July/August 2006 Vol 6 No 7 IN THIS ISSUE

INTERVIEW WITH PALATIN TECHNOLOGIES’ VP & CTO SHUBH SHARMA, PHD Market Evolution 2020 Howard S. Wachtler

Particle- Mediated Epidermal Delivery 3030 John Beadle, MD, MBA

21st CenturCenturyy pMDIs & DPIs 3232 Georgina Fradley

Long-ActingLong-Acting InjectionInjection FormulationsFormulations 3636 Roger G. Harrison, PhD

Sweat Gland Delivery 4242 Wei Chen, PhD

Buccal Adhesive The science & business of specialty pharma, biotechnology, and drug delivery Systems 5151 A.K. Bandyopadhyay, PhD Clifford M. Mr. Girish Miles Davidson, Patel Hutchings, Esq. Oral Colon-Specific PhD Drug Delivery: Accelerating Drug Are Inventions An Overview Based on Delivery Solutions www.drugdeliverytech.com Discoveries of With Polymer & Natural Phenomena Analytical Expertise Patentable?

4 Drug Delivery Technology July/August 2006 Vol 6 No 7 $15.00, US,Canada,andMe 01923; pho Technology LLC for librariesandotherusersregistered withtheCopywriteClearance, 222RosewoodDrive, Danvers, MA items f Periodicals Postage Paid atMontville, NJ07045-9998andadditionalmailingoffices. Postmaster: Delivery T States, Canada,andMexico. AllsubscriptionsarepayableinUSfunds, drawnonUSbanks. Sendpayment to:Drug Subscription rates:$99.00f October (ISSN 1537-2898)ispublished10timesin2006,January, February, March,April,May, June, July/August, September, responsibility f o All editorialsubmissionsarehandledwithreasonable care, butthepublishersassumenoresponsibilityfor thesafety or inf be reproducedortransmitted inanyform orbyanymeans, electronicormechanical,includingbyphotocopy, recording, the U.S.,Internationaland P address changestoDrugDeliveryT f artwork, photographs ormation storageandretrieval system,withoutwrittenpermissionfromthepublisher or internalpersonaluse , and November/DecemberbyDrugDeliveryT echnology LL ne: (978)750-8400, f or theaccuracyo East &Midwest Mailing ListRental International W C est Coast subscription Department,219ChangebridgeRoad,Montville NJ07045.Singlecopies(prepaid) , or manuscripts or 1yearintheUnitedStates 219 Changebridge Road, Montville, NJ07045 an-American CopyrightConventions xico; $24.00inallothercountries ax: (978)750-4470. July/August 2006 f EXECUTIVE EDITORIAL DIRECTOR inf [email protected] , echnology ormation suppliedhereinorfor anyopinionexpressed. Drug DeliveryTechnology or theinternalpersonal useof specificclients, isgrantedbyDrugDelivery Can Ralph Vitaro Warren DeGraff 103 Oronoco Street, Suite200 Cheryl S.Stratos -Account Executive Victoria Geis-Account Executive ADMINISTRA TECHNICAL OPERATIONS CONTRIBUTING EDITORS PUBLISHER/PRESIDENT Corporate/Editorial Office . www.drugdeliverytech.com A d Every precautionistak EDITORIAL SUPPORT CREATIVE DIRECTOR dv y Fax: (973)299-7937 Shalamar Q.Eagel Nicholas D.Vitaro , T Dan Marino, MSc ertising SalesOffices Brecht 219 ChangebridgeRoad,MontvilleNJ07045.Allrights reservedunder Kathleen Kenny Jason McKinnie el: (973)299-1200 Debra Bingham Cindy H.Dubin Debbie Carrillo Mark Newland CONTROLLER Ralph Vitaro E-m Fax: (703)549-6057 Tel: (703)706-0383 E-mail: [email protected] Fax: (973)299-7937 Tel: (973)299-1200 Montville, NJ07045 219 Changebridge Road W E-mail: [email protected] E-mail: [email protected] Fax: (703)548-3733 Tel: (703)212-7735 Alexandria, VA 22314 E-mail: [email protected] Fax: (415)721-0665 Tel: (415)721-0644 San Rafael, CA94901 818 5thAvenue, Suite301 estern Regi echnology LL ail: cbr , TIVE SUPPORT Canada, andMexico. $153.00for 1yearoutsidetheUnited [email protected] . en toensureaccuracy . All rightsreserved.Nopart of thispublicationmay on Vol 6No 7 C, 219ChangebridgeRoad,MontvilleNJ07045. Add $5.00perorderfor shippingandhandling. al M an ag er , but publisherscannotaccept . A uthorization tophotocopy please send

6

Drug Delivery Technology July/August 2006 Vol 6 No 7 p o dr “ yes yrgladmtie,andmulticoating hydrogel andmatrices, lymers, V xlie o h eeomn fcolon-targeted of for thedevelopment exploited gdlvr ytm nld h s fprodrugs, of theuse include systems ug delivery ar io pH-sensitive polymers, bacterial degradable bacterial polymers, pH-sensitive us phar mac time-dependentdelivery systems.”time-dependentdelivery eutical approaches thatcanbe eutical p.62 36 Development &Applications of Development 36 inHarmony –pMDIs Living &DPIs 32 48 Accelerating Drug Delivery Solutions Accelerating Delivery Drug 48 Transdermal Through Delivery Drug 42 the inhalation market. prescribers and willremain the dominant device in offers many advantages todevelopers and global markets. However, research hasshown pMDIs predictions they willincrease inpopularityacross sales havestrengthened their position and ledto Ms. Georgina Fradley saysthatincreases inDPI of and influence onthe entire supply chain. medical device applications, and anoverall vision in boils down toextensive, hands-on experience, an practitioner and hiring the standard consultant between “partnering” withaconsultant Dean Hamel explain thatthe real difference Miles Hutchings, PhD;Michael Ruberto,PhD;and i reduction of anapplied voltage toensure thatthe skin bymeans of sweatgland activation and alternative means of drug transportation through the Huang, PhD;conduct astudy thatintroduces an PhD; Mi Wei Chen, PhD;Vardan Ter-Antonyan, MS; Heidi Kay, Dr d pr safety/effi acting formulations thatoffer improved Long-Acting Injection Formulations in the21stCentury With Polymer &Analytical Expertise the S on rug d od . tim tophoresis issafe. Roger G.Harrison indicates that the injectable u ate knowledge of the materials involvedin ct m elivery m w chael Salewski(PhDstudent); and Feiran e ark cacy an at Glands et, whi ark d et, couldgrow thankstolong- pati ch curr en t en compli tly holds 15%of the an ce .

51 Advances in Buccal Adhesive Drug Delivery Drs. A.K. Bandyopadhyay and Yajaman Sudhakar discuss how buccal adhesive systems are well suited for orally inefficient drugs as well as a feasible and attractive route for non-invasive delivery of potent peptide and protein drug molecules.

56 Palatin Technologies: A Leader in Melanocortin-Based Therapeutics Drug Delivery Executive: Shubh Sharma, PhD, Vice President and Chief Technical Officer of Palatin Technologies, discusses his company’s MIDAS technology and the melanocortin-based therapeutics in the works.

“Recent increases in dry powder inhaler 62 Oral Colon-Specific Drug Delivery: An Overview (DPI) sales have strengthened the position Girish Patel, MPharm student; Gayatri Patel, MPharm student; Ritesh Patel, MPharm student; Sanjay Patel, of DPIs and led to predictions in some MPharm student; Jayavadan Patel, PhD; and Praful Bharadia, PhD; review the considerable amount of reports that DPIs will increase in research on the development of colon-specific drug popularity across global markets. However, delivery systems. research has shown the pMDI offers many advantages both to developers and prescribers and will remain the dominant Departments device in the inhalation market.” Market News & Trends ...... 12

7 Business Development ...... 20 o N Market Evolution & Sector Confusion 6 l o V Attorney Review ...... 24 6

0 Are Inventions Based on Discoveries of Natural 0 2

t Phenomena Patentable? s u g u A

/ Advanced Delivery Devices ...... 28 y l u

J Particle-Mediated Epidermal Delivery of

y DNA Vacciness g o l o n

h Drug Delivery Showcase ...... 59 c e T y r

e External Delivery ...... 74 v i l e D g u r D

8 p.32 9 Drug Delivery Technology April 2006 Vol 6 No 4 10 Drug Delivery Technology July/August 2006 Vol 6 No 7 Degussa Technical Service Manager Nasser Nyamweya,PhD Systems 3M DrugDelivery General Manager James Vaughan Dir Ronald L.Smith,PhD Research Institute Bristol-Myers Squibb Drug Delivery Bi P Research &Development D Jack Aurora,PhD M Clini David C.Klonoff,MD,FACP Dir Philip Green,PhD Dir Clemmons, PhD,MBA,MS Sonya Summerour D M Vice President, Global Sarath Chandar, MBA S MediVas, LLC Development A Development BD Research Institute Mills-Peninsula Diabetes M PI Pharma harmascience, Inc irector, Pharmaceutical evelopm dvan opharm edi arketing &Commercial ector o edi Technology D Director Executive Editorial Dan Marino,MSc ector o ector rug Delivery cal Professor of cin cal Director ced DrugDelivery e , aceuti f Busin e - f nt nt Exploratory UC Busin ess cs & San Fr ess ancisco Pharm A President &CEO Howard S.Wachtler Cardinal Health, PTS Process VP, Strategy &Business Cor Akina, Inc President Kinam Park,PhD B Associate Director PhD, MS Mahesh Chaubal, A President &CEO John A.Bermingham Pharm Associate Professor of Uday B.Kompella,PhD Development Pfizer GlobalResearch & Form Director, Research Keith Horspool,PhD McAuliff, LLPP H Attorney atLaw James N.Czaban,JD U M ctinium mpad, LLC axter Healthcare niversity o eller Ehrm edi nell Stamoran cal Cen ulati aceuticals aceuti on an White& s ter f cs N ebr aska Glax S.R. One, Limited, Investment Manager Philip L.Smith,PhD Pharm Brookwood and Chief Scientific Officer Executive Vice President T at Austin University of Texas Pr James W Labor M Associate Director Henry Y. Wu, PhD,MS Corium International President &CTO Phar Gary W. Cleary, PhD, E Principal Scientist, Matthew D.Burke,PhD GlaxoSmithKline Ex Ravi Kiron,PhD,MBA Eur President, North America John Fraher T ALZA Corporation Planning om Tice, PhD xploratory Pharmaceutics echn er ofessor of Pharmaceutics ecutive Dir an ck Resear oSmithKlin mD, MBA atories d aceuti ology A . McGinity, PhD cals ch ector ssessment & e , N ew

12 Drug Delivery Technology July/August 2006 Vol 6 No 7 making theprocess considerably saferandmoreeffective. for medicationdelivery in thebraincannow bepre-operatively identified, calculate therequireddistrib an individual three-dimensionalmapofthepatient’s brain,physicians can brain andfrompatienttopatient.Using magneticresonanceimagingtorender cor concentration inthe it isextraordinarily toachieve drug difficult sufficient on precisionandaccuratedosage.Clinical experience, however, hasshown that in thebrain. targeted deliveryBBB andsupports moleculestoaffected oflarger drug areas entering thebrain.iPlanFlo from foreignsubstances,preventing potentially effective treatmentsfrom (BBB),atight coatingofblood vesselsBrain Barrier thatprotectsthebrain and treatment ofbraintumorsandneurodegenerative diseases,suchasParkinson's United States. While surgical technology continuestoadvance, theaccurate 5), appro potential ofthetreatment. date, clinicaltrialsinbothGermany andtheUnitedStateshave highlightedthe medications needtobeadministeredinorderprecisely treatbraintumors. To provides physicians withtheabilitytoaccurately locatewhere andhow Clinical Oncology (ASCO) Annual Meeting. This FDA-approved software intablet suchasnausea,vomiting, abdominalpain, metformin form, regimen, willavoid someoftheadverse side-effects associatedwithtaking andeffectivemuch morerapidandproviding amuchmorespecific dosing occur in upto30%ofpatients. metformin for many years. However, acutesideeffects (gastrointestinal sideeffects) of adverse effects formorethan50years alsointheUS but without significant hasbeenusedextensively95% totype2diabetes.Metformin inEurope to type1andapproximately10% ofdiagnosedcasesareattributed 90%to million peoplehave diabetes mellitus worldwide. Itisestimatedthat5%to people intheUSalone.Recently compileddatashow thatapproximately 150 levels. Diabetesisachronicdiseasethataffects approximately 17million tablet form. its current that willdeliver mucosaratherthanin intothebodyviabuccal metformin ofmedicalchewing chewingmanufacture gumtocreateametformin gum technologiesplatform withFertin’s know-how related todevelopment and mellitus andobesity. medicinalchewingmetformin gumforthetreatmentoftype-2diabetes they have established acollaborationforthedevelopment ofa delivery, drug Canada, aleaderintheareaofbuccal jointly announced B BrainLAB AG New With Opens Possibilities Delivery Flow for iPlan Drug F Gum Chewing Fertin Pharma Announce & GenerexDiabetes Collaborationon Biotechnology “The k Successful treatmentofbraintumorsthroughdr According totheCentralBrain Tumor oftheUnitedStates(2004- Registry The companiesexpect thatthisnew delivery method, inadditiontobeing isawell-knownMetformin usedtoregulate blood drug glucose(sugar) The collaborationwillcombineGenerex’s delivery drug buccal proprietary rect areasasthefluiddynamicsdif of medicinalchewing gum,andGenerex Biotechnology Corporation, Pharma ertin A/S, aworld leaderinthedevelopment andmanufacture Alzheimer's diseaseremainsachallenge. showcased itsnew iPlanFlow software atthisyear's American Societyof rainLAB ximatel ey to successful treatmentofcancersites in thebrainisprecise AG, agloballeaderinimage-guidedmedicaltechnology, recently y 40,000 ne w w ution patterns ofthemedication. ution patterns The optimalsite enab brain tumorsarediagnosedeachyear inthe les physicians toeffectively circumvent the fer throughoutdifferent regions ofthe This islar ug deli gely duetothe Blood very directlyvery depends w software isscheduledtobeavailable insummer2006.” in image-guidedmedical technolo systems installedin over 65countries,BrainLAB isamongthemarket leaders as well systems forstereotacticradiosurgery. asintegrated With around 2,280 softw neurosurgery, andENT. Among theproducts developed by BrainLABare marketing ofmedicaltechnology forradiosurgery/radiotherapy, orthopedics, clinical resultsb technologies at BrainLAB. “We thatthissoftware will improve areconfident physicians,” saidDr. ChristophPedain, guidance responsible forpharmaceutical the brainandcreateoppor treatment optionforeachpatient. possibilities, w micro-invasive surgery. This enables ofthreedifferent theintegration therapy offersiPlan platform advanced doseplanningandimageguided radiosurgery tracking ofpatients'w available imagedata,humanatlas-basedautomaticorgan segmentation, and image handlingandprocessingtools,suchasautomaticfusionofall physicians throughtheentireplanningprocess.Itoffers uniquediagnostic whichplatform, isdesignedwithworkflow-optimized architecturetoguide towhereverdrug we want ittogo.” Cancer Centerin Tampa, Florida.“iPlanFlow isthetoolthathelpsusget dr throughout theworld, andMediChew salesin2004exceeded $28million). management alternatives. MediChew tablets aresoldin24countries development tochoosethebestbrand processinorderforthepartner toassessanarray ofprototypesearly withthe opportunity inthe partners andpackagingoftheMediChewmanufacture products.Itprovides its capabilities, beginning withfeasibilitystudiesandleadingultimately tothe Fertin Pharma’s includesfullproductdevelopment topartners support development ofgumbasesthatprotectsitstechnology brand(MediChew). The company release,and owns arangeofpatentswithintastemodification, with a widerangeofwell-respected companies. partnerships pharmaceutical experience withinfunctionalandmedicalchewing gum,working in medical chewing gum.BasedinDenmark,Fertin hasmany Pharma years of people withdiabetes.” the Generex missionofimproving diabetescareandthequalityoflife Generex’s President&ChiefExecutive Officer. “Together, we willcontinue leaderinmedicinalgum,”Fertin theindustry Pharma, said Anna Gluskin, younger patients. tablet thereby form, improving patientcompliance,particularly amongst gumwillavoidmetformin thebittertasteandlarge dosesassociatedwiththe abdominalbloating, andincreasedgas production. Inaddition, diarrhoea, as foundedin1989andisspecialized inthede ug delivery,” says Dr. Andrew E.Sloan,Neurosurgeon attheH.LeeMoffitt BrainLAB, aprivately heldcompany inMunich,Germany, headquartered “The launchofouriPlanFlow software willrevolutionize delivery to drug iPlan Flow isthelatestmoduletobeaddedBrainLABiPlansoftware Fertin isaworld Pharma leader inthedevelopment of andmanufacture “We arepleasedtohave established thiscollaborative relationshipwith are andhardware andradiotherapy componentsforimage-guidedsurgery hich gi y optimizing thebenef v hite matterbrainf es physicians thebestpossible thetoolstodetermine tunities forbothphar gy. its ofleading-edgemedications. The new ibers. InadditiontoiPlanFlo maceutical companiesand velopment, and manufacture, w, the

14 Drug Delivery Technology July/August 2006 Vol 6 No 7 N A Nastech Receives $7-Million Milestone Payment From Procter &Gamble for A Patch Contraceptive Dose Estrogen aLow- of $12-Million for Development Closes Financing Agile Therapeutics and committedinvestors. contraceptives. The company isbacked by asolidmanagementteam patch withthesamehor w strong, andthisnew productwilladdanattractive choiceforwomen 7-day patch. is contraception The market demandfortransdermal estradiol, available timeinasmall,visually appealing forthefirst oralcontraceptivetrusted levonorgestrel hormones, andethinyl milestone underthecompan cur The compan delivery drug technology. transdermal products utilizingitsproprietary company foundedin1997basedondeveloping novel pharmaceutical future potential.” value ourrecentprogress andoutstanding entrepreneurs atthesefirms Rossi, CEOof thattheseasoned Agile gratified Therapeutics. “I’mvery investors,” ofourcurrent the continuedsupport saidDr. Thomas M. Early StagePartners. participated, includingtheHillmanCompany, TL Ventures, andPA to Agile Therapeutics. All investors fromearlierroundsalso patch. The investment was ledby ProQuestInvestments, anew investor for de Inc.,adivisionPharmaceuticals, of The Procter&Gamble Company, tolerated validationfurther ofNastech'scapabilities indeveloping well- President,andCEOofNastech.“Thismilestonerepresents Chairman, PTH1-34 nasalspray program,” statedSteven C.Quay, MD, PhD, will berecognized asrevenue endingJune30,2006. inthe quarter (PTH1-34) nasalspray fortreatmentofosteoporosis. The milestone parathyroid hormone that is an important regulatorparathyroid ofcalcium and thatisan important hormone require injections.” ho wishtoutilizethismethodofcontraceptionb F Agile product developmentTherapeutics, Inc.,isapharmaceutical “I’m delightedtowelcome ProQuestintoourcompany andtoreceive “We arepleasedwiththeprogress thatP&Gismakingonthe PTH1-34 isafragmentofthenaturall d rentl ounded in1998,ProQuestIn receipt ofa$7-millionpayment forattainingadevelopment Company,astech Pharmaceutical Inc.,recently announced the thedevelopmentfurther ofitslow-dose contraceptive transdermal to gile Therapeutics hascompleteda$12-millionequityfinancing v v elopment andcommercializationofP anc y , in PhaseIIclinicaltesting. non-invasive delivery alternatives forproductsthatcurrently y’ s e lead productisasecond-generationcontraceptive patch, me to Parathyroid Hormone (PTH1-34)Nasal Spray Program nt of mone combinationfoundinpopularoral y's collaborationwithProcter&Gamb v estments isahealthcareventure Agile’ y s occur technology ismakingthe arath ring human ut preferasmall yroid Hormone le diabetes, obesity, conditions diseases,andinflammatory respiratory products formultipletherapeutic areas,includingosteoporosis, technologies. aredeveloping Nastechanditscollaborationpartners molecularbiology-based deliveryproducts basedonproprietary drug as aninvestigational nasalspray. into adevelopment andcommercializationcollaborationforPTH1-34 of2006.InFebruary 2006,NastechandP&Gentered quarter first postmenopausal osteoporosisandhad$127millioninsalesduring the Daily injectionsofPTH1-34areapproved forthetreatmentof both v been shown reduce toincreasebonemineraldensityandsignificantly metabolism. phosphorus When given by daily injection,PTH1-34has companies, typicall P fromNew companies locatedinthecorridor York to Washington, DC. experienced family ofventure capitalfundsthatseekportfolio and Silicon Valley. resources andcontacts. than $235millionundermanagementacrossthreeventure funds. hasapproximatelycurrently 30active companiesandmore portfolio entrepreneurial, andf biotechnology, provides theFirm companieswithoperational, portfolio technology,stage companiesininformation communications,and management. Focused onventure early investing incategory-defining, founding investor in Agile Therapeutics. association withRockHill Ventures, theHillmanCompany was the active inventure capitalinvesting forover 25years. Through its The HillmanCompany anditsinvestment isadiversified firm Affiliates with outstandingentrepreneurs. partnerships Investments mutually long-term, seekstobuild beneficial categories asoncology, pain,andinfectiousdisease,ProQuest track recordandover 30investments insuchdiverse therapeutic thatismanagingover $450million. capital firm Withproven a superior A Nastech is a pharmaceutical companyNastech isapharmaceutical developing innovative PA Early foundedin1997,isanactive StagePartners, and TL Ventures, established in1988,hasover $1.4billionunder ProQuest joins Agile’s investors current inthisroundoffinancing. Earl er y tebral and non-vertebral fracturesinpostmenopausalwomen.tebral andnon-vertebral Stage in v ests inearl y as aleadorco-leadin inancial e TL V entures hasof y xpertise andaglobalnetworkxpertise of stage Technology andLifeSciences fices inPhiladelphia, Austin, fices v estor . P A Earl y Stage Sandoz). Inthelatterroles,Mr positions atNo Reproductive HealthatSerono,andheldnumerous Delivery Systems Delivery Innovative Drug Develop e develop new andimproved drugs of formulations Javelin appliesinnovative technologies proprietary to Region. Northeast General ManagerforNovartis’ asasalesrepresentativeserved inhisnative Englandand extensive salesandmanagementexperience having ofdiclofenac.Mr.formulations Matthews alsohas Director of Voltaren andCataflam,two earlier extensive experience inpainmanagementas Brand Bio team for Tysabri (alsoformultiplesclerosis).Priorto Avonex onthelaunch (formultiplesclerosis)andserved he spentse President, Neurology Marketing atBiogen Idec,where to suppor of achie accepted Javelin’s commercialleadershiprole.Hisrecord commented “We aredelighted thatMr. Matthews has for thetreatmentofacutemoderate-to-severe pain. company’s oflate-stage prescriptionmedications portfolio oversee commercialoperationsandmarketing ofthe Phase IIIclinicaldevelopment intheUS.Hewillalso under review formarketing approval inEuropeand of Javelin’s leadproduct,Dyloject,which iscurrently initial focuswillbetoprepareforthesuccessfullaunch as Vice President ofCommercial Affairs. Mr. Matthews a needs inthepainmanagementmarket. f lung functiontobreathe. air mixtures ofheliumandoxygen, isthreetimeslighterthan systems usingHeliox. Heliox, thecommon name for tostudytheeffectsagreement ofgas-enabled delivery drug P & PARI Respiratory Equipment J Commercial Affairs as VPof MarkLaunch; Set Matthews Javelin Prepares for Dyloject deli criticall amiliarity witholderfor xisting dr nnounced thatMarkMatthews hasjoinedthecompany , With corporate headquarters inCambridge,MA, With headquarters corporate Prior tojoiningJavelin, Mr. Matthews was Vice It ishopedthatthe creationofaninno Daniel Carr, MD, ChiefExecutive ofJavelin, Officer innovative productsforpaincontrol,recently avelin Inc.,aleadingdeveloper Pharmaceuticals, of global provider ofmedical gases, have signedan ARI, aw gen Idec,Mr v w BO ery deviceery willhelp withacustomized nebulizer hich mak y vement in the pharmaceutical industry andhis industry vement inthepharmaceutical ill patientsb t ugs totar Ja C veral years incharge ofthemarketing of orldwide leaderinaerosoldeli v elin’ es iteasierforpatientswithcompromised in C v artis (previouslyartis Ciba-Geigyand . Matthe s transition tocommercialsuccess. get unmetandunderser y ollaboration to deli ws ser mulations ofdiclofenacareideal vering oxygen andaerosoltothe . v Matthe ed as V ws g ice President, v ati very, andBOC, a v v ained e ed medical Heliox ” presence in the United States and offices inJapan,United Kingdom,andChina. presence intheUnited Statesandoffices Ultra andPARI Trek. PARI Germany, inStarnberg, isheadquartered withamajor the Fish II,aswell systems, includingthePARI ascompressor/nebulizer PRONEB including thePARInebulizers, LCPLUSandPARI LCSTAR, maskslike Bubbles that helpcontroldisease.Products available includebreath-enhanced, reusable a P deli a billion poundsSterlingin2005. than 50countries.Itemploys some30,000peopleandhadannualsalesofover 4.6 company, services abatement, anddistribution 2millioncustomersinmore serves infor therapies,” saidBrad Walker, ManagingDirector ofBOC'sMedicalDivision. systems thatwillenable doctorstosafely andreliably provide potentially life-saving Werner Gutmann, PresidentofPARI Equipment. Respiratory delivery systemscanimprove patientoutcomeswhen usingHeliox aswell,” stated enriched oxygen. We thatPARI's arecertain 100-yearindeveloping history aerosol COPD, andbronchiolitis. aerosol therapiesusedtotreatexacerbations ofseveral suchasasthma, conditions, lungs withlesseffort thanbreathingair. The goalistoimprove thedelivery rangeof v ARI's primar leading worldwide aerosol developer andefficient offast andmanufacturer ailab PARI Equipmentisthe North ofPARI Respiratory American arm GmbH.PARI is The BOCGroup,theworld-wide industrial gases, vacuum technologies As studyresultsbecomea “We’re delightedthatPARI sharesourvisionofnovel, delivery easy-to-usedrug “Our collaborationwithBOCmarksanimpor v er mation withph le aerosoldeli y systems forpatientswithasthma, chroniclungdisease,andc y focus istopro ysicians andclinics. v er y system thatoptimizesresultsusingg v ailab vide patientswithinno le laterthisy tant stepto ear , P ARI andBOCwillshare v ati v e w products andservices ard acommerciall ases otherthanairor ystic f ibrosis. y

