Drug Delivery Technology May 2010 Vol 10 No 4 States, Canada, and Mexico

* DDT May 2010 Covers:DDT Cover/Back April 2006.qx 4/30/10 2:34 PM Page 2

May 2010 Vol 10 No 4 www.drugdeliverytech.com IN THIS ISSUE

INTERVIEW WITH MALLINCKRODT BAKER, INC.’S DIRECTOR GLOBAL MARKETING HERMAN MITCHELL

Degradable Polymers 20 Aylvin A. Dias, PhD Marc Hendriks, PhD AdminPenTM Microneedle Device 32 Vadim V. Yuzhakov, PhD EP-Mediated DNA Delivery 37 Karen E. Dolter, PhD

FEATURING

Non-ATP Competitive Kinase-Signaling Inhibitors 64 Allen Barnett, PhD

The science & business of drug development in specialty pharma, biotechnology, and drug delivery Biomedical Instruments & Poonam Josef Bossart, John Lynch Devices 68 Velagaleti, PhD PhD Validating Oral Andreas Knaack A Novel Mixed Drug Delivery Products Delivery With Nanomicellar & Technologies, a Absorption Antimicrobial Technology to Treat Decade in Review Enhancing Diseases of the Technology Resistance 71 Anterior & Posterior Ron Najafi, PhD Segments of the Eye

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4 Drug Delivery Technology May 2010 Vol 10 No 4 States, Canada, and Mexico. All subscriptions are payable in US fu US in payable are subscriptions All Mexico. and Canada, States, reproduced or transmitted in any form or by any means, electronic or mechanical, including by photocopy,recording, by including mechanical, or electronic means, any by or form any in transmitted or reproduced 01923; phone: (978) 750-8400, fax: (978) 750-4470. (978) fax: 750-8400, (978) phone: 01923; Drive,Clearance,Rosewood Danvers,MA Copywrite 222 the with registered users Technologyother and LLCforlibraries nentoa ad a-mrcn oyih Cnetos Al ihs eevd N pr o ti pbiain a be may publication this of part No reserved. rights All Conventions. Copyright Pan-American and International changes to Drug to changes coe, n Nvme/eebr y rg eiey ehooy L, 1 Cagbig Ra, otil N 07045. NJ Montville Road, Changebridge 219 LLC, States,United forMexico.the $99.00 and in United rates: Canada, year forSubscription the 1 $153.00 outside year 1 Technology Delivery Drug by November/December and October, tm fr nenl r esnl s, r h itra o proa ue f pcfc let, s rne b Du Delivery Drug by granted is clients, specific of use personal or internal the or use, personal or internal for items Periodicals Postage Paid at Montville, NJ 07045-9998 and additional mailing offices. Postmaster: please send address send offices.please Postmaster:mailing additional and 07045-9998 Montville,NJ at Paid PostagePeriodicals or information storage and retrieval system, without written permission from th (I safety the for responsibility no assume publishers the but care, reasonable with handled are submissions editorial All 1.0 U, aaa ad eio $40 i al te cutis Ad 50 pr re fr hpig n handling. and shipping for order per $5.00 Add countries. other all in $24.00 Mexico; and Canada, US, $15.00, Delivery Technology LLC subscription Department, 219 Changebridge Road, Montville NJ 07045. Single copies (prepaid) responsibility for the accuracy of information supplied herein or for any opinion expressed. Drug Delivery Technology Delivery Drug expressed. opinion any for or herein supplied information of accuracy the for responsibility accept cannot publishers but accuracy, ensure to taken is precaution Every manuscripts. or photographs, artwork, of 944-818X) is published 9 times in 2010, January/February, March, April, May,September,July/August,June,April, January/February, March, 2010, in times 9 published is 944-818X) SSN 1 SSN MailingList Rental CandyBrecht Tel:(703) 706-0383 Fax:(703) 549-6057 E-mail:cbrecht@m D elivery Technology, 219 Changebridge Road, Montville NJ 07045. All rights reserved under the US the under reserved rights All 07045. NJ Montville Road, Changebridge Technology,219 elivery International EastMidwest& WestCoast 219Changebridge Road, Montville, NJ07045 EXECUTIVE EDITORIAL DIRECTOREDITORIAL EXECUTIVE iit.o E-mail:[email protected] gilists.com [email protected] RalphVitaro VictoriaGeisAccount - Executive 103Oronoco Street, Suite 200 WarrenDeGraff ADMINISTRATIVESUPPORT May 2010 2010 May TECHNICAL OPERATIONSTECHNICAL CONTRIBUTING EDITORS CONTRIBUTING PUBLISHER/PRESIDENT Corporate/EditorialOffice www.drugdeliverytech.com AdvertisingSales Offices EDITORIAL SUPPORT EDITORIAL CREATIVEDIRECTOR Fax:(973) 299-7937 Shalamar Q. Eagel Q. Shalamar Nicholas D. Vitaro NicholasD. Tel:(973)299-1200 Dan Marino,MSc Dan Kathleen KennyKathleen Jason McKinnieJason Debra BinghamDebra Cindy H. Dubin CindyH. Debbie Carrillo Debbie Mark NewlandMark CONTROLLER Ralph Vitaro Ralph Tel:(415) 721-0644 Fax:(415) 721-0665 E-mail:[email protected] 219Changebridge Road Montville,NJ07045 Tel:(973) 299-1200 Fax:(973) 299-7937 E-mail:[email protected] Alexandria,VA 22314 Tel:(703) 212-7735 Fax:(703) 548-3733 E-mail:[email protected] WesternRegional Manager 8185thAvenue, Suite 301 San Rafael, CA94901 e MichaelJ.Masters Director- Tel:(973) 299-1200 Fax:(973) 299-7937 -MediaSales Vol 10 No 4 No Vol10 drawn on US banks. Send payment to: Drug to: payment Send banks. US on drawn nds, e p ublisher. Authorization to photocopy 5-9 DDT May 2010 TOC pages:DDT April 06 TOC 5-9.qx 4/30/10 2:37 PM Page 5 5-9 DDT May 2010 TOC pages:DDT April 06 TOC 5-9.qx 4/30/10 2:37 PM Page 6

20 Amino Acid-Containing Degradable Polymers & Their Potential in Cotrolled Drug Delivery Aylvin A. Dias, PhD, MSc, and Marc Hendriks, PhD, MBA, indicate it is worthwhile evaluating both chemically degradable and enzymatically biodegradable polymers and scrutinize the in vitro and in vivo testing results to define the optimal system in the design of degradable polymer-based drug delivery systems.

26 United We Stand: the Power of Alliances in the New Normal Derek G. Hennecke, MBA, continues with part 2 of this 6-part series on business models and best practices for navigating the new normal.

28 Drug Delivery Products & Technologies, a Decade in Review: Approved Products 2000 to 2009 Josef Bossart, PhD; Kurt Sedo; and Tugrul T. Kararli, PhD, MBA; review what Drug Delivery has “delivered” in the past decade. An important perspective is provided by looking at drug delivery products approved by the FDA in the past decade.

37 In Vivo Delivery of Nucleic Acid-Based Agents With Electroporation Karen E. Dolter, PhD; Claire F. Evans, PhD; and Drew Hannaman believe in vivo EP is a robust, adaptable method for achieving 10- to 1000-fold enhancement in DNA uptake and expression in a variety of tissue types, and as such, may be able to overcome the suboptimal clinical potency observed with conventionally administered nucleic acid drugs.

42 Topical Delivery of Hydrophobic Drugs Using a Novel Mixed Nanomicellar Technology to Treat Diseases of the Anterior & Posterior Segments of the Eye “Using the criteria defined earlier, we come up Poonam R. Velagaleti, PhD; Eddy Anglade, MD; I. John Khan, PhD; with a total of 213 drug delivery products Brian C. Gilger, DVM; and Ashim K. Mitra, PhD; suggest this unique nanomicellar drug delivery platform presents potential opportunities approved in the past decade (191 of them for topical administration of additional hydrophobic drugs and the Enhanced and 22 Enabled). While some years ability to non-invasively target retinal and other posterior segment

Vol 10 Vol No 4 diseases. were higher and others lower, there seems to be on average about 20 or so drug delivery products 48 Incorporating Sorbents Into Drug Delivery May 2010 approved annually with the ighh point seen in Technology Adrian Possumato says it is becoming increasingly important for 2006 when 25 Enhanced and 3 Enabled products manufacturers to incorporate sorbent technology much earlier in were approved.” the product development and design process than has previously been the case. Drug Delivery Technology Drug Delivery Technology

6 p.28 5-9 DDT May 2010 TOC pages:DDT April 06 TOC 5-9.qx 4/30/10 2:37 PM Page 7 5-9 DDT May 2010 TOC pages:DDT April 06 TOC 5-9.qx 4/30/10 2:59 PM Page 8

Next-Generation Anti-Cancer Therapy 51 The Importance of Incorporating Aesthetics Into Topical Formulations Gary Watkins, MS, emphasizes that for a skin care product to be “The overall profile of KX2-391 on cancer successful, its sensory characteristics must be specifically developed and produced in a way that cells is that it inhibits cell growth, tumor appeals to the end users. cell spread (metastasis), as well as new 55 Performance Excipients: Finding a Role in the Pharmaceutical Future blood vessel formation (anti-angiogenesis). Drug Delivery Executive: Herman Mitchell, Director of Global We also found that KX2-391 inhibited Marketing for Mallinckrodt Baker, talks about his company’s unique performance excipient brand and its role in future pharmaceutical growth in tumor cells in which Src family technology. kinases had been knocked out. This meant 62 Merrion Pharmaceuticals: Validating Oral Delivery that there was likely a second mechanism Drug Delivery Executive: John Lynch, CEO of Merrion, discusses in addition to its Src-inhibition activity for how his company’s partnership with Novo Nordisk to develop both oral insulin and an oral GLP-1 analogue has helped validate its the superior profile of KX2-391 over multi- technology among the pharma community. kinase inhibitors like dasatinib.” 64 Non-ATP Competitive Kinase-Signaling Inhibitors & Oncology Drug Discovery & Development Allen Barnett, PhD, examines the design of potent (low nanomolar range) and selective Src-signaling inhibitors and identifies two potential clinical development candidates, attesting to the power of the technology platform.

68 Invetech: Creating Innovative Products That Redefine Markets Executive Summary: Andreas Knaack, Director of the Biomedical Instruments & Devices division at Invetech, discusses how the company is working with customers to redefine their market with breakthrough and innovative product design, development, and manufacture.

71 Meeting the Challenges of Antimicrobial Resistance Ron Najafi, PhD, suggests locally administered non-antibiotic anti- infectives, such as NovaBay’s Aganocide compounds, may be much

Vol 10 Vol No 4 more appropriate than antibiotics in situations where the infection or colonization is accessible and not yet systemic

May 2010 DEPARTMENTS

Market News & Trends ...... 12 Advanced Delivery Devices ...... 32 The AdminPenTM Microneedle Device for

Drug Delivery Technology Drug Delivery Technology Painless & Convenient Drug Delivery 8 p.64 Technology Showcase ...... 58 5-9 DDT May 2010 TOC pages:DDT April 06 TOC 5-9.qx 4/30/10 2:37 PM Page 9

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10 Drug Delivery Technology May 2010 Vol 10 No 4 Systems 3M Drug Delivery Drug 3M CorporationGenzyme BionumbersLLC ManagingDirector Division Vice PresidentViceDivision TechnologyDevelopment President,Vice New Josef Bossart,JosefPhD James Vaughan PhD PeterHoffmann, Schering-Plough Development Delivery & Life Cycle Life & Delivery TechnicalService Manager Senior Director,Senior Drug Laboratories MerckResearch MerckBioventures, Devices Delivery Drug Director,Senior ValeoPartners Partner Pharma SPI Development CommercialMarketing& President,Vice Global BASFPharma Solutions Shaukat PhD,Ali, DavidMonteith,PhD, Green,Philip PhD Bingham DebraMs. Chandar,Sarath MBA MBA MSc Technology Delivery Drug Director ExecutiveEditorial MSc Marino,Dan DPT LaboratoriesDPT Management Director,Pharmaceutical Solutions PharmaCatalent Process VP,Business & Strategy VP,ProjectMarketing& Development Upsher-SmithLaboratories Beth A-S.Brown, PhD, CornellStamoran MBA Iacobucci, Marc MS Xcelience Denver Kappel, LLC Kappel, & DavidsonDavidson, FoundingPartner PresidentCEO & TheLang Companies President&CEO University of ColoradoofUniversity PharmaceuticalSciences Professor,Departmentof Inc.,Groton Pfizer DirectorSenior Esq. CliffordDavidson,M. MBA DerekHennecke,G. Bermingham John A. Uday B.UdayKompella, PhD Horspool,Keith PhD University of Mississippi ofUniversity Pharmaceutics Departmentof AssociateProfessor& Chair Michael Repka,A. PhD,DDS Pharmaceuticals,Inc. SurModics Vice President,Vice Research Tom PhD Tice, at Austin at University of TexasofUniversity Professor of PharmaceuticsProfessorof Laboratories MerckResearch ParenteralDelivery Biopharmaceutics& ofDirector PhD James W.McGinity, Henry Y. Wu,PhD,MS Corium InternationalCorium PresidentCTO& Gary W.Cleary, PhD, PharmD,MBA ResearchFellow, R&D Der-YangPhD Lee, Technology,R&D Labs McNeilConsumer Healthcare, Johnson&Johnson Colorcon Technologies ModifiedRelease TechnicalGlobal Director, Eurand President,AmericaNorth PhD Rajabi-Siahboomi, Ali FraherJohn 10-19 DDT May 2010 Market News:Layout 1 4/30/10 2:38 PM Page 11 10-19 DDTMay2010MarketNews:Layout14/30/102:38PMPage12

12 Drug Delivery Technology May 2010 Vol 10 No 4 good fit with Precedex and further demonstrates Hospira's strong Hospira's demonstrates further and Precedex with fit good Squarer, Chief Commercial Officer, Hospira. "Dyloject is also a very a also is "Dyloject Hospira. Officer, Commercial Squarer,Chief and offersattractivereveand Hospira to leverage its Precedex sales force to promote Dyloject. promote to force sales Precedexleverage its to Hospira Precedex. Both drugs are marketed to anesthesiologists,enabling to marketed are drugs Both Precedex. agent, sedation FDAproprietary approval,US Hospira's and Dyloject, a post-operative pain management drug currently awaiting currently drug management post-operativepain a Dyloject, adv Javelin'svalueto shareholders. conditions, and Hospira believes the offer delivers a full and fair and full offerdeliversbelievesa the Hospira and conditions, distal part of the Optima Jet shaft facilitates the treatment of more of treatment the facilitates shaft Jet Optima the of part distal the on hydrophiliccoating procedures. advancedlubricious This minimallyinvasivedevicesin of maneuverability enhance most difficult lesions. difficult most ExecutiveCID.Officer, outcomes,”positiveMr.medical to said Franco Vallana,Chief further advance device deliverability in order to order advancedevicedeliverabilityin further to contributes Balloon PTCA Fluydo the on Coating Hydrophilic anatomies. complex Additionally,ComfortCoat DSM the Fluydo PTCA Balloon Catheter, both with CE marked and launched and marked CE with Catheter,both Balloon PTCA Fluydo Biomedical in improving the quality of medical treatments. Wemedical of quality improvingvaluethe in Biomedical DSM with partnership our extend to excitednewdevices,we are calculated on a fully diluted basis and other customary closing customary other and basis fullydiluted a on calculated Javelin'sof shares majority a of tender the on conditioned is H HospiraJavelin& Enter Definitive Merger Agreement D BiomedicalDSM ContinueCID& Advance toDeliverability Device on the European market last month. last market European the on the and System Delivery Stent Jet Optima the technologyon coating their commitment to support with innovatiwith support to commitment their Biomedical’sDSM and biomaterials in experience long-standing extensive evaluation of Javelin's business and its prospects. offerextensiveits The and evaluationJavelin's of business with CID based on the use of DSM ComfortCoat DSM of use the on based CID with stent Avantgarde last year and our continuous commitment to create stent to Avantgardecommitment continuous our and year last announcedthe companies have entered into adefinitive merger agreementproviding for the acquisition of Javelin by Hospira for $2.20 pershare in cash, or approximately $145 million. Hospira expects to commenceatender offer for all outstanding shares of Javelin common stockin accordance with the terms of the merger agreement. f synergies between Javelin's main product candidate, betweensynergiesJavelin'sproduct f main antage o antage "Dyloject would broaden Hospira's pain management portfolio management pain Hospira's wouldbroaden "Dyloject The acquisition of Javelintake of wouldto allowacquisition Hospira The “Our partnership with CID is based on our shared vision of vision shared our on based is CID with partnership “Our “Following the successful launch of our bio-inducer surfaced bio-inducer our of “Followinglaunch successful the The D The H deliverycompany, and Javelin Pharmaceuticals, Inc., recently ospira,Inc., aglobal specialty pharmaceutical and medication materials biomedical in leader global a Biomedical, SM science, recently announced the extension of its partnership its of extension the recentlyannounced science, ospira omfortCoat Hydrophilic Coating was designed to wasdesigned Coating Hydrophilic omfortCoat SM C SM e ntered into the merger agreement followingan agreement merger the into ntered nue a nue nd margin prospects," said Ron said prospects," margin nd new materials that lead that newmaterials ve r each and cross the cross and each ® Hydrophilic Hospira plans to market the product in the US, Canada, Latin Canada, US, the in product the market to plans Hospira function, and urinary retention. urinary and function, gastrointestinal the slowingvomiting,of and nausea sedation, America, and the Asia-Pacific region. These are areas whe areas region. are the These and Asia-Pacific America, Javelin may be required to pay MPI following termination of its of followingpaytermination MPI to Javelinrequired maybe that expenses stipulated certain and fee termination the paymentof reduce the need for traditional intravenous opioids. Opioids are intravenousOpioids traditional opioids. for need the reduce space." acute-care the to commitment of Europe, where rights are currently licensed to a third party.third a to licensed currently are rights where Europe, of merger agreement with MPI. with agreement merger Javelin'sfor million $4.4 and (MPI) Pharmaceuticals Myriad central to the management of post-operative pain, but are associated are but post-operativepain, of management the to central also markets Precedex and represent a good fit for Hospira's for fit good a represent and Precedexmarkets also with million for Javelin's repayment of the principal and accrued interest accrued and principal Javelin'sthe for repaymentof million approximately$8.3 Hospira, with merger a closing to activitiesprior Javelin'sfund operating to million $4.5 to Javelinup mayborrow strategy.acute-care and Precedex incurred under a similar fina similar a under incurred haemocompatible materials, expressed in a remarkable IP portfolio, IP remarkable a in expressed materials, haemocompatible biomedical materials for use in short- and long-term implantable long-term and short- in use for materials biomedical medical coatings. medical research, development, and clinical experience, allow CID to offerto allowexperience,CID clinical development,and research, of manyyears in gained expertise an with management a and medical devices.medical meet the present and future needs of the medical deviceand medical the of needs future and present the meet being dedicated to improving the quality of patient care and after- and care patient of quality improvingthe to dedicated being the investors a fair return and its customers the necessary tools to tools necessary the customers its and return investorsfair the a contributing to human welfare by improving the quality of patient of quality welfarebyimprovingthe human to contributing of DSM and its acquisition of Polymeracquisition The its and TechnologyDSM of Group, strengths and expertise the on Building industries. biopharmaceutical care through enabling innovation in medical solutions. innovationWeenablingmedical through in care look care and after-care through the development of innovative,developmentof the through after-care minimallyand care meet newchallenges. meet background in the field of implantable cardiovascularimplantable of d field the in background invasivetherapies. strong and A devices,procedures, implantable which is now known as DSM PTG, the company’sthe PTG, nowDSM knownis whichas portfolio product forward to collaborating with them on future technologies,”future on added them with collaborating forwardto includes coatings, drug delivery platforms, and a w a and platforms, delivery drug coatings, includes John Marugg, DSM Biomedical’sDSM Marugg, John Business ignificant adverse events, including respiratory depression, respiratory events,adverseincluding ignificant s Hospira would have global rights to Dyloject with the exception the with Dyloject to wouldhaverights Hospira global Dyloject is a proprietary non-opioid analgesic that will help will that analgesic non-opioid proprietary a is Dyloject Hospira and Javelin also entered into a loan facility under which under facility loan a into Javelinentered and also Hospira DSM Biomedical developsto novelBiomedical solutions DSM materials-based CID (Carbostent & Implantable Devices) is dedicated to dedicated Devices)is Implantable & (Carbostent CID rrangement entered into with into entered rrangement ncing a ncing irector for ComfortCoat for irector D ange of ange ide r ide ev ices and ices re H re ospira 10-19 DDT May 2010 Market News:Layout 1 4/30/10 2:38 PM Page 13 10-19 DDTMay2010MarketNews:Layout14/30/102:38PMPage14

14 Drug Delivery Technology May 2010 Vol 10 No 4 and customer base are a strong fit withComar, manufacturingandcustomerstrongandfit a baseareat Unicon’sfacilitywillcontinueexpanded. be and acquisitionThe theis DevelopmentDeal LiquidMedication Delivery Device Market. C ComarAnnounces Acquisition Universalof Container Corporation G GlaxoSmithKline,Isis Pharmaceuticals $1.5-Billionin Drug messengerRNA (mRNA) inhibitandproductionthe disease- of President and Head of Drug DiscoveryPresidentDrug Headofand GSK."IsisPharmaceuticalsat one or moreindicationsorone commercializedand throughpre-agreedto and is eligibleisand receiveto averageon million$20milestonestoin up nextComar’sstepin strategic plan,which began divestiturewiththe causingproteins. Isisrecently announcedPhasetrialIIIin datafroma per program up to Phase II proof-of-conceptprogramPhaseperIIto up (PoC). willhaveGSK the of its glassitsvialproductof line,focuses andorganicon growth and serving a Classaserving customers,listof A including pharmaceutical is a leaderantisenseina istechnology, thisnewand alliance willenhance salestargets. addition,In Isiswillreceive double-digittoup royalties companies,contract packagers, distriband antisensediscoverydrug developandseekoutplatformto new acquisitionswithinplastic pharmaceutical medicalandpackaging. assets from its current shareholders.assetscurrentfromits Cayey,Basedin Rico,Puerto optionlicensetocompounds PoC at responsible willbeand allfor our discoveryour thispromisingplatformin research area." on salesfromanyon productsuccessfullythatis commercialized. transactionleasedthearerealestate, manufacturing equipment, plant therapeuticsagainst targets seriousrareandfordisease, including further developmentfurther commercialization.and eligibleIsiswillbe to Unicon is a leadingUniconamanufacturer is high-quality of injection molded, infectiousdiseasessomeconditions and causingblindness. operations,management, employees.and operations,The productline, injectionblow molded, extrusionand blow andmoldedparts processesthroughRNAthe involved thatis b in receivelicensemilestonefeesand payments, totaling nearly $1.5 opportunitytargetto severecertain waydiseasesa in notthathas containers.Comar, Buena,basedinNJ, manufacturera isof The IsisdiscoveryThe platformdevelops the specific billion,eventthein programssixall a proprietarypharmaceutical pac previouslybeenpossible," saidDr. Pa programs,Isiswillreceive upfrontan$35 omar,Inc.recentlytransaction a announcedfinalized has it acquiringUniversal100%of Container Corporation’s (Unicon) Unicon’smarketendprimarypharmaceutical is packaging Antisensetherapies target proteinsthe involved diseasein "As a platform,Isisantisensethea"As approach offersexciting an us Under the terms of the agreement,thewhichof Underterms the covers sixtoup laxoSmithKlineIsisPharmaceuticals,and Inc.recently announcednewa strategic alliance thatwillapply Isisthe kaging with a leadershipkagingwitha position the in trick Vallance,Senior Vice- re successfullyre developed for -millionpayment fromGSK utors.Includedthe in uildingtheseproteins. rapiesthatbindto line of oraldispensers,lineof dosagecups,dropper assemblies, closures, and rapidorganic growth. Webelieve Unicon’s Comar’sand customer base the combinedthe entityfutureforgrowth,” saidMikeRuggieri, President will benefit from the choicesfromtheoffered willbenefit bycombined, our expanded otherpackagingprimary products manufactured9001:2008-ISO itsin productline.” of Comar. “Unicon is a perfect fit for our b Comar.ourforof perfect“Uniconafit is and 13845-registeredand facility. has 22 drugs in development.in drugs 22has developmentIsis'drug programs are target a specific protein in a diseaseproteinaprocess, in antisensetarget specific therapiesa packagingmanufacturer, currently servicingpharmaceutical,the do. Weretaincontroldiscoverythe of earlyand development ourof to welcometo Unicon’s staff customersandComarthefamily. to This compoundsalliancetheto targets frominceptionPoC. to focusedtreatingon cardiovascular, metabolic, severeand drugs whiledrugs working together high-qualityverywitha to partner preventproteinsynthesis byeliminating mRNAthetemplate the - or acquisitiongives businesshigh-quality,oura redundant facilityfor biotech,diagnostic, ophthalmic, healthcare, personal care,retailand neurodegenerativediseasescancer. and technologythesenewto therapeutic areas. Weparticularlyare excited maximizelate-stagevalueinthe drugs thedevelopment of and pattern thatguidespatternproductionthe protein. the of heterozygousfamilialhypercholesterolemia patients thatdemonstrated productionwhile alsoexpanding capacityourkeepwith toup pharmacymarkets. productItslineincludes multiple paten to workto noveltheon targets broughtalliance,"GSKtheto saidDr. commercialization." Stanley T.Crooke, ChiefChairmanandExecutive Isisof Officer the therapeuticthe effect thisapproach.of novelproductitsforpipeline partners.drugs its for and companyThe oligonucleotides,representnewclass.opportunity anafor drug c Pharmaceuticals."Thisalliance is has successfullyhas commercialized world'sthe first Wheremostothermedicines s are discoverydevelopmentand RNA-targetedof therapeutics, withIsis retaining omplementenhanceandComar’s existing productlinesposition and Comar is a 60-year-old,aComar is privately owned pharmaceutical plastic "Weexcitedareworking be to applytowithGSK antisense Isis is exploitingIsisis expertiseitsRNA in discover to developand RNA-targetedtherapeutics, antisenseor therapies suchas Thisalliance provides withaccessIsis'GSKexpertisetodrug in “Unicon’sproducts, production capabilities, facilityandwill responsibilitydiscoverythefor developmentand of mallmoleculesbiologics or that exactlydealwetypeofthe want to usiness,weand excited are antisenseand drug ts for itsforts our BIO-005 ƒDDT Ad 1/11/10 11:27 AM Page 1

