February 2007 Vol 7 No 2 IN THIS ISSUE

INTERVIEW WITH 3M DDS’ GENERAL MANAGER MR. JAMES VAUGHAN

Formulating Proteins & Peptides 18 Cindy H. Dubin

Implant Technologies 44 Daniel Ruppar

MDI Valve Technology 48 John Olley

Ocular Delivery 52 Aniruddha C. Amrite Uday B. Kompella, PhD Lecithin Organogels 60 I.M. Shaikh, MPharm K.R. Jadhav, MPharm

Underpaid CEOs 74 The science & business of specialty pharma, biotechnology, and John A. Bermingham

Mr. Derek Mr. John Stephen E. Hennecke Sullivan Zweig, PhD Xcelience: Excelling Growing Global Smart Self- & Accelerating its Market for : Partners’ Science “Combination Incorporating Products” Presents Drug Stability www.drugdeliverytech.com Regulatory Monitors Into the Challenges for Injection Device American Firms

4 Drug Delivery Technology February 2007 Vol 7 No 2 $15.00, US,Canada,andMe 01923; pho Technology LLC for librariesandotherusersregistered withtheCopywriteClearance, 222RosewoodDrive, Danvers, MA items f Periodicals Postage Paid atMontville, NJ07045-9998andadditionalmailingoffices. Postmaster: Delivery T States, Canada,andMexico. AllsubscriptionsarepayableinUSfunds, drawnonUSbanks. Sendpayment to:Drug Subscription rates:$99.00f October (ISSN 1537-2898)ispublished10timesin2007,January, February, March,April,May, June, July/August, September, responsibility f o All editorialsubmissionsarehandledwithreasonable care, butthepublishersassumenoresponsibilityfor thesafety or inf be reproducedortransmitted inanyform orbyanymeans, electronicormechanical,includingbyphotocopy, recording, the U.S.,Internationaland P address changestoDrugDeliveryT f artwork, photographs ormation storageandretrieval system,withoutwrittenpermissionfromthepublisher or internalpersonaluse , and November/DecemberbyDrugDeliveryT echnology LL ne: (978)750-8400, f or theaccuracyo East &Midwest Mailing ListRental International W C est Coast subscription Department,219ChangebridgeRoad,Montville NJ07045.Singlecopies(prepaid) , or manuscripts or 1yearintheUnitedStates 219 Changebridge Road, Montville, NJ07045 an-American CopyrightConventions xico; $24.00inallothercountries ax: (978)750-4470. f EXECUTIVE EDITORIAL DIRECTOR inf [email protected] February 2007 , 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] Vol 7No 2 . en toensureaccuracy . All rightsreserved.Nopart of thispublicationmay on C, 219ChangebridgeRoad,MontvilleNJ07045. Add $5.00perorderfor shippingandhandling. al M an ag er , but publisherscannotaccept . A uthorization tophotocopy please send

6 Drug Delivery Technology February 2007 Vol 7 No 2 pr regulatory process thatissetinplaceto gr m and Asian country thatpresents apotential regulatory environment of eachEuropean recent and upcoming changes inthe they willneed tocontinue tobeaware of m “As American companies develop new ben ark edi otect th ow m efitin etin cal devices and combination products, or g g e e opportunity from them.” sophisticated, sodoes the con sum ers wh . A s o th will be ese pr oducts p.28 22 18 44 28 therapeutic needs of patients. d Stephen E.Zweig, PhD,saysthatbecauseself-injection Device MonitorsStability Into theInjection Incorporating Self-Injection: Smart Drug macromolecules for patients. acceptable and cost-effectivedelivery of proteins and challenge toconduct further research and toachieve c and peptides isincreasing daily, and due tocertain experts who believe interest inthe delivery of proteins Contributing EditorCindy H.Dubininterviews several Proteins &Peptides of FormulationOvercoming Challenges pr compounds inatargeted manner, havethe capacityto frequency of patient-driven dosing and deliver implant technologies, withthe abilitytoreduce the Fr Delivery a Implant Technologies to Remain Expected presents apotential marketing opportunity. envir aware of recent and upcoming changes inthe regulatory combin Am J P Growing Global Market for “Combination d incorporating drug stabilitymonitors into the injection of drug injection devices canbeimproved by improper thermal conditions. The safetyand effectiveness accidentally deteriorate due toinadvertent exposure to setting, there isan increased riskthatthe drugs may for American Firms ohn Sullivanan onstraints, thisarea of research offers aninteresting evi evice. ost &SullivanIn ovi r ih u fetv ehdo Drug Niche Method of but Effective erican companies develop new medical devices and o ces ar d onm d e uc ati a ent of eachEuropean and Asian country that ts on pr differ e ” fr equen Presents Regulatory Challenges Regulatory Presents oducts, they willneed tocontinue tobe entiated waytomeet the unique d H dustry Manager Daniel Rupparsaysthat tly usedoutsi enrik Elbaek,M d e Sc, MBA, believe as of anormal clinical

48 Developments in MDI Valve Technology Ensure Better Patient Compliance John Olley describes the development of a unique MDI valve (BK361 Easifill) designed to have fast fill/fast drain characteristics that allow the metering chamber to fully refill after actuation or storage, eliminating LOP, reducing dosing variability, and helping to improve patient compliance.

52 Nanoparticles & Microparticles: Particle Engineering, Cell Uptake, In Vivo Disposition & Efficacy Aniruddha C. Amrite and Uday B. Kompella, PhD, summarize their investigations in particle engineering, biopharmaceutics, and pharmacokinetics of particulate systems, and safety and efficacy of particulate systems, primarily as they relate to ophthalmic applications.

“To overcome the aforementioned 57 3M Drug Delivery Systems: Providing Customer-Focused limitations of conventional topical and oral Drug Delivery Executive: Mr. James Vaughan, 3M Drug Delivery Systems’ General Manager, details his organization’s modes of administration for retinal delivery, new strategic direction now that it has sold one of its branded pharmaceuticals business segment. local delivery approaches are currently being investigated. The intravitreal and 60 Lecithin Organogels as a Drug Delivery System: A Review periocular routes are alternatives that can I.M. Shaikh, MPharm; K.R. Jadhav, MPharm; V.J. Kadam, PhD; and S.S. Pisal, PhD; review salient features, formation, and various deliver greater dose fraction to the retina, applications of lecithin organogels as drug delivery systems.

resulting in dose reduction and reduced 67 Xcelience: Excelling & Accelerating its systemic toxicity.” Partners’ Science Drug Delivery Executive: Derek Hennecke, Chief Executive Officer of Xcelience, talks about his company as well as its 2

o drug development and manufacturing solutions. N 7 l o V 7

0 DEPARTMENTS 0 2 y r a

u Market News & Trends ...... 11 r b e F Advanced Delivery Devices ...... 40 y g o l

o Needle-Free Injections Using a Spring-Powered Device for n h c

e Subcutaneous, Intramuscular & Intradermal Injections T y r e v i l Drug Delivery Showcase ...... 70 e D

g p.52 u r External Delivery ...... 74 D Why CEOs are Underpaid! 8 9 Drug Delivery Technology April 2006 Vol 6 No 4 10 Drug Delivery Technology February 2007 Vol 7 No 2 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 S Jack Aurora,PhD Schering-Plough Developm Delivery &LifeCycle Seni David Monteith,PhD,MBA 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 enior Director, R&D errigo Company PI Pharma evelopm dvan opharm arketing &Commercial ector o Technology D Director Executive Editorial Dan Marino,MSc ector o ector or Director, Drug rug Delivery ced DrugDelivery , aceuti f Busin ent e f nt nt Exploratory Busin ess cs & ess 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 Director Henry Y. Wu, PhD,MS Corium International President &CTO Phar Gary W. Cleary, PhD, P Investigator, Matthew D.Burke,PhD GlaxoSmithKline Ex Ravi Kiron,PhD,MBA Eur President, North America John Fraher T ALZA Corporation Planning om Tice, PhD echn harmaceutical Development 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 MediVas Announces Collaborations With PacificGMP & Pfizer acificGMP, Inc., and MediVas, LLC recently announced they have formed Using its proprietary family of biodegradable and biocompatible polymers, Pa collaborative effort to develop a commercial-scale production process MediVas has developed a next-generation platform for the delivery of for MediVas' next-generation subunit vaccine utilizing MediVas's novel amino biologics. MediVas is utilizing its novel polymer technology in collaboration acid-based Poly(Ester Amide) copolymers (PEA). MediVas' polymers are the with some of the world's largest pharmaceutical companies, as well as on its first of a new generation of absorbable and biocompatible drug and biologic own internal product development efforts, to create groundbreaking medical delivery platforms. Under this collaboration, PacificGMP will work with advancements. The more than $50-billion biologics market is the next frontier MediVas in developing the capability of manufacturing large quantities of in , and MediVas is uniquely poised to take advantage of this subunit vaccines to protect against such diseases as seasonal and pandemic growing space. By combining therapeutic proteins and other biologics with a influenza, among many other potential candidates. MediVas polymer, delivery routes that were previously unimaginable, such as PacificGMP will utilize its expertise in disposable bioprocessing and its oral, intranasal, inhaled, or , can become a reality. By unique technology to scale up the production process and manufacturing for opening up these delivery routes, MediVas' delivery system can make the MediVas' initial candidates. Use of this disposable bioprocessing technology administration of the biologic more convenient, more efficacious, and safer, will allow for faster production, with greatly reduced overall manufacturing leading to higher patient compliance and overall better health. costs. This process also mitigates the possibility for cross-contamination in PacificGMP is a Contract Manufacturing Organization (CMO) that production, which should ultimately result in vaccines that will be available to specializes in the development and manufacturing of biologics using the public in a much shorter time period. disposable technology. PacificGMP has extensive experience in process MediVas' infectious disease and immunology platforms include rapid development and production of antibodies, recombinant proteins, gene response formulations for next-generation vaccines. MediVas' lead therapy, and vaccine products. PacificGMP assists drug developers through preventative vaccine program represents a novel process to develop and the early stages of process design, development, and scale-up to pre-clinical manufacture vaccines for both seasonal and pandemic influenza. In addition, and clinical manufacturing. the company is also developing therapeutic vaccines with a lead program MediVas also announced the signing of a collaborative research agreement targeted against certain cancers. with Pfizer. The agreement is focused on the research and development of "We continue to advance our capabilities in developing important next- advanced delivery methods for proprietary Pfizer compounds to treat diseases generation biocompatible drug delivery solutions," said Kenneth Carpenter, of the eye. By combining the fully biodegradable and biocompatible MediVas President and CEO of MediVas. "We are confident in our ability to create polymers with the Pfizer compounds, MediVas and Pfizer hope to create a innovative new drug delivery technologies across multiple therapeutic areas. product that can change the paradigm of how ophthalmic treatments are PacificGMP is ideally suited to allow us to take the next step and bring our administered. Financial terms of the agreement were not disclosed. new therapeutic technology into the clinic and then into the public sphere." Commenting on the announcement, Kenneth W. Carpenter, MediVas' "PacificGMP is excited to assist MediVas with this important project. We President and CEO, said, "We are excited to enter this relationship with anticipate that production of MediVas' subunit vaccines in disposable closed Pfizer, and we are confident that by combining Pfizer's compounds with our systems will be a significant milestone in the development of rapid response best-in-class polymer delivery system we can help to increase patient formulations for next- generation vaccines. We are delighted to announce this compliance and significantly improve treatment of diseases of the eye. We collaboration and to assist MediVas in moving forward with this novel look forward to moving this collaboration ahead quickly and to entering into technology," added Leigh Pierce, President of PacificGMP. a broader relationship with Pfizer." Organon Partners With Huya to Identify & Develop Chinese Biopharmaceuticals rganon, the human healthcare business of Akzo Nobel, recently President Research and Development at Organon “We are very excited by this 2

announced it has signed a collaboration agreement with HUYA investment and the prospect of closely collaborating with HUYA.” o O N

Bioscience International, LLC, (HUYA) to search for new, proprietary Mireille Gingras, President and Chief Executive Officer of HUYA, added, 7 l o

biopharmaceuticals or pharmaceutical compounds. As part of this “We are delighted to share the Organon knowledge and harness their V collaboration, Organon has acquired an equity interest in HUYA, a extensive expertise in drug development in three specific therapeutic areas. 7 0

biopharmaceutical company focused on developing Chinese We believe this collaboration is the first one between a biopharmaceutical and 0 2

biopharmaceutical products. biotech company to jointly identify and develop investigational drugs in y r a

HUYA, with offices in San Diego and Shanghai, identifies, licenses, and China. HUYA is highly experienced and uniquely well positioned with our u r b develops Chinese drug candidates for commercialization in Western markets. large network of life science contacts and operating history in China to e F Under the collaboration agreement, HUYA will support Organon in the capitalize on the emerging biotech industry there.” y g

sourcing and development of pharmaceutical or biopharmaceutical No financial details of the transaction were disclosed. The announcement o l o compounds in three specific therapeutic areas. follows other research collaborations that Organon has entered into with other n h c

“This is an important strategic opportunity for Organon. It is consistent leading Chinese biotech companies, such as Shanghai Genomics and HD e T y with our research strategy to forge closer links with China’s highly skilled and Biosciences in the last year. r e v i motivated scientists and significantly expands our own ongoing biotech l e research programs and capabilities,” said David Nicholson, Executive Vice D g u r D

