain a medicinal enabling increased drug solubility in technology that help to facilitate ingredient within the void volume, the adhesive without causing improved TDD system performance. which can temporarily alter the excessive reinforcement or loss of thermodynamic driving force in the PSA properties.2 3M & TRANSDERMAL skin-contacting layer by replenishing These patented PSAs allow DRUG DELIVERY the layer with drug, penetration drug-in-adhesive formulations with enhancers, or other excipients.1 relatively heavy excipient loadings, Beyond adhesives technologies, As such, the invention provides while still maintaining important 3M Drug Delivery Systems draws the advantages of a reservoir-type adhesive properties, such as good on the full array of its 40+ device, such as the maintenance of a skin contact and clean removal.3 technology platforms (both material constant thermodynamic driving Depending on drug properties, this and process technologies) to expand force and steady delivery rates, invention may help pharmaceutical the limits of transdermal drug without the increased patch thickness and discomfort that are FIGURE 2 associated with reservoir devices. A 3M PSA Helps Secure a Label to the Delicate, Powdery Surface of a Monarch Butterfly’s Wing Enhanced Adhesive Compositions for Greater Solubility

6 An acrylic copolymer suitable o N

7 for PSAs needs to contain a l o V significant fraction of monomers 7 0

0 with a low glass transition 2 e

n temperature (Tg) to give the adhesive u J

y its soft, tacky properties. It also g o l o

n needs a means to provide h c e T reinforcement (using high-Tg y r e v i

l functional monomers, for example) e D

g to maintain sufficient mechanical u r D strength and to prevent excessive 46 adhesive flow. Unfortunately, the ADHEADHESIVESIVESS

SIDEBAR 1 companies worldwide. Its partners draw on 3M’s vast range of PRESSURE-SENSITIVE ADHESIVES technologies, 100-plus years of manufacturing experience, and its 3M pioneered pressure-sensitive adhesives (PSAs) more than global regulatory expertise to bring

80 years ago with the introduction of Scotch brand masking tape products to market quickly and efficiently. and later, transparent tapes. Since then, the company has engineered countless PSAs that form permanent or temporary bonds with surfaces simply with the application of light pressure. REFERENCES The magic of PSAs is in their viscoelastic nature. That is, they 1. Flanigan et al. US Patent No. exhibit liquid-like properties at low rates of strain application and 6,893,655 B2; 2005. solid-like properties at high rates of strain application. Tack and 2. Schaberg et al. US Patent No. 6,902,740 B2; 2005. holding power (also known as resistance to creep under load) are 3. Garbe et al. US Patent 7,097,853 the properties most associated with PSAs. Holding power is B1; 2006. controlled by the molecular weight of the base elastomer in the PSA and also by the level of crosslinking (connections between polymer chains). Higher levels of crosslinking help to hold the BIOGRAPHY adhesive together for clean removal. Mr. Richard Sitz is Technical Manager for the Transdermal delivery. The company employs series of exceptional components. Drug Delivery different material technologies, In fact, today, more than 80% of Department in the components, excipients, and patch TDD products in the US contain a Drug Delivery designs to solve unique formulation 3M transdermal component, such Systems Division at challenges posed by specific drugs. as backing, liner, membrane, and 3M. During his 22 Backed by 3M technologies and foam tape. years with 3M, he corporate resources, the division has 6 o has served in various roles, including N generated more than 150 issued and 7 l o

R&D, process development and scale-up, V pending US patents pertaining to WORLD-CLASS RESOURCES 7

FOR A STRONG PARTNERSHIP commercial manufacturing, business 0 transdermal drug delivery, as well as 0 2

development, and program management, e n their foreign equivalents. u With operations in more than all related to the pharmaceutical J 3M’s 30-year track record y g o 60 countries, 3M Drug Delivery industry. Mr. Sitz earned his BS in l o includes the first stand-alone, 7-day n h c

Systems brings inhalation and Mechanical Engineering from Iowa State e transdermal system, specialty T y r

transdermal drug delivery product University and his MBA from California e v i adhesives (including proprietary l e development and manufacturing to Lutheran University. He can be reached D g

drug-in-adhesive technology), and a u r

pharmaceutical and biotech at [email protected] or (651) 736-8567. D

47

PULMONARY DELIVERY Efficient Pulmonary Delivery of Biological Molecules as PROMAXX Microspheres By: Julia Rashba-Step, PhD

INTRODUCTION

Since they first emerged as therapeutic products, the delivery of proteins, peptides, nucleotides, antibodies, and other biologics has been almost exclusively the preserve of the injectable route. However, in recent years, developments in the pulmonary administration of biologics have gathered pace. Today, local delivery to the lung and systemic delivery through the lung both represent viable, proven delivery options for biological therapeutics. Technologically speaking, the key to delivering biological molecules to and through the lung successfully is the ability to produce a suitable dry powder formulation that meets precise specifications using a simple, robust, and cost-effective process. In terms of delivering the successful commercial product, it is equally important that the company developing and carrying out that formulation process has the right credentials to affect an efficient, mutually rewarding, and long- lasting working relationship with its drug partner. In this article, we present robust scientific data combined with a candid account of some of our internal procedures and company culture, as evidence that when it comes to the development of inhalable biologics, the PROMAXX microsphere delivery technology is capable of yielding a suitable inhalable formulation, and that Epic Therapeutics (a wholly owned subsidiary of Baxter Healthcare Corporation) is a company with the necessary credentials to deliver a commercial product.

FORMULATION FIGURE 1 CHARACTERISTICS

PROMAXX microspheres are produced via a controlled phase-separation process, most commonly involving cooling a super saturated solution of aqueous protein and aqueous polymer under 6

o controlled conditions. The conditions, N

7 including ionic strength, pH, polymer l o V concentration, protein concentration, and 7

0 rate of cooling (among others), may all 0 2

e affect formation of PROMAXX n u J microspheres and can be varied to produce y g precisely the required results. PROMAXX o l o n microsphere formation takes place in an h c e T aqueous system and at mild temperatures, y r e v

i yet it is highly versatile, meaning that in l e D addition to proteins and peptides, it is also g u r

D applicable to other classes of biological therapeutic molecules, including nucleic SEM Images of AAT Starting Material & PROMAXX Particles & Aerosizer Particle-Size Range Data 48 acids, siRNA, and small molecules.

PULMONARY PULMONARY DELIVERY DELIVERY

The attributes that differentiate the FIGURE 2 PROMAXX process from other pulmonary powder production techniques, such as spray drying, include the following:

• The process yields homogenous particles within tightly specified size ranges, so no sieving is required.

• Although it is possible to incorporate excipients into PROMAXX formulations, there is not a requirement for excipients, meaning that microspheres consisting of essentially only active molecule can be produced. High-dose loading (comfortably above 90%) means that less powder mass need be delivered to achieve the desired pharmacological effect. SEM Images of hGH Starting Material & PROMAXX Particles & Aerosizer Particle-Size Range Data Epic Therapeutics has produced and characterized multiple PROMAXX the lung can solve the challenge of limited activity after the process, compared with microsphere formulations for pulmonary availability of AAT. activity before the process. AAT is a labile delivery. Here, we discuss in detail two Particles within the target size range of 1 protein prone to aggregation and oxidation. examples of PROMAXX formulations of to 3 microns are essential if AAT is to be An in vitro AAT activity assay quantifying the human growth hormone (hGH), alpha-1 anti- delivered to its site of action in the deep lung. level of elastase inhibition showed that trypsin (AAT), and insulin. The results Time-of-flight measurements made using a PROMAXX AAT retained at least 95% of its demonstrate how PROMAXX microspheres TSI Aerosizer and scanning electron activity compared with the starting material. measure up against the criteria that a microscopy showed that the PROMAXX Finally, shelf stability studies carried out successful inhalable dry powder formulation process generated AAT microspheres within at 4°C and at room temperature for 12 the required size range and very narrow months showed no difference in activity loss 6 must meet. o

N particle size distribution (Figure 1). between PROMAXX AAT microspheres and 7 l

o ALPHA-1 ANTI-TRYPSIN (AAT) Andersen Cascade Impactor (ACI) a lyophilized control drug. V studies showed that high respirable fraction 7 0

0 (73%) of AAT protein particles were 2 The physiological function of AAT is to HUMAN GROWTH e

n delivered to stages 2 to F, with an emitted HORMONE (HGH) u control the levels of the neutrophil elastase J dose of 86% from a CyclohalerTM, a simple, y enzyme. In patients with AAT deficiency, a g o l pocket-size dry powder inhaler developed by Human growth hormone (hGH), o serious hereditary disorder, inadequate levels n h

c Pharmachemie, The Netherlands. These currently administered by daily subcutaneous

e of the protein can cause liver damage and T y

r excellent aerodynamic properties were injection to children with growth hormone

e destruction of the alveolar tissue. The v i l

e condition is traditionally treated with reproducible across different lots of deficiency, is a promising candidate for D

g microspheres. formulation for inhalable delivery. Not only u

r intravenous AAT augmentation, but a D pulmonary formulation allows administration Another critical test of a pulmonary dry would convenience and comfort be 50 directly to the site of action. Also, delivery to powder production process is the retention of significantly enhanced compared with PULMONARY PULMONARY DELIVERY DELIVERY

FIGURE 3 to 2.1 microns, and greater than 80% of the emitted dose of the formulation was delivered to stages 2 to F of the Andersen Cascade Impactor. Figure 3 shows that PROMAXX insulin powder retained its aerodynamic stability over 10 months, with little variation in Andersen Cascade Impactor data over the time period. One investigator commented, “The deposition of the radiolabeled insulin into the peripheral lung was superior to any aerosolized product this investigator has seen.” Preclinical studies in dogs have revealed pharmacokinetic and pharmacodynamic profiles of PROMAXX insulin comparable with subcutaneous injection. Specifically, serum insulin levels following inhalation of 0.44 mg of PROMAXX insulin were comparable with levels obtained following 0.12 mg delivered SC. Figure 4 shows that the effect on serum glucose levels following 0.44 mg of PROMAXX pulmonary insulin mirrored that of the subcutaneous dose very USP Andersen Cascade Impactor Aerodynamic Stability of PROMAXX Insulin closely. A Phase I clinical trial of PROMAXX injection, but therapeutic efficacy is also likely administration resulted in very high serum insulin delivered using a simple DPI was to be improved. The protein is relatively small concentrations of hGH and bioavailabilities of recently completed. A total of 30 subjects at 22 kDa, meaning that high bioavailability in 30% to 50% relative to subcutaneous participated in the randomized, two-way the lungs is likely. Furthermore, using injections. Pulmonary administration of hGH crossover study conducted in Germany. The trial inhalation, it may be possible to mimic the resulted in a considerably lengthened showed the product to be safe and well tolerated pulsatile nature of endogenous release. pharmacodynamic response relative to that of in healthy volunteers. The bioavailability relative The PROMAXX microsphere subcutaneous administration as measured by to SC was more than 12%. No coughing or formulation of hGH yields particle sizes in the IGF-1 serum concentrations versus time post shortness of breath was observed following range 1 to 5 microns with an MMAD of 3 administration. 6 o

inhalation. PROMAXX insulin has performed N microns. As with AAT, the microspheres 7

very well thus far through its development. l o

consisted essentially wholly of active protein INSULIN V Baxter recently presented the Phase I data at the because no excipients are needed, and there 7 0

Respiratory Drug Delivery Europe 2007 0 was a narrow particle size distribution (Figure Inhalable insulin has perhaps the highest 2 e

Conference in Paris. n u

2). Andersen Cascade Impactor analysis profile amongst all of the biological molecules J y

showed the emitted dose from the Cyclohaler under development for pulmonary g o l o

was 62.8%, and the respirable fraction was administration, with one pulmonary insulin n h

FROM SAMPLE API TO CGMP c e

67.4%. SEC and RP-HPLC showed that product having reached the market last year. T y

FORMULATION SCALE-UP r compared with starting material, after the Similar to AAT and hGH, the e v i l e

PROMAXX formulation process, at least 95% PROMAXX formulation process has yielded D

The following is intended to give an g u of hGH activity was retained. positive results when applied to insulin. r account of the various stages a biological D Systemic delivery of hGH PROMAXX Particle size distribution studies have revealed molecule from the partner might go through on microspheres to dogs via pulmonary that 95% of particles fall within the range 0.95 51 PULMONARY DELIVERY

its journey toward full-scale manufacture as FIGURE 4 an inhalable PROMAXX formulation. The process usually begins with Epic being supplied with a small quantity of the molecule by a company interested in finding out whether it is suitable for formulation using PROMAXX technology. A go/no-go decision is usually reached within 8 weeks following rapid screening studies at the > 1 mL scale. These investigations will include solubility profiling, generating phase diagrams for the formation of solid precipitate, and identification of process boundaries. There are two important points to note at this initial stage. Firstly, due to the complex and expensive nature of producing many biological molecules, it is common that only a very small amount of the candidate molecule is made available for Epic to assess. This PROMAXX Insulin Pharmacodynamics (n = 5 dogs at each time point) presents no problem because only a tiny quantity is required for initial studies to assess whether the PROMAXX technology can be studies can be conducted at this stage before benefits from experience, and there are effectively applied to a molecule of interest; a fine tuning the formulation, after which the precedents to use as guides, there is no rigid, far smaller amount than would be required for project moves to process development for standard procedure to follow as a project a similar initial assessment for a spray dried scale-up. progresses. The project design is highly formulation, for example. Figure 5 outlines the complex web of versatile and succeeds because it is readily The second point to note is about the relationships between the key process tailored to the particular needs of each context and the likely events leading up to the parameters. An empirical approach for individual formulation and, crucially, to each initiation of studies to explore the potential of formulation development is possible, but it is individual partner’s requirements and the molecule with PROMAXX technology for time and labor intensive. A high throughput specifications. pulmonary delivery. In many cases, screening approach using DOE rapidly For example, two key factors shaping the

6 companies will approach Epic because they increases efficiency of formulation process design of the project are the amount of test o N have a problem formulating their molecule in- and identifies optimal formulation conditions. substance made available to Epic, and the 7 l

o The final formulation is developed and partner’s time requirements. Indeed, planning

V house using their own approaches. Thus for

7 Epic, the starting point, as it first takes produced in 50- to 500-mL reactors. Process the timing of the project carefully and meeting 0 0

2 delivery of the test quantity of API, is often to characterization and control is carried out at the specified timelines are paramount. e n

u resolve an existing problem. Epic’s team of this stage using online monitoring and data J

y problem-solvers work diligently to create a collection. Molecular integrity, microparticle STEPS OF A TYPICAL g o l

o viable formulation. morphology, and yield analysis are conducted PARTNERSHIP n h c

e After the initial go/no-go decision is as well as in vitro and in vivo aerodynamic T y r

e made, preliminary formulation work can performance studies. In the same way the structure and timing v i l e begin in 1- to 40-mL reactors. A biophysical The last stage is manufacturing scale-up, of the various practical/technical development D g u

r characterization of the formulation, molecular conducted in 1- to 10-liter reactors under stages of each project are unique to that D integrity, microparticle morphology, and yield “clean” conditions. project, the commercial and legal structure of 52 analyses are often conducted. Informal PK Epic is keen to stress that although it every individual project is tailored to that PULMONARY DELIVERY

FIGURE 5 excellent characteristics for pulmonary drug delivery using a simple dry powder inhaler. In addition to proteins and peptides, the technology is being developed for nucleic acids pulmonary delivery. Epic’s team consists of problem-solvers who can use the PROMAXX technology to create innovative solutions for its partners’ problems. Epic benefits from the creativity and attention to detail that it can give to projects through its innovative, dedicated, and agile team, and from its ability to draw on the infrastructure and resources of its parent organization, Baxter Healthcare Corporation.