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16 Drug Delivery Technology May 2010 Vol 10 No 4 PolymerTechnology ParticleSciences’ PharmaceuticalofVP Development. “The P ParticleSciencesAnnounces Acquisitionthe Uniqueof PEG-Based technologywe have acquired covers novel,ofset a biocompatible acquisitionversatilea of PEG-based technology. technologyThe PEGylatedpolymers allowing PEGylationthefor particles and of coversseriesPEG-graftedofacationic polymers thathave wide a biologicalsurfaces. Wefrom clientsthatourwillbenefit confident are varietyapplicationsof pharmaceutical thein arena. thisacquisition haveand alreadyseveralstarted development programsutilizing them.” suspensions,improve solubilitydrug bioavailability,and reduceand toxicityreticuland WithAnterior Uveitis E EyeGateCompletesPharma StudyIIPhaseEGP-437 of Patientsin daymajoritythe28,patients of achieved cellscoreszeroandof scoreof subjectsreceived singleEGP-437dexamethasonedoseofa(a derived uveitis,”studytheinvestigators,ofsaidone VictorPerez,L. MD, requiredchangestreatment.intraocularfurtherinno significant No AssociateProfessorOphthalmology of BascomthePalmerat Eye corticosteroidsolution) delivered fourdoselevelsofone at usingthe and ocularandtherapeutics, recently announced completionthePhase a of pressurecataractsignsofor formation were detected. Datafromthe Institute.“TheEGP-437encouragingdataisPhase II because not it EyeGateDeliveryOcularIIDrug Systemwereand followed 28for II study of its leadproductitsstudyofcandidate,II EGP-437,treatmentthe for of study will be presentedstudywillbethe at AssociationResearchfor in Visionand onlyshows promising efficacyb signsof days.Following singletheEGP-437 treatment, theabouthalfof anterioruveitis. OphthalmologyannualmeetingFortin Lauderdale Mayon 2010. 06, subjectsachieved anterioranw zerowithin cellscoreof2 d octors need a morepredictable,octorsneeda effective treatment severefor Toenrolledbethisrandomized in double-masked study, subjects neededhaveto non-infectious anterior segment uveitis wi adding to its portfolio of drug deliverydrug portfolioaddingitsofto technologies throughthe Sciencesarticleleading Inc.(PSI),apharmaceutical CRO, is “PEGylationrecognizeda is approachstabilize to drug yeGateprivatelyaPharma, heldventure-backed pharmaceutical companydeveloping non-invasivea deliveryoculardrug platform "Foruveitis patients,unmetmedical anthereis need, and ≥ 1.5 (on a 0 to 5 scale, 5 = worstbest).=scale, Enrolled= 5 5 0 toand 0 a(on 1.5 oendothelialsysteminteraction,” Lee,saidRobert ut addressesut compliance eeks.By th a cella th discovery clinic.theand services,focusingemulsions, on gels,particulates, drug/deviceand sometimenow, weandhappy very are performancewiththein and vivotolerability resultsseveralobtained in thusfar different systems. combinationproducts withadditional specialized capabilities in topicaldelivery.mucosalanddrug Throughfullrangeof a Tobolsteracquiredthe technology, we additionalhave filed formulation,analytic, manufacturingand services,Particle Sciences intellectualbothbroadenpropertytoextendand patent itscoverage,” added AndrewLoxley, ParticleSciences’ DirectorNew of providespharmaceutical companiescomplete withaseamless and Technologies. developmentsolution thatmini range of therapeuticsrangeof potential thehasandaddress to many anterior positiveresultshelpdemonstrate thationtophoretically delivered drugs meeting.2010,companyPhasesecondtheIItheofquarter In plansto predictableclinical responsetreating in severe uveitis." and posteriorand segment diseases. EyeGate beenstudiedhasoverIIin initiatemulti-centereyea dry Phasestudypatients.IIIin mayoffer ophthalmologists new treatment optionspatients."for 200 subjects and is the first oculariontophoretic subjectsfirst systemhave200thetois and completedeyestudiesPhaseII(dry uveitis). and iontophoresistechnology deliverto activean compoundeye intothe treatmentsunmetforocularmedical needs by employing EyeGatethe Phase II studies, one for dry eyestudies,anteriorPhase forIIdry oneforand oneuveitis, usingour under an investigationalunderan new(IND)application. drug companyThe II Ocular Drug DeliveryOcularIIDrug System,non-invasivea deliverydrug iontophoresistechnology deliverto EGP-437.,” saidStephenFrom, submittedanteriorthe uveitis studycompletedresultsdatafroma and issues,byproviding doctorthedirect controldosing. the of These PresidentChiefandExecutiv technology. EyeGateThe deliveryII systemcompis resultssugge Phase II study in dry studyPhaseinII ParticleScie “Particl EyeGate is the first company completeEyeGatetostudies Phasefirst IIthe using is EyegatePharmaceuticals, focuseddevelopingInc.ison "WepleasedarethatEyeGate successfullyhas completed two e Sciencesebeenworking has withthistechnology for st that the EyeGatethatthest delivery moresystemacould leadto nces is an integratedanncesis provider developmentdrug of eye end-of-patientsanFDAtheof to part as e Officer of EyeGateof Officer “ThesePharma.e mizes the time and riskbetweenmizestimeandthe atiblewidewitha 10-19 DDT May 2010 Market News:Layout 1 4/30/10 2:38 PM Page 17 10-19 DDTMay2010MarketNews:Layout14/30/102:38PMPage18

18 Drug Delivery Technology May 2010 Vol 10 No 4 release technology. TIMERx technology had its start in generics with generics technology.in release start its technologyhad TIMERx extended- for market the of segment important an drugs, generic of Penwest to leverage its drug delivery technology for the formulation the technologyfor delivery Penwestdrug leverageits to and CEO.“Thi and pharmaceutical industry,” Good,pharmaceutical L. Penwest'sJennifer said President its record for successful product introductions within the generic the within introductions product successful for record its commercialization of the products worldwide.products the of commercialization wellas as formulations, the of each for filings regulatory and trials, clinical manufacturing, for responsible be will markets, complex generic products for the US, EU,US, the and for products generic complex P PenwestSignsMulti-Drug AgreementGenerics With Alvogen identify and select up to five compounds for generic development.generic for compounds five to up select and identify development of each compound. each developmentof compound Penwest'seach for used technologymaybe TIMERx Alvogen, Inc. under which Penwewhich under Alvogen,Inc. receive milestone and royalty payments that are linked to the to linked royaltyare paymentsand that receive milestone and compounds upon agreed the Penwest selected. formulate will Subjects contract influenza as well as common cold viruses. viruses. cold common wellas as influenza contract who patients include to broadened nowbeen has study SG005 the cells, lung infect to influenza of ability the reduced significantly by and influenza viruses) are recognized as the key triggers of keytriggers the recognizedas are viruses) influenza and SNG001 Novemberthat in 2009 announcement the from S SynairgenInitiates TrialIIPhase With Inhaled InterferonAsthmatic in Beta the commencement of its first Phase II study of inhaled interferon inhaled of study II Phase first its of commencement the chronic obstructive pulmonary disease (COPD), recentlyannounced (COPD), disease pulmonary obstructive chronic onset of respiratory viral infection for the prevention or attenuation preventionor the for infection viral respiratory of onset the after subjects asthmatic to administered placebo to compared SNG001 inhaled of safety and efficacy the assess to aims and (SNG001) IFN-beta inhaled of exclusively formulation in-licensed beta (IFN-beta) for the treatment of exacerbations of asthma c asthma of exacerbations of treatment the for (IFN-beta) beta of asthma symptoms caused byrespirato caused symptoms asthma of respiratory viruses, including influenza. including viruses, respiratory enwest Pharmaceuticals Co. recently announced it has signed a signed has it recentlyannounced Co. enwestPharmaceuticals drug development and commercialization agreement with agreement commercialization developmentand drug ynairgen plc, the respiratory drug discovery and developmentdiscoveryand drug respiratory the plc, ynairgen company with a particular focus on viral defense in asthma and asthma in defense viral on focus particular a companywith "We are very pleased to be partnering with of Alvogenpartnering because be to "Wepleased very are Alvogen, the US-based pharmaceutical manufacturer of manufacturer pharmaceutical US-based Alvogen,the The Phase II study, known as SG005, uses the company’sstudy,the II uses Phase SG005, knownThe as Respiratory viral infections (primarily caused by common cold bycommon (primarilycaused infections viral Respiratory ulti-drug, multi-national agreement allows agreement multi-national ulti-drug, s m s st a st nd Alvogento have agreed ry viruses. Following viruses. on o ther international ther aused are pleased to be leveragingbe to pleased are agr eements with Otsuka Pharmaceutical Co., Ltd. workingon Ltd. Co., Pharmaceutical Otsuka with eements product, which was formulated using the Alza Oros technology.the Oros using Alza wasformulated which product, We XL Procardia Pfizer's to generic first the developmentof the demonstrated to improve mitochondrial function in vitro. Penwestvitro. in is improvefunction to mitochondrial demonstrated the development of difficult-to-formulate generic products with the with products generic difficult-to-formulate developmentof the also applying its drug delivery technologies and drug formulation drug technologiesand delivery drug applyingits also expertise of the team from team Alvogen."the of expertise Alvogen focused on generic drug development. drug generic on Alvogenfocused with agreement multi-drug this nowadd will and products, branded under licensing collaborations. licensing under addition to Penwest's growing drug delivery portfolio of developmentof portfolio Penwest'sdelivery to drug addition growing developing A0001, or a-tocopherolquinone, a developinga-tocopherolquinone, or A0001, Penwestsystem. currently nervous is the of disorders rare for primarilyneeds, medical unmet address that developingproducts and expertise to the formulation of its collaborators' product candidates product collaborators' its of formulation the to expertise Penwest currently has four individual research and developmentand individualresearch four Penwesthas currently partnerships. strategic broader upon built being is whichprograms, into the study on March 31, and the trial is expected to be completed be to expected is trial the and 31, March on study the into werevolunteersentered Kingdom. first United The the in sites trial during the summer of 2011. of summer the during contributor to the significant healthcare burden in asthma. in burden healthcare significant the to contributor trial (SG004), and wehavewehaveand evidencethat successfully(SG004), trial Synairgen. “In this study, we are aiming to correct an antiviral(IFN- an correct study,to this aiming “In Synairgen.weare exacerbations (rapid wor(rapid exacerbations presence of virus infections.” virus of presence the in SNG001 nowtest weantiviraldefenses; will the primed beta) deficiency.beta) Wehav of Executive Chief Officer Marsden, schedule,” Richard said results of Synairgen’s Phase I study in moderate asthmatics (SG004), Synairgen’sasthmatics of moderate results in study I Phase the lung. the in activationantiviraldefenses of confirmed analysisthat biomarker which showed that inhaled SNG001 waswelltolerated,the showedSNG001 which and inhaled that The collaboration agreement with valuable a Alvogenagreement represents collaboration The Penwest is a drug development company focused on identifying on developmentcompanyfocused Penwestdrug a is “We are delighted to have been able to commence this study on study this commence to “Wehaveable to been delighted are Confidence in the outcome of SG005 is strengthened bythe strengthened is SG005 of outcome the in Confidence The SG005 study is being conducted a conducted being is study SG005 The hown the drug is well tolerated in a safety a in welltolerated is drug hownthe e s e f symptoms), which are the major the are which symptoms), f sening o sening his valuableadvantageof in his TIMERx t number of clinical of number t a t c oenzyme Q10 analogQ10 oenzyme 10-19 DDT May 2010 Market News:Layout 1 4/30/10 2:38 PM Page 19 20-25-DDT May 2010- Controlled Release:Layout 1 4/30/10 2:39 PM Page 20

CONTROLLED RELEASE

Amino Acid-Containing Degradable Polymers & Their Potential in Controlled Drug Delivery By: Aylvin A. Dias, PhD, MSc, and Marc Hendriks, PhD, MBA

ABSTRACT Biodegradable polymers allow for avoidance of re-interventions related to removal of the drug delivery implant, and therefore minimize risk of complications and adverse events associated with long-term implantable materials. However, it should be noted that these benefits have to be weighed against potential risks caused by degradation products and intermediates. The manner in which degradation proceeds has an influence on drugrelease behavior and can influence the form the polymer has to adopt. Surface versus bulk degradation is dependent on whether the degradation is via a hydrolytic mechanism (eg, ester hydrolysis) or via an enzymatic mechanism. In case of degradation by hydrolysis, bulk degradation takes place, but can be controlled by exerting control over the rate of water penetratio n and material swelling, which is governed by the hydrophilicity of the polymer. In the case of enzyme- or cellular-mediated biodegradation, the mechanism is mainly via surface degradation and erosion. Enzymatic degradation can occur via hydrolytic or oxidative mechanisms. These degradation mechanisms can occur as a result of the inflammatory foreign body response that occurs upon implantation of the polymeric drug delivery system. Enzymes typically involved in biodegradation are esterases, proteases, elastases, and peroxidases. Thus, in the design of degradable polymer-based drug delivery systems, it is worthwhile evaluating both chemically degradable and enzymatically biodegradable polymers and scrutinize the in vitro and in vivo testing results to define the optimal system.

INTRODUCTION opportunity to tune the composition of another feature to control drug release the polymer to give random, is the molecular architecture that can Drug delivery materials to aid alternating, or block copolymers. Yet be used to generate linear, branched, pharmacotherapy utilize polymers to stabilize medication during F I G U R E 1 production and sterilization to obtain desired pharmacokinetics and/or achieve locally controlled and targeted drug delivery.1 Vol 10 Vol No 4 Polymers are preferred matrices for controlled drug delivery because of the large May 2010 degree of variables that can be used to tune release as well as achieve other functional properties. Polymers may be divided into linear (thermoplastic)

Drug Delivery Technology Drug Delivery Technology or cross-linkable (thermoset) polymers. In either of these two 20 classes, there is further Various mechanisms that contribute to the degradation of polymers. 20-25-DDT May 2010- Controlled Release:Layout 1 4/30/10 2:39 PM Page 21

20-25-DDT May 2010- Controlled Release:Layout 1 4/30/10 2:39 PM Page 22

hyperbranched, and comb-like polymers. F I G U R E 2 Finally, polymers can be formulated either as linear polymer blends, linear- cross-linked polymer blends (semi- interpenetrating networks), and blends of cross-linked polymers (interpenetrating networks). This tool box of parameters that can be used to adjust and manipulate polymers offers numerous possibilities to develop solutions when drug delivery needs have to be reconciled against a number of other requirements related to shape, mechanical properties, biocompatibility, process, and biostability. When considering polymers for drug delivery applications, an important Cross-linkable biodegradable polyesterurethane in which the amino acid side-group can be further feature is the form the polymer will have chemically modified for additional functionality. as a drug delivery matrix. Polymers can be fabricated into films, coatings, tablets, Degradation can occur by various Enzymatic degradation can occur via microspheres, nanoparticles, gels, mechanisms that can be classified enzymatic hydrolysis and enzymatic complex 3-D monoliths, and according to Figure 1. oxidation. These degradation mechanisms components, as well as polymer Erodible polymers are those in also occur as a result of the inflammatory prodrugs. So development of an eventual which the polymer mass or volume is lost foreign body response that occurs upon drug delivery matrix is a delicate by gradual dissolution of the polymer implantation of the polymeric drug interplay between the drug-polymer without actual degradation or cleavage of delivery system. Enzymatic oxidation is compatibility and the form required for chemical bonds. Biodegradation refers to the result of the phagocytic action of the selected method of administration. degradation of polymers in the presence inflammatory cells. Enzymes typically of enzymes, cells, or microorganisms. involved in biodegradation are esterases, Mechanical degradation often occurs proteases, elastases, and peroxidases. BIODEGRADABLE POLYMERS in conjunction with biological and/or There remains much debate on the chemical degradation. It should be noted pros and cons of hydrolytically In polymer-based drug delivery, a that in most cases, degradation proceeds degradable versus enzymatically or major area of research and development by multiple pathways and rarely via a biodegradable polymers. It has been is on design of biodegradable polymer single mechanism. The manner in which speculated that polymers that degrade via systems. Biodegradable polymers allow degradation proceeds has an influence on a chemical hydrolytic mechanism offer for avoiding re-interventions related to drug-release behavior and can influence much more control over degradation than removal of the drug delivery implant, and the form the polymer has to adopt. those that degrade via an enzymatic thus minimize risk of complications and Surface versus bulk degradation is mechanism. This is on the basis that the adverse events associated with long-term dependent upon whether the degradation inflammatory foreign body response in implantable materials. However, it should is via a hydrolytic mechanism (eg, ester both patient and implant site are variable. Vol 10 Vol No 4 be noted that these benefits have to be hydrolysis) or via an enzymatic However, polymers that enzymatically weighed against potential risks caused by mechanism. In case of degradation by degrade provide for better control over degradation products and intermediates. hydrolysis, bulk degradation takes place drug release due to their surface erosion- May 2010 The term biodegradable polymers is but can be controlled by exerting control based degradation behavior. In addition, rather all-encompassing, and often, over the rate of water penetration and enzymatically degradable polymers offer derivative idioms are interchangeably material swelling, which is governed by advantages in that they exhibit greater used when describing such polymers. For the hydrophilicity of the polymer. In the storage and packaging robustness when the sake of clarity, degradable polymers case of enzyme- or cellular-mediated compared to hydrolytically degradable biodegradation, the mechanism is mainly polymers, largely because of the latter’s Drug Delivery Technology Drug Delivery Technology are those in which bonds can be broken by chemical or enzymatic mechanisms. via surface degradation and erosion. sensitivity to moisture. 22 20-25-DDT May 2010- Controlled Release:Layout 1 4/30/10 2:40 PM Page 23

Thus, in the design of degradable F I G U R E 3 polymer-based drug delivery systems, it is worthwhile evaluating both chemically degradable and enzymatically biodegradable polymers and scrutinize the in vitro and in vivo testing results to define the optimal system of which to proceed. Polylactic acid (PLA) and copolymers with glycolic acid (PLGA) have been the most widely used materials for drug delivery. PLA- and PLGA-based systems are used as matrix reservoirs in Degradation of polyester urethanes showing reduced pH drop compared to analogous non-lysine- which drug is dispersed within the bearing hydroxyester-based microspheres, and the varying degradation rates obtained by varying the polymer materials and is released both by hydroxyester backbone. diffusion through the polymer and as the polymer degrades. mechanical properties, polarity, or limitations, amino acid-based polyester Whereas these systems have particular diffusion characteristics of the urethanes, polyester amides, and successfully demonstrated the ability to polymer. This has led to the incorporation polycarbonates were developed. deliver drugs in a controlled manner over of biological building blocks in prolonged periods of time, they are degradable polymers for medical associated with significant limitations for applications. Most notably has been the POLYESTERURETHANES further expansion of their use, related to incorporation of amino acid-based items such as acidic degradation products, building blocks. Amino acids offer more The incorporation of amino acids in the relative hydrophobicity, etc. than being biodegradable and polyurethanes originally stemmed from The follwing presents the next metabolizable building blocks; they may observations that supposedly biostable evolution in biodegradable materials that moreover provide one or more reactive polyurethanes were in fact degraded due are prepared via synthetic incorporation sites that allow further modification of the to inflammation-derived enzymatic of amino acid building blocks. The polymer to tailor physicochemical activity, thus generating non-natural and incorporation of amino acid building properties, tune cellular response, or serve often toxic amine-functional degradation blocks provides not only a natural as a handle for the chemical attachment products. The isocyanates used to produce degradation end product but the of functional molecules, including drugs. the polyurethanes resulted in non-natural possibility to address the limitations of Initial development on amino acid- amine degradation products and triggered the conventional degradable polymers. based polyamidoamines was complicated the development of isocyanates that A thermoset degradable polymer by their poor solubility and processability generated natural amine-based (polyesterurethane) and a thermoplastic as well as their low level systemic toxicity degradation by-products. These were most polyester amide both bearing amino acid upon degradation. To address these notably the use of butanediisocyanate and building blocks and their degradation characteristics are described. F I G U R E 4

AMINO ACID-BASED BIODEGRADABLE POLYMERS 10 Vol No 4

With degradation comes the release May 2010 of degradation products into the body, the toxicity of which should be taken into account when selecting building blocks used to synthesize a degradable polymer. The nature of the resultant degradation

by-products is as important as selecting Drug Delivery Technology A new generation of amino acid-based biodegradable polyesteramides for drug delivery and other building blocks for achieving desired medical applications. 23 20-25-DDT May2010-ControlledRelease:Layout14/30/102:40PMPage24 24 Drug Delivery Technology May 2010 Vol 10 No 4 60-micronmicrospheres prepared by lysinediisocyanate that generated emulsionphotopolymerization were modifiedtointroduce functionalities beattributed tothese amino acid-based putresceinand lysine, respectively, as degradedby hydrolysis inphosphate- bufferedsaline are shown inFigure 3. polyurethanesisthe reduced pHdrop degradationend products ofthe resultant relatedtoimaging ormolecular targeting, upondegradation. Thisreduced pHdrop Theresults show that the lysine- polymer. hasbeen demonstrated inboth coatings butalso, drugs can bechemically containinglactide glycolide-based andmicrospheres. Cross-linked 40- to blockscan provide one ormore reactive conjugatedtothe polymer this way. sitesthat allow further modification of thepolymer, such asisexemplified schematicallywith cross-linkablea aminoacid-based polyesterurethane in Figure2. Such polymers can befurther In vitro paclitaxel release profiles from cross-linked phenylalanine-based polyesteramide hydrogels polyesteramide phenylalanine-based cross-linked from profiles release paclitaxel vitro In in pure PBS buffer and in an alpha-chymotrypsin solution at 37 at solution alpha-chymotrypsin an in and buffer PBS pure in Oneofthe main advantages that can Furthermore,amino acid building 5 E R U G I F 3 maintainingthe same cross-link density, alsoshown inFigure 3. Variationsofthe three building blocks allowone tocombine the beneficial blocksnot only ensures safe degradation arebased onalpha-amino acids, aliphatic propertiesofboth polyamides and productsbutalso gives the resultant dicarboxylicacids, and aliphatic alpha- polyesters.Properties that can betuned polymersprotein-like physical properties. omegadiols asshown inFigure 4. arehydrophilicity, biodegradation, and urethanemicrospheres result inlowera biocompatibilityaswell asdrugrelease. pHdrop compared tothe analogous lactideglycolide micropheres. Furthermore,by changing the hydroxyesterbackbone, itispossible to changethe degradation rates while Thepresence ofamino acid building Aminoacid-based polyesteramides AMINO ACID-BASED ACID-BASED AMINO POLYESTERAMIDES o C. 5 4 polyesteramideshydrogel. Invitro release havebeen chemically modifiedand profilesofpaclitaxel inPBS buffer and formulatedtodeliver widea variety of photomicrographsofthe porcine thepolymer-coated stents with bare plasmidDNA binding, and second, they lookingatpolyesteramide nanoparticles polyesteramideshave been tested inchymotrypsin solution have been smallmolecule drugs and biologics. clinicalstudies asbiodegradable coatings coronaryarteries 28days following couldbeused inwide dosage ranges metalstents inpigs. Theseporcine extensivelyand showed good tissue and reportedasshown inFigure 5. andtheir ability totransfect rat smooth bloodcompatibility inapplications like Theirmain advantage isrelated tothe fordrug-eluting stents. Apartfrom small implantationwith polyesteramide-a preclinicaltrials reveal that the coatingsfor stents. Asanexample, the in factthey predominantly degrade by an musclecells revealed thatthese first, coatedstent andbare a metal stent are moleculedrugdelivery, more recently, polyesteramide-coatedstents had similar vivobiocompatibility was tested in enzymaticmechanism; because of polyesteramides have higha degree of showninFigure 6. porcinecoronary arteries by comparing arginine-basedpolyester amides were consequentialsurface erosion polyesteramidepolymers are inhuman injuryand inflammation scores tobarea developedfor their use asnon-viral gene degradation,drugrelease follows mainly Amongthis class ofpolymers, itisthe metalstent. deliveryvehicles. zero-orderkinetics. Asanexample, AA-BBheterochain polymers that offer paclitaxelhas been delivered from a thegreatest versatility interms of cross-linkedphenylalanine-based molecularlevel design totailor drug- releaseproperties. Thesepolyesteramides Theseamino acid-based Currently,amino acid-based 6 Exemplary 7 A recentA invitro study 5 20-25-DDT May 2010- Controlled Release:Layout 1 4/30/10 2:40 PM Page 25

F I G U R E 6 BIOGRAPHIES

Dr. Aylvin A. Dias is R&D Manager at DSM Biomedical, Geleen, The Netherlands, where he currently manages research in drug delivery and tissue engineering for ophthalmic and cardiovascular Photomicrographs of the porcine coronary arteries 28 days following implantation with a applications. He earned his BSc and PhD in polyesteramide-coated stent and a bare metal stent.6 Biological and Polymer Chemistry at the University of Kent at Canterbury. In 1994, without adversely affecting cell over chemistry, molecular architecture, after his PhD, he worked at Total Chemie on morphology, viability, and apoptosis. formulation, and processing methods to materials for food packaging. In 1996, he Rhodamine labeling of the plasmid fabricate these polymers into a given form joined DSM in the Netherlands. In the first 5 confirmed cellular incorporation via or shape presents one a unique ability to years, he worked on coating resins, optical fibre, and stereolithographic materials. In the endocytosis and revealed close to 100% design drug delivery solutions around the subsequent 4 years, he established the transfection efficiency. These are drug and therapy rather than the trial-and- biomedical research program and thereby was promising results, but further optimization error approach that has been pervasive one of the founding fathers of DSM of this delivery system is still required thus far. Biomedical. He managed the start-up of an application development laboratory in medical because most of the DNA remained in the coatings. The research program lead to the endocytotic compartments. Nonetheless, launch of two new medical coatings, a the high cellular uptake combined with ACKNOWLEDGEMENTS lubric ious coating, and an antimicrobial low toxicity suggests that polyester coating. Dr. Dias has over 30 patents and 20 peer-reviewed publications to his credit. amides also show much promise for use in The authors would like to thank Drs. Z. gene therapy. Gomurashvilli and B. Turnell for their Dr. Marc Hendriks is assistance on the polyesteramides, B. R&D and Technology Plum and T. Handels for their assistance Director at DSM SUMMARY on the polyesterurethanes. Biomedical, Geleen, The Netherlands, where he provides scientific and Amino acid-based biodegradable strategic leadership in polymers represent the next frontier in the REFERENCES establishing the use of polymers for drug delivery. The company’s R&D portfolio and ensuring it amino acid building blocks reduce the risk 1. Ratner BD, Hoffmann AS, Schoen FJ, Lemons JE. Biomaterials science. 2nd ed. An Introduction to encompasses the development of novel of toxic degradation products and provide Materials in Medicine. Elsevier, ISBN -10: 0-12-582463- polymeric materials and material technologies means to further chemically modify these 7; 2004. for the enhancement of existing and creation 2. Dias AA, Petit AA. Microparticles comprising a of new biomedical products or therapies. He polymers with additional functionality not crosslinked polymer. WO 2007/107358 A1;2007. joined DSM Biomedical in 2006 after spending least as a means to chemically bind drugs. 3. Dias AA, Boerakker M, Nijenhuis AJ. Polymers comprising polythioester bonds. WO 2007 /028612 15 years at Medtronic’s Bakken Research It is our strong belief that A;2007. Center in Maastricht, the Netherlands. During 4. Gomursahvili Z, Zhang H, Da J, Jenkins TD, Hughes J, his time with Medtronic, Dr. Hendriks served in hydrolytically degradable polymers as Wu M, Lanbert L, Grako KA, Defife KM, Macpherson well as enzymatically biodegradable K, Vassilev V, Katsarave R, Turnell WG. From drug various roles, including Research Director, eluting stents to biopharmaceuticals: poly(esteramide) a where he led various R&D projects on surface polymers will be needed in a drug versatile new bioabsorbable biopolymer. ACS Synposium modification technologies, drug delivery, and 10 Vol No 4 delivery company’s armamentarium of series 977; Polymers for Biomedical Applications. cross-linking technologies for bioprosthetic Mahapatro A, Kulshresthra AS, eds. ISBN 978-0-8412- solutions. There is no “one size fits all” in 3966-1; 2008. tissues; Manager of Biomaterials Technology; 5. Guo K, Chu CC. Controlled release of paclitaxel from Scientist, and Engineer. He holds over 25 US drug delivery; each pharmaceutical May 2010 compound, be it a small molecular weight biodegradable unsaturated pol(ester amide) polytheylene patents, with several more pending. He has glycol diacrylate hydrogels. J Biomater Sci Polymer Edn. also co-authored over 30 journal articles and 2007;18:489. drug or a large molecule biologic, brings a various book chapters in the field of 6. Lee SH, et. al. In-vivo biocompatibility evaluation of variation of challenges for designing an stents coated with a new biodegradable elastomeric and biomedical materials research. Dr. Hendriks optimal polymer-based controlled-release functional polymer. Coronary Artery Dis. 2002;13:237- earned his PhD and MSc from Eindhoven 241. solution. University of Technology and his MBA from 7. Yamanouici D, Wu J, Lazar AN, Craig Kent K, Chu CC, University Maastricht Business School. With both types of polymers Liu B. Biodegradable arginine based poly(esteramides) as Drug Delivery Technology non viral gene delivery reagents. Biomater. available, the diversity provided in control 2008;29:3269. 25 26-27-1-DDT May 2010-Reformulating Success:Layout 1 4/30/10 2:40 PM Page 26

United We Stand: the Power of Alliances in the New Normal Part 2 of a 6-part series on business models & best practices for navigating the new normal. By: Derek Hennecke, President & CEO Xcelience LLC

he headwinds of the New Normal meet us head on. Time-tested qualified CMC providers with - forgive my pun - the right chemistry. In players teeter. Some fall. My question to you is this: are you better February, we announced our partnership with Cambridge, Avantium, and Toff standing against the winds alone, or as a group? I am going to Beckloff Associates. Together, we formed an exciting new alliance called argue that in the New Normal, if you aren’t building solid relationships up Chemistry PlaybookTM, a streamlined approach to CMC solutions. We are and down stream, then it’s just a matter of time until the headwinds blow integrating services, processes, and paperwork to increase productivity you away. and save customers time, money, and headaches. Before I tell you about I’d be hard pressed to think of an industry wh ere going it alone is what this alliance is, let me be perfectly clear about what it’s not. better. Witness Toyota’s network of suppliers, Microsoft’s family of Chemistry Playbook is NOT: software developers, or Cisco, which has become a poster child for the alliance model. In the airline industry, three alliances have come to • A formal merger of four companies. All companies are constitute more than half of global passenger traffic. Alliances are the independent. new norm. So tell me, why does our industry use alliances so infrequently? I see • A one-stop-shop model. Each company in an alliance should be a this as an incredib le shortcoming - and opportunity for the drug recognized leader in its field. The expertise and development business. The lengthy drug development pipeline accountability remains within e ach company. is supremely suited to the formation of alliances. They are out • Required. Customers don’t have to use all the there - Eli Lilly was one of the greatest proponents of alliances, required companies. They are free to use one, pursuing relationships with networks of small companies to some, or all companies. address the problem of higher drug development costs and long approval lead times. Amylin, Lilly, and Alkermes are working together to develop a promising once-weekly, subcutaneous injection of Exenatide for the treatment of type 2 diabetes based on Alkermes' proprietary delivery technology. These working relationships were much less prevalent a decade ago, when the norm was to merge or go solo. In my own company, we have long seen these advantages, but the right group didn’t present itself until recently. That changed earlier this year, when we were able to put Vol 10 Vol No 4 together a group of highly May 2010 Drug Delivery Technology Drug Delivery Technology