11 12 Drug Delivery Technology February 2007 Vol 7 No 2 broader therapeuticophthalmolo welllarge markets withunmetmedicalneeds. intothe fits This platform position thatwilladdress delivery withastrongintellectual property platform MA, inOctoberof2006.” milestoneforthecompanyimportant afterbeginning operationsin Waltham, banking roles. research,and direction basedonthedepthofhisexperience incorporate, fromhis Executive ofEyeGate “EyeGate Pharma. willgreatly benefit Officer Hancock totheBoardofDirectors, joining EyeGate Pharma’s BoardofDirectors. Group andbringsthetotalv to$12million. This additionalfundingcomesfrom financing The Nexus million extension ofitsSeriesBventure round, bringingthetotalof therapeutics forocularindications,recentl transaction, of thesyndicate,securedanadditional$2millioninfunding. ofthe As part tobecomepart and inkeeping theroundopenforpotentialUSventure firms originall andexistingPartenaires investor Ventech, bothofParis, France. EyeGate had E BVenture $12Million Closes Series Eyegate Pharma Financing Brookwoodlicense tocertain technologies oftheassetacquisition. aspart Brookwood delivery aUSdrug company, Pharmaceuticals, andacquireda Naltrexone Depot. begin apivotal PhaseIIItrialin2007with an improved of formulation patients receiving treatmentcomparedtothoseonplacebo.elbionintends results withatrendto is amajorlimitingfactor. adv ,which elbionbelieves willoffer significant daily tablets), Naltrexone Depotisdesigned asasimpleonce-a-month opiate andalcoholab an antagonistthatblocks receptorsinthebrainandisusedtreatmentof disclosed. were terms not considerationincludingelbionshares.Fullfinancial financial Sciencescandidateswas fora acquisition oftheDrugAbuse madeinreturn r t lead product,andthecompany expects ittoenterpivotal PhaseIIIclinical candidate, Naltrexone the French e Alcohol Dependence Acquireselbion Late-Stage Product Candidate for Treatment of rials in2007. Depot,asustained- A secondassetacquiredisBuprenorphine elease b Thomas E.Hancockadded “EyeGate ispleasedtowelcome Nexus toourinvestor and group Tom The first trancheofEyeGate’sThe first SeriesBroundwas co-ledby Innoven The company development iscollaboratingonformulation work with Previous clinicaltrialswithNaltrexone Depothave shown encouraging Naltrexone Depotisanovel, ofnaltrexone, sustained-releaseformulation ofnaltrexone, willbecomeelbion’sDepot, asustained-releaseformulation biotechnology companySciences. DrugAbuse The mostadvanced recently announcedithasacquiredanumberofproductcandidatesfrom lbion NV, discovery aleadingEuropeandrug anddevelopment company, antages inthetreatmentofalcoholismwhere patienttreatmentcompliance of iontophoresistechnology tosafely andnon-invasively deliver companyyeGate aspecialtypharmaceutical pioneeringtheuse Pharma, y uprenorphine indicatedforthetreatmentofopiateaddiction. uprenorphine The announced ithadplannedtosecurefundingforup$10million Thomas E.Hancock,Principalof Adding aprominentUSin use. Unlik ward levels greater ofabstinencefromalcoholfor enture in , “Ey e gy spaceandhasthepotentialtodeli conventional (ie, naltrexone dosageforms eGate has built animpressiveeGate hasbuilt ocular ” said StephenF v estment inEy v y so fNxs caliberisan estor ofNexus’ announced ithasclosedona$2 The Ne rom, PresidentandChief eGate to$16million. xus Group,willbe ver a compan forpartnering. Weopportunities aredelightedtobeworking withthe pipeline ofcommercially attractive compounds.Italsoprovides significant W mark said, “Brookwood strongly Pharmaceuticals believes inthetechnicaland through theirholdingsinelbion. the producttoberealizedandbringvalueSciencesinvestors toDrugAbuse system canbeappliedtosafel was designedby ophthalmologists forophthalmologists. This non-invasive transscleral iontophoresisdeliverytheEyeGate IIDelivery platform, System, needed safeandnon-in area.” de alcohol andopiateab and commercializationofNaltre forw are enthusedtobeworking withsuchadynamicorganization. We look begin 2H2007. Clinical studiesutilizingtheEyeGate IIDelivery Systemarescheduledto patients suf less than5minutesandhasbeenshown tobeextremely well tolerated in increaseinvisualacuity.markers andaconcurrent A typicalapplicationtakes e using thecompany’s delivery device demonstrated first-generation the anteriorandposteriorchambersofeye. An 89-patientpilotstudy Bascom P the EyeGate IIDelivery System,intotheclinicinsecondhalfof2007.” Phar back oftheeye. This additionalfundingwillhelptoaccelerate EyeGate deliverydrops fordrug withhigherlocalizedconcentrationtothefrontand clinical e Langlois, Chair future ofwhat we believe highvalue isavery product,” addedPatrick Sciencesisgoodnewsprogram andotherassetsfromDrugAbuse forthe and throughlicenseesinothers.” Depot throughourown territories salesandmarketing operationsincertain improved oftheproduct,andthentocommercializeNaltrexone formulation treatment. We intendtoinitiateawell-designed PhaseIIIprogram withan believe thatNaltrexone Depothasthepotentialtoplay amajorroleintheir profound effect onthelives of millionsofpeoplearoundtheworld, andwe value drivercan beasignificant forelbion. Alcohol dependencehasa advanced clinicalproducttoaddourpipelineandonewhich we believe Brookwood willsupply theproductfortrials. xceptional patienttolerancewithasignif e v Ar Mr. From continued, “TheEyeGate IIDelivery Systemrepresentsamuch Buprenorphine depotisinpreclinicaldevelopment.Buprenorphine elbionintends to EyeGate was Pharma foundedin1998withtechnology licensedfrom “The announcementofelbion'sacquisitiontheNaltrexone Depot Kastler,Bernd CEOofelbion,said, bringsusanother “Thisagreement elop theproductfortreatmentofopiateaddiction. ha ma’ ard toacceleratingmark et potentialofthelong-actingnaltre thur J v e y s xper developed apositive relationshipwiththeseniorteamatelbionand and theotherinvestors aleadingcompany tobuild inthisexciting clinical candidateforse almer Ey . fering fromse T tise andtheplans ipton, PhD, PresidentandCEO, Brookwood Pharmaceuticals, man of DrugAbuse Sciences.“Weman ofDrugAbuse elbion's areconfident e Institute attheUni use. v asi ” vere oculardiseases. uveitis andotherinflammatory v e alternative toocularinjections,implants,oreye y et impor deli ” xone Depotwillallo vere uveitis, which willbedelivered using y v ha er awiderangeoftherapeuticstoboth v versity ofMiami.EyeGate’s tant productsforthetreatmentof e xone underde put inplaceforthede icant decreaseininflammator w v the fullpotentialof elopment atelbion. v elopment y

14 Drug Delivery Technology February 2007 Vol 7 No 2 Of for skinandnailfungal infectionsandotherindications. atconcentrationshigherthanpresently oftopical drugs availableformulation limited solubility, eg, itraconazole. This technology willbeusedforthe thathave ofdrugs ofsolvency profile applications basedonmodification topicalprostaglandinpreparationforwound-healingformulate indications. female sexual arousaldisorder(FSAD). The sametechnology willbeusedto allow treatmentofED(by simpleapplicationofPGEtoglansthepenis)and treatments formaleerectiledysfunction(ED). isintendedto The formulation prostaglandins thataretemperaturestable. NWLSwilldevelop specific technologyapplications. involvesThe first of topicalformulation (patent pending)thatwillallowforvarious oftopicaldrugs formulation has enteredintoanexclusive fortwo licenseagreement technologies platform American mensuf forNWLS. opportunity business technologiesplatform andtheproductthatwillbedeveloped offer significant methodsoftreatmentandwhich affectefficacious large numbersofpeople." infections aremajorunresolved medicalproblems thatstillawait more negligible orminimalsystemiceffects. Wound healingandfungal skinandnail of never gained popularity. Ournewly acquiredtechnology willallow forcreation a A I N Delivery Drug Agreement ExclusiveNWLS Signs License Relating to Innovative Topical o research indicatethattubulysin derivatives advantages willoffer significant growth anddivision by DataresultingfromR&D’s destabilizing microtubules. in humans.” Tubulysins cytotoxins arenaturally occurring thatprevent cell been to CEO andPresident.“Themajorchallengetoitsuseasacancertreatment has most potentanti-cancercompoundsknown,” saidEdward L.Jacobs,Insert’s commercialize tub announce additional therapeuticcandidatesinthenear future. Insert,” Stewart, of saidR.Bruce Chairman Arrowhead. “We expect to expected thattoxicity willbelimitedandtargeting totumorswillbeimproved. combining tubulysins and/ortheirderivatives withInsert’s itis Cyclosert, effective resistantcelllines,andtobe non-immunogenic. amongmulti-drug By usedchemotherapeutics,tobehighly1000 timesmorepotentthancurrently research licenseandanoptionfore Insert’s delivery system,Cyclosert. drug provides proprietary The agreement a commercialize conjugates ofthepotentanti-cancercompoundtubulysin with GmbHtodevelop withR&D-Biopharmaceuticals collaboration agreement and Cancer CompoundCancer technolo v v ns ailab er cur f for Wieslaw Bochenek,MD, PhD, company PresidentandChiefScientific The secondtechnology allows bioavailability forenhanceddrug fromtopical The NationalInstitutesofHealthestimatesthatmorethan30million The company's andCEO, Chairman Henry Val, declaredthatthenew “With this agreement, Insert has secured proprietary rightstooneofthe “With hassecuredproprietary Insert this agreement, “We areexcited additionalpipelinecompoundat tobeunveiling thisfirst Under the terms ofthecollaboration, R&Dwillsupply withtubulysinUnder theterms Insert icer, said, "We aheadofus.Presently areexcited ontheopportunity o rrowhead recently announcedthatitsmajority- ResearchCorporation new biotechnology recently productsandpharmaceuticals, announcedit Inc.,acompany specializinginthedevelopmentew LifeScientific, of mulations thatwillof e wned subsidiar le xicity. Linkingtubulysincouldprovide toCyclosert trackitsuse afast rently usedcancer treatments. Tubulysins have beenshown tobe100 gy andmaterial. r topical treatmentsforerectiledysfunctionarecumbersometouseand t T he fer somede ulysin-polymer conjugates. y rapeutics Signs Collaboration Agreement Signs for rapeutics &Option , Inser The two companies willwork jointly onthesynthesis fer easeofuseandane t gree ofED.gree DecisionResourcesInc.estimates Therapeutics, Inc.,hasenteredintoa xclusi v e license tode xcellent safetyprof velop and ” ile with repair/re biomolecules topromotestemcellsur forstemcellsandgrowth andother factors, use ofbiomaterialsasacarrier technologiescell-based therapies.BiorigenUSA'smajorproprietary includethe an Italianbiotechnology company, isinvolved indevelopment ofadultstem technologiesproprietary toimprove thetherapeuticpotential ofthosedrugs. own existing productsusing pipelineofin-licensedandreformulates de approvalregulatory oftheirproducts. The othersubsidiary, Invamed Pharma, and medicalde trial ser subsidiaries: onesubsidiary, (PTI),provides PharmaTrials International clinical collaborations, acquisitions,andin-licensing. The company hastwo stem cell-basedtreatmentmodalities,andtoexpand throughitsown research, commercialize novel products,includingvaccines biotech/pharmaceutical and unmet needs. orgasm. Development oftreatmentforthisconditionconstitutesonethe women lackofsexual interestandcloseto25%donotexperience report National HealthandSocialLifeSurvey indicatethatapproximately 30%of sexual excitement, untilcompletionofsexual activity. The datafromthe inabilitytoattainthelubrication-swellingpersistent orrecurrent responseof that continuestogain recognition andattractattention.Itsmainsignis (18% mild, 30%moderate,and14%severe). nations. At age65,62%ofallmenhave oferectile dysfunction somedegree more than76millionmensuffer fromEDintheseven mostindustrialized par researchanddevelopmentits internal andalsothrough collaborations and immunogenic at therapeuticdoses). The company ispursuingthisgoalthrough (linear cyclodextrin-containing polymers thatarenontoxic andnon- b usescyclodextrinssmall-molecule therapeuticsandnucleicacids.Cyclosert as todesign,develop,system, Cyclosert, andcommercialize delivery enhanced of Arrowhead, nano-engineered, isusingitsproprietary polymeric delivery electronics, andener compan on productsales. Arrowhead hasa68%stake inInsert. R&D, milestonepayments onclinicaldevelopment andapprovals, androyalties exploit thevalue of itsnaturalproducts. treatment ofcancer Germany andtoothercompoundclasseswithpromisingpotentialfor the discovered by Prof.HöflefromtheHelmholtzCentreforInfectionResearch in Company hasexclusive accesstothenaturalproductclassof the Tubulysins deriving fromnaturalproductsfordiseaseswithunmet medicalneed. The preclinical development andthecommercializationofuniquesmallmolecules GmbHisaprivateBiopharmaceuticals biotechnology company focusingonthe The ag thepreclinicaltesting. of theconjugate afterwhichintendstoperform Insert uilding blocks tocreateanentirely new classofbiocompatible materials v Biorigen USA, a joint venture of New Life Scientific, Inc.andBiorigenSrl, Biorigen USA,ajointventure ofNew LifeScientific, New Life Scientific, Inc.,was withtheintenttodevelop formed New and LifeScientific, Female sexual arousaldisorder(FSAD)isalessdiscussedsexual problem Arrowhead Research Corporation isapubliclyArrowhead ResearchCorporation tradednanotechnology tnerships withphar elops andcommercializesphar reement includesanup-frontfeetoR&D vices, mark y generation afterimplantationandproprietar commercializing ne vice companiesw et research, and services toenablebiotech, et research,andservices pharmaceutical, . The company strategy tofully ispursuingapartnering gy. Insert Therapeutics, Inc.,amajorityowned subsidiary maceutical andbiotechnolo w technolo orldwide toconductresearchandobtain maceutical/biotech productscomingfromits vival andbiologic activity intissue gies intheareasoflifesciences, , research fundingb gy companies.R&D- y cell culturemethods. y Inser t to BioSante Initiates Phase III Study of LibiGel for Female Sexual Dysfunction ioSante Pharmaceuticals, Inc., recently announced it has initiated a Phase events with LibiGel treatment in the Phase II study," said Michael C. Snabes, BIII safety and efficacy trial of LibiGel ( testosterone ) in the MD, PhD, BioSante's key clinical development consultant. "Because there are treatment of female sexual dysfunction (FSD). The double-blind, placebo- no medications approved by the FDA for the treatment of this common controlled Phase III trial will enroll approximately 360 surgically menopausal disorder, there is significant demand by patients and their physicians. We are women for a 6-month clinical trial, conducted under a Phase III protocol and hopeful that if and when LibiGel is approved by the FDA that LibiGel IND reviewed by and on file with the US FDA. treatment will be able to improve the sex lives of women with low sexual As previously announced by BioSante, treatment with LibiGel in a Phase II desire and activity." study significantly increased satisfying sexual events in surgically menopausal "We are pleased to be moving into Phase III clinical development of women suffering from FSD. The Phase II study results showed LibiGel LibiGel. Female sexual dysfunction is underserved by the pharmaceutical significantly increased the number of satisfying sexual events by 238% versus industry today. LibiGel may help address this unmet medical need. We believe baseline (p less than 0.0001); this increase also was significant versus placebo two Phase III safety and efficacy trials plus 1 year of safety data are the

(p less than 0.05). In this study, the effective dose of LibiGel produced essential requirements for submission and approval by the FDA of an NDA," 2 o testosterone blood levels within the normal range for premenopausal women said Mr. Simes. "With the initiation of this Phase III LibiGel trial and our N 7 l

and had a safety profile similar to that observed in the placebo group. In recent FDA approval of Elestrin (estradiol gel), this is a very exciting time for o V addition, no serious adverse events and no discontinuations due to adverse BioSante.” 7 0

events occurred in any subject receiving LibiGel. The Phase II study was a LibiGel is a gel formulation of bioidentical testosterone designed to be 0 2 double-blind, placebo-controlled study, conducted in the US, in surgically quickly absorbed through the after application on the upper arm, y r a u menopausal women distressed by their low sexual desire and activity. delivering testosterone to the bloodstream evenly over time and in a non- r b e

"Based on discussions with the FDA and our positive results from the invasive and painless manner. Though generally characterized as a male F

LibiGel Phase II study, we are moving forward into Phase III pivotal studies of hormone, testosterone also is present in women and its deficiency has been y g o l women with low sexual desire, the largest component of FSD, also known as found to decrease libido or sex drive. In addition, studies have shown that o n h

Hypoactive Sexual Desire Disorder (HSDD)," said Stephen M. Simes, testosterone therapy can increase bone density, raise energy levels, and improve c e T y

President and CEO of BioSante. mood, in addition to boosting sexual desire and activity. r e v i

"We are encouraged by the clinically significant improvement in sexual l e D g u r D