BIOGRAPHY

Dr. Julia Rashba-Step is the Director of Process Parameters: Interrelation of the Key Factors Formulation Research at Epic Therapeutics, Inc., a particular project’s needs. upon, a feasibility study agreement is signed, wholly owned subsidiary Typically, a partner comes to Epic and the study is conducted. Throughout the of Baxter Healthcare needing to enable or enhance the continued study, Epic communicates with the partner Corporation, located in development of their molecule. An initial non- constantly. There is typically a face-to-face Norwood, MA. Dr. confidential discussion reveals a likely fit and project "kick-off" meeting, and face-to-face Rashba-Step manages a team of 15 scientists then, under a Confidential Disclosure meetings are arranged whenever needed. In who conduct the formulation research work on Agreement, Epic and its partner may share between, a continual exchange of information feasibility studies on behalf of partners’ data on the molecule, the project, the and feedback is maintained. Stages of the proprietary molecules. Her team is also objectives, and the PROMAXX technology. project are defined in the agreement, each enhancing the breadth and depth of the It is important to note that while Epic stage normally culminating in at least one portfolio of technologies that Baxter can apply might be approached by a company with report summarizing results. When the to solve challenging drug delivery problems. She PROMAXX technology in mind, it could be that necessary data are available and the results is a speaker at a number of professional drug 6 o one of Baxter’s many other drug delivery support further development, the parties may delivery conferences, has published in peer N 7 technologies are appropriate. Partners execute a license and supply agreement. A l reviewed journals, and authored many patents. o approaching Epic will have all of Baxter’s broad patent estate surrounds the PROMAXX V

Previous to joining the company in 1997, she 7 0 technologies and services available to them as technology, and Epic’s partners can therefore 0 was engaged in academic research at Mount 2 e potential solutions. If the initial assessments benefit from the enhanced value this strong IP n

Sinai Medical School, Columbia University, and u indicate that the PROMAXX technology can protection provides. J

the University of Southern California. She earned y g o address the project requirements, a work plan is l

her PhD in Biophysics from the Academy of o n h generated outlining the scope of the project, the SUMMARY Sciences of Russia, in Moscow. Dr. Rashba-Step’s c e T y metrics to judge progress, and the API expertise is in the field of protein and peptide r e v i requirements to complete the work. Additionally, Multiple biological molecules, including l formulations for the pulmonary and injectable e D an estimate of the time and resources required to AAT, hGH, and insulin, have been successfully g

routes of administration, particle engineering, u r conduct the study is prepared. formulated using the PROMAXX microsphere coating, and microencapsulation technologies. D When the work plan has been agreed delivery technology as viable products with 53

BIOADHESIVE MICROSPHERES Bioadhesive Microspheres & Their Pharmaceutical Applications By: Jayvadan Patel, PhD

ABSTRACT Bioadhesion is a topic of current interest in the design of controlled or targeted drug delivery systems. Recent advances in polymer science and drug carrier technologies have promulgated the development of novel drug carriers, such as bioadhesive microspheres that have boosted the use of bioadhesion in drug delivery. Bioadhesive microspheres exhibit a prolonged residence time at the site of application or absorption and facilitate an intimate contact with underlying absorption surface and thus contribute to improved and/or better therapeutic performance of drugs. In recent years, such bioadhesive microspheres have been developed for oral, buccal, ocular, rectal, nasal, and vaginal routes for systemic or local effects. This article presents an introduction to and the advanced pharmaceutical applications of bioadhesive microspheres.

INTRODUCTION mucus layer; and specific targeting of drugs to solution of the drug (which may contain a the absorption site achieved by anchoring plant viscosity-building or stabilizing agent) is added The term bioadhesion describes materials lectins, bacterial adhesins, and antibodies on the to an organic phase consisting of the polymer that bind to biological substractes, such as surface of the microspheres. solution in solvents like dichloromethane (or mucosal members. Adhesion of bioadhesive drug Bioadhesive microspheres can be tailored ethyl acetate or chloroform) with vigorous delivery devices to the mucosal tissue offers the to adhere to any mucosal tissue, including those stirring to form the primary water-in-oil possibility of creating an intimate and prolonged found in the eye, nasal cavity, urinary tract, emulsion. This emulsion is then added to a large contact at the site of administration. This colon, and gastrointestinal tract, thus offering the volume of water containing an emulsifier like prolonged residence time can result in enhanced possibilities of localized as well as systemic PVA or PVP to form the multiple emulsion absorption, and in combination with controlled controlled release of drugs. Bioadhesive (w/o/w). The double emulsion, so formed, is then release of a drug, can also improve patient microspheres can be prepared using different subjected to stirring until most of the organic compliance by reducing the frequency of techniques. Application of bioadhesive solvent evaporates, leaving solid microspheres. administration. Carrier technology offers an microspheres to the mucosal tissues of the ocular The microspheres can then be washed, intelligent approach for drug delivery by cavity and gastric and colonic epithelium is used centrifuged, and lyophilized to obtain the free- coupling the drug to a carrier particle, such as for administration of drugs for localized action. flowing and dried microspheres. microspheres, nanospheres, liposomes, Prolonged release of drugs and a reduction in nanoparticles, etc, which modulates the release frequency of drug administration to the ocular Hot-Melt Microencapsulation 7 and absorption of the drug. Microspheres cavity can highly improve patient compliance. In this technique, the polymer is first constitute an important part of these particulate The latter advantage can also be obtained for the melted and then mixed with solid particles of the drug delivery systems by virtue of their small drugs administered intranasally due to the drug that have been sieved to less than 50 size and efficient carrier capacity. However, the reduction in mucociliary clearance of drugs microns. The mixture is suspended in a non- success of these microspheres is limited due to adhering to the nasal mucosa. Microspheres miscible solvent (like silicone oil), continuously their short residence time at the site of prepared with bioadhesive and bioerodible stirred, and heated to 5°C above the melting absorption. It would therefore be advantageous to polymers undergo selective uptake by the M cells point of the polymer. When the emulsion is

6 have a means for providing intimate contact of of Peyer patches in gastrointestinal (GI) mucosa. stabilized, it is cooled until the polymer particles o N the drug delivery system with the absorbing This uptake mechanism has been used for the solidify. The resulting microspheres are washed 7

l membranes. This can be achieved by coupling delivery of protein and peptide drugs, antigens via decantation with petroleum ether. The only o V bioadhesion characteristics to microspheres and for vaccination, and plasmid DNA for gene disadvantage of this method is the moderate 7

0 developing bioadhesive microspheres.1-5 therapy. Moreover, by keeping the drugs in close temperature to which the drug is exposed. 0

2 proximity to their absorption window in the GI

e Bioadhesive microspheres include microparticles n

u mucosa, the bioadhesive microspheres improve Solvent Removal

J and microcapsules (having a core of the drug) of the absorption and oral bioavailability of drugs In this technique, drug is dispersed or y 1 to 1000 microns in diameter and consist g 7 o

l like furosemide and riboflavin. dissolved in a solution of the selected polymer in

o entirely of a bioadhesive polymer or an outer n

h 6 a volatile organic solvent such as methylene

c coating of it, respectively. Microspheres, in e T chloride. This mixture is then suspended in

y general, have the potential to be used for targeted PREPARATION OF r

e 7 silicone oil containing Span 85 and methylene v

i and controlled-release drug delivery, but

l BIOADHESIVE MIRCROPSHERES e chloride. After pouring the polymer solution into D coupling of bioadhesive properties to g

u silicone oil, petroleum ether is added and stirred r microspheres has additional advantages, eg, Solvent Evaporation Technique D until the solvent is extracted into the oil solution. efficient absorption and enhanced bioavailability The solvent evaporation technique is The resulting microspheres can then be dried in a 54 of the drugs due to a high surface-to-volume the most extensively used method of vacuum. ratio; a much more intimate contact with the microencapsulation. A buffered or plain aqueous TRANSDERMAL DELIVERY

Table 1. Measurement of Adhesive Strength / In Vitro Tests 7 TABLE 1 METHOD DESCRIPTION

Wilhelmy Plate Technique The measurement of dynamic contact angles, and involves the use of a microtensiometer or a microbalance.

Novel Electromagnetic The EMFT measures tissue adhesive forces by monitoring the magnetic force required to exactly oppose the bioadhesive Force Transducer force. (EMFT)

The shear stress measures the force that causes a mucoadhesive to slide with respect to the mucus layer in a direction Shear Stress Measurement parallel to their plane of contact.

Determined as the ratio of the number of particles attached to the substrate to the total number of applied particles, Adhesion Number expressed as a percentage.

Quantitative in situ method, wherein an excised intestinal segment cut lengthwise, is spread on a plastic flute and positioned at an incline, and suspension of microspheres is allowed to flow down the intestinal strip. Particle concentrations entering the Falling Liquid Film Method segment from the dilute suspension reservoir and leaving the intestinal segment can be determined with the help of Coulter counter.

Everted Sac Technique A passive test for bioadhesion involving polymeric microspheres and a section of the everted intestinal tissue.

Novel Rheological The rheological properties of the mucoadhesive interface (ie, of the hydrated gel) are influenced by the occurrence of the Approach interpenetration step in the process of bioadhesion.

Measurement of Adhesive Strength / In Vitro Tests 7 Table 2. Measurement of the Residence Time / In Vivo Techniques 7 Hydrogel Microspheres microencapsulation involves relatively little loss of laser particle size distribution analyzer or the Gel-type polymers,Metho dsuch as alginates, are used polymer and drug. Comment microscopic method. for preparation of microspheres and are produced by dissolvingGI Transit the Using polymer Radio-Opaque in an aqueous solution,The use of radio-opaque markers, eg, barium sulfate, encapsulated in bioDeterminationadhesive of Bulk Density Microspheres microspheres to determine the effects of bioadhesive polymers on GI transit time. suspending the active ingredient in the mixture and CHARACTERIZATION OF Accurate weights of microspheres (Wm) were extruding through a precision device, producing BIOADHESIVE MICROSPHERES transfer into a 100-mL graduated cylinder to obtain microdropletsGamma thatScintigraphy fall into a hardening bathDistribution that is and retention time of the bioadhesive intravaginal microspheresthe canapparent be volumes (V) between 50 and 100 mL. Technique studied using the gamma scintigraphy technique. slowly stirred. The hardening bath usually contains Morphological Examination The bulk density was calculated in grams per calcium chloride solution, whereby the divalent The morphology of bioadhesive microspheres milliliter using the following formula: calcium ions crosslink the polymer forming gelled were examined by scanning electron microscopy. Bulk Density = W m/V microspheres.Table The 3. method Applications involves an “all- of BioadhesiveThe samples of microspheres Microspheres were dusted onto aqueous” system and avoids residual solvents in double-sided tape on an aluminum stub and coated microspheres. The particle size of microspheres can with gold using a cold sputter coater to a thickness Route of Drug Bioadhesive Polymers Used AngleCommen tofs/R eReposesults Reference be controlled by using variousAdministration size extruders or by of 100 to 400°A. Acvyaryingclovir the polymer solution flowO crates.ular Chitosan Slow release rate increased AUCThe. angle of repose can be measured by the 8 Methyl Prednisolone Ocular Production Hyaluronic Acid Yield Slow release rates sustainedheap drug carefull conceyntrationbuilt up in bteary dropping fluids. the microsphere 9 Gentamicin Nasal DSM+LPC Increased nasal absorptionsamples. through a glass funnel to the horizontal 10 Spray Drying The percentage of production yield (wt/wt) Insulin Nasal DSM+LPC Efficient delivery of insulin iplatento th ofe s ay spotewdermic c icharacteristicrculation via n atestersal ro. ute. 10 Human TheGrowth drug Hormo may nebe dissolved or dispersed in the was calculated from the weight of dried Nasal DSM+LPC Rapid and increased absorption. 11 (hGH)polymer solution and spray dried. The quality of microspheres (W ) recovered from each of the 1 Addition of LPC causes a five-fold increase in Cmax and two-fold increase Dspray-driedesmopressi nmicrospheres can be improvedNasal by the batchesSt aandrch the sum of the initial dry weight of Zeta Potential Study 12 in bioavailability. The zeta potential of bioadhesive microspheres Haemagglutininaddition of plasticizers, (HA) which promote polymer starting materials (W ) using the following 2 With mucosal adjuvant serum lgG antibody response as compared to i.m. obtained from Nasal HYAFF dispersed in dissolution medium can be determined 13 coalescence on the drug particles and hence equation: immunization. Influenzapromote A the virus formation of spherical and smooth using a zeta meter. The directional movement of 200 Increased bioavailability, higher AUC, effective absorption from the 6 Furosemide GI AD-MMS (PGEFs) microspheres from each formulation were observed 14 o surfaced microspheres. The size of microspheres Percentage of Production Yieldabsorption = W 1 W win 2 dow.x 100 N Amcanox ibecil lcontrolledin by the rate of spraying,GI the feedEthyl Cellulose-Carbopol-934P Greater anti H. pylori activitandy. averaged from three determinations. 15 7

l Delapril HCL GI AD-MMS (PGEFs) MRT of drug is increased. 16 o rate of polymer drug solution, nozzle size, and the V Glipizide GI Chitosan Prolonged blood glucose reduction. 17 drying temperature. Swelling Property 7 Glipizide GI DrugChitosan -ContentAlginate & LoadingProlonged blood glucose reduction. 18 0 The swelling of bioadhesive microspheres 0 Vancomycin Colonic PGEF Coated With Eudragit S 100 Well absorbed even without absorption enhancers. 19

2 Efficiency

e Insulin Colonic PGEF Coated With Eudragit S 100 Absorbed only in the presenwceree o fconductedabsorption ine ndissolutionhancers, e gmedium., EDTA s Theiralts. 19

n Phase Inversion Bioadhesive microspheres of each

u Nerve Growth factor Increased absorption from HYAFF microspheres as compared to aqueous J Microencapsulation Vaginal HYAFF diameters were periodically measured using a laser20 (nGF) formulation were extracted in solutiondissolution of the medium drugs.

y particle size distribution analyzer or microscopic g The process involves addition of drug to a and assayed by suitable analyticalIncreased methods. absorption The for HYAFF microspheres as compared to aqueous o

l Insulin Vaginal HYAFF 21 o dilute solution of the polymer. The mixture is solution of the drugs. method until they were decrease by erosion and

n actual amount of drug loaded relative to the h

c Increased absorption from HYAFFdissolution. microsp Theheres percentage as compared of swelling to aqueous is

e Salmonpoured Calcitonin into an unstirred bath of Vaginala strong non- theoretical HYAFF amount in the microspheres was 22 T solution of the drugs.

y determined at different time intervals by the

r solvent (petroleum ether) in a solvent-to-non- calculated as a percentage and expressed as the

e CMC as Mucopolysaccharide+

v Pipedimic Acid Vesical - 23

i difference between diameter of microspheres at l solvent ratio of 1:100, resulting in the spontaneousEduragitloading RL as Matrix efficiency. Polymer e

D time t (D ) and initial time (t = 0 [D ]) as calculated production of microspheres through phase t 0 g

u CMC (carboxy methyl cellulose), DSM (degradable starch microspheres), EDTA (ethylenediaminetetraacetic acid), GI (gastrointestinal), HYAFF (hyaluronic acid esters), r from the following equation: D IgGinversion. (immunoglo The microspheresbulin G), LPC are (lysophosphatidylcholine), then filtered, Particle PGEFs (polyglycerol Size Measurement esters of fatty acids) washed with petroleum ether, and dried at room The prepared bioadhesive microspheres were 56 temperature. This simple and fast process of suspended in suitable solvents and sized by using a Percentage of Swelling = D t - D 0/D 0 x 100