26 26-27-1-DDT May2010-ReformulatingSuccess:Layout14/30/102:40PMPage27 assigned as Program Manager.Program as program assigned A is person point single a charts. Then Gantt submitted,byare linked quotes Coordinated project tasks are assigned betweenpartners. assigned are tasks project mapped,and and defined is strategy project t huge. simplyare process this in consumed hours RFQ is evaluatedre is byall RFQ through the entire process in an integrated an in process entire the through drug single a take to promises shop one-stop the savingswith of kinds these accomplish purchased other shops to fill in the gaps and gaps the in fill to shops other purchased offerings. The benefits of alliances through alliances of offerings. benefits The operating and cultures similar with CDAs (which are harmonized). the harmonized). Then CDAsare (which logisticsof API. the as such details, traditionallybothersome out smooth will person suppliers. single A individualof series a than rather contact one just with negotiating and months) weeksor of daysinstead takes process who those discard and needs heir (the time don’t,of savingvastamounts meet t meet only it workedway.onlyit that manner.If seamless Howtantalizing! and the distance, a shop. from one-stop Alluring expand their offerings in the chain. But the But chain. the offeringsin their expand the drug development are overwhelming.developmentare drug the The service complementary in philosophies risk inherent in it, and hope for the best. the for hope and it, in inherent risk derogatory term. Large companies ha companies Large term. derogatory purchase whateveravailable.purchase is Customers they so sale, rarelyfor are companies best usual approach for clients is to approach to is clients for approach usual complain that while some shops maydelivershops some while that complain each of the myriad of contract providerscontract myriadof the of each processes, and set out legal paramete legal out set and processes, agreements, confidentiality discuss individually,prices, negotiate bids, out put stands to excel. In an alliance like the like alliance an In excel. to stands high-quality, top people and efficient high-quality,and people top Chemistry Playbook, each shop is in itself a itself in is shop Playbook,each Chemistry the system, they are stuck with all the playersthe all with stuck are they system, the into suckedwhen But not. do others systems, stand-alone expert in one area. Weone in expert simplify stand-alone in it, forced to forced it, in parameters, etc). The client is free to pick to free is etc). client parameters, The legal agreements, (confidentiality documents client’sthe byharmonizing experience and choose among the alliance members who members alliance the among choose and raditionally started in one area and area one in raditionallystarted However,companies of union a IS it In the past, the industry has tried to tried has industry the past, the In Here’sworks.howweFirst,executeit Instead, one-stop shop has become a become has Instead,shop one-stop This is precisely where an alliance an preciselywhere is This ride w ride ith all the bumps and bumps the all ith nt partners. partners. A nt leva he rs. T ve copies. Master service agreements align on align agreements service Master copies. of retention and expectations, standard of data, methods, and materials betweenmaterials and methods, data, of flowthe manages manager program/project d termination and its effects,paymentterms its and termination jurisdiction, of state/country term, jurisdiction, of country and obligations,state negotiation with all. with negotiation involvingcompanies. all company.held is kick-offmeeting A sites. Each project manager is in charge in is manager project Each sites. the legal fees normally associated with t with associated normally fees legal the limitations of liability.of limitations and indemnifications, warrantees, and the other players, tensions will emerge.players,will other tensions the effort to make it work. The second is that the that work.is it make second to The effort all alliances fail, and an additional 30% are 30% additional an and fail, alliances all of percent Fifty thing. good a are alliances Project Manager is assigned from each from assigned is Manager Project client. the A from be can or companies the of one within from be can manager and a substantial something. At the risk of risk something. the substantial At a and everyone- for it in something be must there that is first keyfactors. The three addressed while the project is in his/her facility.his/her in is project the while talking a quarter of the time and a quarter of quarter a and time the of quarter a talking stating the obvious, the alliance must add must alliance obvious,the the stating with all partners, making the hand-offfrom the making partners, all with Weekly/bi-weeklyheld are teleconferences levels. This should come naturally from the naturallyfrom levels.come should This senior the ownershipat clear down with CEO the from commitment organizational showstrong must companies member described as struggling. Let’s struggling. the as it, described face bottom line. If that’sIf line. success bottom then happening, customers. valueto That’ssubstantial the company to company easy. companyeasy. companyto doesn’talways way.workthat a is there If it but benefits, substantial aforementioned human race doesn’t have a fabulous track- doesn’t race havefabulous human a should flow to all of the member companies. member the of all flowto should agreements agree on terms and terms on agree agreements Confidentiality documents. harmonized of major player in one company that isn’tcompanythat playerone major in record for getting along with everyone.with along getting for record If all players benefit significantly,will they playersall benefit If willing to dedicate the people, capital, and capital, people, the dedicate to willing Chemis successes? established are that alliances be willing and e and willing be intell ocuments. A negotiation of one term is a is term one of ocuments. negotiation A roperty to the same degree as degree same the to roperty ectual p ectual It’s important to note that not all not It’sthat note to important With four companies involved,companies Withfour we’re I can’t stress enough the customer valuecustomer the can’tenough I stress What attributes characterize the 9% of 9% the characterize attributes What try Playbook has identified and identified Playbookhas o put in the time and time the in put o ager t ager om then on, the on, then om Fr o n-going hese Strategic alignment and fit is also a also is fit and alignment Strategic companies have both the capital and the and capital havethe companies both ability to do so alone in all segments of their of segments all in alone so do to ability investment.on Few return adequate generate and compete to able be to volumes significant and share quicklyachieveglobal requirement. We all have to be heading in the requirement. Wein heading havebe all to value chain. In the New Normal, success will success NewNormal, the In valuechain. to companies require cycles life Shortened chain needed to grow profitably.grow to needed chain come to those companies who do one thing one do who companies those to come some degree of divergence, as long as they as divergence,long of as degree some mayhavecultures Corporate direction. same and do it extremely well, while uniting with extremelywell,uniting it while do and partners to compl to partners are able to establish and environmentof and establish to able are product life cycle, you should expect to see to expect should youcycle, life product trust. more alliances like Chemistry Pl Chemistry like alliances more anti-infectivesplant that was originally slated for internationalturn-around manager in the decadesof international experience in the healthcare scientificand business background with nearly 2 Egypt,as GM, he oversaw aradical turn-around in an Tampa-basedbusiness while also overseeing a foundingXcelience, Mr. Hennecke managed the same theY coveted whenMr. Hennecke was selected as afinalist for the growth.This growth was recognized in May 2008, andGermany. Mr. Hennecke earned his BSc Rotterdam,The Netherlands. industryand atrack record as ahighly successful staffBiologics plant for more than 2years. In Cairo, conglomerateDSM. In Montreal, he was GM of a25 than10 years abroad working for the Dutch-based Biopharmaceuticals.Prior to that, he spent more andGeneral Manager, Pharmaceutics and Seattleand aMontreal-based plant as Vice President BayChamber of Commerce, also this year. Before ofinnovation, financial performance, personal demonstrationof extraordinary success in the areas immediatelyembarked on arobust pattern of strong PharmaServices in 2006. The newly formed company havinglaunched amanagement buy-out from MDS developmentcommunity. Xcelience is the first America.He also worked for Roche, both in Canada asCommercial Director covering Central and South newPharma intermediates, and two years in Mexico closure.He also spent 2years in Holland developing Canadaand his MBA from the Erasmus University in Microbiologyfrom the University of Alberta in commitmentto community, and the company’s companyMr. Hennecke has managed as an owner, for in2008. This is in addition to Xcelience’s nomination UltimateCEO Henneckewas also recognized as afinalist for the perpetualgrowth since its official formation. Mr. SmallBusiness of th I believe with the ever-shrinkingthe believewith I ear 2008Ernst &Young Florida Entrepreneur of award,anomination based on the Y H P A R G O I B awardsby the Tampa Business Journal he pieces of the valuethe of pieces he ete t ete eYear theworld. He balances a strongbusinesses around longhistory of growing Xcelience CEOand President. He has a Xcelienceand its current President & CEO & President Derek G. Hennecke, MBA foundingmember of DerekG. Hennecke is a bythe Greater Tampa book. ay global drug u in 0-

27 Drug Delivery Technology May 2010 Vol 10 No 4 28-31-DDT May 2010-Delivery Report:Layout 1 4/30/10 2:41 PM Page 28

DeliveRy RePoRT Drug Delivery Products & Technologies, a Decade in Review: Approved Products 2000 to 2009 By: Josef Bossart, PhD; Kurt Sedo; and Tugrul T. Kararli, PhD, MBA

ith the new decade upon us, it seems a good time to review what Drug Delivery has “delivered” in the past decade. An important perspective is provided by looking at drug delivery products approved by the FDA in the past 10 years. The Wdefinition of Drug Delivery Product is open to many positions and opinions. For the purpose of this review, the working definition is a pharmaceutical product that depe nds on a novel formulation technology that deliberately impacts uptake, distribution, or excretion so as to realize a desired therapeutic effect, or improve convenience. We will separate our analysis into two separate areas: (1) products that primarily depend on drug delivery to enhance, expand, or transform their utility (Enhanced) and (2) products that depend on drug delivery technologies to enable their usefulness (Enabled).1,2 Examples of Enhanced technologies are those targeted to improving efficacy, safety, tolerability, and convenience or compliance. These include sustained-release oral dosage forms and 28-31-DDT May2010-DeliveryReport:Layout14/30/102:41PMPage29 s Enabled). 22 and A Enhanced them of (191 decade past approvedthe products in presented in presented Tableyears some 1. While make them difficult to analyzeand to difficult them make that standards regulatory widelyvarying yo are source. excluded to Also difficult more consistent and Reliable injectors. come up with a total of 213 drug delivery drug 213 of total a with up come d include not does Enabling technologies, the focus is on is focus technologies,the Enabling of case the In patches. transdermal compare. to subject are products these products, US publiclyex-availableless on information pump inhibitors. Once again, wesugg again, Once inhibitors. pump proton with used technologyas coating enteric simple wouldexamplebe An toolbox. formulation standard the of part a become have,time, technologiesthat with solelyon depend that products much is products these on information and notablystents products, delivery hasn’t, been included. This still leaveshasn’t,included. still us been This and has, what understand to products such as solubility and bioavailabilityand and solubility as such improvecan parameters technologiesthat include nano- and microparticle and nano- include using transdermal, inhalation, oral, inhalation, transdermal, using deliverydrug of number large a with this article are availableare online. article this for used products Enhanced and Enabled the for technologies.lists product The NDA (not ANDA) products is grounded in NDAgrounded (not is ANDA)products technologies.sustained-release injectable and quick-dissolve, sustained-release, those consider,including to products based a desire for desire a ummary of products approvedproducts is byyearof u check the online compilation of compilation online the check u Using the criteria defined earlier,we defined criteria the Using analysisthis It’sthat note to important This article’sThis FDA-approvedon focus FDA-APPROVED DRUG DRUG FDA-APPROVED DELIVERY PRODUCTS PRODUCTS DELIVERY evice-focuseddrug onsistency.there onlyis Not c (2000-2009) 3 est for about one third of the Enabled the of third one about for variety of solubilization technologies.solubilization varietyof bya up made balance the with products, average about 20 or so drug so or average20 about on lower,be to seems there nanoparticle technologies each accounted technologieseach nanoparticle a tail-offin a of bit a Despite 25 when 2006 in seen point high the annuallywith approvedproducts delivery others and werehigher 2%. Of the remaining 48%, inhalation 48%, remaining the Of 2%. SR liquid oral and 12%, ODT 38%, for delivery systems (SEDDS) and (SEDDS) systems delivery the past couple of years, of couple past the wereapproved.products Enabled 3 and Enhanced injection 9%. Of the inhalati the Of 9%. injection and 12%, transdermal 13%, for accounted accounted formulations modified-release the averagethe number overin obviouschange time anybe doesn’tto there seem enhanced products, sustained- and sustained- products, enhanced approvedoral products. these Among all of 52% for accounting common, MDIs and nebulization accounted for 5% for accounted nebulization and MDIs delivery products, oral delivery wasmost delivery oral products, delivery for 3%. for accounted DPIs while total, the of 4% and pr approved22 the of 32% injectables and implants. byfor wasaccounted 4% remaining each. 5% The with products nasal and formulated products accounted for 68% for accounted products formulated and inserts for total this in included not are stents Drug-coated inserts. and implants nnual approvals.nnual oducts i oducts n this class. Self-emulsifying class. this n Of the Enhanced products, 21% were21% products, Enhanced the Of Among the approveddrug the Enhanced Among Lagging behind werebuccal/lingual behind Lagging For the Enabled products, oral products, ForEnabled the DELIVERY ROUTE DELIVERY ANALYSIS BY BY ANALYSIS of on gr on oup, FDA-Approved Drug Delivery Products (2000-2009) Products Delivery Drug FDA-Approved Total 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 191 191 Enh Pr i transdermal for hormone replacement). hormone for transdermal were intended to provide a sy providea to were intended 79%, products, asthma). remaining The for inhalation effect(ie, therapeutic locoregional or local providea to intended Only one of the 22 Enabled technologyEnabled 22 the of Onlyone applications. systemic wereto targetedproducts remaining activity;the locoregional or local for approvedwasintended products products. The CNS products wereproducts products. CNS The approvedall two-thirdsEnhanced of targeted to targeted ADHD-t often release, technologies.Modified (7/53) buccal/lingual or (10/53), dissolve oral quick (26/53), release modified- or sustained- using products primarilyconvenience-enhanced oral almost cardiovascularcomprising (10%); (12%), endocrinology (11%), and endocrinology(11%), (12%), accounted for 6 of the 53 approved53 the of 6 for accounted products were CNS (28%), respiratory (28%), wereCNS products Enhanced CNS products. CNS Enhanced indication is presented in presented Tableis both indication for 2 Enhanced and Enabled products. big Enabled The and Enhanced indicat ndication (ie, oral for incontinence or incontinence for oral (ie, ndication odu 3 3 2 1 3 17 4 17 2 24 1 25 3 19 1 23 2 17 15 15 19 an ANALYSIS BY INDICATION INDICATION BY ANALYSIS The distribution of approvalsof by distribution The ce cts 1 E L B A T ions f ions or Enhanced drug delivery drug Enhanced or d

Pr & DELIVERY & Enabled odu 22 ype a ype pplications, cts

stemic 3 213 All 20 19 25 28 23 15 18 18 16 21

29 Drug Delivery Technology May 2010 Vol 10 No 4 28-31-DDT May 2010-Delivery Report:Layout 1 4/30/10 2:41 PM Page 30

Almost all respiratory products were T A B L E 2 immediate release (22/23). Among the Enhanced Enabled endocrinology products, (18/21) were All intended to provide an extended-release Products Products Allergy 11 0 11 (5%) profile, while cardiovascular Enhanced Cancer 9 0 9 (4%) products primarily targeted SR applications CNS 53 3 56 (26%) (13/19). Of the 22 Enabled products, all Cardiovascular 19 8 27 (13%) but one were targeted to immediate-release Endocrinology 21 0 21 (10%) indications. Gastrointestinal 8 2 10 (5%) Infectious Disease 12 5 17 (8%) DRUG DELIVERY TECHNOLOGY Neurology 14 0 14 (7%) SOURCING Respiratory 23 0 23 (11%) Urology 8 1 9 (4%) Other 16 3 19 (9%) It’s interesting to look at how many of FDA-Approved Drug Delivery Products by Indication (2000-2009) the Enh anced products approved in the past decade depended on external technology. and/or commercialization. Companies like companies for further development or What we mean by external technology is a DepoMed and NovaDel are examples of commercialization, but the ir roots trace technology sourced from a third party by a smaller companies considered to have back to drug delivery companies. development company to develop its own sourced their drug delivery technology The leading providers of drug delivery drug delivery product. This would include internally. But by far the largest number of technology to external development a Big Pharma or Specialty Pharma these internally sourced drug delivery companies are presented in Table 3. These company working with an outside technology products arose within Big and other companies also provided the company to access necessary drug delivery Pharma who have internal teams able to technology for products not captured in know-how or intellectual property. It would provide at least the more common drug this review, notably OTC and ex-USA not include a simp le contracting delivery technologies. products. arrangement related to production in which If we look at the data in terms of Cima had a great run of oral dissolve- the drug delivery know-how did not reside products that have arisen from technologies based products starting in the late 1990s with the third party. discovered and developed by drug delivery that continued through the middle of the Based on this definition, about one companies, we find more than half of the decade, but Elan powered the greatest third of approved products looked to 212 approved products are the direct result number of approved drug delivery outside providers for the drug delivery of drug delivery company-derived products. Elan’s strength was a broad technology incorporated into their technologies. Many of these products and portfolio of drug delivery assets that could products. The remaining two thirds used technologies and products were passed on both enhance and enable their clients’ technology already in their portfolio, or to Big Pharma and Specialty Pharma products. they developed internally for use as part of the product concept. T A B L E 3 The large number of internally sourced drug delivery technologies may be Enhanced Enabled Vol 10 Vol No 4 Company Total surprising and warrants explanation. Many Products Products pulmonary products, particularly those Elan 5 6 11 Cima 10 0 10 May 2010 from experienced Big Pharma companies, SkyePharma 6 1 7 such as GlaxoSmithKline and AstraZeneca, 3M 6 0 6 were developed using internal technology. Eurand 5 0 5 There were also a large number of Nektar 5 0 5 companies that conceived and developed Catalent 4 0 4 their products before licensing them out to CyDex 0 4 4 Drug Delivery Technology Drug Delivery Technology a third par ty for further development Approved Product Technologies by Technology Supplier (2000-2009) 30 28-31-DDT May 2010-Delivery Report:Layout 1 4/30/10 2:41 PM Page 31

3M was the go-to company for MDI predict. The most common form of non- BIOGRAPHIES companies, while SkyePharma and Eurand specific inhalation, jet nebulization, will provided their partners with a broad probably not warrant mention, but the new Dr. Josef Bossart is portfolio of validated, often oral, drug electrosonic devices may well define levels Managing Director of Pharmanumbers LLC, a delivery technologies. Interestingly, the of performance that could prove very boutique research and Nektar technology most often incorporated important. Similarly, inhalation delivery consulting group providing the into its partners’ approved products did not for the treatment of systemic diseases and biopharmaceutical arise from their considerable pulmonary the delivery of macromolecules will be industry with analysis and insights that improves expertise, but rather the PEGylation important and unarguably big business for business outcomes. In addition to issuing technology they added with their companies possessing the technology, industry reports, such as DD09 - Drug Delivery Product Success Rates, Development Times, acquisition of Shearwater in 2001. know-how, and intellectual property Costs and Marketing Exclusivity under its Catalent’s claim to fame, like Cima’s, was protection to power these products. Bionumbers division, Pharmanumbers provides strategy consulting and forecasting support with ODT technology. CyDex was a leader Simple transdermals, topical creams, for emerging and commercial-stage biopharma in the solubilization technology area. and gels intended for systemic delivery, may companies. Dr. Bossart has more than 3 decades of experience in the not warrant mention 10 years from now. biopharmaceutical sector, including senior REFLECTIONS Active transdermal products will certainly be sales, marketing, business development, and management positions with Enzon included on any list if they are able to Pharmaceuticals, GeneMedicine, US Ethicals, That’s it, a quick overview of efficiently deliver macromolecules or provide and Rhône-Poulenc Rorer. Dr. Bossart earned his PhD in Medicinal Chemistry from The Ohio prescription drug delivery products unique features, such as dose on demand. State University, College of Pharmacy. approved in the past decade. There And speaking of macromolecules, Mr. Kurt Sedo is a certainly were many more drug delivery- there certainly will be a warm reception Director at PharmaCircle based products approved beyond this for companies able to enhance and enable LLC. He earned his BS in Chemistry and Mathematics group, notably branded OTC products and the delivery of siRNA, oligonucleotides, from the University of generic formulations (prescription and antibodies, and proteins by either Wisconsin Stevens Point. Prior to joining OTC). A nd there are also the integrated injectable or non-injectable delivery routes. PharmaCircle in 2003, he drug/device products. These products All in all, it has been a great decade held various R&D Scientist positions within define their own group of opportunities for Drug Delivery, but the success of this Searle/Pharmacia’s Pharmaceutical Sciences and warrant separate analysis and next decade will depend on developing Department in Analytical Development and Drug Delivery. discussion. Many of these products, innovative technologies that deliver next- notably drug-coated stents, have provided generation patient benefits rather than Dr. Tugrul T. Kararli earned his PhD in important therapeutic benefits and simply exploit technologies of the past Pharmacology from the recorded remarkable sales. decade. Like Big Pharma, Drug Delivery University of Florida in 1984 and his MBA from What might we see if we were to do a needs to continuously renew itself or risk DePaul University in 2000. similar review a decade from now? Here becoming irrelevant. Dr. Kararli worked at Searle/Pharmacia for 18 are some predictions. It is likely that many years and held various of the most important technologies of the REFERENCES positions and responsibilities within the Pharmaceutical Sciences department, past decade will become part of every participating in pharmaceutics, product company’s formulation toolbox. Much as 1. Bossart J. Benchmarking drug delivery development, and drug delivery activities. As

the Chairman of the Global Drug Delivery 10 Vol No 4 enteric coating technology is now a - defining the potential of drug delivery. Technology Team at Pharmacia, he was standard toolbox technology, it is Drug Delivery Technology. responsible for identifying, planning , and executing the drug delivery technology reasonable to expect formulators will have 2005;5(3):22. strategies for marketed and development May 2010 some collection of oral SR and ODT 2. Bossart J. Benchmarking drug delivery products. Dr. Kararli has authored 20 research articles on various aspects of pharmaceutics technologies available for use without - defi ning product benefit and value. and drug delivery and holds more than 13 US calling in external assistance. Whether oral Drug Delivery Technology. and international patents. Currently, he is the Founder and President of PharmaCircle LLC, a ODT and SR products will even warrant 2005;5(2):22. knowledge management service company in listing on the next decade’s list of approved 3. Website www.pharmacircle.com/DDT- the drug delivery and pharmaceutical/biotechnology fie lds. Drug Delivery Technology drug delivery products remains to be seen. 2010-05. 31 Inhalation technologies are harder to 32-36-DDT May2010-AdvancedDelivery:Layout14/30/102:42PMPage32

32 Drug Delivery Technology May 2010 Vol 10 No 4 The AdminPen The By: Vadim V. Yuzhakov,PhD Convenient Drug Delivery Drug Convenient thatpainlessly and conveniently injects Nevertheless,the earlier developed A withmany subjects have shown that the liquiddrugformulations, and therefore microneedlearrays are essentially painless pharmaceuticaldrugs orcosmetic actives ther microneedletechnologies are not well thatawide range of pharmaceutical unclearand lengthy regulatory approval cosmeticdermal (hyaluronicfillers acid drugdelivery devices. Thecurrent pipeline suitedfor commercialization because of throughthe skin. Thisbreakthrough compoundscan be delivered using andhave no adverse side effects. processes. technologyrevolutionizes the way inwhich microneedlearrays, including small comprisesanadvanced microneedle array- veryhigh manufacturing costs due touse andPMMA micro-spheres) would be medicinescan beadministered, increasing asClassa IImedical device with 510(k)a excellentinitial indications for this device. molecules,peptides, and proteins. ofexotic fabrication techniques, need for basedpen-injector device (the AdminPen efficacy,safety, and compliance. regulatoryapproval route and can be significantchanges indrugformulations economicallyproduced toscale using duetotheir inability todeliver stand maturehigh-volume low-cost processes. Theinjection ofvaccines (influenza, HIV, cancer,smallpox, and anthrax), hormones (PTHand hGH), insulin, obesity- mana A apeuticlevels ofstandard liquid Previousstudies have demonstrated AdminPenisexpected tobeclassified gementdrugs (leptin, liraglutide), and dminMedisdeveloping an innovativeline ofnovel microneedle-basedtransdermal 4-6,17 1-3 4-16 Studies ard TM TM Microneedle Device for Painless & Painless for Device Microneedle ) hoursneeded for the currently marketed amountsofdrugainshorta period oftime transdermalpatches. Existing transdermal similartostandarda injection with a patchesare limited tousing only verya few hypodermicneedle. Bycomparison, (lessthan 10compounds are currently conventionaltransdermal patches deliver beingdelivered indrugpatches), small onlysmalla fraction ofthe pharmaceutical molecule(<500 Daltons), lipophilic drug conventionalliquid-reservoir microneedle ingredientincorporated intransdermala formulationsthat can cross intact skin ata transdermalpatch that can beattached toa patch.Inaddition, the technology can fluxsufficient tobeclinically useful. delivertherapeutic levels ofpharmaceutical standardsyringe. One substantial difference drugsin10to 60 seconds versus the fromstandarda transdermal patch isthat thisinnovative AdminPendrugdelivery d evicewill have the ability todeliver large AdminPatch Thesystem substantially mimics a ® 300 Microneedle Array (left: drawing, right: SEM image) SEM drawing,right: (left: Array Microneedle 300 1 E R U G I F 1 to12 (TheraJect,Corium). prop generallyfall into one ofthree design stratumcorneum toovercome its barrier categories:(1) microneedles with centrala properties.Inparticular, several companies, hollowbore that are similar inshape to including3M, NanoPass, Zosano, conventionalhypodermic needles butmuch TheraJect,and Corium, aswell asacademic smaller(3M and NanoPass); (2) solid groupsatthe University ofCalifornia and microneedlescoated with speciala atthe Georgia Institute of Technology,have pharmaceuticaldrugformulation (Zosano); beenworking onthe development of microneedlearrays that would make largea and(3) solid biodegradable microneedle numberoftiny holes inthe stratum arraysthat have drugaencapsulated inthe corneum. dissolvablemic osedfor making small pores inthe Theseknown microneedle arrays Severalmethods have been recently Hollowmicroneedles with centrala MICRONEEDLE ARRAYS MICRONEEDLE BACKGROUND - - BACKGROUND roneedlematerial 32-36-DDT May 2010-Advanced Delivery:Layout 1 4/30/10 2:42 PM Page 33

F I G U R E 2 product development timelines; very expensive and long-term clinical efficacy, drug toxicity, and stability studies; as well as an unclear regulatory approval pathway. Biodegradable microneedle arrays are made of a material that encapsulates the drug and dissolves when inserted into skin. This approach also requires completely reformulating the drug. In addition, there exist significant technical difficulties and risks in designing a biodegradable material that would be strong enough for inserting into the skin without breakage and would be compatible with a specific drug. And of course, a completely new microfabrication method should be developed for making such arrays in high volumes. Moreover, such biodegradable microneedles arrays would be subject to even more intense scrutiny from the FDA that would lead to even longer product development process. AdminPatch® Microneedle Array Also, the skin of a patient is quite flexible. Thus, it may be difficult for other bore are expensive to make and require exotic arrays of projections that are used to make microneedle arrays having a rigid, planar and expensive microfabrication methods. In holes in the stratum corneum. Since 1996, substrate to be inserted uniformly into skin particular, it is difficult to make sharp tips on Zosano (previously a part of Alza during the application step when the hollow microneedles. Consequently, insertion Corporation) has developed a method of microneedles in the central area of the array of the microneedles into a patient’s skin can be depositing a drug directly on the surface of may not have sufficient engagement with difficult and often painful. In addition, the these solid microneedles. However, the deformed concave skin tissues. For example, a central bore of the microneedle is quite small deposition process is unreliable, and the thin microneedle array having a base made of and may be easily plugged by skin tissue layer of drug formulation on the microneedle silicon is flat and inflexible, and even though a during the insertion process, thereby blocking could be easily chipped off during storage, polymeric or metal microneedle base can be the drug delivery conduit. Furthermore, transport, or administration (insertion) of the slightly bent in one direction, such arrays of because the length of microneedle central bore microneedles. Although demonstrated on a microneedles cannot readily be applied to is much greater than its diameter, the laboratory scale, the high-volume microneedle concave skin surfaces formed during the diffusional transport of the drug through the coating process itself is very complex, insertion step. The microneedle array may

central bore may be unacceptably slow. It may unreliable, and expensive. Application of a need to have a convex shape to ensure uniform Vo be even slower than the diffusion of the drug thicker and stronger layer of drug formulation insertion of all microneedles into the skin through the stratum corneum in the absence of was found to be undesirable because it during the application step. l 10 No 4

the microneedle. To our knowledge, only two reduced the sharpness of the microneedles and It therefore would be desirable to provide May 2010 companies were able to fabricate hollow therefore made insertion more difficult and a microneedle array for drug delivery that microneedle arrays. NanoPass fabricated painful. Zosano even disclosed a special avoids the disadvantages associated with silicon micro-pyramids with internal lumen insertion device because patients were unable known solid and hollow microneedle array using an exotic microfabrication technology, to insert the microneedle array by themselves designs as well as can be flexed and stretched and 3M made samples of plastic microneedle without it. Most importantly, the drug-coated to better conform to a convex, contoured, or

arrays using its proprietary technology. microneedles require completely moving surface. In summary, there is an Drug Delivery Technology unmet need for a painless, effective, user- Solid microneedle arrays are essentially reformulating the drug that leads to long 33 32-36-DDT May 2010-Advanced Delivery:Layout 1 4/30/10 2:42 PM Page 34

friendly, simple, and inexpensive technology F I G U R E 3 for transdermal delivery of a variety of already

approved standard liquid pharmaceutical drugs AdminPenTM Microneedle Pen-Injector Device to a patient.