15 Drug Delivery Technology July/August 2006 Vol 6 No 7 16 Drug Delivery Technology July/August 2006 Vol 6 No 7 dry powder formulation extends the shelf-life and simplifies thedistribution powderdry extends theshelf-lifeandsimplifies formulation sonication beingrequired. patient administrationwithnoadditionalpreparationsteps.suchas freeze-dried andthensimpl tobe enables asliposomalnanoparticles siRNA preformulated drugs then combined, inamulti-stepprocess. The new process SRPharma ha benef temperature andreconstitutedinonesimplestep,thusproviding significant dried) liposomall ofsiRNA lyophilized thatenablesformulation itsproprietary drugs (freeze- Prefer interest,convertedin March2006,plusaccrued intosharesofSeriesE addition, $1.5millionofconvertible SMHaffiliates notesissuedtocertain Stockatapriceof$1.37pershare.In of sharesSeriesEPreferred conditions, thecompany received proceedsof$3millionfromtheissuance uponshareholderapprovalaffiliates, ofotherclosing andsatisfaction withtheSMH oftheagreement ofSMH.Undertheterms Stock toaffiliates approved theissuanceofapproximately $4.5millionofSeriesEPreferred needle-free device. development andsupply withMerial,Ltd.forthe agreement Vitajet 3 For loanwithPartners term Growth (PFG). The company alsoenteredintoa and shareholderapproval oftheequityconversion featureofitsMarch2006 (SMH) Harris ofSandersMorris affiliates withcertain million financing follo Stock includesan8%annualpayment-in-kind dividend for24months C Technology Delivery Drug Used in Orapred ODT CIMA LABS’ S L AnnouncesSR Pharma Key Technical Breakthrough With itsLyophilized B debt financing of $1.25 million entered into with Partners forGrowth of$1.25millionenteredintowithPartners L.P.debt financing in and patients. taste-masking andorall CIMA LABS.“OrapredODTisa good example ofthevalue ourinnovative to ourgrowing portfolio,” said Todd MacLaughlan,General Managerof orally ofprednisoloneavailable tablet disintegrating form intheUS. recentl (prednisolone sodiumphosphateorally tablets). disintegrating The USFDA Inc.,and Pharmaceutical, Inc.,in OrapredODT Alliant Pharmaceuticals, developed by CIMALABS. OraSolvtablets onthetongue, disintegrate countries utilizing orallydelivery technologies drug disintegrating now products approved 11pharmaceutical forsale intheUSandother US inthethirdquar asthma inchildren. Alliant expects tobegin marketing OrapredODT inthe Bioject MedicalBioject Technologies Agreement &Signs Completes Financing v ip “This is a significant breakthrough in the manufacture ofsiRNA breakthroughinthemanufacture drugs. “This isasignificant A To date,the AtuRNAi andliposomalcomponentsof AtuRNAi drugs At theannualshareholdermeeting,heldMay 24,2006,theshareholders The shareholdersalsoapproved theconversion featureincludedinthe “We pleasedtoaddanotherproductandsuccessfulpartnership arevery Orapred ODTwillbeprescribedprimarily foracuteexacerbations of e recently announcedithasmade atechnicalbreakthroughinthe R IMA LABSINC.,aCephaloncompan delivery systems,recentlydrug announced thecompletionofits$5.75- i OraSolv dr wing the closing of the Series E Preferred Stocksale. wing theclosingofSeriesEPreferred oject Medical Technologies, Inc.,aleadingdeveloper ofneedle-free needed tobeseparately lyophilized (freeze-dried),reconstituted, and its, mostnotab Phar red Stock,alsoatapriceof$1.37pershare. os y granted marketing approvalgranted forOrapred ODT, which isthefirst omal-Based siRNAomal-Based Formulation ma plc,aleaderinthede ” ug deli y for ter of2006. With theadditionofOrapredODT, thereare l y mulated siRN v extended shelf-lifeandeaseofadministration. y er disinte y y technolo reconstituted withw grating technologiesgrating canprovide physicians A velopment ofRNAi Therapeutics, gy isbeingusedb (AtuRN y , recentl Ai) dr ater immediatel The SeriesEPrefer ugs tobestoredatroom y announced thatits y BioMarin y prior to red Germany, andStanfordRookLtd, basedinLondon,UK. The company hastwo operatingsubsidiaries Atugen AG, basedinBerlin, said IainRoss,Ex the dr powder only formulation requiredtheadditionofwater drug torehydrate conferences. Klaus Giese,CSOofSRPhar our productsaswe take oursiRNA forward drugs toward theclinic.” saidDr administration. We willbeapplying thistechnology of tothemanufacture chain, withtheone-stepreconstitutionprocessenhancingeaseof SR Phar ofsiRNA-basedformulations productsunderlinestheleadershippositionof M leading pharmaceutical, biotechnology,leading pharmaceutical, companies. andveterinary The company with isfocusedon developing agreements mutually beneficial fluid penetratingtheskinanddepositingmedicationintissuebeneath. streamofhigh-pressure heldagainst theskin. tinyThis createsafine orifice Needle-free injectionw innovative developer delivery systems. ofneedle-freedrug andmanufacturer the next 15to18months.” to continueexecute within ourstrategy andachieve operatingprofitability we withMerialandfutureanticipatedagreements, arepositioned agreement Bioject. “We believe withtheadditionalfunds,signingof withMerial,”agreement President,andCEOof saidJimO’Shea,Chairman, transactions. We arealsopleasedthatwe have enteredintoanother animal market. vaccinesVitajettheir proprietary withamodified 3foruseinthecompanion Merial, aworld leadinganimalhealthcompany, forthedelivery ofone common stockatapriceof$1.37pershare. without che of s CIMA LABSalsode or theneedforw technologies. The tablets quickly disintegrate inthemouthwithoutchewing based onOraSolvandDuraSolvorally tablet disintegrating (ODT) globallyproducts aredistributed andare by partners its pharmaceutical eightprescriptionandthreeover-the-counter technologies. CIMALABS’ phar develops prescriptionandover-the-counter andmanufactures a review by theFDA. Minneapolis, Minnesota, CIMAis Locatedinsuburban product candidateusingOraVescentThe first technology isunder currently cancer, and pain. marketing ofinnovative medicinestotreat sleepandneurological disorders, Frazer, Pennsylvania, isfocused onthediscovery, development, and w arch 2006. The debtisconvertible by PFGatany timeintoBioject's SR Phar Details ofthenew processwere presentedatrecent scientific “This new processofliposomal-based breakthroughin the manufacturing Bioject Medical Technologies, Inc.,basedinPortland, Oregon, isan “We arepleasedwiththeoverwhelming shareholderapproval ofthese addition, thecompanyIn signedadevelopment andsupply agreement CIMA LABS INC. is a leading drug deliveryCIMA LABSINC.isaleadingdrug technology company that holly owned in ofCephalon,Inc.headquartered subsidiary w maceutical productsbasedonproprietary, orally disintegrating allo ug andprepareitforinjection. ma intheemer wing. ma plcisaEuropeanbiophar wing ortheneedforw The presentationssho ater ecuti , v making iteasierforpatientstotake medication. eloped OraV ve Chairman ofSRPharma. ve Chairman ging sectorofRN orks b y ma. forcing medicationathighspeedthrougha ater w escent, anoraltransmucosaltechnolo ed how thisstable andlyophylized dry , enabling convenient dosing andease maceutical compan A interference and drug delivery,”interference anddrug y , listed on AIM. gy . injection underthene weeks. hydrochloride Endoalsoplanstorelaunchitsoxymorphone expected tobecommercially available intheUScoming will bea to-severe acutepainwhere theuseofanopioid isappropriateand immediate-release version) isindicatedforthereliefofmoderate- ER will beavailable Opana inanoral,extended-release formulation. timeoxymorphone used onanas-neededbasis. This isthefirst treatment forane pain inpatientsrequiringcontinuous,around-the-clockopioid patients, OpanaERisindicatedforthereliefofmoderate-to-se the tradenamesOpanaERtablets andOpanatablets. hydrochloride.oxymorphone These productsarenow known under of extended-release andimmediate-releaseformulations approvalUS FDA final ofthecompany’s hasgranted NDAs forits E “W pro over 3,000patients.Further, excited Endoisvery tobeable to an opioidanalgesic,withmorethan15clinicaltrialsenrolling represents oneofthemostcomprehensi FDA approval. The clinicalprogram forOpanaERand represent Endo’s internally developed NDAs first tobegranted relief inmultiplemoderate-to-severe painmodels,inboth opioid- Bothproductshaveformulation. beenproven to achieve effective hydrochloride, which hadbeenavailable only asan injectable Opana ERandw hour period, helpingpatientsmaintainasteadylevel ofpainrelief. de Opana ERutilizesapatenteddelivery systemthatwas specifically the-clock coverage withananalgesicagenttosustainpain relief. chronic pain,which ispresentmuchoralloftheday, needaround- thatpatientssuffering agree frommoderate-to-severeExperts company believes highlightsthedurabilityofitsanalgesiceffect. over the3-monthperiod ofthepivotal clinicaltrials,which the demonstrated maintenanceofef and iswell-tolerated when titratedeffectively. OpanaERhasalso Endo iscommittedtotheappropriateuseofopioids,andw for painmanagement.” demonstrates itcanbedosedconsistentl opioid analgesics,a$3.2-billionmarket in2005.Itsclinicalprofile andguidanceonresponsibleinformation opioiduse.” program thatgives healthcareproviders andpatientsessential worked closely withtheFDA consultantstodevelop andexternal a Commercialization PartnerCommercialization Penwest & isDevelopment Release Tablets CII; Release Immediate- &Opana ERExtended- for Opana Endo Receives FDA Approval veloped toprovide continuousdeliveryof medication over a12- A Peter A. Lankau,PresidentandChiefExecutive Officer, said Mr. Lankauadded, “As amarket leaderinpainmanagement, Opana ERwillcompeteinthemark vide ph e will beavailable in5-,10-,20-,and40-mgtablets. Opana(the Pharmaceuticals Holdings,Inc.,recentlyPharmaceuticals announcedthatthe Inc.,awhollyndo Pharmaceuticals, owned ofEndo subsidiary are pleasedwiththeappro ne w vailable in5-and10-mgtablets. Bothproductsare oral extended-release opioidanalgesicoptionfor ysicians andpatientswiththeseimpor xtended periodoftimeandisnotintendedtobe w trade nameinthehospitalsetting. ere bothfor v fecti al ofOpanaERandOpana,w mulated usingo ve paincontrolatastable dose et forlong-acting,strong ve ever conductedfor y on atwice-dail tant ne xymor w y options basis phone e have hich v ere sales ofapproximately $0.20to$0.24perdilutedshare. OxyContin ofapproximately attributable toitsgenericOxyContin $50to$60millionand earnings achieving theseresults. These 2006estimatescontinuetoinclude netsalesofthecompany’s generic employer payroll taxes fundedby LLC. Ofcourse,therecanbenoassuranceofEndo EndoPharma (estimated tobeappro milestone payments stockcompensationcharges relatedtotheadoptionofSFAS topartners, 123 per sharefor2006tobeappro persharebyearnings approximately $0.20. The company now estimatesadjusteddilutedearnings impact ofthelaunchOpanaERand Opanaisexpected toreduce Endo’s 2006adjusted diluted atthattime. Opana ER,which willberecognizedAs such,the asanincreasedshareoftheprofits its launchphase.Endoexpects torecover Penwest's of shareoftheselossesfromthefutureprofits fund OpanaER;therefore,Endowillrecognize 100%ofthelossesattributable toOpanaERduring signif in 2006connectionwiththislaunch.However, thecompany believes thislaunchprovides another in andFrova.products, includingLidoderm Additionally, Endowillsubstantially increaseits representatives ofOpanaas well topromoteallformulations ofbranded as itsexisting portfolio weeks, 370-personsales forceby Endoplanstoexpand approximately itscurrent 220sales in 2006continuetobeestimatedappro be approximately $20to$30million,substantially composedofOpanaER.Netsales ofLidoderm approximately $880to$910million.CombinednetsalesofOpanaERandareexpected to naïve andopioid-experienced patients. v At thistime,Penwest Co.,Endo'sdevelopment Pharmaceuticals partner, continuestoelectnot Endo isrevising expects itsguidancefor2006andcurrently netsalesin2006tobe estment intheOpanafranchiseand icant g ro wth oppor ximatel tunity tocomplementitse y ximatel $0.05 perdilutedshare)andcompensation expense andrelated y , accordingly, expects toincuralossforthisproductfranchise $1.55 to$1.60. ximately $530 to $540million.Over the next few xisting por This e xcludes estimatedupfrontand tfolio.

17 Drug Delivery Technology July/August 2006 Vol 6 No 7 18 Drug Delivery Technology July/August 2006 Vol 6 No 7 f Eli L transdermal anti-emeticproduct, transdermal AB-1001. Basedonapreliminary completed aPhaseIstudyunderanUSIND Application fora of representsanotherstepforward“This agreement intheadvancement A proprietar and allo technology Itcomplementsourongoingproductinitiatives platform. effective therapies. transdermal anddevelopment theformulation permitting ofnew andhighly high concentrationsofactive directly drug throughtheskin,thereby andenables properties therapidpenetrationof skin's naturalbarrier thathelpovercome consistsofbiodegradable ingredients platform the were terms notdisclosed. technologyfinancial The proprietary patchapplications. technology foralltransdermal platform The for diabetes. system), w for registration fortheir AIR InhaledInsulinSystem(AIRinsulin pro “ThisPhaseIIIstudyis a vitalcomponentoftheregistration platform. Research LaboratoriesandleaderofLilly’s development pulmonary overall healthoutcomes,” saidDr. CarlosPaya, Vice PresidentofLilly help patientsgain controloftheirblood sugar andachieve better, needfornew therapeuticoptionsthatcan continues tobeasignificant E study progress inourPhaseIIItrialsthroughouttheyear.” the w 2 studies andadditionallong-ter program thatbegan inJuly 2005,which includes pivotal efficacy diabetes. ofacomprehensiveThis studyispart PhaseIIIclinical ofthe and efficacy AIR insulinsysteminpatientswithtype1 the safetyandef ofinhaledinsulin.”the safetyandefficacy establishare committedtoconductingthe studiesneededtofurther compiled fromour AIR insulinsystemstudiesconducted todateand “WeAlkermes. andLilly arehighly encouragedby theclinicaldata the AIR insulinsystem,” of saidElliot Ehrich,ChiefMedicalOfficer pre-meal insulin innearly 400non-smokingpatientswith type1 Technology for Transdermal Patch Applications In-Licenses WorldwideAbeille Pharmaceuticals Exclusive Rights to or I diabetes patients. “Abeille continuestoexecute planandrecently itsbusiness “We areextremely pleased toannouncethein-licensingof “We arepleasedtohave completedenrollmentinthisPhaseIII andisbecomingoneof “Diabetes hasreachedepidemicproportions This PhaseIIIopen-label, randomizedstudyisdesigned toe our strategic planasaproductdevelopment company.” g li Lill completion ofpatientenrollmentinapi ram forour AIR insulinsystem,andwe expect tomake continued an agreement granting granting an agreement Abeille worldwide, exclusive rightstoa b , orld's mostpre eille Pharmaceuticals, Inc.,recentlyeille Pharmaceuticals, announcedtheexecution of w ws us to pursue product opportunities thatarebasedonthis ws ustopursueproductopportunities nhaled Insulinnhaled hich isak illy &Alkermes Complete Patient Study Enrollment IIISafety for Phase y y hich isbeinginvestigated asaninnovative treatmentoption and Compan platfor The goalofthestudyistomorefull f icacy of the AIR insulinsystem comparedtoinjected m, e y v ” alent, costl step inourpro stated SureshBorsadia,PresidentandCEO y and Alk m y safety studiesinbothtype1and , er and debilitatingdiseases. mes, Inc.,recently announcedthe g ress toward for theNDA filing v otal safetystudyrequired y define thesafety define There valuate . and metabolicdisorders,CNS. usedtotreatoncology-related diabetes will beondrugs discomforts, improve thequalityoflifeforpatients. The company’s initialfocus commercialization ofproductsthataddressunmetmedicalneedsand prescribed. medication, thereb medicine, reducedsideeffects, andeasieradministrationof new patientsby requiringalower productsmay benefit doseof deliveryinclude oralcontrolled-releaseandtransdermal systems. The technologies toexisting drugs. These advanced delivery technologies ofproductsbythe formulation applying advanced delivery company basedinPrinceton,New Jersey. The company isfocusedon pivotal studiesin4Q,2006.” PhaseIIIefficacy continued Mr. Borsadia.“Thecompany’s planscallforinitiating study, which areexpected tobecompletedby August, 2006,” r follo diabetes. P a (AIR insulin)toinjectedinsulinlisprowithrespect safety. The trial willalsoevaluate thenoninferiorityof AIR Insulin small, simple inhaler that fits inthepalmofahand. small, simpleinhalerthatfits managing type1and2diabetes. The AIR insulinsystemuses a treatment optionthatcanhelpaddress thechallengesassociatedwith Lilly/Alkermes program isfocusedondeveloping aninnovative Alkermes' delivery drug technology.AIR pulmonary The (AIR insulinsystem)thatdeli inhaled insulinsystem,known asthe AIR InhaledInsulinSystem, months. assessed at6months,andthesafetywillbeevaluated at12and24 treatment groups. ofthe The efficacy AIR insulinsystemwillbe antidiabetic medicationwillberandomizedtooneofthetwo naive patientswithtype2diabeteswho aretakingatleastoneoral injected pre-mealinsulinover 6months. Approximately 400insulin- insulin systemisatleastasef label, noninferioritystudyisdesignedtoevaluate whether the AIR ofthePhaseIIIpivotalas part trialprogram. This PhaseIIIopen- States, Canada,Belgium,Croatia,Hungary, andIndia. The 66-sitestudybegan enrollingpatientsinJuly 2005 in theUnited all patientshave beenenrolledandrandomizedtoreceive treatment. eview ofthedata,company hasinitiatedactivities foraPhaseII v erage measureofblood glucoseover a3-monthperiod. At thistime, Abeille Pharmaceuticals, Inc.,isaprivatelyAbeille Pharmaceuticals, heldpharmaceutical Lilly and areconductingPhaseIIIclinicaltrialsforan Alkermes In addition,thecompaniesrecentl w-up period.Pulmonar atients arebeingtreatedfor24monthswitha2-month Abeille isdedicatedtothede y encouraging apatienttousethemedicationas y safety tests(PFTs)areusedtoassess fecti v ers insulinviainhalationbasedon v e y in impro initiated anotherstudyrequired v elopment and ving glucosecontrolas A1C levels, the

Market Evolution & Sector Confusion By: Howard S.Wachtler

hen we look at companies engaged in G A few decades ago, pharma companies were pharmaceuticals, biotechnology, very traditional. They did not stray too far from their WWdiagnostics, medical products, specialty knitting. That strategy has worked for years and pharma, and drug delivery, their fields of work often satisfied shareholders through significant returns. overlap to the point that it is getting increasingly Well, it works well when the company has significant difficult to define their respective focuses. Of course, revenue (to maintain shareholder return) and a vibrant these convergences between once fairly well-defined pipeline. Unfortunately for large pharma, the sectors do not emerge randomly. Market characteristics blockbuster era took hold so that for companies to change, which give rise to new markets. New strategic remain economically sound and acceptable to initiatives emerge from new definitions of markets. shareholders, they needed “billion dollar” molecules. Successes and failures loom large as barometers for As we have all come to realize, only a small number new endeavors. Timing remains omnipotent. of products ever make it to that elite class. Thus, that If we take the case of Big Pharma and Biotech, the is not a viable, long- term strategy. challenge is to “really differentiate” the two. Once, the

difference was clear. Biotech companies were engaged G Biotech came into existence with new in discovering and developing protein-based drugs that technologies, etc. in an effort to start a new industry could not be made through chemical synthesis. They segment. The segment soon took hold and is today had to be produced in genetically engineered living stronger than ever. The segment is composed of many cells. This novel approach lead to a new business model small, early stage companies backed by venture in which biotech companies were focused on capitalists, etc. and a handful of large companies that developing their drugs only to a certain point and hoped have been able to “put it all together” to provide their to sell them off to larger pharmaceutical partners. own acceptable shareholder return. Alternatively, they sought to raise money to finalize

their drug development through an IPO not on the G The synergies between the two segments became 7 strength of revenue, but on the trust in novel science. apparent when both entities realized they needed each o N

6 Other people, who had no interest in biotechnological other. This became obvious due to weak pipelines,

l o V

genetic engineering, seized on that business model, and patent expirations, etc. Pharma companies became

6 0

0 soon, biotech came to denote the described business logical partners of biotech enterprises, which helped 2

t s

u model, rather than real biotechnological engineering. them with new products, technologies, pipeline g u A

/ So the real question is how well has this business additions, sustainable IP, etc. As a matter of fact, many y l u J

model worked? Being quite cynical, if we look at the pharma companies have actually established pools of

y g

o biotech sector after many years of existence and capital to invest in biotechs. This combination has kept l o n

h billions of dollars of expenditures, what do we really both segments together and remains vibrant today. c e T

y

r observe? Many executives would admit, maybe e v i l

e not openly, that the biotech sector is really an G Pharma has by necessity come a very long way D

g u

r outgrowth or subset of the pharma sector. Why? from its traditional thinking. In addition to licensing, D Below are some justifications. 20

Specialty Pharma. Here, we have two additional sectors that have grown and prospered in today’s marketplace. Whether we call these variations on a theme or new businesses doesn’t really matter. The market has accepted both and has valued them accordingly, and by the way, they too (in the eyes of some) can be extensions of the pharma and biotech sectors. Below are some thoughts on these sectors.

G The drug delivery sector has evolved as a clever, necessary, and attractive business. This sector stems from serious issues that face pharma companies: How best to deliver a drug? What form should the drug be? Can the required number of doses be reduced while receiving the same amount of drug? Can a medical device be positioned as a delivery device or conduit? These are some of the critical questions this sector has addressed very well.

G As mentioned earlier, pharma companies desperately need to formulate strategies to offset diminished pipelines and loss of IP. Drug delivery to the rescue. Controlled release meds have added a whole new dimension to pharma. Once-a-day or once-a-week formulations from partnerships and alliances, which many times can result in three- or four-times-a-day or several times-a-week drugs acquisitions, have become a staple in their business model. have represented very significant patient-accepted advances Very significant dollars have been invested in biotech, and made by drug delivery companies. Therapeutics have also we expect that this will continue. It is a necessary been priced accordingly to maintain acceptable margins and component of growth and shareholder satisfaction. Pharma provide shareholder acceptance. 7

o (not having the entrepreneurial bent of biotech) has forged N

G Medical devices, implantable or external, have also 6

l ahead with alliance management teams to interact with and o V

represented notable advances in the drug delivery sector.

manage alliances. This has been a 6

0 The “hassle factor” of a drug/device combo that has riddled 0

2 very prudent move by big pharma as it quickly defines

t

s regulatory experts is becoming more acceptable. Some u those who have been assigned to the project and key to g u

A examples would include insulin pumps, patient-controlled / its success. The smaller biotech company can take y l u

J pain medication, medicated stents, etc.

advantage of the disciplines available at pharma without

y g o

l all of the beaurocratic red tape. Let us not forget that o n

h G Specialty pharma represents yet another successful

c the biotech sector has been and continues to be e T

y sector built upon (depending on who you ask) many if not r entrepreneurial. Tradition would not have spawned e v i l all of the aforementioned sectors. It can incorporate drug e

D this exciting, innovate sector.

g

u delivery, generic, Pharma, and biotech disciplines. It is all r Now, let’s move our thinking to Drug Delivery and D in how one defines things. 22 G Many generic companies now carry the banner of being specialty pharma companies. Some will attempt to B IOGRAPHY command higher prices by identifying themselves as “branded generics.” Really, this is nothing more than having Mr. Howard S. Wachtler is a name associated with the generic. In some cases, it really President and CEO of Actinium Pharmaceuticals, Inc., an works. As a matter of fact, some mid-tier pharma emerging biotechnology company companies have had success with this. Good companies headquartered in Florham Park, will have employed GMP practices, and their products will New Jersey. Mr. Wachtler is a senior be bioequivalent. healthcare industry executive, who brings with him more than 25 years

G Specialty pharma has also boasted drug delivery of broad-based and diversified experience in venture capability to boost its own company and be more attractive capital, business development, strategic planning, general to pharma and biotech alike. All of the technologies that are management, and sales and marketing management. Mr. Wachtler joined Actinium Pharmaceuticals from the deployed by Drug Delivery companies are quickly being position of Managing Officer of QED Technologies, Inc., a deployed by the Specialty Pharma sector. life science-based strategic consulting and transactional group. Prior to joining QED Technologies, Mr. Wachtler As a result of all these new needs and challenges, served as Managing Director of Medical Venture Holdings, sector differentiation has become clouded, with all of these Inc., an affiliate of Oppenheimer and Co., where he sectors working off a common theme. Early on, we managed a series of globally diversified healthcare venture mentioned the importance of timing. There is no substitute capital funds. Before joining Oppenheimer,. Mr. Wachtler for proper timing to achieve success. And there are no directed Business Planning and Development for Pfizer, Inc., Hospital Products Group with responsibility for exceptions in these paradigms. All of the aforementioned business/strategic planning, acquisitions, strategic segments can be characterized (to a greater or lesser extent) alliances, licensing, and venture programs for the division as outgrowths of the pharma and biotech sector. All have and corporate management worldwide. Prior to his tenure their places and have achieved great success. Success does at Pfizer, Mr. Wachtler directed Corporate Development for not have to be measured in huge revenues, but rather in Organon, Inc., where his responsibilities included the extending the life of the product, making it more identification, evaluation, and consummation of acquisitions, new ventures, and technologies opportunities convenient for a patient (just think of the difference 7

o

for all divisions of the company. He also directed and N

between ingesting one versus several pills a day), selling 6

coordinated the Strategic Planning process for all l o less expensive (but equivalent) versions of products, and V

divisions. Mr. Wachtler also held management positions in 6 having the ability to work closely through funding and 0 sales and marketing research at Sandoz, has served on 0 2

t alliances with the key companies in the industry. More numerous corporate boards globally, and was a member of s u g u

today than in the past, Wall Street recognizes real the Board of Governors of the Emerging Companies Section A / y l performance versus “promises” that are rarely fulfilled. of the Biotechnology Industry Organization (BIO). He is a u J

frequent speaker at industry meetings and has lectured y

Some of the best among the life sciences companies have g o l

and taught undergraduate and graduate level courses. In o achieved success in building value and infrastructure by n h c

addition, he currently serves on the Editorial Advisory e T positioning themselves as being more synergistic than y r

Board of Drug Delivery Technology magazine and is a e v i competitive with their brethren. l

N e

regular contributor. Mr. Wachtler has earned his D

g u

undergraduate and graduate degrees in Business from Pace r D College and Long Island University, respectively. 23

Are Inventions Based on Discoveries of Natural Phenomena Patentable? By: Clifford M. Davidson, Esq.

INTRODUCTION Whether a method patent setting forth an indefinite, undescribed, and non-enabling step directing a party to Recently, a patent litigation that appeared to mainly “correlat[e]” results can validly claim a monopoly over a involve a dispute over the scope of patent claims for a basic scientific relationship used in medical treatment diagnostic test for detecting vitamin B deficiency spilled such that any doctor necessarily infringes the patent over into an apparent dispute over whether the claims merely by thinking about the relationship after looking at (which are based on a naturally occurring relationship a test result. between elevated levels of total homocysteine and a deficiency in either cobalamin or folate) are so broad as to On March 21, 2006, the Supreme Court heard oral cover natural phenomena outside the scope of patentable argument in this case. The oral argument went well beyond subject matter as defined in 35 U.S.C. §101. Many patent the issues of indefiniteness, lack of written description and holders were interested in the future outcome of this case, enablement, and ventured into the realm of whether the as it could have implications to broad patent claims in the subject matter of the claim itself is patentable. medical field, where the claims are based on diagnostic A significant part of the oral argument centered tests or treatments that are based on an underlying around Claim 13 of the 658 patent, which reads as follows: naturally occurring phenomena. 13. A method for detecting a deficiency of cobalamin or THE CASE folate in warm-blooded animals comprising the steps of: assaying a body fluid for an elevated level of total US Patent No. 4,940,658 (658 patent) is owned by homocysteine; and correlating an elevated level of total Competitive Technologies and was licensed to Metabolite homocysteine in said body fluid with a deficiency of Laboratories. LabCorp obtained a sublicense from cobalamin or folate. Metabolite, and from 1991 to 1998, LabCorp tested for homocysteine using the specific method encompassed by Petitioner LabCorp argued that the correlation the claims of the 658 patent and paid royalties to between elevated homocysteine levels and vitamin Metabolite and Competitive Technologies. In 1998, deficiencies stated in Claim 13 does not qualify as a novel LabCorp began utilizing a method developed by Abbott invention, but instead is a basic scientific principle or law Laboratories and stopped paying the royalties associated of nature that cannot be the basis of a valid patent claim with the 658 patent. Metabolite and Competitive under 35 U.S.C. § 101.5 LabCorp argued that neither the Technologies, Inc., sued LabCorp for infringement of the activity of assaying nor the activity of thinking about the 658 patent. A jury verdict in the US District Court found scientific correlation transforms Claim 13 into a that LabCorp indirectly infringed the 658 patent and patentable invention, and further notes the absence of any breached its contract with Metabolite, doubled the transformative process in the claim that might otherwise

7 infringement award based on willful infringement, and allow the claim to qualify as proper patentable subject o N issued a permanent injunction. The case was appealed to matter. LabCorp advanced a general policy argument that 6

l upholding the validity of Claim 13 will effectively allow o the Court of Appeals for the Federal Circuit, which V reconsidered (i) the proper interpretation of the claims1; for the patenting of any scientific principle or natural 6

0 correlation by merely including a “test and correlate” 0 (ii) whether the specification complied with the written 2 2 3 6 t claim similar to Claim 13 into a patent.

s description, enablement, and definiteness requirements of u

g A central issue brought to bear by LabCorp was that u 35 U.S.C. §112; (iii) whether the prior art rendered the A / including scientific principles, such as those set forth in y claims unpatentable; and (iv) whether the claims were l u J infringed; among other things. The Federal Circuit Claim 13 within patentable subject matter, would allow any

y 4 person who discovers a new correlation a means to demand g affirmed the lower court’s decision. o l

o a royalty from any person or entity who thinks or tells

n In November 2004, LabCorp filed a petition for a writ h

c others about the correlation. This in effect would discourage e of certiorari with the Supreme Court posing three T y

r questions for review. On October 31, 2005, the US additional researchers from developing new methods or e v i l Supreme Court granted certiorari to review only the practical applications, which are based on the correlation, e D thus impeding future discovery and scientific research due g following question in this matter: u

r 7

D to fear of incurring patent infringement liability. Respondent Metabolite argued that the Supreme 24 Court should dismiss the writ of certiorari on the grounds that patentable subject matter under 35 USC § 101. The IPO argues the issue of 35 U.S.C. §101, subject matter patentability, was that the requirements of novelty, nonobviousness, and not raised in the lower court proceedings (although it noted that description sufficiently protect against over-reaching patents, the LabCorp’s answer asserted invalidity based on § 102 thus obviating the need to further restrict the scope of (novelty), § 103 (nonobviousness), and §112 paragraph 2 patentable subject matter. (definiteness). This led to a discussion (and possible Several members of the financial services industry disagreement among the Justices) as to whether the issue of (including IBM, AMEX, Bear Stearns, and Lehman Brothers) subject matter patentability was adequately raised (e.g., by filed amicus briefs arguing that upholding the validity of Claim construing LabCorp’s arguments broadly). 13 of the 658 patent allows for the impermissible patenting of If the Supreme Court did find that this issue was abstract ideas and mental thought processes, stemming from adequately raised by LabCorp in its papers, then this case could their collective concerns regarding the potential impact that have far-reaching implications not only in this case, but with affirming the lower court decision in this matter would have on respect to many patents that have been issued throughout recent the scope of allowable business method patents. Consequently, years where an inherent or natural phenemona is the “heart” of these parties advocate that patentable subject matter under 35 a granted patent claim. USC §101 should be restricted to inventions that involve technological contributions that are both physical and material in nature, thereby excluding abstract ideas from the scope of POSITIONS OF THIRD PARTIES patentable subject matter.