15 16 Drug Delivery Technology February 2007 Vol 7 No 2 them bringP Chief Executive ofDURECT. Officer D DURECT S ifcompanies,which areconnectedthroughproductslike Sanofi- surprised December thathebelie to dosomethinggoingforw dele needsincreasedexposure totheUSmarket. “Sanofi They have substantially look atUS-basedBristol-Myers inrecentmonths. executivesindustry willhave areconvinced beentakingalong,hard Sanofi company didnotcommentonpressspeculation.Still,many analysts and Plavix, aswell as Avapro forhypertension. spokesman saidthe A Sanofi since they work together in marketing thehugely successfulblood thinner sales andpushGlaxoSmithKlinePlcbackintothirdplace. companyleapfrog Inc.,asthebiggestpharmaceuticals intheworld Pfizer, by company, which hasamarket value ofaround$51.5billion,would seeSanofi attheendof2009. The acquisitionoftheUS to retirefromtheFrench firm andveteran dealmaker,ambitious chairman Jean-Francois Dehecq,who isdue been signedlateJanuary. BuyingBristol-Myers would beacoupforSanofi's newsletter LaLettredel'Expansionsaidapremerger dealwas thoughttohave company, Inanunsourcedstory, accordingtorecentreports. French financial S Pre-Merger Deal Sanofi-Aventis &Bristol-Myers SquibbRumored to Have Signed de quality parenteralproductsandleading-edgetechnologies tomarket." withitsclientsfromdevelopmentpartners tocommercialization todeliver how"Our collaborationwithDURECTexemplifies HospiraOne2 President andGeneralManager, Hospira. Services, Contract Manufacturing phar commercialization collaborationwithNycomed, now oneofthe25largest followingagreement, ontheheelsofourrecentdevelopment and forus,andtheestablishmentproducts makes ofthis themanidealpartner begun development manufacturing activities inaccordancewiththeagreement. commercial suppliesofPosidur onaworldwide basis. The two have parties willprovide services One contractmanufacturing DURECT'sclinicaland is cur P of bupivacaine providing inacontrolledfashion, upto72hoursof to beinjectedduringsurgery, where itcontinuously releasestherapeutic levels second k osidur, DURECT'spost-surgical painmanagementinvestigational which drug, v "We needstohelp lookforward DURECT'smanufacturing tosupporting Novartis andChiefExecutive Chairman Daniel Vasella saidonly thispast "This wouldn't me,” surprise said WestLB Analyst Oliver Kaemmerer. andBristol-Myers haveSanofi longbeentippedaspossible merger partners, P parenteral andcapacity inmanufacturing "Hospira's capabilities,expertise, elopment b veraged theirbalancesheetsincethey tookover Aventis, sothey areprone osidur (Saber-Bupivacaine) isalong-actinglocalanestheticunder merger dealwithinthenext few weeks tocreatetheworld's biggestdrugs anofi-Aventis andBristol-Myers SquibbCocouldannounceafriendly maceutical companiesinthew manufacturing andsupply with Hospira manufacturing agreement Worldwide, Inc.for recently announced ithasenteredintoalong-term URECT Corporation rently Hospira'sOne2 inPhaseIIclinicaltrials.Undertheagreement, e y milestone inourP osidur tomark y DURECT forthetreatmentofpost-sur v ig ed suchadealcouldbeinthecards."Iw et aroundthew ard." ns P osidur de orld asaresultofits Altana acquisition,isa osid v elopment pro orld ur M ," said g Anthony Cacich, Vice ram," saidJamesBro gical pain.Itisintended an ufacturing Agreement Withufacturing Hospira ould notbe wn, v toitspipeline. drugs fromaddingtheUScompany's would many new benefit experimentalSanofi vulnerable toatakeover forsometime,following management upheaval, while then cleartheway forafull-blown merger. Bristol-Myers hasbeenseenas Apotex. A verdict oftheyear. isnotexpected beforethethirdquarter achallengefromCanadiangenericdrugmaker with thetwo alliesfighting Plavix. A key caseover court Plavix patentsopenedintheUSthispastJanuary, likely theblockbuster tobecontingentontheoutcomeoflitigation surrounding times, accordingtoReutersdata. getsjust13.3 whiletrades onaround21timesforecast2007earnings Sanofi shares have beenbuoyed by inrecentmonthspart takeover speculation, Bristol-Myers, earnings. whose diluteSanofi acquisition couldsignificantly Bristol-Myers, itssharesarelesshighly but rated, andanalysts believe an Swiss newspaper. Aventis andBristol-Myers aboutamerger," Squibb,think Mr. Vasella tolda inte injectab broadestlinesofgenericacute-care includesoneoftheindustry's portfolio patient care. With tothehospitalindustry, 70years ofservice Hospira's marketing productsthathelpimprove theproductivity, safety, of andefficacy company dedicated to Advancing Wellness by developing, and manufacturing, variety ofother therapeuticareas. in painmanagement,withanumberofresearchprograms underway ina products inde conditions. technologiesplatform focusedon treatingchronicandepisodicdiseases deliverydevelopment drug systemsbasedonitsproprietary ofpharmaceutical Phase IIIin2007. development. DURECTandNycomedanticipatemoving theprogram into Europe andotherselectcountries.Posidur inPhaseIIclinical iscurrently todevelopsigned a$202-millionagreement andcommercializePosidur in pol deli Saber deliveryproprietary system,which isaninjectable, biodegradable drug localanalgesia.Posidur's isduetoDURECT's performance uninterrupted commented. leading USinjectable business. contractmanufacturing er "Bristol-My andBristol-Myers willwinthecase,whichMost analysts could betSanofi is itssmallerUSpartner tobuy Analysts believe dealforSanofi any final withamarket capitalizationof$123billion,istwicethesize Sanofi, Hospira isaglobalspecialtyphar DURECT is an emerging specialty pharmaceutical companyDURECT isanemerging specialtypharmaceutical focusedonthe ymer-based systems.OnNovember 29,2006,DURECTandNycomed y very technologyvery thatallows thanistypicalof forlesspost-injection burst g rated solutionsformedicationmanagement andinfusiontherap solid pipeline,oncethePlavix issueisresolved," asecondanalyst les, which pharmaceuticals; helpaddress thehighcostofproprietary The compan v ers becomes a very attractiveers becomesavery takeover prospectbecauseithas elopment initiall y currently hasanumberoflate-stagepharmaceutical currently y focused onsignif maceutical andmedicationdeli icant unmetmedicalneeds v y; andthe er y Altea Therapeutics Announces Positive Clinical Results for its Basal Insulin t the 11th Annual Drug Delivery Partnerships Conference in Las Vegas convenient, and cost-effective alternative to repeat insulin injections. Athis past January, Altea Therapeutics announced positive clinical results Approximately 40 to 50 million people with type 2 diabetes and 10 million from Phase I human clinical studies for its basal insulin transdermal patch people with type 1 diabetes worldwide require insulin therapy. The worldwide showing efficient, sustained, and constant delivery of insulin at therapeutic market for all forms of insulin was over $7 billion in 2005 and is estimated at levels. over $11 billion by 2011. The basal insulin is the fastest growing market and In a glucose-clamp study in normal subjects, Altea Therapeutics achieved generated over $2.6 billion in 2005. constant insulin delivery at therapeutic levels over a 12-hour patch application Altea Therapeutics is an emerging specialty pharmaceutical company period. The data show efficient delivery of the applied dose of insulin and developing and commercializing products based on a new transdermal patch demonstrate favorable pharmacodynamics of transdermal insulin delivery when technology that can deliver sustained therapeutic levels of highly water-soluble compared to a subcutaneous injection of a long-acting insulin analog. Altea drugs, carbohydrates, nucleic acids, peptides, and proteins in a convenient, Therapeutics is developing both 12-hour and 24-hour transdermal patches painless, and cost-effective manner. based on its proprietary PassPort System to provide constant “basal” levels of Altea Therapeutics has demonstrated in several clinical studies that its insulin for people with type 1 or type 2 diabetes. patented PassPort transdermal system achieves what existing patches are unable “We are delighted to achieve such promising results,” said Dr. Eric to do, namely the continuous delivery through the skin of compounds that are Tomlinson, President and CEO of Altea Therapeutics. “These findings are very typically administered by needle injections. important to our clinical development program as they confirm efficient and The company is conducting several clinical trials in the US for its products, constant delivery of basal insulin from our PassPort Patch. These results give us including for an insulin transdermal skin patch that provides continuous confidence that basal insulin transdermal patches can be a cost-effective delivery of basal levels of insulin for people with diabetes, a fentanyl citrate alternative for people currently using insulin injections to manage their transdermal skin patch that provides for rapid and safe management of diabetes. A higher patient acceptance of a basal insulin transdermal patch over moderate-to-severe pain, and an apomorphine hydrochloride transdermal skin needle injections enables physicians to start subjects earlier on insulin in the patch for the convenient management of advanced Parkinson’s disease. The management of type 1 and type 2 diabetes.” company is also in preclinical development for a low molecular weight heparin Market research conducted by Altea Therapeutics on its transdermal basal patch for thromboses, parathyroid hormone analog for osteoporosis, and an insulin product confirms significant market potential for a pain-free, atypical antipsychotic for the management of psychoses. Penwest Pharmaceuticals Begins Next Study in Development of Nalbuphine ER enwest Pharmaceuticals Co. recently announced it has begun a Phase I The study will employ a randomized sequential dose-escalation design, with Psafety study on a nalbuphine hydrochloride extended-release a planned total enrollment of 32 healthy adult subjects in two separate formulation (Nalbuphine ER) that the company is developing for the treatment alternating cohorts. The study will examine a total of four dosage levels. Each of pain. Nalbuphine ER is a controlled-release formulation of nalbuphine subject will receive treatment at two different dose levels sequentially, with a hydrochloride that Penwest is developing using its TIMERx drug delivery number of days at each dosage level until steady state plasma concentrations technology. It is designed to be taken as a twice-daily tablet. are achieved. The company expects subject participation to be complete by the The primary objective of the Phase I safety study is to evaluate the safety end of February, with data available in the second quarter. and tolerability of the drug in healthy subjects of escalating dosage levels Penwest is a specialty pharmaceutical company dedicated to bringing to the during multiple-dose steady-state administration. The secondary objective is to marketplace innovative products that help improve the lives of patients. The evaluate the pharmacokinetics of nalbuphine during steady-state administration company's goal is to identify, develop, and commercialize prescription products and the effect of different nalbuphine ER dosage levels on typical opioid- that address unmet medical needs, primarily for diseases of the nervous system. 2

related side effects. At the core of this strategy, Penwest applies drug delivery technologies, o Alan F. Joslyn, PhD, Penwest's Senior Vice President of Research and including its own proprietary technologies, to new and existing compounds to N 7 l

Development, said, "This next step in the clinical development of nalbuphine enhance their therapeutic profiles. The launch by Endo Pharmaceuticals of o V ER demonstrates our progress in building our own product portfolio. We are Opana ER (oxymorphone hydrochloride extended-release tablets) in mid-2006 7 0 conducting the Phase I safety study to enhance our understanding of the safety demonstrates the execution of this strategy and the value of Penwest's TIMERx 0 2 y and pharmacokinetics of multiple doses of nalbuphine ER over the projected extended-release delivery technology. Penwest is currently applying its r a u clinical dose range. We believe that, combined with the single dose safety expertise to a pipeline of potential products that are in various stages of r b e and efficacy data we already have, this study will give us the information development. The company intends to commercialize these products F y necessary to advance to the Phase II program we intend to begin in the first independently and through third-party alliances. g o l o

half of this year." n h c e T y r e v i l e D g u r D

17

Overcoming Formulation Challenges of Proteins & Peptides By: Cindy H. Dubin, Contributing Editor

he discovery of insulin in 1922 marked the through biological membranes is very limited. As a result, beginning of research and development to protein drugs are almost exclusively administered “Timprove the means of delivering protein parenterally. The latter requires the drug to be in , therapeutics to patients. From that period forward, but many proteins cannot be stored in solution for investigators have contemplated every possible route of prolonged periods, due to their physicochemical delivery,” says Larry Brown, Chief Technology Officer, instability. Thus, delivery of protein drugs is a challenge Epic Therapeutics, Inc., a wholly owned subsidiary of with respect to biological and formulation aspects. Baxter Healthcare Corporation. But formulators are intrigued by the challenges, and The company’s research efforts have followed two the pharma companies for which they work are even more basic pathways: one path has focused on non-invasive intrigued by the financial bounty. Today’s market for means of delivering proteins to the body; and the second peptides drugs is estimated to be $12 billion with an has been primarily aimed at increasing the biological half- annual growth rate of 10%; the estimated market for life of the therapeutic molecules. Thus far, the commercial proteins is much larger. successes of protein delivery by the nasal, oral, and pulmonary routes have been more opportunistic rather ORAL DRUG DELIVERY than the application of platform technologies applicable to every protein or peptide, stated Dr. Brown in his 2005 To date, the development of oral formulations for the Commercial Challenges of Protein Drug Delivery article, effective delivery of peptides, proteins, and (Expert Opinion on Drug Delivery, 2005;2(1):29-42). macromolecules has been an elusive target. Poor In several limited cases, sustained delivery of peptides membrane permeability, enzymatic instability, large and proteins has employed the use of polymeric carriers. molecular size, and hydrophilic properties are four factors More successes have been achieved by chemical that have remained major hurdles for peptide and protein modification using amino acid substitutions, protein formulations. In order to develop an efficacious oral pegylation, or glycosylation to improve the formulation, the peptide must be protected from the pharmacodynamic properties of certain macromolecules. enzymatic environment of the (GIT). Today, commercial successes for protein and peptide This is where Cytogen Corp. is focusing its efforts. delivery systems remain limited. The needle and The company has been issued a patent covering its oral 2

o remain the primary means of protein delivery. Major N drug delivery agents — random peptide compositions

7 hurdles remain to overcome the combined natural barriers l

o that bind to GIT transportreceptors. These agents can V of drug permeability, drug stability, pharmacokinetics, and

7 facilitate transport of an active agent through a human 0

0 pharmacodynamics of protein therapeutics. 2 or animal GIT. y r

a The delivery of macromolecules may present the

u According to Vernon Alvarez, PhD, listed inventor on r b

e greatest challenge yet to the delivery marketplace, agrees F the patent and a consultant to Cytogen, by binding

y Jack Aurora, Senior Director of Research and g

o (covalently or noncovalently) one of Cytogen’s delivery l o

n Development with the Perrigo Company. While many of

h agents to an orally administered drug or by coating the c e

T these protein drugs are used for serious, life-threatening

y surface of nanoparticles or with the delivery r e

v and chronic diseases, such as cancer, rheumatoid arthritis, i l agent, the drug can be targeted to specific receptor sites or e D hepatitis, and diabetes, the development of protein drugs is g

u transport pathways that are known to operate in the human r

D not without challenges. Due to their large size, charge, GIT, facilitating its systemic absorption into the hydrophilicity, and enzymatic degradation, absorption 18 bloodstream.