Table 2. Measurement of the Residence Time / In Vivo Techniques 7 Infrared Absorption TABLE 2 Study The IR spectra of drug and Method Comment additives in the bioadhesive microspheres were examined via the GI Transit Using Radio-Opaque The use of radio-opaque markers, eg, barium sulfate, encapsulated in bioadhesive potassium bromide disc method Microspheres microspheres to determine the effects of bioadhesive polymers on GI transit time. using an infrared spectrophotometer in the require range. Gamma Scintigraphy Distribution and retention time of the bioadhesive intravaginal microspheres can be Technique studied using the gamma scintigraphy technique. In Vitro/In Vivo Bioadhesion Study 7 To evaluate bioadhesive MeasurementTable of3. the Applications Residence Time / In Vivoof TechniquesBioadhesive Microspheres microspheres is to evaluate the and 2 L, which is sufficient to hydrate oral mucosal have been investigated for peroral gene delivery.6 The effectiveness of bioadhesive polymers to prolong the dosage forms.Route This of water-rich environment of the increased bioactivity of insulin and plasmid DNA residence time of drug at the site of absorption,Drug Bioadhesive Polymers Used Comments/Results oral cavityAdministration is the main reason behind the selection of can be accounted to the uptake of microspheres by thereby increasing absorption andA bioavailabilitycyclovir of Ocular Chitosan Slow release rate increased AUC. hydrophilic polymeric matrices as vehicles for oral cells lining the GI epithelium. Thus, these uptake the drug. The methods used to evaluateMethyl bioadhesive Prednisolone Ocular Hyaluronic Acid Slow release rates sustained drug concentration in tear fluids. 9 transmucosal drug delivery systems. Vyas and Jain pathways can be used as a platform for the systemic microspheres are listed in Tables 1G andenta 2.m icin Nasal DSM+LPC Increased nasal absorption. Insulin prepared polymerNasal grafted starch microspheresDSM+LPC deliveryEf fofici ean varietyt delive rofy otherapeuticf insulin int oagentsthe sy showingstemic circulation via Human Growth Hormone bearing isosorbideNasal dinitrate and evaluatedDSM their+LPC poor absorptionRapid and throughincreas eGId a epithelium.bsorption. Bioadhesive In Vitro Drug (hGH) potential as a sustained-release buccal bioadhesive microspheres,Addition bofy LPCkeeping causes the druga five-fold in the increase region in Cmax and two-fold increase Release Study Desmopressin Nasal Starch 1 system both by in vitro release studies and in vivo proximalin bioavailability. to its absorption window, allow targeting The in vitro drug release test of the Haemagglutinin (HA) 25 absorption studies. Starch microspheres grafted and localizationWith mucosal of the adjuvant drug at serum a specific lgG a sitentibody in the response as compared to i.m. bioadhesive microspheres were performedobtained fromusing a Nasal HYAFF 1 with polymethyl methacrylate (PMMA) exhibited GIT. Animm adhesiveunizatio micromatrixn. system (AD-MMS), a Franz diffusion cell with dialysis membraneInfluenza A or virus a relatively slow drug release as compared to novel forIncreasedmulation bioavailability, approach, reported higher AUC,by Akiyama effective absorption from th USP dissolution test apparatus. Furosemide GI AD-MMS (PGEFs) 1 polyacrylate- (PAA) grafted microspheres. Moreover, and Nagaharaabsorption consists window. of the drug and an adhesive Amoxicillin GI Ethyl Cellulose-Carbopol-934P Greater anti H. pylori activity. the C and AUC recorded for the acrylic acid- polymer dispersed in a spherical matrix of the Drug Permeation StudyDelapril HCL max GI AD-MMS (PGEFs) MRT of drug is increased. grafted starch microspheres were found to be more PGEFs with a diameter of 177 to 500 microns.14 This Cell cultures techniques wereG lmostlyipizide used for GI Chitosan Prolonged blood glucose reduction. Glipizide than that for GPMMA-I grafted starchCh microspheres.itosan-Alginate It formulationProlon shogedwbedlo ostrongd gluc oadherencese reducti oton .the stomach the drug permeation study. Vancomycin has been reCvoealedlonic by the inP GvivoEF Cabsorptionoated Wit hstudiesEudragit S 1mucosa.00 W eDrll augbs releaseorbed e fromven w thisitho usystemt absor pcouldtion e benhancers. Insulin Colonic PGEF Coated With Eudragit S 100 Absorbed only in the presence of absorption enhancers, e Nerve Growth factor that steady state plasma levels can be maintained regulatedIncreased by appropriate absorption selection from HYAFF of the microspHLB valueheres as comp Pharmaceutical Applications Vaginal HYAFF 2 (nGF) above the minimum effective concentration (MEC) of the PGEFs.solution Variousof the drugs. channeling agents were Bioadhesive microspheres have been Increased absorption for HYAFF microspheres as compared to aqu Insulin over a periodVag ofin a12l hrs after buccal administrationHYAFF of reported to regulate drug release through the 2 extensively studied for a number of applications. The solution of the drugs. the grafted microspheres. micromatrix systems, eg, mannitol, acrylic acid, and ajority of these can be understood by classifying Increased absorption from HYAFF microspheres as compared to aq Salmon Calcitonin Vaginal HYAFF lactose. In experiments using rats, prolongation of GI 2 these applications on the basis of route of solution of the drugs. CMC as Mucopolysaccharide+ Pipedimic Acid Gastrointestinal Vesical (GI) transit -time and improvement in the bioavailability of administration. All these applications have been Eduragit RL as Matrix Polymer The development of peroral controlled-release furosemide (with a narrow absorption window) has reviewed in the subsequent sections and listed in DDS has been hindered by the inability to restrain been shown. The MRT values after PGEF Table 3. CMC (carboxy methyl cellulose), DSM (degradable starch microspheres), EDTA (ethylenediaminetetraacetic acid), GI (gastrointestinal), HYAFF (hya IgG (immunoglobulin G),and LPC localize (lysophosphatidylcholine), the drug delivery system PGEFs in selected (polyglycerolmicrospheres esters of fatty and acids) the AD-MMS administration were regions of the gastrointestinal tract (GIT). found to be 6.1 ± 0.6 and 6.7 ± 0.7 hrs, respectively. ORAL APPLICATIONS Bioadhesive drug delivery systems form an While the AUC (0 to 24 hrs) after AD-MMS important approach to decrease the GI transit of administration (11.57 ± 1.84 µg h/ml) was 1.8 times Buccal drugs. Drug properties especially amenable to that of the PGEF microsphere (6.56 ± 0.93 µg/ml). The oral cavity is used for both systemic bioadhesive formulations include a relatively short The results could be explained to be due to the delivery and local treatment. Systemic delivery of biological half-life of about 2 to 8 hrs, a specific adherence of the AD-MMS to a more proximal area drugs is either sublingual (through the mucosal window for the absorption of drug by an active, of the GIT rather than the absorption window, and membranes lining the floor of the mouth) or buccal saturable absorption process, and small absorption furosemide was thereby effectively absorbed from (through the mucosal membranes lining the cheeks). rate constants.26 The GI epithelium consists of a the absorption window.28 AD-MMS containing Furthermore, oral transmucosal drug delivery single layer of simple, columnar epithelium lying amoxicillin have been evaluated against the bypasses the first-pass effect and avoids pre-systemic above a collection of cells called the lamina propria amoxicillin suspension for Helicobacter pylori elimination in the GI tract. These factors make the and supported by a layer of smooth muscle known as clearance in vivo using Mongolian gerbils as the oro-mucosal cavity a very attractive and feasible site 6 the muscularis mucosae. Tight junctions or the zona animal model. A ten-fold greater anti H. pylori 24 o for systemic drug delivery. Composition of the oral N occludens hold the cells together. A special type of activity after oral administration of AD-MMS as

7 epithelium varies depending on the site in the oral l GI epithelium, the Peyer’s patches (PP) of the gut- compared to the amoxicillin suspension has been o

V cavity. The areas exposed to mechanical stress (the associated lymphoid tissue (GALT), is also present. reported that could be due to the difference in gastric

7 gingivae and hard palate) are keratinized similar to 29 0 Polymeric microspheres can also be phagocytized by residence provided by the two dosage forms. 0

2 the epidermis. The mucosae of the soft palate, the these microfold cells and hence can be used for Amoxicillin AD-MMS adheres to the infected e

n sublingual, and the buccal regions, however, are not 27 u

J vaccination purposes. mucosa and thereby provides a higher H. pylori keratinized. The keratinized epithelia contain neutral

y Specially engineered polymeric bioadhesive eradication or clearance rate. Patel et al prepared g

o lipids, such as ceramides and acylceramides, which l microspheres can traverse both the mucosal glipizide microspheres containing chitosan using a o

n have been associated with the barrier function. It is h

c absorptive epithelium and follicle-associated simple emulsification phase separation technique e

T estimated that the permeability of the buccal mucosa epithelium covering the lymphoid tissues of the using glutaraldehyde as a cross-linking agent.17 In y r

e is 4 to 4000 times greater than that of the skin. In

v Peyer’s patches, depending on the particle size, vivo testing of the mucoadhesive microspheres to i l

e general, the permeabilities of the oral mucosa

D polymer composition, and the surface charge of albino Wistar rats demonstrated significant

g decrease in the order of sublingual greater than 6 u

r bioadhesive microspheres. Bioerodible bioadhesive hypoglycemic effect of glipizide. D buccal and buccal greater than palatal. The daily microspheres have been reported to increase the salivary volume secreted in humans is between 0.5 58 peroral bioavailability of dicumarol and insulin and D Technique studied using the gamma scintigraphy technique.

Table 3. Applications of Bioadhesive Microspheres TABLE 3 Route of Drug Bioadhesive Polymers Used Comments/Results References Administration Acyclovir Ocular Chitosan Slow release rate increased AUC. 8 Methyl Prednisolone Ocular Hyaluronic Acid Slow release rates sustained drug concentration in tear fluids. 9 Gentamicin Nasal DSM+LPC Increased nasal absorption. 10 Insulin Nasal DSM+LPC Efficient delivery of insulin into the systemic circulation via nasal route. 10 Human Growth Hormone Nasal DSM+LPC Rapid and increased absorption. 11 (hGH) Addition of LPC causes a five-fold increase in Cmax and two-fold increase Desmopressin Nasal Starch 12 in bioavailability. Haemagglutinin (HA) With mucosal adjuvant serum lgG antibody response as compared to i.m. obtained from Nasal HYAFF 13 immunization. Influenza A virus Increased bioavailability, higher AUC, effective absorption from the Furosemide GI AD-MMS (PGEFs) 14 absorption window. Amoxicillin GI Ethyl Cellulose-Carbopol-934P Greater anti H. pylori activity. 15 Delapril HCL GI AD-MMS (PGEFs) MRT of drug is increased. 16 Glipizide GI Chitosan Prolonged blood glucose reduction. 17 Glipizide GI Chitosan-Alginate Prolonged blood glucose reduction. 18 Vancomycin Colonic PGEF Coated With Eudragit S 100 Well absorbed even without absorption enhancers. 19 Insulin Colonic PGEF Coated With Eudragit S 100 Absorbed only in the presence of absorption enhancers, eg, EDTA salts. 19 Nerve Growth factor Increased absorption from HYAFF microspheres as compared to aqueous Vaginal HYAFF 20 (nGF) solution of the drugs. Increased absorption for HYAFF microspheres as compared to aqueous Insulin Vaginal HYAFF 21 solution of the drugs. Increased absorption from HYAFF microspheres as compared to aqueous Salmon Calcitonin Vaginal HYAFF 22 solution of the drugs. CMC as Mucopolysaccharide+ Pipedimic Acid Vesical - 23 Eduragit RL as Matrix Polymer

CMC (carboxy methyl cellulose), DSM (degradable starch microspheres), EDTA (ethylenediaminetetraacetic acid), GI (gastrointestinal), HYAFF (hyaluronic acid esters), IgG (immunoglobulin G), LPC (lysophosphatidylcholine), PGEFs (polyglycerol esters of fatty acids)

Applications of Bioadhesive Microspheres

Colon 934) were tested for sustained delivery in the lower systems increases the residence time of Colon drug delivery has been used for GIT using rat and dog animal models. Optimized formulations in the nasal cavity, thereby improving molecules aimed at local treatment of colonic formulations were designed for porcine insulin, absorption of drugs. It has been shown by gamma diseases and for delivery of molecules susceptible which was then tested in the non-diabetic dog scintigraphy studies that radiolabelled microspheres to enzymatic degradation, such as peptides. The model for bioavailability and pharmacological made from diethyl amino ethyl dextran mucosal surface of the colon resembles that of the response. Microspheres of triglyceride mixtures and (DEAE–dextran), starch, and albumin are cleared small intestine at birth but changes with age, low-melting fat composition were prepared using a significantly more slowly than solutions after nasal 32 causing the loss of villi leaving a flat mucosa with spinning disk method and subsequently administration in human volunteers. Hence, it was deep crypt cells. Therefore, the absorptive capacity incorporated in two-part gelatin capsules containing suggested by Illum et al that the intranasal of the colon is much less compared to the small Carbopol 934 or chitosan film prior to placement in application of bioadhesive microspheres (in powder intestine. The mucus layer provides not only a two-part gelatin capsules. Improved bioavailability form) causes them to swell upon coming in contact stable pH environment but also acts as a diffusion for the enteric-coated oral insulin formulation was with the nasal mucosa to form a gel and decrease barrier for the absorption of drugs. Mucus observed in the dog model with prolonged decrease their rate of clearance from the nasal cavity, thereby production is seen more in the elderly as the in plasma glucose. Recently, Varshosaz et al have providing poorly absorbed drugs a longer time for 33 number of mucous-secreting goblet cells increase developed mesalazine (5-ASA)-chitosan coated absorption. with age. Colonic mucosal environment is also microspheres via the emulsion-solvent evaporation Bioadhesive microspheres have also been 30 effected by the colonic microflora as they degrade technique based on a multiple w/o/w emulsion. investigated as vehicles for peptides and proteins. the mucins.7 Bioadhesive microspheres can be used The drug is effective in Crohn's disease and An increased bioavailability of FITC-dextran was during the early stages of colonic cancer for ulcerative-colitis but is rapidly absorbed from the observed in rats when microspheres made from enhancing the absorption of peptide drugs and small intestine, hence it is necessary to develop a Carbopol were used as a vehicle in comparison 34 vaccines, for the localized action of steroids, and colon-specific delivery system for it. with reference lactose microspheres. A drugs with a high hepatic clearance (eg, significantly greater hypocalcaemic effect was budesonide), and for the immunosuppressive agents observed after administration of salmon calcitonin such as cyclosporine. Colon-specific bioadhesive TOPICAL APPLICATIONS in gelatin microspheres in comparison with salmon 35 microspheres can be used for protection of peptide calcitonin in buffer. The bioavailability of salmon 6 o drugs from the enzyme rich part of the GIT and to Nasal calcitonin was greater when using positively N 7

charged spheres than when using negatively l release the biologically active drug at the desired The basic function of the nose, in addition to o charged spheres of the same size. Long-term use of V site for its maximum absorption. Insulin was found functioning as a sensory organ, is the pretreatment 7

bioadhesive microspheres however may reduce 0 to be absorbed well in the colon only in the of inspired air. The air is heated and humidified, 0 bioavailability. For example, after 8 days of nasal 2 presence of absorption enhancers, eg, EDTA salts, and its passage through the nose will help clear e n

delivery of insulin from microspheres made from u which cause chelation of calcium ions present in particles and bacteria from the air before it reaches J starch and Carbopol, a reduced bioavailability and the tight junctions and hence opening of water y

the lung. The nasal cavity offers a large, highly g o

lower decrease of blood glucose levels were l channels in the cell membranes. Geary et al vascularized subepithelial layer for efficient o 36 n noticed. h prepared targeted release formulations of absorption. Also, blood is drained directly from c e ® The excellent absorption-enhancing properties T vancomycin and insulin (utilizing Eudragit S100 y

nose into the systemic circulation, thereby avoiding r e

31 of bioadhesive microspheres are now being used v enteric coating and a decreased GI transit time), i first-pass effect. However, nasal delivery of drugs l e comparing two bioadhesive polymers (chitosan and has certain limitations due to the mucociliary extensively for both low molecular weight as well D g

® 19 as macromolecular drugs like proteins. The nasal u Carbopol 934). Salicylate microspheres clearance of therapeutic agents from the site of r cavity as a site for systemic drug delivery has been D incorporated in enteric and non-enteric deposition, resulting in a short residence time for investigated extensively, and many nasal formulations with chitosan or Carbomer (Carbopol absorption. Use of bioadhesive drug delivery 59 formulations have already reached commercial (P) as filler and shaper, were prepared using the At pH 5, presence of protonated carboxyl groups status, including leutinizing hormone-releasing spray-drying technique. Prepared microspheres were permits enhanced adhesion due to hydrogen bonding hormone (LHRH) and calcitonin.33 at loadings exceeding 80% and yields between 24% between the polymer and mucin strands resulting in Chitosan and starch are the two most widely and 74%. Bulky, free-flowing microspheres with a reduced clearance values. Clearance of microspheres employed bioadhesive polymers for nasal drug particle size between 15 and 23 microns were that significantly limits their residence time in the delivery. It has been reported that the clearance half- obtained. ocular cavity is a direct function of the pH and life was 25% greater for chitosan microspheres than hydration state of microspheres and follows a for starch microspheres. This may be due to the Ocular biphasic process with an initial rapid clearance differences in the surface charge, molecular contact, Topical is the route of choice for the treatment followed by a much slower basal phase. The initial and flexibility of two polymers. Chitosan exerts a of ophthalmic diseases because of the blood-ocular clearance phase is independent of the pH and transient inhibitory effect on mucociliary clearance barrier. Achieving therapeutic concentrations in the hydration state, while the basal phase clearance value of the bioadhesive formulations. The concept of eye via systemic administration necessitates the varies with these factors. Coating the microspheres using a bioadhesive delivery system in the form of usage of such high systemic concentration that, in with bioadhesive polymers has also been evaluated degradable starch microspheres (DSM) for nasal many cases, systemic side effects and toxicity as a potential way of increasing the bioavailability. delivery of drugs was introduced in 1988. A DSM results. Traditional ophthalmic formulations, such as Chitosan-coated microspheres, which increased the system, when combined with absorption enhancers, aqueous solutions and ointments, have low (typically bioavailability of indomethacin in rabbits and PEG- such as lysophosphatidylcholine (LPC), successfully 2% to 10%) bioavailability of drugs due to the small coated microspheres, resulted in an increased in the improved the nasal absorption of gentamicin.3 The surface area available for penetration, the presence of bioavailability of acyclovir.42,43 bioavailability of gentamicin was increased to 10% absorption barriers, and a number of precorneal with the use of bioadhesive microspheres and was elimination factors.40 These elimination factors Vaginal further increased to 57% by the addition of LPC to include drainage of instilled solutions: lacrimation Traditionally, this route of administration is the microsphere formulation. The DSM/LPC system and tear turnover, drug metabolism, tear evaporation, used for delivery of therapeutic and contraceptive has also been proposed as an efficient method for and possible binding to lachrymal proteins. To agents to exert a local effect (antifungal, spermicidal) delivery of insulin into the systemic circulation via prolong the residence time of drugs in the pre-ocular and for the systemic delivery of drugs.44 It has been the nasal route.10 A rapid and much higher absorption area, bioadhesive drug delivery systems have been used for the delivery of drugs, which are susceptible of human growth hormone (hGH) has been observed developed, taking advantage of the presence of a to gastrointestinal degradation or hepatic metabolism when hGH was administered in the form of a mucin-glycocalyx domain in the external portion of following peroral delivery, eg, oestrogens and DSM/LPC system of microspheres.11 the eye. progestogens for the treatment of postmenopausal Critchley et al evaluated bioadhesive starch Various bioadhesive systems employed for symptoms and for contraception. This route has also microspheres as a nasal delivery system for ocular delivery of drugs include the semi-solids, been explored for the delivery of therapeutic desmopressin, and observed significant improvement viscous liquids, solids/inserts, and the particulate peptides, such as calcitonin and for microbicidal in the absorption of drug, both in terms of peak DDS, including bioadhesive microspheres and agents to help prevent the transmission of human plasma levels and bioavailability.12 A five-fold liposomes. The advantages of microspheres, ie, immuno-deficiency virus and other sexually