At the request of the Supreme Court, the Solicitor General filed an amicus brief urging the Supreme Court to deny the DISCUSSION writ of certiorari. The Solicitor General believed that the 658 patent appeared to inappropriately claim “all substantial During oral argument, Justice Kennedy noted that the practical applications of the natural relationship,” and that the Federal Circuit did not address the subject matter patentability record was not sufficiently developed in the lower court issue, and Justice Scalia noted that it was not mentioned in proceedings for the Supreme Court to make a determination LabCorp’s petition to the Supreme Court. It was pointed out by on that issue. counsel for LabCorp that this issue was raised in both the An amicus brief was filed by Affymetrix, Inc., a supplier district court and Federal Circuit briefs, and that those briefs of commercial DNA microarrays. Affymetrix took the position discussed numerous cases on claiming natural phenomena. On that patent rights should not be granted on basic laws of nature the other hand, Justice Breyer noted that LabCorp thought it because such rights would directly impede scientific progress. obvious from the cases it cited and discussed that it was Affymetrix’s interest in the matter stems from the fact that its making a Section 101 subject matter challenge, and both business is primarily in the areas of DNA and gene expression Justice Breyer and Justice Souter noted the intersection analysis. Similar to the positions set forth by Lab Corp, between this issue and the definiteness issue (where the claim Affymetrix argues that the correlation between a vitamin if construed broadly fails as covering unpatentable subject deficiency and elevated levels of an amino acid in the blood is matter under §101 and if construed narrowly fails because it is a natural phenomenon that is not patentable subject matter indefinite). Under that reasoning, it is possible that Claim 13 under current law. could be construed narrowly such that claims are limited by the 7

Similarly, in its amicus brief, the Public Patent Foundation “assaying” language; it could also possibly be found to be o N took the position that the Federal Circuit had over-reached the indefinite, e.g., on the basis that the claim is unclear as to what 6 l o current legal defined boundaries of patentable subject matter by tests outside of the natural phenomena would or wouldn’t be V allowing claims similar to Claim 13 of the 658 patent. In covered by the claim. 6 0 0 addition, the American Medical Association and the American Is this case similar to previous cases argued to the 2 t s

Heart Association filed amicus briefs in favor of the petitioner, Supreme Court, such as O’Reilly v. Morse, 56 U.S. (15 How.) u g u

Lab Corp, arguing that Claim 13 improperly claims patent 62 (1853), where the Supreme Court rejected Samuel Morse’s A / y l

rights to a scientific principle and is overly broad because the patent claim because it extended a telegraphy invention through u method stated in Claim 13 is not limited to any particular the use of electromagnetism to all uses of electromagnetism, or J y g o method of testing homocysteine levels. On the other hand, the is it more similar to Dolbear v. Am. Bell Tel. Co., 126 U.S. 1 l o n

American Intellectual Property Law Association and the (1888), where a patent claim to voice transmissions using h c e Federal Circuit Bar Association filed amicus briefs in favor of continuous undulating current was held to be not infringed by T y r e the positions set forth by respondent, Metabolite. other uses of that undulating current? v i l e

In its amicus brief, the Intellectual Property Owner’s As Justice Alito stated during the oral argument, a finding D g u

Association (IPO) did not align itself with either party in the that Claim 13 was invalid under §101 for covering unpatentable r underlying matter. Instead, the IPO argued that any ruling in subject matter, would call into question the validity of perhaps D this matter by the Supreme Court should not further limit “thousands” of other patents. Certainly, one can imagine the 25 implications to diagnostic claims where a diagnosis is made by REFERENCES assaying a body fluid for the presence or absence of a substance, which indicates, e.g., a disease state. On the other 1. The proper interpretation of the claims is typically considered in a pre-trial hearing conducted by the court, which is referred to as a “Markman Hearing” and is discussed in an article by this author that appeared in the January ’06 issue of Drug Delivery hand, Metabolite was not taking the position that either the Technology. 2. 35 U.S.C. §112, first paragraph, provides that the specification of a patent “…shall contain a written description of the homocysteine/vitamin B relationship or the step of invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any “correlating” this natural relationship was independently person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. patentable. Rather, Metabolite took the position that the 3. 35 U.S.C. §112, first paragraph, provides that the specification of a patent “..shall conclude with one or more claims combination of the two steps (“assaying” and then particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 4. Metabolite Labs., Inc. v. Lab. Corp. of Am. Holdings, 370 F.3d 1354 (Fed. Cir. 2004). “correlating”) into a practical application with concrete results 5. 35 U.S.C. §101 states that “[w]hoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent thereof, subject to the conditions and was the heart of the patentable invention in that claim. The requirements of this title.” author notes that despite this argument, there is no “practical 6. LabCorp also argued that Claim 13 also fails the definiteness, enablement, and written description requirements of 35 U.S.C. §112 paragraph 1 because neither the claim nor the specification of the 658 patent disclose the specific steps a person application” within the terminology of Claim 13 (the concrete of ordinary skill in the art would use to “correlate” a particular homocysteine level to a particular vitamin deficiency. result arguably being the determination of an elevated level of 7. LabCorp made the powerful argument that, according to the Federal Circuit’s interpretation of Claim 13, the Court finds that every doctor who orders a homocysteine test and looks at the result, regardless of how or why the test is done, automatically homocysteine). Rather, if that were the case, one would have engages in the patented "correlating" step by merely thinking of the relationship between homocysteine and vitamin deficiency, expected to find additional language concerning the step of and thus would infringe the patent. treating a patient (or not treating a patient) with a therapeutic agent for that disease state as the “practical result.” Underlying many issues in the case is the simple fact that the 658 patent discloses only one particular assay method and B IOGRAPHY is directed for the sole use of detecting vitamin deficiencies. For that reason, the Federal Circuit’s holding essentially gave Clifford M. Davidson, Esq. is a Metabolite a monopoly on all homocysteine testing regardless founding partner at Davidson, of intended use of the results or the specific assay employed. Davidson & Kappel, LLC, an Intellectual Property law firm with ACTION BY THE SUPREME COURT offices in New York City and Frankfurt, Germany. He counsels On June 22, 2006, without providing any written opinion pharmaceutical clients in as to its reasons, the U.S. Supreme Court dismissed the writ as pharmaceutical patent-related improvidently granted, thereby preserving the decision to matters, including patent prosecution, freedom to uphold the validity of the ‘658 patent. Although having no operate and infringement opinions, due diligence and precedential value, the dissent by Justice Breyer (joined by tech-transfer, and litigation (including ex parte and inter Justices Stevens and Souter) provides some insight as to the partes proceedings worldwide). He has assisted specialty factors considered by three Justices of the Court: that “this case pharma and drug development companies to create is not at the boundary” between the realm of patentable subject matter and non-patentable “natural phenomenon” subject significant patent portfolios, and the patents he has matter, but rather “claim 13 as invalid no matter how narrowly written and the patent portfolios he has created have one reasonable interprets the doctrine. There can be little doubt been recognized as creating significant value for his that the correlation between homocysteine and vitamin clients. He has written patents covering virtually all areas deficiency set forth in claim 13 is a natural phenomenon.” of drug development, and has pioneered strategic patent 7

o Should the discovery of a single assay method to test for a focus on the pharmacokinetic profiles and the N

6 correlation known in the art prevent others from developing pharmacologic activity of drug/drug formulations. Mr. l o V better assay methods for the same test? That is the essence of Davidson earned his BS in Pharmacy and his JD from

6 patent claim draftsmanship, and the eternal fight between the

0 Rutgers University and is a member of the New York and 0 2 patentee’s right to obtain broad patent claim coverage New Jersey Intellectual Property Law Associations, the t s

u commensurate in scope with his contribution to that art, versus

g American Pharmaceutical Association, and The Controlled u

A the desire of others to design around that claim and/or to improve

/ Release Society. His area of expertise includes new y l the technology. That fight was not solved in the LabCorp u J litigation, and is unlikely to be resolved in the near future. chemical entities; new pharmaceutical formulations y

g (including controlled-release oral dosage forms, o l o

n injectables, transdermals, ophthalmics, inhalation,

h ACKNOWLEDGEMENT c e

T intranasal, sublingual, suppository, and implantation y r

e Special thanks to Sunil Raval, Esq. of DDK for assisting administration); new combinations of previously known v i l e me with this article. drugs; new modes of administration of previously known D N g

u drugs; method of treatment; pharmaceutical excipients; r D and methods of preparation. 26

28 Drug Delivery Technology July/August 2006 Vol 6 No 7 y onBal,M,MBA MD, John Beadle, By: DNA Vaccines of Particle-Mediated Delivery Epidermal requires milligram doses. requires milligram fold lower thanintramuscularDNA, which immune responsesatdoses1000- robust PMED vaccine technology, which produces This low dosageisuniquetoPowderMed’s PMED withmicrogram dosesofDNA. immunity have beenproducedusing including humans,protective levels of DNA vaccine. Importantly, inallanimals, published clinicaltrialusingany influenza andonly positivewriting, thisisthefirst boost administrations. At thetimeof seroprotection withnorequirementfor the topdoseproducing100% 4 doses testedinthisclinicaltrial(1,2,and broad immuneresponse. vaccine tohumansproducesastrongand single doseofPMEDDNA influenza trial, PowderMed hasdemonstratedthata helium-po usingahand-held (APC) oftheepidermis directly intothe Antigen PresentingCells coated ontomicroscopicgoldparticles deli humans andprimates. produce rob Epidermal DeliveryEpidermal (PMED In starkcontrast,P at humans oreven non-humanprimates,even consistently converted intopositive datain of DN v produced b early enthusiasm,theinitialexciting data commercialization. However, despitethe new vaccine design,development, and present anumberofuniquepossibilitiesfor and cell-mediatedimmuneresponses,they have beenshown toinducebothhumoral vaccines and aresimpletomanufacture influenza vaccine strategy. BecauseDNA within thefutureUSbiodefenseand listed DNA vaccines asakey component Allergy &InfectiousDisease, USA)has Fauci (Director, NationalInstituteof since the1990s.Recently, Dr Anthony breakthroughinvaccinologyan important accines hasconsistentl micrograms) were immunogenic with very highintramuscularDNAvery dosages. v ering micro DNA vaccines have beenmootedas A in smallmammalshasnotbeen w y ered de ust immuneresponsesin intramuscular administration ABSTRACT gram amountsofDNAgram article-Mediated vice. Inarecentclinical This isachieved by y All threesingle been sho TM ) of DNA wn to commercialization. The only questionthat research, de ofvaccinerevolutionize theentirefield also revolutionize vaccine commercialization. manuf v research. Fur approach isalreadyre vaccines. This “reverse vaccinology” amounts ofproteinforuseassub models withouthaving toproducelarge for theirprotective capacityinanimal ability torapidly screencandidatevaccines DN e infectious diseasesandforthetreatmentof roleasaprophylaxisimportant against immunity. DNA vaccines canthushave an induce bothhumoralandcell-mediated side effects ofaviralvector, they can viral infection,withouthaving therisksand vaccines mimictheeffect ofanintracellular as prophylactically. DNA Becauseplasmid potential tobeusedtherapeutically aswell and humoralimmuneresponsesmay have vaccine thatcouldelicitbothcell-mediated to eliminateinfectedormalignantcells. A targets extracellular pathogens isunable but induce ahumoralimmuneresponse,which xisting chronicinfectionsandcancers. accines cannow besynthesizedand PMED Cuta A DNA vaccines thushave theabilityto Traditional proteinvaccines primarily technology alsoprovides aunique actured rapidl INTRODUCTION v elopment, and thermore, becauseDNAthermore, way (alabeledcross-section ofthedevicecompared toIMinjection) y v and easil olutionizing v y, they will unit FIGURE 1 accine transfect cells compelling evidence thatnaked DNA can remains ishow tounlockthatpotential. cellular uptake ofextracellular DNA. are noknown mechanismsforthe efficient of lar ef the cellularplasmamembranepresentsan Unfortunately, thephospholipidbilayer of processed andpresentedby the APC. translate themintoproteinsthatcanthenbe the nuclearmachiner delivered intothenucleusofcellwhere used at milligram doses. used atmilligram weakly immunogenic inhumans,even when intramuscular DNA delivery proved only Despite initialpromisingresultsinrodents, using intramuscularDNA vaccination. prompted attemptstovaccinate animals lik where thedetectionofinfectionismost (APC) arefoundaccumulatedatsites Professional Antigen Presentingcells adapted forimmunological surveillance. organ, muscletissuelackscellsspecifically First,has failed. asanon-immunological intramuscular delivery ofDNA vaccines w local inflammation.Second, inorderto large numbersinthepresence ofsignificant muscle tissueandareonly in recruited ork, plasmidDN ficient hydrophobictotheuptake barrier ficient el y, they but arevirtually absent from In 1990, Wolff andcolleaguesprovided There aretwo principlereasonswhy ge polarDNA molecules,andthere in vivo A . vaccines needtobe y 1 This observation can transcribeand 2 -10

30 Drug Delivery Technology July/August 2006 Vol 6 No 7 and cancer proph new inthetreatmentand opportunities humoral immuneresponses,and offers PMED reliably inducesbothcellularand directly intothisrich APC population. DNA vaccines by delivering theDNA can overcome thelimitations ofconventional results show thatPMEDofDNA vaccines DNA vaccine delivery. Recentclinicaltrial rich in APCs andisthusanidealsitefor capabilities. Inparticular, itisexceptionally evolved immunesurveillance highly efficient between theenvironment andthebody, ithas into the APC. delivery ofDNAefficient vaccines directly toensure including man,itisnecessary good immuneresponsesinlarger mammals, against acuteinfections,suchasinfluenza. What isno intramuscular injectionoflar local traumaandinflammationinducedby the neighbouring cellspossib uptake ofDNA by non-specific the inefficient, seen isthoughtpossib mouse models. tw takingthese exceptionally Infact, inefficient. into theextracellular spacesandisthus Needle andsyringeinjectiondelivers DNA DN controversial astoexactly how intramuscular odpril ncl N RA–poen etc.) gold particle incell-DNAmRNA–protein, DNA Immunotherapy(themechanismofactionpicture- o A f Because the epidermis sitsattheinterface Because theepidermis actors intoconsideration,itremains ylaxis ofchronicdiseases,suchas AIDS v accines areab , w as well asoffering protection clear isthatinordertoproduce 11 The immunogenicity thatis le tow l y FIGURE 2 to beattrib l y ork atall,even in augmented b ge fluidvolumes. utab le to y 12-16 the administer thevaccine. then pressedto the actuationb is tobedeli site where thevaccine the skinatdelivery de nozzle endofthe minimal training. The device itselfrequires cheapl stored simpl sealed, PMEDcanbe and thecassetteis ambient temperature vaccine isstable at As thepowdered device process. attheendofmanufacturing vaccine ispreloadedintothebodyof helium. The cassettecontainingthepowdered disposable device powered by high-pressure assembly andpackagingprocess. product PMED device duringthefinal intothe product containerandareinserted drug These cassettesactastheprimary intosealedcassettes. powder isthenfilled asastablepowder.formulated dry This APCs. are These microscopicparticles the vaccine directly intothetarget epidermal has theappropriatedensityneededtodeli and plasmid DNA becauseitisinert carrier par (mean Microscopic elementalgoldparticles micro vice isplacedag ticle diameter~2microns)areusedasthe The PMEDdevice isasingle-use, g y rams ofDN . Using the v y ered and utton is gold particles (typicallygold particles 2 precipitated ontomicroscopic the therapeuticvaccine is for PMED de gas-powered, single-use cassette and(2) contained withinasealed microscopic goldparticles of precipitated ontothesurface powdersdry ofDNA therapeutic vaccines asstable, ofDNAformulation distinct elements:(1)The technology comprisestwo , PARTICLE-MEDIATED and A ainst ms theacti The DNA plasmidthat The corePMED on 1mgofgold). EPIDERMAL DELIVERY vice (F preparedness & annual fluv PowderMed Influenza DNAVaccine (uniquelysuited forpandemic v e The helium component of igure 1). ver surf then processedandpresentedonthecell translated intotherele transcribed intoRNA. The RNA is inturn DNA elutesoff andis thegoldparticle combination ofbiolo toasbiolisticdelivery (a sometimes referred cellsoftheskin. epidermal This processis themdirectly intothe carries particles silencer, themomentumofgold but velocity. The heliumisvented throughthe nozzle andtoward athigh theskinsurface stateinthecassettethrough stationary fromtheir entrains andacceleratestheparticles the cassettemembrane. The gas stream from theself-containedmicrocylinder ruptures immunized withahepatitisBvaccine. immune responseisthusinduced(F protein. cellularandhumoral An efficient health responses and antigen elicitedmeasurab with 1to4micrograms ofhepatitisBsurface In thestudyby Roy etal.,DNA vaccination antigen-specif that PMEDDNA vaccination canelicit hepatitis B-specif subjects alsoseroconverted withlevels of all12previouslyFurthermore, non-vaccinated vaccine. safety ofaprophylactic DNA hepatitisBvirus conducted toassesstheimmunogenicity and FIGURE 3 ace asifitw accine production) Following delivery intothe APC, the Upon actuation,thereleaseofhelium A y series ofclinicaltrialsha adults w 12-15 CLINICAL RESUL These studieshave demonstrated ic humoraland Th cellresponsesinall12 ho hadnotpreviously been ere anintracellularviral ic antibodyrangingfrom gical andballistic). v ant antigen,w le cytotoxic T cell T cell responses. v e TS been igure 2). hich is 13 REFERENCES TABLE 1 1 Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247(4949 Pt 1):1465-8. 2. MacGregor RR, Boyer JD, Ugen KE, Lacy KE, Gluckman SJ, Bagarazzi ML, et al. First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. J Infect Dis. 1998;178(1):92-100. 3. Ugen KE, Nyland SB, Boyer JD, Vidal C, Lera L, Rasheid S, et al. DNA vaccination with HIV-1 expressing constructs elicits immune responses in humans. Vaccine. 1998;16(19):1818-21. 4. Wang R, Doolan DL, Le TP, Hedstrom RC, Coonan KM, Charoenvit Y, et al. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science. 1998;282(5388):476-80. 5. Boyer JD, Chattergoon MA, Ugen KE, Shah A, Bennett M, Cohen A, et al. Enhancement of cellular immune response in HIV-1 seropositive individuals: A DNA-based trial. Clin Immunol. 1999;90(1):100-7. 6. Boyer JD, Cohen AD, Vogt S, Schumann K, Nath B, Ahn L, et al. Vaccination of seronegative volunteers with a human immunodeficiency virus type 1 env/rev DNA vaccine induces antigen-specific proliferation and lymphocyte production of beta-chemokines. J Infect Dis. 2000;181(2):476-83. 7. Le TP, Coonan KM, Hedstrom RC, Charoenvit Y, Sedegah M, Epstein JE, et al. Safety, tolerability and humoral immune responses after intramuscular administration of a malaria DNA vaccine to healthy adult volunteers. Vaccine. 2000;18(18):1893-901. 8. MacGregor RR, Boyer JD, Ciccarelli RB, Ginsberg RS, Weiner DB. Safety and immune responses to a DNA-based human immunodeficiency virus (HIV) type I env/rev vaccine in HIV-infected recipients: follow-up data. J Infect Dis. 2000;181(1):406. PowderMed Table (table of the clinical study results compared to the CPMP criteria) 9. MacGregor RR, Ginsberg R, Ugen KE, Baine Y, Kang CU, Tu XM, et al. T-cell responses induced in normal volunteers immunized with a DNA-based vaccine containing HIV-1 env and rev. AIDS. 2002;16(16):2137-43. 10. Wang R, Epstein J, Charoenvit Y, Baraceros FM, Rahardjo N, Gay T, et al. Induction in humans of CD8+ and CD4+ T cell and antibody responses by sequential immunization with malaria DNA and recombinant protein. J 10 mIU/ml to more than 5000 mIU/ml. This is responses in all groups continued to increase Immunol. 2004;172(9):5561-9. of particular significance as intramuscular up to day 56 (the last day monitored), 11. Donnelly J J, Wahren B, Liu M A. DNA Vaccines: Progress and Challenges. J Immunol. 2005, 175: 633-639. delivery of DNA with up to 1000-fold more indicating that responses to PMED vaccination 12. Tacket CO, Roy MJ, Widera G, Swain WF, Broome S, Edelman R. Phase 1 safety and immune response studies of a DNA vaccine encoding hepatitis B surface DNA has generated only low or no antibody may show a more sustained increase than is antigen delivered by a gene delivery device. Vaccine. 1999;17(22):2826-9. 13. Roy MJ, Wu MS, Barr LJ, Fuller JT, Tussey LG, Speller S, et al. Induction of 2-6, 8-10 responses. The same PMED hepatitis B typically seen with protein vaccines. By day antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA DNA vaccine was also shown to increase 56, 100% of those subjects vaccinated with the vaccine. Vaccine. 2001;19(7-8):764-78. 14. Rottinghaus ST, Poland GA, Jacobson RM, Barr LJ, Roy MJ. Hepatitis B DNA serum antibody titres in 7 of 11 subjects who 4-microgram dose were seroprotected. vaccine induces protective antibody responses in human non-responders to conventional vaccination. Vaccine. 2003;21(31):4604-8. had previously failed to seroconvert after 3 or The cross reactivity of the serological 15. Roberts LK, Barr LJ, Fuller DH, McMahon CW, Leese PT, Jones S. Clinical safety and efficacy of a powdered hepatitis B nucleic acid vaccine delivered to more doses of conventional vaccination with responses to variant H3 strains was measured the epidermis by a commercial prototype device. Vaccine. 2005;23:4867-78. 14 16. Drape RJ, Macklin MD, Barr LJ, Jones S, Haynes JR, Dean HJ. Epidermal DNA licensed recombinant protein vaccine. Finally, by HIA assay and demonstrated that the degree vaccine for influenza is immunogenic in humans. Vaccine. 2006;24(21):4475-81. this plasmid DNA construct has been used of cross reactivity was very similar to that seen to successfully bridge between the earlier with protein-based vaccines. Cell-mediated bulky experimental device and the simple, immunity was not measured in this trial, hand-held disposable device that will be used although studies with other PMED DNA for product commercialization.15 vaccine indicate that CMI responses to HA A Phase I study has been carried out to may be generated and may further contribute investigate the safety and immunogenicity of to protection. BIOGRAPHY PMED administration of an influenza Overall, vaccination was very well prophylactic plasmid, which encodes a single tolerated with no treatment emergent SAEs Dr. John Beadle, is HA antigen of influenza A/Panama/2007/99 reported, and local reactogenicity results were Co-founder, CEO, and (H3N2).16 A total of 36 healthy subjects with typical of those seen in other PMED studies. Chief Medical Officer low pre-existing serological responses to this 7

at PowderMed Ltd. He o strain received a vaccination of either 1, 2, or 4 CONCLUSION N

was previously the 6 micrograms of DNA at a single administration l o session. The antibody response was then By delivering DNA directly into the APCs Vice President of V 6 assessed according to the CHMP criteria for of the epidermis, PMED DNA vaccines have Medical and Product 0 0 Development at PowderJect, and before 2

the approval of annual flu vaccines in the the potential to revolutionize the discovery, t s u

European Union. Table 1 summarizes these development, and commercialization of DNA that the Vice President of Global g u A humoral responses, determined as a vaccines. Figure 3 lists the potential Medical Operations at GlaxoSmithkline. / y l haemagglutination inhibition titre elicited on advantages for a PMED influenza vaccine, u Dr. Beadle gained extensive experience J Days 0 (predose), 14, 21, and 56. Time points, which is just one of the many applications for y

of product development, from preclinical g o where responses met the levels required by the which this technology may be applied. Clinical l o

to post-marketing phases, in roles of n

CHMP guidelines for licensing of annual studies are currently being conducted or h c

ascending seniority at The Wellcome e influenza vaccine, are shown in bold and red. planned either by PowderMed or its partners in T y r

The 4-microgram dose group met the the following fields: hepatitis B, influenza, Foundation and Glaxo Wellcome. Dr. e v i l

CHMP criteria at day 21, demonstrating the genital herpes, human papilloma virus (HPV), Beadle graduated as a Medical Doctor at e D g ability of PMED DNA vaccination to stimulate HIV/AIDS, Hantaan virus, melanoma, and a the University of Witwatersrand and u r serological responses equivalent to those seen variety of other cancers. N earned his MBA from the London D in protein-based approaches. Furthermore, the Business School with distinction. 31 MARKET OVERVIEW

Living in Harmony – pMDIs & DPIs in the 21st Century By: Georgina Fradley

ABSTRACT 2006 marks the 50th anniversary of the position of DPIs and led to predictions in some pressurized metered dose inhaler (pMDI). First reports that DPIs will increase in popularity across launched in 1956 by Riker Laboratories (now part of global markets. However, research has shown the 3M), the pMDI has become a favored device in the pMDI offers many advantages both to developers and treatment of asthma and chronic obstructive prescribers and will remain the dominant device in pulmonary disease (COPD). Recent increases in dry the inhalation market. powder inhaler (DPI) sales have strengthened the

INTRODUCTION CHANGES IN THE MARKET the first 2 years sales. In 2004, 86% of DPI revenues in the US were directly 2006 marks the 50th anniversary of Dry powder inhalers were first attributable to Advair. the pressurized metered dose inhaler introduced in the 1970s, but didn’t From this evidence, we came to (pMDI). First launched in 1956 by really take a hold on the inhalation realize that the predicted swing toward Riker Laboratories (now part of 3M), market until the signing of the Montreal DPIs was actually based on the success the pMDI has become a favored device Protocol in 1987.2 The challenges of of a single product within the US in the treatment of asthma and chronic transitioning to CFC-free inhaler market. Although DPIs clearly have a obstructive pulmonary disease (COPD). devices led many developers to invest in strong role within the inhalation market, The success of AdvairTM, GSK’s dry DPIs, and they began to increase in it seemed unlikely that they would take powder inhaler (DPI) combination of popularity across most of the developed the market shares predicted and replace Salmeterol Xinafoate and Fluticasone world through the 1990s. The US pMDIs in future markets. This opinion Propionate in the DiskusTM device, in market was slower to adopt DPIs, and was confirmed through our discussions the US has captured the attention of the they only accounted for 3% of units in with industry experts and medical industry. This has led to predictions in 2000. However, the US inhalation professionals. Advances in DPI some reports that DPIs will increase in market began to change in 2001, and technologies and the introduction of popularity across global markets and DPI sales began to grow at significant blockbuster products, such as Advair,

7 1 have certainly strengthened the position

o take up to 50% of the MDI/DPI market. rates (over 150% growth from 2000 to N 3 of DPIs in the 21st century. However,

6 In 2005, 3M Drug Delivery Systems 2001). The US accounts for l

o there was no question in the minds of V set out to understand the current approximately 45% of the global

6 industry experts or clinicians that the

0 inhalation market, the changes that have inhalation market and, with such growth 0

2 pMDI will remain the dominant device t occurred in recent years, and the position rates, it is no wonder that analysts took u s

u (by volume) in the market.

A of the pMDI going forward through a note and predicted such a substantial / y

l 4 Additionally, the US market is once

u series of primary and secondary research. shift in market preferences. Be that as it J again stabilizing following the

y Part of the research included interviewing may, upon closer inspection, it is clear g o

l introduction of a blockbuster drug. The

o a cross-section of experts from the that the DPI growth observed is due n h

c growth rate of pMDIs and DPIs from

e industry, respiratory clinicians and nurses, almost entirely to GSK’s Advair. T

y 2004 to 2005 can be seen in Figure 1, r

e and representatives from patient groups. Launched in the US in 2001, Advair is v i l the trend has now reversed so that, once e This has provided a thorough the only CFC-free combination product D

g again, higher growth can be seen for the u

r understanding of the opinions and needs on the US market and has been a D of pharmaceutical developers, medical tremendously successful product, pMDI. Furthermore, pMDI growth is 32 professionals, and patients themselves. generating triple figure growth rates in expected to increase over the next few years with the introduction of new MARKET OVERVIEW

FIGURE 1 - US Growth Rates 2004-2005 new drug (IND) or Clinical Trial Application (CTA) within 80 working days.5 Such experience can also decrease the time approval. The continuity in principle between different pMDIs empowers regulators to apply expectations across all pMDI submissions. When this is combined with a thorough understanding of regulatory requirements, the pain of the approvals process can be eased and the time taken significantly reduced. This is illustrated by the recent single cycle approval of Sepracor’s Xopenex, which gained approval in just 304 days.6 Other advantages of the long history of pMDI technologies include the well- products, such as Sepracor’s XopenexTM considered against company preferences developed and robust manufacturing pMDI. Xopenex was recently approved in and product requirements. The advantages processes that can be used across different the US, and Altana’s AlvescoTM, and limitations of both pMDIs and DPIs products, and the ability to source Astrazeneca’s SymbicortTM, and GSK’s can be seen in Figures 2 and 3. components from a number of different and Advair pMDIs are currently under review The pMDI is a proven technology, well-established suppliers. This is a by the FDA. This indicates that the US which offers a number of advantages to significant advantage in itself, as given the market has settled into a similar market to the pharmaceutical developer. First, time taken to develop a new product and the that in the rest of the world, where there is technical advances build upon a solid and life cycle of that product once marketed, a place for both devices in the market and proven history, thus utilizing vast financial stability was one of the most choices can be made according to experience to minimize the time and risk critical factors to pharmaceutical companies individual product needs. involved in developing new products. For when selecting a drug delivery partner. example, 3M Drug Delivery Systems can Finally, but possibly of primary WHY CHOOSE A pMDI provide data to support an investigational importance, is patient acceptability. The OR A DPI? 7 o FIGURE 2 - Advantages of pMDIs & DPIs N 6 l

Pharmaceutical companies must o V

consider a number of factors when 6 0 0 developing a new inhalation product in 2 t s order to select between a pMDI or a DPI u g u A as the delivery system. The most / y l u significant of these is company capability. J y

If a company has the facilities and the g o l o experience of developing one device type, n h c e then the investment to switch to the other T y r e is a substantial barrier, both in terms of v i l e cost and time. However, when a selection D g u r

is to be made, the advantages and D limitations of each device type should be 33 34 Drug Delivery Technology July/August 2006 Vol 6 No 7 MARKET O are currently beingaddressed. are currently which limitationsforpMDItechnologies Ho address beyond individual device options. fordeveloperslimitations aredifficult to de distinct differences across thevariety of infancy ofthetechnologies andthe these tendtobearoundtherelati emerging inhaledmacromoleculemarket. features arekey requirements forthe can beseeninF Altering P can deli pMDIsandcapsuledevices than current able todeliver awiderrangeofdosesizes indication. Someacti DPIs, suchasbreathactuationanddose features thatha are moder Added tothisistheperceptionthatDPIs advantage forthedevicecurrent type. associated pressithasgained, isclearly a transition away fromCFCpropellents. asthe patient, even onesosignificant technological advances seamlesstothe hassucceededin making The industry and view themaseasytouseanddiscreet. withthedevicesprofessionals arefamiliar the past50years. Patients andmedical has remainedeffectively unchangedover basic principleofoperationthepMDI on features,such asbreathactuationand patient familiarity, itispossible touseadd- and appearanceofpMDIstomaintain tomaintainthebasicoperations important dif when comparedagainst thenew andvery viewed asoldtechnology, particularly f amiliarity isthatpMDIsma vices available. Therefore, these ferent DPIde w The limitationsforeachde The riseoftheDPIinUS,and The flipsideofpatientacceptanceand e ver, thereareanumberofways in v er fromonedoseupw n de erceptions vices, oftenduetotheadded v vices. igure 3.F e become standardfor ve DPIdevices are VERV Whilst itis or DPIdevices, y become ard. vice type v e These IEW management oftheirtherap and dosecountingcanimprove patients’ acceptance. Inaddition,breathactuation pMDI withoutcompromisingpatient companies canupdatethelookof aesthetic designofactuators,delivery combination ofaddedfeaturesand (dose counters). Therefore, by usinga Technological Advances parent) andphysician tomonitortherapy. an individual countcanaidthepatient(or indicates w coordination, anddosecountingnotonly actuation removes theneedforpatient (breath actuation)andtherap ofimprovingboth interms easeofuse devices, andthey have beenwell received, associate thesefeatureswiththe“new” DPI dose countingtoupdatede will betechnolo patients, althoughcur ofeaseuseforasthmaandCOPD terms storage. This will offer improvement in a before priming is necessary. allow storageperiods ofupto14days patient toprimethepMDIafter periodsof FIGURE 3-Limitationsof pMDIsandDPIs One ofthekey advances forthepMDI hen theunitisnearl gies thatne rent technolo vices. P g y 7 ate theneedfor . y However, this Breath monitoring y empty, but gies can atients small packsizes.Itisno wastage. This canalsobeachieved through de dosing andexpensive actives; therefore, therapies arelikely torequireintermittent systemic therapiesviathepMDI.Such represents acriticalstepto Gaining Access to Technologyto Gaining Access doses. withpacksofferingfurther asfew as7 pMDIs, andthereispotentialtoreducethis packsizesdownformulate to30dosesfor negotiate away forward. withthepatentlandscapeto familiar with dr use suchtechnologies, itispossible towork orexpensivedifficult toobtaintheright Although previously itmay have been b landscape, which hastraditionally beenheld pMDIs was (IP) theintellectualproperty assembly tocreateaspray directly. pierced by theactuatorstemandnozzle dose iscontainedwithinab develop single-shotpMDIs,whereby the y v a elopers mustmak The final limitationhighlighted for The final few key companies. pharmaceutical 8 ug delivery companiesthatarevery It may ultimately bepossible to e moves toreduce w w possib lister thatis ard deli le to 9 v ering MARKET OVERVIEW