Cytogen’s technology is based on proprietary peptides that colleagues at 3M Health Care Ltd. However, various studies facilitate the transport of macromolecules across membranes have been performed on the formulation of these proteins as while preserving the structure and biological effects of the aerosols for pulmonary delivery, and promising results have drug as well as the integrity of the intestinal membrane. The been obtained. binding of Cytogen’s delivery agents to these receptors has The pulmonary route is considered suitable for proteins been confirmed in preclinical models, and successful in vivo because these are taken up through the epithelium in the delivery of both insulin and leuprolide in animal models has alveoli, providing systemic delivery without the first-pass been demonstrated. effect. To this end, the YKI Institute for Surface Chemistry “Cytogen’s proprietary technology may represent an (official name: YKI, Ytkemiska Institutet AB), an important advancement for patients with a variety of disorders internationally leading industrial research institute in applied who can greatly benefit from the availability of an oral dosing surface and colloid chemistry, is investigating spray-drying as option,” says Dr. Alvarez. “Through future collaborations, we a technology for producing particles that are large enough to look forward to the development of products for oral avoid phagocytosis, but have a low density to allow delivery to administration that, until now, could only be administered the alveoli. The relationship between droplet and particle size by injection.” has been investigated, and the company is currently studying formulation of proteins in particles for pulmonary delivery. PULMONARY DELIVERY & SPRAY-DRYING Spray-drying has recently been recognized as a viable method to dry peptides and proteins. The spray-drying process Pulmonary delivery is gaining increasing interest as an can result in aerodynamic particle diameters that are within the alternative method for the systemic delivery of various drugs, desired range for pulmonary delivery. Thus, spray-drying including proteins. A major advantage of the pulmonary route potentially provides a single-step preparation procedure of dry is rapid absorption, thus providing a useful administration to protein for . treat symptoms that come on suddenly or require a quick However, there is still limited knowledge on how the response. Moreover, the deep lung provides a higher process, as well as formulation strategies, affect the protein bioavailability for protein drugs than any other noninvasive and stability. It is clear that certain stabilizers are . Thus, pulmonary delivery may help to required to protect the protein against some of the stress overcome poor patient compliance associated with the factors throughout the process, but these may have both parenteral delivery of many of these protein drugs. positive and negative effects on the particle characteristics. The main challenge for pulmonary delivery is to deliver Epic’s PROMAXX protein microsphere technology offers the particles to the deep lung, especially the alveoli. Apart narrow control of microsphere size and the ability to vary from proper design of the system, this requires that the drug-release profiles. PROMAXX consists of a simple, robust,

2 particle/droplet diameter is within the range of 1 to 4 microns, gentle process that is water-based, which has been shown to o N

7 making pulmonary delivery a significant technological preserve the drug’s protein structure and activity. PROMAXX l o V challenge. For proteins, an additional challenge is the relatively microspheres of proteins, peptides, low molecular weight 7 0

0 low physicochemical stability of these drugs. In many cases, drugs, and DNA are manufactured by adjusting formulation 2 y

r prolonged storage of peptides and proteins is only possible by conditions to account for the specific physical/chemical a u r

b drying the formulation, but even under those conditions, characteristics of the molecule. e F

y stabilizers are still required. Microspheres may be engineered to either release drug g o l

o Proteins’ susceptibility to proteolytic enzymes in the gut immediately (for pulmonary delivery) or in specific cases n h c

e makes quite challenging. While various yield sustained release (for injectable delivery). For example, T y r

e routes such as ocular, transdermal, nasal, and buccal have been microspheres with a 1- to 5-micron diameter are ideal for v i l e

D tried, none of these have proved to be a potential alternative to pulmonary drug delivery while larger microspheres (10 to 50 g u r

D the invasive injection, according to S.A. Shoyele and microns) can be used in injectable applications.

20 macroc example. Studiesontheoralbioavailability ofthesenew indications isbeingstudiedas ananti-obesityagent,for from cellularmolecules. combining cellularcomponentsandcellmembranesor cellular elongation, orexpression ofvarious proteins, by proliferation, differentiation, cellularshapealteration, a In addition,thetechnology provides amethodformodulating enable molecules smallenoughtoreachtheirintendedtarget. selection ofthemostactive compound. chemical andpositionaldiversity, thereby allowing forthe differ fromeachotherinringsizeaswell astheconventional diagnostics, andradiotherapy. The membersofeachlibrary uplibrariesofleadcompoundsfortherapeutics, build other biological barriers. These smallmoleculescanbeusedto molecules smallenoughtopassthroughcellmembranesand manipulation ofpeptidesandproteinstoproduceaseries medicine. human andveterinary The technology allows the developed toprovide candidatesforavariety ofapplicationsin no physical sizeofpeptideandproteinmolecules.Libraries properties. appropriate ADME in proteinsintosmall-ormedium-sizemoleculeswiththe that willenab Chemistry, ofOrganic Department Chemistry. University-Givat RamCampus,Faculty ofScienceInstitute discovered, accordingtoProf.ChaimGilon, The Hebrew ofmanystructures new proteinswithclinicalpotential willbe andthesequencesthree-dimensional bioinformatics, Butadvancesproperties. ingenomics,proteomics, and metabolism,andexcretion distribution, (ADME) absorption, becauseofalackselectivityor notusedasdrugs andpoor protein- orpeptide-mediatedcellacti v el macroc The applicationofthistechnology toavariety ofmedical Prof. Gilonsa A Researchers herehave demonstratedaneedfortechnology new technology isbeinginvestigated thatreducesthe yclic compoundsarecur Many proteinsandpeptidesareeitherinclinicaluse, CONVERTING PEPTIDES&PROTEINS yclic moleculeswithspatialdiversity arebeing le thecon INTO SMALLMOLECULES ys thatthene v ersion ofpeptidesandacti w rentl technolo y being pursued. vity , gical platfor such as v e re m gions will inhaled proteinsandpeptides. The futureliesinaparadigmshiftthatwillseethef topical andnasaldelivery aswell assustained-releasedelivery. waves deliveryfirst ofproteinand peptidedrug focusedon increase patientcomplianceandtherapeuticoutcomes. improvements delivery ofexisting .Betterdrug can new were drugs approved from1995-2000thatwere immunogenicity, andbetterdelivery routes.Morethan300 safetyandefficacy,need forgreater decreased impro ofNektar Officer Therapeutics, “Thedrive to Scientific in thenearfuture.” based upontheoutcomeofongoingresearchwork willappear expected thatnew andimproved drugs treatment protocol proteins andmacromoleculesforpatients.Itcanalsobe work andtoachieve acceptable andcost-effective delivery of offers research aninterestingchallengetoconductfurther due totheaforementionedconstraints,thisareaofresearch increasing day by day,” says Dr. Aurora ofPerrigo. “However, Ex the prestigious Neal Award Committeefor Journalistic on n Society of Business Press Editorsfor anarticle she wrote development. She hasbeenrecognized bythe American focusing her writing onpharmaceutical formulation and Business Logistics from Pennsylvania StateUniversity. T emple University inPhiladelphia and her certificate in According toDr. JohnS.Patton, Founder andChief “Interest inthedelivery ofproteinsandpeptidesis cellen v e an toda otechn ce . y's proteinandpeptidetherapiescomesfroma Ms. Dubinearned her BA inJournalism from ology , B an a o She iscurrently the Editor-In-Chief professional journalist since 1988. Ms. Cindy H.Dubin Delivery T positions, she spent several years THE FUTURE IOGRAPHY f d Con Speci her writing has beenawarded by tributin ” alty Pharm N echnology. Prior tothese g Editor toDrug a m agazine and is has beena irst The

21 Drug Delivery Technology February 2007 Vol 7 No 2

22 Drug Delivery Technology February 2007 Vol 7 No 2 ef conditions. thermal The safetyand to inadv dr there isanincreasedriskthatthe clinicalsetting, outside ofanormal from simpleSyrettes devices of varying complexity, ranging many different types ofself-injection devices device. stability monitorsintotheinjection can beimpro w such asonthebattlefield,athome,or medication innon-clinicalsettings, have beenusedtoadminister de non-clinic environments. These unskilled usersinawidevariety of tobeinjectedbydosages ofdrugs injection pens)allow forprecise easil mechanical meanstoallow apatientto container, aneedle, andsome storage of acombinationdrug conf devices have many different injection de However,purpose. becauseself- forthis industry pharmaceutical are increasingl administer biotherapeuticdr By: Monitors Into Device Injection the Smart Self-Injection:Incorporating Stability Drug hile tra fecti For decades,self-injectiondevices Self-injection devices (, ugs ma vices areacon y Stephen E.Zweig, PhD igurations, they generally consist v self-inject thedr TM eness ofdr er v y eling. to prefilled ,spring- to prefilled tent e INTRODUCTION accidentall vices arefrequentl ABSTRACT v ed b y xposure toimproper Although these being usedby the v enient w ug injectionde y incor TM y ug. and Uniject deteriorate due porating dr There are a y ugs and to y used vices ug challenges. injection devices presentsomeuniquedesignand safety by unskilledpatientsinalmostany situation,self- cutting-edge biotherapeuticdrugs. arebeingusedwithanever-growingmorphine, array of introduced forstablesuchas smallmoleculedrugs high con sophisticated multiple-useinjectionpens.Duetotheir loaded autoinjectors,single-useinjectionpens,andhighl can range from simple printed instructions for usetothe can rangefrom simpleprintedinstructions prevent against accidental misuse. These safetydevices ideally containoneormoresafetydevices designedto Because self-injectiondevices aredesignedtobe used visual displayfroma+to-. theLifeTrack When theequationreacheszero(noliferemaining), device’s 10minutes. temperatureandrunthestabilityequationevery TheLifeTrack monitorisprogrammedtosamplethe equation. thetwographsshowscompleteLifeTrackabove stability Theequation corresponding LifeTrack stabilityP(temp)algorithm. at 25 1day biotherapeutic thathasastoragelifeof2yearsat2°Cto8°C, graph ofthestoragestabilityahypotheticalinterferon Figure1Ashowsa stability sensinginjectionpensmaybedesirable. betterstabilitymonitoringwith “smart” treatment sideeffect, neutralizing antibodiesareknowntobeacommoninterferon Because can rendersometypesofinterferonimmunogenic. interferon. Injection pensarefrequentlyusedtoadministervarious typesof FIGURE 1 C n hc hudntb rzn Figure1Bshowsthe andwhichshouldnotbefrozen. °C, venience, self-injection devices, originally The de Studies haveshownthatanadversetemperaturehistor vices mustberob 1 ust, easytouse,and y y

complex mechanical safety interlock and dosage metering schemes present in many biotherapeutic injection pens. Until now, however, one type of safety problem has been difficult to handle. Because self-injection devices are designed to be used anywhere, they are more likely to be subjected to storage and transportation temperatures that are more extreme than those encountered in a standard clinical environment. A self-injection FIGURE 2 Shows three different ways to incorporate LifeTrack stability monitors into injection pens. A: device is at risk of being Stability monitor incorporated as an integral part of the injection pen; B: Stability monitor accidentally frozen, accidentally incorporated as a clip-on to the injection pen; C: Stability monitor incorporated as part of the injection pen’s external packaging. In cases A and B, the user can instantly assess the drug’s being left out at room temperature fitness for use for the entire use-life of the injection pen. In case C, the user determines if the pen by a forgetful patient, or even or cartridge is adequate for use before opening the outer packaging. Various refinements are also possible. The clip-on stability monitor shown in B may be initially stored with the drug cartridge, accidentally being left in an and then transferred to the injection pen when the drug cartridge is loaded into the pen. automobile trunk during the hot Alternatively, the injection pen in case A can incorporate a reset switch that resets the stability summer. If the particular drug used monitor to “fresh” whenever a new drug cartridge is added. in the device is temperature sensitive, there is a risk that the patients when the drugs have and a unitized dose of (a drug will become degraded. deteriorated. relatively temperature-stable small- Because unskilled patients often molecule drug). use the self-injection devices, this Autoinjectors, essentially spring- degradation may not be detected. REVIEW OF INJECTION loaded syringe-needle devices Currently, there is no good DEVICES prefilled with a drug, also have a measure to protect unskilled military history. Autoinjectors are 2 patients from the risk of injecting o

N As previously discussed, the term designed to immediately release a

7 themselves with deteriorated l “self-injection device” covers many unit dose of the drug when the user o V medication. Fortunately, as this different types of drug presses a button and are used to 7

0 article will discuss, modern 0

2 administration systems and drugs. administer emergency medical y r electronics have advanced to the a

u One of the first and simplest types drugs (epinephrine, lidocaine) and r b

e point at which it is now feasible to F of injection device is the , chemical warfare antidotes, such as y

g address this issue. Electronic drug o

l used during World War II to self and Pralidoxime choloride o

n stability monitors, customized to h

c administer morphine to soldiers in (2-PAM). e T the particular stability y

r battle. The Syrette consisted of Epinepherine autoinjectors, such e v i

l characteristics of the drug and self- ® e little more than a plastic squeeze as the EpiPen are popular in D

g injection device at hand, can u

r bottle containing an attached needle civilian life as well and are widely D provide a way to warn unskilled 24 XX Drug Delivery Technology October 2006 Vol 6 No 9 no epinephrine. epinephrine isusuall 15 stored atroomtemperaturebetween rather subjected tohighheat,but ideally shouldnotbefrozenor somewhat temperaturesensitive and Epinephrine autoinjectorsare stability begins tobecomeanissue. emer tobeeffective inan epinephrine remainsinthe long asenoughundeteriorated and itisalsorelatively harmless. As detected visually brown), (itturns deteriorated epinephrinecanbe tofollow.difficult Fortunately, storage recommendationscanbe the penwhile traveling, these Epipen usersneedtoha to deteriorate.Sinceinman this rangecancausetheepinephrine shock. used fortreatinganaphylactic No mechanisms, including the various typesofdigitaldispensing injection pensw 1980s, various typesofmodern more than50years ago. Bythe injection pentechnology began syringes. usingtraditional difficulties insulin multipletimesada precisely meteredamountsof and diabetics,who neededtoinject eyesight andhand-eye coordination, Diabetes oftentakes atollonboth administration by diabetics. developed forinsulinself- Injection penswere originally o v C oP genc to 30 2 en Here, however, drug ® As y , o C. Temperaturesoutside and No situation, deteriorated a result, early work in 3 ere introducedwith v oLet y better than ve accessto ® . These y , y had cases, stored above 30 the typeofinsulin,shouldnotbe w molecule thatwithstandsabuse insulin isacomparati these statedrecommendations, that diabeticsfrequently violate or 28days. Although itislikely to 8 frozen; 2)shouldbestoredat2 that insulinpens:1)shouldnotbe manuf temperatures. As aresult,insulin when itisstoredatadverse tendency todenatureandaggregate protein moleculethathasa stability issues.Insulinisasmall accuracy andeaseofuse. complex mechanismsdesignedfor highly sophisticatedsystemswith devices have now evolved into antibodies, g including interferon, FSH, protein-based biotherapeutics, pens foranincreasingv toinjection hasturned industry surprisingly, thebiopharmaceutical clinical settings. Thus, not to administerthesedr chronic diseases,ways were needed biotherapeutics areusedtotreat Because many ofthesenew diseases have beenintroduced. designed totreatawidevariety of wide variety oftherapeuticproteins advancing. Inthepast20years, a biotherapeutic technology was also pen technology was advancing, widel ell, andinsulinpensha Insulin pensalsohave drug At thesametimethatinjection o C y acturers usuall until use;3)dependingon adopted. ro wth f o C for morethan10 actors, y vely robust ugs innon- recommend ariety of v e been o C most quickl stored underimproperconditions. injectiondevicedrug isaccidentally ifthe forms detected orharmless and don’t always intoeasily degrade temperature sensitive thaninsulin, some biotherapeuticdr be discussedinthenext section, mechanisms. Unfor to lackdr epinephrine, andinsulin,continue suchasmorphine, drugs temperature degradation-tolerant originally developed formore injectionpens, kept pace.Modern increased, safetytechnology hasnot administered by injectionpenshas although therangeofdrugs andmanyerythropoietin, others. alter into aninactive or form, that mostquickl for use. This can bethemechanism most clearly unfit rendersthedrug mechanism that the degradation ultimate stabilityisdeter dependency. Usually, thedrug’s other authors. that hasbeencovered indepthby de energy, andallshow astrong unique kineticsandactivation chemical reactionhasitsown different chemicalreactions.Each fromawidevarietydegrade of One problem, however, isthat Drug stabilityisacomplex topic Drug g ree oftime-temperature nati REVIEW OFDRUG v el ug de y ST y the mechanism that con 4 ABILITY g Briefly, can drugs y radation safety v con erts the drug into thedrug erts tunately, aswill v er ugs aremore ts thedr mined by ug