increase in maximum plasma concentration (Cmax) increased residence time and decreased frequency of transmitted diseases. Using absorption enhancers, and a doubling of bioavailability was observed upon administration, were quite evident with chitosan such as surfactants and bile salts, can increase addition of LPC in a concentration of 0.2% to the microspheres of acyclovir and methyl prednisolone- absorption of peptides from the vagina. However, the starch microspheres. Other bioadhesive microspheres loaded hyaluronic acid microspheres.8,9 Acyclovir adverse effects of absorption enhancers on the used for nasal administration of peptides and loaded chitosan microparticles showed an increased mucosal integrity can be bypassed by employing proteins include the cross-linked dextran drug bioavailability in the eye as compared to the bioadhesive microspheres within the vaginal cavity. microspheres, which are water insoluble and water drug administered alone. Genta et al reported an The retention of microspheres made from a absorbable. Sephadex and DEAE-Sephadex were approximately a four-fold increase in the aqueous benzyl ester of hyaluronic acid (HYAFF) was studied found to improve the nasal absorption of insulin, but humour concentration of suspension (39.37 µg/ml using gamma scintigraphy in sheep.44 The to a lesser extent than the starch microspheres.37 min) after a single instillation into the rabbit’s eyes.8 microspheres were either delivered as a dry powder

Hyaluronic acid ester microspheres were used for the Increase in levels and the prolonged release of or included in Suppocire BS2X pessaries. A nasal delivery of insulin in sheep, and the increase in acyclovir from bioadhesive microspheres can be substantial percentage of the radiolabelled spheres nasal absorption was found to be independent of the used to overcome the inconvenience caused by remained in the vagina until the 12th hr after dose of microspheres in the range of 0.5 to 2.0 frequently applied ointments. The release of methyl administration. The retention was greater for the dry mg/kg.21 prednisolone from hyaluronic acid ester films and powder formulation than for the pessary formulation, Preda et al studied in vitro and in vivo microspheres has been investigated in vitro and in which the authors suggested might be caused by loss experiments in rats showed good adhesive vivo (in tear fluid of rabbits).8 Methyl prednisolone of microspheres on leakage of the molten base. characteristics of the gelatin/poly(acrylic acid) was either physically dispersed in the polymeric HYAFF microspheres have been successfully 6

o microspheres, which were greater if the poly(acrylic matrix or covalently linked to hyaluronic acid. used for the incorporation of peptides, such as nerve N 38 20

7 acid) content was greater. A significant retardation Microspheres containing methyl prednisolone growth factor and salmon calcitonin. HYAFF l o

V in gastric and intestinal emptying time of the beads chemically bonded to the polymeric backbone of microspheres have demonstrated good bioadhesive

7 was observed. This was also suggested by the hyaluronic acid showed slower release of drug in properties both in vitro and in vivo. In an 0 0

2 bioavailability of the model drug after intragastric vitro and produced sustained drug concentrations in unconscious rat model, these microspheres e

n and intranasal administration of the microspheres. the tear fluids of rabbits. maintained contact with the vaginal epithelium for at u J The pharmacokinetic parameters after microsphere Durrani et al investigated the effect of these least 6 hrs after administration. Hypocalcemic effects

y 111 g administration were more appropriate to a slow- parameters on the precorneal clearance of In - in the rat and sheep confirmed that absorption of o l o

n release drug delivery system. Harikarnpakdee et al labelled microspheres prepared using Carbopol salmon calcitonin was increased after administration h

c 41 e

T prepared spray-dried mucoadhesive microspheres for 907. Clearance of microspheres administered in dry of bioadhesive (HYAFF) microspheres compared

y 39 22 r

e nasal delivery. Microspheres composed of form was faster than in the hydrated form, probably with an aqueous solution of calcitonin. HYAFF v i l

e hydroxypropyl methylcellulose (H), chitosan (CS), due to incomplete hydration in the tear fluid. The in microspheres, due to their high biocompatibility and D

g Carbopol 934P (CP), and various combinations of vivo slow basal phase clearance constants were controllable degradation rate, have been used for the u r -1 D these mucoadhesive polymers, and maltodextrin (M), found to be 0.007 and 0.034 min for the suspension localized drug delivery of steroids, analgesics, anti- colloidal silicon dioxide (A), and propylene glycol of microspheres at a pH of 5.0 and 7.4, respectively. inflammatories, and anti-infectives. This has led to a 60 ca tissue, includingthosefoundinthee and canbetailoredtoadherean a Bioadhesivedelivery purposes. microspheresoffer for bioadhesive delivery systems,therearemany drug with changesinvaginal histology. by theoestrouscycle andwas thoughttocorrelate appearedtobeinfluenced from eachformulation enhanced by LPC. Vaginal ofinsulin absorption compared toinsulinsolutionalone,andwas further improved usingthemicrospheresdelivery system, response tovaginally administeredinsulinwas also latter solutionwas 13%. The hypoglycaemic absolute bioavailability ofthepeptidefrom inplasmaglucoselevels.pronounced fall The LPC resultedinarapidriseplasmainsulinand from insulinsolutionwas minimal,theadditionof studied. ofinsulin While thevaginal absorption was ofinsulinfrombothformulations absorption lysophosphatidylcholine (LPC)onthevaginal with bioadhesive starchmicrospheres. The effect of as anaqueoussolutionandalyophilized powder STDs. c contraceptive andanti-infective to formulations safe andeffective bioadhesive vaginal dealofenthusiasminthedevelopmentgreat of surf vaccine thatadheretothemucosal formulation future directionofbioadhesive microspheresliesin deli technolo emplo required toovercome thesechallengesandto approachwillthereforebe multidisciplinary the successfuldeli w cellsormucosa,and bioadhesive forspecific ofbeingbiodegradable,attributes biocompatible, g ne to specif alsofortargetedrelease but delivery ofthedrugs microspheres canbeusednotonl and de universally acceptable standardevaluation methods Veryin thisfield. isthedevelopment important of bioadhesives, therearestillmany challengesahead advances of havesignificant beenmadeinthefield andgenetherapy.protein/peptide drugs Although pol medicine have envisaged thedevelopment of P ontrol pregnancy andhelpprevent thespreadof astrointestinal tract. ol hich couldalsofunctionasenzymeinhibitorsfor unique car vity w mulations thatma ymeric drug deliveryymeric drug systemsfor ymeric scienceneedstobee very of newvery aswell asexisting drugs. The ace andresultinmucosalimmunity er bioadhesive polymers withtheadded Due tothelar Insulin was administeredvaginally tosheep , y 44 v and throughouttherespirator elopment ofne bioadhesi gy forsite-tar ic sitesinbody rier systemforman v SUMMARY v e ge numberoftar ery ofproteinsandpeptides. ery A microspheres asacutting-edge y The bioadhesi geted controlled-releasedr be e w . er site-directedpol Recent adv xplored fordr xplored tof y y phar 45 y for controlled v ances in get sitesof y, urinary, and mucosal e y es, oral maceuticals . ug ymers. ind ug 18. 23. 28. Akiyama Y, Nagahara N, NaraE,KitanoM,Iwasa S, Yamamoto I, Azuma J, 27. CarinoPG,JacobJS,ChenCJ, SantosCA,Hertzog BA, Mathiowitz E. 26. LongerMA,Ch’ngHS,RobinsonJR.Bioadhesive polymers asplatforms 25. Vyas SP, JainCP. Bioadhesive polymer starchmicrospheres bearing grafted D,24. Harris delivery viathemucousmembranesoforal RobinsonJR.Drug 21. IllumL,Farraj NF, Fisher AN, GillJ, MigliettaM,BenedettiLM. 20. 19. 17. 16. Akiyama Y, Yoshioka M,HoribeH,Inada Y, HiraiS,Kitamori N, Toguchi H. 15. 22. RichardsonJL, Armstrong TI. Vaginal delivery ofcalcitoninby hyaluronic 12. 11. IllumL,Farraj NF, Davis SS,JohansenBR,O’Hagan DT. Investigation ofthe 10. Farraj NF, JohansenBR,Davis SS,IllumL.Nasaladministrationofinsulin 9 8 7. Vasir JK, Tambwekar K,Garg S.Bioadhesive microspheresasacontrolled 6 5 4. Schaefer MJ, SinghJ. Effect ofisopropyl myristic acidesteronthephysical NF,3. Illum L,Furraj Critcheley H,Davis SS.Nasaladministrationof 2 1. Ikeda K,MurataKobayashi M,NodaK.Enhancementofbioavailability of 14. Akiyama Y, Nagahara N. Novel approachestooralmucoadhesive formulation 13...... v Methylprednisolone estersofhyaluronic delivery: acidinophthalmicdrug Kyyronen K,HumeL,BenedettiUrtti A, Topp E,Stella V. 1997;49:737-742. microspheres forophthalmicadministrationofacyclovir. Pharmacol. JPharm Genta I,ContiB, Perugini P, Pavanetto F, Spadaro A, PuglisiG.Bioadhesive 2003;255:13-32. delivery system.IntJPharm. drug Mathiowitz E,Chickering DE,JacobJS.USPatent No.6,197,346;2001. Autumn/Winter 2004;16-19. ResearchandMarkets:Delivery Dublin, CompaniesReport. Ireland. Hannah B. Novel bioadhesivedelivery. indrug formulation In: The Drug Sci AAPS Pharm Tech. 32. 2000;1(4):article characteristics andinvitroreleaseofetoposidefromPLGAmicrospheres. 1 g insulin fornasaladministration.JControlRelease.1984;1:15-22. Nagai T, Nishimoto Y, N, Nambu Suzuki Y, SekineK.Powder of dosageform 2158. dopamine vianasalrouteinbeagledogs. Bull.1992;40:2155- ChemPharm entamycin usinganovel microspheredelivery system.IntJPharm. itro andinvivo 1992;80;161-169. release studies.IntJPharm. 988;46:261-265. controlled releasemucoadhesi P m Bo Development. MarcelDekker: New York, NY; 1998:563-599. Bioadhesive Delivery Systems-Fundamentals,Novel Drug Approaches, and 166. 1998;50:159- Pharmacol. sites.JPharm limited gastrointestinal absorption offurosemideandriboflavin,of thepharmacokinetics compoundswith Og Dekk Systems-Fundamentals, Novel Approaches andDevelopment. Marcel Mathiowitz E,Chickering DE,LehrCM,eds.Bioadhesive Delivery Drug Bioadhesive, bioerodible polymers forincreasedintestinaluptake. In: a delivery,for oralcontrolleddrug using III:oraldelivery part ofchlorthiazide 464. isosorbide dinitrateforb cavity. Sci.1992;81:1-10. JPharm 1999;177:211-220. and intestinalmucosa.IntJPharm. biological releasefrommicrospheresadheredonvesical parametersondrug Hyaluronic acidestermicrosphereasanasaldeli 1992;87:21-29. vitro releasecharacterization.IntJPharm. deri Ghezzo E,BenedettiL,RochiraN, Biviano F, Callegaro L.Hyaluronane delivery ofpeptides.JControlRelease.1993;23:65-74. S,SchlameusHW.Geary Vancomycin andinsulin usedasmodelsfororal deli P 661-665. ACE 1994;46: inhibitor(Delaprilhydrochloride) Pharmacol. inrats.JPharm A 144. mucoadhesive microspheresofamoxicillin. JControlRelease.2005;102:135- Liu Z,Lu acid for Control Release.1994;29;133-141. De B Phar in ratsandsheep-effect ofabioadhesive microspheredelivery system.J Critchley H,Davis SS,Farraj NF, ofdesmopressin IllumL.Nasalabsorption bioadhesive 1990;63:207-211. microspheredelivery system.IntJPharm. ofbiosynthetichumangrowthinsheep-usea hormone nasal absorption 1990;13:253-261. using bioadhesive microspheresasadelivery system.JControlRelease. d 2 system forinactivated influenzavaccines. JControlRelease.2001;70:267- Singh M,BrionesO’Hag r 76. atel JK, atel JK,P ioadhesive Delivery Systems-Fundamentals,Novel Drug Approaches and bioadhesive polymer. Sci.1985;74:406-411. JPharm nti-hypertensive effect oforalcontrolledreleasemicrospherescontainingan ucoadhesive glipizidemicrospheres. Sci AAPS Pharm Tech. 2005;6:49-55. ug deli v g awa Y. Evaluation oforalmucoadhesive microspheresinmanonthebasis very using factorial design. Drug Delivery design.Drug usingfactorial very Technology. 2004;4:48-53. vative microsphereasNGFdelivery device: preparationmethodsandin elopment. MarcelDekk ataj M,Mrhar m er: New York, NY; 1998:459-475. Phar mulations. In:Mathio v A er W atel RP min macol. 1994;46:651-656. y , Qian L,ZhangX,ZengP, Pan J. Invitroandinvivo studieson system. In:Mathio AF, Patel MM.Formulation optimizationandevaluation of , A, K Amin REFERENCES orosec L.Influenceofph uccal administration.JMicroencap.1992;9:457- A F, Patel MM.Formulation andevaluation of e an DT. A novel bioadhesive intranasaldelivery r: Ne witz E,Chick v e w microspheres ofglipizidefororaldr w itz E,Chick York, NY;1998:477-505. ering, DE,LehrCM,eds. ering DE,LehrCM,eds. ysicochemical and v ery systemforinsulin.J ery ug [email protected]. Singapore. He canbereached at d an and has 50publications ininternational supervised 19MPharmthesis candidates teaching and research experience. He has University, Gujarat, India, with 11yearsof has pr systems and bioadhesive technology. He research includes novel drug delivery 4 44. 43. 4 41. Durrani AM, Farr SJ, Kellaway IW. clearanceofmucoadhesive Precorneal 4 3 3 37. EdmanP, BjorkE,RydenL.Microspheresasanasaldelivery systemfor 3 3 3 33. IllumL.Bioadhesive fornasaldelivery. formulations In:Mathiowitz E, 3 3 30. Varshosaz J, Dehkordidelivery JA. of GolafshanS.Colon-specific 29. Nagahara N, Akiyama Y, Nako M, Tada M,KitanoOgawa Y. elivered lectures inthe UK,US, and 5. RichardsonJL,Farraj NF, ofinsulinin IllumL.Enhancedvaginal absorption 2. Calvo P, VilaJato JL, Alonso MJ. Evaluation ofcationicpolymer-coated 0. SaettoneMF, Burgalassi S,ChetoniP. Ocularbioadhesive delivery drug S,Lipipun 9. Harikarnpakdee V, Sutanthavibul N, RitthidejGC.Spray-dried 8. PredaM,LeucutaSE.Oxprenolol-loadedbioadhesive microspheres: 6. CallensC,CeulemansJ, Ludwig A, Foreman P, RemonJP. Infuenceof 5. MorimotoK,KatsumataH, Yabuta T, Iwanaga K,Kakemi M, Tabuta Y, Ikada 4. El-Shafy AM, Kellaway IW, Taylor G,DickinsonPA. Improved nasal 2. IllumL,Jorgensen H,Bisgaard H,Krogsgaard O, RossingN. Bioadhesive 1. SoaneRJ, Perkins AC, JonesNS,Davis SS,IllumL.Evaluation ofthe d system. IntJPhar sheep usingl C andretentionofabioadhesivedistribution vaginal delivery systeminsheep.J Benedetti L,IllumL.Gammascintigraphy asanovel methodtostudythe Richardson JL, Whetstone J, Fisher NF, Watts P, Farraj NF, Hinchcliffe M, Sci.2001;90:288-297. Pharm coated polymethyl-2-cyanoacrylate nanospheres-encapsulatedacyclovir. J Ocular tolerabilityandinvivo bioavalability ofpoly(ethylene gycol)(PEG)- F 1997;153:41-50. IntJPharm. carriers. nanocapsules asoculardrug m M Delivery Systems-Fundamentals,Novel Approaches, andDevelopment. systems. In:Mathio m mucoadhesive throughnasalcell microspheres:preparationandtransport 7 preparation andinvitro/invivo characterization.JMicroencap.2003;20:777- JControlRelease.1992;21;165-172. peptide drugs. bioavailability. 2003;250:415-422. IntJPharm. multiple nasaladministrationsofbioadhesive powder ontheinsulin 2001;124:173-182. of salmoncalcitonin.EurJPharm. Y. Evaluation ofgelatinmicrospheresfornasalintramuscularadministrations Target.Drug 2007:355-361. b York, NY: 1998:519-539. Fundamentals, Novel Approaches andDevelopment. MarcelDekker: New Chickering DE,LehrCM,eds.Bioadhesive Delivery Drug Systems- 189-199. 1987;39: delivery system.IntJPharm. microspheres asapotentialnasaldrug 1999;178:55-65. clearance characteristicsofbioadhesive systemsinhumans.Int JPharm. m Helicobacter pylori. Antimicrob Agent Chemother. 1998;42:2492-2494. Mucoadhesive microspherescontainingamoxicillin forclearanceof ioavailability ofFITC-dextran frommucoadhesive microspheresinrabbits.J 89. r ontrol Release.1996;42:133-142. icrospheres fromtherabbite onolayer. Sci AAPS Pharm Tech. 12. 2006;7(1):Article esalazine chitosanmicrospheres.JMicroencap.2006;23(3):329-339. esta M,Fontana G,BucoloC,Cavallaro G,GiammonaPuglisiG. arcel Dekker: New York, NY; 1998:629-630. n ational journals of repute. Hisarea of esen ysophosphatidylcholine andabioadhesi ted r BIOGRAPHY m. 1992;88:319-325. witz E,Chickering DE,LehrCM,eds.Bioadhesive Drug esear y Ed of Pharmaceutical Shree S.K.Patel College Pharmaceutics atthe Professor in is anAssistant Dr. Jayvadan K.Patel Research, Ganpat e. JPhar ch papersan u cati m Phar on an macol. 1995;47:581-584. v e d d microspheres delivery 61 Drug Delivery Technology June 2007 Vol 7 No 6