FUTURE NEEDS FOR THE pMDI allowing for better therapy management. REFERENCES However, as these future inhaler 1. Greystone Associates. Dry Powder Inhalation Advancing Technology – technologies are developed, the pMDI Emerging Therapies. 2003. The pMDI has come a long way since 2. Montreal Protocol on Substances that Deplete the Ozone Layer its advent in the 1950s. Advances, such as devices will need to remain simple and 3. www.imshealth.com 4. Pulmonary Drug Delivery 2004 Global Industry Analysis report the transition to non ozone-depleting elegant if they are to preserve the familiar 5. Pritchard JN. Accelerating drug development. Drug Delivery to the Lungs XV. appearance and basic operation principles (The Aerosol Society, Portishead, UK). 2004;15:84-87. propellents and material selection to 6. Pritchard JN. The future of metered dose inhalers. Pharm Tech Eur. of current devices. 2005;17(9):22-31. reduce extractables have presented 7. Williams L, Velasco V, Heyworth D, Bradley L. EPDM SpraymiserTM valve significant technical challenges. However, robustness. Drug Delivery to the Lungs XVI. (The Aerosol Society, Portishead, UK). 2005:38-41. one of the strengths of the pMDI is its SUMMARY 8. Moore JM, Bradley L, Charnock P, Brown S. Container closure system solutions for delivering low numbers of doses from a pressurised metered dose familiarity and the fact that, despite the inhaler. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, eds. Proc Recent market predictions that DPI Respiratory Drug Delivery IX. Davis Healthcare International Publishing: River advances made, the basic appearance and Grove, IL. 2004:333-336. principle of operation remains unchanged devices will replace the pMDI in many 9. Pritchard JN, Genova P. Adapting the pMDI to deliver novel drugs: insulin and beyond. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, eds. Proc for the patient. areas and take up to half of global unit Respiratory Drug Delivery IX. Davis Healthcare International Publishing: River Grove, IL. 2006:133-142. Looking to the future, the industry sales have been confirmed to be 10. Jinks P, Marsden S. The development and performance of a fluoropolymer unfounded. A combination of primary and lined can for suspension metered dose inhaler products. In: Drug Delivery to foresees advances in two main areas. the Lungs X. (The Aerosol Society, Portishead, UK). 1999:177-180. First, the industry would like to see secondary research has shown that whilst 11. Wilby M. Increasing dose consistency of pMDIs. Drug Delivery Technology. 2005;5(9):59-65. advances to improve product robustness, the popularity of DPIs has increased in 12. Fulton C, Koppenhagen F, Tilley K, Johnson P, Brown B, Thatcher M. Long term stability of calcitonin and deoxyribonuclease 1 in HFA-based thus increasing the chances of success of recent years, particularly in the US metered dose inhaler formulations. Drug Delivery to the Lungs XIV. (The market, the pMDI remains the most Aerosol Society, Portishead, UK). 2005:219-222. development programs and decreasing 13. Stein SW, Stefely JS. Reinventing metered dose inhalers: from poorly efficient approval times. Technical advances in commonly prescribed device, with almost CFC MDIs to highly efficient HFA MDIs. Drug Delivery Technol. 2003;3(1):46-51. container closure systems, such as three quarters of global unit sales. The coatings and new valve designs, are pMDI offers many advantages both to making significant progress in the area by developers and prescribers. For enabling reduced deposition and improved developers, cost benefits, not only in the dosing uniformity.10,11 New formulation cost of componentry, but also as both BIOGRAPHY technologies can also improve robustness, development and manufacturing Ms. Georgina with particle engineering to improve capabilities for pMDIs are more generic stability and excipients to increase and widespread than are the specific Fradley is a solubility and efficiency of delivery, individual capabilities needed for each Development pushing the boundaries of molecules that different DPI, and faster regulatory Specialist in 3M can be delivered via inhalation.12,13 authority approval times are key drivers. 7 Drug Delivery o For medical professionals, the pMDI is a N

The second area of interest for both 6

Systems. A l o the industry and medical professionals is respected device that is effective and well V

accepted by patients. Building on their graduate in Chemistry from the 6 ease of use for the patient. Pharmaceutical 0 0 long successful history, technical advances University of Nottingham, Ms. Fradley 2 developers are already including t s u technologies to assist patients, such as to increase product robustness, and ease of g joined 3M HealthCare in 1998 as an u A / breath actuation to remove the need for use for patients, pMDIs will continue to y l

Analytical Chemist for inhalation u co-ordination and dose counters/indicators be the chosen delivery system for J

systems development. Having y g

developers over the next 50 years for both o

to help patients manage their therapies. As l o

worked across as range of n container closure systems and formulation respiratory and systemic therapies. h c e development phases, she is now T technologies develop, pharmaceutical y r e v i companies can improve product responsible for aligning new l e D

performance in the hands of patients, g

technology development with u r D industry and market needs. 35

FORMULATION DEVELOPMENT

Development & Applications of Long-Acting Injection Formulations By: Roger G. Harrison, PhD

INTRODUCTION Injectable products hold approximately 15% of the with patient management, providing benefits to payors current drug delivery market. This proportion could and health professionals. continue to grow, relative to other product forms, For the Specialty Pharma company, a focus on owing to the increasing proportion of new product technology that enables injectable products to be approval applications for complex biomolecules, which made more acceptable can provide new life to an old generally can be given only by injection. While several product or ensure optimal acceptance for a new groups are pursuing alternatives to injection for some product. The rationale, therefore, for long-acting of these molecules — for example the well-publicized formulations for injection can be improved program by Nektar and Pfizer for inhaled insulin safety/efficacy, improved patient compliance and (Exubera), which gained approval in Europe and the US outcomes, cost-of-care reduction, and product life- in 2006 — it is unlikely that such approaches can be cycle optimization. generalized. Consequently, despite many concerns from Long-acting injection formulations are not new patients about receiving injections, and from and have played a key role in the success of several healthcare staff about needlestick injuries and sharps past products. These include penicillin plus probenicid, disposal, injections are going to remain an important where the latter was added to block renal tubular part of the future of drug delivery. In recognition of secretion of penicillin and prolong its action at a time this, there have been approaches to making injections of short supply; NPH (Neutral Protamine Hagedorn) more acceptable, including the development of insulin, introduced in 1946, in which insulin is autoinjectors and needle-free injection devices. These formulated with protamine derived from herring or can reduce the psychological concerns that patients salmon milt, in which the precipitated complex have with conventional injection and, for the devices provides a longer half-life than insulin alone; that have no exposed needle before and after benzathine penicillin, an intramuscular pro-drug that injection, reduce the issues associated with releases benzyl penicillin over a 2- to 4-week period; inadvertent needlestick. Alternatively, there has been and depot forms of neuroleptics/antipsychotics that a significant effort to reduce the frequency of were introduced in the 1960s. injection by development of long-acting injection Such early work provided a foundation of 7

o formulations, and several of these are now being understanding about the potential for products of this N

6 successfully marketed. It is reasonably rationalized type and, in combination with more advanced l o

V that an injection once per week or even less formulation options, there has been a resurgence of

6 frequently will be more acceptable to patients, opportunities in this area in the past decade. 0 0 2 encourage compliance, and reduce costs associated t s u g u A / creating a formulation that delays release are several attributes that should be sought y

l LONG-ACTING INJECTION u J PRODUCTS of the active drug from the injection site; in creating a long-acting injection y g

o secondly, covalently changing the formulations (Table 1). The most l Long-acting injections clearly offer o n

h chemistry of the parent molecule in order significant challenges facing the c several benefits, but these need to be e T

y to alter its apparent circulating half-life; or formulation scientist are: 1) ensuring as r balanced against the complexity and cost e v i l third, generating a non-covalent complex near to zero-order release from the e associated with development of such D

g with the drug and a second agent that formulation as possible, avoiding any dose u products. Three fundamental methods r D typically have been used to create long- impacts the release of the drug. dumping or burst effect; 2) dealing with 36 acting injections. The first requires From a formulation perspective, there the limitations imposed by the relatively

FORMULATION DEVELOPMENT

release and creating longer-acting TABLE 1 formulations. The acceptance of such Controlled release from a single injection formulations is based upon their ability to Biodegradable/biocompatible formulation excipients affect drug release over a range of desired profiles, the breakdown of the polymers to Easy to manufacture on conventional equipment innocuous sub-units, and the range of Easy to ship, store, and administer presentations that can be developed. Compatible with sensitive molecules (e.g. proteins) Presentations can be as rods inserted subdermally or subcutaneously, Low- or high-loading capacity microparticle suspensions in which the Can deliver water soluble of water insoluble products polymer is used to coat small particles of the Provides proprietary protection drug, or free-flowing liquids in which the Low toxicity polymer/drug complex is precipitated after injection. Such free-flowing formulations All GRAS materials have advantages of ease of delivery by Does not require modification of parent drug to achieve desired profile conventional injection. An example of such Formulation goals for a long-acting formulation a product is the sustained release of leuprolide acetate (Eligard) that uses Atrigel few approved excipients that are readily produced by melt polymerization and are technology (QLT Inc.) to create 1-, 3-, 4-, or available for this purpose; and 3) ensuring primarily linear structures. Racemic DL- and 6-month dosage forms. The drug is drug stability both during storage and in situ L-polymers are available commercially with formulated with PLGA and N-methyl-2- following injection. L-polymers typically being resorbed more pyrollidone, the latter rapidly dispersing after Of particular importance has been the use slowly than DL-polymers. Formulations vary injection, leaving a solid intramuscular depot of polylactide/polyglycolide copolymers in in the ratio of lactide to glycolide, with the from which the drug pays out over time. developing sustained-release injections. The higher glycolide composition limiting drug Liposomes have also proven to have an versatility and safety of these polymers have been well established and proven with several marketed products (Table 2). TABLE 2 While such products may appear Product Polymer Drug Indication 7

o to have substantial benefits, this does N Lupron depot PLA Leuprolide acetate Prostate cancer, endometriosis 6

l not always prove to be the case in o V practice. Nutropin depot was Nutropin depot PLGA Human growth hormone Growth deficiencies 6 0

0 withdrawn from the market after 2

t Sandostatin depot PLGA-glucose Octreotide Acromegaly s

u limited commercial success. The g u

A benefit of a longer-acting injection / Trelstar depot PLGA Triptorelin pamoate Prostate cancer y l u

J appeared not to have overcome

y Zoladex PLA Goserelin acetate Prostate cancer, endometriosis g disadvantages associated with o l o

n perceived lessening of efficacy h c Arestin PLGA Minocycline Periodontitis e T compared with more frequent y r e v

i injections, and increased pain at the l Atridox PLGA Doxycycline Periodontitis e D injection site, owing to the wider gauge g u r

D needle required for injection. Risperdal Consta PLGA Risperidone Psychoses The polymers are generally 38 Examples of PLA (polylactic acid) and PLGA (polylactic acid/glycolic acid) copolymer formulations FORMULATION FORMULATION DEVELOPMENT DEVELOPMENT

formulated in sesame oil and benzyl TABLE 3 alcohol that further delays the release of Product Generic Name Route of Delivery Indication the active agent from an intramuscular site. Ambisome Amphotericin B Intravenous Antifungal Of particular importance has been the pegylation of proteins. Polyethylene DepoCyt Cytarabine Intrathecal Antineoplastic glycols (PEGs) are amphophilic molecules that are generally non-toxic. PEGs DaunoXome Daunorubicin Intravenous Antineoplastic chemically bind to proteins, increasing the Doxil Doxorubicin Intravenous Antineoplastic apparent molecular size and limiting kidney secretion, as well as limiting Liprostin Prostaglandin E2 Intravenous Peripheral vascular disease enzyme recognition and breakdown of the Examples of commercially available liposome formulations parent structure. In pegylation, covalent links are created between the amino or important role in creating long-acting as nanoparticles with a polyethylene glycol sufydryl groups of the protein with ester, injection formulations (Table 3), particularly coating. The particle size and the coating carbonate, or aldehyde links with the for anti-infective and antineoplastic agents. avoid detection by the RES and can lead to polyethylene glycol. The pegylation reaction Not only can such approaches produce the required longer release of the drug into is controlled, among other parameters, by long-acting formulations, but there can be, as the circulation. PEG/protein type, reaction time, temperature exemplified in the case of amphotericin B, a Chemical modification of the parent and pH. Products that have been developed significant reduction in toxicity associated drug to create a new entity with a longer half- from this technology are shown in Table 4. with the use of the liposomal product life has also been an important way of Additional significant benefits from compared with the parent drug. creating longer-acting injections. This can be pegylation include enhanced product Liposomes can be produced as multi- achieved by creating a pro-drug that releases solubility, offering formulation benefits, lamellar or uni-lamellar vesicles, and provide the active agent over time or by creating a enhanced product stability in storage, carrying capacity for water-soluble drugs in longer-acting form of the drug that has and a decrease in potential immunogenicity, their aqueous cores, or for lipid-soluble drugs inherent activity in its own right. Early as well as the decrease in proteolysis, which dispersed within their lipid bilayers. examples of pro-drugs are benzathine leads to the prolonged circulating half-life Liposomes can now be produced penicillin, which releases benzyl penicillin for such products. economically, and reproducibly, at large from an intramuscular injection over 2 to 4 Alternative chemical modification

scales offering further opportunity for their weeks, and haloperidol dodecanoate, a lipid 7 strategies for proteins rely on the power of o application. Particulate injections, including soluble ester of haloperidol. The latter is N 6 l o

liposomes, given by the intravenous route, V 6

are typically recognized as foreign particles 0 TABLE 4 0 2

by the reticular endothelial system (RES) and t s

Product Generic Name Indication u g

consequently disproportionately accumulate u A /

Pegasys Pegylated · 2a interferon Neutropenia y in certain organs (liver, spleen, etc). This can l u J be advantageous where a tumor or an y

Neulasta PEGfilgrastin Neutropenia g o l

infection is located in one of these organs o n h c

and a high drug concentration is beneficial, Adagen Pegadenosine Enzyme replacement e T y r

but not if prolonged circulating levels of the e v i l

Oncospar Peg l-asparginase Acute lymphocytic leukemia e

drug are required. So called “stealth D g u

liposomes” are being developed to address r Somavert PEG growth hormone antagonist Acromegaly D this challenge. Such liposomes are described Examples of pegylated products 39 FORMULATION DEVELOPMENT

TABLE 5 Company Technology Technology Name Application Examples Flamel Aminoacid polymers Medusa Long-acting proteins

Macromed Thermosetting gels ReGel Paclitaxel depot

Alkermes Cryogenically processed PLGA Prolease, Medisorb Human growth hormone, Risperdal consta

SkyePharma Lipid chambers Depofoam Depocyt®

QLT Thermosetting gels Atrigel LHRH

Alza PEG-coated liposomes Stealth Dexil®

Durect Sucrose acetate isobutyrate SABER SABER-bupivacaine

Examples of companies specializing in long-acting injection technology SUMMARY BIOGRAPHY recombinant technology to create variants of Several approaches are available to the parent structure that retain the inherent provide long-acting formulations for existing activity, but prolong the half-life of the product. products. These systems can improve safety Most work in this regard has focused on and/or efficacy, potentially improve patient insulin. Insulin has been a target for improved compliance and hence outcomes, reduce costs convenience of injection for many years with (although the drug cost may be substantially the development of NPH insulin in the 1940s increased), and allow for product life-cycle and Lente and Ultralente products in the 1960s. optimization. Additionally, it has become However, the 1990s and 2000s have focused on apparent that creation of new active Dr. Roger G. Harrison is the alternative routes of delivery (eg, inhaled pharmaceutical ingredients, designed to former CEO and President of insulin) or protein engineering of the parent prolong half-life, can provide patient and molecule to create changes in the primary company benefits. It appears that there will Antares Pharma, Inc., and now structure. The first of these to be introduced be a continuing demand for such products and works as an independent that conferred a longer-action profile was a continuing evolution of technologies that consultant. Prior to joining Antares

7 insulin glargine. This molecule was designed to can afford solutions to these needs. All of Pharma, his career had been with o N have low aqueous solubility at neutral pH, but these factors will lead to a willingness to 6 Eli Lilly and Company with l

o to readily dissolve and have good stability at pH V launch optimized dosage forms at the time of responsibilities ranging from

6 4. These characteristics allowed for the

0 product entry or introduce such products after 0

2 development of a solution formulation, which is discovery research, project t establishing a market position with a parent s u

g converted into a microcrystalline precipitate management, product development,

u product form. The latter has the advantage of A /

y when neutralized in the subcutaneous injection and alliance management. He l potential greater speed to market, but needs to u J site. Insulin glargine is then released at a be balanced against consideration of non- earned his PhD in Organic y g o l relative constant rate over 24 hours, providing a optimal product performance. Whichever o Chemistry from the University n h

c patient with their basal insulin requirements. approach is adopted, the patient and e

T of Leeds in the United Kingdom y r Several specialty companies are now providing healthcare provider requirements for greater e v

i and conducted Post-doctoral l

e long-acting injection technology to the industry product convenience, as well as the need for D

g research at the University of

u (Table 5).

r market competitiveness, will continue to drive D this important business sector. Zurich in Switzerland. 40 FORMULATION DEVELOPMENT

TRANSDERMAL DELIVERY

Transdermal Drug Delivery Through the Sweat Glands

By: Wei Chen, PhD; Vardan Ter-Antonyan, MS; Heidi Kay, PhD; Matthew Salewski (PhD student); and Feiran Huang, PhD

ABSTRACT Although iontophoretic transdermal drug delivery physiological conditions showed that the activation of is known as an effective means for drug transportation sweat glands led to the increase of the skin through the human skin, it is not widely used because conductance up to 10 times, which enabled us to use of the various side effects that come to life due to a a lower voltage of 2 V in order to achieve noticeable high applied voltage (40 to 60 V) and current. This results during the actual drug delivery experiment. In study introduces an alternative means of drug addition, the application of Vaseline on the transportation through the skin by means of sweat experimental surface does not allow the decrease of a gland activation and reduction of an applied voltage skin conductance for as long as 24 hrs, which enables to ensure that the iontophoresis is safe. The skin- drug delivery over a long period of time. Finally, the conductance studies (using 50 mM of NaCl solution) drug delivery was performed and tested by means of on subjects of different gender, physical, and psycho- an HPLC method.

INTRODUCTION to overcome the skin barrier that has a ducts, we can decrease the resistive force resistance of ~1-5 MW. Side-effects and of the skin. The conductance of the sweat Transdermal drug delivery has been reactions, such as itching, erythema, duct can be maximized by many a century-old discovery, nevertheless, the irritation, skin pigmentation, permanent mechanisms. There are places on a topic still attracts new and revolutionary skin diseases, and vascular and non- human body where the resistance of the ideas of researchers everywhere in hope vascular diseases often occur under the skin is about 500 KW, and those are the to find one transdermal method that delivery area.4 best places for this experiment. would be efficient, practical, safe, and An alternative method would be to In addition, the sweat glands must cost effective. One of the leading avoid the passage across the stratum be open to create some passage ways. transdermal drug delivery methods out corneum, where the resistance is so high, Sweat can be induced by increasing the on the market and still in intense research by utilizing the porous components of the body temperature via the following: is iontophoresis. The technique provides skin, such as the sweat ducts and the hair applying a heating pad to the delivery a noninvasive method to administer a follicles, where the resistance is much area or drinking hot tea/water/soup, or by

7 controlled amount of drugs through the lower. By doing so, the voltage needed to attaching some external object (such as o N skin by applying an electric current. To overcome the resistance can be lower, polyethylene) to the skin so that the 6 l

o and side-effects can be eliminated. The temperature balance of the skin will be

V simplify its mechanism, iontophoresis is areas of the sweat glands and the hair violated and begin inducing sweat by 6 a process of transportation of ionic 0 0

2 molecules into the tissues by passing the follicles are small compared to the total itself, gradually increasing its intensity in t s

u area of the skin; which is why using these order to get rid of the attachment.

g electric current through the electrolyte u

A pathways for drug delivery had been The main problem that had to be / solution containing the ionic molecules y l 5 u 1 ignored; until now. The following overcome was sweat gland closure due to J using a suitable electrode polarity. 6 y method focuses on the efficiency of drug the swelling of the stratum corneum. The

g There are three main passages o l

o delivery through the sweat glands. sweat gland is prevented from closure by n through the skin’s barrier: the stratum h c

e applying a thin layer of thick Vaseline on T corneum, the sweat duct, and the hair y

r 2,3 e follicles. The first passage is used by METHOD the surface of the skin in the delivery v i l

e area. The Vaseline not only prevents the D current iontophoresis methods. Although g

u The sweat pores provide a pathway r this method has its advantages, it is not pore closure, but also provides a higher D entirely safe. Iontophoresis is carried out from the surface of the skin into the conductance because it hydrates the skin 42 using high voltage of up to 60 V in order blood vessels. By utilizing the sweat and increases its permeability. By TRANSDERMAL DELIVERY

FIGURE 1 applying Vaseline, we have managed to hold a high conductance reading for a day; this is enough to be convinced that Vaseline solves the problem caused by pore closure. So the objective of the method is to maximize drug delivery transdermally through the sweat glands.

SKIN-CONDUCTANCE STUDY

The systematic components of drug delivery through the sweat glands include a DC power supply, two electrodes, and an ionic solution. Each component must be The molecule of Diphenhydramine Hydrochloride C17H22ClNO a) in 3-dimensions; b) in 2- carefully chosen in order to provide an dimensions efficient and safe method. A DC power supply of 2 V applied to Location of the Electrodes: Positive electrode is on the internal side of a biceps. Negative electrode is on the external side of a biceps. the delivery area gives an average current of Active Area: 7.6 cm2 5 mA, which is much safer than the current Fill Volume: 1.5 cc iontophoresis method that utilizes 60 V. Drug Concentration: 10 g in 100 mL of water The power supply can be provided by a Resistance of the biceps skin: ~ 0.5 MW 2-V battery for portable and practical Applied Voltage: 2 V purpose since the drug delivery period can Applied Current: ~ 50 mA last up to a day. Current Dosage: ~ 7.2 mA-min The electrodes chosen for the current skin conductance study and the drug to prevent leakage of drug solution. Where = dm/dt, which is the mass of delivery are the TransQ-1GS electrodes, F The Gel-Sponge also provides greater the drug, m, passing per unit area through manufactured by Pro-Med. These Ag/AgCl conductivity and consistent current and drug the skin, which is also a steady-state flux of electrodes stabilize the pH of the drug and distribution. Also, the gel makes sure the the drug. C is the drug concentration in prevent a shift of pH in a drug or in a drug solution does not make a direct contact donor solution, K is the partition coefficient tissue.2 Prevention of pH shift eliminates

with an electrode to prevent the electrolyze of solute between the skin and the solution, 7 possible skin irritation, stabilizes drugs, and o phenomenon. These electrodes provide an and D is the diffusion coefficient . N improves drug delivery. Ag/AgCl electrodes 6 l

easy and practical way to inject the drug So factors that affect drug delivery o are also nonpolarizing. This means the skin V solution into the electrodes. The larger area include the ionized state of the drug and its 6 and the sweat glands do not get polarized, 0 0

of the electrodes covers more area of sweat pH range in which the transdermal 2 and so the development of a counter- t

1 s 2 pores, which maximize the total drug that permission of ionized state is maximum. u g

electromotive force (emf) can be prevented. u

can be delivered. Other factors, include good solubility in A / y

Also, one of the most important advantages l

Factors that affect drug permeation oil/water, low melting point (correlating u of Ag/AgCl electrodes is that they have J

through the stratum corneum can be with good water solubility), low molecular y g a very low junction potential and do not o l

distinguished from a simple, steady-state weight (less than 600 Daltons), and a high o n get oxidized (and consequently do not h

1,5,7 c

flux equation for a given thickness of the concentration of the drug. e enter the electrolyte). T 5 y r

skin (Equation 1). The drug solution chosen for delivery e v

The electrodes contain a Gel-Sponge i l

is Benadryl (diphenhydramine e element that maximizes a uniform skin D g u

Equation 1. ~ CDK hydrochloride), which is a known r contact, and are the best for longer adhesion F D antihistamine (Figure 1). This drug has been chosen for delivery because its solubility in 43 44 Drug Delivery Technology July/August 2006 Vol 6 No 7 TRANSDER the sameasC Cl T melting pointisalsolo relatively low (~291.8Daltons),andits mL ofw w beha of ionsisatypical and also,theformation salt for non-or radical Rwithchar following: C becomes ionized, sowe the observe water, ofDimedrol theneutralform enter intoareaction. When dissolved in only bedissolved inwater, anditdoesnot (C process iscalleddissociationor ionization. ionized par aredissolved inaqueoussolutions, drugs D oda ater is very high(morethan10gin100 ater isvery line), sweating(red pinkline), skin, The averagepotentialversustimegraphsfortheControl(dry - 6 , H whichorganic representsacomplicated vior forallthewater-soluble and drugs The chemicalfor This isclearbecausewhen saltsof y 5 , ) g 2 m almost allthedr CHOCH and sweatingwiththeVaseline (blueline) anic acidwithchar ater), itsmolecularweight is because ofg ticles areformed, andthis 17 17 H H 22 2 CH 22 ClNO +H ge (+1)andaremaining ClNO. 2 N(CH mula ofBenadr reat w w ugs area (~166ºC). 9 ge (-1). Benadryl can Benadryl 3 2 ) ater solubility O 2 HCl, which is => R-H vailable in 8 yl is FIGURE 2 + + , 10 ELI lifestyle. The resultspresented arethe psycho-physiological condition,and four subjectsof different gender, nationality, others. through theiontophoresisprocessby many experiment, blood orurinetestafter8hoursof driven intothebloodstream. 2-V electricf the casewe have. Undertheinfluenceofa ion, lik chemicals thatha central nervoussystem. also promotessleepinessandtar and uncontrollab hypersensitive reactions, motionsickness, medication thatrelieves allergy symptoms, into theskinthroughs CONDUCT Multiple experiments were doneon Benadryl canbedetectedeasilyBenadryl by a 10 e Benadryl isalsoanon-prescription Benadryl salts ofnon-organic acids,which is MAL 11 VERY ield and ithasbeendelivered ANCE STUD le musclemo , ve atleastonenon-organic these ionsaretranspor 12 w eat glandsand Y vements. It RESULTS gets the ted increase significantly. open thesweat ducts,thepotentialreadings subject s where theelectrodesareplaced.Sooncea areasoftheexperiment the particular to besuccessful,asubjecthassweat in on different days. Inorderforanexperiment outatdifferent timesofthedaycarried and averages ofmany similarexperiments of NaCl)and solution (duetoalow molecularweight were outusinga50-mM NaCl carried The studiesoftheconductanceskin the conductanceenoughtodeliver drugs. skin, andtheactivated sweat glandsincrease contrib which meansthatthesweat glands and his/herpsycho-physiological situation, s times lessthantheconductanceof skinwasthe conductanceofdry 8to10 and notjustthroughtheskin. istraveling throughthesweatfield glands electrode, w straight fromthepositi opposite sitesothattheelectricf a the positi f stayspotential versus timegraph thesame. different ofthe thepattern readings,but e skin conductancestudiesandallour conductance isalsodifferent. The human different peopleisdifferent, their each other;positi under it,bothelectrodeswere placedfacing electrode throughthesweat glands located presented inFigure 2. average resultsoftheexperiments are minutes, itincreases untilabout6mV. The potential isabout 3mVandafter30 w ield goesthroughthes xperiments showed thatdifferent peopleget biceps andthenegative electrodeonthe eating skin,dependingontheindi The experimental resultsshowed that In ordertomake surethattheelectric The “Control”v Because theph ute alottotheconductanceof weats well enoughtoactivate and v e electrode tothenegative hich makes surethattheelectric Ag/AgCl electrodes. v e electrode ononesideof alue oftheaverage skin ysiolo ve tothenegative w eat glandsunder gical conditionof ield goes The vidual TRANSDERMAL DELIVERY

FIGURE 3 the sweat glands using our iontophoretic method, some skin-conductance studies were performed using a 10-g solution of Diphenhydramine Hydrochloride

C17H22ClNO with 100 mL of deionized water. The results of these experiments showed that the increase in conductance due to the sweat gland activation is about three to four times, which is lower than in the cases of the experiments using NaCl solution with water. That can certainly be explained by the low mobility of the Benadryl molecules due to their large molecular mass and large size. But that increase is enough to get a noticeable result after at least 24 hours of drug delivery. Finally, transdermal drug delivery was performed on a subject for 8 hours, and the urine was collected to determine the amount of Diphenhydramine Hydrochloride in it. That urine was then An 11-hour experiment with Vaseline (blue line) and an approximate 2-hour experiment worked up under the solid phase extraction without Vaseline (pink line), which clearly prove that Vaseline is very efficient in preventing (SPE) process. The SPE process eliminates pore closures and holding the conductance constant. The potential of the skin without Vaseline is not as high as that with Vaseline in this case because prior to using any source all kinds of contaminants and big particles of heat to the skin, we did a “Control” for an hour, which means that by the time the skin from the urine so they do not interfere with was sweating intensely, the stratum corneum was already swollen, and the sweat glands getting the final urine analysis by means of were closed. In contrast, when we put Vaseline on, the stratum corneum does not swell, and a special High Performance Liquid the pores do not close even after an hour of “Control.” Chromatography (HPLC) method. The HPLC method used to separate the Diphenhydramine Hydrochloride was potential (therefore the conductance) conductance was still holding. One of the carefully chosen to get the best separation: increased tremendously (with respect to the results is shown in Figure 3. 7

“Control” value) in the case of the sweating In order to make sure the Vaseline still o Column: ZORBAX Rx/SB-C8 (4.6 x 150 mm) N experimental area. Over the course of 10 prevents closure of the stratum corneum 6 l

Eluent: 20 mM of KH2PO4 Phosphoric o minutes, the conductance reached its peak even if the experiment lasts as long as 24 V

Acid/Acetonitrile (60/40) (v/v) 6 value and stayed there for about 5 minutes, hours, a series of 5- and 6-hour experiments 0 0

Flow Rate: 2 mL/min 2 t

then decreased. The decrease of the were conducted and eventually the longest s

Temperature: 25ºC u g conductance was due to the closure of the experiment, which lasted 17 hours, in which u A

Detector: UV at = 254 nm /

l y sweat glands. The “Sweating with the the electrodes were still on when the subject l u Vaseline On” experiments were carried out was sleeping at night, and after the 17 J y

The first experiment was done just g o the same way as the previous ones, but here hours, the potential was still holding. l o

on the pure sample of 1 mg of n the experimental area was covered with h c e

Diphenhydramine HCl in 100 mL of T

Vaseline, which prevented the closure of RESULTS OF THE DRUG y r

HPLC-grade water to find out the retention e v i the pores. To prove that the pores remain DELIVERY EXPERIMENT l e

time of the drug, which turned out to be tR D

open for a longer period, we did g u

= 3.655 minutes. After that, 5 consequent r experiments on different subjects for 2 In order to make sure the Benadryl D experiments were performed at 10-, 8-, 6-, hours and eventually for 1 day, and the molecule is able to be transported through 45 46 Drug Delivery Technology July/August 2006 Vol 6 No 7 TRANSDER D 0.255 V solid phaseextraction process, and5 w the samesubjectfor8hours. constructed, delivery was drug on performed are can beseenonthecurve. The Xand Y errors which themeasurementerrors, determine Each experiment was repeatedafew timesto ispresentedintheFigurecalibration curve 4. calibration pur Diphenh result isshown inFigure 5. using thesameaforementioned method. The it was passedthough theHPLCinstrument 4-, and2- calibration curve as abigsquarehavingcalibration curve a function canbeseen. obtained from5- represents theDiphenhydramineHClpeakwithitsparameters(amountandsize) the 100mLofHPLC-gradewateralongwithmeasurementerrors. obtained fromtheHPLCinstrumentafteranalysisof1mgpureDiphenhydramineHClin Eachroundpointrepresentsexperimental data reportispresented. acalibrationcurve Here, the same, as collected presented asbarsaroundthepoints. After the calibration curve wasAfter thecalibrationcurve In Figure 5,itisclear toseethepeakof * ydramine HClha sec. This pointisrepresented onthe m L but from1- , injection v poses. it w m as passedthroughthe L The constr rn neto oueatrdu eiey Thebigtrianglerepresents urine injectionvolumeafterdrugdelivery. m olumes for L ving anareaof urine injectionvolume. After theurine ucted IUE4 FIGURE m L of ELI the urine, the same drug deliverythe urine,same drug experiment activation foundin totheamount ofdrug which isabout4%. much morethanthemeasurement error, the areaunderDiphenhydramine peakis shows reliable theresults arevery because Diphenhydramine peakwas found, which fluctuation. Noe peak isthesoughtafterorare whether todetermine thefound performed Diphenhydramine Hydrochloridewas also asabigtriangle. calibration curve 2.92 peak sizeof0.255 0.584 0.055 V injection volume, apeakhaving anareaof Also theR T An analysis ofurinewithout m o m L. * L. This pointispresentedonthe f MAL sec canbeseenwithanamountof ind thecontrib Consequentl 2 VERY coefficient andthecalibration vidence ofan V The bigsquare * sec andanamountof y , ution ofs for the1- y sor w m eat gland t L gular of Diphenhydramine Hydrochloride. deli acti to thediffusion, andthesweat gland delivery tothedrug due contribution This meansthatthereisnosignificant else istaken asanoiseorfluctuation. whichinstrument, isabout1ng,everything urine issmallerthanthesensitivity ofthe inthe means thattheamountofthisdrug the chromatogram ofthaturine,which Diphenhydramine peakwas foundin diffusion process. As aresult,no intotheskinbythat introducesthedrug was withoutanelectricfield but performed increase theskin conductancemorethan8to is 25mg/da theacceptable(Benadryl), dosageforadults Hydrochloride in1 about 6+/-0.24ngofDiphenhydramine 6 Diphenhydramine Hydrochloridein1 about18+/-0.72ngof we willfind Consequentl was obtainedfrom8hoursofexperiment. urine after24hoursofexperiment. Diphenhydramine Hydrochlorideinthe 5.4+/-0.2mgof mL, sowe find of urineaftertheexperiment isabout300 urine injectionvolume. The average amount for childrenyounger than age6. which meansthatour methodcouldbeused a 12 mg/day, andforkidsyounger thanage6, dosage lower than6mg/day isacceptable, to 12y v very ofthewholevery amountof ation isresponsib The methodcan beimproved ifwe For like Diphenhydramine adrug HCl Analysis datashows thatwe found ears old y y, after24hoursofexperiment, APPLICATIONS . For childrenaged DISCUSSION SUMMARY , the dosageisabout m L le forthe of injectedurinethat m L of TRANSDERMAL DELIVERY

9. www.chemistry.org. Website accesses June 2006. FIGURE 5 10. Paddock Laboratories, Inc. Compounding for Iontophoresis: Current & Practical Compounding Information for the Pharmacist “Secundum Artem” 2006;10(4). 11. Ohtsuji M, Ohshima T, Takayasu T, Nishigami J, Kondo T, Lin Z, Minamino T. Screening of antihistamine agents (diphenhydramine) with blood and urine samples by REMEDi-HS system. Schaffer Library of Drug Policy. 2004:1-6. 12. www.medfriendly.com. Website visited June 2006.