ADMINPATCH® MICRONEEDLE ARRAY IS REFINED MICRONEEDLE TECHNOLOGY

AdminMed has developed the patented Advanced micro-needle array (AdminPatch® Array), which painlessly and instantaneously forms hundreds of tiny micropores through the stratum corneum and epidermis. Numerous drugs, including proteins and water-soluble molecules, can enter the body through these micropores for local effect or by entering the circulation for systemic effect. The created aqueous channels stay constantly open while the AdminPatch array is applied on the skin, and therefore enables the rapid, sustained, and MICRONEEDLE-BASED array technology called AdminPatch efficient delivery of drugs through these ADMINPENTM PEN-INJECTOR DEVICE microneedle array (covered by US Patent No. aqueous channels formed in the skin surface. 7,658,728 and Patents pending in the US and When the microneedle array is removed from AdminPen™ pen-injector device is based other countries). A simple low-cost molded the skin, the micropores simply collapse, and on our own patented proprietary microneedle plastic part is simply attached on the back the skin barrier is quickly restored. The human skin has three distinct layers: the outer layer (stratum corneum), having a T A B L E 1 reported thickness of between 10 to 30 microns; the viable epidermis, containing Addresses Unmet Patient Needs AdminPen sentinel cells of the immune system; and the dermis, within which are capillaries and Painless YES various trauma-sensing receptors. Simple, intuitive operation YES The aqueous channels formed by the microneedles in the stratum corneum using the Compatible with a standard syringe YES AdminPatch system have a depth of about 100 Eliminates sharps hazards YES Vol 10 Vol No 4 to 1000 microns, sufficient to extend through

the viable epidermis into the dermis to reach blood capillaries but shallow enough to avoid Attractive to Pharma Partners AdminPen May 2010 most pain receptors. 510(k) regulatory approval strategy YES AdminMed has completed studies that show that while the AdminPen microneedle Existing drug formulation YES devices are kept applied on the skin, the Low-cost high-speed manufacturing YES micropores formed by microneedles allows injection of drug or any other liquid from an Uniformly inserted into flexible skin YES Drug Delivery Technology Drug Delivery Technology attached syringe into the underlying tissues. AdminPenTM Competitive Advantage 34 32-36-DDT May 2010-Advanced Delivery:Layout 1 4/30/10 2:42 PM Page 35

surface of the AdminPatch microneedle array to provide a fluidic connection of AdminPen F I G U R E 4 device to an externally connected liquid drug reservoir. The AdminPen pen-injector device can be mounted on any commercially available standard syringes or injector pens with a prefilled drug cartridge. The AdminPen needle substitute should be an excellent fit for user-friendly and painless delivery of vaccines (influenza, smallpox, anthrax); cosmetics (hyaluronic acid, Botox); or pharmaceutical drugs requiring frequent injections, such as parathyroid hormone, human growth hormone, obesity-management drugs (leptin, liraglutide), anemia drugs (epoetin alfa), and pre-meal insulin. The device is expected to be classified as a Class II 510(k) medical device. During each injection, the drug is uniformly injected into a 1-cm2 area of the skin. Clinical benefits of the AdminPen pen-

injector device includes the following: AdminPenTM Connected to a Regular Syringe Filled With Blue Dye

• Promotes patient compliance through eliminating the use of painful regular discovery and the risks of bringing a new delivery, a study is underway to obtain a needle injections. compound to the market, as well as provides a pharmacokinetic profile comparable to that significant pipeline of potential products observed by subcutaneous injection with a • Improves drug efficacy and safety by based on existing already-approved drugs. standard needle. ensuring proper injections through This painless microneedle injection The AdminPen device is expected to simple, intuitive operation and by using device could potentially address the limited have attractive profit margins because the a standard prefilled glass cartridge or a appeal of injections and avoid the first-pass microneedle array and the injection-molded standard syringe. metabolism issues presented by oral delivery. support/syringe connector can be • Enhances product safety by To demonstrate the feasibility of using the manufactured at low cost using mature, large- eliminating sharps hazards and AdminPen device for subcutaneous drug scale processes. The device does not use any offering safe, easy disposal of consumables as well as by eliminating F I G U R E 5 electrical and high-pressure parts. Vol 10 Vol No 4 The painless AdminPen device combines effective delivery of drugs through the skin with excellent skin sensation and cosmetics, is May 2010 easy and intuitive to use by patients and medical personnel alike, and can be economically produced to scale using mature high-volume low-cost processes. The strategy of applying the AdminPen device to the existing already-approved liquid drugs avoids Drug Delivery Technology Drug Delivery Technology both the costs and time spent on drug Injection of a Dye With AdminPenTM 35 32-36-DDT May 2010-Advanced Delivery:Layout 1 4/30/10 2:42 PM Page 36

electronic components and can be entirely COMMERCIAL POTENTIAL BIOGRAPHY outsourced to low-cost precision stamping and There is an unmet need for a user- Dr. Vadim plastic molding vendors. friendly, painless, simple, effective, and Yuzhakov is an A patient simply connects the AdminPen inexpensive technology for delivery of a inventor on 12 to a standard syringe and applies it to the skin. variety of already approved liquid drug types granted and numerous The microneedles penetrate the upper layers of to a patient. AdminMed estimates the pending patents the skin, thereby painlessly and instantaneously AdminPen transdermal pen-injector device to related to microneedle cutting the stratum corneum and epidermis to have an annual worldwide market potential of technologies. His create hundreds of micro-channels near each approximately $2 billion. u microneedle. Each microneedle also keeps career includes these channels open to allow injection of significant experience in the research and pharmaceutical drugs from the syringe through REFERENCES development of medical devices and the microporated skin. When the AdminPen pharmaceutical drug delivery systems. He 1. Yuzhakov VV. Microneedle array, patch, and applicator for established and coordinated several research microneedle device is removed from the skin, transdermal drug delivery. US Patent No. 20070161964, WO Patent No. 2007081430;2007. and development projects. As a Program the micropores simply collapse, and the skin 2. Yuzhakov VV. Advanced micro-needle Patch (AdminPatch®) for barrier is quickly restored. minimally invasive transdermal drug delivery. Invited presentation Manager IV, he managed a development at First Annual Skin Summit: Transdermal Drug Delivery & Development & Beyond, Philadelphia, PA, February 22-23, 2007. program at Abbott Diabetes Care. Previously, TM 3. Yuzhakov VV. Tissue conforming microneedle array and patch for as a Principal Engineer at Altea Therapeutics, CURRENT ADMINPEN DESIGN transdermal drug delivery or biological fluid collection. US Patent No. 20080125743, WO Patent No. 2008067290;2008. a specialty pharmaceutical company, he 4. Sivamani RK, Stoeber B, Wu GC, Zhai H, Liepmann D, Maibach actively participated in the development a The current design of the AdminPen is H. Clinical microneedle injection of methyl nicotinate: stratum corneum penetration. Skin Res Technol. 2005;11(2):152-156. new advanced transdermal insulin patch based composed of a “button” with a convex front- 5. Sivamani RK, Liepmann D, Maibach HI. Microneedles and end and a back-end having a luer connector transdermal applications. Expert Opin Drug Deliv. 2007;4(1):19- on a thermal microporation method. As a 25. Review. Senior Scientist at LifeScan, a Johnson & for connection to a standard syringe. The 6. Sivamani RK, Stoeber B, Liepmann D, Maibach HI. Microneedle penetration and injection past the stratum corneum in humans. J Johnson company, he significantly contributed AdminPatch microneedle array is applied on Dermatolog Treat. 2009;20(3):156-159. 7. Henry S, McAllister DV, Allen MG, Prausnitz MR. to the development of an “all-in-one” system the front convex surface of the button, which Microfabricated microneedles: a novel approach to transdermal for convenient glucose monitoring; and as a also has microfluidic channels that direct the drug delivery. J Pharm Sci. 1998;87:922-925. 8. McAllister DV, Wang PM, Davis SP, Park J-H, Canatella PJ, Allen Scientist at Procter and Gamble, he led the injected drug from the syringe into the MG, Prausnitz MR. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication development of microneedle patches for drug microchannels on each microneedle. methods and transport studies. Proc Natl Acad Sci USA. and cosmetics delivery. He is a Certified The initial testing of the AdminPen 2003;100:13755-13760. 9. Chabri F, Bouris K, Jones T, Barrow D, Hann A, Allender C, Brain Project Management Professional (PMP) and microneedle device prototypes has shown the K, Birchall J. Microfabricated silicon microneedles fornonviral cutaneous gene delivery. Br J Dermatol. 2004;150:869-877. earned his MS in Mechanical Engineering from successful insertion of the microneedle array 10. Martanto SP, Davis NR, Holiday JW, Gill HS, Prausnitz MR. Lomonosov Moscow University and his PhD in and delivery of a dye through the skin as can Transdermal delivery of insulin using microneedles in vivo. Pharm Res. 2004;21:947-952. Chemical Engineering from the University of be seen in Figure 5. The cross-sectional view 11. Lin W, Cormier M, Samiee A, Griffin A, Johnson B, Teng CL, Hardee GE, Daddona PE. Transdermal delivery of antisense Notre Dame. Dr. Yuzhakov can be contacted at demonstrates the successful delivery of dye oligonucleotides with microprojection patch (Macroflux) [email protected]. under the skin using the device. technology. Pharm Res. 2001;18:1789-1793. 12. Cormier M, Johnson B, Ameri M, Nyam K, Libiran L, Zhang The results of the initial tests are very DD, Daddona PE. Transdermal delivery of desmopressin using a coated microneedle array patch system. J Control Release. encouraging and a more rigorous design 2004;97:503-511.

Vol 10 Vol No 4 optimization and more extensive in vitro 13. Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, Nyam K, Daddona PE. Macroflux microprojection array patch testing of the device is being undertaken. technology: a new and efficient approach for intracutaneous immunization. Pharm Res. 2002;19:63-70. Several approaches to fully optimize and 14. Mikszta JA, Alarcon JB, Brittingham JM, Sutter DE, Pettis RJ, May 2010 improve the design of AdminPen are currently Harvey NG. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted being evaluated. Meanwhile, a web store has epidermal delivery. Nat Med. 2002;8:415-419. 15. Roy CJ, Ulrich RG, Harvey NG. Protective immunization against been established to quickly provide samples of inhalational anthrax: a comparison of minimally invasive microneedle arrays and AdminPen delivery platforms. J Infect Dis. 2005;191:278-288. 16. Martanto W, Moore JS, Kashlan O, Kamath R, Wang PM, microneedle devices to our partners for O’Neal JM, Prausnitz MR. Microinfusion using hollow microneedles. Pharmaceut Res. 2005;23:104-113. evaluation. Several AdminPen products based 17. Gill HS, Denson DD, Burris BA, Prausnitz MR. Effect of Drug Delivery Technology Drug Delivery Technology on microneedle arrays of different lengths microneedle design on pain in human volunteers. Clin J Pain. 2008;24:585-594. 36 from 600 to 1500 microns are available. 37-41-DDT May 2010-Electroporation:Layout 1 4/30/10 2:44 PM Page 37

ELECTROPORATION

In Vivo Delivery of Nucleic Acid-Based Agents With Electroporation By: Karen E. Dolter, PhD; Claire F. Evans, PhD; and Drew Hannaman

INTRODUCTION Electroporation (EP) is a delivery technique that improves the intracellular uptake of agents such as small molecule drugs and biological molecules in a local region of tissue. EP induces a transient state of membrane destabilization/permeability, during which time substances present in the extracellular space at the site of EP application can be taken up into the affected cells with high efficiency. Shortly following EP, the cell membrane stabilizes, and the cells resume normal function.

ELECTROPORATION-MEDIATED spleen, kidney, brain, blood vessels, disruption.1 DELIVERY OF NUCLEIC ACIDS bladder, lung, skin, and tumors of different When used to increase the in vivo origins, while minimizing tissue delivery of nucleic acids, EP has been EP was initially discovered to increase DNA delivery to in vitro cell cultures; F I G U R E 1 adaptation of EP to in vivo use has yielded an efficient method for nucleic acid delivery to tissues.1 In vivo, EP is typically initiated with the administration of an agent to the target region of tissue, usually by local injection. This is immediately followed by the application of electrical fields capable of inducing the EP effect. The electrical signals are administered using an electrode array contacting the target tissue where the agent is distributed.

This procedure greatly increases Integrated, Automated Device Configurations for EP-Mediated intracellular uptake in tissues where the DNA Delivery agent is present in the extracellular Based on the TriGrid Delivery System (TDS) platform, devices for environment during generation of the EP administration in skeletal muscle (A) and skin (B) have been developed. Each device includes a reusable Integrated Applicator Vol 10 Vol No 4 effect. EP is therefore an effective method (left) and a single-use Application Cartridge (right), containing the for the local delivery of agents with DNA dose for administration and conductive electrodes for intracellular activity that are unable to enter electroporat ion application. May 2010 the cell passively. Experience in a variety of animal species has demonstrated that, with appropriate refinement in application devices, administration conditions, and electrical parameters, EP can be adapted for nucleic acid delivery in a wide variety of Drug Delivery Technology tissues, including skeletal muscle, liver, 37 37-41-DDT May 2010-Electroporation:Layout 1 4/30/10 2:44 PM Page 38

F I G U R E 2

Enhanced Potency of DNA Vaccines Delivered With EP Immune responses were evaluated in BALB/c mice (A) and New Zealand White rabbits (B) following immunization with a plasmid encoding the hepatitis B surface antigen (HBsAg) by conventional intramuscular injection (-EP) or by intramuscular injection followed by EP using Ichor’s TDS-IM device (+EP). (A) 2 micrograms of plasmid was delivered into one tibialis anterior muscle per mouse on days 0 and 28, and HBsAg-specific T-cell responses were evaluated in spleens at day 35 by measuring IFN-gamma responses to two HBsAg peptide epitopes (H1 and H2) in an ELISPOT assay. Results are plotted as spot-forming cells (SFC) per million splenocytes. (B) 0.5 milligrams of plasmid was delivered to one quadriceps muscle per rabbit on days 0 and 28. Serum titers of antibodies specific for HBsAg were assessed in serum by ELISA 2 weeks following the second immunization.

demonstrated to increase the potency of these inconsistent biological responses when tissue judged by the operator to be the site of agents by 10- to 1000-fold compared to administered in humans, primarily due to the DNA distribution. The susceptibility of this administration using conventional injection inefficient and inconsistent intracellular procedure to substantial intra-operator alone. Compared to delivery by viral vectors, delivery associated with conventional variability led to the development of improved EP delivery of nucleic acids is advantageous methods for the delivery of this class of systems that integrated the means for agent due to the absence of any live vector agents.2 Based on the encouraging results of administration and electroporation application components (and the attendant safety studies investigating EP-mediated nucleic acid into a single, simple-to-use administration concerns) and to the inherent non- delivery in animals, several research groups device. By ensuring the agent and electrical immunogenic nature of nucleic acids as have progressed to clinical testing of DNA fields are administered to the same tissue site, vectors, resulting in the ability to administer drugs delivered by EP. integration of the entire procedure into a the agent multiple times without inducing An important consideration for clinical single device reduces the need for operator inhibitory responses to the vector itself. evaluation of novel agents delivered by EP is training, facilitates reproducibility, and lowers Importantly, EP delivery of nucleic acid- the development of administration procedures the risk of false negative results in clinical based agents into the cytosol can be achieved and devices suitable for use in the clinical trials due to improper or inconsistent in the absence of complex formulations or setting. Of foremost importance, a clinical EP administration of the procedure. In addition, transfection reagents. As a result, the device must ensure that propagation of the device technologies capable of simple and manufacture and administration of the nucleic electrical fields coincides with the site of rapid administration are likely to be preferred acid-based agents is greatly simplified. Taken nucleic acid distribution within the target by both patients and healthcare personnel. together, these properties indicate that EP has tissue in a consistent manner across Several integrated EP device formats the capability of overcoming what has been an heterogeneous patient populations.3 In currently in clinical testing include Inovio

Vol 10 Vol No 4 important limitation of nucleic acid-based addition, device features that enhance the Biomedical’s Twinjector (Elgen®) and drugs, namely the inability to efficiently cross clinical acceptability and tolerability of the Cellectra® and Ichor Medical System’s the cell membrane in order to reach the procedure will be important in determining TriGridTM Delivery System (TDS).3 Although May 2010 intracellular site of action. the range of clinical indications for which the initially developed for intramuscular delivery, technology can be deployed. Initial clinical devices are now being adapted for other testing of in vivo EP was conducted using routes of administration. For example, the CLINICAL EP DEVICES FOR devices based on a manually controlled two- Ichor TDS platform includes devices for both NUCLEIC ACID DRUG DELIVERY step procedure. Specifically, a manual intramuscular (TDS-IM) and intradermal injection of the agent using a conventional (TDS-ID) administration. Each TDS device

Drug Delivery Technology Drug Delivery Technology Clinical development of nucleic acid- syringe was followed by insertion and consists of three components: a Pulse

38 based products has been limited by low and activation of an electrode array in the area of Stimulator, an Integrated Applicator, and a 37-41-DDT May 2010-Electroporation:Layout 1 4/30/10 2:44 PM Page 39

single-use Application Cartridge (Figure 1). The Application Cartridge injection site with array dimensions that match the fluid distribution is packaged sterile for single use and is attached to the Integrated profile for injection into the target tissue. The Integrated Applicator is a Applicator at the beginning of the procedure. The cartridge encloses a reusable hand-held device that automatically deploys the electrodes and TriGrid Electrode array composed of four electrodes arranged in two administers the DNA, providing user-independent control over the rate interlocking triangles (hence the name TriGrid) around a central and site of DNA administration. The Integrated Applicator connects to the Pulse Stimulator, which monitors the procedure for safety and F I G U R E 3 generates the EP-inducing electrical fields. The integrated, automated design of the TDS allows application of the entire procedure within a few seconds, while ensuring that EP is applied to the tissues at the site of nucleic acid distribution in a consistent fashion. The TDS devices use deployable electrodes with integrated stick protection that engages automatically when the procedure has finished, minimizing visualization and exposure to sharps during the procedure. The TDS-IM has been used in clinical testing for a therapeutic DNA vaccine encoding a melanosomal antigen in melanoma patients at high risk for recurrent disease. It has also been evaluated in a placebo-controlled comparative study of EP delivery and conventional intramuscular injection for delivery of a prophylactic HIV vaccine.4 The ability to conduct this first study of EP-mediated DNA delivery in healthy human volunteers confirms the progress that has been made in the evaluation of procedure safety and tolerability and suggests that EP may be suitable for a variety of applications.

DNA VACCINES

DNA vaccines contain sequences encoding immunogenic proteins or peptides that when expressed, can elicit immune responses against a target protein antigen. DNA vaccination provides benefits for safety and efficacy compared to conventional immunization. Most important is the ability to elicit broad, antigen-specific cellular and humoral immune responses without the safety concerns associated with live pathogens or immunomodulatory adjuvants.2 The ability to induce long-term expression of the antigen in the individuals’ own cells may provide advantages in potency that result in a reduction of the number of immunizations required to achieve target immune responses and/or an increase in the duration of protection achieved. As an alternative to conventional protein-based vaccines, development of DNA vaccines can be rapid and cost effective, with the potential to improve upon the performance of existing vaccines and facilitate the development of novel vaccines addressing pathogens and diseases for which there are no current vaccines. Preclinical investigation of EP-based DNA immunization has been performed in a wide range of animal models demonstrating significant improvements in vaccine potency achievable with this delivery method.5 In the context of DNA vaccines, EP greatly increases the magnitude of both cellular and humoral immune responses for a wide range of 10 Vol No 4 antigens.3 Increased response rates and reductions in the number of immunizations required to achieve target levels of immunity have also May 2010 been observed. For example, immunization of mice and rabbits with Electroporation-Based siRNA & shRNA Plasmid Delivery for Knock-Down plasmid DNA encoding hepatitis B virus surface antigen induces of Reporter Gene Expression immune responses that are significantly increased when the plasmid is 1 microgram of luciferase reporter plasmid (luc DNA) was coadministered with (A) 1 microgram of siRNA (luciferase-specific or negative control) and (B) 10 delivered by EP (Figure 2). Studies in non-human primates have micrograms of shRNA plasmid (luciferase-specific or negative control) on day 0 demonstrated that, in addition to the induction of potent cellular with Ichor’s TDS-IM device to the tibialis anterior muscle of Swiss Webster immune responses, DNA vaccines delivered by EP can also induce

mice. Muscles were harvested at the indicated time points, and luciferase Drug Delivery Technology activity was assayed in muscle lysates. antibody responses and protection against experimental disease 39 37-41-DDT May2010-Electroporation:Layout14/30/102:44PMPage40 40 Drug Delivery Technology May 2010 Vol 10 No 4 and responseshave the potential for inhibiting the challengeatlevels comparable tocurrently mediatedadministration of a hepatitis C virus from a target tissue following a single indicatethat EP is safe, tolerable, and capable suggestthe feasibility of vaccination with sustained endogenous production of therapeutic investigatinga human papillomavirus (HPV) developmentof cervical cancer in women licensedvaccines. immunizationhave been initiated for a variety (HCV)DNA vaccine in patients with chronic administration, nucleic acid-based drugs proteins in a subject’s own tissues may provide DNAvaccine delivered by EP in patients with ofenhancing immune responses to DNA DNAin humans. In a study of a DNA vaccine alreadyinfected with HPV. Finally, interim ofdisease indications, including cancer therapy HCVinfection resulted in T-cellresponses and candidateencoding a prostate-specific an alternative to long-term therapy based on previousprecancerous cervical lesions resulted delivered with EP provide possible benefits vaccinesin humans. resultsfrom a trial for a preventive HIV DNA andtreatment or prevention of viral infection transientreductions of viral load in some compared to the frequent injections required to membraneantigen epitope fused to a modified repeated administration of the proteins in T-celland antibody responses in some vaccinein healthy volunteers showed that (vanden Hurk and Hannaman, Expert Review patients. achieve and maintain effective levels of a formof tetanus toxin delivered to prostate themselves. By inducing sustained product patientsat deliveryof the vaccine with EP resulted in of Vaccines,in press). Recently reported cancerpatients, EP-based DNA vaccine higherfrequency and breadth of T-cell resultsfrom a number o deliverywas associated with a significant responsescompared to intramuscular injection increasein antibody responses to the tetanus withoutEP. toxincompared to conventional injection. secretion of protein for weeks to months Nucleic acid-based drugs enabling the Humanclinical trials for EP-based DNA THERAPEUTIC PROTEINS THERAPEUTIC 8 Interimresults from a trial the first two dose levels. 4 Takentogether, initial trial results 5,6 fthese clinical trials 9 These 7 ion EP- factors, endocrine hormones and transcription Therapeutic protein-encoding DNA drugs growth Figureshows3 the effects ofEP-mediated vivodelivery ofDNA vectors expressing therapeutic levels of the protein as well as ischemic tissue, and expression of a delivered with EP are also currently under EP-based product approved for commercial use gene-specificsiRNA and shRNA plasmid RNAinterference (RNAi). Thetechnique has shorthairpin interfering RNA (shRNA). factors, as well as monoclonal antibodies for licensed in Australia to allow sustained GHRH inmuscles receiving plasmid DNA encoding reduced potential for adverse side effects transcription factor for healing burn wounds. deliveryonexpression ofluciferasea reporter beendemonstrated toinduce transient production in female swine, thereby enhancing investigation for various human clinical was a DNA plasmid encoding the porc infectious diseases, cancer, and chronic downregulationofgene expression following associated with high protein concentrations that the viability and health of their offspring. applications, including intratumoral expression gene.Byday post-transfer,3 luciferase inflammatory diseases, suggest that DNA drugs deliveryofsmall interfering RNA (siRNA). activityinmuscles receiving luciferase siRNA commonly occur after the bolus dosing of of immunomodulatory cytokines, local may provide cost-effective alternatives for Alternatively,more sustained downregulation certain protein-based drugs (for example, type I production of proan wasreduced to0.7% ofthe level inmuscles oftarget genes can bea locoregional or systemic protein delivery. therapeutic protein when administered in the receivingnegative control siRNA (Figure interferons). Preclinical data from studies of 3A).Byd form of the protein itself. These benefits EP-mediated delivery of DNA drugs encoding include the convenience and cost effectiveness therapeutic proteins, such as of fewer a immunomodulatory cytokines Building on this concept, the first DNA EPmay also have utility ofinthe field hormone-releasing hormone (GHRH) RNA INTERFERENCE RNA dministrations aypost-transfer,4 luciferase activity growth factors in giogenic chievedthrough in required to maintain hematopoietic , ine 14 1,10-13 18 15-17 Anacceptable safety inprofileinitial diseaseindication. Todate, EPhas been thistechnology. Collectively, the recent indicatethe potential suitability ofEPfor inDNA uptake and expression invarietya of fora yetbeen implemented for RNAi delivery in therapeuticindications combined with the adaptedtoenhance RNAi inthe research advancesand promising outlook for EP-based tissuetypes, and assuch, EPmay beable to theclinical setting, the initiation ofclinical indicationsinwhich RNAi therapy could be settingtostudy the effect ofspecificgene deliverysuggest that the technology is developmentofmore devicerefined overcomethe suboptimal clinical potency luciferase-specificshRNA was reduced to usedfor local downregulation oftarget genes capableofenabling nucleic acid-based drugs technologyhas enabled the initiation of observedwith conventionally administered knock-downinlocalized tissues aswell asin studiesfor locoregional RNAi therapy in totreat conditions manifesting locoregional 17%ofthe level inmuscles receiving requiringlocal orlocoregional delivery. prophylacticstudies. Inaddition tothe nucleicacid drugs. animalmodels ofdisease. diseases,such asage-related macular negativecontrol shRNA (Figure 3B). sequalae. Altho ongoingopportunities inDNA-based protein degeneration,skin disorders, and cancer, andvaccine delivery, preclinical progress with aciddrugpotency observed with EP-mediated locoregionalnature ofthe increased delivery suggestthat EPcould have futurea role inthe EP-baseddelivery ofvectors for RNAi and nucleicacid delivery has provided the basis deliveryofRNAi-based therapeutics for achievablewith EPisan important othernovel classes ofnucleic acid drugs may forthe initiation ofearly phase clinical trials selectedindications. considerationwhen assessing the suitability of increasethe range ofclinical thetechnique for RNAi delivery ingivena chieving10- to1000-fold enhancement Invivo EPisrobust,a adaptable method Thesignificant enhancements innucleic Whilethese results are encouraging, the ughEP-based delivery has not SUMMARY 22,23 19-21 applications for Suchresults . 37-41-DDT May2010-Electroporation:Layout14/30/102:44PMPage41 1.Andre F, Mir LM. DNA electrotransfer: its 8.Sällberg M,Diepolder HM, Jung MC, Frelin L, 10.Jaini R,Hannaman D, Johnson JM, Bernard 2.Liu MA, Ulmer JB. Human clinical trials of 5.Bodles-Brakhop AM,Heller R,Draghia-Akli R. 7.Low L,Mander A,McCann K,Dearnaley D, 3.Luxembourg A,Evans CF, Hannaman D. 11.Liu L,Marti GP, WeiX,Zhang X,Zhang H,Liu 9.Inovio Biomedical Corporation. Inovio 6.Livingston BD, Little SF,Luxembourg A, 4.Vasan S,Hurley A,Schlesinger S,Hannaman D, EllefsenB, Hannaman D. Comparative 2009;20:1269-1278. GardinerD, etal. Invivo electroporation performanceoflicenseda anthrax vaccine versus Clinical Trial.Press release: Inovio Biomedical principlesand anupdated review ofits enhancesthe immunogenicity of ADVAX,a MathiesenI,Fons MP, Hultcrantz RW, Carlsson T, therapeuticapplications. Gene Ther. DNA-basedHIV-1 vaccine candidate, inhealthy electroporationbased delivery ofPAa encoding Corporation,Feb 8,2010. WeilandO. Antiviraleffects oftherapeutic 2004;11:S33-42. volunteers.Retrovirol. 2009;6:O31. DNAvaccine inrhesus macaques. Vaccine. vaccinationwith naked DNA delivered by invivo plasmidDNA vaccines. AdvGenet. 2005;55:25- 2010;28:1056-1061. electroporationinpatients with chronic hepatitis Electroporationfor the delivery ofDNA-based 40. Electroporation-basedDNA immunisation: Tjelle T,Mathiesen I,Stevenson F, Ottensmeier vaccinesand immunotherapeutics: current clinical C.Hepatol. 2008;48:1022A-1023A. CH.DNA vaccination with electroporation translationtothe clinic. Expert Opin Biol Ther. inducesincreased antibody responses inpatients BiomedicalCervical Cancer Therapeutic Vaccine developments.Mol Ther.2009;17:585-592. 2007;7:1647-1664. withprostate cancer. Hum Gene Ther. GeneratesDose-Related Immune Response in indiabetic mice: correction with electroporation-facilitatedgene therapy increaseswound healing, angiogenesis, and RM,etal. Gene-based intramuscular interferon- betatherapy for experimental autoimmune encephalomyelitis.Mol Ther.2006;14:416-422. YV,Nastai M,Semenza GL, Harmon JW. Age- dependentimpairment ofHIF-1alpha expression REFERENCES 20.Matsuda T,Cepko CL. Electroporation and 18.Takahashi Y,Nishikawa M, Takakura Y. 16.Gaffney MM, Hynes SO, F,Barry O'Brien T. 14.Person R,Bodles-Brakhop AM,Pope MA, 23.Tiemann K,Rossi JJ. RNAi-based therapeutics- 21.Schiffelers RM, XuJ, Storm G, WoodleMC, et 17.Johns Hopkins University, National Institutes of 19.Akaneya Y,Jiang B, Tsumoto T.RNAi-induced 12.Bakker JM, Bleeker WK,Parren PW. 15.Daud AI,DeConti RC, AndrewsS,Urbas P, et 13.Trollet C,Scherman D, Bigey P. Delivery of 22.Leachman SA, Hickerson RP, Schwartz ME, currentstatus, challenges and prospects. EMBO MolMed. 2009;1:142-151. targetedsiRNA phase Ibtrial ofaninherited RNAinterference inthe rodent retina invivo melanoma.ClinJ Oncol. 2008;26:5896-5903. advantagesand challenges. Methods Mol Biol. NCT00796627. Nonviralvector-mediated RNA interference: its 2008;423:199-214. skindisorder. Mol Ther.2010;18:442-446. andinvitro. Proc Natl AcadSci USA. Cardiovasculargene therapy: current status and BrownPA, etal. Growth hormone-releasing 2004;101:16-22. genesilencing characteristics and important therapeuticpotential. BrPharmacol.J hormoneplasmid treatment by electroporation al.Effects oftreatment with small interfering factorstoachieve RNAi-based gene therapy. 2007;152:175-188. circulatingangiogenic cells. CellJ Physiol. decreasesoffspring mortality over three AdvDrugDeliv Rev. 2009;61:760-766. 2008;217:319-327. Health.HIF-1 Regulated EPC recruitment in RNAonjoint inflammation inmice with genesilencing by local electroporation in pregnancies.Mol Ther.2008;16:1891-1897. Therapeuticantibody gene transfer: anactive collagen-inducedarthritis. ArthritisRheum. burnwound healing. ClinicalTrials.gov targetingbrain region. Neurophysiol.J al.Phase trialI ofinterleukin-12 plasmid approachtopassive immunity. Mol Ther. 2005;93:594-602. [Internet]2000. Bethesda (MD): National 2004;10:411-416. 2005;52:1314-1318. electroporationinpatients with metastatic LibraryofMedicine (US). NLM Identifier: DNAinto muscle for treating systemic diseases: BulloughEE, et al. First-in-human mutation- for drugs and biologics.anddrugs for systemsdevice-baseddeliveryspecializing in developmentmedicaltechnologies,novelof in the areas of molecular v molecularof areas the in academicpost-doctoralreceivedtrainingshe responsible for guidingresponsibledevelopmentforof over 14 years of experience in theexperienceofin years 14 over at MediGene and Stratagene,MediGeneand at previously,and Ichorbeen MedicalSystems,Inc.,has University of California, Los Angeles,has California,andLos ofUniversity to joining Ichor,joining to scientistpositionsheldshe studies.preclinicalPriorsafety GLP as well expressionandgenedeliveryexperiments as He holds a degree in Cybernetics from theCyberneticsfromdegree in a holdsHe 2002. NeurologicalDisorders-Drug& Targets since Michigan, Ann Arbor.Michigan,Ann She has been a Co-Editor of the journal CNS journalthe of Co-Editor a been has She TherapeuticofcurrentlyDirectorPrograms. Scripps Research Institute in the Departmentthe in InstituteResearch Scripps Immunology from the University ofUniversitytheImmunology from into clinical testing for multiple indications.multiplefor testing clinical into of Neuropharmacology.of S TheAssistantProfessorat an became she earned her PhD in Microbiologyandin PhD herearned TriGrid Delivery System from initial conceptinitialfrom System TriGridDelivery Medical Systems in 2003, where she is whereshe 2003, in MedicalSystems biology,generegulationandresearch.She S E I H P A R G O I B irology,cell tumor he joined Ichorjoinedhe Developmentfor & Research Presidentof Vicethe as during his 7 years 7 duringhis and,technology electroporation TriGridthe is a Co-Inventor ofCo-Inventor a is DrewHannaman Chemistry at the at Chemistry Biological immunovirology, post-doctoral Arbor.After Michigan,Ann ofUniversity in PhD herearned Dr.EvansClaire trainingin projects,including vitro and in vivo in andvitro Investigator for in forInvestigator Principal as served has She Scientist.Research 2005 as a Senior a as 2005 Medical Systems in MedicalSystems Ichorjoined Dr.KarenDolter the