EURAND:CREATION OF ADVATAB® - A NEW TECHNOLOGY FOR ORALLY DISINTEGRATING TABLETS

urand has successfully established itself as a leading innovator in drug delivery, and a proven developer of specialty pharmaceutical products. An EEexample of Eurand’s track-record of innovation in the drug delivery field is the development and commercialization of a new technology platform for orally disintegrating tablets (ODTs). Eurand entered into this area of drug delivery, initially with the development of its Ziplets® technology, then followed with the licensing of Mr. John Fraher certain technologies from the Japanese company Kyowa Hakko Co., Ltd. in early 2003. Chief Commercial Officer ® Eurand Eurand created a new brand, AdvaTab , for the technology and initiated efforts to promote the advantages of the new technology. Four years later, Eurand has multiple “We also signed a AdvaTab products under internal development, and has announced co-development very significant partnerships that are leveraging the technology to create important life-cycle co-deco-developmentvelopment management opportunities for its partners. Drug Delivery Technology recently agreement with interviewed Mr. John Fraher, Chief Commercial Officer of Eurand, to discuss the GlaxoSmithKline company’s successful strategy behind AdvaTab and how Eurand views its co- in 2006 fforor the development programs in light of its specialty pharma growth strategy. dedevelopmentvelopment of an ODT formulation fforor an undisclosed Q: What prompted Eurand to an area in which we wanted to create new GSK compound. The enter into the highly technologies to complement our taste- GSK transaction masking platform, Microcaps. We also provides Eurand competitive field for ODTs? believed there was a need in the

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g solubility enhancement technology u progressingprogressing towardtoward r patient benefits. We identified the orally D an NDNDAA filing later disintegrating tablet field in the late 90s as platforms with the benefits of an ODT. We 62 this year.” ODT withourMicrocaps product combinedourZiplets European countries. This Cibalgina DueFast, incertain which launchedaproduct, commercialized b technology was successfully products andmark was anODTsuitable forcertain ODT technology, Ziplets,which for extremely and bitterdrugs, provide loadingeven high-drug other technologies, beable to our ODTproductswith wanted tobeable tocombine for ourODTplatform. We mark wide v challenges presentedb to themany formulation would provide uswithsolutions to develop that abroadplatform of ourtechnologies, we wanted As isourstrategy with anumber this technology worldwide. a numberofissuedpatentsfor ib A: its ODTfr Eur What strategy has Q: technology. coupling itwithasuperiorODT our broadtechnology baseby saw toleverage theopportunity uprofen product. In 1999,we developed an etplace. and employed for ariety ofmoleculesinthe This w anchise? y No ets. We obtained as alsotrue v This y the ar ® tis, use thistechnology. product development programs the majorityofourODT characteristics of AdvaTab, outcomes. Duetotheunique developmentformulation technolo appl and w successfull Bothhaveplatform. been technologies withintheODT So, we now have two trademarked as AdvaTab. This technology has now been exclusive rightswithKyowa. for Japan,where we have semi- technolo exclusive rightstothe Kyowa thatprovided uswith with licensing arrangement products. We enteredintoa technolo successfull Kyowaplatform. had requirements fortheentireODT technology andmeet our toourother be complementary Japan, which we believed would developed by Kyowa Hakko in technology thathadbeen We anODT identified standard blister packs. materials, suchasbottlesand packaged instandardpackaging create aproductthatcouldbe ying theappropriate e no gy todeliver thedesired gy w gy inJapanwithtwo w ha y commercialized y commercializedthe orldwide, except v e fle xibility in , tab physical requirementsforthe time, as oraldisintegration characteristics ofanODT, such achieving thedesired whilemaintain tasteintegrity thereby ensuringthatwe release technolo our Dif Adv de the ODTandMicrocapsare development approachinthat product, we take an integrated processes. withtheirproductsand integrity dif that the companies, andw products tootherODT of Microcapstaste-masked many years, we suppliedarange technologies intheindustry. For the foremosttaste-masking w with ourMicrocapstechnolo Eurand cancombine AdvaTab features ofanODTisitstaste– A: other technologies? technologies versus Eurand’s ODT advantages of What are the Q: products. Our ODTsdiffer from highly differentiated CRODT hich isreco v f let, stabilityetc. eloped asoneproduct, iculties inmaintainingtaste aT One ofthemostimportant ab canbecombinedwith fucaps y generall When we develop a gnized asoneof ® controlled- gy tode y encountered e obser Additionall velop v ed gy, y ,

63 Drug Delivery Technology June 2007 Vol 7 No 6 others on the market in that the establishing a comprehensive would expand the boundaries of tablets are less friable, can development program to expand the technology. We used high- incorporate high-drug loading, the application of the dose active ingredient are cost-effective to manufacture technology. The IP team was molecules, molecules with and package, and can be applied responsible for continued known stability issues, and a to actives that are soluble or prosecution of the patent estate variety of Microcaps products to insoluble. We saw these as we acquired, and continues to create the specifications for the key differentiation factors that pursue patent applications that AdvaTab technology. We also made entry into this field extend the utility of the conducted pharmacokinetics strategically sound. technology and integrate it with studies on one of those our other technologies. The products, Cetirizine, to commercial team established a demonstrate that we were able to Q: How did Eurand go worldwide strategy for achieve bioequivalence with about implementing differentiating the technology in immediate-release dosage and creating a new the marketplace and created the forms. In parallel, our business ODT brand, AdvaTab, AdvaTab brand name, marketing development team began in a crowded field? materials, and an advertising promoting the new AdvaTab campaign. Also, our operations technology to potential staff began scale-up trials as customers worldwide. Our A: There were a number of soon as the technology was competitive differentiation initiatives we had embarked transferred so we could combined with the continued upon to establish the new demonstrate the capacity and growth of the ODT marketplace technology platform and take validation goals necessary to began to pay dividends. To date, advantage of the market attract co-development partners. we have completed seven co- opportunity. We formed a cross- Finally, the integration team development agreements for this functional global integration selected several internal technology platform in the past team to represent the key areas programs to work on to 2 years. For confidentiality required to make AdvaTab 6 demonstrate the capability of reasons, a number of these o

N successful – R&D, Intellectual

7

the technology. projects have not been made l

o Property (IP), Commercial, and V

public. Some that have been 7

0 Operations worked closely 0

2 announced include, EUR-1047, Q: What product e together on the project. We n u

J a project with Pfizer Consumer

development efforts has

decided to make Eurand’s y g

o Healthcare, now J&J, for a new

l Eurand initiated?

o Vandalia, Ohio, site the “center- n h

c ODT formulation of the e T

of-excellence” for the AdvaTab

y ® r

e A: Once the technology Benadryl product line. We are v i

l technology. The R&D team at e D

transfer was complete, we very pleased that this new and g

u that site was responsible for the r

D initiated a number of product improved formulation should be technology transfer to the development programs that available on US pharmacy 64 company and also for shelves this quarter. We also intellectual property. In terms of intend to continue to enter into signed a very significant co- strategy, we will continue to offer co-development partnerships development agreement with this state-of-the-art technology to with other pharmaceutical GlaxoSmithKline in 2006 for the our current and future partners, companies. We believe that we development of an ODT and we will continue to apply it are an attractive partner for formulation for an undisclosed to a select number of our internal larger pharmaceutical companies GSK compound. The GSK pipeline candidates. due to our broad portfolio of transaction provides Eurand with proprietary technologies, our attractive commercial terms, and development track- record, and as a big pharma partner, this Q: Looking forward, our multinational infrastructure collaboration provides us with how do you see Eurand and manufacturing capabilities. further validation of the growing and evolving? In 2005, we had revenues of AdvaTab platform. The GSK approximately $92 million, program is progressing toward A: Our strategy is to be a leader primarily from sales of products an NDA filing later this year. in the development, manufacturing, using our formulation In November 2006, and commercialization of technologies that our co- Questcor, a US specialty CNS innovative specialty pharmaceutical development and licensing company, announced the filing and biopharmaceutical products. partners commercialize. In of an IND for a formulation of We have had three products 2006, we signed six new co- Acetaminophen/Hyrocodone approved by the FDA since development agreements with product developed using our 2000, and we have a pipeline of companies located in the United AdvaTab and Microcaps products in development for States, Europe, and Japan. We technologies. We are very ourselves and our co- foresee continued growth of our pleased to have entered into development partners. Our lead company as these products are these co-development product candidate, EUR-1008, is commercialized. N partnerships and others, and we a new proprietary enzyme consider it as a validation of our replacement product for the technologies, intellectual treatment of exocrine pancreatic 6

o

property, and development N

insufficiency (EPI). EPI is a 7

l capabilities that such companies o deficiency of digestive enzymes V

chose Eurand as their partner for 7 normally produced and secreted 0 0 2

these projects. e by the pancreas, and it can result n u J

It is worth mentioning that in y

from a number of diseases, g o l o

all of our license transactions, n

including cystic fibrosis, chronic h c e T

Eurand retains manufacturing y

pancreatitis, and other diseases. r e v i rights as we have a core l The product has completed e D

g competency in this component of u Phase III clinical trials in the r D our business, and it provides us United States. Additionally, we with more control of our 65

TRANSDERMAL & FILM DELIVERY PREFILLABLE DELIVERY SYSTEMS

BD Medical - Pharmaceutical Systems is dedicated to developing prefillable drug delivery systems designed to fit the needs of the pharmaceutical Aveva Drug Delivery Systems owns proprietary transdermal formulation industry. Whether a and manufacturing technologies that focus on elegant “matrix” patch glass or plastic designs for the incorporation of drugs into adhesives that attach the prefillable syringe, a nasal spray system, a dry drug reconstitution system, patch to the skin. The broad range in technology and experience includes an injection or self-injection device, BD Medical - Pharmaceutical Systems solubilized matrix, crystal dispersions, multi- or single-layer systems, provides the expertise and experience required by the pharmaceutical membrane-controlled systems, specialized proprietary adhesives, and industry in a packaging partner. We deliver cost-effective alternatives to packaging technologies. These technologies can be optimized to suit conventional drug delivery methods, which differentiate pharmaceutical particular drug characteristics and product needs, and rapidly developed products and contribute to the optimization of drug therapy. All of its from feasibility stage through clinical and commercial production stages. prefillable devices are designed to meet healthcare professionals’ The company provides vertical integration of adhesive, film coating, and demands for safety and convenience and to fulfill patients' needs for transdermal formulation technologies to produce the most efficient and comfort. BD’s worldwide presence, market awareness, and cost-effective products. The company is applying its transdermal delivery pharmaceutical packaging know-how allow it to propose suitable system technology to proprietary as well as generic drugs. Patches can solutions for all regional markets and parenteral drug delivery needs. For be designed to deliver from 1 through 7 days. For more information visit more information, contact BD Medical - Pharmaceutical Systems at (201) Aveva DDS at www.avevadds.com. 847-4017 or visit www.bdpharma.com. MICRO-FILLING SYSTEM ORAL MODIFIED-RELEASE TECHNOLOGIES With the XcelodoseTM system, creating manufacturing batches for clinical trials and small- scale production has never been easier or more precise. This unique technology allows companies to fill capsules with drug substances 6

o alone, thereby eliminating N

7 the need for excipient The Pharmaceutical Technologies and Services Group of Cardinal l o

V compatibility and Health is the global leader in development, drug delivery

7 preformulation activities. technologies, contract manufacturing, and packaging, serving the 0 0

2 By implementing the pharmaceutical and biotechnology industries. We have a range of e

n Xcelodose system, experience with innovative and traditional controlled-release u J pharmaceutical companies benefit from a shorter drug development technologies, such as EnCirc® pellets for higher drug loading and y

g process by reducing the need for costly and time-consuming stability uniformity of dose, which can be used for immediate- and controlled- o l

o ®

n studies, not to mention the avoidance of labor costs and possible release capsules and tablets; EnVel system for taste-masking, which h c

e can greatly improve patient acceptance of Rx or OTC chewable T inaccuracies associated with hand-filling. This in turn reduces the time

y ® r tablets; and EnSolv for improved dissolution, which can provide a e taken to reach the “first-in-man” clinical trial decision point, which v i l

e allows for an increase in throughput of candidate compounds for formulation solution for new chemical entities as well as extend life D

g development. For more information, contact Capsugel at (888) 783- cycles of many marketed products. For more information, contact u r

D 6361 or visit www.capsugel.com. Cardinal Health at (866) 720-3148 or [email protected] to explore how our advanced delivery technologies can enhance your drug’s 66 performance. P www (973)257-8011 orvisit contactDSMPharmaceuticalsat information, For more customers’uniquemanufacturingneeds. solutions tosatisfy the highestlevelofser commercial ser From clinical to services. III; fillfinishmanufacturing;andlypholization and manufacturing; scheduleddrugs;clinical manufacturingPhaseI,II, areas ofsteriles, Pharmaceuticals providesabreadthofmanufacturingser DSM pharmaceutical andbiopharmaceuticalindustries. tothe aglobalproviderofcustommanufacturingservices Products, DSM Pharmaceuticals, EUDRAGIT informa For more customer-specific solutionstoout-licensingstrategies. these drugdeliver Polymers’ of Pharma businessmodelsforcommercialization so far. are theachievementsofthisintensiveresearchanddevelopmenteffort Protective Coa and ControlledRelease, polymers areidealforEntericDelivery, 764-6872 (Option4)orvisit different brandsofEUDRAPULSE The technologies. intellectual propertyonadvancedoraldrugdelivery Polymers Pharma hasdeveloped pharmaceutical applications, C OLYMERS USTOM .dsmpharmaceuticals.com tion, ® polymer design and formulation know-how for know-how polymer designandformulation contact DegussaCorpora tings. vices, orals, y M & technologies rangefromthedevelopmentof Based onmorethan50yearsofexperiencein DSM focusestherightresourceson providing vice andqualitywhilea and topicals, Inc. ANUFACTURING D ELIVERY is abusinessunitofDSMPharmaceutical www TM EUDRACOL , .pharma-polymers.com . including doseform tion, Rohm T ECHNOLOGIES TM pplying innova andEUDRAMODE , America LLCa S EUDRAGIT industry. pharmaceutical forthe coatings of functional and supplying manufacturing leaders inthe of theworld Polymers isone Pharma ERVICES vices inthe tive t (877) ® TM more information, contact DPT at (866)CALL-DPTorvisit contactDPTat more information, contact DPT– To getyournextproducttomarketfastandwithconfidence, packaging. forbothconventionalandspecialized procurement resourcesnecessary encompassengineeringand Packaging services management. controlled substanceregistra full-scalecommercialproduction, clinical trialmaterials, facilities, include Specializedproductioncapabilities fourcGMP development. throughprocess analyticaldevelopmentandvalidation, development, ser biotechnolog manufacturing solutionstotheworld’s leadingpharmaceutical, technolog www.dptlabs.com nomto,visittheFiltertek at information, For more foritsparticularapplication. qualify andvalidate Filtertek forthe customerto canprovidemembranealternatives orventingapplications, of proteinsolutions, microbial filtration ofgassesformedicalprocedures, Whetherforsterilization options. welded versioninawiderangeofstandardinlet/outletconnection Filtertek’s 50-mmproductsareofferedineitheran over-molded or industries. andfoodbeverage pharmaceutical, biotechnology, vices range from preformulation, formulation andbiopharmaceutical formulation vices rangefrompreformulation, D y RUG , and ser y , F The Industr and consumerhealthcarecompanies. ILTRATION D vice, . EVELOPMENT the compan y Source forSemi-SolidsandLiquids.SMFor tion ClassII-IV www.filtertek.com y P delivers drugdevelopmentand RODUCTS andcompletesupplychain , S ERVICES Through innovation, forms. dosage semi-solid andliquid specializesin that (CDMO) organization manufacturing development and contract integrated isafully Ltd, DPT Laboratories, Drug development applications inthe applications filtration venting orliquid designed for This productlineis products. filtration line of50-mm launched anew recently filters, manufacturer of designer and F letk aleading iltertek, .