25 Drug Delivery Technology February 2007 Vol 7 No 2 26 Drug Delivery Technology February 2007 Vol 7 No 2 biotherapeutic’ may have a negligible impacton the state aggregated toan biotherapeutic proteinfrom anon- few percentconversion of a deteriorationthatresultsin a drug proteins as“foreign.” As a result, is designedtoattackagg This isbecausetheimmunesystem dr and temperature. expressed assomefunctionoftime for use”equationcanusually be environmental stress),the“fitness humidity, light,andothernormal a otherwise packagedcompetently in is case (assumingthatthedrug a for rather may belimited by the be limitedby lossofactivity, but foruse”may not stability “fitness protein-based biotherapeutics, dr biotherapeutics andsmall-molecule this deca the caseofbiotherapeuticdrugs, device inquestion.By contrast,in characteristics oftheself-injection mechanical andchemical that isrelatively unaffected by the simple injection device. chemical characteristicsoftheself- dependent onthemechanicaland of to thechemicalcharacteristics comple potentially harmful form. Ineither potentially form. harmful way from thatprotectsthedrug In thecaseofsmall-molecule One impor ugs, thisequationma ugs, however, isthatinthecaseof the biotherapeutic,isalso mation ofagg Arrhenius decayArrhenius equation x y function that,inaddition equation ma tant distinctionbetw s acti re g vity, may but ated protein. y y regated be amore be a 5 een biotherapeutics. par good stabilitymonitoringis adv occasionally even generatean (neutralizing antibodies),or effectiveness ofthebiotherapeutic antibodies candiminishthe ofthebiotherapeutic. form These antibodies against theaggregated because patientsmay develop immunogenic. This isundesirable render thebiotherapeutic monitoring drug stability monitoring drug and accuratew The technique w deteriorated due tomishandling. users whenever have drugs microprocessors toinstantl rapidly programmable approach useslow-cost, low-power, containment system. the surf temperatures), itisalsoaffected by storage conditions(freezingorhigh Usuall lik injectiondevicedrug will,most capable ofhandingthiscomplexity. stability monitoringtechnology is discussed complexity. Fortunately, aswillbe of copingwiththistype monitoring device must becapable function. immunolo LIFETRACK Protein aggregationiscomplex. LifeTrack el ticularly for important erse dr y , y ha ace proper induced b v , Thus, any stability- gical stabilityrisk e ug reaction. modern electronic modern ® its o technology isanew ay ofelectronically ® 6 wn unique orks b TECHNOLOGY y ties ofthedr improper 7 Each dif As aresult, y obtaining .8,9 y The w ferent ar ug n result (+=stillgood LifeT and injection pain. to overall reliability, ease ofuse, as e injection penusersranksafe storage shown inFigure 2. LifeTrack stability monitors are injection pensequippedwith sho LifeTrack stability algorithm is per unit. many years, andcostsafew dollars de into man system canbeminiaturizedtof on anLCDvisualindicator. The still f continually is computes ifthedrug question. The stabilitymonitor remaining lifetimeofthedr temperature hashadonthe that thestorageatobserved minutes andcomputestheimpact de monitor electronicall device. The LifeTrack stability meshed withtheself-injection stability monitor, which isthen algorithm intotheLifeTrack and embeddingthisstability sophisticated stabilityalgorithm, experimental dataintoa data,abstractingthis drug-stability experimental time-temperature SELF-INJECTION DEVICES Recent surveys have shown that vices, iscapablefor ofrunning vice’ wn inFigure 1,andexamples of xtremel it foruseanddispla rack technolo s INCORPORA LIFETRACK INTO temperature every few y An e types ofself-injection y impor xample ofa 10 gy intoself- tant, secondonl , Incorporating y - measures the TING = ys thef e xpired) ug in it inal y XX Drug Delivery Technology October 2006 Vol 6 No 9 de intoself-injection incorporated these stabilitymonitorscanbe a produced eachyear atacostofabout digital watch, millionsofwhich are components aresimilartothoseina also beadded. light, orturbidity, thesesensorscan If thedr sensor, andaminiatureLCDdisplay. battery, apinhead sizetemperature good. F kno freedom totravel, secureinthe Itgivesdrugs. patientsmore more feasible touselow-stability of adverse events. Italsomakes it standpoint andlowers thefrequency fromahumanfactors more robust Itmakes thesedevicespurposes. severalinjection pens,serves useful injection devices, particularly this stability model willlikely differ stability model selected. Although experimentation, andanappropriate must beassessedby careful self-injection de accurac a LifeT and w from idealhandlingaresignif better understandwhich deviations embedded stabilitymonitor, users handling conditions. to minordeviations from ideal injection devices are discarded due present, perfectl dollar each. As Figure 2shows, microprocessor chip,ab Here, thekey tosuccessishigh The essentialelementsofa vices inv wledge thattheirdr rack stabilitymonitorconsistof hich arenot. y inall ug issensiti . The drug’s stabilityinthe arious w y, itreduceswaste. At The electronic y vice configuration good self- v a e ys. W to ith an ugs arestill motion, utton-size icant, generation self-injection devices. ofnext- become astandard part stability monitorsmay eventually automobiles,drug ofmodern part Self-injection de deliverypharmaceutical technology. represents asignif and seatbeltsareno stability monitors.Justas airbags thisriskcanbereducedbydrugs, of accidentalusedeteriorated injection devices increasetherisk anybody” characteristicsofself- the “goanywhere” and“beusedby almost any environment. Although administered by unskilledusersin sophisticated dr de self-injection device from a“dumb” the stability monitortransforms use-life oftheinjectionde throughoutthe deteriorated drug users fromaccidentaluseof stability monitorswillthenprotect constantl Once acti microprocessors beforeshipment. oftheLifeTrackmemory electronically downloaded intothe parameters canthenbe parameters areselected, these the appropriatestabilitymodel will otherwisebeconsistent.Once qualitycontrol,it manufacturing injection devices, assuminggood between different and drugs the user. Self-injection device technology vice intoa“smar y v ated, theLifeTrack on guardandprotecting SUMMARY ugs tobe vices enab icant adv t” de w a standard vice, vice. le ance in This 1 LifeT 10. 9. 3 2. Sicherer SH,Forman JA, NooneSA.Useassessment 5. 4 8. 7. 6. company. M Research Director, and Founder of Avocet Medicine. He isaformer J&J(LifeScan) o the NIH,and wasanAssistant Professor his post-doctoral workinImmunology at . . . f edical, Inc., amedical diagnostics p French D. Market trendsininjectiondevices for lo Zw 2 children andpediatricians.Pediatrics. of self-administeredepinephrineamongfood-allergic D technolo therapeutic proteins.Phar W H Carstensen J Clin Immunol.2000;105(5):1025-1030. E Simons, FE,GuX,SimonsKJ. OutdatedEpiPen and Zw Cytokine Res.1997;17(suppl1):S15-21. e Hochuli E.Interferonimmuno No.10/747,926; 2004. protein immuno Zw 903. p Mono P Pharmacology atBaylorCollege of v harmaceuticals. harmaceuticals. Touch FutureDrug Briefings: rinciples andpractices.Dr 000;105(2):359-362. de needs ofthoseusingg Dumas H,etal.Understandingandmeetingthe har piPen Jr autoinjectors:pasttheirprime?J Allergy er elivery. June2006:20-24. gger . aluation ofinterferon-alpha2a.JInterferon rack isatrademarkofCliniSenseCorporation. eig SE.Electronictime-temperatureindicatorand eig SE. eig SE.Methodandde Str vices. BMCEndocrineDisorders.2006;6:5. meling S,CrommelinDJ maceutical Sciences:aSeriesof g . ucture-immuno r US Patent No.7,102,526;2006. aphs. Infor gy BIOGRAPHY . Advances invaccine stabilitymonitoring Vaccine. 2006;24(33-34):5977-5985. , REFERENCES Rhodes C,eds.Dr genicity San Di University of California, (Biophysics) from the his PhDinBi Corporation. He earned CEO of CliniSense Dr ma Healthcare.2000. . genicity relationshipsof Ste ro . US P eg wth hormone injection wth hormone m vice todetecttherapeutic ve Zweig ugs andthe Res. 2004;21(6):897- o. He conducted , Schellek atent genicity: technical u g och stability: Application T ens H,Jisk e emistry x tbooks and is th e oot

27 Drug Delivery Technology February 2007 Vol 7 No 2

28 Drug Delivery Technology February 2007 Vol 7 No 2 y John Sullivan andHenrik Elbaek, By: for American Firms Challenges Regulatory Presents Products” for “Combination Growing Market Global the USaswell as Asia andEurope. The phar in gaining approval tomarket new and willalways beperceived challenges Kong, andCopenhagen. There have been inBeijing,Hong through ouroffices introduction ofcombinationproducts, issues regardingregulatory the dealing foryears withtheinternational (www.RadiusPD.com), we have been and Spainarethelar Union, Ger and Japan(11%). follo market, 43%oftheglobalrevenues, total, theUSrepresentedlar increase eachsubsequenty $220 billionfor2006anda10%to14% $130 billionin2003,withprojectionsof billion in2004,uproughly 14%from device reached$148 andproductindustry states thatglobalrevenues forthemedical F industr & T T Discussion rost &Sulli P oor’ maceuticals and medicaldevices in At RadiusProductDevelopment MSc wed by theEuropeanUnion(30%) y s repor products ise devices andcombination he globalmarket formedical medical de Special E) MBA (EE), man v t, incitingthemostcur an mark y , F W rance, Ital vice andproducts ithin theEuropean gest mark xploding. Standard et researchrepor ear. Ofthis y, theUK ets. gest rent t, create the Office ofCombination create theOffice combination products ledtheFD help promotehealing. an elementofengineeredbiologics that products asdevice implantsthat contain developments couldincludesuchexotic and engineeredtissues.Future such asgrown cultures,blood, vaccines, isengineeredbiologics,Another group plaque andprevents itfromdeveloping. ar as adr antibiotic-coated bandageorascomple These productscanbeassimplean combined therapy, treatment, orsurgery. biolo the USFDA. di they requireapproval frommultiple challenge withgaining approval because Combination productshave aninherent in thecombinationproductcate tr ul visions ofhealthadministrations,like ter y The complexity andnuancesof Combination productsinte y gics, de inno w ug-coated stent,w hile thedr v ati vices, and/or drugs intoa vices, and/ordrugs ve productsarebeingseen ug breaksdo hich inflatesthe grate wn gor A the y to . x process, safety Products in2002too re are beingmadein becoming clearerinEurope,andstrides intheUS,itisonly recently defined path tore re ensure thattheappropriatedivisions are applications intotheircomponentpar that would helptotranslate new product recognized theneedforacentralbody combination products. The FDA Japan isrigorous andcanbeafr for amedicalde combination products.Gaining approval seeking approval ofinnovative that isripewithchallengesfor companies (MHLW) withtheFDA, you seeasystem ofHealth,Labor,Ministry and Welfare viewing respective elements. While the gulations andre Contrasting thestateofJapan’ ASIA: FOCUSONJAPAN gulator , and accountabilityof vice orphar y gulator Asia toimpro approval isbetter v ersee theappro y agencies. maceutical in v ustrating e s ts to v al

Special Discussion

“As American companies develop new medical devices and combination products, they will need to continue to be aware of recent and upcoming changes in the regulatory environment of each European and Asian country that presents a potential marketing opportunity. As these products grow more sophisticated, so does the regulatory process that is set in place to protect the consumers who will be benefiting from them.”

process. Industry may also experience marketed as quickly as possible. EUROPE a market and medical practitioners that The effects on industry are more appear resistant to change and overly costs associated with managing the In contrast to Japan, regulation is bureaucratic. review process and more costs a much more efficient process in the The following are examples of the associated with maintaining product European Union. However, just a few lengthy processes required for approval lines that are considered obsolete in years ago, it was a difficult challenge, in Japan and elsewhere in Asia: other markets. The impact can be felt especially in the medical products area. even at the manufacturing efficiency Different member countries of the EU • Approval times are typically 12 level, if the innovation in the product had varying requirements for approval. months for PMA (efficacy plus includes the introduction of new These rules affect the introduction of a safety) devices versus 6 months in technologies that reduce manufacturing product. the US. costs. In this scenario, both the For medical devices in Europe, the • Approval times for 510K (efficacy American-based industry and the Medical Device Directive (93/42/EEC) only) devices are 3 months in the Japanese consumer are losing with the regulations provide guidance for US versus 4 months in Japan, 6 higher costs of using the older- gaining marketing approval through months in China and 6 to 8 months generation product. the declaration of conformance in Korea. In recognition of these approval process. Ultimately achieving the right challenges facing the industry, the to bear the CE mark designates a It is not uncommon for an Japanese regulatory process was device as marketable in the EU. The American medical device manufacturer revised in 2005 to accommodate extent of the requirements for CE to have a product line that has been combination products, biologics, and marking depends upon the product’s made obsolete by a new product in the medical devices, and to allow third- classification. US or EU, but which is still on the party review for approval. This process To some degree, CE marking market in Japan, due to the effort and 2

o is in line with changes implemented at works on the honor system with non- N time required to gain approval. It 7 the FDA and in the EU. However, these l combination, Class I products. All o

V should be noted that the time required processes and systems are new and large European companies can actually 7

0 to gain approval is lengthened not only 0

2 will require a period of adaptation by CE mark themselves. For a new entrant y

r by the process, but also for a

u regulatory personnel in Japan.

r in the market and for certain b

e administrative reasons — the MHLW F Ultimately, these regulatory classifications of product,

y is perceived to be both understaffed g o l improvements will lead to a more manufacturers are required to work o

n and carrying a backlog of applications. h

c efficient approval process, but will e with notified bodies (BSI, TUV, T

y The impact of these delays and lengthy r

e require that industry remain patient DEMKO, SEMKO) who will perform v i l processes is that new products e D while long-standing practices are third party certifications of quality g

u providing better care are not being r D supplanted by new review methods. assurance systems and products. The