41 Drug Delivery Technology May 2010 Vol 10 No 4 42-47-DDT May 2010-nanomicellar tech:Layout 1 4/30/10 3:06 PM Page 42

NANOMICELLAR TECHNOLOGY Topical Delivery of Hydrophobic Drugs Using a Novel Mixed Nanomicellar Technology to Treat Diseases of the Anterior & Posterior Segments of the Eye By: Poonam R. Velagaleti, PhD; Eddy Anglade, MD; I. John Khan, PhD; Brian C. Gilger, DVM; and Ashim K. Mitra, PhD

INTRODUCTION Instillation of topical eye drops is the preferred and most convenient route of drug administration for treating ocular diseases. However, formulating hydrophobic drugs for topical applications is challenging. Hydrophobicity limits the feasibility of producing aqueous formulation concentrations sufficient to achieve therapeutic levels in the ocular tissues. Hydrophobic drugs are therefore usually applied as oil-in-water emulsions, which appear less well tolerated than homogeneous aqueous solutions. Emulsion formulations also limit the amount of drug that can be applied. To overcome these problems, a novel nanomicellar technology has been developed. Solubilization of hydrophobic drugs is achieved through entrapment in a mixed micellar hydrophobic core with a corona composed of hydrophilic chains extending outward, resulting in a clear aqueous formulation. This nanomicellar formulation appears to discharge its active ingredient in a manner that establishes high ocular tissue concentrations in both the anterior and posterior eye segments. The unique formulation technology has been validated using a hydrophobic cyclic undecapeptide, voclosporin. This novel calcineurin (CN) inhibitor is directed at activated T-helper cells, inhibiting their proliferation and attenuating the immune response. This mechanism is clinically utilized for immunosuppression in organ transplantation and in autoimmune diseases. An oral formulation (LUVENIQ, LX211) of voclosporin has demonstrated efficacy and safety in treating non-infectious uveitis and is currently under review by the US FDA and European Medicines Agency for marketing authorization. The same active ingredient is formulated into LX214, a topical mixed nanomicellar aqueous solution, for treating dry eye syndrome and other anterior segment inflammatory diseases. In this article, data are presented demonstrating the tolerability and initial signals of efficacy for LX214, which is then compared to Restasis®, a 0.05% emulsion of cyclosporine A (CsA), a molecule that shares the same mode of action as voclosporin. Restasis® is approved in the US for the treatment of dry eye syndrome. LX214 is able to deliver drug to posterior ocular tissues of sufficient therapeutic value. This unique nanomicellar drug delivery platform presents potential opportunities for topical administration of additional hydrophobic drugs and the ability to non-invasively target retinal and other posterior segment diseases.

BENEFITS/LIMITATIONS OF segment. This reasoning stems from (1) FIGURE 1 OCULAR TOPICAL DRUG the high-resistance drug penetration ADMINISTRATION Vol 10 Vol No 4 barriers presented by the corneal and conjunctival layers of the eye; (2) the Topical administration of hydrophilic rapid irrigation within the eye caused by May 2010 molecules to the anterior segment is often lacrimation and drainage that washes relatively straightforward. However, highly fluids out into the nasolacrimal ducts or hydrophobic drugs present a significant overflow from the eyelids; (3) the challenge, and the active ingredient metabolism of active drug by enzymes discharge from oil-in-water emulsions is present in tear fluid; and (4) the removal Drug Delivery Technology Drug Delivery Technology not well understood. Topical application is of the active drug by highly vascularized Chemical structure of voclosporin (a 42 considered ineffective for delivery of ocular tissues (ie, conjunctiva, choroid, hydrophobic molecule). hydrophobic drugs to the posterior eye uveal tract, and inner retina). 42-47-DDT May 2010-nanomicellar tech:Layout 1 4/30/10 3:06 PM Page 43

two non-ionic surfactants, D-alpha- Schirmer tear test (STT), (2) clinical FIGURE 2 tocopheryl polyethylene glycol 1000 observation of the cornea, (3) feedback from succinate (Vitamin E TPGS) stabilized with dog owners, and (4) overall assessment of octyl phenol ethoxylate (octoxynol-40) in a participating ophthalmologists. Six dogs having defined ratio. A transmission electron residual lacrimal function and a response to micrograph of the drug-loaded nanomicellar topical Cyclosporine (CsA) ointment “fluid bubbles” is shown in Figure 2. LX214, (Optimmune®) treatment prior to enrollment packaged in single-use sterile low-density were switched directly to twice daily (12 hrs) polyethylene, blow-fill -sealed vials (Figure topical ocular administration of 0.2% LX214 3), has demonstrated stability for at least 1 (~50 microliters, 0.1 mg voclosporin/eye/dose). year under refrigeration and for 2 months at LX214 treatment was considered successful if room temperature. pre-study STT values, obtained during CsA treatment, were maintained or increased. A control group was not included given the LX214 EFFICACY IN CANINE reproducibility of the model and ethical A transmission electron micrograph (TEM) of KERATOCONJUNCTIVITIS mixed nanomicellar formulation with Vitamin SICCA (KCS) considerations. The expected decrease in STT E TPGS and octoxynol-40 loaded with 0.2% with placebo (Figure 4) was therefore based on voclosporin. The mode of action of voclosporin is historic controls. Upon study completion, there were no However, many investigators are now calcineurin (CN) phosphatase inhibition. CN adverse corneal findings, and both the re-evaluating the potential of topical delivery inhibitors reversibly inhibit ophthalmologist and dog owners’ assessments for the back-of-the-eye opportunities to immunocompetent lymphocytes, particularly were positive (no obvious decline in ocular address large markets, including glaucoma, T-lymphocytes, and inhibit lymphokine 8,9 Voclosporin comfort level). The data shown in Figure 4 age-related macular degeneration, diabetic production and release. mediates its suppressive effects on T- indicated that twice daily topical ocular retinopathy, and inherited retinal lymphocytes by binding to a ubiquitous LX214 treatment maintained the STT value degenerative diseases.1-7 Topical delivery (> 20 mm/min) in dogs with KCS for 30 days. offers benefits of easy application, reduced intracellular protein, cyclophilin. This risk of infection compared to complex inhibits the calcium- and implantation/injection-based systems, as well calmodulin-dependent serine-threonine FIGURE 3 as ease of dose adjustment. phosphatase activity of the CN enzyme. CN inhibition then prevents the activation of Clear nanomicellar ophthalmic solution of various transcription factors necessary for 0.2% voclosporin (LX214) in a single-use NOVEL NANOMICELLAR CLEAR the induction of cytokine genes (IL-2, IFN- LDPE, sterile BFS vial. AQUEOUS FORMULATION OF A HYDROPHOBIC DRUG gamma, IL-4, and GM-CSF) during T-cell activation. LX214 is currently in early stage

LX214, a nanomicellar formulation, clinical trials as a treatment for anterior 10 to 15 nm in size containing up to 0.2% segment inflammatory diseases, such as KCS 10 voclosporin, was developed by Lux and blepharitis. Efficacy of topical ocular LX214 Biosciences Inc. in collaboration with Dr.

administration for KCS treatment was 10 Vol No 4 Ashim Mitra at the University of Missouri, demonstrated in an outpatient 4-week dog Kansas City. The chemical structure of study. The work was conducted under voclosporin is shown in Figure 1. Voclosporin supervision by a veterinary ophthalmologist as May 2010 was developed by Isotechnika Pharma, Inc. an open-label, single-group study utilizing dogs (Edmonton, AB, Canada) for use in the diagnosed with chronic immune-mediated prevention of organ graft rejection and the KCS at the North Carolina State Veterinary treatment of autoimmune diseases, such as Teaching Hospital. Efficacy was quantified by uveitis and psoriasis. (1) tear production measurement using the Drug Delivery Technology Mixed nanomicelles are composed of 43 42-47-DDT May 2010-nanomicellar tech:Layout 1 4/30/10 3:06 PM Page 44

F I G U R E 4 in both healthy disease. In LX214 treated groups, the volunteers and maximum systemic voclosporin exposure was subjects with KCS. low (0.18 ± 0.08 ng/mL). Thirty healthy Although the five KCS patient results in volunteers (14 men the Phase I study were uncontrolled and from and 16 women) a small cohort, the objective signals of received three efficacy (STT and OSDI) are intriguing. Of consecutive doses of note, these signals were observed within 14 LX214 (one drop of days of treatment initiation, suggesting a either formulation) or rapid onset of effect. Substantially higher placebo in each eye at tissue concentrations, as determined in 4-hour intervals animal studies described further and seen in followed by evaluation Figure 6, may translate into early onset of

Mean Schirmer tear test values (± SD) of KCS dogs through 30 days of at 12 and 24 hours action and early efficacy. However, larger treatment with LX214 (n = 6). post-dosing. Five controlled clinical trials are needed to explore female patients with this further. TOLERANCE OF LX214 VERSUS moderate-to-severe KCS self-administered RESTASIS IN NZW RABBITS 0.2% LX214 twice daily every 12 hours for TOXICOLOGICAL EVALUATION 14 days, with evaluations on days 7 and 14. A pilot comparative animal study was OF LX214 (0.2% VOCLOSPORIN) In all groups, tolerability was assessed by IN ANIMALS conducted in New Zealand White (NZW) treatment-emergent ocular symptomatology rabbits to evaluate the tolerability of LX214 using the Ocular Surface Disease Index Topical ocular LX214 administration formulation containing 0.02% or 0.2% (OSDI). Safety evaluations included adverse (0.2% voclosporin) and placebo were also voclosporin versus Restasis® (oily emulsion events, Snellen visual acuity, ophthalmic evaluated in 14-day and 3-month toxicity of 0.05% CsA). Rabbits (n = 3 per treatment) evaluations, intraocular pressure (IOP), vital studies in NZW rabbits, and in a 14 day were given four consecutive topical ocular signs, and clinical laboratory evaluations. study in Beagle dogs. In all studies, LX214 administrations of LX214 or Restasis® at Additionally, systemic voclosporin exposure was administered to both eyes as 2, 4, or 8 30-minute intervals. Microscopic ocular was measured in LX214 treated subjects. topical applications daily (up to eight hourly examinations were performed prior to dosing The results showed that both LX214 applications) corresponding to doses of and at 1, 24, and 72 hours following final formulations were administration. Ocular irritation was assessed similarily tolerated using the Hackett-MacDonald Scoring F I G U R E 5 compared to placebo system.11 Mean examination scores are in healthy volunteers. presented in Figure 5. The results After the 14-day demonstrated that repeated topical ocular study, mean OSDI administration (four applications in 2 hrs) of scores were decreased either LX214 formulations was well tolerated (62 at baseline in rabbits and, at the end of treatment, LX214 compared to 42), and induced significantly less irritation than STT scores increased Vol 10 Vol No 4 equivalent ocular dosing with Restasis®. (68% and 31% for right and left eyes, May 2010 TOLERABILITY OF respectively) in the TOPICAL OCULAR LX214 five KCS female ADMINISTRATION IN HUMAN subjects. Hence, CLINICAL TRIALS (PHASE I) improvements were seen in both sign Comparative microscopic ocular irritation scores of a repeat dose acute A Phase I dose escalation study (0.02% tolerability study in NZW rabbits topically administered every 30 minutes for Drug Delivery Technology Drug Delivery Technology (STT) and symptom and 0.2% LX214 formulations) was four treatments with LX214 or Restasis. 44 (OSDI index) of the conducted in humans to evaluate tolerability 42-47-DDT May 2010-nanomicellar tech:Layout 1 4/30/10 3:06 PM Page 45

characterize systemic was well tolerated without signs of adverse F I G U R E 6 exposure. effects on specific functional and In both rabbits histopathologic ocular indices. No systemic and dogs, there were toxicity was demonstrated, and only low no dose-dependent or systemic exposure with minimal reproducible ocular accumulation was observed. In all studies, or systemic findings the no-observed-effect-levels were the after 14 days or 3 highest dose tested (~ 0.56 mg/eye/day). months (rabbits only) of consecutive daily DRUG LEVELS IN RABBIT dosing with LX214. ANTERIOR & POSTERIOR EYE Low incidental ocular SEGMENTS FOLLOWING observations of TOPICAL APPLICATION 14 minimal-to-mild ( C-LX214) conjunctival irritation 14 Mean concentrations of [ C]voclosporin (Cmax ± SD) after single or repeat (conjunctival Pharmacokinetic studies of topical topical ocular administrations (once daily for 7 days) of [ 14 C]LX214 (0.2%) in ocular [14C]LX214 (0.2% voclosporin) ocular tissues of NZW and DB rabbits. congestion, discharge) was administration to albino NZW and approximately 0.14, 0.28, and 0.56 sporadically noted macroscopically or pigmented Dutch Belted (DB) rabbits mg/eye/day, respectively (control animals microscopically, primarily in animals dosed demonstrated rapid voclosporin distribution received eight hourly placebo doses). Safety at hourly intervals, but was absent during in anterior and posterior ocular segments. and toxicity was evaluated using recovery periods. There were no other The maximum anterior and posterior ocular macroscopic and microscopic macroscopic or microscopic changes noted tissue concentrations (Cmax) of drug-derived ophthalmologic evaluation; tonometry; upon ophthalmologic examination. No radioactivity achieved after a single topical 14 electroretinography; gross and microscopic LX214 administration-related tonometry application of [ C]LX214 and once-daily pathology of the eye (including optic nerve), effects or treatment-related effects on retinal application for 7 days (NZW only) are submandibular lymph nodes, spleen, and function were observed in either species. presented in Figure 6. The drug thymus; and hematology, blood chemistry, In both rabbits and dogs, systemic concentration in both anterior and posterior and coagulation parameters. Voclosporin exposure to voclosporin was low (< 4 ng/mL) tissues was high except in the lens, aqueous, blood concentrations were measured on the after bilateral ocular dosing of LX214 and vitreous humor. No gender differences first and last days of each study to (0.2%) with eight daily applications/day up were observed. to 3 months. In Selected ocular tissues were extracted F I G U R E 7 both species, the at the Cmax and at 24 hours post single dose exposure increased or post final repeat dose (day 7). The with increasing extracted radioactivity was analyzed by dosing-frequency, HPLC coupled with fraction collection and ® TM and no gender Packard TopCount NXT analysis. Most of difference was the radioactivity (60-93%) was associated observed. with voclosporin 24 h post the final dose Vol 10 Vol No 4 Preclinical following once daily ocular administration 14 C-LX214 (ng eq/g) of [ C]LX214 for 7 days, suggesting 14 toxicity study results demonstrate insignificant metabolism occurred in the May 2010 that bilateral ocular tissues. These results also topical ocular demonstrated a lack of specific melanin

14 binding (albino NZW versus DB rabbits) as [ C]Voclosporin concentrations (mean ± standard error) in posterior ocular LX214 tissue of NZW rabbits after a single or 7 days of once-daily topical administration well as insignificant drug accumulation in administration of LX214 containing 0.2% voclosporin. (0.2% voclosporin) ocular tissues with repeat dosing. Systemic Drug Delivery Technology exposure to voclosporin was also low in 45 42-47-DDT May 2010-nanomicellar tech:Layout 1 4/30/10 3:07 PM Page 46

multiple dosing. Post single molecules like voclosporin, the intraocular F I G U R E 8 dose, the choroid/retina Cmax route is often unsuccessful because the

= 50 ng eq/g (Tmax of 1 hr) hydrophilic stroma becomes a rate-limiting in both strains. The optic barrier for trans-corneal absorption.13

nerve Cmax = 86 ng eq/g Moreover, aqueous humor in the anterior and

(Tmax of 0.5 hrs) in NZW posterior segments flow in opposite directions

and 199 ng eq/g (Tmax of and hinder the passage of molecules from the 1 hr) in DB rabbits. These aqueous humor to the lens and, subsequently, tissue concentrations were through the lens zonular spaces to the above the expected vitreous humor, thus making this an voclosporin therapeutic unfavorable pathway. The trans-scleral route threshold of ~ 30 ng eq/g. offers a more viable pathway for back-of-the- After once-daily dosing for eye delivery of hydrophilic molecules by 7 consecutive days in NZW passive diffusion through the scleral water Schematic representation of transport of a topically applied rabbits, choroid/retina and channels/pores. hydrophobic drug to the back segments of the eye. optic nerve Cmax was Hydrophobic molecules, such as

both rabbit strains after a single LX214 dose 79 ng eq/g (Tmax of 2 hrs) voclosporin, encapsulated in 15 nm

and 170 ng eq/g (Tmax of 0.5 hrs), nanomicelles, form spherical structures of (Cmax = 1.73 and 1.28 ng/mL, respectively, respectively. amphiphilic molecules in water.14 Due to their both at time to maximum concentration [Tmax] Notably, even after multiple dosing, the hydrophilic corona, these micellar of 1 hr) or after multiple doses (Cmax = drug concentration in the lens, aqueous nanocarriers can hypothetically pass through 1.16 ng/mL at Tmax of 0.5 hrs after 7 days) in NZW rabbits. humor, and vitreous humor was very low the aqueous channels/pores of the sclera, Importantly, these results demonstrate (Figure 6). This observation indicated that the which range from 30 to 300 nm in size 15 voclosporin penetration into the posterior eye corneal route was not a major drug uptake (Figure 9). Nanomicelles may then be and attainment of therapeutic drug levels with pathway. Incidentally, the low levels in the absorbed onto the basolateral side of the repeated once-daily dosing. Figure 7 presents lens, aqueous humor, and vitreous humor Retinal Pigment Epithelium (RPE) through these tissue levels following single and might suggest no effect on IOP or cataract endocytosis. Their contents are discharged formation in the eye. The low drug blood inside the cell after fusion with the cell levels, even after multiple dosing, excludes membrane.16 During the transit, the F I G U R E 9 the systemic route as a drug uptake source hydrophilic nanomicellar corona should also for posterior ocular tissues. A proposed help evade drug washout into the systemic mechanistic hypothesis is given below for circulation by the conjunctival/choroidal how topically applied nanomicellar LX214 blood vessels and lymphatics. formulations may successfully transport voclosporin into the posterior eye. SUMMARY

A NOVEL DRUG DELIVERY The presented data demonstrate that PLATFORM FOR POSTERIOR topically applied clear, aqueous, non-irritating OCULAR DISEASE TREATMENT nanomicellar LX214 formulations Vol 10 Vol No 4 successfully delivered the hydrophobic There are two potential pathways for molecule voclosporin to anterior and posterior molecules to reach posterior eye tissues May 2010 segments of the eye at therapeutic levels. This following topical administration: (1) the technology, as validated using LX214 (0.2% intraocular route through the cornea, aqueous voclosporin), opens doors for delivery of Schematic representation of how a hydrophobic humor, lens, vitreous humor, and finally drug in nanomicelles can permeate through the other hydrophobic drugs targeted for non- retina; and (2) the trans-scleral route around water channels/pores of the sclera, thus evading invasive treatment of diseases affecting the conjunctival/choroidal blood vessels and the conjunctiva, through the sclera, choroid, Drug Delivery Technology Drug Delivery Technology anterior and/or posterior ocular segments. lymphatics. and retina (Figure 8).12 For hydrophobic 46 42-47-DDT May 2010-nanomicellar tech:Layout 1 4/30/10 3:07 PM Page 47

REFERENCES BIOGRAPHIES 1. Booth BA, Denham LV, Bouhanik S, Jacob JT, Hill JM. Sustained-release ophthalmic drug delivery systems for Dr. Poonam Velagaleti, a biochemist with 20 years experience in treatment of macular disorders: present and future drug development, is currently Vice President of Preclinical applications. Drugs Aging. 2007;24:581-602. Development and Alliance Management at Lux BioSciences, a 2. del Amo EM, Urtti A. Current and future ophthalmic drug Pharmaceutical Company in New Jersey dedicated to drug delivery systems: a shift to the posterior segment. Drug development for ocular diseases. She directs preclinical research Discov Today. 2008;13:135-143. and manages alliances with research partners involved in the 3. Hughes PM, Olejnik O, Chang-Lin JE, Wilson CG. development and evaluation of various ocular drug delivery Topical and systemic drug delivery to the posterior platforms. segments. Adv Drug Deliv Rev. 2005;57:2010-2032. 4. Kaur IP, Kanwar M. Ocular preparations: the formulation Dr. Eddy Anglade is the Chief Medical Officer and Co-Founder of approach. Drug Dev Ind Pharm. 2002;28:473-493. 5. Koevary SB. Pharmacokinetics of topical ocular drug Lux Biosciences, Inc. He previously served as Vice President of delivery: potential uses for the treatment of diseases of the Clinical Development at Enzon Pharmaceuticals, Inc., with posterior segment and beyond. Curr Drug Metab. responsibilities in clinical development, R&D strategy, portfolio 2003;4:213-222. management, due diligence, and licensing/partnering activities. He 6. Mainardes RM, Urban MCC, Cinto PO, Khalil NM, also served as Medical Director/Team Leader at Roche Laboratories, Chaud MV, Evangelista RC, Gremiao MPD. Colloidal Inc. Dr. Anglade earned his MD from Yale University. carriers for ophthalmic drug delivery. Curr Drug Targets. 2005;6:363-371. 7. Mannermaa E, Vellonen KS, Urtti A. Drug transport in Dr. John Khan is currently a Consultant at Lux Biosciences Inc. He corneal epithelium and blood-retina barrier: emerging role earned his PhD in Biomedical Engineering from Rutgers University, of transporters in ocular pharmacokinetics. Adv Drug New Jersey, and has over 13 years of experience in the medical Deliv Rev. 2006;58:1136-1163. device industry in research & product development engineering. His 8. Granelli-Piperno A, Andrus L, Steinman RM. Lymphokine and nonlymphokine mRNA levels in stimulated human expertise includes advanced polymer characterization, device cells: kinetics, mitogen requirements, and effects of design, and fabrication of Class III products for vascular and cyclosporin A. J Exp Med. 1986;163:922-937. ophthalmic diseases. 9. Stepkowski SM. Molecular targets for existing and novel immunosuppressive drugs. Expert Reviews in Molecular Medicine. 2000;2(4):1-23. Dr. Brian Gilger, a veterinary ophthalmologist and ocular 10. Anglade E, Yatscoff R, Foster R, Grau U. Next- toxicologist, is the head of the Ophthalmology Service and a generation calcineurin inhibitors for ophthalmic Professor at North Carolina State University. He has nearly 2 indications. Expert Opinion on Investigational Drugs. decades of experience in ocular drug delivery, toxicology, and drug 2007;16:1525-1540. development. Specific research interests include sustained-release 11. Hackett RB, McDonald TO. Ophthalmic Toxicology and drug delivery for treatment of posterior segment and immune- Assessing Ocular Irritation. In: Marzulli FN, Maibach mediated ocular disease, such as uveitis. HI, eds. Dermatoxicology, 5th Edition. Washington, DC: Hemisphere Publishing Corporation;1996:299-305,557- 566. 12. Maurice DM. Drug delivery to the posterior segment Dr. Ashim K. Mitra is Vice Provost for Interdisciplinary Research, from drops. Surv Ophthalmol. 2002;47(Suppl 1):S41- UM Curators’ Professor of Pharmacy, and Chairman of S52. Pharmaceutical Sciences at the School of Pharmacy, University of 13. Loftsson T, Sigurdsson HH, Konradsdottir F, Gisladottir Missouri-Kansas City. He earned his PhD in Pharmaceutical S, Jansook P, Stefansson E. Topical drug delivery to the Chemistry at the University of Kansas. He has over 25 years of posterior segment of the eye: anatomical and experience in drug design and delivery with over 225 research physiological considerations. Pharmazie. 2008;63(3):171- articles and has made significant contributions in ocular drug 10 Vol No 4 179. delivery. 14. Torchilin VP. Micellar nanocarriers: pharmaceutical

perspectives. Pharm Res. 2007;24(1):1-16. May 2010 15. Komai Y, Ushiki T. The three-dimensional organization of collagen fibrils in the human cornea and sclera. Invest Ophthalmol Vis Sci. 1991;32(8):2244-2258. 16. Hu X, Jing X. Biodegradable amphiphilic polymer-drug conjugate micelles. Expert Opin Drug Delivery. 2009;6(10):1079-1090. Drug Delivery Technology Drug Delivery Technology

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SORBENT APPLICATIONS

Incorporating Sorbents Into Drug Delivery Technology By: Adrian Possumato

INTRODUCTION Drug delivery technologies are evolving at a rapid rate with new drug product formulations and enhancements in current drug delivery device designs. Treatments for chronic conditions and growth in patient-administered drugs are factors leading to greater focus on ease-of-use and convenience. While these developments offer tremendous potential in the marketplace, they also pose some unpre cedented challenges to manufacturers. With new drug formulations becoming increasingly unstable and the advent of user-friendly device designs, manufacturers must seek solutions that can ensure drug delivery technologies work effectively. Drug formulations are subject to a variety of degradation pathways that compromise drug safety and shelf-life. By far, the most frequent mechanisms of degradation a re caused by hydrolysis and oxidation, mainly due to moisture and oxygen ingress through packaging and materials of construction. An important means to confront these threats is the adoption of sorbent technology. Sorbents, also termed active packaging components, are designed to adsorb moisture, oxygen, odors, and/or volatized hydrocarbons to protect drug formulations from degradation and extend shel f-life through the supply chain and consumer use. They can be incorporated into drug product packaging or device designs in a variety of ways: a sachet can be inserted into a package, a compressed sorbent can be fitted into a drug delivery device, a thermoformed sorbent can serve as a structural component, etc. Sorbent technology must be considered an integral part of all drug delivery technologies. In fact, it is increasingly important for manufacturers to incorporate sorbent technology much earlier in the product development and design process than has previously been the case.