67 Drug Delivery Technology June 2007 Vol 7 No 6

CORIUM:NEW DIMENSIONS IN TRANSDERMAL SOLUTIONS

orium International, Inc. is a privately owned company engaged in the research, development, and manufacture of advanced transdermal CCdrug delivery technologies and therapeutic products. Through the combination of its proprietary delivery technologies and its development and Gary W. Cleary, PhD manufacturing expertise, Corium has developed a range of novel transdermal President & CTO Corium International, products. Corium also enjoys a strong patent estate with 150 US and Inc. international issued and pending patents protecting its drug delivery “We have products in several therapeutic technologies, processes, and expertise. Drug Delivery Technology recently areas, including CNS, interviewed Dr. Gary W. Cleary, Co-Founder, President, and Chief Technology cardiovascular, and endocrine to name a Officer of Corium to discuss the exciting opportunities on the forefront of novel few. We also have a number of vaccine drug delivery. candidates. The passive products in development have Q: Please give us an overview Corium because we saw a need in the never been delivered of Corium and your business marketplace for a company that could deliver transdermally before, innovative transdermal solutions from concept to and the active model. products include drug commercialization. And hence, the Corium

6 molecules that mission was born. o Corium was established in 1999, and is a

N A:

previously have been

7

l administered by Initially, Corium funded itself by utilizing its

o privately owned company engaged in the V

injection.” 7 research, development, and manufacture of proprietary technologies and web-based 0 0 2 manufacturing expertise to develop and e advanced transdermal drug delivery technologies n u J

manufacture non-prescription products on a and products. My business partner and Co- y g o l

o contract basis. This strategy provided a steady

n Founder Adrian Faasse and I have been involved h c e

T revenue stream that allowed us to further the

y in the transdermal medical product field for more r e v i

l development of our polymer technology platform e than 3 decades. Our experience dates back to the D

g TM u r introduction of the first transdermal patch called Corplex , and begin internal development D products introduced into the market. We started of transdermal Rx products. Today, Corium has 68 products inthemarketplace. emer b market potential, with significant non-strate oppor contracttransdermal to entertain marketing partner. We willcontinue and subsequently seek a commercial through PhaseIorIIclinicaltrials develop andfundtheseproducts funded products.Ourgoalisto de concentrated focusonthe modeltoa partner manufacturing from acontractdevelopment and MicroCor microporation technolo technology aswell asthe polymerbased onboththeCorplex These self-fundedproductsare of itsown products. proprietary Corium began tofunddevelopment technology fromProcter&Gamble, mechanical microporation asaresultofthiseffort. drugs ofFDA-approved forms transdermal many projectsfor partner-funded ut ourmissionremainsf Our b In 2005,afteracquiringa v elopment ofproprietar ge astheleaderoftransder tunities andout-licenseany usiness modelhase TM gic intellectualproper . gy w ir y self- m: to v e call olv ty mal ed A: readers? technologies toour your drugdelivery Canyou describe Q: enab microporesintheskinto temporary “microneedles,” thatcreates toas sometimes referred microporation technology, mechanical is aproprietary acquired fromP&G.Specifically, it technologytransdermal thatwe skin. MicroCoristheactive and large moleculesthroughthe that allow ustodeliver bothsmall two technologies coreproprietary can beutilizedinman versatile polymer technology that patents. pending USandinternational consisting ofover 65issuedand impressive patentportfolio technology andnow have an enhancedthe significantly Since acquiringMicroCor, we have therapeutic proteinsandvaccines. delivery oflarger moleculeslike adhesi of acomposite blend ofnon- transder applications —notjustatraditional deli Our Corplex technologyOur Corplex isa very andmedicalproduct very As Ijustmentioned, we have le thepainlesstransder v e h mal patch.Cor ydrophilic pol y dr ple ymers that x consists ug mal dev technologies in A: micr other mec advantages over the Micr tec transdermal” from other “active microporation differ mechanical How does Q: technolo one ofseveral “active” transdermal and inter more than80issuedandpendingUS covered by of apatentportfolio is patch.Corplex transdermal se dissolving f matter ofseconds(lik developed sothatitdissolves ina canbe the oralmucosa.Corplex hydrated biological tissues,suchas skin andcaneven adheretovery maintain itsadherencetomoistened substrate becomeswet, can Corplex lose “tack”when ofthe thesurface pressure-sensitive adhesives that orwetdry Unlike surfaces. typical resulting productcansticktoeither can beprocessedsuchthatthe v eral da hnologies? Does Mechanical microporationis elopment? opor oCor ha gies. F national patents. ys inacon ilm) orcanadherefor ation irst, let’ hanical v v e anoral entional e an s tak e astep y

69 Drug Delivery Technology June 2007 Vol 7 No 6 back and compare “passive” to mechanical microporation offers the skin (drug-sparing). We also have “active” technologies. When a advantages over other active the ability to deliver the drug in a conventional passive patch is transdermal technologies in that its controlled fashion after the patch is adhered to the skin, the drug simply simpler format does not require a removed. Finally, we are able to diffuses through the upper layers of separate power source, so the produce this integrated system at a the skin into the dermis where it regulatory and development risk very low cost with an enhanced accesses the blood vessels to reach profiles are lower. safety profile, positioning us the systemic circulation. In order for Now, let me explain the uniquely in this marketplace. this process to happen, the drug must advantages that MicroCor offers over be lipophilic and have a low other mechanical microporation molecular weight and dose, that’s technologies. As far as we are aware, Q: What types of why there are relatively few drugs we are the only company in this molecules are most that are available in conventional space that has a fully integrated suitable for MicroCor? patch form. In contrast, “active” device that incorporates the transdermal technologies utilize microstructure array, drug, and force A: That’s the beauty of MicroCor. some mechanism to cause a applicator. The other mechanical The possibility for delivering drug “temporary” disruption of the technologies have a separate force molecules is infinite. As I mentioned stratum corneum to create a passage applicator device that causes the earlier, we can deliver large way, like a tunnel, through the skin microstructure array to porate the therapeutic proteins and vaccines as layers so the drug can more readily skin and applies a drug-containing well as small, high-dose hydrophilic reach the systemic circulation. patch to the skin. With our system, drugs. We have even demonstrated Because you are creating an artificial the patient would simply apply the the ability to deliver particles as micropore in the skin, additional patch using a small amount of large as 1 micron in size into the types of molecules, such as pressure with the forefinger or skin in vitro. MicroCor can also be macromolecules and hydrophilic thumb, wear it for a predetermined used broadly across many small molecules, can now traverse period of time, and remove. It is therapeutic areas from pain, 6

o N

the skin. The “active” mechanisms to extremely user-friendly and provides cardiovascular, endocrine, and

7

l o

V porate the skin include heat, a convenient, painless way to deliver depression to neurological diseases,

7 0

0 electricity (iontophoresis), drugs that are normally administered autoimmune diseases, and vaccines. 2

e n

u ultrasound, radiofrequency, and by injection. J

y

g mechanical (microneedles). Most In addition to the integrated o l o n

h mechanical microporation system design, Corium has a number c e T

y r technologies include a microthin of proprietary mechanisms to e v i l e D

array of microstructures that can associate the drug with the g u r D penetrate the skin when an external microstructures to maximize the

70 force is applied. In my opinion, amount of drug that is delivered to Q: Can you talk about through Phase I or II trials before in earlier stages of development and your product pipeline? seeking a commercial marketing have yet to be commercialized. How do you plan to partner. This strategy takes commercialize your significant development risk off the Q: Where do you see products? table for our potential partner and in the company in 5 years turn provides Corium with increased and beyond? A: Currently, our product pipeline rewards. Corium is uniquely consists of both previously executed positioned because we are fully A: These are very exciting times partner-funded projects as well as equipped to manufacture both for the drug delivery industry. In 5 our self-funded proprietary projects. passive and active transdermal years, Corium will be on the The partner-funded projects are products in all regulatory/clinical forefront of novel transdermal drug made up of several passive phases from Phase I through delivery. The combination of our transdermal products and range in continuous commercial supply. I like Corplex and MicroCor technologies clinical status from Phase I to to think of us as Films ‘R’ Us. will yield truly market-disrupting awaiting final FDA approval. For products. The conventional needle most all of these projects, Corium will be replaced with a painless, will also manufacture the Q: Have any products self-administered, easy-to-use patch. commercial product. The proprietary been commercialized Drugs taken by injection will now be pipeline products utilize our with either Corplex or as simple as putting on a Band-Aid. MicroCor and Corplex technologies MicroCor? Beyond that, you’ll see more and offer both active and passive technologies converging and drug delivery. We have products in A: Yes, we initially developed non- emerging. Corium’s ingenuity will several therapeutic areas, including prescription products as a means to play a role in personalized medicine CNS, cardiovascular, and endocrine ensure a faster stream of income in that will biosample, monitor, and to name a few. We also have a the early days. As such, we have had deliver biomolecules, all integrated number of vaccine candidates. The the opportunity of developing and into a single wearable device. 6

manufacturing some excellent oral Imagine the advancement of the

passive products in development o N

care, foot care, and wound care medical world with such effective, 7

have never been delivered l o V

products based on our Corplex affordable, and available treatments

transdermally before, and the active 7 0 0 technology for some of the largest for disease. N 2 products include drug molecules that e n u J

marketers in these areas. We also previously have been administered y g o l

have several prescription transdermal o by injection. Corium plans to n h c e T

products in various stages of

introduce the first of these products y r e v i development that utilize Corplex, l to the marketplace by 2011. e D

g u As mentioned previously, Corium including some awaiting final FDA r D plans to take its proprietary pipeline approval. Our MicroCor products are 71

Clinical Trials

Imaging CROs & Their Impact on Clinical Trials

By: RichardRichard Taranto, President,WorldCare Clinical, LLC 3 6 o N o N 7 l 7 o l V o V 7 0 7 0 0 2 0 2 H C E R N A U J M A A M M R R A A H H P P Y Y T T L L A A I I C C E E P P S S

72xx independent radiologist reading with a specific modality and Introduction services, quality control, regulatory therapeutic outcome. As the use of medical imaging in submissions, and other related tasks. clinical trials increases, imaging An imaging CRO can increase biomarkers are more frequently the overall efficiency of the clinical Therapeutic & Modality accepted as surrogate endpoints. In trial program and decrease the costs many cases, imaging technologies, Expertise associated with the overall such as computed tomography (CT) Regardless of the operational development of a compound by and magnetic resonance imaging model the imaging CRO relies upon, reducing the length of a clinical trial. (MRI), and functional imaging its readers should be board-certified With the appropriate expertise, an techniques, such as dynamic contrast radiologists with relevant experience imaging CRO will be able to assist in enhanced (DCE)-MRI, and nuclear in the therapeutic area and affected imaging trial design and acquisition medicine techniques, such as positron anatomical region being studied for a protocols that can potentially reduce emission tomography (PET), can help particular protocol. Some imaging the study’s size and duration. prove the efficacy and safety of drug CROs may specialize in certain There are several critical qualities therapies and medical devices faster disease states, such as oncology or to consider when choosing a central than traditional clinical endpoints. musculoskeletal diseases. imaging CRO. These qualities, which Medical imaging can help The imaging CRO must have include knowledge of specific biopharmaceutical and medical device access to enough seasoned operational procedures, access to companies meet the demands of the radiologists to efficiently control both therapeutic and modality expertise, continued market pressure to shorten small and large volumes of images adherence to rigid quality control the therapeutic development process. and data. The capacity to conduct processes, use of technology that By changing the way disease small studies and quickly scale to improves workflow, and the ability to progression is measured, medical manage large trials means that trial provide regulatory support, should be imaging can assist clinical trial sponsors sponsors are not burdened with evaluated carefully as they can in increasing their clinical trial additional fixed costs or delays as the significantly influence the success of efficiency and decreasing their costs. imaging CRO works to find a clinical study. Clinical trial sponsors turn to additional radiology support. organizations variously known as Imaging CROs that deploy imaging core laboratories, central Operational Procedures several radiologists from the same Imaging CROs manage physician imaging laboratories, or imaging hospital, university, or reading readers using various operational services organization have an edge in 6

CROs to manage the medical o N

procedures. An imaging CRO may reducing reading variability because 7

imaging process for clinical trials. l

rely only on in-house radiologists or o For clarity, this article will use the all physicians are similarly trained V it may outsource the reading to a term imaging CRO to describe these and have the same “reading culture.” number of independent radiology organizations. When all radiologists belong to the 7

groups, a single “nighthawk” same organization, any issues that 0 A critical component of many 0 2

radiology group, or a research-based E successful clinical trials, the imaging arise can be addressed immediately N U academic institution or hospital. J CRO helps to secure the collection of and consistently. Some imaging CROs focus on consistent, high-quality imaging data Before each trial, the imaging providing services for specific CRO should require that all study and ensure minimal variability A M

therapeutic areas, while others are R through central reading. Imaging radiologists complete training that A H P

dedicated to specific measurement ensures a low variability level CROs guide the sponsor in designing Y T modalities, tools, or other L A

between image reads, resulting in the I appropriate imaging acquisition C E

technologies. Regardless of the P protocols and provide the services to generation and submission of S modality and therapeutic focus, an implement and manage the imaging consistent data. Variability training imaging CRO must have the portions of trials, including imaging should cover intra-variability — the necessary reading expertise and site qualification and coordination, variability in image reads produced technology in place to manage a trial by a single reader — and inter- 73 variability — the variability in image • Positron emission tomography process for imaging sites, a review of reads among multiple readers. (PET), a new technique that is equipment variability at all To ensure low variability, the growing in importance because participating facilities, technical imaging CRO determines the it can provide researchers with support to imaging sites, and quality variability threshold, a certain metabolic data about disease control of images. It should extend to percentage that variability should not status. all parts of the imaging protocol, exceed. During variability training, from the protocol and imaging radiologists evaluate representative • Dual energy X-ray charter design through the regulatory scans, discuss the review process of absorptiometry (DEXA), a submissions process. the relevant imaging modalities, technique used to measure determine a standardized assessment bone mineral density that is procedure, and complete an considered the gold standard Technology & Efficient independent assessment of test scans for osteoporosis trials. Workflow that are compared to confirm that Imaging CROs should have state- intra- and inter-variability is within • Dynamic contrast enhanced of-the-art technology at their the appropriate limits. (DCE)-MRI, a specialized disposal, such as: The trial must then be monitored MRI technique that can show continually to make certain that metabolic changes, such as the • Picture archiving and variability stays below the variability rate of blood flow to a tumor. communications systems threshold. If more than one (PACS), the radiology image, radiologist is reading cases, a lead Quality Control & Data and information management radiologist should serve as the gold system that stores, retrieves, standard. Variability transmits, and displays digital In addition to therapeutic Imaging for clinical trials is often images and patient information. knowledge, imaging CROs should conducted at multiple global sites, have access to major imaging perhaps with substantial differences • Software applications, modalities (or its specific expertise) in equipment, acquisition techniques, preferably customized to meet used in clinical trials. Some or post-processing software tools. the needs of each specific frequently used and emerging Data variability increases with the study, that provide a complete imaging modalities are: number of imaging sites in a clinical audit trail, centralized database, 6

trial. The imaging CRO is responsible and image manager that tracks o N

• Magnetic resonance imaging

7 for verifying that the image the image as it moves from the

l o V (MRI), a technology that uses acquisition was managed according imaging site to the independent magnets and radio waves to to the acquisition protocol, and must review process. produce two- and three- regularly provide feedback to the 7