30 Special Discussion

FDA and MDD regulations rules are benefiting from them. BIOGRAPHIES similar, but for American companies, There are organizations working John Sullivan is CE marking regulations present to harmonize methods of study, Director of Quality and additional work to develop application, and review devices and Implementation at documentation that is not necessarily pharmaceuticals. In the pharmaceutical Radius Product required by the FDA. industry, the International Conference Development Under the EU regulation system, on Harmonisation (ICH) is leading the ([email protected]), one country cannot have more effort, and in the medical device where he manages quality and regulatory compliance during product restrictive regulations without a special industry, the Global Harmonization development and launch. His medical dispensation. A country with very Task Force (GHTF) is doing so. These device experience includes working strict rules cannot enforce them if the organizations hope to harmonize the for and consulting with Fortune 500 other countries have more liberal rules. methods, clinical burdens, and medical device companies and If a country tries to do so without documentation required to gain managing quality assurance for an FDA-registered medical device being approved by the EU, it is approval for pharmaceuticals and contract manufacturer. He has considered a trade barrier and the devices. The objective will be to achieved ISO 9001 & ISO 13485 companies can actually sue that reduce variations in regulatory certification for software, consulting, country in the EU court. pathways and expectations that are and manufacturing companies. Mr. Nevertheless, while European encountered by industry. Ultimately, Sullivan earned his BS in Computer countries have a common set of rules, there may be one process that allows Science, is a Certified Lead Auditor, and has achieved his Regulatory they each have their own authorities to the submission of the same application Affairs Certification. handle approval of combination package to all target nations. products, and they operate on different In the meantime, these Henrik Elbaek timetables. A combination product will organizations and their member Pedersen is Managing typically have an unpredictable road nations are making great strides to Director at Radius Product Development’s ahead for regulatory approval in each reduce the varying complexities that Copenhagen office country within the European Union. industry (particularly medical devices ([email protected]), and combination products) is currently responsible for the operations, confronting in gaining access to productivity, growth, and financial international markets. N vitality for its European operations. MOVING FORWARD Mr. Pedersen was Director of New Product Management for GN Netcom, a leading brand for hands-free As American companies develop 2 o

communication products, fulfilling N

new medical devices and combination 7 customers’ needs and product l o products, they will need to continue to roadmaps and setting a clear V 7 0 be aware of recent and upcoming direction for R&D. He was previously 0 2 y r changes in the regulatory environment at Medtronic Inc., managing program a u r b

teams and growing the Neuro e of each European and Asian country F Headquartered outside Boston in Clinton, MA, Radius Product

Diagnostic business. He earned his y g

that presents a potential marketing o Development (www.RadiusPD.com) is an award-winning l

MSc (EE) from the Danish Technical o n

international product design and development firm that h opportunity. As these products grow c

University and his MBA from e provides user research, industrial design, engineering, and T y more sophisticated, so does the r

Copenhagen Business School. e

manufacturing implementation for clients in the consumer and v i l e regulatory process that is set in place healthcare industries. The firm has offices in Chicago, D g u

Copenhagen, Beijing, and Hong Kong. r

to protect the consumers who will be D

31

FAST-DISSOLVING TABLETS Fast-Dissolving Rofecoxib Tablets: Formulation Development & Optimization Using Factorial Design By: D.M. Patel, MPharm; N.M. Patel, PhD; and M.M. Patel, PhD

ABSTRACT

The purpose of this investigation was to develop fast-dissolving tablets of rofecoxib. Granules were prepared by wet granulation using a deposition method. The dried granules were then compressed into tablets. The tablets were evaluated for disintegration time and wetting time. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: amount of crospovidone and mannitol. The results of multiple regression analysis indicated that for obtaining fast-dissolving tablets, an optimum amount of mannitol and higher percentage of crospovidone should be used. Response surface plots are also presented to graphically represent the effect of the independent variables on the disintegration time and wetting time. The optimized tablet formulation was compared with conventional marketed tablets for percentage drug dissolved in

30 minutes (Q30). From the results, it was concluded that fast-dissolving tablets with improved rofecoxib dissolution could be prepared by balancing the quantities of soluble filler (mannitol) and disintegrant (crospovidone) in the formulation.

INTRODUCTION water-insoluble, tasteless drug. Hence, METHODS it was considered a suitable drug for Elderly persons have poor the preparation of orodispersible Preparation of Rofecoxib physiological and physical abilities tablets. The present work was Tablets due to the effects of aging. Hence, undertaken to study the effect of A preliminary study was carried many elderly persons will have variables on the characteristics of out for screening of four disintegrants difficulties in taking conventional oral orodispersible tablets of rofecoxib namely, CCS, CLP, LHPC, and SSG. dosage forms because of hand tremors utilizing factorial design. Mannitol was incorporated as a and dysphagia. It is difficult to soluble filler to improve palatability, MATERIALS 2 administer tablets or capsules to to impart cooling sensation and sweet o N patients who are uncooperative, on taste upon dissolution. Granulation 7 l

o Rofecoxib was a gift sample from

V reduced -intake plans, or are was carried out using the solid

7 Torrent Pharmaceuticals Ltd.,

0 nauseated. To overcome these deposition method on 0

2 Ahmedabad, India. Croscarmellose

y problems, mouth-dissolving tablets are superdisintegrants assuming that the r a

u sodium (CCS), crospovidone (CLP), r an ideal option. The development of a method might enhance the wettability b e F fast-dissolving tablet also provides an low substituted hydroxypropyl and dispersion of the drug particles y g

o cellulose (LHPC), and sodium starch l opportunity for a line extension in the that disintegrate from the tablets being o n

h glycolate (SSG) were gift samples c marketplace. Fast-dissolving/dispersing that rofecoxib is hydrophobic and a e T

y from Zydus Cadila Healthcare Ltd., r tablets are prepared by techniques water-insoluble drug. Disintegrant e v i l Ahmedabad, India. Mannitol was e such as tablet molding, spray drying, (CCS, CLP, LHPC, or SSG) was D g

u purchased from Laser Chemicals, r lyophilization, sublimation, or mixed with mannitol. The powder D addition of disintegrants.1-9 Rofecoxib Ahmedabad, India. All other blend was mixed and kneaded with 32 is a non-steroidal anti-inflammatory, ingredients used were of purified water to obtain a coherent pharmaceutical grade.

FAST-DISSOLVING TABLETS

(model ED2, Electrolab, India). To TABLE 1 determine wetting time, a filter paper † Batch Code Variable Levels in Coded Form DT (seconds) WT (seconds) was kept in a petri dish having a X X 1 2 diameter of 9.5 cm and containing 15 F1 -1 1 6.66 8.00 F2 0 1 6.33 7.00 mL of purified water. A tablet having a F3 1 1 5.33 6.66 small amount of amaranth powder on F4 -1 0 4.33 5.33 the upper surface was placed on the F5 0 0 4.00 5.00 filter paper. The time required to F6 1 0 3.33 4.66 develop a red color on the upper surface F7 -1 -1 4.66 6.66 of the tablet was recorded as wetting F8 0 -1 4.33 6.00 time. For uniformity of dispersion, two F9 1 -1 4.00 5.00 tablets were kept in 100 mL of water Coded † Actual Values and gently stirred for 2 minutes. The Values X X 1 2 dispersion was passed through a 22 -1 4 80 0 8 85 mesh. The tablets were considered to 1 12 90 pass the test if no residue remained on *All batches contained 25 mg rofecoxib, 2% wt/wt talc, 1% wt/wt magnesium the screen. For drug content analysis, 20 stearate, 0.5% wt/wt sodium lauryl sulphate. tablets were accurately weighed and

† finely powdered. Quantity of powder X1 is amount of crospovidone (mg); X2 is amount of mannitol (mg). equivalent to 20 mg of rofecoxib was DT indicates disintegration time; WT indicates wetting time. taken into a 100-mL volumetric flask and dissolved in acetonitrile. Exactly 5 mL of the filtrate was diluted to 100 mL 2 damp mass. Rofecoxib was mixed with kg/cm . The prepared tablets were stored with distilled water and assayed for drug wet mass for 5 minutes. The damp mass in a tightly closed glass container and content at 237 nm using a double beam was passed through a 30 mesh. The wet evaluated for various parameters. UV/Vis spectrophotometer (Shimadzu, granules were dried in a hot air oven at model-1601).

2 65°C for 1 hour. The dried granules Evaluation of Prepared Tablets o N were re-sifted through a 30 mesh and Compressed tablets were evaluated 7 Optimization of Formulation l o V retained on a 100 mesh. The dried for hardness, friability, wetting time, Variables 7

0 granules (30/100 mesh) were mixed disintegration time, uniformity of 0 From the results of preliminary 2

y 2

r with a glidant lubricant bland containing dispersion, and drug content. Hardness

a studies, a 3 randomized full factorial u r

b talc (2%), magnesium stearate (1%), was measured using a Monsanto type

e design was adopted to optimize the F and sodium lauryl sulfate (0.5%) for 3 hardness tester. Friability was y variables. In this design, two factors g o l o minutes. This blend was compressed determined in a friabilator (model EF-2, were evaluated (each at three levels), n h c

e into tablets using an 8/32-inch diameter Electrolab) by evaluating 20 tablets. A

T and experimental trials were performed y r

e flat face round tooling on a Rimek-I disintegration test was carried out using 10

v at all nine possible combinations. The i l e D rotary tablet machine (Karnavati Eng. distilled water as a disintegrating media amounts of disintegrant, crospovidone g u r

D Pvt. Ltd, Ahmedabad). The hardness of at 24 ± 2°C. One tablet was placed in (X1), and soluble filler, mannitol (X2), tablets was kept between 2.5 and 3 each tube of a disintegration apparatus were selected as independent variables. 34 FAST-DISSOLVING TABLETS

The disintegration time and wetting time quantity of water penetrating into the Factorial Design were selected as dependent variables. The tablet bed is limited. The soluble filler The amount of disintegrant

formulation and evaluation of factorial (mannitol) will compete for the available (crospovidone, X1) and the soluble filler

batches (F1 to F9) is shown in Table 1. water, consuming it partially and leaving (mannitol, X2) were chosen as only a part of the total water penetrating independent variables in a 32 full The Response Surface Plot the tablet for the development of force factorial design. The following statistical The response surface plot was drawn necessary for disintegration. The results model incorporating interactive and using Sigma Plot software (Jandel of preliminary studies revealed that the polynomial terms was used to evaluate

Scientific Software, San Rafael, CA). tablets containing crospovidone exhibit the responses: Y = b0 + b1X1 + b2X2 + 1 Figures 1 and 2 show the plots of quick disintegration and wetting followed b12+X1+X2 + b11X1X1 + b22X2X2. disintegration time and wetting time by tablets containing croscarmellose Where Y is the dependent variable,

versus the amounts of crospovidone (X1) sodium, sodium starch glycolate, and b0 is the arithmetic mean response of the

and the amount of mannitol (X2), low substituted hydroxypropyl cellulose. nine runs, and bi is the estimated

respectively. The probable reason for delayed coefficient for the factor Xi. The main

disintegration and wetting of the tablets effects (X1 and X2) represent the average In Vitro Dissolution Study might be slow water uptake or more result of changing one factor at a time The in vitro dissolution study was gelling tendency of croscarmellose from its low to high value. The

performed using a USP dissolution sodium, sodium starch glycolate, and low interaction terms (X1X2) show how the apparatus-II (model TDT-06T, Electrolab, substituted hydroxypropyl cellulose than response changes when two factors are India) at 100 rpm using distilled water or crospovidone. Hence, crospovidone was simultaneously changed. The polynomial

1% w/v SLS in water or isopropyl selected as a disintegrant for the further terms (X1X1 and X2X2) are included to alcohol: water mixture (30:70) as a studies. The tablet dissolution medium.11 The dissolution granules failed to FIGURE 1 media was maintained at 37 ± 0.5°C. separate and hence, a Samples were withdrawn at a small core remains even predetermined time (30 minutes), filtered after wetting of the through a 0.45-micron membrane filter, tablet. This may be due diluted suitably with the dissolution to formation of a

media, and assayed at 237 nm. network of wetted 2 o particles of disintegrant N 7 l o

that counteract the V RESULTS & DISCUSSION disintegration force. 7 0 0 2

From the preliminary y r

Preliminary Trials a u

study results, it was r b

Four disintegrants were selected by e observed that the F y

keeping in mind that efficiency of g o

optimum concentration l o

disintegrants can be affected in different n h

of crospovidone might c e magnitudes by the presence of soluble T y

be less than 15%. r e v

filler in the tablet formulations. This i l e D

expectation arises from the fact that the g u r Response Surface Plot for Disintegration Time D 35 FAST-DISSOLVING TABLETS

disintegration time and therefore can be TABLE 2 omitted from the full model. From the Coefficients For Disintegration Time reduced model generated for disintegration time, it can be concluded Response (disintegration time) b b b b b b 0 1 2 12 11 22 that amount of crospovidone (X ) had FM 3.99 -0.498 0.888 -0.167 -0.168 1.33 1 RM 3.89 -0.498 0.888 - - 1.33 negative effect while concentration of mannitol (X2) had a positive effect on Coefficients For Wetting Time disintegration time. It means that as the amount of crospovidone is increased, the Response (Wetting time) b b1 b2 b12 b11 b22 0 disintegration time decreases, while as FM 4.96 -0.612 0.667 0.08 -0.052 1.56 RM 4.96 -0.612 0.667 - - 1.56 the amount of mannitol is increased, the disintegration time increases. So, a high *FM indicates full model; and RM indicates reduced model. level of crospovidone and low level of mannitol should be selected for the investigate nonlinearity. The data clearly calculated F value is greater than the rapid disintegration of the tablets. The indicate that the values of disintegration critical value of F. data of the response surface plot (Figure time and wetting time are strongly 1) demonstrate that both X1 and X2 dependent on the selected independent Full & Reduced Model for affect the disintegration time. It may variables. The fitted equations (full and Disintegration Time: The significance also be concluded that the high level of

X1 (crospovidone) and low level of X2 reduced) relating the disintegration and level of coefficients b12 and b11 were wetting time responses to the found to be p > 0.05, hence they were (mannitol) favor the disintegration. transformed factor are shown in Table 2. omitted from the full model to generate The polynomial equations can be used the reduced model. The results of Full & Reduced Model for Wetting to draw conclusions after considering statistical analysis are shown in Table 2. Time: The significance of the level of

coefficients b12 and b11 were found to be the magnitude of coefficient and the The coefficients b1, b2, and b22 were mathematical sign it carries (ie, positive found to be significant at p < 0.05; p > 0.05; hence they were omitted from or negative). Table 3 shows the results hence they were retained in the reduced the full model to generate the reduced of the analysis of variance (ANOVA), model. The reduced model was tested in model. The results of the statistical

2 analysis are shown in Table 2. The

o which was performed to identify portions to determine whether the N 12 coefficients b , b , and b were found to

7 1 2 22 insignificant factors. The high values coefficients b12 and b11 contributed l o V of correlation coefficient for significant information for the be significant at p < 0.05; hence they 7

0 were retained in the reduced model. The

0 disintegration time and Wetting time prediction of disintegration time or not. 2 y r indicate a good fit, ie, good agreement The results for testing the model in reduced model was tested in portions to a u r

b determine whether the coefficients b12

e between the dependent and independent portions are shown in Table 3. The F and b11 contribute significant y variables. The equations may be used to critical value of F for ∞ = 0.05 is equal g o l

o obtain estimates of the response as a to 9.55 (df = 2, 3). Because the information for the prediction of wetting n h c

e time or not. The results for testing the

T small error of variance was noticed in calculated value (F = 6.76) is less than y r

e model in portions are shown in Table 3.

v the replicates. The significance test for the critical value, it may be concluded i l e

D The critical value of F for ∞ = 0.05 is regression coefficients was performed that the interaction terms b12 and the g u r equal to 9.55 (df = 2, 3). Because the D by applying the student F test. A polynomial term b11 do not contribute coefficient is significant if the significantly to the prediction of calculated value (F = 0.146) is less than 36 FAST-DISSOLVING TABLETS

FIGURE 2 wetting time. The data of the response surface plot (Figure 2) demonstrate that both X1 and X2 affect the wetting time. It may

also be concluded that the high level of X1 (crospovidone) and

low level of X2 (mannitol) favor the wetting of tablets. From the aforementioned discussion, batch F6 (disintegration time 3.33 seconds and wetting time 4.66 seconds) was selected as a promising batch.