IMPACTING FACTORS products need to be compact, portable, used to create molded components and easy to use if they are to be built into drug delivery devices. By effective. Also, treatments for chronic molding the desiccant directly into the Vol 10 Vol No 4 One must pay careful heed to the conditions need to be integrated into device itself, designers can create the three critical factors when considering the lives of patients to truly render the smallest possible profile without how sorbent technology should be May 2010 benefits of the therapy. Additionally, sacrificing other performance integrated into a drug delivery device: these drugs must retain their efficacy parameters. This approach is convenience, formulation stability, and even when exposed to a wide range of particularly useful when patients are new drug delivery technologies. unpredict able environments. required to carry the device with them Convenience has far-reaching and These factors have led to the in their daily lives. very real influences in the success or Drug Delivery Technology Drug Delivery Technology development of innovative built-in The increasing trend of failure of a treatment. Patient- 48 sorbent solutions, such as polymer- complexity of drug substances and/or administered drug/device combination desiccant blends. These blends can be drug products is another factor that 48-50 -DDT May 2010 -Sorbent Applications:Layout 1 4/30/10 2:45 PM Page 49

SORBENT AP PLICATIONS

has placed greater importance on by volatized hydrocarbons and moisture. Multisorb's DesiMax® Desiccant Label moisture and oxygen control to maintain A range of similar applications can be is a pressure-sensitive desiccant label formulation stability. New successfully stabilized using a sorbent easily applied and designed to blend in pharmaceuticals are coming into the that combines moisture-regulating with the interior of the transdermal market based on chemistries that were capability with oxygen absorption and patch pouch. DesiMax SLF® is a previously considered too unstable to volatilized hydrocarbon management. blended hot-melt adhesive/desiccant that commercialize as viable therapies. has proved to be an extremely versatile Thanks to new formulation and delivery method for adsorbing moisture within INCORPORATING SORBENTS technologies, some of these molecules packaging. It is also available in INTO NEW DRUG DELIVERY are being reintroduced into drug product TECHNOLOGIES pressure-sensitive tape formats. formulations that can be tested clinically Designing a sorbent into the packaging and eventually manufactured and sold. Incorporating sorbent technologies through a label provides a flat, For these types of formulations that into drug delivery technologies is a multifunction component that saves were previously unstable, sorbent critical step in the successful space, simplifies use for patients and technologies can play a critical role in commercialization of new therapies. medical workers, and is effective in ensuring drug product efficacy through Examples of two such applications can preventing hydration and crystallization the shelf- life of the device. While be seen in transdermal therapy systems of components. Other label types, such ® traditional sorbent technologies can and respiratory drug delivery devices. as Multisorb’s StabilOx Labels, can reduce moisture content within an provide oxygen-absorbing capabilities enclosed space, solutions for unstable Transdermal Therapy Systems that prevent oxidation of hormone-based formulations need to control and The arena of transdermal transdermal patches. regulate moisture to a specified level to applications has seen significant As transdermal delive ry systems avoid product degradation. Finding this developments recently. Transdermal become more widespread and more delicate moisture management balance delivery offers patients convenience and complex, sorbent technology will is crucial for successful controlled dosage over time. A wide become more central in their commercialization of new drug range of transdermal options exists for development. The important factors of products. delivering drugs to patients. These convenience and effectiveness all work Finally, there are new and unique include passive transdermal systems, in tandem to ensure a successful technologies for drug delivery that are such as gel reservoir and matrix patches, transdermal product.

so different from traditional delivery and active transdermal systems like 10 Vol No 4 methods that they require entirely new ionthophoretic, radio frequency ablation Respiratory Drug Delivery thinking about controlling the moisture Devices matrix, and microneedle systems for May 2010 in packaging, storage, and/or during transcutaneous or intradermal drug There are important concerns for device use. delivery. respiratory treatments centering on For example, innovative For transdermal applications, moisture, hydrocarbon, and/or oxygen dru g/device combination products that sorbents are usually incorporated into management. Numerous device combine electrical components would presentations require sorbent technology the packaging itself. For example, Drug Delivery Technology need protection from corrosion caused solutions: HFA (hydroflouroalkane) 49 48-50 -DDTMay2010-SorbentApplications:Layout14/30/102:45PMPage50

50 Drug Delivery Technology May 2010 Vol 10 No 4 In some cases, the pre-measured drug pre-measured the cases, some In reservoir, each with highlyspecific with reservoir,each amount the devicebyreducing DPI the of performance the compromise could the DPI device itself. Reservoir DPI Reservoir deviceitself. DPI the into incorporated are packages product d pre-measured with (DPI) powderinhalers dry inhalers, dose metered aerosol silica gel or molecular sieveto maymolecular lead or gel silica of made sorbent consistent. simple A moisture management needs. In the pre- the In needs. management moisture and pre-measured formats, distinct inhaled. is that product drug of doses, and DPIs with a reservoir of drug of reservoir a with DPIs and doses, capsules, or other small pouches, which pouches, small other or capsules, blisters, in contained is product drug separatelypackaged format, measured humidity of the container holding the holding container the of humidity relativeover-drying,the reducing are inserted into a DPI d DPI a into inserted are (consumer use) stability profiles. The profiles. stability use) (consumer secondary and primary their both during agglomeration subsequent and hydration preventparticle to moisture manage to desiccants customized product. This excessively dry state could promote could excessivelystate This dry lowpercentage. very powdera downto potency and stability of the particles the of stability and potency materials in a device (eg, plastics and plastics device(eg, a in materials dissimilar when particles of charge static must be maintained so that airfl that so maintained be must triboelectrification t triboelectrification foil) come in close proximity.close in come foil) The SORBENT P A ispersion of the drug is accurate and accurate is drug the of ispersion DPIs deliver drug formulation in twoin formulation deliverdrug DPIs DPIs, in particular, often require often particular, in DPIs, PLICATIONS hat might result might hat evice before use. evicebefore ow arrive at an optimized level of moisture levelof optimized an at arrive management for primary and secondary and primary for management employedis to formats delivery sorbent intelligent these of use synergistic solutions. Verycoordinated,the often, polymers)(sorbent built-in or sorbents), (compressed fit-in sachets), (sorbent technologies have been thought of as the as of technologieshavethought been central. Traditionally,sorbent s drop-in include formats Delivery sorbents. intelligent these in included be can hydrocarbonmanagement required,If and oxygenfree). could very well determine the success of success the welldetermine very could market. to drug deliveringa in step last more become technologieswill sorbent a treatment both medicallyand both treatment a Today,delivery a of functionality the of diverse,adoption and complex more measuring doses for inhalation. for doses measuring device,DPI the from product drug of reservoir central a devicesincorporate commercially. Howsorbent treatment. drug a of success the break or make can system sorbents can be deployedthe be for can sorbents technology is incorporated into deliveinto incorporated technologyis management of moisture based on the on based moisture of management device design and drug product drug and devicedesign formulation (lactose carrier or carr or carrier (lactose formulation tability for the DPI device.DPI the for tability As drug delivery systems become systems delivery drug As In either instance, intelligent instance, either In SUMMARY ier- ry the pharma the more than 15 years of experienceofin years 15 morethan pharmaceuticalformulations. has He stabilize to packagedsorbents determine the best selection ofselection best determinethe and manufacturingand departmentsto R&D, quality,R&D, regulatory, engineering, pharmaceuticalmanufacturerstheir in genericandinnovators drug with closely works He NY). 849-3005. [email protected](908) or Multisorb Technologies,Multisorb Inc.(Buffalo, HealthcarePackaging- Directorwith Adrian PossumatoAdrian industries. He can be reachedat industries.be can He ceutical and chemicalandceutical Y H P A R G O I B is the Global the is 51-54-DDT May 2010-Topical Aesthetics:Layout 1 4/30/10 2:46 PM Page 51

TOPICAL AESTHETICS

The Importance of Incorporating Aesthetics Into Topical Formulations By: Gary Watkins, MS

INTRODUCTION There are many ways to administer a drug to a patient, and patient compliance with each route can be affected by the properties of the dosage form (formulation). Therefore, the formulator of a drug product should not only consider the drug delivery aspects of the final product, but also the aesthetic properties of the finished product in an effort to minimize patient non-compliance result ing from a formulation that is effective, but unpleasant to use. The following will focus on topical formulations for the delivery of actives to the surface of tissue, usually skin. Furthermore, the article will be limited to a consideration of emulsion-based vehicles, such as lotions or creams, that deliver the active pharmaceutical ingredient (API) or other ingredients onto, into, or through the skin. Briefly, an emulsion is a two- phase system prepared by combining two immiscible liquids, in which small globules of one liquid are dispersed uniformly throughout the other.1 Typically, the liquids are some type of oil and water. Attempting to make these immiscible liquids thermodynamically and physically stable requires incorporating other ingredients or excipients, such as surfactants, thickeners, and preservatives. Because the incorporation of such excipients can affect the way the formulation feels when applied to the skin, the formulator should make an informed choice when choosing them, and the resulting formulations should be tested for aesthetic appeal. Currently, formulators of topically applied preparations are compelled to meet consumer demand for skin care products that combine per formance with pleasing aesthetics. Although skin feel has always been a key aesthetic parameter, consumers increasingly select skin care products based on a more complete sensory experience and pay attention to product texture, appearance, skin feel, and scent.2 They also desire products that contribute to a sense of well-being, through visual aesthetics of the formulation, tactile effects on applicatio n, aroma, and the performance of active ingredients, such as vitamins or sunscreen. Sensory expectations are related to culture, age, skin type, gender, setting, and climate. In the case of climate, for example, light, dry products with minimal residue are often preferred for day wear, particularly in warm regions. In contrast, rich, viscous creams designed for moisturization or protection are ofte n sought for night wear or during cold weather. For a skin care product to be successful, its sensory characteristics must be specifically developed and produced in a way that appeals to the user.

THE STRUCTURE OF SKIN lipid layers. The lipid composition among The sensory perception of the the epidermal layers varies from one layer emulsion on the SC can be as different as No discussion of the effect of topical to another. Polar phospholipids, which are the individual users themselves. formulations on the skin would be complete components of living cell membranes, are Furthermore, the area of the body where without discussing the skin organ itself. The absent in the dead cells of the SC. These the formulation is designed to be applied

barrier function of the skin prevents both phospholipids form bilayers, and their acyl could determine the type and amount of 10 Vol No 4 water loss and the entrance of external chains can exist in amorphous and liquid excipients to be used. Certain ingredients agents. The skin consists of two distinct crystalline forms. The transition between may be acceptable for foot application but these two forms occurs at certain not for a formulation that is to be applied to layers; the epidermis and dermis (Figure May 2010 1).3 The epidermis consists of three main temperatures without the loss of bilayer the face. People with drier skin may prefer layers, the stratum corneum (SC), the structure. The principal lipids of the SC are creams for their moisturizing properties, granular layer, and the basal layer. The SC ceramide and fatty acids. Although the SC whereas those with oilier complexions may is considered the most important barrier to does not contain phospholipids, the mixture prefer the lighter feel of lotions. Less drug transfer. It is a heterogeneous non- of ceramides, cholesterol, and fatty acids is viscous formulations, such as lotions, are living structure, formed by keratinized capable of forming bilayers. These lipid better suited for application on larger cells, protein-rich cells, and intercellular bilayers provide the barrier function of the surface areas and regions with greater hair Drug Delivery Technology SC. density as they are easier to spread and do 51 51-54-DDT May 2010-Topical Aesthetics:Layout 1 4/30/10 2:46 PM Page 52

TOPICAL AESTHETICS

not cause uncomfortable pulling of the hair. The formulator may minimize skin irritation F I G U R E 1 by using wholly aqueous vehicles rather than those containing alcohol or certain permeation enhancers. Poor compliance is more common in topical treatment compared to systemic treatment.4 Application of a topical product is more time consuming than “popping a pill.” Sometimes the smell of a topical medicament is a deterrent to its use, or it may be that it stains clothes or is messy. Some may cause a stinging or burning sensation, or redness at the point of application. All of these affect the adherence to dosing or application. Granted, oral formulations present their own unique challenges to compliance, but the cosmetic elegance of a topical formulation is extremely important in developing topically applied products and is often the key to the success of the product. For example, the delicateness with which a topical product can be applied or the avoidance of a greasy or tacky feel can be paramount.

SOME KEYS TO TOPICAL Basic Human Skin Structure FORMULATION gain the sensory experience necessary to pacemakers. What is new to the Traditionally, a formulator will receive differentiate and select a product prototype pharmaceutical world, however, is the the API with general physicochemical that is likely to be accepted. For example, commercialization of a broad range of information along with an ideal product experience may inform the formulator that the silicones for topical semi-solid (emulsion) profile based on marketing data. Initially, the whitening occurring as the small sample of formulations that positively impact treatment formulator could perform systematic formulation is rubbed and spread on the skin compliance and product differentiation. solubility studies on the API with solvents could be the result of foaming and may be that are generally regarded as safe (GRAS), remedied by adding a small amount of COMPLIANCE DEPENDS ON along with gaining insight into the specific silicone fluid to the formulation. The result of AESTHETICS disease the API will treat. For example, the multiple evaluations of various prototypes patients with rosacea claim to be sensitized to and improved formulations should be the Being too greasy, and whitening of skin oily products, so the recommended successful selection of an optimized drug on application, are among the leading de Vol 10 Vol No 4 formulation prototypes should contain a livery vehicle. concerns stressed by consumers and patients minimum amount of oil in the emulsion. Silicones were introduced for use in skin alike regarding topically applied formulations When the prototypes have been prepared, the care applications in the 1950s and have since with undesirable aesthetics. A topical become so widely used that now, more than prescription medication may be very May 2010 formulator will test a small amount on the back of their hand or forearm to assess the half the consumer skin care products contain efficacious; however, if it has poor aesthetics, 5 feel of the formulation. This part of some silicone. Silicones are also not new to the product will not be used or applied often development has been referred to as the “art the pharmaceutical and medical world; they enough to reap the benefits. The sensory of formulation” and like art, it is open to are used as transdermal delivery systems, as properties of excipients can be important interpretation. Usually, it takes years of antifoams in the production of vaccines, and factors in assisting patients and consumers practice and a great deal of trial and error to as raw materials of construction for catheters who do not comply with treatment regimens Drug Delivery Technology Drug Delivery Technology and specialized medical devices like or product application because their topical

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TOPICAL AESTHETICS

combination of low pH, drying of the skin by F I G U R E 2 the alcohol, and a lack of aesthetic feel. Indeed, repeated application of these solutions may disrupt the equilibrium of the skin and may in particular irritate, or even burn it. In order to overcome some of these issues, Mathur and Sewell suggested a method of stabilizing free L-ascorbic acid from oxidation by dispersing the free acid in a mixed glycol carrier.8 The carrier contains a mixture of at least propylene glycol and butylene glycol, but may contain other glycols, such as polyethylene glycol, along with stabilizing and solubility-assisting agents. From this, an emulsion may be prepared incorporating this mixed glycol carrier in the aqueous phase, without the use of alcohols or lowered pH.

QUANTITATION OF SENSORY PERCEPTION Sensory Profile Comparison of Two Water-in-Oil Creams Apart from the required tests for topical preparations have poor aesthetics. Poor patient or eryhtema (redness). This occurrence has formulations, such as preservative compliance and its impact on treatment failure been apparent for formulation chemists, for effectiveness, stability, human patch for is a growing concern. A recent journal article example, in the challenge of formulating a sensitivity, and erythema, there will be estimated the economic impact in the US at stabilized vitamin C (L-ascorbic acid) for aesthetic testing to support marketing claims $100 billion annually due to excessive use of topical application.8 For many years, usually performed by clinical or marketing healthcare resources in response to medication researchers have been investigating methods personnel. A panel of subjects, typically noncompliance.6 For example, psoriasis has for stabilizing L-ascorbic acid due to its volunteers or colleagues, will test samples of been a focus of the dermatology community in beneficial properties. Indeed, L-ascorbic acid the topical formulations and record their an effort to understand the causes of has many known biological functions, such as sensory experiences as a result of applying the medication non-compliance. It has been the stimulation of collagen synthesis, the product. Their remarks will be tabulated reported that more than one third of psoriatic strengthening of skin tissue against external utilizing a numerical system similar to a patients are not compliant with their attack, depigmentation, activity against free hedonic scale with, for example, one being the prescribed medication. radicals, and the compensation for vitamin E lowest and eight the highest in categories such Another study of psoriatic patients links deficiency. However, due to its alpha-keto as greasiness, tackiness, ease of application, medication compliance and successful patient lactone structure, L-ascorbic acid is very etc. The sensory evaluation is designed to outcomes.7 The vehicle-related factor that the sensitive to the influence of environmental compare the product-specific or formulation- “medication felt unpleasant” was rated as parameters, such as light, oxygen, and water. specific differences on each sensory property.5 important, while the “medication stained An unavoidable degradation of L-ascorbic acid

Wetness, spreadability, and speed of 10 Vol No 4 clothing” factor and the convenience of in solution occurs over time due to its pH and absorbance (absorbency) are evaluated before application (“application was time- the presence of trace metals. In order to reduce product absorption, whereas gloss, film consuming”) factor were rated as some of the or delay the degradation of L-ascorbic acid in

residue, greasiness, silkiness, and slip are May 2010 most important issues. Choosing a fast-drying solution, previous science recommends evaluated after absorption. In the sensory vehicle that is easy to apply may improve stabilization by introducing it into aqueous- evaluation testing, “absorption” means the usage in patients concerned about alcoholic solutions formed using up to 20% perception of absorption felt by the subjects. It inconvenience of application. alcohol and having a pH below 3.5. Skin pH is does not mean the product is biologically An additional situation that may hinder approximately 5.5, so the pH of the absorbed by the skin. Tackiness is evaluated compliance by the recipient is whether the formulation may change following application. before and after absorption. The numerical

other ingredients leave an undesirable effect These solutions are not usable in the cosmetic Drug Delivery Technology values are plotted as a spider web diagram to on the skin after application, such as dryness and/or pharmaceutical field because of a allow formulation comparisons to be made. 53 51-54-DDT May 2010-Topical Aesthetics:Layout 1 4/30/10 2:46 PM Page 54

TOPICAL AESTHETICS

F I G U R E 3 REFERENCES

1. Swarbrick J, Rubino JT, Rubino OP. Remington: The Science and Practice of Pharmacy. 21st Ed. Lippincott Williams & Wilkins: Philadelphia, PA;2006. 2. Van Reeth I, Corel B, Van Doorn S. Beyond Skin Feel: Innovative Methods for Developing Complex Sensory Profiles with Silicones. Dow Corning Europe. Form No. 27-1072A-01. 2003. 3. Sinko PJ. Chapter 22: Drug Delivery Systems. Martin’s Physical Pharmacy and Pharmaceutical Sciences. 5th ed. Lippincott Williams & Wilkins: Philadelphia, PA;2006. 4. Valia RG. Non-compliance in dermatologic diseases. Ind J Derm Ven Lep. 2008;74(6):553-557. 5. Séné C, Neun D, Tan-Sien-Hee L, Ulman K. Silicones as Excipients for Topical Pharmaceutical Applications: The Silky Touch Product Family. Dow Corning (Life Sciences). Form No. 52-1034-01, 2002. 6. Lee IA, Maibach HI. Pharmionics in dermatology: A review of topical medication adherence. Am J Clin Dermatol. 2006;7(4):231-236. 7. Schalau II GK, Ulman KL. Silicone Excipients in Sensory evaluation (paired comparison) of an all-petrolatum ointment versus an ointment containing Drug Development. Cont Pharm. June 2009. Website petrolatum and silicones. Percentages indicate level of confidence, and the ratings for absorption were visited: based on panelists’ perceptions, not biological skin absorption.7 www.contractpharma.com/articles/2009/06/silicone- excipients-in-drug-development. 8. Mathur R, Sewell NJ. Stabilized Vitamin C Figure 2 is a spider web diagram SUMMARY Formulations. US Pat No. 6087393. App. No. summarizing the results of one such sensory 09/328608. 2000. 9. Wegener, MR. PhD Thesis: A Psycho-Rheological panel test comparing two water-in-oil This article emphasized the importance Study of Skin Feel. Univ of Bristol. UK. 1997. creams; one based on a silicone elastomer, of considering product aesthetics (the feel or and the other on a silicone gum. Note how the effect on the skin) when formulating topical cream containing the silicone elastomer products. Generally, the feel of topical spreads more easily and has a higher formulations has been determined by BIOGRAPHY absorbancy. In contrast, the cream containing individual perception. For products containing the silicone gum is more tacky and greasy, APIs, the formulator should choose Gary Watkins is but also more glossy and silky. compendial excipients or those listed in one a Formulation Similarly, Figure 3 shows the differences of the respective Pharmacopeia (USA, Scientist in the between formulations based on petrolatum Formulation Services Europe, or Japan) where possible, especially Department of compared to those based on silicone fluids. when the topical formulation is intended to be Particle Sciences, These comparisons can be used to develop Inc. Presently, his Vol 10 Vol No 4 a product prescribed by dermatologists. The state-of-the-art consumer products that meet research interest is in FDA recommends the safety evaluation of nanotechnology and special needs and correspond to potential new excipients that are intended for the effect manufacturers’ individual product positioning. nanoparticles have

May 2010 use in topical drug products. Although each In order to make aesthetically driven on the efficacy of excipient should be justified by function and active ingredients. In formulations more rational and scientifically need in a formulation whether for prescription his nearly 20 years of experience in the industry, based, as well as remove the subjective or personal care preparations, in order to his primary focus has been in the development of component of development, attempts have ensure maximum usage compliance, formulations for application in skin health, been made to correlate certain sensory having co-authored a formulation patent for the formulators should strive to formulate a treatment of rosacea. Mr. Watkins earned his BS perception values with measured physical topical product with pleasing sensory and MS in Pharmaceutical Sciences from the Drug Delivery Technology Drug Delivery Technology properties of the formulation, such as qualities and confirm their performance with University of Buffalo. rheology.9 This approach has yet to gain 54 meaningful tests employing expert panels widespread use. and/or consumer testing. 55-57-DDT May 2010-DDE MB :Layout 1 4/30/10 2:47 PM Page 55

PERFORMANCE EXCIPIENTS: FINDING A ROLE IN THE PHARMACEUTICAL FUTURE

n 1995, Mallinckrodt Chemical and J.T.Baker formed Mallinckrodt Baker, Inc., a global chemical company that offers two brands - the Mallinckrodt® and J.T.Baker® Herman Mitchell Director of Global brands of high-purity products for the laboratory, biopharmaceutical, Marketing II microelectronic, and industrial markets. Mal linckrodt Baker is a basic manufacturer of Mallinckrodt chemicals with plants and distribution centers around the globe in Deventer, The Baker, Inc. Netherlands; Mexico City, Mexico; and Kuala Lumpur, Malaysia; as well as our US- based operations in Phillipsburg, NJ; and Paris, KY. The company launched its “We are preparing to PanExceaTM performance excipient portfolio in July 2008, addressing multiple drug launch several new PanExcea performance delivery systems through immediate-releas e (IR) and oral disintegrating tablet (ODT) excipients to give us a technologies. At the same time, Mallinckrodt Baker entered a strategic business more comprehensive agreement with Rubicon Research, putting them in position to take a global leadership range of products for emerging marketplace role in the development and commercialization of performance excipients. Drug needs. We plan to offer Delivery Technology recently interviewed Herman Mitchell, Director of Global controlled-release, extended-release, and Marketing for Mallinckrodt Baker, to discuss his company’s unique performance sustained-release excipient brand and its role in future pharmaceutical technology. products to make the PanExcea product line more versatile and Q: Let’s start with some additional J.T.Baker® and Mallinckrodt® chemicals, supported by functional for our background about the history of strong quality control systems. customers. In fact, these Mallinckrodt Baker and the current Our market objectives are to collaborate with new projected launches customers to increase speed to market while 10 Vol No 4 are based on feedback structure of its business. we’ve heard from the providing risk mitigation, proactive applications marketplace regarding support, and assurance of regulatory compliance. We

A: Mallinckrodt Baker, which is a business unit of May 2010 the success of the IR and Covidien, a leading global provider of healthcare also offer the capabilities to design and manufacture ODT excipients.” products, was formed in 1995 when Mallinckrodt specialty chemical solutions, including bulk Chemical and J.T.Baker, Inc. merged, resulting in a pharmaceutical excipients, biopharmaceuticals, new organization with more than 150 combined years process chromatography media, and process

of experience. Today, we offer two global brands, intermediates. PanExcea performance excipients will Drug Delivery Technology