BIOGRAPHIES

Dr. Wei Chen (Temple University, 1988) is a Professor of Biophysics at the University of South Florida. He started his professorship at the University of Chicago in 1992 and later moved to the University of Illinois. He is interested in the interaction of electromagnetic fields with living systems, and his research has been continuously funded since 1994 by the NIH and NSF. Here, a chromatogram is presented from the urine analysis of a subject who was in the 8- hour drug delivery experiment. Mr. Vardan Ter-Antonyan (USF, 2005) is currently a QC Analyst–II at AVEVA 10 times, which would allow more drug to ACKNOWLEDGEMENTS Drug Delivery Systems go in through the sweat glands. But we can pharmaceutical company also change the drug and use a drug with a The authors would like to thank Prof. in Miramar, Florida. lower molecular mass. Diphenhydramine Edward Turos, PhD, from the Chemistry Dr. Heidi Kay (USF, 1999) Hydrochloride has a molecular mass of Department at USF for his advice on the is an Assistant Professor almost 300 Daltons, so if we choose to chemistry of Diphenhydramine in the College of Public deliver, for example, Vitamin C with a Hydrochloride. Also, special thanks to Health at the University molecular mass of almost twice as less as Zhongsheng Zhang, Robin Dando, and of South Florida. She the Benadryl, then we might find a few Hoang Nguyen for all the help they provided. currently supervises over times more of it in the urine. This study is partially supported by research 5 projects, including cancer treatment, drug delivery systems 7 o

grants from National Institute of Health, N in supercritical fluid, and Alzheimer’s 6

CONCLUSION NIH, NIGM50785 (W.C.) and National l

disease treatment. o Science Foundation, NSF0515787 (W.C.) V 6 0

The new method of the sweat gland Mr. Matthew Salewski (USF, 2004) 0 2 t

activation enables us to overcome skin REFERENCES is currently a PhD student in the s u g

resistance. The swelling of the stratum Department of Biophysics at University u A

1. Korula M. Iontophoretic delivery of drugs. Ind Anesthetist’s Online J. April /

of Edinburgh, England. y corneum is prevented by applying a thin 2004. www.theiaforum.org/april2004.htm. l u

2. Nair VB, Panchagnula R, Pillai O, Ramarao P. Transdermal iontophoresis J layer of thick Vaseline to the skin. We revisited. Curr Op Chem Biol. 2000,4:468-473. Dr. Feiran Huang y 3. Martin I, Venables PH. The relation of palmar sweat gland activity to level of g o deliver about 10 times less amount of drug l skin potential and conductance. Psychophysiol. 1967;3(3):303-311. (Rensselaer Polytechnic o n

4. Gazelius B. Iontophoresis-theory. December 12, 1999. PeriMed. April 22, 2004. h than the leading methods and instruments, Institute, 2003) is a Post- c www.perimed.com. e T

but we deliver drugs up to 30 times safer, 5. Barry BW. Novel mechanisms and devices to enable successful transdermal doctoral Research y r

drug delivery. Eur J Pharmaceut Sciences. 2001;14:101-114. e v i

Associate in the Center of l which is why this method provides a 6. Fowles DC, Venable PH. The effects of epidermal hydration and sodium e reabsorption on palmar skin potential. Psychological Bulletin. 1970;73(5):362-378. Cellular and Molecular D foundation to deliver drugs more safely and g

7. WebMD Health Source. Clinical pharmacology of diphenhydramine u Biophysics in the Department r efficiently without any possible side effects. hydrochloride.August (2004). www.rxlist.com/cgi/generic3/diphenpo_cp.htm. D 8. www.chemfinder.com. Website accessed June 2006. of Physics at the University of South Florida. 47

TESTING SERVICES

Accelerating Drug Delivery Solutions With Polymer & Analytical Expertise By: Miles Hutchings, PhD; Michael Ruberto, PhD; and Dean Hamel

INTRODUCTION With the high degree of risk involved, results and leave clients challenged with consulting in the pharmaceutical and drug implementation, those specialized consultants delivery industry can and should be a partnership who are also practitioners with extensive between the specialist and client. The client and knowledge and a wealth of relevant experience consultant should share common goals: less will actually help clients put theory into practice plant downtime, faster time to market, and the in a more efficient manner. Consultant most accurate and scientifically documented Practitioners will give clients what they demand results possible. for their own products, paving the way for a long- While many consultants will present their test term relationship that’s built to last.

TRUE STORY industry. For pharmaceuticals and drug experts everything outside of their delivery systems, the repercussions of core competencies. Recently, a new pharmaceutical losing a 2-year head start can have a product involving a plastic inhaler devastating ripple effect not to mention A PERFECT FIT delivery system was poised for an the significant losses in revenues. impressive introduction into the For a variety of reasons, companies This market need, plus its own marketplace. Expectations were high are increasingly opting to outsource many, unique blend of experience and core (clinical trials had already demonstrated if not all, of the necessary stages in a competencies, encouraged Ciba Specialty the safety and effectiveness of the product’s journey to market. Some Chemicals, a pioneer in polymer product), but the pharmaceutical companies find themselves in the quality stabilization, to create and launch Ciba® company was unable to seek FDA control phase of a new product Expert Services in 2004. One of Ciba’s approval until it could identify the introduction without definitive answers to many core competencies, analytical mysterious substance that was leaching critical questions. Has the stabilization testing, became the foundation of Ciba® out of the polymeric inhaler mouthpiece. package added to the plastic components Testing Services, the service arm of 7 o

N This company spent 2 years investigating of your drug delivery system changed due Expert Services that offers Leachables 6

l the substance with its partners to no to un-notified supplier changes? Are the and Extractables testing services for the o V avail. They finally sought the help of additives, stabilizers, and colorants worldwide pharmaceutical industry. 6 0

0 specialized outside consultants from leaching out, transforming as a result of Because transdermal patches, 2 t

s interaction with other chemicals, or inhalers, IV bags, syringes, and more are

u Expert Services, a new business g

u degrading over time? These questions can all high-risk examples of polymeric A introduced by Ciba Specialty Chemicals / y l be answered and the implications dealt delivery systems that can potentially u Corp. Within a few short months, they J with by Expert Services because of its impact consumers, the idea of Ciba’s y had identified not only the substance but g o l knowledge and expertise along the specialized experts consulting o its commercial trade name as well. n h

c polymer supply chain. Many find with drug delivery manufacturers and e Health and safety evaluations were then T y

r outsourcing to be both cost effective and pharmaceutical companies appeared to

e possible, and ultimately the FDA v i l

e approved the product and the drug was efficient, simplifying the way they do make perfect sense. While some D g

u business by focusing on what they do companies were initially reluctant to share

r finally launched – more than 2 years later D than planned. That’s a long time in any best, and outsourcing to specialized confidential information with consultants, 48 TESTING SERVICES

“Because transdermal patches, inhalers, IV bags, syringes, and more are all high-risk examples of polymeric delivery systems that can potentially impact consumers, the idea of Ciba’s specialized experts consulting with drug delivery manufacturers and pharmaceutical companies appeared to make perfect sense. “

it became a non-issue when the actual and assessment of health and safety by another consultant, you’re usually experience of working in tandem with Ciba implications, etc., Ciba occupies a unique on your own. specialized experts began. Growing a position in the world of polymers. Ciba Expert Services practices what it knowledge-based services business relies on Specialty Chemicals had its genesis in two preaches. When its safety consultants cultivating excellent client relationships 18th century companies (Ciba and J.R. present test data, they don’t leave clients to while maintaining an unblemished Geigy). From 1758, when Johann Rudolf figure out how this information should be reputation. The growing list of clients who Geigy set up a drugs and dyestuffs shop in applied. A vital part of their brief is to aid now use Ciba Expert Services on a regular Basel, Switzerland, until today, Ciba clients in safely introducing a new product basis is the best testament to a trust that has continues to launch breakthrough products. into their own manufacturing facility. been earned. The extensive knowledge of such a long- They’re able do this because parent term practitioner is now being employed to company Ciba Specialty Chemicals has a THERE’S NOTHING LIKE alert pharmaceutical and drug delivery head start, as an actual practitioner of the EXPERIENCE…. system manufacturers to chemicals that art of safe chemical production, it has could migrate out of plastic packaging and already introduced many chemical Many pharmaceutical and drug delivery systems, interact with the manufacturing processes for a broad variety manufacturing companies have already drugs, and even enter the consumer. of chemistries in their own facilities. discovered that outsourcing has been Chemical manufacturing is Ciba’s core

proven to be more cost effective and PUTTING THEORY INTO competency and, everyday, it must insure 7 o efficient because it enables them to do what PRACTICE that its own chemicals are manufactured to N 6 l

they do best (drug research and the highest safety standards in its own o V development, manufacturing, and Pharmaceutical consulting is hardly a plants. Armed with this extensive practical 6 0 0

marketing), while everything outside of new idea. There are as many types of experience, Expert Services consultants 2 t s their core competencies are assigned to consultants available as there are problems simply translate their testing data into real- u g u specialty consultants. A company with over to solve and challenges to be met. Some world implementation for clients’ A / y l u

100 years of experience in all areas of the consultants offer safety auditing and provide manufacturing plants. Only then is a J

polymer industry (analyzing, testing, and safety and compliance recommendations. consulting project considered to be y g o l producing) can help bring a client’s product Others will supply test data. But virtually no successfully completed. o n h c e

to market economically, safely, and quickly. other specialized consultant can personally T y r

With all the necessary information at its bring to the table actual chemical THERE’S ALWAYS MORE! e v i l e

fingertips so to speak, such as manufacturing experience. When it’s time to D g u comprehensive knowledge of compounds, implement changes in your manufacturing The relationship that started with r D degradation and transformation profiles, environment, based on the test data provided client-customized analysis and dedicated 49 50 Drug Delivery Technology July/Ausut 2006 Vol 6 No 7 TESTING

do and hiringthestandardconsultantboils withaconsultantpractitioner “partnering” in lessthanaday. couldhave beenaccomplished identification laboratories,and its state-of-the-art already hadstandardsforthatcomponentin identify anunknown component.Ciba labored fornearly ayearto inanattempt their testingtime. A caseinpoint:one client allo gained fromdecadesofexperience thathas chemical andpol bring toe tosolutions. andcontribute participate They their to that studye groups industry members ofpharmaceutical the designofnew medicaldevices. As and caneven helptoselectmaterialsduring easil personnelcan Services Expert manufactures, pigment productssimilartothoseCiba such asantio related plasticproductscontainadditives, up foraser answers toallrelevant questionsby signing analytical standards,additionaltraining,and updates onnew testingandin-house who “want itall”cangetinformation flexibility (“your placeorours”),andclients needed, andsometimesitrequirescertain stabilization methods. Training mightbe in acomponentorinvestigating better example, trackingdown thecauseoffailure for andinformation, system-related services access tomany delivery typesofdrug test methodsusually continueswithclient succeed for itso whatServices thechemicalleader demands entire supply chain. ClientsgetfromExpert an overall visionofandinfluenceonthe involved inmedicaldevice applications, and intimate kno SER wn toe wed cut many clientstosignificantly y The realdifference between Because somany pharmaceutical- car xicolo wn products. , so doestheconsultant. r v xtensi y er xtractab vice contract. out thenecessar wledge ofthematerials y xidants, antistaticagents,and gical impact,theseconsultants project asophisticatedle v ymer industry knowledgeymer industry e, VICES les andleachab hands-on e And w hen itsclients y testing studies xperience, an les and vel of I around the globe. He isa member of the AIChE, the Society of Plastic Engineers, and the management, product management, sales, and business management atseveral Cibasites Ruberto hasbeenemployedbyCibaf chemical characterization, migration studies, applications support,and technical service. Dr. 2892 [email protected]. his PhDinAnalytical Chemistry from SetonHall University. He canbecontacted at914-785- Switzerland.Dr. Rubertoearned hisBSwiththesis from Stevens Institute of Technology and harmonization process byperforming ajobrotation atCiba’sheadquarters inBasel, testin Resear [email protected]. pr performing migration studies and GLPtesting, including aprioritization of tests, experimental additives. He ledthe efforts togloballyharmonize the Cibainternal analytical protocols for characterization and BaseSetstudies needed for globalproduct registration of novel An Laboratory Practice (GLP)and GoodManufacturing Practices (GMP)program inCiba’s additives, pigments, and polymers. He waspartof ateamcommissioned toestablish aGood studies tosupportFDA and European Union indirect food contact notification for various Ch U Hutchings earned hisPhDinChemistry and hisBScinIndustrial Chemistry from the had numerous articles and paperspublished inindustry and scientific publications. Dr. for oilanalysis and basestockresponse research programs. He holds several patents and has Chemical Corporation and BritishPetroleum inthe United Kingdom, where he wasresponsible Bioengineering at the University of Oxford. He hasgained Industrial experience withExxon plastics stabilizers. Prior tojoining Ciba,he wasaResearch Fellowwithinthe department of gained plastic industry experience asaProduct Range Manager for Ciba’sspecialty line of SPE. H niversity W oced emistry alyti g ch, wh ur cal Research Department and servedasStudy GLP Director for many product e associ es can becon , , PD analytical method validation, and report formats. Dr. Rubertocompletedthis ales inCardiff. He isaChartered Chemist and Member of the RoyalSociety of ere he ledafull-service analytical laboratory thatspecialized inperforming A, ISPE, and ASTM.He canbecontacted at914-785-2533or ated withth positions inprocess development, engineering, production, resource years of experience inthe chemical process industry. He hasheld avariety of Chemical Engineering graduate from Northeastern University and hasover23 L&E W packaging, and labelsusedondrug containers and isamember of the PQRI leachable and extractable studies for the FDA approval of medical devices, compliance of Cibachemicals. He isactivelyworking inthe area of designing notifications of new products, food contact notifications, and regulatory at CibaSpecialty Chemicals. Hisgroup isresponsible for worldwide Mr Dr. MichaelRuberto ed development of environmental, safety, regulatory, laboratory, and Services, Americas. He isresponsible for allaspectsof the commercial H Dr. MilesHutchings development intransportation and industrial lubricants. Inaddition, he technical programs tosupporttechnical service and new product Director for Process and Lubricant additives withresponsibilities for Ciba inBasel,Switzerland, in1987.He hasheld the positions asTechnical a s is responsibilities involvethe internal provision of services toCibaaswell u . tacted at251-436-2397 ord the development of external, third-party business. Dr. Hutchings joined cati Dean Hamel orking Group. Dr. Rubertowaspreviously the Director of Analytical onal services inCiba’sExpertServices Organization. Mr. Hamel a is e development and commercialization of new products, including BIOGRAPHIES is H or 11years ead o is Head of RegulatoryServices for the NAFTA region is the head of ExpertServices inthe NAFTA region. f Cli , ean.ham en wh t er Servi e he hasperformed numerous migration el@cibasc ces , NAFT .com A and Head of EHS

BUCCAL DELIVERY

Advances in Buccal Adhesive Drug Delivery By: A.K. Bandyopadhyay, PhD and Yajaman Sudhakar, PhD

ABSTRACT Since the early 1980s, delivery of therapeutic accessible site for the delivery of therapeutic agents. agents through various transmucosal routes has gained Selecting a suitable route of drug delivery within the significant attention, owing to their presystemic oral cavity is mainly based on anatomical and metabolism or instability in the acidic environment permeability differences that exist across the various associated with oral administration. Among the various oral mucosal routes. Buccal adhesive systems are well absorptive mucosae that include nasal, pulmonary, suited for orally inefficient drugs as well as a feasible rectal, vaginal, buccal and sublingual, the mucosa of and attractive route for non-invasive delivery of the oral cavity is viewed as a convenient and easily potent peptide and protein drug molecules.

BUCCAL MUCOSA AS A SITE lipophilic in nature; hydrophilic solutes inclusion of a permeation enhancer, FOR DRUG DELIVERY will have difficulty in permeating due protease inhibitor, or pH modifier in to a low partition coefficient. the formulation to modulate the Between the two well-established Therefore, the intercellular spaces pose environment at the application site. routes of the oral cavity, the buccal is a as the major barrier for permeation of Limitations include involuntary more preferred route for systemic drug lipophilic compounds, and the cell swallowing of saliva containing delivery than the sublingual. The membrane acts as the major transport dissolved drug or swallowing of the buccal mucosa has an expanse of barrier for hydrophilic compounds. delivery system itself that might lead to smooth muscle and relatively immobile Drug permeation may involve a major loss of drug from the site of mucosa that make it a more desirable combination of these two routes.2 absorption. Talking, eating and region for retentive systems. The Advantages of the buccal route drinking may affect the retention of the buccal route avoids hepatic first-pass include excellent accessibility for delivery system. Taste and irritancy effect and presystemic elimination of application in a painless, precisely may also limit the number of drugs. drugs associated with the oral route of located manner to the site of Overhydration may lead to formation

1 application to get uniform drug release. of a slippery surface, and this swelling 6 administration. Thus, the buccal o N

Moreover, the delivery system can be may disrupt structural integrity of the 6

mucosa is emerging as an alternative l o for the parenteral route and is more designed to be unidirectional in drug device. Drugs with the potential of V 6 0

release so that it can be protected from changing the physiological condition of 0

fitted for sustained delivery 2 t s applications of orally ineffective drugs. the local environment of the oral cavity. the oral cavity may not be suitable for u g u A Drug transport across the buccal It has gained direct access to the buccal delivery. / y l u mucosa occurs by the two permeation systemic circulation and is not subject J y g

to the hepatic first- pass metabolism. MUCO/BIOADHESION o pathways that exist for passive l o n h diffusion: paracellular and transcellular Relative to the nasal and rectal routes, c e T y

the buccal mucosa has low enzymatic Bioadhesion is the phenomenon in r

routes. As the intercellular spaces and e v i l

activity and drug inactivation; hence, which two materials, at least one being e cytoplasm are hydrophilic in character, D g u

biochemical degradation is not rapid of biological in nature, are held r

lipophilic compounds have low D permeability. The cell membrane is and extensive. It also permits the together for extended periods of time 51 BUCCAL DELIVERY

by interfacial forces at the desired site. environment-related factors (pH, applied Buccal Adhesive Polymers The term has also been defined as the strength, initial contact time, swelling, These are the substances that ensure ability of a synthetic or natural dehydration of the mucosa, interfacial the attachment of the delivery system macromolecule to adhere to a biological tension, bioadhesive component at the site of application and release tissue, which can be either an epithelial proportions, carrier solubility, particle the drug at desired rate. The surface or the mucus layer covering a size, fracture path, rate and capacity of muco/bioadhesive should possess tissue. In the first case, it is generally water absorption etc), and physiological characteristics, such as the polymer, and referred to as bioadhesion, and in the variables (such as mucin turnover, its degradation products should possess a later case, the phenomenon is generally pathological conditions etc) will play a wide margin of safety both locally and referred to as mucoadhesion.3 The steps major role on the adhesive interactions. systemically. It must spread over the involved in the muco/biooadhesion substrate to initiate contact and to process include (1) spreading, wetting, FORMULATION DESIGN increase the surface area of contact. It and swelling of the dosage form at the should allow easy incorporation of the mucus surface, which initiates contact Generally, a device featuring a drug and must release the drug at the between the polymer and the maximal duration of delivery of desired rate. The bioadhesive polymers mucus/epithelium; (2) interdiffusion and approximately 4 to 6 hrs, 1 to 3cm2 in may be polyacrylic acid derivatives interpenetration between the chains of size, and a daily dose of 25 mg or less, (polyamides, polycarbonates, the mucoadhesive polymer and the would be preferable for buccal delivery. polyalkylenes, polyalkyleneglycols, mucus gel network; and (3) formation of The buccal mucosal turnover rate, polyalkyleneoxides, secondary chemical bonds between the salivary secretion, composition of mucus, polyalkyleneterephthalates, polyvinyl polymer chains and mucin molecules. physicochemical parameters (such as alcohols, polyvinyl ethers, polyvinyl solubility, permeability, and stability of esters, polyvinyl halides, polyglycolides, Methods for Measuring drugs), degree of ionization, mechanism polysiloxanes, and polyurethanes etc) or Muco/Bioadhesion of absorption, dose, taste, surface area cellulose derivatives (alkylcelluloses, The majority of the bio/mucoadhesion required for application, additives that hydroxyalkylcelluloses, cellulose ethers, methods are based on measuring the interfere with salivary secretion, disease cellulose esters, and nitrocelluloses etc). force required to break the adhesive bond conditions that brings the change in

7 Substances of natural origin (chitosans, o N between the model membrane and the thickness of the buccal mucosa, purpose guar gum, xanthum gum, carrageenan, 6 l

o adhesive. Depending on the direction in of the dosage form, and drug interactions V pectin, sodium alginate, dextrans, lectins,

6 which the adhesive is being separated with the mucin are to be considered in 0 aminated gelatin, aminated pectin, 0 2 from the substrate, peel, shear and t the formulation design. As the dosage

s hyaluronic acid, inulin), proteins such as u

g tensile forces can be measured. The u form is to be resident near the tongue,

A zein, serum albumin, or collagen, and / y l peel adhesion tests are mainly used for organoleptic factors are also to be u mucilaginous substances from edible J buccal adhesive drug delivery devices. y considered. For local delivery, the

g vegetables can also be used. o l o

n residence time and local concentration of h c

e Important Factors for T the drug, and for a systemic effect, the Penetration Enhancers y r

e Muco/Bioadhesion v

i amount of drug transported across the l Enhancers are capable of decreasing e

D Polymer-related factors (molecular

g mucosa into the circulatory system, are

u the penetration barrier of the buccal r

D weight, its concentration, flexibility of its important considerations in designing mucosa by increasing cell membrane chains, spatial conformation etc), 52 dosage forms. BUCCAL

DELI VER Y BUCCAL

animal modelsw insulin usingvarious enhancersindifferent octreotide, LHRH,insulin,andinterferon. salicylic acid, andpeptidessuchas weight like acyclovir, drugs propranolol,and ionizableacid andbutanol, low molecular enhancers aresmallmoleculeslik lauryl sulfate (5% w/v). sulfate lauryl sodium glycocholate (5%w/v)andsodium about 0.7%to27%inthepresence of increase ininsulinbioa rat anddog mucosae,showed buccal an salicylate, sodiumEDTA, andaprotinin on sodium glycocholate, sulfate, sodiumlauryl studies. Enhancers,suchassodium various alkyl glycosides. taurodeoxycholate, Sulfoxides, and Sodium taurocholate, Sodium laur glycocholate, Sodiumglycodeoxycholate, Polysorbate 80,SodiumEDTA, Sodium Phosphatidylcholine, P Methyloleate, Oleicacid, Menthol, Methoxysalicylate, Lauric acid, Lysophosphatidylcholine, bromide, Cyclode chloride, Cetyltrimethylammonium Benzalkonium chloride,Cetylpyridinium ether,are 23-lauryl Aprotinin, Azone, penetration enhancersstudiedexclusively andrheology.mucus structure The various altering cellularproteins,or intercellular and/orintracellularlipids, fluidity, extracting thestructural properties ofthe dosageform. properties because itwillaffect thebioadhesive enhancer taken inselecting thepermeation The feasibility of buccal deliveryThe feasibilityofbuccal of Dr ugs investigated usingvarious ylsulf DELI as studiedthrough xtrin, De ate, Sodiumsalicylate, vailabilities from ol 4 Care mustbe y o xtran sulf xy ethylene, e butyric VERY in vivo ate, suggested asuseful lossasafunctionoftime. of drug well characterizedandcontrolled. layerscomposition ofthebarrier mustbe differentiated celllayers andthelipid thenumberof transport, drug buccal However, toutilizetheseculture cellsfor prob transfer cantake place,hasnoleakage used thatoffers larger areasover which drug placed inthemetaldiesealedatlo dissolution medium. The tablet istobe inter consisting ofawater jacket andan using simulatedsaliva inanapparatus e mounted indiffusion cells. The end b an ice-cold(4 membranes arethenplacedandstoredin them. immediatelyThe aftersacrificing animal modelsthatarecollected studies have tissuesfrom usedbuccal Permeation Studies b 15 minutesb 25-ml sampleofthetestsolution forupto test involvesabsorption theswirling ofa candidate drug. Mostofthe candidate drug. routeofadministrationforthe the buccal thefeasibility of conducted todetermine b amount of drug remainingintheexpelled amount ofdrug rpm w release fromoneendalone. The medium xperiments were generally conducted y uccal dr as stirred with a rotating stirrer at250 witharotatingstirrer as stirred the e 5 lem, andpro Buccal cellcultureshave alsobeen In vivo Permeation studiesmustbe nal compar . y A paraf xpulsion ofthe solution. buccal perfusioncellapparatuswasbuccal ug per absorption studies like buccal absorption f y in w ° C) Krebsb human v meation andmetabolism. vides continuousmonitoring tment containing50mlof ax toensurethedr in vitr olunteers follo uf o fer until models for in vitro The ug w w ed er intervals forestimationofdrug. and blood samplesaredrawn atfrequent easy tohandle. keratinized mucosa,andthey buccal are are thebestchoicebecauseoftheirnon- de solutioniscirculatedthroughthe drug to thetissueby cement. cyanoacrylate The do attached totheupperlipofanaesthetized studied usingasmallperfusionchamber Sulfadimethoxine andDiltiazemwere and repor and h sprays, non-erodible multiplelayer films, bilayeredmatrix tablets, systems, films, routeusingconventionalthe buccal b less expensive thanmonkeys, andtheir are easiertomaintainandconsiderably single 15-minutetrial. enables kineticdatatobecollectedina using apositive displacementpipette, samples beingwithdrawn fromthemouth test,which involvesabsorption multiple improvement over thetraditionalbuccal hamsters have keratinized mucosa. experimental studies,whereas theratsand and hasbeenextensively utilizedin mucosal liningsimilartohumantissue monk as rats,hamsters,rabbits,do assess the amount of drug absorbed. assess theamountofdrug volume inorderto isthendetermined uccal mucosaisnon-k vice forapredeter gs. P Deli Researchers have usedanimalssuch DRUG DELIVERYS ydrogel systems hasbeenstudied eys. The rabbithasanon-keratinized The perfusionchamberisattached er meation studiesforSalic v ted. er y of v 10 arious dr mined periodoftime, 7 eratinized. Pigs ugs via gs, pigs,and YSTEMS 8 ylic acid, 9 Dogs 6 An