0 dimensional images and is

0 imaging sites to ensure that • A secure portal, or intuitive 2

E particularly well-suited for the N consistent, high-quality data is user interface, for U J study of soft or non-calcified obtained. In addition to having administering the receipt and tissues. seasoned radiologists who have been processing of scans, managing trained to read images for each queries with the imaging sites, A M

R • Computed tomography (CT), an

A specific trial, a precise and well- and providing the sponsor with H P

X-ray-dependent technology that

Y documented quality control (QC) an instant view of the status of T L

A provides two- and three- I process is required to reduce data a trial. C E P S dimensional images that are variability. ideally used to view bones and A thorough QC process will • Site communication software detect calcified areas, air, and gas. include a rigorous qualification that notifies the imaging site of

74

subject visits and automatically development and submitting data for identifies and tracks missing regulatory audit and approval, the Richard Taranto scans. imaging CRO should be evaluated on President WorldCare Clinical, LLC its ability to support the trial sponsor In addition to guaranteeing high- at meetings with regulatory agencies, quality data, advanced technology respond to agency questions about ensures the most logical and efficient image analysis and management, workflow among the imaging sites, produce electronic data sets for case the CRO, and the trial sponsor. A report tabulations and reports that smooth and productive operational meet electronic submissions Mr.Taranto has been in the clinical process enables the imaging CRO to requirements, and log and track trial imaging industry since 1997 meet the trial sponsor’s demand for regulatory correspondence. and has experience managing fast turnaround times, without sacrificing data quality. multiple clinical imaging trials for Summary biopharmaceutical and medical An experienced imaging CRO device companies. Mr.Taranto has Quality Assurance & assists the clinical trial sponsor in overseen more than 25 Phase II-IV Regulatory Support developing imaging trial design and studies in multiple therapeutic Imaging CROs must develop and acquisition protocols that can areas, including oncology, execute imaging studies that conform potentially reduce the study’s size cardiology, diagnostic imaging, and and duration. As medical imaging to the Good Clinical Practice women’s health. He also has continues to increase overall clinical guidelines. The imaging CRO is often extensive experience with multiple responsible for compiling, archiving, trial efficiency and decrease imaging modalities, such as MRI, and submitting imaging data to the development costs by reducing trial CT, bone scan, echocardiogram, regulatory agency once the study is length, imaging CROs will continue completed. The imaging CRO’s to play a critical role in managing the ultrasound, and radiograph imaging quality assurance process — a clinical trial medical imaging studies. systematic and independent process. examination of all trial-related In evaluating the abilities of an activities and documents — imaging CRO, clinical trial sponsors 6

o must consider its operational

N determines whether the imaging

7

l procedures, access to therapeutic and

o process was appropriately conducted V and the data was accurately modality expertise, adherence to generated, recorded, analyzed, and stringent quality control processes, use of workflow-improving 7 reported according to the protocol, 0 0

2 technology, and the ability to provide standard operating procedures, and E N

U regulatory support. A proven track-

J good clinical practice. The study methods and analysis record in managing images from must be defined, monitored, and around the globe for different

A therapeutic indications, combined M audited, and the resulting data must R A

H with access to radiologists with the

P be verified, archived, and submitted

Y

T relevant therapeutic expertise, is the L according to regulatory requirements. A I

C best indicator of an imaging CRO’s E For example, the FDA emphasizes P S blind readings with a physician ability to successfully manage and reader that is independent of the submit an imaging study. I sponsor and the clinical site. 76 In addition to imaging charter

Bionumbers: Facts Specialty Pharma Market & Figures Indices Through April 30, 2007

Index Trends Commercial Stage Emerging Stage Index Like the Big Market, both of the Specialty Pharma indexes were on a run Index Trends (CSPI) Trends (ESPI) in April. The Commercial Stage The strong keep getting stronger. With the engine of growth for this Specialty Pharma Index (CSPI) was up Except for Abraxis, the top five index, New River, acquired by Shire mid- almost 7% for the month and 11% for companies by market capitalization are month, other companies picked up the year-to-date, while the Emerging all up by 19% or more for the year. The slack for a 5% growth for the month. The Specialty Pharma Index (ESPI) was up leading gainers for the year on a index now is positive for the year, up 5% for the month and 4% for the year. percentage basis are to be found in the about 4%. The larger part of monthly Through the middle of May, the CSPI small to mid-cap companies, with Avanir growth for the index came from the has held onto its April gains, while the picking itself up off the canvas for a smaller to mid-tier players. Epicept was ESPI has slumped to end of 2006 values. remarkable 80% YTD gain. Even the up 80% for the month, followed by laggards have either stopped their slide Somaxon at 50%, and Acusphere at 46%. or shown a gain for the month. The index It will be interesting to see who breaks market capitalization increased to $63.9 out of the pack to follow New River to billion, fueled by overall growth and the $2-billion market cap level. Index Shire’s acquisition of New River. market capitalization (but not the Index Value) will drop next month when New River is removed. I 6 o N 7 l o V 7 0 0 2 E N U J A M R A H P Y T L A I C E P S

78 Bionumbers Commercial-Stage Specialty Pharma Index 1,350

r

a APRIL 1,300 1,350

e Y 2007 1,250

1,300

/ r

1,200 a

h 1,250

e t

Y 1,150

n 1,200 /

o 1,100 h 1,150 t

M n 1,050 o 1,100

1,000M 1,050 950 1,000 2006-NOV 2006-DEC 2007-JAN 2007-FEB 2007-MAR 2007-APR I n d e x 1,128 1,1 45 1,203 1,191 1,197 1,279 950 2006-NOV 2006-DEC 2007-JANI n d ex Va l u2007-FEB e 2007-MAR 2007-APR I n d e x 1,128 1,1 45 1,203 1,191 1,197 1,279 I n d ex Va l u e

Key Figures April 2007 Top 5 Gainers YTD Change Top 5 Laggards YTD Change Top 5 Capitalizations YTD Change Index Value: 1279 Avanir +80% Columbia Labs -50% Shire $12.9 Billion 23% Change YTD: +11.7% Vivus +79% Questcor -38% Hospira $6.4 Billion 19% Total Index ISTA +38% Angiotech -34% King $5.0 Billion 29% Capitalization: -$63.9 Billion Indevus +34% Medicines Co. -27% Abraxis $4.6 Billion 4% King +29% Novavax -27% Warner $4.2 Billion 22%

Bionumbers Emerging-Stage Specialty Pharma Index

APRIL 2, 0 0 0

r

2007 1, 9 0 0 a 2, 0 0 0

e 1, 8 0 0 Y

1, 9 0 0

6 /

r

1, 7 0 0 o N a

1, 8 0 0

h

7

e

t l

1, 60 0 o Y

V

n 1, 7 0 0 /

o 1, 5 0 0 h 1, 60 0 t

M n 1 , 4 0 0 7 0 o 1, 5 0 0 0 2

M 1, 3 0 0 E

1, 4 0 0 N U 1, 2 0 0 J 1, 3 0 0 2006-NOV 2006-DEC 2007-JAN 2007-FEB 2007- MAR 2007- APR I n d e x 1,579 1,655 1,564 1,634 1,629 1,722 1, 2 0 0 2006-NOV 2006-DEC 2007-JANI n d ex Va l2007-FEB u e 2007- MAR 2007- APR A M R

I n d e x 1,579 1,655 1,564 1,634 1,629 1,722 A H P

Key Figures April 2007 Top 5 Gainers YTD Change Top 5 Laggards YTD Change Top 5 Capitalizations YTD Change

I n d ex Va l u e Y T L

Epiicept +116% A

Index Value: 1722 Scolr -45% New River $2375 Million +21% I C E P

Change YTD: +4.0% Acusphere +65% Penwest -27% Nektar $1134 Million -17% S Total Index Cadence +37% AP Pharma -27% Aspreva $795 Million +8% Capitalization: $5.7 Billion Somaxon +30% Keryx -23% Cadence $472 Million +37% Antares +28% NovaDel -18% Keryx $444 Million -23% 79

Therapeutic Focus

immunotherapy must be continued Revimmune: Delivering a Knockout indefinitely, maintaining an impaired immune system, and often resulting in Punch to Autoimmune Diseases cumulative adverse side effects. Despite this, the vast majority of patients on By: Douglas Kerr, MD, PhD, and Adam Kaplin, MD, PhD conventional immunomodulatory treatment for MS continue to accrue disability. Introduction Depending on the disease, immune- modulating treatments for autoimmune Autoimmune diseases are the third attacking various organs and tissues. In disease fall far short of the goals of safe, most common category of disease in the the case of type I diabetes, the target long-term relief and acceptable quality of United States after cancer and heart tissues are insulin-producing islet cells in life for many patients. Therapies must be disease, affecting approximately 5% to the pancreas; in lupus, it is connective administered chronically, from several 8% of the population or 14 to 22 million tissues and sometimes major organs. times a day to every few weeks, for life. people.1 There are 80 recognized Many of these treatments are quite autoimmune diseases, and nearly three- expensive, in the range of $30,000 per year.

6 Conventional

o

N fourths of those affected are women.

7

Treatment l

o Among the most prevalent autoimmune V diseases are lupus, type I diabetes, Potential Treatment In recent years, more than 30 scleroderma, multiple sclerosis (MS), neurologic diseases have been recognized A potential treatment for 7

0 Crohn’s disease, chronic active hepatitis, 0 TM 2

either to be caused primarily by autoimmune diseases is Revimmune , E

N rheumatoid arthritis, Graves’ disease, U

J autoimmune mechanisms or to have which includes high-dose myasthenia gravis, myositis, important autoimmune components. cyclophosphamide. Revimmune, a antiphospholipid syndrome (APS), Although many of these diseases can be patent-pending pharmaceutical treatment

A Sjogren’s syndrome, uveitis, M

R treated clinically by currently available in late-stage development for a variety of A

H polymyositis, Raynaud’s phenomenon, P

Y conventional immunosuppressive autoimmune diseases, is a potential T

L and demyelinating neuropathies. A I

C regimens, important problems remain. treatment option for severe, refractory, E

P Autoimmune diseases occur when S Some patients are refractory to standard immune-mediated illnesses, such as MS. the body’s immune system no longer immunotherapy, and others respond only Revimmune uses an ultra-high intensity, differentiates between “self ” and “other,” partially. In nearly all cases, short-course of an intravenous meaning the immune system cells begin 80

formulation of cyclophosphamide to “reboot” a patient’s immune system, "Depending on the disease, immune-modulating thereby eliminating the autoimmunity. treatments for autoimmune disease fall far short of the Revimmune temporarily eliminates peripheral immune cells, including the goals of safe, long-term relief and acceptable quality of immune cells causing the autoimmunity, life for many patients. Therapies must be administered while selectively sparing the stem cells in the bone marrow, which are chronically, from several times a day to every few weeks, subsequently able to repopulate the for life. Many of these treatments are quite expensive, in body with a nascent immune system. By inducing immunoablation and the range of $30,000 per year." subsequent immune reconstitution, Revimmune eliminates or reduces immune system reconstitutes itself Johns Hopkins University School of dependence on chronic during a 2- to 3-week period. Medicine is Douglas Kerr, MD, PhD. In immunosuppressive therapies, which are Revimmune includes a risk management a follow-up of up to 2 years, most patients potentially more toxic, carcinogenic, program to enhance patient safety by have shown substantial improvement and inadequate, inconvenient, and very ensuring appropriate patient selection, many have a complete elimination of expensive, especially in the case of supportive care, and tracking of signs of the disease. The co-principal monoclonal antibodies. Revimmune’s outcomes data, which could be critical to investigators on this study are Dr. Daniel use would also obviate the risk and reimbursement coverage and malpractice Drachman and Dr. Robert Brodsky. expense of allogeneic (donor) stem cell protection for healthcare providers. “Revimmune offers the hope of transplantation to treat severe cases of Developed by Dr. Richard Jones, Dr. sustained remissions and cures for autoimmune diseases. Robert Brodsky, and colleagues at the autoimmune diseases, says Frank E. Accentia Biopharmaceuticals, Inc. Johns Hopkins University School of O’Donnell, Jr., MD, Chairman and CEO has acquired the exclusive worldwide Medicine, Revimmune works by of Accentia. “Moreover, it eliminates the rights for Revimmune. Based on long- temporarily eliminating peripheral dependence on chronic term follow-up showing durable immune cells responsible for immunosuppressive therapies, which are remissions, there is substantial evidence autoimmunity, while selectively sparing toxic, carcinogenic, inconvenient, not

6 that Revimmune has the potential to cure the stem cells in the bone marrow. very effective, and in the case of o N

cases of severe refractory autoimmune 7 Investigators at Hopkins discovered that monoclonal antibodies, quite expensive.”

l o V diseases, such as aplastic anemia and stem cells possess high levels of a Accentia is preparing an IND myasthenia gravis. To date, more than protective enzyme that makes them application for Revimmune for severe 175 patients, mostly those with severe

7 impervious to Revimmune. Over the refractory MS, and is proposing to enter 0 0 2 refractory autoimmune diseases, have course of 2 to 3 weeks after treatment, a Phase III clinical trial to support E N U J been treated with Revimmune. The these stem cells produce a new, licensure under the abbreviated company believes that Revimmune is a improved immune system. Newly 505(b)(2) regulatory pathway. According “platform” technology that can be used reconstituted peripheral immune system to the National Multiple Sclerosis A M

R in any autoimmune disease. A cells lack the misdirected immunity to Society (www.nationalmssociety.org), H P

Revimmune is administered as an Y self-antigens, which is characteristic of approximately 400,000 people in the US T L A I

C in-patient or outpatient infusion for 4 autoimmune diseases. suffer from the disease, 85% of whom E P S hours per day for 4 consecutive days. The principal investigator for the are classified within the “relapsing- Patients can recover at home while their ongoing Revimmune MS study at the remitting” category, meaning that

82 symptoms wax and wane over time, with References Douglas Kerr, the overall trend toward worsening MD, PhD symptoms.2 Two published studies of 1. Fairweather D, Rose NR. Women and Associate Professor of Revimmune in 20 MS patients found a Neurology, Molecular autoimmune diseases. Emerg Infect Microbiology & reduction or elimination of new and Immunology Dis. 2004 November. Available from Director, Johns Hopkins enhancing lesions in all patients.3,4 Transverse Myelitis http://www.cdc.gov/ncidod/EID/vol10 Center Furthermore, no patient experienced a no11/04-0367.htm. clinical exacerbation following 2. Hirtz D, Thurman DJ, Gwinn-Hardy treatment, and most showed reductions K, Mohamed M, Chaudhuri AR, Dr. Douglas Kerr earned his MD and PhD or stabilization of clinical markers for from Jefferson Medical College at Thomas Zalutsky R. How common are the Jefferson University in Philadelphia. He then the disease. In clinical studies, the drug “common” neurologic disorders? completed an internship in Medicine at The regimen improves function in most Graduate Hospital, also in Philadelphia. He Neurol. 2007;68:326-337. went on to complete his residency in patients and stops progression in over Neurology at The Johns Hopkins Hospital in 3. Krishnan C, Drachman D, McArthur 90% of cases refractory to standard Baltimore. Now an Associate Professor of J, Irani D, Nath A, Pardo-Villamizar Neurology at Johns Hopkins, Dr. Kerr serves therapies. as the Director of the Transverse Myelitis C, Yousem D, Brodsky R, Calabresi P, Center, focusing on comprehensive Kerr DA, High-dose evaluation of TM. His research strives to determine the causes of TM and develop The Company cyclophosphamide in the treatment of new treatment options. Dr. Kerr further focuses on stem cells as a tool for functional aggressive multiple sclerosis. recovery in patients with TM and motor Accentia Biopharmaceuticals Baltimore, MD. AAN Abstract neuron diseases. specializes in development of late-stage (P01.072); April 4, 2006. under-utilized drug products, in 4. Gladstone DE, Zamkoff KW, Krupp particular, approved medicines in new L, Peyster R, Sibony P, Christodoulou Adam Kaplin, formulations and/or for new, patentable C, Locher E, Coyle PK. High-dose MD, PhD indications. The company’s lead cyclophosphamide for moderate-to- Assistant Professor of respiratory product candidate, Psychiatry severe refractory multiple sclerosis. Johns Hopkins University TM SinuNase , is currently in clinical Arch Neurol. Vol 63. Published development for treating chronic Online August 14, 2006. sinusitis (rhinosinusitis). SinuNase, a Dr. Adam Kaplin graduated Magna Cum 6

Laude from Yale University before earning o novel application and formulation of a N

his MD and PhD from The Johns Hopkins 7

l known anti-fungal compound licensed o

School of Medicine, where he was a V from the Mayo Foundation for Medical Medical Science Training Program awardee. He went on to complete an internship in Education and Research, has been fast- Internal Medicine at Johns Hopkins Bayview

Medical Center and a residency in 7 0

tracked by the FDA and is now in Phase 0

Psychiatry at Johns Hopkins Hospital, where 2

E

III clinical trials. Accentia’s other lead he served as the Chief Resident of N U

Psychiatry. Now an Assistant Professor of J TM product, BiovaxID , a patient-specific Psychiatry at Johns Hopkins, Dr. Kaplin anti-cancer vaccine for treating non- focuses on the psychiatric complications of neurological diseases. He researches the A

Hodgkin’s lymphoma, has also received immune-mediated mechanisms of M R

depression and cognitive impairment in A H

FDA fast-track status and is in Phase III P

transverse myelitis, multiple sclerosis, and Y T testing. I related autoimmune neurologic disorders, L A I

and the role of cytokines in these C E P

processes. S Dr. Kaplin is on the Board of Medical Advisors to the Transverse Myelitis Association (TMA) and the Montel Williams MS Foundation. 83

Executive Ron Wooten President Summary NovaQuest

Q: What makes a company attractive to NovaQuest: Strategic NovaQuest in terms of partnering or investment?