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56 Drug Delivery Technology May 2010 Vol 10 No 4 servesas the building block for the formulationof a variety of active Q: TellPanExceaabout us helpus extend the range of services and canalso offer full regulatory support for more efficient drug development and A: competition. your whatdifferentiatesfrom them and performanceexcipients pharmaceuticaling supportthat we can offer. manufacturing. The PanExcea family of manufactured using novel particle ourcustomer applications. PanExcea engineering technology designed to provide excipientsare currently available for IR excipients features homogenous particles, ODTs. Thisproduct offers flexibility to multifunctional properties and enhanced helpcustomers achieve cost-effective high andODT applications manufactured by designed to enable implementation of performance with the objective directcompression; however, PanExcea Quality by Design (QbD) drug initiatives performanceby combining two excipientsfor other drug delivery systems while minimizing formulation complexity arein development. as much as possible. linecan help our customers meet their lineare composed of highly characterized, objectives.One of our performance widelyused Generally Regarded as Safe excipients,PanExcea MC200G (GRAS)pharmaceutical ma Allproducts in the PanExcea product Here’san example of how this product PanExcea performance excipients are redients(APIs) into terials. We of faster, ODT, packagingequipment. Thathelps eliminatethe costs of ODT technology thatdisinteg licensingand new equipment investment. dispersedin the mouth, while offering Q:HowPanExceathehas mentioned,we are preparing tolaunch platformbeenreceived thein goodtaste and texture. Theproperties of receptionofour PanExcea platform, and severalnew PanExcea performance marketplace?youCan PanExceaMC200G also help our provideupdatehowanon excipientstogive usmorea customersare beginning toadopt our IR theseproducts have customersgain increased APIloading performed sinceJuly 2008? comprehensiverange ofproducts for andODT excipient produc capacityalong with good taste-masking. A: emergingmarketplace needs. Weplan to Finally,PanExcea MC200G is engineered offercontrolled-release (CR), extended- toreduce per-tablet cost for our customers ingredientsthat interact at a sub-particle release(ER), and sustained-release (SR) becauseit’s an excipient-based solution level. Thatfeature is designed to enhance productstomake the PanExcea product thatuses standard manufa linemore versatile and functional for our desirableaspects and mask undesired propertiesof individual excipients. This,in customers.Infact, these new projected turn,helps launchesare based onfe Weare pleased with the market our customers provide a tablet ratesrapidly and is widely edbackwe’ve cturingand ts. AsI enabled us to offer the kind of ODT of kind offerthe to us enabled h Q: a developyou did Why Baker’sforstrategy Q: Mallinckrodtis What the kind of support and service service and support of kind the bybacked products, application-based with providecustomers technologyto taste-masking, is an ideal co ideal an is taste-masking, as such areas, specialized in expertise need. customers Their our product heardfrom the marketplace regarding the drug products cost effectively,cost products drug What advantage does it advantagedoes What Rubicon? with partnership PanExcea technology? Acceptancecan take six orseven years, regulatory needs. regulatory efficiently,global meeting while provide to you and your and youprovide to A: A: customers? successofthe IRand ODT excipients. possiblymore, depending onthe product. Thatmeans our PanExcea platform, Additionally,we’re collaborating with our launchedless than two years ago, isstill a customerstohelp usoffer the features relativelynew market entry. theywant and bring these products to marketmore quickly. PanExceaexcipients, we’ve also kept in mindthe fact that marketplace acceptanceofnewa concept orproduct canbeslow inthe pharmaceutic elps customers developnext-generationcustomers elps Whenevaluating the performance of Partnering with Rubicon has Rubicon with Partnering PanExcea use to is strategy Our mbination alarena. that 55-57-DDT May2010-DDEMB:Layout14/30/102:47PMPage57 u Baker’s Certified Excipient Baker’s Certified Q: Mallinckrodtdoes What creating ownin experienceour with A: RubiconResearch’s industry-leading performanceexcipients and in particle pharmaceutical companies? companies? pharmaceutical programDistributoroffer we can collaborate with Rubicon to help to Rubicon with collaborate wecan formulation, a in excipients performance develop a complete solution. Workingcomplete developa expertisein formulation and drug delivery (CED)program aligns Mallinckrodt with Rubicon, we can deliver not onlya deliverwenot can Rubicon, with engineering. Thatcombination puts us in offer to our customers. our offerto wecan services of range the extends value-added proposition that wefeel that value-addedproposition manufacturer.It’sthe for instructions a and resources, information, of dossier complete a but formulation, finished Bakerwith select channel partners to technologywill assist us in providing excellentposition to enter global additionalleading-edge products for the customermarkets and play aleadership CR,ER, and SR market segments. rolein the development and commercializationof performance extensive network of customers in the in extensivecustomers networkof global pharmaceutical industry and a and industry pharmaceutical global This means that when a customer a customer a when that means This systems. dispersed and forms dosage solid oral in record track solid excipients. Aswe expand our presence as asupplier of performance excipients throughoutthe pharmaceutica s the best way to use one of our of one wayuse best to the s R OurCertified Excipient Distributor ubicon Research also has an has also Research ubicon

llandscape, sks knowledgedevelops. Baker an ideal partner? partner? ideal an Baker Q: Mallinckrodtmakes What asre-palletizing products at the distributor documentedchain of custody, A: managementof change services, and bulkpharmaceutical development and site,incoming inspection, chemical assurancethat the distributor is operating manufacturing,so our customers can be inventorymanagement, special product confidentthat as apartner we can act as inan environmentally monitored facility. providethe pharmaceutical industry with labeling,and less-than-truckload anextension of their business. We’re Inorder to achieve certified status, each shipping.Mallinckrodt Baker is actively anoptimized supply chain that’s committedto working with our customers compliantwith the International auditingother channel partners worldwide channelpartner must pass an audit tomeet objectives like increased speed to PharmaceuticalExcipient Council’s andexpects to expand its list of certified conductedby our quality department to market,supply chain risk mitigation, (IPEC)guidelines for Good Distribution ensurethat they are compliant with IPEC distributorsin Europe and Asiain the Practices future. Weexpect the CED program to GDPguidelines. growin value as excipient t excipientdistribut TheCED program provides a Allcertified Mallinckrodt Baker Wehave along history of expertise in (GDP). orsoffer services, such echnologyand Baker’sforstrategy Q: Mallinckrodtis What Inc., unless otherwise noted. Mallinckrodt noted. otherwise unless Inc., Baker,MallinckrodtTrademarks by owned are h Q:the on is What there any new anythere MallinckrodtBaker? Are trademark of Mallinckrodt Inc. Mallinckrodt of trademark PanExcea technology? A: soon? expect can we announcements regulatorycompliance. arevery excited for future products from technologyto provide customers with A: CR,ER, and SR excipient products, we application-basedproducts, backed by the haveseveral other strategic initiatives in MallinckrodtBaker. kindof support and service that helps thepipeline. Some of these involve customersdevelop next-generation drug developingnew technology in-house, whileothers focus on collaboration and productscost-effectively, efficiently, and licensing.Ultimately, our future whilemeeting global regulatory needs. developmentswill be designed to enable thenext gener proac Ourstrategy is to use PanExcea Inaddition to the projected launch of tiveapplication support, and ationof dosage forms. We u orizon fororizon ® is a is

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MDI COMPONENTS PREFILLABLE DELIVERY SYSTEMS

BD Medical - Pharmaceutical Systems is dedicated to developing prefillable drug delivery systems designed to fit the needs of the pharmaceutical industry. BD offers a 3M Drug Delivery Systems has been a major supplier of metered-dose range of products, inhaler valves and canisters for more than 50 years. As the developers of including glass and the first CFC-free MDI, we are experienced at overcoming the challenges plastic prefillable syringes, a nasal spray system, and a variety of self- that designing components for use with CFC-free propellants presents. 3M injection systems. We deliver cost-effective alternatives to conventional is the only MDI component supplier that manufactures both valves and drug delivery methods, which differentiate pharmaceutical products and canisters, allowing optimization of these components simultaneously, contribute to the optimization of drug therapy. With a broad range of ensuring compatibility, while delivering the convenience of a single source. innovative systems and services, BD provides pharmaceutical companies For more information, contact 3M Drug Delivery Systems at (800) 643- with support and resources to help them achieve their goals. Our 8086 or visit www.3M.com/dds. worldwide presence, market awareness, and pharmaceutical packaging know-how allow us to propose suitable solutions for all regional markets and parenteral drug delivery needs. Only BD offers the range and depth of expertise and packaging solutions to guide your drug from early phase development through product launch and beyond. For more information, contact BD at (201) 847-4017 or visit www.bd.com/pharmaceuticals.

PHARMACEUTICAL SOLUTIONS ORALLY DISINTEGRATING TECHNOLOGIES

CIMA LABS INC. a world leader in the drug delivery partnering business, specializes in the formulation, taste-masking, and manufacturing of pharmaceuticals utilizing our orally disintegrating tablet (ODT), oral transmucosal (OTM), tamper Catalent Pharma Solutions is a world leader in patented drug delivery deterrent, solubilization, and technologies. For more than 70 years, we have developed and oral powder drug delivery manufactured advanced drug delivery systems and partnered with ® Vol 10 Vol No 4 technologies. OraSolv , nearly every major global pharmaceutical company. We continually work DuraSolv®, and LyocTM ODTs disperse quickly in the mouth without to advance the science of drug delivery and enhance the therapeutic chewing or the need for water. OraVescent® is an oral transmucosal and market performance of our customers’ drugs. Our advanced drug tablet that can be administered buccally or sublingually. OraGuardTM May 2010 delivery technologies bring new options to resolve the technical extended release/tamper deterrent technology provides a robust challenges development scientists face every day. These patented extended release PK profile, even during co-administration with technologies can improve the odds of successful formulation by alcohol, and is resistant against various tampering methods. CIMA enhancing bioavailability, optimizing the rate of release, and targeting has proven commercialization success with more than 20 products ® the site of absorption. Our technologies include softgel and Vegicaps marketed in more than 70 countries around the world. For more ® Soft capsules; Zydis fast-dissolve dosage form; modified-release information, contact CIMA at (763) 488-4843 or visit technologies; and a range of inhaled technologies, including MDIs, DPIs, www.cimalabs.com.

Drug Delivery Technology Drug Delivery Technology nasal sprays, and solutions/suspensions for inhalation, nebulizers, and liquid inhalers. For more information, contact Catalent Pharma Solutions 58 at (866) 720-3148 or visit www.catalent.com. 58-61- DDT May 2010-Tech Showcase:Layout 1 4/30/10 2:48 PM Page 59

FORMULATION SERVICE NGI CUP COATER

The NGI cup coater is a new tool from Copley Scientific for use in semi- automated inhaler product testing. The Next Generation Impactor (NGI) is used increasingly for aerodynamic particle size measurement, as prescribed by the HyperStart® is a service specially designed to provide a starting regulators for all inhaled formulation for solid oral dosage (SOD) forms, which deliver immediate- drug products. Applying a sticky layer to the cups of the impactor and extended-release profiles. The HyperStart predictive formulation improves measurement accuracy, particularly for DPI formulations, by model is based on broad experience for design of immediate- and reducing particle bounce and re-entrainment. Copley Scientific’s NGI cup extended- release SOD forms, and is supported by mathematical coater automates this process, replacing conventional coating methods, relationships and extensive experimental data. The model generates an such as spraying, dipping, or pipetting, that are often manual, messy, and initial formula based on inputs, such as drug dose and solubility, dosage time-consuming. Automating the coating process frees analysts to weight, and target-release profile. Formulations can be designed for perform other tasks, eliminates the variability associated with a manual various rates of release and have been validated for a variety of model procedure, and reduces solvent wastage. The cup coater is easy to use actives. Access to this confidential service is available through Colorcon’s and holds a full set of 8 cups for simultaneous coating of all collection specially designed questionnaire provided by our Technical surfaces. For more information, contact Copley Scientific at Representatives or located on our website (www.colorcon.com) under [email protected] or visit www.copleyscientific.com. Formulation Tools.

BIOAVAILABILITY ENHANCEMENT PHARMA POLYMERS

Elan Drug Technologies’ Evonik Industries is a global market NanoCrystal® technology leader in specialty chemicals, is a drug enablement and offering a broad portfolio of optimization technology products and services to meet the applicable to poorly drug delivery challenges of the water-soluble pharmaceutical market. Evonik compounds. Improved Pharma Polymers manufactures ® bioavailability provided EUDRAGIT acrylic polymers used by the NanoCrystal for enteric, sustained-release, and technology can result in protective formulations. The unique the following benefits: functionality of EUDRAGIT polymers increased rate of can also meet high sophisticated absorption, reduction in drug delivery requirements (eg, fed/fasted variability, pulsed drug release). We have improved dose adapted our services to meet the 10 Vol No 4 proportionality, rapid formulation development, and reduction in required requirements of the pharmaceutical dose with smaller and more convenient dosage forms. Five products industry’s value chain. As a result,

incorporating the technology are now launched in over 100 markets we are able to support our May 2010 worldwide with over $1.8 billion in market sales achieved in 2008. With customers in the development over 1,300 patents/patent applications worldwide, it has been optimized process to bring products safely and simplified from over 15 years in development. Applicable to all and quickly to the market. From dosage forms, it has been manufactured at commercial scale since excipients supply to the 2001. For more information on our range of technology solutions, development of custom tailored drug delivery solutions, our contact Elan Drug Technologies at [email protected] or visit customers benefit from our knowledge and expertise. For more information, contact Evonik Degussa Corp., Pharma Polymers at (732)

www.elandrugtechnologies.com. Drug Delivery Technology 981-5383 or visit www.eudragit.com. 59 58-61- DDT May 2010-Tech Showcase:Layout 1 4/30/10 2:48 PM Page 60

COMBINATION CAPSULE TECHNOLOGY PERFORMANCE EXCIPIENT

InnerCap offers an advanced patent- Mallinckrodt pending multi-phased, multi- Baker’s compartmentalized capsular-based PanExceaTM delivery system. The system can be MC200G used to enhance the value and performance benefits of pharmaceutical and excipient for Oral biopharmaceutical products. Utilizing Disintegrating two-piece hard shell capsules, the Tablet (ODT) technology offers the industry applications solutions to problems affecting combines two pharmaceutical companies, patients, ingredients for and healthcare providers. The delivery rapid tablet system will be licensed to enhance disintegration pharmaceutical and and dispersion biopharmaceutical products. It is a with good taste and texture. Designed for more flexibility at a lower cost, very effective way to deliver multiple PanExcea MC200G performance excipients enable more API loading active chemical compounds in different physical phases with controlled- capacity while reducing tableting, licensing, and equipment expenses. For release profiles. The delivery system provides the pharmaceutical and more information, contact Mallinckrodt Baker at (800) 943-4747 or visit biopharmaceutical industries with beneficial solutions to the industry’s www.mallbaker.com/panexcea to request a free sample. highly publicized need to repackage and reformulate existing patented blockbuster drugs with expiring patents over the next 5 years. For more information, contact InnerCap Technologies, Inc., at (813) 837-0796 or visit www.innercap.com.

KNOWLEDGE MANAGEMENT CONTRACT MANUFACTURING

Stason Pharmaceuticals, Inc. has the experience and capabilities to manage the most challenging solid dose formulations. The company is a PharmaCircle is an innovative knowledge management company fully integrated cGMP specializing in the drug delivery, pharmaceutical, and biotechnology contract development organization that provides complete turn-key fields, with a current client base ranging from start-up life science drug development services for oral products. We offer services for companies to world leaders in Big Pharma. Clients choose both non-High Containment and High Containment Products. Stason

Vol 10 Vol No 4 PharmaCircle’s services and content for its comprehensive technical offers a range of services for New Chemical Entities (NCEs), generics, (pipeline, products, molecule, and technology) and business (deals, and upgrades to existing formulations, and provides development and acquisitions, royalty, licensing, drug revenues, market information, etc) manufacturing services in its FDA-inspected facilities. We currently related information and analysis, which are ideal for all segments of produce finished products at all scales through to commercial scale. May 2010 small and large companies. PharmaCircle helps facilitate product life All solid and semi-solid dosage forms are covered, including cycle management (LCM), partnering, licensing, and competitive immediate- and delayed-release tablets and capsules, fast intelligence efforts as well as supplements internal efforts and costs at a disintegrating tablets, creams, and lotions. For more information, fraction of the cost if performed internally. For more information, contact contact Stason Pharmaceuticals at (949) 380-4327 or visit PharmaCircle at (847) 729-2960 or visit www.pharmacircle.com. www.stasonpharma.com. Drug Delivery Technology Drug Delivery Technology

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MERRION PHARMACEUTICALS: VALIDATING ORAL DELIVERY

or Dublin, Ireland-based Merrion Pharmaceuticals plc, there is much to be gained by developing oral forms of drugs that improve the bioavailability of poorly absorbed products that are typically F given by injection. This has been the focus of the pharmaceutical development company that F ® commenced business in 2004, after acquiring the GIPET drug delivery technology that was being divested as part of a corporate refocusing by Elan Pharmaceuticals. Since opening its doors, Merrion has followed a two-fold business strategy that includes first, developing its own products internally based on the GIPET John Lynch oral absorption enhancing technology, and second, to apply GIPET to the compounds of pharmaceutical CEO partners. This business model has resulted in significant milestones at Merrion throughout the past year. Merrion From a financial standpoint, the company realized a 373% increase in revenue at the end of 2009, from $1.7 Pharmaceuticals, million to $8.5 million. In October, Merrion opened a 29,000-sq-ft, state-of-the-art, purpose-built facility in plc Dublin to expand its research and development and manufacturing capabilities, build up its own product portfolio, and double its talent. And, just this past March, the company was issued a US patent on its Solid Oral Dosage Form Containing an Enhancer, which covers the GIPET enhancer system used with the “In a database bisphosphonate class of drugs. A similar European patent had already been granted to Merrion. John comprising more than 30 Lynch, CEO of Merrion, recently spoke with Drug Delivery Technology magazine about how the company’s compounds having poor partnership with Novo Nordisk to develop both oral insulin and an oral GLP-1 analogue has helped permeability, GIPET has validate Merrion and its technology among the pharma community. Additionally, Mr. Lynch discusses how shown the ability to Merrion is applying GIPET to develop OrazolTM, an oral alternative to an infusion-based drug for bone improve their absorption metastases in cancer patients. by as much as 200 times, achieving excellent Q: Please describe GIPET as an making GIPET a platform technology with very intersubject absorption enhancer and its benefits. broad applicability. reproducibility. This GIPET uses Generally Regarded As Safe database covers a range A: GIPET allows drugs that currently can only be (GRAS) rated ingredients, permitting the of compounds with given parenterally to be converted into oral development of low risk new oral products, which varying physiochemical tablet/capsule forms, as well as improve the can be brought rapidly and inexpensively to properties and molecular absorption of current oral drugs. GIPET uses market–505(b)(2)–to address major unmet clinical weights, and includes specifically designed oral formulations of patented and patient needs. small molecules as well absorption enhancers that activate micelle formation, facilitating transport of drug and substantially Vol 10 Vol No 4 as biopharmaceutical peptides and proteins, increasing absorption with good reproducibility and a Q: What does your partnership with making GIPET a platform strong safety profile. Novo Nor disk entail? In a database comprising more than 30 May 2010 technology with very compounds having poor permeability, GIPET has A: Insulin is the bedrock of Novo Nordisk, which is broad applicability.” a biopharmaceutical company. Almost all shown the ability to improve their absorption by as biopharmaceuticals are delivered parenterally. Back much as 200 times, achieving excellent intersubject in November 2008, Novo Nordisk wanted to change reproducibility. This database covers a range of insulin delivery (usually 4 injections per day) to a compounds with varying physiochemical properties more convenient tablet form and make the delivery and molecular weights, and includes small molecules Drug Delivery Technology Drug Delivery Technology more liver targeted. Injected insulin remains systemic as well as biopharmaceutical peptides and proteins, rather than targeting the liver before general 62 62-63 DDTMay2010-DDEMerrion:Layout14/30/102:55PMPage63 can Q: TellaboutOrazolus and circulation. Additionally,Novo Nordisk 1(Glucagon-Like Peptide-1) is anatural ourpartner at ascientific meeting in the homologyto natural human GLP-1 whatexpectedthe impact is peptide,has helped patients maintain waslooking for adelivery system that hormoneand is part of the body’s own from a once-a-month trip to the hospital cancer often learn that the disease has A: market.theon firsthalf of 2011. Insulin injection is a normalblood sugar levels via aonce-daily wouldenhance absorption. By mixing the systemfor primarily controlling blood for an infusion of market-leading spread (metastasized) to the bones, which insulinanalog (NN1952) with GIPET, we injection. Wehope to be in the clinic this glucoselevels. It stimulates the release of $9-billion-a-yearmarket. Weexpect the zoledronic acid (Zometa), which is used to wereable to improve absorption of the yearwith the oral delivery of GLP-1. oraltablet to be abig breakthrough and reduce and delay bone complications due insulinonly when blood glucose levels drug.Merrion developed an insulin tablet to multiple myeloma and bone metastases becometoo high. GLP-1 appears to be experiencesales in the billion-dollar impairedin people with type 2diabetes, forPhase Istudies of people with type 1 from solid tumors (eg, breast, prostate) and rangeas well. andthis may be one reason why these andtype 2diabetes. Weexpect final has recently also been filed as an adjuvant anotherlicensing agreement with Merrion peopleare at risk for abnormally high resultsfrom the trial to be presented by bloodglucose levels. Todate, Novo tohave us develop and commercialize an Nordisk’s Victoza oralformulation of their GLP-1 receptor agentusing our GIPET technology. GLP- cause severe pain. Relief may come In2009, Novo Nordisk entered into Patients suffering from late-stage ® ,which has 97% and how do partn howdo and company focused on deliveringon companyfocused Merrion’smodel business describe you Q:Howdo whichcan beburdena onthe healthcare into that model? model? that into to process is reduced. This is important technology, Merrion has been able to A: commercialization. system. Thiscost issignificantly reduced formulate a sufficiently bioavailable oral because kidney deterioration is associated theUS. Wehope tohave our oral version withtablet.a Inaddition, infusion chairs dosage to make a once-per-week tablet. with the infusion. And, side effects availableby that time. Thesales of The quality-of -life benefits are arefreed upatthe hospital togive associated with the intravenous delivery zoledronicacid asanintravenous chemotherapyorother treatments. infusionwere $2billion in2009. The don’t seem to be present in the weekly exponential. Rather than having to visit a marketfor oral zoledronic acid could be tablet. Often, patients will experience flu- Proof-of-principleforweekly a oral hospital for the infusion, the patient can biggerbecause greatera patient like symptoms from the infusion. conveniently take the tablet at home. In the formulationhas been demonstrated ina populationwill have access toit. Orazol Phase II program, patients reported cancerpatient population clinical study. ofmonthlya infusion (excluding drug treatment in breast cancer. much quicker pain relief. By taking a costs)has been calculated to be$359, PhaseIIwas completed in2009, and we weekly dose, the drug arenow seeking partnera toperform the drug, zoledronic Phase IIIstudy and take the product to Orazol is a tablet form of the same Zometacomes off patent in2013 in Fromthe payer’s perspective, the cost Wedevelopmentproduct a are acid. By using its GIPET load the kidney has erships fi erships t Q: Describe what is next fornext whatis Q:Describe and partners to work with us. workwith to partners and products right the identify to keyis The partners;. our for developingproducts GIPET with other delivery platforms innovation to the market. Developingmarket.innovation the to the potential to acquire to potential the tooral product opportunities. Oral are working on and therefore delivertherefore and workingon are weproducts of number the maximize wecan products, develop other products i products other of terms in Merrion platforms. platforms. delivery complementary validatesusand our technology. Moving products and have recently gone through a our own products and partnering to partnering and ownproducts our risk and to allocate our resources our allocate to and risk shareholders. our Tovalueto mitigate A: efficiently we have a balance of wehavebalance efficiently a formulationcan maximize the product forward,we are interested inworking because right now we have a broad range rigorous process of identifying new product internally developed products alon developedproducts internally of opportunities with GIPET. withother large companies. Because opportunities and hope to address those opportunitybutit isnot just about convenience,GIPET formulations can GIPETcan work with rangea of opportunities this year. We have just compounds,there are multiple scratched the surface in terms of how we are alsoimprove productsa safety profile,be partnershipopportunities for us. Weare using GIPET in product development today. farmore economical for hard pressed lookingtopartner with pharma There is no immediate need to complement healthcare systems and really open up companiesthat have interesting injectable newmarket opportunities that only a tabletcan address. TheNovo Nordisk partnership We do have a lot of ideas for new n t n he pipeline or pipeline he u ith g w g

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Therapeutic Focus Non-ATP Competitive Kinase-Signaling Inhibitors & Oncology Drug Discovery & Development

By: Allen Barnett, PhD, CEO Kinex Pharmaceuticals Vol 7 Vol No 3 Vol 10 Vol No 4 MARCH 2007 MAY 2010 MAY SPECIALTY SPECIALTY PHARMA SPECIALTY SPECIALTY PHARMA

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inex Pharmaceuticals was formed in 2004 based on the very beginning is that when a kinase-like Src is removed a technology platform licensed from SUNY at from the cell and studied in isolation, the ATP site is intact. KBuffalo for the design and synthesis of non-ATP Thus, it is straightforward to screen kinase inhibitors in vitro. competitive kinase inhibitors. The novelty of this approach was However, a kinase-like Src functions within the cell as a attested to by the US Patent Office, when it issued broad complex with other proteins to maintain the substrate pocket patents covering the basic approach (US Patent Nos. 7,070,936 confirmation. So if one wants to screen for compounds that B1 & 7,005,445 B2). The first target chosen was Src, the first will inhibit Src signaling at the substrate or an adjacent site, it oncogene discovered and a target of significant interest for has to be done with intact cancer cells. While this is various tumors. As part of the early work on this target at the technically possible for determining drug potency, it makes University at Buffalo, the Kinex effort started with structural other studies like drug selectivity more difficult. Despite this leads in the low micromolar potency range and worked on hurdle, Kinex was able to design potent (low nanomolar range) lead optimization and screening via the outsourcing route. and selective Src-signaling inhibitors, and within 1 year after Kinex started with just the experienced co-founders who are the program was initiated, two potential clinical development all pharmaceutical veterans and no additional employees, so candidates were identified, attesting to the power of the the overhead (G&A) was kept to a minimum (less than 15% of technology platform. The final candidate was KX2-391, and total expenditures) with the rest being R&D. This rate of G&A while it was proceeding to an IND, many other in vitro and has been maintained over its 5+ years of existence. The animal model studies were done to more fully characterize its management team has over 50 years of experience in the profile. What became obvious was that the Kinex candidate pharmaceutical industry and this clearly facilitated the use of has broader and greater anti-tumor efficacy than dasatinib, the outsourcing approach. including situations in which there is resistance to this drug. The overall profile of KX2-391 on cancer cells is that it inhibits cell growth, tumor cell spread (metastasis), as well as Novel Src-Signaling Inhibitors new blood vessel formation (anti-angiogenesis). We also found At the start, it was projected that non-ATP competitive Src that KX2-391 inhibited growth in tumor cells in which Src inhibitors would be at least as effective as ATP-competitive family kinases had been knocked out. This meant that there ones but be more selective and less likely to induce resistance. was likely a second mechanism in addition to its Src-inhibition Dasatinib (Sprycel, BMS) was chosen as the main standard for activity for the superior profile of KX2-391 over multi-kinase comparison because it was the only FDA-approved drug with inhibitors like dasatinib. potent Src inhibitory activity. It is an ATP-competitive kinase 10 Vol No 4 inhibitor, and as such, also inhibits many other kinases leading to a variety of side effects, including cardiovascular ones. The Search for a Second Mechanism Thus, it and many other ATP-competitive inhibitors are called Several more conventional approaches were tried to 2010 MAY “multi-kinase inhibitors,” and the current dogma was that identify the second mechanism, without success, to determine because they inhibited so many targets, these would be more the other potential binding targets of KX2-391 within the cell. effective in cancer treatment than other, more selective One technique we had not tried was photoaffinity labeling chemotherautic drugs. Dasatinib was approved by the FDA for because of the difficult and time-consuming chemistry

Gleevec-resistent, chronic myleogenous leukemia (CML) and involved. The basic approach is to synthesize a compound with SPECIALTY PHARMA is currently being studied clinically for its effects on a variety a photo-activatible group on the molecule in a position that of solid tumors. One of the difficulties faced by Kinex from retains as much of the original activity of the molecule as 65 64-67-DDT May 2010 -SP Feat-Thera Foc 3:Layout 1 4/30/10 2:56 PM Page 66

possible. After a sterling chemistry effort, Kinex was able to more lipophilic analog (KX2-391 is highly hydrophilic), synthesize a photoaffinity ligand (PAL) that retained all of the which might get into the CNS more efficiently. KX-02 was original potency of KX2-391. This helped confer very high then created with this objective, and it is now in advanced affinity binding to possible protein targets, and it turned out preclinical development. KX-02 is very potent in treating a the second mechanism was binding to tubulin, resulting in variety of brain tumor cell lines, including Glioblastoma inhibition of tubulin polymerization. When this tubulin Multiforme (GBM), one of the most aggressive and deadly binding was studied further, it was found that KX2-391 was ones. We then tested the compound in a mouse model in bound to a unique site on tubulin compared to other drugs like collaboration with Roswell Park Cancer Center scientists. KX- taxol and colchicine. Thus KX2-391 is a drug that binds to a 02 significantly increased the survival of these mice, as did unique part of Src and tubulin, which may explain its superior Temodar (temazolamide), which is part of the current standard preclinical profile. Kinex has called this technology platform treatment for GBM. The most surprising finding was that a Optimized Photoaffinity Technology (OPAL) platform. significant percentage of the mice on KX-02 survived completely, and there was a total disappearance of tumor, as demonstrated by MRI. This finding was confirmed in several Phase I Clinical Profile of KX2-391 other studies. The retained survivors are living their normal The Phase I safety clinical trial for KX2-391 is now life spans with an absence of re-occurrence of tumor. Studies complete, with Phase II studies scheduled to start this year. are in progress to further define this phenomenon and to look The selectivity and projected safety profile of this drug have for methods for possibly increasing the percentage of “cured” been confirmed by the results in Phase I. Oral doses mice. The highest percentage obtained thus far was 60%. The associated with very high plasma levels in human cancer IND filing for this compound and the commencement of patients have been achieved, and these have not been Phase I clinical trials is expected to be in the second half of associated with any side effects perceived by the patients. The 2010. dose-defining signs for the maximum tolerated dose (MTD) were subclinical changes in some of the liver chemistry values. These were all reversible within a week after the end Immunoinflammatory Diseases of dosing. So there was an absence of nausea, vomiting, hair Another area of therapeutic opportunity for the Kinex loss, cardiovascular effects, edema, etc. There were also signs platform involves diseases such as arthritis and inflammatory