53 Drug Delivery Technology July/August 2006 Vol 6 No 7 BUCCAL DELIVERY

Buccal Adhesive Tablets was tested in dog buccal mucosa and was administration of E2 with this A buccal adhesive double-layered shown to remain in place for up to 17 hrs formulation allowed the maintenance of tablet containing Triamcilone acetonide without any obvious discomfort. In vivo plasma level at over 300 ng/ml per cm3 for the treatment of aphthous stomatitis studies in human subjects on the buccal for 7 hrs.38 using HPMC and polyacrylic acid for patch device consists of a flexible A novel mucosal adhesive ointment which Nagai has received the award of mucoadhesive matrix composed of a for treatment of lichen planus containing the Japan National Invention Prize has blend of poly (acrylic acid), Carbopol treninoin (vitamin A acid) and been reported.11 Similarly, buccal 934P, and poly (isobutylene) with a neutralized polymethacrylic acid methyl adhesive tablets of Cetylpyridinium polyurethane-backing layer have revealed ester, showed neither any local irritation chloride5, Clotrimazole, Diltiazem, effective bioadhesive characteristics for in human buccal mucosa nor any Hydrallazine, Insulin, Isosorbide 12 hrs of application. systemic side effects. On twice daily dinitrate, Miconazole, Morphine, Similarly, buccal adhesive patches of treatment, the macroscopic lesions Nimesulide, Nitroglycerin, Nystatin, Buprenorphine, Isosorbide dinitrate, disappeared after an average of 3 to 4 Omeprazole, Propronolol hydrochloride, LHRH, Lidocaine, Miconazole nitrate, weeks in 15 to 18 patients.39 Sodium fluoride, Testosterone, Propronolol, and Proterilin were prepared Thicolchicoside, Tetracycline, Verapamil, using different bioadhesives polymers Buccal Adhesive Gels etc were studied by several research either alone or in combinations and Hydrogels formed by the groups using different bioadhesives evaluated.30-36 combination of xantham gum and locust either alone or in combinations.5,12-28 bean gums was studied. The mechanism Buccal Adhesive Ointments of gel formation is due to the formation Buccal Adhesive Patches Three different hydrogel-based of a three-dimensional network between Buccal adhesive patches consisting ointments using sodium CMC, Pectin, the double helical structure of xantham of two-ply laminates of an impermeable and gelatin combination in a gum and the straight molecular chain of backing layer and a hydrocolloid polymer polyethylene-paraffin base, Carbapol locust bean gum. Though it showed only (HPC, HEC, PVP and PVA) layer 934P, and neutralized Poly (MAA-co- a low mucoadhesion, it can be applied to containing the drug was developed and methyl methacrylate) was developed and a buccal mucosa because of its safety, gel evaluated. The integrity of the laminate investigated by Electron Paramagnetic strength, sustained-release properties, and

7 40 o was based on adhesive bonds between the Resonance. The study showed that good mouth feel. N 6

l hydrocolloid layer and an agarose layer P(MAA-co-methylmethacrylate) was the o V grafted to one side of the backing layer most appropriate for ointment 6 0 0

2 sheet and found that among the cellulose formulation in terms of stability, SUMMARY t s u

g ethers studied, HEC and HPC possessed transport of molecules, and washing out u

A 37 / 29 The buccal mucosa offers several y time from the oral mucosa.

l superior mucosal adhesion. A patch u J consisting of a unidirectional buccal A hydrogel ointment containing advantages in delivery of drugs for y g o l absorption enhancers for the buccal extended periods of time. The mucosa is

o patch comprising three layers (an n h

c well supplied with both vascular and e impermeable backing layer, a rate- delivery of 17 -estradiol to treat

T b y r

e limiting center membrane containing the osteoporosis was developed to overcome lymphatic drainage. The first-pass v i l e

D drug, and a mucoadhesive layer its low bioavailabilities due to hepatic metabolism in the liver and presystemic g u r elimination in the gastrointestinal tract is D containing bioadhesive polymer first-pass effect. In vivo studies using polycarbophil) was developed. This patch hamsters demonstrated that the buccal avoided. The area is well suited for a 54 BUCCAL

DELI VERY BUCCAL

18. Anlar S,Capan Y, Guven O, Gogus A, Dlakara T, Hincal AA. Formulation and S,SchautteetH,Lefebvre17. Bouckaert RA,RemonJP, Van CloosterR. 16. Yukimatsu K,Nozaki Y, MakumotoM,Ohta M.Development ofa 15. Tanaka M, Yanagibashi N, FukudaH,Nagai T. ofsalicylic acid Absorption 14. Dinsheet,development, andevaluation ofHydralazine dosageforms ofbuccal 13. 12. RajeshK, Agarwal SP, Ahuja A. Buccoadhesive forlocal erodible carriers Nagai 11. T, Machida Y. MucosaladhesiveInt.1985;196-200. Pharm dosageforms. 10. SquierCA,HallBK. ofmammaliannon-keratinized oral The permeability 9. 8. 7. 6. 5. 4. 3. potent peptide and protein drug molecules. potent peptideandproteindrug alternative fornon-invasive delivery of 2. 1. dr systemic deli continued researchwiththeaimof ofdeliveryform isapromisingareafor delivery. drug in theareaofbuccal This componentforaprospectivecrucial future enhancersisa permeation/absorption need forsafeandeffective buccal permeation. adjust therateofdrug The mucosa canbemanipulatedinorderto design, thelocalenvironment ofthe patient. With therightdosageform roughness andiscomfortabletothe retentive device becauseofitssurface Yamahara H,Lee metabolismintheoralcavity.VH. Drug DelRev.Adv Drug Aungst BJ. effect Sitedependenceandstructure relationshipsforalkyl Delivery. MarcelDekker, Inc.:,New York, NY;1996:1-26. delivery.implications fordrug In:RathboneMJ, ed.OralMucosalDrug Squier CA, 1993;12:25-39. human b Gonzalez YI, Wagner JG,GainesDA. offlubriprofen through Absorption Phar an invivo modelofpassive transferthroughlipidmembranes.JPharm drug Beckett AH, Triggs EJ. anditsapplicationas ofbasicdrugs Buccalabsorption cetylpyridinium Sci.1990;79(2):116. chlorideJPharm Collins 1994;105:219-225. promotersforinsulin.IntJPharm. glycosides astransmucosalabsorption 29(8):821-832. Hao J, Paul W, HengS.BuccaldeliveryDev 2003; systems.Drug IndPharm. Phar Shojaei delivery: areview.AH. Buccalmucosaasarouteforsystemic drug J NY Rathbone MJ. Delivery MarcelDecker, OralMucosalDrug Inc.:New York, ugs asw Ahuja Pharm Res.1994;11:231-236. Pharm in vitroandvivo evaluation ofbuccoadhesive sulphate tablets. morphine 1992;43:137. bioadhesive slow-release tablet buccal andanoral gel.EurJClinPharmacol. Comparison ofsali Dev 1994;20:503. Drug IndPharm. andpharmacodynamics. pharmacokinetics transmucosal controlled-releasede Bull. 1980;28(4):1056-1061. through theoralmucousmembraneofhamstercheekpouch. ChemPharm Jamia Hamdard. hydrochloride usingbioadhesive polymers. dissertation. 1994MPharm hydrochloride. Sci.1995;57:26. IndianJPharm delivery:1996;138:168. drug Designandstandardization.IntJPharm. Biol. 1984;29:45-50. epithelia tohorseradishpero ;1996. macol. 1967;19:31S-41S. m Phar A, AE, DeasyPB. Bioadhesive lozengefortheimproved delivery of uccal mucosa. J Pharm Sci.1991;80:820-823. uccal mucosa.JPharm Do maceut Sci.1988;1(1):15-30. W g er ra M, Agarwal SP. Development tablets ofbuccal ofdiltiazem tz PW ell asafeasib v ar . very oforallyvery inefficient REFERENCES Structure andfunctionoftheoralmucosa Structure y miconazole concentrationsafteradministrationofa DELI xidase appliedinvi vice forsystemicofantianginaldr le andattracti vo andinvitro. Arch Oral VERY ugs ve 22. ChoiHG,JungJH, Yong CS,RheeCD, LeeMK,HanJH,Park KM,KimCK. 21. LlabotJM,ManzoRH, Allemandi A. Double-layered mucoadhesive tablets 2 19. CeschelGC,Maffei P, LombardiSB. Designandevaluation ofanew 3 2 28. Gupta A, Garg complexation S,KharRK.Interpolymer anditseffect on 27. 26. M,SantiP,Artusi ColomboP, JungingerHE. Buccaldelivery of 25. Voorspoel J, RemonJP. ProcIntSympControlRefBiactMater. 1994;21:539. 24. Bottenberg P, Cleymaet R,MynckCD, RemennJP, CoomansD, Michotte Y, 2 40. 3 3 3 39. 38. KitanoM,Mitani Y, Takayama K,Nagai T. ofgolden Buccalabsorption 37. 35. RaniCS,Pandit JK,SampathKD,Abstracts, 47thIndian SinghR.Scientific 34. Noha A, NafeeFA, IsmailNA, M.Mucoadhesive BoraieL,Mortada buccal 36. 0. 0. 9. 3. 3. 2. 1. Anders R,MerckleH.Evaluation oflaminatedmucoadhesive patchesfor Anders R,MerckleHP W F containing nystatin. AAPS PharmSciTech. 22. 2002;3(3)article Schor JM,Davis SS,Nigalaye Dev 1983;9:1359. A, BoltonS.Drug IndPharm. Delivery.administration. Drug 2004;11:225-230. m b Cassidy JP, delivery NM,QuodrosE.Controlledbuccal of Landzert b Dev 1994:20:315-325. systems. Drug IndPharm. delivery drug bioadhesion strengthanddissolutioncharacteristicsofbuccal t controlled releasecompactcontainingtetrac Collins, 2003;250(1):203-213. Thiocolchicoside: invitroandvivo studies.IntJPharmaceutics. permeation P a Slop D. Comparisonofsalivary fluorideconcentrationafteradministrationof Control Rel.1996;38(1):11-20. adhesivesustained releaseandbuccal propronololhydrochloride tablets. J Buket T, Caplan Y, Guven O, Kes S, Atilla AH. Designandevaluation of Control Rel.2000;68(3):405-412. Jpn. 1991;51:29-35. behavior Sci JPharm fromhydrogelTechn preparedwithwater fibres. dietary Sci.1984;73:548-552. ointment. JPharm Ishida M,Namb York, NY1996:285-318. Rathbone MJ, Delivery. ed.OralMucosalDrug MarcelDekker, Inc.:New delivery R.Specializedoralmucosaldrug systems:patches.In: Scherrer F, G,BenesL,Horriere Degrande KarsentyF,R,Guo LacosteC,McQuinnJ, Bull.1994;42:2598-2603. ChemPharm particles. of strengthgranular Danjo K,KatoH,Otsuka K.FundamentalstudyontheevaluationA, Ushimaru Bremeck 1998;174:19-28. containing threetypesofenhancers.IntJPharm. hamsters cheekinvitroandvivo of17‚-estradiolfromhydrogels Pharm.1998;173:193-202. ointments fordelivery intotheoralmucosa.IntJ ofliposomes Petelin M,SentjurcStolicZ,SkalericU. EPRstudyofmucoadhesive 1983;72:1481-1483. an effective way tostimulate Thyrotropin Sci. andProlactin.JPharm Phar a patches ofmiconazolenitrate:invitro/invivo andeffect performance of using h ooth for the treatment of peridontal disease. Int J Pharm. 1989;51:103-114. ooth forthetreatmentofperidontaldisease.IntJPharm. ging. IntJPhar uprenor u ormulation andinvivoormulation evaluation adhesive ofOmeprazolebuccal tablet. J harmacol. 1991;43:457. harmacol. bioadhesive slow-release tablet andaconventional fluoridetablet. JPharm ucoadhesive bilayered tablet containingnimesulideforbuccal atanabe K, ccal dr m aceutical Cong ydro AEM, DeasyPB er KD p u hine. JControlRel.1993;25:21-29. g x deli ypropyl Bull.1982;30:980. celluloseandcarbopol.ChemPharm Yakou S, Takayama K,Machida Y, Nagai T. release Drug , v Strempel H,KleinG.No u maceutics. 2003;264:1-14. er N y. 1989;49:231-240. IntJPharm. , Nagai T. oflidocainefortoothache Mucosaldosageform ress. 1995. , Schur , Mac Carthy DJ, Shanley DB. Evaluation ofa r W , Ziegler R. Buccal absorption ofprotirelin: Ziegler R.Buccalabsorption vel conceptforamucosal adhesive y cline hydrochloride bondedto in bothth Pharm Technology. Inthisrole, he teaches Department of Pharmaceutical completed Diplom Jadavpur University, Kolkata. He his PhDinPharmaceutics from courses. Dr. Bandyopadhyay earned synthetic and peptide drugs. invasive drug delivery systems for interest isdevelopment of non- papers and reviews. Hisarea of published more than10scientific U PhD inPharm course. Dr. Sudhakar earned his Pharmaceutics inthe DPharm In thisrole, he teaches than 90sci published more Bandyopadhyay from Kyoto University, Japan. Dr. an and peptide drugs. drug delivery systems for synthetic interest isdevelopment of novel niversity d abstr aceuti BIOGRAPHIES acts an , e en Kolkata. He has cs an BPharm and MPharm aceutics from Jadavpur tifi P Governm Lectur Sudhakar Dr. Yajaman Bandyopadhyay Dr. AmalKr. Jadavpur University, Pharmaceutics at Professor of d c olytechni d a papers, reviews, his ar Clini in Bi er atS.V. cal Pharm ea o en otechn c is Senior t , f Tirupati. ology is acy

55 Drug Delivery Technology July/August 2006 Vol 6 No 7

56 Drug Delivery Technology July/August 2006 Vol 6 No 7 on theother of smallmolecules like characteristics one handanddrug- lead generation on candidates for rapid peptides asideal and diversity of between versatility to bridgethegap uniquely positioned believe MIDAS is belie different projects, we different projects, we molecules on molecules on candidate drug candidate drug as smallmolecule as smallmolecule peptide-like aswell peptide-like aswell both stabilized both stabilized success ingenerating success ingenerating “Based onour “Based onour on theother.” o lik one handanddrug- lead gener candidates for rapid peptides asideal and diversity of between versatility to bridgethegap uniquely positioned Shubh Sharma,PhD P f smallmolecules alatin T Vice President &CSO e char v e MID acteristics echnologies, Inc. ation on AS is .” invented MIDAS, a new design rational drug radiotherapeutic products.Duringthisprocess, I w program, whichpeptide-based radiopharmaceutical equivocal appendicitis.I joined RhoMedtoleadits product asNeutrospec inflammation inthebody. Palatin developed this radioimaging ofsitesinfectionand w company specializinginradiopharmaceuticals, RhoMed Incor A: on board? P Q: P M P programs, anchored byitsproprietary MIDAS heart failur pr leader to de has f the MID Sharma, PhD Pharmaceuticals. DrugDelivery orking onamonoclonalantibodyfordiagnostic alatin Technologies andhow you came as focusedonde oduct candidatesf ALATIN P Can you provide abriefhistoryof alatin ELANOCORTIN ormed partner velop pr s inor therapeutics. The Company’s internalresearch anddevelopment primarily engaged inthedevelopment ofmelanocortin-based alatin Technologies, Inc.(Palatin) isabiopharmaceuticalcompany AS tec T echnologies originally as started porated e , cac der tomaximizetheircommer oducts andthenf , v Vice ofPalatin President Officer and ChiefScientific todiscuss hnology andthemelanocortin-basedtherapeutics intheworks. eloping radioimaging and , ® hexia, anddia w T for thedetectionof hich was aprivately held ships with or thetr ECHNOLOGIES eatment ofsexualdysfunction,obesity Tyco Healthcare Mallinckrodt, andKing orm mar gnosis ofsitesinfection. Palatin’s strategy is -B T ec hnology recently interviewed Shubh ASED keting collaborations withindustry de We arenow usingtheMIDAS technology to and ithassincebecomeourdr this technolo After we becamePalatin, we soughttobroaden system basedonmetalionchelationtopeptides. dysfunction, andcongestive failure. heart products intheareasofobesity A: anddiscovery? design, drug the areas ofpeptideresearch, Q: joining Palatin, Ihave worked onpeptide-based have focusedonthisthroughout my career. Priorto cial potential. v elop andcommercializeav What hasbeeny I w T M as trainedinpeptide-baseddr :A L T technology, haveprovided HERAPEUTICS gy basebeyond radiopharmaceuticals, To date, theCompany AE IN EADER our experiencein ug designengine. ariety oftherapeutic , se , cong xual ug designand estive drug design projects at Swiss Federal types and enzymes. Also, specific Unlike approved treatments with the Institute of Technology, Zurich (ETH- turnkey technologies, such as phage PDE-5 inhibitor class of drugs, Zurich), Switzerland, and University display technologies, are routinely Bremelanotide works through a CNS of Arizona, Tucson. Key concepts that applied to generate peptide leads for mechanism of action. It is currently I have developed for using peptides as any target. In fact one can generate undergoing separate Phase II clinical the basis of drug discovery programs peptide leads for any target studies for the treatment of both male have been embodied in the MIDAS irrespective of whether the natural and female sexual dysfunction. In our drug design system. ligand for that target happens to be a previous four Phase II male erectile peptide or non-peptide. Converting dysfunction (ED) efficacy studies with Q: Please describe your these peptides into pharmaceutically over 300 enrolled men, Bremelanotide MIDAS technology and what useful entities is, however, a showed therapeutic promise without makes it unique. challenging job. Based on our success the cardiovascular effects of currently A: Palatin’s patented drug design in generating both stabilized peptide- available ED drugs. We also platform, MIDAS, streamlines the like as well as small molecule conducted a Phase I study in normal drug discovery process with an candidate drug molecules on different 32 premenopausal women, in which efficient approach to create lead projects, we believe that MIDAS is the drug was shown to be safe and compounds by identifying and fixing uniquely positioned to bridge the gap well tolerated. A Phase IIa pilot bioactive conformations. Metal ion between versatility and diversity of clinical study evaluating chelation makes a peptide segment peptides as ideal candidates for rapid bremelanotide in premenopausal rigid in a defined turn structure, with lead generation on one hand and drug- women diagnosed with female sexual amino acid side chains in a like characteristics of small molecules dysfunction (FSD) has shown determined position. This is the first on the other. encouraging results. Following important step in the process. This ongoing Phase II studies in men with Q: Can you describe the provides us a 3-D map of spatial erectile dysfunction, we plan to development of Palatin’s lead alignment of key functional groups initiate a Phase III trial. product, Bremelanotide that are determined to be critical for (formerly PT-141)? Q: Why was a nasal spray 7 bioactivity. This configuration is then o

chosen for the delivery of N

translated to a drug-like template. The In addition to the MIDAS 6 A: l

PT-141? o V

end product resulting from MIDAS technology, Palatin has developed an 6 0 0

can be either an optimized peptide- in-depth knowledge of the biology of A: More and more data now 2

t s u like peptidomimetic or a small the melanocortin family of G-coupled becoming available suggests that nasal g u A / y molecule. The overall attempt in receptors. The first product developed delivery may be a viable approach to l u J

MIDAS is to take the drug discovery from this work is Bremelanotide, a deliver therapeutic levels of drugs to y g o l o

process toward industrialization. nasally administered drug candidate the brain. This may present an n h c e T

As you know, the flexible for the treatment of male and female advantage for delivering CNS drugs y r e v i structure of peptides causes them to sexual dysfunction. It is first in a new because it may minimize problems due l e D

g fold freely, thereby facilitating their class of melanocortin agonists for the to higher systemic exposure of drugs. u r D interaction with multiple-receptor treatment of sexual dysfunction. We have seen clear advantages in 57 terms of efficacy with Bremelanotide toward development. The progress is generated from those territories. This in humans. We also have similar very good and based on current data, is a win-win collaboration for both results with some ongoing internal we believe that our molecules have the partners, serving their respective projects in animal models. right pharmacology. Our molecules strategic needs. King’s large primary are efficacious in decreasing both care/cardiovascular-focused sales Q: What are some of the food intake and associated body force makes King an ideal partner for challenges facing nasal weight without causing penile Palatin and Bremelanotide. In King, delivery systems today? erections. This is a major challenge in we have a partner that is well A: Certainly there are key the melanocortin-based obesity target. energized and focused to move prerequisites for commercial and You need to separate these two effects, quickly in realizing the full potential development success of nasally and we have done that for our obesity of Bremelanotide. administered drugs. Because nasal molecules. Throughout this process, Q: What are the company’s formulations are liquid formations, the we have learned a lot about CNS long-term goals? drug needs to be highly soluble in melanocortin receptors and have aqueous formulations. For example, in developed a good understanding of A: Palatin is moving forward with order to deliver 10 to 15 mg of drug in their mechanisms. Industry wide, this development of its first therapeutic 100-ml volume, you are talking about is a highly competitive area, and we product. This is a good example of solubility higher than 100 to 150 believe we have an edge. We are also what we are capable of accomplishing. mg/ml. This can pose limitations for a exploring use of melanocortin receptor- We took Bremelanotide from number of new chemical entities. The 4 antagonists for the treatment of discovery to its current extensive formulation needs to be simple and cachexia. We have developed potential clinical trial stage, moving on a compatible with the nasal mucosa. lead molecules and are profiling these development path toward Stability of the drug in liquid in animal models. commercialization. We have built formulation to meet intended shelf-life highly effective teams and an Q: Can you touch upon and storage conditions can be infrastructure in the areas of drug Palatin’s alliance with King problematic for some drugs. Cost of discovery, preclinical and clinical Pharmaceutical and the the delivery device contribution research, and product development. strategic importance? toward cost per unit dose also needs We have leveraged our proprietary 7

o careful evaluation, particularly for A: We formed a collaboration with MIDAS drug design system to garner N

6

l single-use disposable devices. King Pharmaceuticals in August 2004 organic growth by discovering new o V

6 to jointly develop and commercialize chemical entities to continually feed 0

0 Q: What other melanocortin- 2

t Bremelanotide in North America for into a pipeline of product s u

g based therapeutics are in the u

A both male and female sexual opportunities. We strive to be an / y

l works for Palatin? u

J dysfunction. Palatin and King will efficient drug discovery and

y g o l A: Palatin is in the process of jointly seek a partner for development company developing and o n h c Bremelanotide for territories outside managing a pipeline of new e finalizing lead optimization of small T

y r

e of North America. We are jointly therapeutic products. v molecule candidate drugs for the N i l e D

sharing development and marketing

g treatment of obesity. We are evaluating u r D drug-like characteristics as we move costs and will split all revenues 58 contact InSite For moreinformation, be administeredoveralongerperiodoftime. DuraSite remainsintheeyeallo The increased time which theactivedrugisgraduallyreleased. levels, drug only lastafewminutesandareunabletosustaintherapeutic whereasconventionaleyedropstypically Importantly, drug candidates. canbecustomizedtodeliver awidevarietyofpotential formulation, early andla www completed PhaseItrials. target annualandpandemicinfluenza, PowderMed's leadproductisaDNA-basedprophylactic vaccineto forstockpiling. requiresnorefrigeration administration,and self- allows requiresminimalmedicaltraining, The PMED “gene gun” doses ofDNA;1,000-foldlessthanwithintramuscularDNAinjection. small(microgram) immuneresponsesareseenwithvery means that a whichisimpossibleto access using the immunenetworkofskin, goldmicroparticlesto shootDNA-coated 1,500milesperhourinto at edeadsrne Thetargetingofthisimmunecellrichtissue needle andsyringe. N .powdermed.com. DuraSite remainsintheeyeforuptoseveralhours, EEDLE te-stage development. DuraSite, a patented eyedrop apatented DuraSite, development. te-stage O Vision a PHTHALMIC -F t REE 510.865.8800 orvisit F or moreinforma E ws lo PIDERMAL wer concentra which hassuccessfully D tion, ELIVERY www thera and diagnostic has aportfolioofboth Thecompany delivery. and retinaldrug genomics, (DuraSite), topical drugdeliver technologies: platform specializes inthree Thecompany disease. andretinal glaucoma, ocular infection, focusedon company ophthalmic products InSite Vision isan visit P pressurized helium which relieson Epidermal Delivery), (Particle Mediated called PMED platform technology proprietary a employs approach ground-breaking PowderMed’s .insitevision.com. tions ofadrugto D peutic productsin o wedrMed a ELIVERY during y t systems. for partnersinterestedintransdermalandimplantablea productsandthusprovidinglicensingopportunities proprietary own Novosis AG isalsodeveloping development andGMP-manufacturing. ofpharmaceutical solutionsandthesuccessfulintegration on creative pharmaceutical customersrelyonthepartnershipwithNovosisbased osue o oeifrain visitControlled at Therapeutics For moreinformation, moisture. whenexposedtobody highly predictableandreproducible rate pharmaceutical use, Specificallydesigned for forlocalorsystemictreatments. vaginally thehydrogel maybeadministeredbuccallyor For example, www.ctscotland.com. M ULTIPLE P F or moreinforma OLYMER the polymer is capable of delivering drugs at a ofdeliveringdrugsat the polymeriscapable P LATFORMS tion, D ELIVERY visit Novosisa & of administration. given bydifferentroutes levels ofadrugwhen to maintaintherapeutic anability demonstrated release technolog of time. over anextendedperiod ofdrugs administration for theprecise polymer deliver pa has developeda Controlled Big international continuous drugrelease. controlled andnon- technologies foractively andpatented proprietary Novosis hasdeveloped systems. delivery and implantabledrug transdermal, dermal, manufacturing of development and to dedicated company pharmaceutical Novosis AG isa S t www tented hydrogel P YSTEM RODUCTS .no This controlled Thera pplication vosis.com. y peutics system y has

59 Drug Delivery Technology July/August 2006 Vol 6 No 7 60 Drug Delivery Technology July/August 2006 Vol 6 No 7 44 x.2671orvisit ext. 5454, (888)327- at Inc., contactLoparex, For moreinformation, needs. a uniquely qualifiedtodeveloparelease linerdesignedforyourunique Loparexis development, andsubstrate technologies inchemistry Because ofourcontinuingcommitmenttoleading-edge is critical. liners tha and topicaldeliver parenteral, Phareshasexpertiseandsolutionsfororal, techniques. www.phares.biz. compound selection, rangingfromlead ofpharmaceuticaldevelopment, for eachstage bioa and Solubilization ofpoorlysolublecompounds. formulation tothe related andpatents Phares hasdevelopedindepthknow-how auatrn rcse.Frmr nomto,visit For moreinformation, manufacturing processes. acceptabilityofexcipientsand importance ofregulatory aswellcGMPandthe preclinical andclinical development, intoanexpertunderstandingoftherealrequirements translates This experienceworkingoninsolublecompounds. cumulative withdecadesof areexperiencedindustrialpharmacists, formulators Its up andmanufacturingofcGMPsuppliesforhumanclinical trials. pplica S vailability improvementarekeygoalsoftheformula ILICONE in LooktoLoparex forallyourmedicaldevicereleaseliner tion. t satisfy therequirementsofbothmanufacturerandend user satisfy S OLUBILITY y . -C The compan through prec www.loparex.com. OATED cutability anddie- moisture resistance, cleanliness, complete traceability, medical PSAproductsinclude: characteristics ofreleaselinersfor Dressings. and Wound Medical Devices, EKG/ECG ElectrodesandElectro- Transdermal Systems, DrugDelivery medical PSAmarketinclude: definethe that The majorcategories sensitive adhesive(PSA)products. of releaselinersformedicalpressure on flexiblewebsinthemanufacture Loparex specializesinthincoa y linical development, delivers therightlevelofser S P OLUTIONS APERS . Manufacturing release Key performance & to thescaling tion F ILMS vice tings [email protected] or(858)794-8889;visit Business Development(Halozyme at Therapeutics) VicePresidentof contactMark Wilson, For moreinformation, comfort. andimprovepatient withoutEnhanze, toSub-Qdelivery relative volumes (upto10cc)ofantibod of large topermittheSub-Qadministration Enhanze isanticipated with co-delivery Baseduponthismechanismofaction, “jungle.” toclear thesubcutaneous enzyme actasa “molecular machete” microgramquantitiesofafullyhuman recombinant Technology, www.halozyme.com. visit contact Spray (800) 95SPRAY at Analysis and Research Services or tests, development andtesting, nozzle spraydry include optimization, tabletanddevicecoating www.sprayconsultants.com. A n pa hrceiainsuis For moreinformation, studies. and spraycharacterization DVANCED S UB -Q P S a ROTEIN tomizer prototyping, PRAY eae rbes Typical projects problems. related andsolvespray- and testingtime, product quality improve processefficiency and tohelpcustomers technology Spray Analysis usesadvancedspray ser A could benefitfromoptimization. processthat microencapsulation or drying, coating, new waytosprayorha manufacturing ifyou'relookingfora and expedite drugdelivery Ser Spray y drugs, vice ofSprayingSystemsCo., vices offerswaystoimproveand T Analysis andResearch speed onsetofaction D ECHNOLOGY ELIVERY , proof-of-concept shorten development Enhanze compounds? With existing Sub-Q dispersion ofyour enhance the or Q) delivery subcutaneous (Sub- from IVto convert yourdrugs W ould youliketo ve anexisting TM Systems at Systems at dama includingwhilereducingskin patches theabilitytoreapply properties, forunique Thisallows corneumcells. significant amountofstratum exceptional adhesionandweartotheskinwithoutremovalofa for allow adhesivehasunusualpropertiesthat This Gel-Matrix whichaddressestheseproblems. adhesivecomposition, proprietary technolog The totheskin. andirritation resultingindamage adhesive surface, corneumcellsareremovedandtransferredtothe amount ofstratum pa toadherethe matrix astheprimary polyisobutylene- basedpolymers, trademark R specialities include sterileall-glasssyringesystemsunderthe Itsparticular marketofprefillablesyringesandcartridges. growth www.buenderglas.com. Buender Glas North America, Chris King, at (267)895-1722orvisit at ChrisKing, Buender GlasNorth America, requirements andareFDAregistered. comply a Thecompany’s products 10,000 class setthebasicstandards. water-processingart ultrapure plantsandclean-room systemsinthe Buender Glashasauniquetechnolog G C tch totheskin. EL ONTRACT ge andirrita t y M least withtheEuropean, emplo www.avevadds.com. TF ATRIX ® (Read yed by in o oeifrain visit Aveva DrugDelivery For moreinformation, tion. With thesetraditionaladhesivetypes, y-to-F M Aveva andNittoDenkoisbasedupona A ANUFACTURER DHESIVE ill). F or theproductionofsterilesyringes, US, y F center inwhichsta and Ja or moreinforma T technolog is aninterna Thecompany injections. toallaspectsof relating on problemsolutions concentra BuenderGlas systems, pharmaceutical glass As aspecialistin Duesseldorf, headquartered in Gerresheimer Group a Buender GlasGmbHis panese pharmacopoeia business unitofthe ECHNOLOGY rubber- or and silicone-, primarily acrylate-, which include sensitive adhesives, traditional pressure- relied upon has technology transdermal Conventional /S y a tes primarily tion, UPPLIER leader inthe significant tional te-of-the- German contact y . T contact Emisphere For moreinformation, biological integrity. deliver athera Emisphere’s makesitpossibletoorally eligentechnology levels. pharmacological activitythemselves a noknown have agents Thedelivery desired pharmacologicaleffect. molecules toexerttheir thetherapeutic allowing gastrointestinal tract, suchasthose ofthe macromolecules acrossbiologicalmembranes, a competitive developmentandproductioncosts. drug deliver reliability type ofmedicineandprovidescontrolledreleasewithprecision unique injection-mouldingtechnique, eroded bybod pharmaceuticalintoapolymericmatrix almostany tablet incorporates TheEgalet pivotalstudies. two ofwhichareenteringintolate-stage hasfourproductsinclinical Thecompany development, technologies. informa For more andmanufacturing. submissions, regulatory clinical testing, for controllingdrugdevelopmenteffortsfromproductformula C echnologies at (914) 347-2220orvisit echnologies at preferred partner for the pharmaceutical industry withitsstrategy preferred partnerforthepharmaceuticalindustry ONTROLLED tion visitEgaleta/sa M . The Parvulet technology is a novel approach forpediatric isanovelapproach TheParvulettechnology . y ACROMOLECULE peutic moleculewithoutalteringits chemical formor combining improvedconsumeracceptancewithhighly y fluids a t a R constant ra t ELEASE www .egalet.com. t can beusedforvirtuallyan te. the intendedc www The tablet, T D .emispehere.com. ECHNOLOGIES transport oftherapeutic orenable facilitate agents delivery “carriers.” or agents, delivery kno chemical compounds, synthetic proprietary, based ontheuseof is eligen technology, pla deliver based oraldrug Technologies’ broad- Emisphere ELIVERY Egalet aimstobecome tform, known asthe known tform, wn asEMISPHERE and Parvulet Egalet delivery drug proprietary products usingits controlled-release development oforal and formulation focusing on company delivery Egalet a/sisadrug y made byasimple, linical dose technolog These tion to ® y ® y