Results of Evaluation Hardness of the prepared tablets was found to be 2.5 to 3 kg/cm2. Percentage friability of the tablets was observed in the range of 0.22 to 0.53 that was within the acceptable limit. The % assay found was 100% ± 5%, which was within the acceptable limit.

Comparison of Promising Batch With Marketed Formulations Batch F6 was selected as a promising batch, and it was Response Surface Plot for Wetting Time compared with two marketed samples (brand A and B) of rofecoxib tablets for Q in three different dissolution media as FIGURE 3 30 mentioned earlier. Scientists experienced with dissolution studies will appreciate the selection of three different categories, ie, with surfactant (SLS), hydro alcoholic liquid (IPA:water), and distilled water. The selection of three different dissolution media was done to discriminate the effect of dissolution media on dissolution. Rofecoxib follows Beer’s-Lambert law in a concentration range 1 to 12 mg/mL in all the dissolution media used. All the media exhibited good correlation (R2 greater than 0.99). From the results shown in Figure 3, it can be concluded that the tablets of batch F6 exhibited better in vitro drug dissolution after 30 minutes than the tablets of brand A and B in

all the media used for dissolution studies. A stability study of 2 o N

batch F6 was carried out at 40°C in a humidity jar having 75% 7 l o RH. Samples withdrawn after 3 months showed no change V 7

Comparative In Vitro Release After 30 Minutes regarding in vitro drug-release pattern, hardness, wetting time, 0 0 2 y

and disintegration time. r a u r b e the critical value, it may be concluded that the interaction F y g o

CONCLUSION l terms b12 and b11 do not contribute significantly to the o n h c

prediction of wetting time and therefore can be omitted from e 2 T y

The results of a 3 full factorial design revealed that the r

the full model. From the results of multiple linear regression e v i l

amount of crospovidone and mannitol significantly affect the e

analysis, it can be concluded that factor X1 has an inverse D g u

dependent variables, disintegration time, and wetting time. It is r effect on wetting time, while factor X2 has a positive effect. D thus concluded that by selecting a proper amount of disintegrant Hence, a high level of X2 should not be selected for low and soluble filler in the tablet formulation, tablets with fast 37

FAST-DISSOLVING TABLETS

TABLE 3 BIOGRAPHIES For Disintegration Time Mr. D.M. Patel is a PhD DF SS MS F R2 Fcal = 6.76 scholar presently working as Ftable = 9.55 an Assistant Professor in Regression the Department of FM 5 9.9404 1.9881 159.39 0.996 DF = (2, 3) Pharmaceutics at the Shri RM 3 9.7715 3.2572 78.94 0.979 B.M. Shah College of Error Pharmaceutical Education & Research, FM 3 0.0374 0.0125 Modasa, Gujarat (India). He has 6 RM 5 0.2063 0.0413 research papers published and 10 research For Wetting Time paper presentations to his credit. He is a life member of IPA. Fcal = 0.146 DF SS MS F R2 Ftable = 9.55 Dr. N.M Patel is presently Regression working as a Principal at FM 5 9.7888 1.9578 18.58 0.969 DF = (2, 3) the Shri B.M. Shah College RM 3 9.7579 3.2526 46.85 0.966 of Pharmaceutical Error Education & Research, FM 3 0.3162 0.1054 Modasa, Gujarat (India). He RM 5 0.3471 0.0694 is Dean, Faculty of Pharmacy, and an *DF indicates degree of freedom; SS, sum of squares; MS, mean of squares; F, Fischer’s approved PhD guide at Hemchandracharya ratio; R2, regression coefficient; FM, full model; and RM, reduced model. North Gujarat University, Patan (India). He has 15 research publications to his credit. He has 28 years of academic disintegration can be produced with REFERENCES experience, including 20 years of minimum efforts. It was also concluded administrative experience. He is a life 1. Cousin G, Bruna E, Gendrot E. Rapidly disintegratable multiparticular tablet. that the deposition of the drug on US Patent No. 5 464 632; November 7, 1995. member of IPA, ISTE, IHPA, and APTI. 2. Allen LV, Wang B, Davies JD. Method of making a rapidly dissolving tablet. disintegrant prior to tabletting is helpful US Patent No. 5 635 210; June 3, 1997. 3. Remon JP, Corveleyn S. Freeze-dried rapidly disintegrating tablets. US Patent Dr. M.M. Patel is presently to improve the drug dissolution. No. 6 010 719; January 4, 2000. 4. Jaccard TT, Leyder J. LYOC: new pharmaceutical form. Ann Pharm Fr. a Vice-Chancellor at 1985;43:123-131.

5. Roser BJ, Blair J. Rapidly soluble oral dosage forms, methods of making the Hemchandracharya North 2

same and composition thereof. US Patent No. 5 762 961; June 9, 1998. o N 6. Koizumi K, Watanabe Y, Morita K, Utoguchi N, Matsumoto M. New method Gujarat University, Patan

ACKNOWLEDGMENTS 7

of preparing high porosity rapidly saliva soluble compressed tablets using l

(India). He has 35 research o

mannitol with camphor, a subliming material. Int J Pharm. 1997;152:127-131. V 7. Ito A, Sugihara M. Development of oral dosage forms for elderly patients:

publications to his credit. 7

The authors would like to thank Torrent use of agar as base of rapidly disintegrating oral tablets. Chem Pharm Bull 0 0 Pharmaceuticals Ltd., Ahmedabad (India) and (Japan). 1996;44:2132-2136. He has 28 years of academic experience, 2 8. Wells JI, Walker CV. Influence of granulating fluids upon granule and tablet y r

properties: role of secondary binding. Int J Pharm. 1983;15:97-111. including 10 years of administrative a Zydus Cadila Healthcare Ltd., Ahmedabad (India) u 9. Bolhuis GK, Zurman K, Wierik GHP. Improvement of dissolution of poorly r b

soluble drugs by solid deposition on a super disintegrant. Eur J Pharm Sci. experience. He is a life member of IPA, e for providing gift samples of rofecoxib and F 1997;5:63-69. disintegrants, respectively. ISTE, IHPA, and APTI. He has visited De y

10. Bolton S, ed. Pharmaceutical Statistics. 3rd ed. Marcel Dekker, Inc.: New g o York, NY; 1997:591. l Mont Fort University, Leicester, UK, as a o 11. Shah VP, Konecny JJ, Everett RL, McCullough B, Carol Norizadeh A, n h

Skelly JP. In vitro dissolution profile of water-insoluble drug dosage forms c delegate from North Gujarat University. e in the presence of surfactants. Pharm Res. 1989;6:612-618. T y 12. Mendenhall W, Sincich T. Multiple regression. In: A Second Course in r e v

Business Statistics, Regression Analysis. 3rd ed. Dellen Publishing Co: San i l Francisco, CA; 1989:141-226. e D g u r D

39

40 Drug Delivery Technology February 2007 Vol 7 No 2 urzR oraO ahd ,Lna ,Gri ,AecbaE hnr-es ,WiC andMaciasJ Wai C, N, Chinery-Hesse Arencibia E, Garcia M, LandauS, Davis Machado A, Y, Taylor D, Correa MD, O, MelanieFein, MD, Quiroz Freeland, R, Peter J. MD, Gutierrez, MariaJ. MD, Stout, Richard R. By: Intramuscular Injections &Intradermal Subcutaneous, Needle-Free Using Injections for aSpring-Powered Device spring de benef need foragas energy sourcemightbe spring technology thateliminates the repor successfully usingtheB2000 withno injections have beenadministered or intrader via theintramuscular, subcutaneous, thedeliverypermits ofmedications cumbersome tanks,etc). device cleaning, site, difficult patient, lacerationsattheinjection cross-contamination frompatientto associated withprevious devices (eg, eliminates orreducescomplications to-date jetinjectiontechnology and (B2000) isadevice thatprovides up- Injection ManagementSystem As analternative, adevice using The Biojector assess the injection findings. These measures included of subjectiveand objectivemeasures were usedto thr participated inthe study. Eachparticipant received Method: with thissprin years Biojector® 2000hasbeenusedclinically for many gas-powered device, such asthe Biojector® 2000.The (ID), an device coulddeliver Subcutaneous (SC),Intradermal demonstrate thataneedle-free “spring-powered” Purpose: ts ofmajorcomplications. icial forsome mark ee injections, SC,ID,and IM,and then anumber , vice should perform SC,ID,vice shouldperform INTRODUCTION th mal routes.Millionsof d us pr Sixty (60)h The purposeof thisstudy wasto Intramuscular (IM)injections similartoa ® ovi 2000 Needle-Free g ding agood standard for comparison device calledthe Vitavax. 1-11 ealth ets. Sucha The B2000 y ad ult volun In vitrotestingdocumentationsho it usesaspringforitspower source. differs designbut performance inthat 1). The Vitavax isbasedontheB2000 injector known asthe Vitavax (Figure developed anew spring-powered three typesofinjections. has conf pressure prof perfor and IMinjectionshave thesame teers Bioject’ iaa edeFe neto eiefrS,I,andIMInjections ID, Vitavax Needle-Free InjectionDeviceforSC, mance characteristicsand irmed successwiththese irmed s engineering teamhas ABSTRACT ile astheB2000,which injection sites. as wellcolor, wetness, and induration atthe both averbalan likelihood of use. The objectivemeasures included preference, pain,safety, positiveexperience, and verbal questioning astooverall impression, an that reported inthe literature for the Biojector® 2000, 2000. Injecti SC, ID,and IMinjections similartothe Biojector® Results: were no adverseevents inthisstudy. d other subjectivefindings were also similar. There Th e FIGURE 1 on sen data indicates the Vitavaxsystem delivers ws d visual analog scaletoassesspain sati essentially equivalent. ofthetwoperformance devices is V injections withtheB2000and clinical e Additionall vir that the Vitavax is pressureprofile on (pain)wasverysimilarto ita tuall v ax ha y valuations ofSC,ID, andIM the sameasB2000. ve shown thattheclinical y, extensive preclinicaland METHODS FIGURE 2 FIGURE 3

The Vitavax study was a three treatment, single blind, Phase I study conducted at a single clinical center. After meeting all eligibility criteria, a total of 60 healthy subjects, Left to Right – Needle-Free IM, SC, and ID equally divided between males and Injections females whose ages ranged from 18 to 56, were enrolled in this study. Comparisons were made between DEVICE DESCRIPTION the intradermal (ID), subcutaneous (SC), and Intramuscular (IM) Subject Participant Receiving an Injection The Vitavax is a needle-free injection injections using the Vitavax. system composed of a spring-powered Sixty (60) subjects received the injections evaluated the injection injector device and a single-use injections in the left or right arm as well sites. The sites were evaluated for disposable cartridge (needle-free as in the left or right abdomen; a block surface wetness using a three-point syringe). The device is capable of randomization scheme determined the scale, with 0 corresponding to no visible delivering up to 0.5 ml SQ and IM, and site assignment. Using the Vitavax, all moisture, 1 corresponding to visible 0.1 ml ID to children and adults without subjects were given injections as moisture without flow, and 2 changes or adjustments; it uses multiple follows: corresponding to moisture with visible disposable cartridges (needle-free flow. Within 5 minutes after the syringes) that are unique for each of • 0.5 ml normal saline SC in the injections, the degree of pain each these applications (Figures 2 and 3). The abdominal region; subject experienced was elicited and Vitavax is self-contained, manually documented via a Visual Analog Scale • 0.5 ml normal saline IM in the powered, and requires no external power and a Verbal Scale. The injection sites deltoid region; and supply. The single-use cartridges are were also evaluated immediately for filled on site by a healthcare • 0.1 ml of normal saline ID in the local reactions (bruising, redness, and professional before each injection. opposite arm. wheal formation). The follow-up, which Except for the power source, it is identical to the B2000 in use and The order of the FIGURE 4

performance. three injection 2 o Beyond clinical verification studies, methods was per the N 7 l the next generation of the Vitavax device randomization o V

will be offered with autodisabling schedule. The study 7 0 0 disposable cartridges to ensure single- consisted of an 2 y r a use compliance in immunization “Injection Phase” u r b e programs around the world. The Vitavax (Day 1) and F y could also be employed in therapeutic “Follow-up” (Day g o l o applications, including self-injections. 2). Immediately n h c e The Vitavax device is complete as following each T y r e

injection, a trained v i

packaged and requires no additional l e

healthcare D

parts or modifications for full g u r functionality. professional who D had not witnessed Overall Preference of the Vitavax Injections 41 consisted of injection site evaluations and a few questions FIGURE 5 regarding preference/subject acceptance, was conducted 24 hours after the initial injection. One specific question related to preference between needle-free and needle/syringe was “How likely are you to receive a needle-free injection over the needle and syringe?” Figure 4 shows that 73% indicated they are extremely likely and 25% indicated they are likely to receive a needle-free injection over a needle and syringe, with only 2% unlikely to use a needle-free device.