Partnering to Optimize A: We want to partner with companies on their most important products and work on their most critical Portfolio Value, Growth challenges. We’re all about helping companies maximize the value of their portfolios, manage financial challenges, and optimize growth and profits. You can’t do that by & Profits operating on the fringes. One key thing that makes a company attractive is the commitment of its senior management to adopting new ways of doing business. It’s By: Cindy H. Dubin, Contributor not easy to break from traditional models of development and commercialization, especially for pharma companies with huge fixed costs in R&D infrastructures and sales ach year, the strategic and financial challenges faced forces. However, with the recent well-publicized examples by pharmaceutical and biotech companies grow and of blockbuster-category drugs being halted in E development or pulled from the market because of safety change: maximizing investment needed for the future and concerns, we’re seeing increasing interest from big and mid-size pharma in risk-based partnering. Rather than dealing with the escalating risk and cost of development, bearing all development costs and risks for a product — all within the context of infrastructure and financial at $800 million to $1 billion a pop — partnering can 3 mitigate that risk and allow a company to accelerate 6 o

N o

N pressures. Strategic investment partnerships are development of several promising products. It makes

7

l 7

o

l sense to spread your bets rather than hoping for one V o V increasingly seen as the best way to break through the blockbuster. Market pressures are forcing pharma to try to logjam of resource constraints. NovaQuest provides get more and more products through the pipeline — more shots on goal — and therefore, they’re interested in 7 0 7 alternative growth strategies designed around partners’

0 partnering on a broader array of their portfolio. 0 2 0 2 H

C E

R specific challenges and goals. Ron Wooten, Executive Vice N A U J M President of NovaQuest, recently shared with Specialty Q: What makes NovaQuest unique? Pharma magazine what the company brings to the table A A A: M M Four things: our intellectual capital, financial resources, R R when entering into a partnership. These include: product A A H H management expertise, and Quintiles. We know how to P P

Y Y development and commercialization expertise from analyze, structure, and manage alliances. We screen 150 T T L L A A I I to 200 opportunities a year and conduct full due diligence C C E E Quintiles and Innovex, and access to the investment P P on 15 or so. We’ve signed more than 60 partnerships since S S expertise of TPG-Axon Capital. NovaQuest was formed in 2000. In the vast majority of those there was a valuable intellectual exchange about how to improve development or commercialization. So it’s not just about money; it’s about doing things better, 84xx

smarter, and faster. Our financial resources also set us apart. In 7 Q: What companies have you partnered with, and years, we’ve committed more than $1.6 billion in either cash or on what products? Quintiles’ services to customer partnering, and we plan to pick up the pace of our investment. Our alliance with TPG-Axon, an A: Our partner companies include Eli Lilly, Solvay Pharmaceuticals, independent investment fund with almost $6 billion in capital, and Astellas UK, plus others that cannot be disclosed for gives us the resources to fund partnerships of virtually any size. confidentiality reasons. We’ve partnered with many biotech Another characteristic that makes us unique, I believe, is our companies — Scios to help market Natrecor®, its treatment for “managed partnership” approach. Each of our partnerships is acute congestive heart failure [J&J later acquired Scios]; Kos overseen by an experienced, well-trained alliance manager. They’re Pharmaceuticals to co-promote its Advicor® and Niaspan® responsible for ensuring the partnership works as structured and treatments for cholesterol disorders; and with Columbia for developing a collaborative win-win mindset. Finally, we’re a Laboratories to help co-promote several products. These are just a part of Quintiles, so we can craft partnering solutions that use few of our biotech partnerships. Quintiles’ global clinical development and commercialization Our largest and most well-known alliance is with Lilly to resources in a dedicated, long-term “managed partnership” help develop and promote its Cymbalta® antidepressant. We manner. That is a tremendous advantage. provided more than $100 million for development and marketing support prior to its approval in the summer of 2004, and since then, we’ve provided a 550-member NovaQuest sales team to co- Q: promote Cymbalta in the US in return for royalties on Cymbalta Can you discuss with our readers your business sales. That agreement exceeded our expectations and has led to model and why it’s working? other further partnering opportunities with Lilly. A: Our partnership with Astellas UK to help promote We have three main models. First is what we call “strategic VESIcare®, its treatment for overactive bladder, also has been very resourcing,” which helps companies manage their budgets by successful. Using Quintiles’ contract sales organization, Innovex, converting fixed costs to variable costs. Pharma has huge fixed we helped Astellas build an integrated UK sales force that was costs associated with development and sales, often on the ready faster and was larger than Astellas could have done on its development side those people are underutilized. We’re in own. Since launching in January 2005, the VESIcare team has conversations with at least the top 20 of the top 50 pharma exceeded its sales targets and tripled the product’s market share. companies about how we can take over those resources, make them more “virtual,” and get full utilization out of those fixed costs. This can significantly improve the efficiency of development and commercialization. We believe there’s the Q: What does the Solvay partnership mean to potential on the development side to improve efficiency enough to NovaQuest and Quintiles? deliver three products to market for the costs now needed to deliver two. A: To me, the Solvay alliance represents the future of product Second is risk-based co-development or co-promotion in

6 development. It’s a great example of how alliances — when

o which NovaQuest provides money or, more typically, Quintiles’ N

executed properly — expand as the partners see the benefits and

7

development or sales resources. In exchange, we receive milestone l build trust. Back in 2000, Solvay’s challenges were typical of a o V or royalty payments on the products. Therefore, our repayment is mid-size pharma company. It didn’t have the global clinical based on the clinical, regulatory, and commercial success we structure or resources needed to realize the full value of its achieve. Typically, we invest resources and services and not cash, pipeline, which was strong — more than 30 compounds — but

7 which combines our intellectual capital and management expertise

0 most stuck in Phase II. Quintiles Clinical Development sat down 0

2 along with our partners. They like the notion of partnering with with Solvay and in 2001 formed a preferred provider alliance that E

N someone who has global experience and expertise, so it’s more U consolidated most of Solvay’s outsourced Phase I to III clinical J than just money. projects to Quintiles. Our third model is what we call “eBio,” which is tailoring The results have been fantastic. Since 2001, the alliance has strategic and financial solutions for biotech companies. We completed three Phase III trial programs, and Solvay has filed two A provide investment dollars to facilitate their development M NDA submissions, including one in October for its schizophrenia R

A programs, along with consulting on their drug development and H treatment, bifeprunox. Two compounds moved from Phase II to P

regulatory plans. This approach, combined with co-development Y

T Phase III a year earlier than expected, and Solvay was awarded a L

A and co-promotion partnerships, helps them hold onto their I $298 million contract from the US Health and Human Services to C E

P products longer and creates an opportunity for them to realize full

S develop cell-based influenza vaccines with Quintiles to conduct 9 value for their innovation excellence. clinical trials. That success led to more discussions. In 2004, NovaQuest and Solvay signed a risk-sharing development partnership, with

86

NovaQuest providing $25 million in Quintiles’ development Check out the latest online issue of Drug Delivery Technology at services for 10 of Solvay’s Phase II products. Solvay will make milestone payments to us for each compound that moves onto www.drugdeliverytech.com Phase III. This agreement basically doubled Solvay’s early development capacity.

Q: NovaQuest has an alliance with the investment fund TPG-Axon. How much easier does this Visit make funding your partnerships?

A: Much easier. TPG–Axon has almost $6 billion in capital. It has already invested $375 million in strategic partnering opportunities along with us, and it’s our first-line partner for major co- DrugDelivery development and co-promotion alliances. Until now, most of our investment dollars have come from Quintiles, but I expect that in the future we’ll rely more on TPG–Axon and possibly other outside investment groups in part because of the sheer volume and size of Technology... the opportunities we’re considering.

Q: What are your long-term goals or ultimate online! objectives for NovaQuest? • No special software required A: Our long-term and short-term goals are the same. We want to be • Table of contents navigation the unquestioned partner of choice for pharmaceutical and biotechnology companies. We want to be unsurpassed in terms of • Click through to advertisers’ sites and content adding value to our partner’s products. We want to be known for • Print, send, and share articles with colleagues our responsiveness, for our flexibility, innovation, and above all, for delivering on what we promise. • Interactive correspondence with editors and advertisers • Content searchable by keywords • Faster online distribution Q: What is the one mistake you must avoid going 6

o forward? N

7

l

o A: V We must avoid chasing marginal opportunities that are not strategic for our customers. We’ve been successful mainly because we partner on our customers’ most strategic assets. This creates a partnership whose success is critical for both parties. This means 7 0

0 we get the best thinking and experience behind the product 2

E

N opportunity and the chances for success go up. U J

Q: A What keeps you awake at night? M R A H P

A:

Mostly the same things that keep pharma executives up. These Y T L include worries about the changing regulatory and commercial A I C

E environments for drug development and product sales. Will these P S force changes in our development or commercial plans that drive profitability out of our partnerships? Will older, generic technologies dominate prescriptions because of cost alone? A worry unique to NovaQuest is — Will the pharmaceutical industry 88 move slowly in embracing a more effective way to do business? I Company Pg Phone Web Site

3M Drug Delivery Systems 5 800-643-8086 www.3m.com/dds Aveva Drug Delivery Systems 13 954-624-1374 www.avevaDDS.com Azopharma 4 954-433-7480 www.azopharma.com Baxter BioPharma Solutions 2 800-422-9837 www.baxterbiopharmasolutions.com BD 31 800-225-3310 www.bdpharma.com Bilcare 37 610-935-4300 www.bilcare.com Bilcare 75 800-310-4445 www.bilcare.com Capsugel 20 www.capsugel.com Cardinal Health 92 866-720-3148 www.cardinal.com/pts Coating Place Inc. 41 608-854-9521 www.encap.com Davidson, Davidson & Koppel 87 212-736-1940 www.ddkpatent.com Degussa 11 732-981-5383 www.pharma-polymers.com Dow Chemical Company 24, 25 1-800-447-4369 www.dowexcipients.com DPT Laboratories 91 866-CALL-DPT www.dptlabs.com Drug Delivery Technology 88 973-299-1200 www.drugdeliverytech.com DSM Pharmaceuticals 77 973-257-8011 www.dsmpharmaceuticals.com Eurand 7 937-898-9669 www.eurand.com Filtertek Inc. 33 1-800-648-0791 www.filtertek.com FMC Biopolymer 15 www.fmcbiopolymer.com Frost & Sullivan 85 www.frost.com Genzyme Pharmaceuticals 45 800-868-8208 www.genzymepharmaceuticals.com Glatt Pharmaceutical Services 27 201-825-8700 www.glattpharmaceuticals.com Halozyme 57 858-794-8889 www.halozyme.com 6

o N

InnerCap Technologies 3 813-837-0796 www.innercap.com 7

l o V

Iomed 35 801-975-1191 www.iomed.com

7 0

Nektar Therapeutics 81 www.nektar.com 0 2

e n

www.nof.co.jp/dds u

NOF Corporation 49 914-6819790 J

y

www.pharmacircle.com g PharmaCircle 17 847-729-2960 o l o n h

PharmaForm 4 512-834-0449 ext 201 www.pharmaform.com c e T

y r

Safety Syringes 55 760-918-9908 www.safetysyringe.com e v i l e D Scolr Pharma, Inc 9 425-373-0171 www.scolr.com g u r Zeon 19 1-877-ASK-Zeon www.zeonchemicals.com/Medical2 D 89

Resumes 101 By: John A. Bermingham

t one time or another, almost everyone has had to follow me to my office. I had to have security remove him create a resume, me included of course. That from the building. The sad part for him was that I would have AAdocument can be the world’s greatest personal sell offered him the position without Harvard. sheet or the most dangerous document known to man kind. Another classic was a resume sent directly to me when I We all know the basics of a resume: Two pages in length; was with AT&T by a person who also listed his education as no typos; no gimmicks, such as your picture or clip art, total Harvard College in Boston, Mass. He also listed his most honesty; use of power words; printed on high-quality paper recent position as President of Sony Magnetic Products and envelopes; great cover letter; etc. Group. The following two things were wrong with that: As a CEO, I have the opportunity to read many resumes. The good ones are pretty similar to each other, and the bad 1. I went to Harvard Business School and recall quite ones are all different from each other. The good ones contain clearly that Harvard is in Cambridge, Mass. bullet points that provide enough information to peak a hiring manager’s interest, and the bad ones either don’t provide you 2. His claim to be President of Sony Magnetic Products enough information or have so much information that it is put Group happened to be at the same time that I was aside because the reader loses interest. So what is the purpose President of Sony Magnetic Products Group. of a resume you ask? A resume should have only enough information on it to get Okay, one more. I recently interviewed a candidate for a you to the interview. It should not be a complete and detailed senior position here at Lang Holdings, Inc. During the history of your career. Just a snap shot. A lot of people interview, he had to refer to his resume to answer my believe that they only require one resume. That is a mistake. questions on the companies he had worked for and the detail Every resume you send out should be tailored to the I was looking for. Do you think that I may have had some position you are looking to secure. As an example, if you are concerns about why he had to refer to his resume to answer a trying to obtain a position that is for a sales and marketing, question? So there is a huge difference between falsifying then that version of your resume should emphasize your your resume and tailoring it in a truthful manner to expertise in sales and marketing. If it is for an R&D position, emphasize your value for the position. And don’t forget to then you should emphasize your resume in that direction. review your resume prior to an interview so that you do not I have one basic format of my resume that I tailor for the have to refer to your resume to answer a question! N position I am seeking. So, as an example, when a recruiter or a private equity firm calls me to discuss an opportunity, I interview the recruiter or private equity partner to gain as B IOGRAPHY much knowledge as I can on the position and what type of person they are seeking. That accomplished, I then tailor my John A. Bermingham is currently the CEO of The resume to fit the position. I do not add fluff or false Lang Companies, an innovative leader in the social sentiment and home décor industries. He was information; I just tailor the resume to fit the opportunity by previously the President, Chairman, and CEO during the emphasizing certain key areas. successful turnaround and sale of Ampad, a leading What continually astounds me is the number of people who

6 manufacturer and distributor of office products. With

o

N falsify their resume and believe they will never get caught. more than 20 years of experience in guiding enterprises

7

to new levels of performance, Mr. Bermingham also held the positions of

l When I was with Sony, I retained a recruiter to help me find o V

Chairman, President, and CEO of Centis, Inc., a diverse multinational

a Vice President of Advertising. After many interviews, I

7 manufacturer and marketer of office, storage, and human resources

0 finally settled on a candidate and made him an offer 0

2 products. Among many career highlights in the role of President and CEO, contingent on passing our background check. He listed e

n he also successfully reorganized Smith Corona Corporation and refocused u

J Harvard College for his undergraduate degree. Well, the operations and a strategic vision for a dramatic turnaround for Rolodex

y background check showed that he never attended Harvard,

g Corporation. Mr. Bermingham’s expertise has also been deployed at industry o l

o which prompted a call to him from our Human Resources giants, such as AT&T Consumer Products Group, and by having served as the n h

c person telling him that the offer was revoked. The following EVP of the Electronics Group and President of the Magnetic Products Group, e T

y Sony Corporation of America. Mr. Bermingham served three years in the U.S.

r Monday, I arrived at the office and there he was, standing in e v

i Army Signal Corps with responsibility for Top Secret Cryptographic Codes l our lobby waiting for me to try to explain away his e D

and Top Secret Nuclear Release Codes, earned his BA in Business

g falsification on his resume. I told him there was no excuse u

r Administration from Saint Leo University, and completed the Harvard

D for submitting false information and that he should leave the building. With that, he broke down into tears and started to University Graduate School of Business Advanced Management Program. 90