61 Drug Delivery Technology July/August 2006 Vol 6 No 7

COLON-SPECIFIC DELIVERY Oral Colon-Specific Drug Delivery: An Overview

By: Girish N. Patel, MPharm; Gayatri C. Patel, MPharm; Ritesh B. Patel, MPharm student; Sanjay S. Patel, MPharm student; Jayavadan K. Patel, PhD; Praful D. Bharadia, PhD; and Madhabhai M. Patel, PhD

INTRODUCTION Oral administration has been the most convenient that protein drugs can be absorbed better from the and commonly used method for drug delivery. For large bowel owing to hypothetic reduced proteolytic novel controlled drug-release systems, the oral route activity in this organ; and (f) the unique metabolic of administration has received the most attention. activity of the colon, which makes it an attractive Many protein and peptide drugs like insulin cannot be organ for drug delivery systems designers.1-4 administered through the oral route because of their Colonic drug delivery can be achieved by oral or degradation by the digestive enzymes of the stomach by rectal administration. With regard to the rectal and the small intestine. route, the drugs do not always reach the specific sites Colon- specific drug delivery systems offer several of the colonic diseases and the sites of colonic potential therapeutic advantages. Medical rationales absorption.5,6 To reach the colon and to be able to for the development of orally administered colonic specifically deliver and absorb the drug there, the drug platforms include: (a) the opportunity to reduce dosage form must be formulated tacking into account adverse effects in the treatment of colonic diseases the obstacles of the gastrointestinal tract. The various (eg, ulcerative colitis, colorectal cancer, Chorn’s strategies developed to achieve this goal have used diseases, and amoebiasis) by topical application of the specific characteristics of this organ, ie, pH, drugs, active at the mucosal level; (b) the elucidation microflora, enzymes, reducing medium, and transit of the mode of action of some nonsteroidal anti- time. Neverthless, these parameters can vary from one inflammatory drugs (NSAIDs), such as sulindac individual to the next, and also according to (metabolized in the colon to the active moiety, pathological conditions and diet. sulindac sulfide) that were found to interfere with the Various pharmaceutical approaches that can be proliferation of colon polyps (first stage in colon exploited for the development of colon-targeted drug carcinoma), possibly in a local manner; (c) the delivery systems include the use of prodrugs, pH- recognition that in some cases, the colon is capable of sensitive polymers, bacterial degradable polymers, absorbing drugs efficiently; (d) accumulated evidence hydrogel and matrices, and multicoating time- that drug absorption enhancement works better in the dependent delivery systems. colon than in the small intestine; (e) the anticipation 7 o N

6 xenobiotics in the alimentary canal. The direct prodrugs for topical treatment of

l EVOLUTION OF o V COLON-SPECIFIC predominance of this comprehensive inflammation processes confined to its 6

0 DELIVERY TECHNOLOGY research has led to improvements in the epithelium. Nonetheless, colonic delivery is 0 2

t design of drug products aimed at far from fully exploited as it still awaits s

u Ongoing research in the area of oral g performing in the lumen of the small bowel. appropriate medical targets and u

A delivery of drugs, a discipline that has / The large bowel, however, because of its physiologically driven rational drug y l

u basked in the spotlight of pharmaceutical J remoteness, different physiology, and delivery designs. Smart engineering might

y sciences for the past 70 years, has led to

g relatively poor absorption capacity acquired not be sufficient, and new creative o l

o improved and profound insights into the

n the status of an outcast. The advent of slow- approaches are most probably needed. For h

c physiology, biology, and physical chemistry e

T release technologies increases the chances example, it is improbable that a single y

r (pharmacokinetics, partitioning

e for a drug to be released in the colon and dosage form, taken orally, will be able to v i l phenomenon) of organs, compartments, e thus this organ has an important role to play make the long road to the large bowel and D

g cells, membranes, cellular organelles, and u

r in drug absorption from oral sustained- allow precise regional treatment or cellular D functional proteins (eg, transporters) release formulations. Its unique luminal targeting within the colon. associated with absorption processes of 62 metabolic activity makes it possible to In 1942, Svartz discovered that COLON-SPECIFIC DELIVERY

Sulfasalazine, the sulfanilamide prodrug of 5-aminosalicylic acid (5-ASA) (Figure TABLE 1 1) is effective in the treatment of rheumatoid arthritis and anti-inflammatory Region of GI Tract Characteristics disease.7 The exact mode by which the Length (cm) drug targets itself to the colon was Entire GI Tract ...... 500-700 elucidated much later in 1970: colon- Small Intestine specific azoreduction splits sulfasalazine -Duodenum ...... 20-30 causing the release of the active moiety, 5- -Jejunum ...... 150-250 8 ASA, in a local manner. Once this was -Ileum ...... 200-350 understood, several other azo-bond- Large Intestine containing compounds, designed to locally -Cecum ...... 6-7 release 5-ASA, were synthesized: -Ascending colon ...... 20 bensalazine (Intestinol 1), balsalazide, and -Transverse colon ...... 45 the newer prodrug olsalazine (Dipentum -Descending colon ...... 30 1), which spares the superfluous systemic -Sigmoid colon ...... 40 9 appearance of the carrier molecule. -Rectum ...... 12 An exciting study, which was -Anal canal ...... 3 published in 1986 by Saffran and co- workers, described the use of azo- Internal Diamater (cm) containing acrylic polymers for the Small Intestine ...... 3-4 delivery of protein drugs (insulin, Large Intestine ...... 6 lysine–vasopressin) to the colon. The uniqueness of this approach, which was pH tested in rats and later in dogs, was its Stomach suggestion to use a biodegradable polymer -Fasted ...... 1.5-3 not as a polymeric backbone of a -Fed ...... 2-5 particular drug but rather as a general Small Intestine platform to ferry a variety of molecules -Duodenum (fasted) ...... ≈6.1 without the need to invest in efforts to -Duodenum (fed) ...... ≈5.4 10 design a carrier for each drug separately. - Ileum ...... ≈7-8 The major concern was that the delayed Large Intestine drug release observed was a result of the 7 -Cecum & Colon ...... ≈5.5-7 o delayed polymer hydration, similar to that N -Rectum ...... 7 6 l o

occurring with enteric coated polymers, V

which already existed commercially, rather 6

Summary of anatomical and physiological features of small intestine and colon. 0 0 than a specific cleavage phenomenon. (Adapted From Reference 45) 2 t s u g u A

FACTORS TO BE /

(Table 1). Its caliber is higher near the cecum first part of the colon and leads to the right y l u AFFECTED IN THE DESIGN and gradually diminishes to the rectum, where colon or the ascending colon (just under the J

OF COLON-TARGETED y as it enlarges just above the anal canal. The liver) followed by the transverse colon, the g o l

DRUG DELIVERY SYSTEMS o colon is the upper 5 feet of the large intestine descending colon, sigmoidal colon, rectum, n h c

12 e

and mainly situated in the abdomen. The and the anal canal (Figure 2). Unlike the T y Anatomy & Physiology of Colon r colon is a cylindrical tube lined by a moist, small intestine, the colon does not have any e v i l

The large intestine extends from the e

soft pink lining called mucosa, the pathway is villi. However, because of the presence of D distal end of the ileum to the anus. The g u

called the lumen and is approximately 2 to 3 plicae semilunares, which are crescentic folds, r human large intestine is about 1.5 m long D inches in diameter.13 The cecum forms the the intestinal surface of the colon is increased 63 64 Drug Delivery Technology July/August 2006 Vol 6 No 7 of K concentrating thefecalcontent,andsecretion subject tobothinter pH in The Colon to approximately 1300cm Absor contents ofthecolonatasuitab Enterobacteriaceae. 3)Expulsionofthe Bacteroides, Eubacterium,and g 2) Creationofasuitable environment forthe w the colonthroughileocecalv high, eachday about2000mloffluidenters until e water andelectrolytes andtostorethefeces ofthe contents intofecesby theabsorption colon are:1) in thedistalcolon. The majorfunctionsofthe change, fromliquidinthececumtosemisolid of theluminalcontentcolonalso ateachsite. absorption The physical properties several respectsthatcanhave aneffect ondrug of tract hasbeenused asameansfortargeted The changeinpH alongtheg influence thepH ofthegastrointestinal fluid. variations. Diet,diseasedstate,andfoodintake rowth ofcolonicmicroorganisms, suchas COLON-SPECI D hich morethan90%ofthefluidisabsorbed. From Reference11) sulf onemolecule of Uponcolonicazoreduction, sulfapyridine (iii). Hydrolysis ofsulf the proximal anddistalcolondiffers in + The pHofthegastrointestinal tractis asalazine releasesasinglemoleculeof5-ASA. and HCO ption ofw xcretion. The consolidationoftheintestinal 3 The absor - ater andNa . 12 asalazine(i) into5-aminosalysilicacid(ii)and - and intrasubject FIGURE 1 pti 2 . 14 + v The physiology e from thelumen, astrointestinal capacity isvery le time.4) alve from (Adapted arising frombacterialfer acids chainfatty due tothepresenceofshort intothecolon inpHontheentry There isafall (Adapted FromReference 46) Drug metabolizing enzymesinthecolonthat catalyzereactions Azoreductase Sulfatase Glucuronidase Glucosidase andamidases Esterases Hydrogenase sulf N-Oxide reductase, Nitroreductase o xide reductase Enzymes ELI p intestine (Table 1). of about7.5inthedistalsmall proximal smallintestinetoapeak in thestomachthrough6.6 tract withvalue rangingfrom1.2 can beashigh8or9. pH ofthesmallintestine,which the colonisoftenlower thanthe pH-sensitive entericcoatings. to thesmallintestineby way of been exploited todeliver thedrug and smallintestinehashistorically difference between thestomach and 7.0,respectively. values ofapproximately 6.4,6.6, mid, andleftcolonhave pH delivery.colon drug H gradient inthegastrointestinal gradient VERY mentation of FIC Streptococci Clostridia, Eubacteria, aerogenes A. coli, E. Eubacteria Clostridia, mycoides B. subtilis, B. vulgaris, P. coli, E. Clostr coli E. Coli E. Lactobacilli, Clostridia, E. 17 coli, 16 The right, 17 Microorganism There isa The pHof idia, Bacteroids 17 The pH TABLE 2 Lactobacilli Bacteroides. 20% to30%ofwhich areofthegenus 400 distinctbacterialspecieshave beenfound, Over fromaprodrug). (ie, releaseofadrug andanactivebetween carrier agent aninert coatings/matrices aswell astobreakbonds colon. These enzymesareusedtodegrade microflora residinginhighnumbersthe Usually, theseenzymesarederived fromgut releaseinvarious oftheGItract. drug parts Enzymes Colonic Micr f predominantly consistsofGram-positive smallnumberofbacteriaand tract hasavery the pHtoabout5.0. amounts oflacticacid, resultinginadrop f polysaccharides. For example, lactoseis ermented byermented colonicbacteriatoproducelarge acultati Intestinal enzymesareusedtotrigger v e bacteria. and sulfamates Clea of alcoholsandphenols Clea of alcoholsandphenols Cleavage of‚ amidases ofcarbo or Cleavage ofesters and aliphaticdouble bonds Reduce carbonyl groups sulfoxides Reduce N-Oxidesand azo compounds Reductiv heterocyclic nitrocompounds Reduce aromaticand 19 The upperregion oftheGI Metabolic Reaction vage of‚ vage ofO-sulfates oflora & Their 18 The concentrationof e Catal clea b- b- vage of glucuronidases glycosidases yzed xylic acids COLON-SPECIFIC DELIVERY

bacteria in the human colon is 1011 to tripeptide analogues, FIGURE 2 1012 CFU/ml. The most important cyclosporine.23,24 A variety of anaerobic bacteria are Bacteroides, protein and peptide drugs like Bifidobacterium, Eubacterium, Peptococcus, calcitonin, interferon, interleukins, Peptostreptococcus, Ruminococcus, erythropoietin, growth hormones, Propionibacterium, and Clostridium.20 A and even insulin are being summary of the most important metabolic investigated for their systemic reactions carried out by intestinal bacteria is absorption using colon-specific 25 provided in Table 2. delivery. Inflammatory bowel disease (IBD), such as ulcerative Transit of Material in the Colon colitis and Crohn’s disease, require Gastric emptying of dosage forms is selective local delivery of the drug highly variable and depends primarily on to the colon. Sulfasalazine is the whether the subject is fed or fasted and on the most commonly prescribed properties of the dosage form, such as size medication for such diseases. The Anatomy of the Colon and density. The transit times of different other drugs used in IBD are dosage forms in the GI tract are provided in steroids, such as dexamethasone, Table 3. prednisolone, and hydrocortisone. In Colonic where the drug is attached to hydrophilic The effect of transit abnormalities has cancer, anticancer drugs like 5-flurouracil, moieties like amino acid, glucuronic acid, been examined using gamma scintigraphy. doxorubicin, and nimustine are to be glucose, galactose, cellulose, coating Transit data following oral administration of a delivered specifically to the colon. The site- materials over drug cores, etc (Table 5). radiolabelled liquid meal to UC patients specific delivery of drugs like, metronidazole, Polysaccharides are used as glucuronic during active and quiescent disease are shown medendazole, albendazole are used in the prodrugs, which are specifically degraded by in Table 4.22 Gastric half-emptying time and treatment of infectious diseases, such as Colonic-glucuronidases, and glycosidic mouth-to-cecum transit times of the amoebiasis and helmenthiasis.26-28 Because of prodrugs, which are specifically degraded by 35,36 radiolabelled meal were about the same the small extent of paracellular transplant, the Colonic glycosidases. The most widely 37 regardless of disease site or activity. Whole colon is a more selective site for drug used polysaccharide of this type is dextran. gut transit times were relatively long, ranging absorption at the small intestine. Drugs The action of bacterial glycosidase enzymes from 56 to 78 hours. Colonic transit times shown to be well absorbed include on the glycosidic bond permits the release of (estimated from the difference in mouth to glibenclamide, diclofenac, theophylline, the attached drug, then triggers its 38 cecum and whole gut transit times) ranged ibuprofen, metoprolol, and oxprenolol.29-34 pharmacological activity. The metabolism of from 50 to 70 hours. Stool weights increased azo compounds by the intestinal bacteria is significantly with active disease presumably STRATEGIES FOR COLON- one of the most extensively studied bacterial 7

metabolic processes. Both intracellular and o due to exudates from inflamed epithelium, SPECIFIC DRUG DELIVERY N

extracellular reduction has been observed. 6 increased mucus secretion, and reduction in l o reabsorption of fluid and electrolytes.22 Prodrugs Back in 1942, it was realized that V

sulphasalazine given for the treatment of 6 A prodrug is pharmacologically inactive 0 0 rheumatoid arthritis was also useful in 2 derivative of a parent drug molecule that t DRUGS SUITABLE FOR COLONIC s u

patients with IBD. Furthermore, Khan et al g

DRUG DELIVERY requires spontaneous or enzymatic u A

found that the active moiety effective in IBD / y

transformation in vivo to release the active l

Drug delivery selectively to the colon u drug. For colonic delivery of drugs, prodrugs was 5-amino-3 salicylic acid (5-ASA), and J 39 through the oral route is becoming y

sulphapyridine (SP) only acted as a carrier. g

are designed to undergo minimal absorption o l increasingly popular for the treatment of large o

The high-site specificity of prodrugs clearly n

and hydrolysis in the tracts of the upper GI h intestinal diseases and for systemic absorption c indicates the involvement of the colon for the e tract and undergo enzymatic hydrolysis in the T y of peptide and protein drugs. It is well r

prodrug to drug conversion. e

colon, thereby releasing the active drug v i l recognized that peptides and proteins are well For colonic delivery of drugs, prodrugs e moiety from the carrier. A number of other D absorbed intact from the GI tract, but the g are designed to conversion is strengthened by u linkages susceptible to bacterial hydrolysis r bioavailability is invariably extremely low, D specifically in the colon have been prepared the studies carried out on germ-free animals with exceptions, such as dipeptide and 65 66 Drug Delivery Technology July/August 2006 Vol 6 No 7 (Adapted FromReference47) T and coloniccontents. contents, b wereprodrug incubatedwithratGItract succinic acidasaspacer, andtheresultant prednisolone w de chemicall possess carboxylicandmustbe acidgroups such conditions. inhibitedunder moiety was significantly stomach andofthe proximalofthesmall part able towithstand thelower pHvalues of the used forcolontar fromgastric fluid. drug The polymers (Table 6) provide delayed releaseandprotecttheactive pol the distalileum. The coatingofpH-sensitive the siteofdigestion,andincreases to78in during digestion),smallintestine(pH6to7)at stomach (pH1to2,which increasesto4 GI tractincreasesprogressively fromthe generally acceptedview thatpHofthehuman pH-Dependent System kanam or animalspretreatedwithantibioticslike deli usefulness oftheconjugates forselective the h ransit timesofvarious dosageformsacrossthesegmentsofGItract. Dosage Form COLON-SPECI D xtran. De ymers tothetab very of glucocorticoids tothelarge intestine. ofglucocorticoids very ydrol The pH-dependentsystemsexploit the Anti-inflammator Capsules Solution ycin. Tablets Pellets y ysis of the prodrug toactiveysis oftheprodrug drug ut were rapidly incaecal degraded transfor xamethasone andmethyl These studiesha ere attachedtodextran using 40,41 geting, ho med inordertoreactwith lets, capsules,orpellets 42,43 y This illustratesthe glucocorticoids donot glucocorticoids Stomach w v ever, shouldbe e . 0.07 0.3 ± . 1.2 0.8 ± 1.3 1.2 ± 1.5 2.7 ± sho wn that TABLE 3 rni ie (h) Transit Time (Eudragits), w Widely usedpolymers resins aremethacrylic 1:1, 2:3,1:4,1:5,and0:1. combinations (w/w)studiedwere 1:0,4:1,3:2, Eudragit S. different combinationsofEudragitLand lactose placebotablets were coatedusing groups dissolve andatalower muchfaster groups pH phthalicacid polymers withnonesterified le media, and3)thecoating of thedisintegration combination usedtocoatthetablets, 2)thepH tab rateofthe demonstrate thatdisintegration data obtainedfromtheplacebotablets and naproxane. c prednisolone, quinolones,salsalazine, resinshavemethacrylic beenusedforinsulin, tar the smallbowel andlarge Colon- intestine. above andisusedtodeliver totheendof drugs pol pH 6orabo meth and Sarecopolymers acidand ofmethacrylic solub ileum andpreferab neutral ofslightl intestine andalsobeable atthe todisintegrate yclosporine, beclomethasonedipropionate, ml netn Total Small Intestine v geted drug deliverygeted drug systems based on el ofthetab lets isdependenton1)thepol ymer, while EudragitSissoluble atpH7or yl methacr In a study performed byIn astudyperformed Khanetal, le andwater-insoluble EudragitL forms. . 0.57 4.1 ± . 0.8 3.2 ± 1.0 3.4 ± 0.4 3.1 ± ELI 59 v The EudragitL-EudragitS e hich area lets. Ithasbeenshown that and isusedasanentericcoating 48-58 ylate. EudragitLissolub y alkaline pHoftheter l y at theileocecaljunction. v VERY ailab The disinte FIC le inw ymer 4.4 4.0 4.6 5.8 ater g ration minal - le at pellets coatedwiththew release.Comparedto5-ASA strength triggerdrug taurocholate andlecithin)norchangesinionic exhibited an dosage for the treatmentofulcerative colitis, themulti-unit marketedS, andtocurrently productslicensed for sho proximalfasting smallintestinefluid, itwas In abiorelevant medium,which simulatesthe pol colon obser oftheileumand appropriate tothe pHprofile scintigraphic studies. scintigraphic with humanvolunteers usinginvivo specif effectiveness ofthisproductasacolon- compared withtheoriginalpolymer. The to dissolve inwater ataslightly higherpH ulcerati containing5-ASAforthetreatmentof form Markus etalde andtenthhour.of theratbetween thefifth system was inthecolon foundtoreleasedrug inner la period. predetermined The thicknessofthe retarding agenttodelay releasefora drug Hydroxypropyl methylcellulose, actedasa above 5. The innerlayer, madeupof an entericcoating,dissolved atapHlevel partially methylated. the freecarboxylicofEudragit-Swere groups polymeric layers. developed consistingofacorewithtwo and co-workers, was anoraldosageform w 7.2, dr rapidly atpHvalues above 7.5.Between 6.8and studies, itw to theileocaecalv releaseclose drug 30D) toachieve site-specific and thencoatedwithane by andspheronizationprocess agranulation the dissolutionrate. the saltsindissolutionmediuminfluence The presenceofplasticizerandthenature t han those with acrylic or methacrylic groups. ormethacrylic han thosewithacrylic hile atpH6.5andbelo y(meth)acr wn thatneithersurf In arecentstudyby Peeters andKinget, ic coatingmaterialhadbeenestablished ug releasewas foundtobezero-order, v y e er determined thelagtime. er determined This m colitis. v as concludedthatpelletsreleased in vitro ed inulcerati coated withthene ylate copol veloped amulti-unitdosage 64 6 alve. From thedissolution 3 P The outerlayer, which was dissolution profile more dissolution profile 60 ellets w 6 6 1 actants (sodium 2 The productwas found In astudyby Gazzaniga ell-estab w ve colitis patients. ymer (EudragitFS w , no releaseoccur ere prepared pH-sensiti w lished Eudragit pol ymer ve red. COLON-SPECIFIC DELIVERY

TABLE 4 Total Colitis (n=6) Distal Colitis (n=8)

Active Quiescent p Active Quiescent p Half-time for gastric 46 ± 22b 41 ± 6 N.S.c 51 ± 23 78 ± 33 <0.005 emptying (min) Mouth-to-cecum 298 ± 62 310 ± 60 N.S. 313 ± 87 78 ± 33 N.S. transit (min) Whole gut 64 ± 22 56 ±29 N.S. 68 ± 49 293 ± 82 N.S. transit (h) Mean daily stool 253 ± 72 159 ± 62 <0.02 192 ± 99 144 ± 79 <0.005 weight (g) Mean daily stool 4.1 ± 1.0 1.9 ± 1.0 <0.002 3.0 ± 0.8 1.2 ± 0.7 <0.001 frequency

a From Reference 22; b Data Are Means F.S.D.; c N.S.= Not Significant

Time-Dependent Systems the hydrogel plug, it is possible to achieve complex microflora, especially the colon that Time-dependent dosage forms are drug release after varying lag times. is rich in microorganisms that are involved in formulated to release their drug load after a A pulsed system, called the Time-Clock the process of reduction of dietary predetermined lag time. While not a site- System, has been developed. The system components or other materials. Drugs that are specific drug delivery system per se, it has comprises a solid dosage form coated with a coated with the polymers, which are showing been suggested that colonic targeting can be hydrophobic surfactant layer to which a degradability due to the influence of colonic achieved by incorporating a lag time into the water-soluble polymer is attached to improve microorganisms, can be exploited in formulation equivalent to the mouth-to-colon adhesion to the core.67 The thickness of the designing drugs for colon targeting. These transit time. A nominal lag time of 5 hours is outer layer determines the time required to bacterial-degradable polymers, especially azo usually considered sufficient, since small disperse in an aqueous environment. After the polymers, have been explored in order to dispersion of the outer layer, the core release an orally administered drug in the 7 intestinal transit has been considered o N

relatively constant at 3 to 4 hours. A number becomes available for dispersion. An colon. Actually, upon passage of the dosage 6 l o of systems have been developed based on this advantage is that common pharmaceutical form through the GI tract, it remains intact in V

excipients can be used to manufacture the the stomach and small intestine where very 6 principle, with one of the earliest being the 0 0 somewhat complex Pulsincap device (Figure system. Studies performed in human little microbially degradable activity is present 2 t s

66 volunteers showed that the lag time was not that is quite insufficient for cleavage of the u 3). This device consists of a non- g u A disintegrating half capsule shell sealed at the affected by gastric residence time. Also, the polymer coating. / y l u open end with a hydrogel plug. The plug dispersion of the hydrophobic film was not Chavan et al synthesised a urethane- J

influenced either by the presence of intestinal based analogue containing an azo aromatic y hydrates on contact with gastrointestinal fluid, g o l

digestive enzymes or by the mechanical linkage in the backbone for use in colon- o and swells to an extent that it is expelled from n h c

action of the stomach. specific delivery systems by reacting toluene- e

the capsule body, thus releasing the drug. T y 2, 6-diisocyanate with a mixture of an r Usually, the time it takes the hydrogel plug to e v i l hydrate and eject from the capsule shell Microflora-Activated Systems aromatic azo diol, (bis-4-hydroxyphenyl)-4, e D g defined the lag time prior to drug release, and The bioenvironment inside the human 4'-diazobiphenyl, poly (ethylene glycol) and u r hence, by altering the composition and size of GI tract is characterized by the presence of 1, 2-propanediol (propylene glycol).68 The D 67 68 Drug Delivery Technology July/August 2006 Vol 6 No 7 an impermeablepolymer. encapsulated inagelatincapsule coated with coworkers inwhich insulinorvasopressin was by azoreductase. offilms degradation lactobacillus culture. The resultsindicated was usingmediainoculatedwith performed susceptibility ofazobondtobacterialenzymes testtodemonstratethe bacterial-degradation inthestructure. crystallinity An andhad properties, lacked film-forming compounds exhibited low molecularweight, attributable which tovariability inabsorption, intestine. Ho inthestomachandsmall degradation based ondivinylazobenzene, was resistantto b y umr fclnseii rgdlvr taeis (AdaptedFromReference44) strategies. ofcolon-specificdrugdelivery Summary COLON-SPECI D Design Strategy using azofunctionalcross-linking agents pH-Dependent A Dependent Micr Activated system was developed by Saffran and Prodrugs Systems Systems Systems Time- oflora- wever, problems were encountered 69 The coat,prepared system viaf upper GItr ing timefactor systeminthecolonby incorporat- ing thedelivery releaseisalignedwithposition- The onsetofdrug andglucuronidase. glycosidase, ductase, from colonbacteria.Typical enzymesincludeazore- viareductionandhydrolysis by enzymes carrier and Cleavage ofthelinkagebondbetween drug Pr r r the GItract. ubility totak withpH-dependentsol- Combination ofpolymers ides ha polysaccha- ides by colonanaerobic bacteria.The rgRlaeTigrn Mechanisms Drug-Release Triggering imar in vitro il y v e f er been incor act. ilm-coating andmatr mentation ofnon-starchpolysaccha- e , advantage ofthepHchangesalong sim ulating thesystemtr layer ofHydroxypropyl methylcellulose and locustbeangum. guar gum,inulin,amylose, sodium alginate, chondroitin sulphate,c systems, suchaschitosan,pectin, carrier drug studied fortheirpotentialascolon-specific number ofpolysaccharides have alreadybeen therefore generally regarded assafe. A large constituents ofthehumandietandare orare formulations used asexcipients indrug the colon.Many ofthesepolymers arealready substrate forthebacterialenzymespresentin coating thatmay notbehydrophilic enough. differences ofthe inmicrobialdegradation may bebecauseofintra-andintersubject por ated intothedeliv Chitosan capsules entericcoatedwitha Polysaccharides offer analternative ELI ix TABLE 5 f ormation. ansit inthe yclodextrin, dextrans, VERY er y FIC treatment ofIBD. toactives relatedtothe constricted primarily thisapproachhasbeen Sofar, chemical entity. itwillbeconsideredasanew However, isable toachieve sitespecificity.Prodrug 12 hrs for completedegradation. 12 hrs over usually requiring isaslow process, matrix enzymatic degr in thecolon. canonly bedegraded starch polysaccharides This str in predictingtheaccur retention timesmak ofgastric highvariation consistent, are rather times insmallintestine Even thoughthetransit because ofinter/intr release Unpredictable sitespecificity ofdrug and thecolon. similar ity ofpHbetw ategy ishighl 4 from thecapsules20to100% inthenext CF fluid increasedthereleaserateofdrug; of ratcecalcontents(33%)inthedissolution intestinal juice(next thepresence 4hours), but hours (transittimeinstomach)andartificial little releaseinsimulatedgastric juicefor2 dye, 5-(6)-carboxyfluorescein (CF)showed showed thatthecapsulesloadedwithasoluble dissolved underacidiccondition. its contents,and chitosan ma cecal contentsmay have decreasedthepHof alternatively, inthe thebacterialfermentation enzymes forthede the ratcecalcontentmay have produced colon delivery ofdrugs. (HPMC) phthalatehave beenevaluated for It shouldbepointedoutthat hours. This suggeststhattheflorapresentin adation ofapol Comments y es thisapproachcomplicated a een smallintestine promising becausenon- ate locationofdr subject var gradation ofchitosanor gradation ysaccharide ysaccharide iation and 70 In vitro y ug release have easily studies . COLON-SPECIFIC DELIVERY

technique using starch paste as a binder. The TABLE 6 tablets were evaluated for drug content uniformity and were subjected to in vitro Threshold drug-release studies. The results of the study Polymers pH revealed that matrix tablets containing either Eudragit® L 100 6.0 20% or 30% of guar gum are most likely to provide targeting of mebendazole for local Eudragit® S 100 7.0 action in the colon. Amylose-Ethocel coating systems, resistant Eudragit® L-30D 5.6 to gastric acid and small intestinal enzymes, but degradable by colonic bacteria, were prepared Eudragit® FS 30D 6.8 and evaluated in vitro for their potential as a colon drug carrier. Varying concentrations of Eudragit® L 100-55 5.5 Amylose and Ethocel in the form of aqueous dispersions were used to coat 5-ASA pellets. A Polyvinyl Acetate Phthalate 5 coating formulation comprising Amylose and Ethocel in the ratio of 1:4 w/w showed optimum Hydroxypropyl Methylcellulose Phthalate 4.5- 4.8 drug-release-retarding properties in gastric and intestinal fluids.79,80 Hydroxypropyl Methylcellulose Phthalate 50 5.2 IN VITRO EVALUATION OF Hydroxypropyl Methylcellulose Phthalate 55 5.4 COLON-SPECIFIC DRUG DELIVERY SYSTEMS Cellulose Acetate Phthalate 4.8 A successful colon-specific drug delivery system is one that remains intact in Cellulose Acetate Trimellate 5.0 the physiological environment of stomach and small intestine, but releases the drug in the Threshold pH of commonly used polymers. (Adapted From Reference 48) colon. Different in vitro methods are used to evaluate the colonic drug delivery systems. The ability of the coats/carriers to Macleod et al have studied the synthesized, and aqueous solutions of potential of pectin:chitosan:Hydroxypropyl Methacrylated inulin upon free radical methylcellulose films for colonic drug polymerization were converted to cross-linked FIGURE 3 delivery.71 The results showed that in all cases, hydrogels.74 These hydrogels were then 75,76 7 the tablets were able to pass through the studied for their swelling properties. o N stomach and small intestine intact. The tablets Degradation studies carried out in the 6 l o started to break up once they were in the presence of inulinase showed that increasing V 6

colon, as a result of degradation of the enzyme concentration and incubation time 0 0 2

coating by colonic bacteria. degraded inulin faster. t s u

Cross-linked chondroitin sulphate Alginate beads coated with dextran g u A /

was used to form a matrix tablet with acetate were prepared. These beads showed y l