Vol 10 Vol No 4 of efficacy based on a lowering of selected biomarkers and bowel disease. The initial attraction was the number of kinases other anecdotal efficacy reports, which are very encouraging. involved in these processes and the achievement by Kinex scientists in developing very selective drug candidates against

MAY 2010 MAY kinase targets. Moreover, Kinex has built up a significant KX-02, An Opportunistic Approach library of targeted molecules that can be used to screen for to Brain Tumors new targets. With respect to the latter, Kinex has now found a potent in vitro lead compound for inhibiting an important An area of great interest to Kinex is the treatment of pathway of interest for modulating immune function. Efforts brain tumors. There has not been a new drug approved for this

SPECIALTY SPECIALTY PHARMA are in progress to optimize the compound for oral area in many years. When we observed that KX2-391 bioavailability and activity in animal models. The objective inhibited the growth of a variety of solid and liquid tumors, will be to identify a clinical candidate by the end of 2010. we realized there was no reason why we could not design a 66 64-67-DDT May 2010 -SP Feat-Thera Foc 3:Layout 1 4/30/10 2:56 PM Page 67

Summary Kinex has been in operation for 5 years and has two Allen Barnett, Ph.D. clinical development candidates with good prospects for a third Chief Executive Officer Kinex Pharmaceuticals by the end of 2010. The concept of target selectivity resulting [email protected] in reduced clinical side effects has been supported by clinical development data thus far on KX2-391 and the expected profile of KX-02. The creation of a significant chemical library Dr. Barnett is a successful drug development executive against kinases from the oncology progr am has created a who brought four drugs to the marketplace during his resource that is already paying off in the newer immunology tenure at Schering-Plough, two of which were effort. The development of the OPAL technology for blockbusters. His career was spent in Drug Discovery, identifying the second mechanism of action of KX2-391 has where he led the effort that resulted in the discovery of created a powerful experimental tool that is now being applied Claritin, a non-sedating antihistamine that was to identifying targets of known potent activity but with off- Schering-Plough's leading product and the fifth leading drug, based on sales, in the world. Dr. Barnett target activities. A third development candidate by the end of managed a discovery program that led to Doral, a 2010 is also now a possibility. Kinex has come a long way in sedative-hypnotic that was out-licensed by Schering. its first 5 years and is well on its way toward creating a very He and his colleagues made a major contribution to strong pipeline. the field of dopamine receptors by discovering and developing the first D1 receptor antagonists. He managed the discovery program that led to Zetia, a novel cholesterol-lowering agent that was introduced to the market in November 2002, and to Clarinex, the successor to Claritin. In 1994, Dr. Barnett assumed the duties of Vice President of Technology Acquisition and External Collaborations with the objective of facilitating all areas of drug discovery-based collaborations for SPRI. Dr. Barnett is a graduate of Rutgers University and the University of Buffalo School of Medicine. He has authored or co-authored more than 100 scientific Vol 10 Vol No 4 publications. MAY 2010 MAY SPECIALTY SPECIALTY PHARMA

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Executive

Andreas Knaack Director of the Biomedical Instruments & Devices division Summary Invetech

Invetech: Creating Innovative Products That Redefine Markets

nvetech has been creating breakthrough products and custom automation systems for more than I30 years. With a wealth of experience drawn from over 5,000 projects, Invetech delivers product design and development, contract manufacturing, and custom automation services to a range of global market sectors, including diagnostics, life sciences, medical devices, cleantech , industrial, and consumer products. Operating out of locations in North America, Europe, and Asia Pacific, its clients range from multi-nationals to start-ups and include seven of the world's top 10 clinical diagnostic companies. Specialty Pharma recently spoke with, Andreas Knaack, Director of the Biomedical Instruments & Devices division at Invetech, on how the company is working with customers to redefine their market with breakthrough and innovative product design, development, and manufacture. Vol 10 Vol No 4

Q: What are Invetech’s key services and range of skills, in-house capabilities, and broad industry offerings? experience are combined with proven processes and

MAY 2010 MAY innovation and management tools to deliver tangible results. Invetech’s focus is on developing easy-to-use products and A: Invetech offers development of specialist instrumentation, processes with exceptional reliability that deliver highly commercial products, and custom automation as well as valued benefits to users. Our broad expertise ranges from low- contract manufacturing. From idea to market and covering all volume, quality critical, automated cellular processing major discplines (from industrial design through to

SPECIALTY SPECIALTY PHARMA systems to high-volume, low-cost consumer products. electronics, software, and mechanical engineering), Invetech integrates creativity, commercial know-how, and technical acumen to help its clients create business success. Invetech’s 68 68-70-DDT March 2010 -SP-Exec Sum:Layout 1 4/30/10 2:56 PM Page 69

Q: In what markets does Invetech including clients such as Bayer, Bio-Rad, The Coca-Cola operate in? Company, and bioMérieux. Operating out of locations in North America, Europe, and Asia Pacific, our clients include some of the world’s top clinical diagnostic companies. A: Invetech specializes in product development, custom automation, and contract manufacturing for the medical, Q: industrial, and consumer markets. With more than 200 staff, How are you helping your customers the company works in a range of global sectors, including achieve commercial success? clinical diagnostics, life sciences, drug discovery, pharmaceutical, and medical devices. A: Invetech combines integrated in-house capabilities, specialist knowledge, and diverse experience to deliver better Q: How do you apply your expertise solutions, in the shortest possible time and with less risk. Tailoring the degree of innovation to the specific project across such diverse markets? needs, Invetech applies rigorous processes that have been proven over thousands of projects. Whatever solution A: Invetech provides in-house experts for all its major Invetech provides, these processes ensure the best possible markets and is applying a consultative approach to ensure commercial outcome, balancing development risk, schedule, immersion of the Invetech team into the client’s target and cost with product cost and features or performance. market, combining this expert know-how with generic in- depth engineering expertise. Working in the given range of Q: Invetech’s innovative design has markets allows Invetech to cross-leverage skills and know- recently been recognized with an how from these different markets. For example, Invetech’s award. What was the award for? expertise in design and manufacture of high-volume consumer goods (manufactured in millions per year) is A: Invetech has recently been recognized for its innovative directly applicable to medical or scientific consumables. design capabilities by being awarded a prestigious Medical Invetech’s specialist expertise in design, engineering, and Design Excellence Award (MDEA) for TearLab manufacturing enables the company to deliver solutions that Corporation’s revolutionary TearLab Osmolarity System. are as practical as they are marketable. Our range of skills TearLab Corporation requested Invetech to assist with the across the product life cycle - from concept development development and industrial design of this novel system. The

through to manufacture - ensures our clients can be 10 Vol No 4 TearLab Osmolarity system is the first technology that can confident of achieving a successful commercial outcome, quantitatively and objectively measure Dry Eye Disease in a whatever the project. Invetech’s industry-specific knowledge doctor’s office in seconds. Dry Eye Disease is a chronic and

enables clients to break new ground in many diverse areas. 2010 MAY progressive condition that if left untreated can lead to serious Q: eye damage. This product won the award for its breakthrough Can you describe the types of design that significantly reduced the complexity, cost, and customers Invetech works with? patient discomfort of conventional tear-testing technologies. Through application of Invetech’s tools and know-how in A: Throughout the past 30 years, Invetech has completed Human Factors Engineering (HFE) and closely working with SPECIALTY PHARMA more than 5,000 projects for international companies ranging end-users, the Invetech and TearLab teams were able to from Fortune 500 to start-ups to Government Departments, provide a solution for the collection and diagnosis of tear 69 68-70-DDT March 2010 -SP-Exec Sum:Layout 1 4/30/10 2:56 PM Page 70

fluid that is easy to use while minimizing risk of user error or Q: What makes Invetech an ideal patient harm. TearLab was designed to achieve CLIA waiver partner? status, reflecting its focus on ease of use and consideration for

the needs of both the patient and the clinician. TearLab was A: For more than 30 years, Invetech has been at the forefront selected as a winner by an impartial panel of expert judges for of breakthrough product development and automation, helping its innovation, user-related design, product features, and companies bring new products to market through innovative engineering that improves the manufacturer’s profitability. design, engineering, and manufacturing. The key to establishing a successful long-term relationship stems from core expertise, Q: Why are more companies turning to open communication, knowledge sharing, and trust building. outsourcing? It is Invetech’s capacity to bring ideas to market that sets the company apart. Invetech is recognized for its enthusiastic A: A significant number of companies are turning to approach in addition to the resulting commercial successes of outsourcing, driven by the benefits and availability of access to our clients. The company’s multi-award-winning portfolio has new skills and knowledge. Companies increase competitiveness led advances across industrial, medical, and consumer markets. by lowering the cost structure of R&D and offering new Invetech values innovation, integrity, enthusiasm, excellence, products to customers more quickly and efficiently. Some and collaboration. Our clients value our ability to effectively companies have an infrequent need for specialist product combine industrial design and innovative engineering when design and development services, and it is not feasible to build designing new products. Leveraging skills and experience from and maintain these in-house capabilities. Outsourcing can offer 60+ biomedical and scientific instrument developments, better solutions than recruiting ad hoc design teams because Invetech is able to shorten time-to-market. Invetech is ISO external service providers can tap into scale and learning 9001:2008 certified and its quality system and development economies that they have developed through their experience processes are compliant with FDA QSR (Quality System and longevity in the business. Regulation) for biomedical products and with GAMP (Good Automated Manufacturing Process) for custom automation. Q: What does a company need to consider Throughout the product development journey, Invetech’s if looking to outsource? consultative approach ensures strategic objectives are met. Invetech’s manufacturing facilities are ISO13485:2003 A: A company needs to consider a number of factors when certified, supported by regular reviews and audits with world-

Vol 10 Vol No 4 making strategic R&D outsourcing decisions. Besides the typical leading biomedical clients, such as Abbott, bioMérieux and technical requirements, reviews should also focus on hidden Bio-Rad. n factors, such as negotiations, lower costs of contracting, and greater value added. Other factors include performance and MAY 2010 MAY measurement of achievement and investments in the relationship. When considering international outsourcing, companies should think about protecting rights over valuable intellectual property in countries with significantly different protection regulations,

SPECIALTY SPECIALTY PHARMA the development of inter-company processes to ensure a common understanding of design standards and metrics, language, and cross-cultural difficulties and telecommunications infrastructure.

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Therapeutic Focus

Meeting the Challenges of Antimicrobial Resistance By: Ron Najafi, PhD, Chairman & CEO, NovaBay® Pharmaceuticals, Inc.

Resistance to mupirocin began to availability of over-the-counter Introduction emerge shortly after the drug’s antimicrobial agents, particularly those Antibiotics may rightly be called introduction . By 2007, the incidence of that were once sold only by prescription, “wonder drugs,” but their use throughout mupirocin-resistant S. aureus increased can potentially reverse the positive the past 80 years has come at a price. from 1.6% during the period from 1995 impact of best hospital practices, and Through evolutionary mechanisms to 1999, to 7% between 2000 and 2004.2 lead to pockets of high bacterial assisted by overuse and misuse, bacteria Resistance was related to a mutation on a resistance that will be difficult to will invariably develop resistance to new gene coding for the enzyme isoleucyl- eradicate. For example, it has been antibiotic compounds soon after their tRNA synthetase.3 Moreover, it became reported that mupirocin resistance in introduction. Today, some of the most apparent that MRSA could confer New Zealand hospitals had reached 28% virulent bacterial pathogens are resistant resistance to mupirocin through gene by 1999, due in part to sales of to all but one or two antibiotic agents. transfer to other bacteria treatment.4 mupirocin over the counter.8 Upton urged Experience with one topical antibiotic, A more recent study on peri- that “current patterns of mupirocin mupirocin, demonstrates that resistance operative patients confirmed that 7% of consumption …be reviewed and its use can emerge even against agents that are Stapholococcus isolates from nasal rationalized to maximize the chances of not administered systemically. passages of orthopedic/vascular patients this antibiotic retaining benefi cial anti- GlaxoSmithKline’s Bactroban were mupirocin-resistant, a figure that staphylococcal activity.” (mupirocin ointment) anti-infective was 5

increases to 9% among elderly patients. Mupirocin is a perfectly good 10 Vol No 4 introduced in 1985 and rapidly adopted In 2007, David Warren and co-workers antibiotic, but therein lies the problem. into clinical practice for treating topical reported that 13.2% of MRSA isolates Bacteria have evolved over hundreds of Staphylococcus infections and from patients at Washington University millions of years to evade and adapt to 1 colonizations. Numerous studies 6

Hospital were mupirocin-resistant. These antibiotic mechanisms, particularly when 2010 MAY demonstrated mupirocin’s effectiveness figures have immediate consequences, these agents are administered in treating primary skin infections, such as failures in decolonizing patients systemically. It therefore makes no sense surgical incisions, and accidental infected with mupirocin-resistant to expose every organ and system to wounds. Bactroban soon became the MRSA.7 antibiotic treatment when an infection is agent of choice for these indications; Bacterial resistance to antibiotics localized to one area that is easily within 15 years, the drug was registered

generally rose throughout the 1990s and accessible to topical agents. An SPECIALTY PHARMA in 90 countries for eradication of 2000s, and will continue to increase unintended consequence of the overuse Staphylococcus, including such virulent despite efforts to introduce “clean” of systemic antibiotics has been the rise strains as methicillin-resistant S. aureus treatment practices in hospitals. The of resistant strains on the skin, which (MRSA). 71 71-75-DDT May 2010-SP-Therapeutic Focus:Layout 1 4/30/10 2:57 PM Page 72

complicates treatment even in accessible rapidly in the body and are labile in species and over millions of years of areas of the body. conventional pharmaceutical evolution. These agents are usually While antibiotics may be the only formulations. The Aganocide amphiphilic, allowing them to operate in recourse for treating systemic compounds overcome this deficiency of aqueous environments as well as infections, their use on the skin and the natural compounds through a entering lipid-rich membranes. particularly in nasal decolonization is chemical modification that imparts Unfortunately, no antimicrobial peptide clearly unwise when options exist with a long-term stability. or analog has proven to be commercially low risk of contributing to resistance to Like their natural analogs, viabl e because their selectivity for antibiotics. Aganocide compounds fight MRSA and bacterial versus mammalian membranes other resistant Staphylococcus bacteria is extremely low. Antimicrobials, Not through the chloronium ions, a form of chlorine suitable for eradicating Is Nasal MRSA a Risk Antibiotics bacterial colonizations and infections on In a recent paper, NovaBay the skin, in other accessible areas of the Factor for Hospital- scientists described a novel class of body, and on some implantable medical antimicrobial compounds known as Acquired Infections? devices. Chloronium ions have been By contrast, Aganocides have N,N-dichloro-2,2-dimethyltaurines employed in water disinfection for at shown remarkably high therapeutic Aganocides®, which are effective against least 150 years. indices, a measure of a therapeutic dose MRSA and mupirocin-resistant Aganocides, which deliver an compared with a toxic dose, in Stapholococcus.9 NovaBay’s Aganocides attenuated form of chloronium ion, are laboratory studies. Our findings suggest are synthetic analogs of naturally not antibiotics. Their mode of action is that the Aganocide compounds could occurring antimicrobial agents that non-specific and does not dependn o replace mupirocin and similar agents, belong to a class of molecules, the N- cells being in reproductive phase. and possibly eliminate the need for chlorotaurines, which operate within the Aganocides do not inhibit cellular systemic antibiotics for localized human immune system and do not give processes, DNA replication, enzymes, bacterial infections. Antibiotics remain rise to bacterial resistance of any kind. or any pathways that might, through the agents of choice for infections that The natural model for Aganocides, evolutionary processes, adapt to their have entered the blood or major organs, N-chlorotaurine, was described in 2000 mode of action. while Aganocide compounds could be a as a “novel” agent for treating infectious Rather, chloronium ions generated more suitable option for infection or conjunctivitis.10 A number of papers by Aganocides rapidly inactivate colonization sites that are easily have been published using this organisms by attacking sulfur- and accessible. compound as a topical antimicrobial nitrogen-containing amino acids on the Studies suggest that a fair number agent. Nagl et al reported the broad- bacterium’s surface. Microorganisms of hospital-acquired MRSA infections spectrum biological activity of the cannot adapt, either individually or originate from nasal colonies of “long-lived oxidant” N-chlorotaurine, through evolutionary processes, to this Stapholococcus bacteria. Colonization which achieves 4-log reduction of mode of action, which is not unlike in the nasal passages serves as a Vol 10 Vol No 4 bacterial and fungal pathogens at being run over by a Sherman tank or hit reservoir for transmission of S. aureus, micromolar concentrations.11 by a nuclear bomb. Developing including MRSA and mupirocin- Biologists know that species related immunity to Aganocide compounds resistant organisms, to wound sites as to N-chlorotaurine are responsible for would require the genetic impossibility well as the sinuses, ears, and eyes. MAY 2010 MAY up to 90% of the “heavy lifting” in of MRSA bacteria completely changing Approximately 30% of all humans are bacterial clearance through white blood the fundamental nature of their chemical colonized by S. aureus, including by cell lysosomes. During oxidative bursts, composition. resistant strains. hypochlorous acid (HOCl) is neutralized In this respect, Aganocides Antibiotics are inappropriate as by taurine to form N-chlorotaurine, an resemble antimicrobial peptides, another first-line therapies for colonization or oxidant that attacks and inactivates group of natural defense compounds infections for two reasons. First, SPECIALTY SPECIALTY PHARMA bacteria and other pathogens. N- that do not induce microbial resistance. systemic antibiotic administration is chlorotaurine and the related N,N- Antimicrobial peptides are overkill when the infection is limited to dichlorotaurine possess broad-spectrum “evolutionarily conserved,” meaning a part of the body from which it may antimicrobial activity, but both degrade their structures are similar across 72 easily be eradicated without the use of 71-75-DDT May 2010-SP-Therapeutic Focus:Layout 1 4/30/10 2:57 PM Page 73

antibiotics; antibacterial treatment can be bladder and kidney. Cardiovascular payments, $70 million of milestones more effective, less expensive, and spare catheters are prone to similar related to clinical progress, and good the patient potential side effects. Second, colonizations. royalties. We expect to be able to enter because antibiotics slowly lose their Individuals who are permanently into agreements for additional effectiveness, they must be used catheterized (eg, paraplegics, indications with other corporate partners judiciously to prolong their useful life quadripleg ics, and those with other when our compounds are in later stages for deadly blood-borne infections. serious spinal conditions or injuries) are of development. The best time for us to Our lead Aganocide compound, often on lifelong antibiotics to prevent make deals is when we have Phase II or NVC-422, is active against Gram- systemic infection. Systemic treatment is later clinical data that indicates efficacy positive and Gram-negative bacteria, expensive and puts these patients at risk in a specific indication. It was for this yeasts, and viruses. A recently completed for serious, long-term side effects. reason, the costliness of clinical trials, Phase I trial demonstrated that topical Catheters coated with antimicrobial that we took NovaBay public. However, application of NVC-422 to the nostrils is silver are sometimes used in such the advantage of the Aganocide safe and well-tolerated in healthy situations, but they are expensive and compounds is that our indications volunteers. An exploratory Phase II trial only effective for a few days. require short periods of treatment using a prototype formulation of NVC- NovaBay is investigating a (typically 1 week for most infections), so 422 in saline in volunteers colonized formulation of one of the Aganocide we can conduct more trials for less with Stapholococcus showed 88% compounds that could be used to flush money than the typical decolonization within 1 day. urinary and cardiovascular catheters. We biopharmaceutical company. Additionally, NVC-422 does not enter expect that such a product might prevent As an entirely new class of the bloodstream, a key safety factor. tens or hundreds of thousands of cases of antimicrobial agent active against NovaBay Pharmaceuticals is preparing urinary and systemic bacterial infection bacteria, fungi, and agents, Aganocides for a second Phase II trial with a more per year, and save lives and save the enjoy very broad market potential. advanced formulation that is expected to healthcare system hundreds of millions Aganocides are not suitable for systemic show even greater effectiveness in of dollars. administration because extended decolonization of MRSA in nasal interaction with blood components passages. results in loss of potency. The NovaBay has entered into an Bringing Aganocides to compounds are most appropriately used agreement with Alcon, the largest Market when applied locally to tissues where producer of ophthalmic products in the Because Aganocide compounds infection or colonization has been world, to investigate Aganocide have such a large variety of potential localized. Our strategy is to focus on compounds for a number of topical (non- applications, NovaBay cannot hope to applications where Aganocides address systemic) infections, such as eye, ear, develop on its own all the indications for an unmet medical needs. Our analysis and sinus, as well as for use in contact which $34 billion worth of antibiotics has identified the following critical lens solutions. Additionally, NovaBay is are sold. Our strategy is to partner with markets: in partnership with Galderma, the largest market leaders in relevant therapeutic Vol 10 Vol No 4 skin care company in the world. areas to ensure the appropriate clinical SKIN INFECTIONS - The market for topical Another important potential use for development of our products, their treatments of classical skin infections is the Aganocide compounds is in the maximum market penetration, the very large, for example, impetigo has prevention of catheter-associated urinary highest return to our shareholders, and been estimated at approximately $600 MAY 2010 MAY tract infections (CAUTI). Almost half of the greatest benefit to patients. It was million per year. In this category, acne all hospital-associated infections follow with these goals in mind that we entered treatments are perhaps the most lucrative urinary catheterization and its associated into our agreements with Alcon and area. Americans spend $2.4 billion in urinary tract infections. Up to 10% of all KCI, and we expect to continue to prescription acne treatments, some of hospitalized patients require partner additional opportunities. which carry serious side effects and at catheterization. Shortly after insertion, a While our agreement with Alcon least twice that amount on ineffective SPECIALTY SPECIALTY PHARMA biofilm begins to form on the inner was entered into when the Aganocides over-the-counter products. surface of the catheter, which becomes a were early preclinical stage compounds, reservoir for bacteria that may eventually it was still a very valuable one, with $10 BIOFILMS- Catheter-related biofilm

cause life-threatening infections of the million up-front, ongoing research infections affect approximately 900,000 73 71-75-DDT May 2010-SP-Therapeutic Focus:Layout 1 4/30/10 2:57 PM Page 74

US patients per year. Of these, 40,000 treating superficial infections and develop serious kidney or major organ colonizations with little chance of Ron Najafi, PhD infections, and one-third of these patients successfully treating the condition has Chairman & CEO die. Because these infections are acquired therefore become a “luxury” that we can NovaBay Pharmaceuticals, in hospitals, most involve antibiotic- no longer afford. Our experience with Inc. resistant bacteria. We conservatively mupirocin-resistant Stapholococcus estimate the market for preventing these should serve as a warning, that fighting infections at $200 million. This figure colonizations of the skin and nasal will be many times as large if agents passages with antibiotics will only were routinely prescribed for all patients exacerbate the problem of antimicrobial receiving urinary or venous catheters. resistance. Dr. Ramin (Ron) Najafi is the Founder, The catheter-infection problem has Newer approaches, including locally CEO, and Chairman of NovaBay been exacerbated in the last several years administered non-antibiotic anti- due to over-use of antibiotics, particularly infectives, such as the Aganocide Pharmaceuticals, Inc. He has served as ciprofloxacin (a result of the anthrax compounds, are much more appropriate President since July 2002 and as Chief scare). Acute infections are particularly than antibiotics in situations where the Executive Officer since November 2004. worrisome because patients can die infection or colonization is accessible and Previously, Dr. Najafi served in various before a culture comes back positive. In not yet systemic. Because development of management positions within NovaBay, addition, leading payors are increasingly resistance to their active agent cannot including Chief Scientific Officer. Before refusing to reimburse hospitals for costs occur, we believe that the use of such of treating hospital-acquired infections. agents will extend the useful life of founding NovaBay, Dr. Najafi was the systemic antibiotics by saving their use President and CEO of California Pacific OPTHALMOLOGY - Through our partner for conditions where they are truly Labs, Inc., a chemical laboratory safety Alcon, we are testing Aganocides to treat needed. u devices company. He has also held conjunctivitis. Aganocides have the scientific roles at Rhone Poulenc Rorer potential to revolutionize this market (now Sanofi-Aventis), Applied because they treat infections of bacterial References Biosystems, a division of PerkinElmer, and viral origin equally well. 1. Cookson BD. The emergence of mupirocin resistance: a challenge to infection control and antibiotic prescribing practice. J Antimicrob Chemother. Approximately half of all conjunctivitis 1998;41:11-18. Inc., and Aldrich Chemical. Dr. Najafi 2. Simor AE et al. Mupirocin-resistant, methicillin-resistant Staphylococcus aureus cases are caused by viruses and 40% by strains in canadian hospitals. Antimicrob Agents Chemother. 2007;51(11):3880- earned his BS and MS in Chemistry from 3886. bacteria. This market is conservatively 3. Gilbart J, Perry CR, Slocombe B. High-level mupirocin resistance in the University of San Francisco and his Staphylococcus aureus: evidence for two distinct isoleucyl-tRNA synthetases. estimated to be $1 billion. Antimicrob Agents Chemother. 1993;37(1):32-38. 4. Hurdle JG et al. In vivo transfer of high-level mupirocin resistance from PhD in Organic Chemistry from the Staphylococcus epidermidis to methicillin-resistant Staphylococcus aureus associated with failure of mupirocin prophylaxis. J Antimicrob Chemother. University of California at Davis. 2005;56(6):1166-1168. Delaying the Inevitable 5. Fawley W et al. Surveillance for mupirocin resistance following introduction of routine peri-operative prophylaxis with nasal mupirocin. J Hosp Infect. Current antibiotics are clearly losing 2006;62(3):327–332. 6. Jones JC et al. Mupirocin resistance in patients colonized with the war against bacteria. The question is methicillin‐resistant Staphylococcus aureus in a surgical intensive care unit. Clin Infect Dis. 2007;45:541–547. Vol 10 Vol No 4 will the current crop of antibiotics tide us 7. Graber CJ, Schwartz BS. Failure of decolonization in patients with infections due to mupirocin-resistant strains of community-associated methicillin-resistant over until the next generation of therapies Staphylococcus aureus. Infect Control Hosp Epidemiol. 2008;29:284–284. 8. Upton A, Lang S, Heffernan H. Mupirocin and Staphylococcus aureus: a recent emerge? Antibiotic approvals in the US paradigm of emerging antibiotic resistance. J Antimicrob Chemother. 2003;51:613-617. are at all-time lows. While several 9. Wang Lu, Khosrovi B, Najafi R. N-Chloro-2,2-dimethyltaurines: a new class of remarkably stable N-chlorotaurines. Tetrahedron Letters. 2008;49:2193-2195. MAY 2010 MAY antibiotics are currently in human Phase 10. Nagl M et al. Tolerance of N-chlorotaurine, a new antimicrobial agent, in infectious conjunctiv itis - a phase II pilot study. Ophthalmologica. III clinical trials, their approvals are by 2000;214:111-114. 11. Markus N et al. Bactericidal activity of micromolar N-Chlorotaurine: evidence no means certain. A big unknown for for its antimicrobial function in the human defense system. Antimicrob Agents development-stage antibiotics is how Chemother. 2000;44(9);2507-2513. quickly they will engender resistance once the drugs enter widespread use.

SPECIALTY SPECIALTY PHARMA Finally, there is always the possibility that these agents, like systemic antibiotics of the past, will be used improperly. The use of systemic antibiotics for 74 71-75-DDT May 2010-SP-Therapeutic Focus:Layout 1 4/30/10 2:57 PM Page 75 * DDT May 2010 Covers:DDT Cover/Back April 2006.qx 4/30/10 2:34 PM Page 1