72,73 u indomethacin. Release of indomethacin minimal drug release in the absence of J y from this tablet was studied in the presence of dextranase, but significant drug release was g o l

77 o rat cecal contents as compared to the release seen in presence of dextranases in vitro. n h c e

in phosphate buffer saline. A significant Compression-coated tablets of 5-ASA T y r difference in drug release was observed after and matrix tablets of mebendazole have been e v i 78 l e

14 hours in the two dissolution media. prepared using guar gum as a carrier. Matrix D

® g Schematic Representation of Pulsincap System u A series of studies were carried out on tablets containing various proportions of guar r D chicory inulin.74 Methacrylated inulin was gum were prepared using a wet granulation (Adapted From Reference 66) 69 70 Drug Delivery Technology July/August 2006 Vol 6 No 7 estimated tof set-up ofdissolution apparatusIII(ie, incubation ofthedr contents. de the presenceofeitherenzymes(eg, pectinase, colonic for system toreleasethedr the periodoftesting. The abilityofthedelivery w pectin w flo evaluation. Another in vitro method different actives basket anddosageforms: are recommendedintheUSPtoaccommodate apparatus. Currently, fourdissolutionapparatus apparatus orflow throughdissolution time) usingaUSPdissolutionratetest buffer for3hours(meansmall intestinal transit time) andinpH7.4Sorensen’s phosphate 0.1N HClfor2hours(meangastric-emptying assessed by studiesin conductingdrug-release of thestomachandsmallintestineisgenerally remain intactinthephysiological environment provides thebestconditionsfor obtained after7da medium withratcaecalcontents(4%w/v) delivery,specific established thatabuffer forcolon- usefulness ofguargumasacarrier understudy.carrier dif assess (reciprocating c human colonbacteria. because itin This methodisconsideredmorespecif released atdif anaerobic conditionsandtheamountofdr Bacteroide o colonic bacterialik withcommonlyfermentor foundhuman COLON-SPECI D as found that drug wasas foundthatdrug notreleasedduring xtranase) orrat/guineapig/rabbitcaecal w-through cellmethod. ferent timeinter Tablets covered withcompressioncoatsof Rama Prasadetal,w USP Dissolution in vitr , by incubatingitinabuffer mediumin ere e paddle method 81-85 mulations. The amount of drug releasedat The amountofdrug volves theuseofcommonly found v o v atus inasuitab ind outthede ferent timeinter aluated b the perfor ylinder) was employed to ys ofenzymeinduction v e ug deli als duringtheincubationis in vitro Streptococcus f 86 Apparatus III , Because oftheunique y ug inthecolonistested mance ofguar Bio-Dis method this method hile reporting the hile reporting very systemina very g method involves le mediumunder radation ofthe v als isfoundout. in vitro aecium or , and it -based ic , and ug coming y 5. Hardy JG,LeeSW, Clark AG, Reynolds JR.Enemavolume andspread- 4. 3. Haupt S,Rubinstein A. The colonasapossible target fororally adminis- 2. Fetih G.Improvement enhancingeffects ofn-dodecyl-beta- of absorption 1. notsulindacsulfone,inhibitscolorec- but Williams CS.Sulindacsulfides, for administration. Itisprobab molecules canbeabsorbedafteroral outtowhat extent these conducted tofind safety. A lotofresearch remainstobe gum, etc,aremoref natural polymers, suchasdextran, pectin,guar testedtodate,the carriers colon-specific systems willgive site-specificity. true Ofthe are only encounteredinthecolon,sincesuch systems arethosethatrely onconditionsthat delivery suitable. colon-specific The preferred based uponpH-dependentpol pH makes theapproach ofdelivery systems lar delivery drug systems. The colon-specific outonthedevelopmenthas beencarried of guar gum. galactomannanase thatcouldhydrolyze the colonic fluidduetothepresenceof that dr gastric andintestinalfluids,resultsshowed releaseinsimulated compared withdrug galactomannanase. As expected, when simulated colonicfluidscontaining 1.2), simulatedintestinalfluid(pH7.5),and Apparatus IIIinsimulatedgastric fluid(pH guar-based using colonicformulations successively. Wong etalevaluated several release canbeevaluated indifferent medium move alongsuccessive rows ofvessels), drug the dissolutiontubescanbeprogrammed to ing. IntJPhar microorganisms. Rev. Pharmacol 1973;25:451-523. Scheline RR.Metabolismof foreigncompoundsby gastrointestinal 2002;19:499-545. tered peptidesandproteins.CritRev Syst. Carrier Ther Drug Int JPhar deliveryD- maltopyranoside usingchitosancapsules. by itscolon-specific tal cancerg ge inter mulations willreachthemark A ug releasew considerab m. 2005;293:127-135. rowth. Neoplasia.1999;1:170-176. ears. - ELI m. 1986;35:85-90. and intrasubjectv REFERENCES SUMMARY le amountofresearchw as acceleratedinthe a vorable withrespectto VERY le thatsuch FIC ariation intheGI ymers less et inthe ork 6 1 approachestocolon-targeted 11. ChourasiaMK,JainSK.Pharmaceutical 1 9. Bartalsky A. Salicylazobenzoic acidinulcerative colitis.Lancet. 7. Svartz II,somenotesonthe discovery N. part Sulfasalazine anddevelop- 1 1 1 8 18. 17. Evans DF, Pye G,Bramley R,Clark AG, Dyson TJ, HardcastleJD. 1 25. Mackay M, Tomlinson E.Colonicdelivery oftherapeuticpeptidesand 24. Reynolds JEF, ed.Martindale: 31st ed. The ExtraPharmacopoeia, 23. SmithPL, Wall DA, GochocoCH, Wilson G.Routesofdelivery: case 22. RaoSSC,ReadNW, C,Brown Bruce C,Holdsworth CD. Studiesonthe Ency21. Lee of Delivery: OralColon-Specific. VHL, MukherjeeSK.Drug 2 1 32. 31. Staib AH, Loew D, R.Measurementoftheo- HarderS,GraulEH,Pfab 30. GleiterCH, Antonin KH,BieckP, GodbillonJ, Schonleber W. 29. BrockmeierHG,GrigoleitLeonhardtH. ofgliben- Absorption 28. JainSK,RaiGopal,SarafDK, Agraval GP. The preparationandevalua- 27. Krishnaiah YSR, Veer RP, DineshKB, BhaskarRPR,Styanarayana V. 26. Krishnaiah YSR, BhaskarReddyPR,Styanarayana V, Karthikeyan RS. 34. Antonin KH, BieckPP, ScheurlenM,Jedrychowski M,Malchow H. 33. . 2. Macfarlane GT,2. Macfarlane CummingsJH. and The colonicflora,fermentation, 0. Saffran M. A new approachtotheoraladministrationofinsulinand 5. 4. Mrsny RJ. delivery.The colonasasitefordrug JControlledRelease. delivery systems.IndJPharm drug 3. SarasijaS,Hota A. Colon-specific . 6. 0. Krishnaiah delivery drug systems. YSR, Styanarayana S.Colon-specific 9. Wood E, Wilson CG,Harday JG. The spreadingoffoamandsolutionene- m 1982;1:960. l m Peppercorn MA,GoldmanP. The roleofintestinalbacteriainthemetabo- ism ofsalicylazosulfapyridine. Exp JPharmacol Ther. 1972;181:555-562. T T W l dr Science.1986;233:1081-1084. other peptidedrugs. Binders HJ 1992;22: 15-34. Sci. 2002;62(1):1-8. D S subjects. Gut.1988;29:1035-1041. M t Rhodes J. ofdelayed-releaseAbsorption prednisoloneinulcerative coli- Gastroenterol. 1987;93:449-455. indistalcolonofthe rat. troneutral sodiumchlorideabsorption Ne proteins. In:BieckP, ed.ColonicDrug andMetabolism. Absorption London, England:Royal Society;1996:2739. Pharmaceutical Rev. 1992;8:253. studied: (5)oralabsor 1987;93: 934-940. mechanism ofbo Phar Delhi, India:CBSPublishers andDistributors;2000;89-119. I Sci. 2002;62(1):1-8. delivery systems.IndJPharm drug Sarasija S,Hota A. Colon-specific 1988;60:476. cous polysaccharides andstooloutputinhumanbeings.BritJNutr. the colon.BriJClinPhar fromthegastrointestinal-tract ofman3metoprololin absorption drug 1986;30(6):691-697. deliveryusing aremotecontrolleddrug device. EurJClinPharmacol. ph teers. GastrointestEndosc.1985;31:71-73. Colonoscopy intheinvestigation inhealthy absorption volun- ofdrug 1985;29:193-197. Pharmac. clamide fromdif 2004;12:66-71. tion ofalbendazolemicrospheresforcolonicdeli 2002;236:43-55. for metronidazoleinthetreatmentofamoebiasis.IntJPhar Studies onthedevelopment delivery oforalcolon-targeted drug systems Pharmac. 1985;19:137S-142S. Pharmac. ments ofthecoloncompared withthatafteroraldosing.BriJClin inmanafter singlebolusdosingintotwoOxprenolol absorption seg- Godbillon J 1991;72:79-86. data. IntJPharm. andpharmacokinetics using scintigraphic HClformulation buflomedil Lampard JF. Predictive modelingofthebehaviour ofacontrolledrelease Controlled Release.2001;77:87-95. Development delivery ofcolon-targeted drug systemformebendazole.J arge bowel digestive function.In:SFPhillips,JHPemberton, RG as. Int J Pharm. 1985;25:191-197. as. IntJPharm. ent ofsalazopyrin. Amer JGastroenterol.1988;83:497-503. is and Crohn's disease. Int J Pharm. 1985;37:757. is andCrohn'sdisease.IntJPharm. n: JainNK,ed. Advances inControlledandNovel Delivery. Drug New o horter, eds. The Large Intenstine:Physiology, Pathophysiology and homas P isease. New York, NY: Raven Press;1991:51. ug delivery systems. J Pharm Pharmaceut Sci.2003;6(1):33-66. ug deliveryPharmaceut systems.JPharm ilson CG, easurement of gastrointestinal pH profiles in normal ambulant human ambulant innormal easurement ofgastrointestinal pHprofiles ylline absor mlin J w m. Y ork, NY T , ech. Dekk , Read NW Richards D , , F W Ev o ption fromdifferent regions ofthegastro-intestinal tract : ashingon N ster ES,BudingerME,Ha ard D, Vidon N, Duval M,Schoeller JP. Investigation of Marcel Dekker;1933:159-176. ferent sitesoftheg wel disturbanceinulcerative colitis.Gastroenterol. er Encyclopedia. 2002;871-885. . T , he relationbetw ption ofpeptidesandproteins. Advan Deliv Drug Richards A, RojersL,Evans BK,Drew MJ, mac. 1985;19:S113-S118. , Grea ves JL,KamaliF, ReesJA, Sempik AK, astrointestinal tract.EurJClin e en bacterial degradation ofvis- en bacterialdegradation yslett JE.Mechanismofelec v er y. Pharm Tech. m. - COLON-SPECIFIC DELIVERY

35. Haeberlin B, Empey L, Fedorak R, Nolen H, Friend DR. In vivo stud- 63. Pozzi F, Furlani P, Gazzaniga A, Davis SS, Wilding IR. The time-clock ies in the evaluation of glucuronide prodrug for novel therapy of ulcer- system: a new oral dosage form for fast and complete release of drug BIOGRAPHIES ative colitis. Proceedings of the International Symposium on after a predetermined lag-time. J Controlled Release. 1994;31:99-108. Controlled Release of Bioactive Materials. 1993;20:174-175. 64. Markus W, Rudolph KS, Beckert TE, Petereit H, Dressman JB. A new Mr. Girish Patel earned his 36. Friend DR, Chang GW. Drug glycosides: potential prodrug for colon- 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcera- specific drug delivery. J Med Chem. 1985;28:51-57. tive colitis. Eur J Pharm Biopharm. 2001;51:183-190. MPharm from the S.K. Patel 37. Hovgard L, Brondste H. Current application of polysaccharides in 65. Vandamme THF, Lenourry A, Charrueau C, Chaumeil JC. The use of College of Pharmaceutical colon targeting. Crit Rev Ther Drug Car Syst. 1996;13(3-4):185-223. polysaccharides to target drugs to the colon. Carbohydrate Polymer. Education and Research, 38. Ashford M, Fell JT. Targeting drug to the colon: delivery systems for 2002;48:219-231. oral administration. J Drug Target. 1994;2(3):241-257. 66. Wilding IR, Davice SS, Bakhshaee M, Stevens HNE, Sparrow RA, et Ganpatvidyanagar, Kherva, 39. Khan AKA, Piris J, Truelone SC. An experiment to determine the al. Pharm Res. 1992;9:645-657. Gujarat, India. Presently, he is active therapeutic moiety of sulphasalazine. Lancet. 1977;2:895-896. 67. Ueda S, Ibuki R, Kawamuza A, Murata S, Takahashi T, Kimuza S, working as a Lecturer in the 40. Nakamura J, Kido M, Nishida K, Sasaki H. Effect of oral pretreatment Hata T. Development of a novel drug delivery system: time-controlled with antibiotics on the hydrolysis of salicylic acid tyrosine and sali- explosion system (TES). J Drug Targeting. 1994;2:133-140. Department of Pharmaceutics cylic acid methionine prodrugs in rabbit intestinal charides by intestin- 68. Chavan MS, Sant VP, Nagarsenker MS. Azo-containing urethane ana- and Pharmaceutical Technology at S.K. Patel al microorganisms. Chem Pharm Bull. 1992d;40:2572-2576. logues for colonic drug delivery: synthesis, characterization and in college of Pharmaceutical Education and Research, 41. Haeberlin B, Empey L, Fedorak R, Nolen H, Friend DR. In vivo stud- vitro evaluation. J Pharm Pharmacol. 2001;53:895-900. ies in the evaluation of glucuronide prodrug for novel therapy of ulcer- 69. Saffran M, Kumar GS, Neckers DC, Pena J, Jones RH, Field B. Kherva, Ganpat University, India. His research ative colitis. Proceedings of the International Symposium on Biodegradable azopolymer coating for oral delivery of peptide drugs. activities focus on formulation & evaluation of Controlled Release of Bioactive Materials. 1993;20:174-175. Biochem Soc Trans. 1990;18:752-754. colon-specific drug delivery. He has presented 10 42. MacLeod AD, Friend DR, Tozer TN. Synthesis and chemical stability 70. Tozaki H, Komoike J, Tada C, Maruyama T, Terabe A, Suzuki T, of glucocorticoid-dextran ester: potential prodrug for colon-specific Yamamoto A, Muranishi S. Chitosan capsules for colon-specific drug research articles in various conferences and 3 delivery. Int J Pharm. 1993;92:105-114. delivery: improvement of insulin absorption from the rat colon. J articles published in different journals. 43. MacLeod AD, Friend DR, Tozer T. Glucocorticoid-dextran conjugates Pharm Sci. 1997;86:1016-1021. as potential prodrug for colon-specific delivery: hydrolysis in rat gas- 71. Macleod GS, Fell JT, Collett JH, Sharma HL, Smith AM. Selective trointestinal tract contents. J Pharm Sci. 1993;83:1284-1288. drug delivery to the colon using pectin: chitosan:hydroxypropyl Dr. Jayvadan Patel is currently 44. Libo Y, James SC, Joseph AF. Colon-specific drug delivery: new methylcellulose film-coated tablets. Int J Pharm. 1999;187:251-257. working as an Assistant approaches and in vitro/in vivo evaluation. Int J Pharm. 2002;235:1-15. 72. Rubinstein A, Nakar D, Sintov A. Chondroitin sulphate: a potential Professor in Pharmaceutical 45. Vandamme THF, Lenourry A, Charrueau C, Chaumeil JC. The use of biodegradable carrier for colon-specific drug delivery. Int J Pharm. polysaccharides to target drugs to the colon. Car Poly. 2002;48:219-231. 1992a;84:141-150. Technology at the S.K. Patel 46. Lee VHL, Mukherjee SK. Drug Delivery: Oral Colon-Specific. Ency 73. Rubinstein A, Nakar D, Sintov A. Colonic drug delivery: enhanced College of Pharmaceutical Pharm Tech. Dekker Encyclopedia. 2002:871-885. release of indomethacin from crosslinked chondritin matrix in rat cecal Education and Research. He 47. Chawla G, Gupta P, Koradia V, Bansal AK. Gastroretention a means to content. Pharm Res. 1992b;9:276-278. address regional variability in intestinal drug absorption. Pharm Tech. 74. Vervoort L, Van den Mooter G, Augustijins P, Busson R, Toippet S, earned his PhD in 2003;7:50-68. Kinget R. Inulin hydrogels as carriers for colonic drug targeting, part I: Pharmaceutics and 48. Touitou E, Rubinstein A. Targeted eternal delivery of insulin to rats. Int synthesis and characterization of methacrylated inulin and hydrogel J Pharm. 1986;30:95-99. formation. Pharm Res. 1997;14:1730-1737. Pharmaceutical Technology. Dr. Patel has 9 years 49. Thomos P, Richards D, Richards A. Absorption of delayed release 75. Vervoort L, Van den Mooter G, Augustijns P, Kinget R. Inulin hydro- of academic and research experience. He is prednisolone in ulcerative colitis and Chron's disease. J Pharm gels, part I: dynamic and equilibrium swelling properties. Int J Pharm. actively involved in projects on novel Pharmacol. 1985;37:757-758. 1998a;172:127-135. 50. Van Saene JJM, Van Saene HFK, Geitz JN, Tarko-Smit NJP, Lerk CF. 76. Vervoort L, Rambant P, Van den Mooter G, Augustijns P, Kinget R. formulation development and has 40 national Quinolones and colonization resistance in human volunteers. Pharm Inulin hydrogels, part II: in vitro degradation study. Int J Pharm. and international research papers publications. Weekbl Sci Ed. 1986;8:67-71. 1998b;172:137-145. 51. Azad KKA, Piris J, Truelove SC. An experiment to determine the 77. Kiyoung L, Kun N, Yueim K. Polysaccharides as a drug coating poly- active therapeutic moiety of sulphasalazine. Lancet. 1977;2:892-895. mer. Polym Prep. 1999;40:359-360. Ms. Gayatri Patel earned her 52. Bogentoft C, Eskilsson C, Jonsson UE, Lagerstorm PO, Lovgren K, 78. Krishnaiah YSR, Veer Raju P, Dinesh Kumar B, Bhaskar P, MPharm from the S.K. Patel Rosen L. Delivery of drug to the colon by means of a new microen- Satyanarayana V. Development of colon-targeted drug delivery systems College of Pharmaceutical capsulated oral dosage form. Acta Phrarm Suec. 1983;20:311-314. for mebendazole. J Control Rel. 2001;77:87-95. 53. Watkinson G. Sulphasalazine: a review of 40 years experience. Drugs. 79. Milojevic S, Newton JM, Cummings JH, Gibson GR, Botham RL, Education and Research. 1986;32(1):1-11. Ring SG, Stockham M, Allwood MC. Amylose, the new perspective in Presently, she is working as a 54. Riley SA, Lecarpentier J, Mani V, Goodman MJ, Mandal BK, Turnberg oral drug delivery to the human large intestine. STP Pharm Sci. Lecturer in the Department of L. Sulphasalazine induced seminal abnormalities in ulcerative colitis: 1995;51:47-53. results of mesalazine substitute. Gut. 1987;28:1008-1012. 80. Milojevic S, Newton JM, Cummings JH, Gibson GR, Botham RL, Pharmaceutics and 55. Al MH, Lindsay DC, Deighton CM, Record CA. Effect of polymer Ring SG, Stockham M, Allwood MC. Amylose as a coating for drug Pharmaceutical Technology at coating on faecal recovery of ingested 5-aminosalicylic acid in patients delivery to the colon: preparation and in vitro evaluation using 5- S.K. Patel college of Pharmaceutical Education with ulcerative colitis. Gut. 1987;28:1084-1089. aminosalicylic acid pellets. J Control Release. 1996a;38:75-84. 7 56. Kim CK, Shin HJ, Yang SG, Kim JH, Oh Y. Once a day oral dosing 81. Ashford M, Fell JT, Attwood D, Sharma H, Woodhead PJ. An in vivo and Research, Kherva, Ganpat University, India. o N regimen of cycloscoporin A: combined therapy of cycloscoporin a pre- investigation into the suitability of pH-dependent polymers for colonic Her research activities focus on evaluation of 6

microemulsion concentrates and enteric coated solid-state premi- targeting. Int J Pharm. 1993;95:193-199. l

hydrophilic matrix tablets by using natural gum. o croemulsion concentrates. Pharm Res. 2001;18:454-459. 82. McLeod AD, Friend DR, Tozer TN. Glucocorticoid-dextran conjugates V 57. Levine DS, Raisys VA, Ainardi V. Coating of oral beclomethasone as potential prodrugs for colon specific delivery: hydrolysis in rat gas- She has 4 national and international research 6

dipropionate capsules with cellulose acetate phthalate enhances deliv- trointestinal tract contents. J Pharm Sci. 1994a;83:1284-1288. papers and 4 articles presented in various 0 0 ery of topically active anti-inflammatory drug to the terminal ileum. 83. Rubinstein A, Nakar D, Sintov A. Chondroitin sulphate: a potential conferences. 2 Gastroenterol. 1987;92:1037-1044. biodegradable carrier for colon-specific drug delivery. Int J Pharm. t s

58. Hardy JG, Evans DF, Zaki I, Clark AG, Tonnesen HH, Gamst ON. 1992a.84:141-150. u g Evaluation of an enteric coated naproxen tablet using gamma scintigra- 84. Larsen C, Harboe E, Johansen M, Olsen HP. Macromolecular prodrugs Mr. Ritesh B. Patel is u A

phy and pH monitoring. Int J Pharm. 1987;37:245-250. XVI. Colon-targeted delivery: a comparison of rate of release of / y

currently working as Lecturer l

59. Khan MZ, Prebeg Z, Kurjakovic N. A pH-dependent colon-targeted naproxen from dextran ester prodrugs in homogenates of various seg- u oral drug delivery system using methacrylic acid copolymers, part I: ments of the pig gastrointestinal tract. Pharm Res. 1989;6:995-999. in the Department of J

manipulation of drug release using Eudragit L 100-55 and Eudragit 85. Kopeckova P, Rathi R, Takada S, Rihova B, Berenson MM, Kopecek J. Pharmaceutics and y g

S100 combinations. J Controlled Release. 1999;58:215-222. Bioadhasive N-(2- Hydroxypropyl) methacrylamide copolymers for o Pharmaceutical Technology at l 60. Peeters R, Kinget R. Film-forming polymers for colonic drug delivery: colon- specific drug delivery. J Controlled Release. 1994;28:211-222. o n

synthesis and physical and chemical properties of methyl Dderivatives 86. Wong D, Larrabee S, Clifford K, Tremblay J, Driend DR. USP dissolu- the S.K. Patel college of h c e

of Eudrajit S. Int J Pharm. 1993;94:125-134. tion apparatus III (reciprocating cylinder) for screening of guar-based Pharmaceutical Education and T y

61. Peeters R. Studie over de ontwikkeling van een colon-specifieke art- colonic delivery formulations. J Controlled Release. 1997;47:173-179. r

Research. He worked on e

senijvorm. Lueven KU. Doctoral Thesis. University of Leuven. v i l

Leuven. Belgium. controlled-release dosage forms during his post- e 62. Gazzaniga A, Bussetti C, Moro L, Sangali ME, Giordano F. Time- D

graduation and continues to focus his research g

dependent oral delivery systems for colon targeting. STP Pharma u activity on the advancements in this field. r Sci.1995;5:70-76. D

71

Company Pg Phone Fax Web Site

3M Drug Delivery Systems 3 800-643-8086 www.3m.com/ddsadv

AAPS 27 www.aapspharmaceutica.com/annualmeeting

ALZA Corporation 2 www.alza.com

ASSA International 17 203-312-0682 www.assainternational.com

Baxter BioPharma Solutions 19 800-422-9837 www.baxterbiopharmasolutions.com

BD 29 800-225-3310 www.bdpharma.com

Cardinal Health 76 866-720-3148 www.cardinal.com/pts

Ciba Expert Services 4 800-242-2669 x2397 www.cibasc.com/cxs

CIMA 5 952-947-8700 www.cimalabs.com

Degussa 13 732-981-5383 www.pharma-polymers.com

Drug Delivery & Deal Making Summit 41 800-599-4950 www.srinstitute.com/cs375

Eurand 7 937-898-9669 www.eurand.com

Filtertek Inc. 37 1-800-648-0791 www.filtertek.com

Genzyme Pharmaceuticals 21 800-868-8208 www.genzymepharmaceuticals.com

Hovione 15 609-918-2600 www.hovione.com

NOF Corporation 75 914-6819790 www.nof.co.jp/dds 7 o N Scolr Pharma, Inc 9 425-373-0171 www.scolr.com 6 l o V SST 73 215-979-1506 6 0 0 2 t

s Weiler Engineering 11 847-697-4900 www.weilerengineering.com u g u A / y l u J y g o l o n h c e T y r e v i l e D g u r D

72

Time to Throw in the Towel By: John A. Bermingham

have often said that being a CEO is the best job and the when the current CEO has retired in place and didn’t tell worst job in the world. I noted in a recent CNN survey anyone. If the Board won’t do anything, then you should IIthat, of the top 50 jobs in the United States, being a look for a new job and, at the appropriate time, you throw in CEO did not make the list. Pessimistic fools or are they? the towel. It makes no sense to fight a losing fight, resulting When I was Senior Vice President of Sales and in a knock out to you. Marketing at Sony, I was always treated like one of the guys. Finally, you as an employee of your company may be The day that I became President of the Magnetic Products facing the same issues as a CEO when you have been in the Group, everything changed. I was no longer treated like one same position for too long. Burnout, boredom, complicacy, of the guys by the same people who did so before. And this etc. is killer on your performance. The solution? Throw in change was instant, not over time. This was one of the worst the towel and find a new career position that stimulates you parts of becoming a CEO. That’s why the expression, “it’s and brings your performance level up to your true potential. N lonely at the top” is very true and it can be a drag! Management styles of CEOs tend to stay the same. They B IOGRAPHY may make minor changes over time, but they do not change very much. When it comes to style, most CEOs think their John A. Bermingham joined Ampad as style never goes out of fashion. This generally causes the President and CEO in August 2003 when Ampad was acquired by group of investors work place culture to pass the CEO by, resulting in morale composed of an affiliate of Crescent Capital issues for the people. Investments, himself, and another private Being the CEO of a company can be a real grind. They investor. He also serves as Chairman of the continually face financial problems, revenue problems, company’s Board of Directors. Previously at product issues, people problems, competitive problems, the helm of numerous industry-leading companies, Mr. Board issues, yadda, yadda, yadda. It burns you out fast. Bermingham brings more than 20 years’ experience in guiding This definitely causes CEO performance issues. When you enterprises to new levels of performance. Most recently prior to work in the same company, deal with the same customers, joining Ampad, Mr. Bermingham held the positions of the same employees, the same vendors, the same products Chairman, President, and CEO of Centis, Inc., a diverse or services, the same-old-same-old, the CEO gets bored, multinational manufacturer and marketer of office, storage, and then goes stale. As a result, there are more CEO human resources products. Prior to joining Centis, Mr. performance issues. Bermingham successfully leveraged the potentials of two start- Oftentimes, when a CEO is with a company for too long, up companies, raising capital, forging key relationships, and he or she becomes complacent in their position and establishing the structure and direction that would pave the way for future growth and achievement. Among his many responsibility. This is a very dangerous situation for a career highlights in the role of President and CEO for company and its people. When a CEO begins to march in companies serving the office products industry, Mr.

7 place satisfied that all is well with the company, look out!!! Bermingham successfully reorganized Smith Corona o N The CEO’s responsibility to the shareholders or equity Corporation, restoring the company’s stability, profitability, and 6

l sponsors is to maximize the value of their investment. Thus,

o reputation. At Rolodex Corporation, he refocused operations V the CEO must always be moving the company forward. and a strategic vision for a dramatic turnaround in corporate 6 0

0 Otherwise the company, in reality, is going backward. culture, and phenomenal increases in both revenue growth and 2 t

s Mediocre-to-poor CEOs are content to mark time in cashflow. Mr. Bermingham’s expertise in leveraging technology u g

u their companies. They remain with their company for many and optimizing resources for the business products/services A /

y markets has also been deployed at industry giants, such as

l reasons: a place to go everyday; continuation of income and u J benefits; perks; the social atmosphere; ego; you name it. AT&T Consumer Products Group, and by having served as the y

g EVP of the Electronics Group and President of the Magnetic

o Great CEOs know when enough is enough and that new l

o Products Group, Sony Corporation of America. Mr. Bermingham n blood needs to be brought into the company. They bow out h c

e served three years in the U.S. Army Signal Corps with

T gracefully on their own with dignity and respect. They know y

r responsibility for Top Secret Cryptographic Codes and Top e

v when to throw in the towel. i

l Secret Nuclear Release Codes. Earning a BA in Business e D So what should happen when a CEO is no longer adding Administration from Saint Leo University in Florida, Mr. g u

r value but will not leave the company? The answer is that the

D Bermingham has also completed the Harvard University Board of Directors, if they are doing their job, should take Graduate School of Business Advanced Management Program. 74 the step to bring in a new CEO to re-energize the company