RESULTS

Assessment by Injection Site. SC Injections Were Given in the Abdomen, IM and ID Were Given in the Arms At the 24-hour follow-up, each subject was asked “What is your overall impression of each type of needle-free injection (SC, ID, and IM)?” In Figure 5, the subjective results indicate that overall, the ID injection was preferred over the FIGURE 6A SC and IM injections administered with the Vitavax. All the SC injections were administered in the abdomen, and many subjects indicated it was extremely unfavorable. It was believed that this was a sensitive area for this group of subjects and not an area they preferred for an injection, although the SC was reported less painful than the ID or IM. Assessment of pain was performed within 5 minutes after the injection was given by a visual analog scale and a verbal scale, which are considered to be more objective than responses to questions posed by a coordinator. Using the visual analog scale, 40% of the subjects indicated they felt no pain with the SC injection followed by 33% who felt no pain with ID and 30% who felt no pain with IM. As Figure 6 Pain Scores for SC, ID, and IM Injections shows, similar results emerged when reviewing responses to the verbal scale, which shows 47% of subjects felt no pain when given the subcutaneous injection followed by 40% who felt no pain with ID and 33% who felt no pain with IM 2 FIGURE 6B o

N (Figure 6A). Note that this pain data is very similar to data 7

l reported previously [Drug Delivery Technology, o V 2004;4(3):48-52] when the Iject needle-free SC device was 7 0

0 studied (Figure 6B), showing needle and syringe to report 2 y r

a 40% no pain with a SC injection compared to Iject showing u r b

e 62% no pain. The Iject needle-free device, which is similar to F

y the B2000, had results comparable to the Vitavax. Thus g o l

o again, needle free is reported less painful than a needle and n h c e

T syringe, at least for SC injections. y r

e There were some interesting results seen in the pain data. v i l e

D Subjects overwhelmingly favored the ; g u r

D however, they felt that the SC injection caused less pain. It Drug Delivery Technology, 2004;4(3):48-52. “SC Injections” Only appears that the anatomical site (arm versus abdomen) of the 42 FIGURE 7 REFERENCES

1. Hingson RA, Davis HS, Rosen M. Clinical experience with one and a half million jet injections in parenteral therapy and in preventative medicine. Military Med. 1963;525-528. 2. McKenzie R. New technology. Clinical applications of jet injection. New Zealand Med J. 1982;95:815-817. 3. Hingson RA, Davis HS, Rosen M. The historical development of jet injection and envisioned uses in mass immunization and mass therapy based on two decades’ experience. Military Med. 1963;128:516-524. 4. Elisberg BL, McCown J, Smadel JE. Vaccination against smallpox part II: jet injection of chorio-allantoic membrane vaccine. J Immunol. 1956;77:340-351. 5. Anderson EA, Lindberg RB, Hunter DH. Report of large-scale field trial of jet injection in immunization for influenza. JAMA. 1958;167:549-552. 6. Davies JW, Simon WR. Antibody to influenza immunization by jet injection. Can J Pub Health. 1969;60:104-108. 7. Lemon SM, Scott R McN, Bancroft WH. Subcutaneous administration of inactivated Hepatitis B vaccine by automatic jet injection. J Med Virol. 1982;12:129-136. 8. deRizzo E, Cardozo BS, Lascalla DL, Tuchiya HN, Mendes IF. The jet Injection Site Reaction With Each Type of Injection injection apparatus (Ped-O-Jet) for use in mass vaccination against measles — an effective procedure for its disinfection. Res Inst Med Trop Sao Paulo. 1982;24:263-267. 9. Warren J, Ziherl FA, Kish AW, Ziherl LA. Large-scale administration of vaccines by means of an automatic jet injection syringe. JAMA.1955;157:633-637. 10. Lipson MJ, Carver DH, Eleff MG, Hingson RA, Robbins, FC. Antibody response to poliomyelitis vaccine administered by jet injection. Am J Pub Health. 1958; 48:599-603. injection participated in the subject’s easier and accessible for worldwide 11. Shah R, et al. Hepatitis B associated with jet gun injection. Calif J Amer Med Assoc. 1986;256(4):446-447. acceptance/assessment. usage. Other injection site evaluations With the Vitavax having the similar BIOGRAPHIES included redness, bruising, induration, performance profile to the B2000, it and wetness. Figure 7 shows only a may reduce the need for large amounts Dr. Richard R. Stout small incidence of redness and no of detailed performance testing of a new joined Bioject in April 1994 as Director of Clinical and Regulatory bruising reported. Induration (wheal generation needle-free device. The Affairs. He was promoted to Vice formation) was found in 88% of ID B2000 has demonstrated its successful President of Clinical Affairs in injections, which is typical for ID performance over many years and December 1994. From 1992 to 1993, he was the Director of Clinical and injection placement. The remaining SC millions of injections. The Vitavax only Regulatory Affairs at EndoVascular Instruments, and IM showed none or no significant changes the energy source to provide a Inc., a developer of surgical devices and methods indurations. Wetness (surface moisture) totally self-contained needle-free system for endarterectomy and intraluminal graft was also reported in almost all ID for professionals and self-injection of placement. Dr. Stout acted as the Manager of Tachycardia Clinical Studies at Telectronics Pacing injections but was minor, and there were any type for any injection needed. Systems from 1990 to 1992, an international little or no wetness reports with SC and In conclusion, the data clearly medical device company involved in manufacturing IM (data not shown). indicates the injection effectiveness and and distributing cardiac pacemakers and acceptability of the Vitavax jet injection implantable defibrillators. From 1987 to 1989, Dr. DISCUSSION Stout was Director of Medical Programs at technology system for SC, ID, and IM Biotronic, Inc., manufacturer and distributor of injections. From historical data and implantable cardiac pacemakers.

This study supports the successful published studies, the B2000 has the 2 o evaluation of both subjective and same or similar clinical results. Due to Dr. Maria J. Guitierrez is N 7

the Principal Investigator of l objective assessment of the Vitavax for o patient fear of needles, it would have V Comprehensive Phase One, a clinical applications. It demonstrates for 7 been difficult to perform a study giving division of Comprehensive 0 0 the first time that all three types of NeuroScience, Inc. Born in Cuba, 2

three injections using a needle and y r Dr. Gutierrez came to the United a injections (SC, ID, IM) can be u syringe. Because all subjects were r b

States in 1979. She studied medicine in Cuba and e administered with a spring-powered F healthy volunteers and were not needle in the Dominican Republic and completed her y device. It also demonstrates the Vitavax g phobic, the actual results might be more o

residency in NEOUCOM at Canton, Ohio. Dr. l o n performance to be the same or similar to favorable for needle free than reported Gutierrez completed a fellowship in Rheumatology h c e that of the B2000. Eliminating an at the University of Florida in Gainesville, Florida, T in these results. y r

and is board certified in Internal Medicine. Since e v i

alternative power source, such as gas, l

1999, she has served as Principal Investigator of e D chemical, or others that require Comprehensive Phase One, a research unit g u r alternative means, and using a self- specializing in Phase I and early Phase II clinical D trials. powered spring makes the device much 43

IMPLANT TECHNOLOGIES

Implant Technologies Expected to Remain a Niche but Effective Method of Drug Delivery By: Daniel Ruppar, Industry Manager, Pharmaceuticals & Biotechnology, Frost & Sullivan

ABSTRACT

The method of drug delivery is a concern for Pharmaceutical and Biotechnology companies for every project from the point of R&D conception. Implantable drug delivery is one technology sector that is often overlooked in the quest for companies to develop their next big drug. Implant technologies, with the ability to reduce the frequency of patient-driven dosing, and to deliver compounds in a targeted manner, have the capacity to provide a differentiated way to meet the therapeutic needs of patients. Overall, products utilizing implant delivery technologies are being utilized for niche therapeutic applications, such as certain oncology therapies or eye diseases.

INTRODUCTION products that have drug delivery as treatment types and drug regimens their main purpose and goal of available to patients, there are Many drugs, such as those therapy. places for other options to be based on protein and peptide During the drug discovery developed and explored by the hormones, are forced down the process, companies often relegate pharmaceutical industry. The use pathway of parenteral injection their prospective development of implantable drug delivery, with due to their PK/PD profile. Once a programs to one method of the capacity for long-term company seeks to explore other delivery for their research and controlled dosing and delivery methods, one that could development efforts. This is set on targeted delivery, is a niche that be considered is the use of an the front end, based on therapeutic can be explored for product implantable drug delivery system. targets and the compound types to development, especially when This approach has been embraced which the company has rights, thus there are potential synergistic by a variety of companies driving the focus of their R&D benefits of having a drug dosed throughout the industry, many of programs and clinical candidate via that platform. This mechanism which have successfully brought to development. Most 2 o

N market drugs utilizing implant drugs that are dosed

7 FIGURE 1 l to patients operate in

o technology. V a frequently dosed,

7 In terms of related 0 0

2 technologies, there are also devices systemic fashion to y r a achieve the desired u that elute a drug in a targeted r b e

F capacity, such as a drug-eluting therapeutic goal. This y

g stent (DES). This, however, is a is also usually o l o

n achieved through the

h hybrid product, with therapeutic c e T outcomes a result of both the more common y r e v

i delivery pathways, l device and drug technologies. If e D

g one stays true to the concept of an including oral and u r D implantable drug technology, then injectable delivery. In the maze of 44 that relegates the discussion to Valera Pharmaceuticals’ Hydron Implant Technology IMPLANT TECHNOLOGIES

FIGURE 2 (histrelin implant). Vantas Bayer Corporation. Viadur is used as received FDA approval on a palliative treatment for advanced October 12, 2004, for the prostate cancer, over a 12-month palliative treatment of implanted cycle. Previously, patients metastatic prostate cancer. receiving injections of leuprolide The company’s Hydron acetate underwent dosing every 1, 3,

Alza’s DUROS Implant Technology technology utilizes polymer or 4 months from products such as blends to deliver histrelin Lupron Depot (TAP for a continuous 12-month Pharmaceuticals). cycle. The implant is DUROS is a non-biodegradable inserted into the patient’s implant technology that is able to upper arm in the provide systemic and tissue-specific physician’s office under delivery of small molecules, proteins, local anesthesia. In peptides, and DNA/bioactive addition to the technology’s macromolecules for up to 1 year. The use in Vantas, Valera has titanium cylinder implant is powered identified multiple other by an osmotic engine. potential areas of therapeutic use, including antihypertensives, FIGURE 3 osteoporosis, antipsychotics, and corticosteroids. of delivery is not expected to The active drug in Vantas, achieve massive use, but it could histrelin, a lutenizing hormone- help patients with certain types of releasing hormone (LH-RH) agonist, diseases or dosing/delivery needs. was originally a parenteral injection

The following reviews some of the product marketed by Shire 2 o Pharmaceuticals as Supprelin, N

implantable drug delivery 7 l

indicated for the control of central o technologies and products that are V

idiopathic precocious puberty. Valera 7 being utilized and developed by 0 0 reformulated histrelin for this new 2 y

pharmaceutical and drug delivery r a u

use in Vantas. r companies. b e F y

ALZA CORPORATION g o

VALERA l o n

PHARMACEUTICALS h c e ALZA Corporation’s DUROS T y r e v i

implant technology (Figure 2) is l

Valera Pharmaceuticals’ Hydron e D

currently utilized in Viadur g

Implant technology (Figure 1) is u r used in the marketed product Vantas (leuprolide acetate implant) from Durect’s DURIN Biodegradable Implant System D 45 IMPLANT TECHNOLOGIES

matrix coating that is utilized in the I- FIGURE 4 vation system was also used, in collaboration with Johnson & Johnson, in the Cypher drug-eluting stent.

PSIVIDA, LTD.

pSivida, through the 2005 acquisition of Control Delivery Systems, has two implant products for the treatment of back-of-the-eye diseases, Vitrasert and Retisert, both marketed by Bausch & Lomb. pSivida also has Medidur (Figure 5), an SurModics’ I-vation Sustained Drug Delivery System implant for Diabetic Macular Edema, in clinical trials. This next-generation product is able to be inserted into the DURECT CORPORATION delivery profiles for products. Dosing patient utilizing an injection, rather profiles that are well suited for than a surgical procedure, which is an DURECT Corporation is DURIN are ones that are needed for attractive characteristic for this type involved in more than one type of several weeks to several months. of delivery form. implant technology. The company has Overall, DURIN has the positive licensed DUROS from ALZA point of being a biodegradable HOW TO ACHIEVE Corporation for select indications and implant not requiring surgical ACTIVE CONTROL is also developing a catheterized removal. However, it would not suit version of the implant. The new applications needing long dosing Once the implant is placed in the catheterized version is to enhance the cycles, such as 12 months. patient, the drug’s dose control is set delivery of the drug to a precise and for the time the implant is to remain targeted location, such as a tissue, SURMODICS, INC. in the patient. This is governed by the

2 organ, or synthetic medical structure. formulation and technology utilized o N

7 Additionally, DURECT has SurModics’ I-vation Sustained l o V developed the DURIN biodegradable Drug Delivery System (Figure 4) is

7 FIGURE 5 0 implant system (Figure 3). DURIN utilized in the company’s I-vation TA 0

2 pSivida’s Medidur y

r can deliver a wide variety of drug intravitreal implant currently in clinical a u r

b compound types and has the trials for the targeted delivery of e F characteristic of not needing surgical triamcinolone acetonide to the y g o l posterior of the eye. This system offers

o removal once the therapeutic dosing n h c drug delivery for as long as 2 years, e cycle for the implant has been T y r

e completed. This implant is also able and can utilize several different types v i l e of polymer systems to control a wide D to deliver the release of the drug g u r through several mechanisms, variety of therapeutic compound types. D allowing for multiple types of drug SurModics’ proprietary Bravo polymer 46 IMPLANT TECHNOLOGIES

FIGURE 6 therapeutic use, especially for areas that are under-served by other dosing methods. Many products could bring added benefits to patients from the elimination of a repetitive dosing regimen, or through targeted site-specific direct delivery. However, finding those that translate to a beneficial marketed implantable product is something that we are only now starting to successfully see.

Key to the implantable MicroChips device (top) are 100 ptramid-shaped drug reservoirs (bottom) BIOGRAPHY about 50 micrometers wide at the top. A wireless signal from outside the body prompts the device to melt a thin metal metal membrane covering a specific reservoir, releasing a drug directly into human tissue. A solder seal holds the drug in place. Daniel Ruppar is the Industry Manager of Frost & Sullivan’s in the implant itself. Post technology is an interesting step in North American implantation, the dose of the drug is implant technology in that it could Pharmaceutical & not able to be adjusted without provide patients and physicians with Biotechnology analyst removal of the implant delivery “smart” dosing control. One team. He focuses on system. The ability to actively important difference with monitoring and analyzing emerging control the dose could increase the MicroCHIPS’ active control trends, technologies and market use of implant technologies as a technology relative to other implant dynamics in the Pharmaceutical and drug delivery method. Furthermore, technologies is the ability to provide Biotechnology Industry in North America. it could be a widely desired product different dosages over different Since joining Frost & Sullivan, Mr. Ruppar characteristic, once fully developed periods of time, all the while has assumed primary coverage of the and marketed. controlled ex vivo. In addition to cardiovascular sector, with recent work active control, the company’s focusing on cholesterol therapy, diabetes, 2

MICROCHIPS, INC. and thrombosis. He also has performed o

reservoir technology has the ability N

consulting duties for the Venture Capital 7

to be applied in a passive format l o MicroCHIPS is developing with possible targeted use as part of industry. Prior to this, Mr. Ruppar spent 9 V 7

years in the pharmaceutical industry as a 0 technologies for implant devices to 0

several types of orthopedic implants. 2

medicinal chemist. Additionally, he is a y r

enable not only passive delivery, but a u co-author of multiple scientific r b

also active delivery of drugs (Figure e THE BOTTOM LINE publications in peer-reviewed journals for F

6). Utilizing the company’s reservoir y g o

his work in chemistry, is a co-inventor on l array technology to house the drug, o n

four patents for his work in drug h The use of implant technologies c e

products can be delivered through T

discovery, and has published articles in y is expected to remain a niche area r e

active control by using v i Drug Delivery Technology. He earned his l for the pharmaceutical industry. e microprocessors or wireless D BS in Biochemistry with a minor in g u

However, this delivery application r telemetry that in turn initiate the Economics from Trinity University. D opening of the reservoirs. This can be very effective in the right 47

INHALER TECHNOLOGY

Developments in MDI Valve Technology Ensure Better Patient Compliance By: John Olley

INTRODUCTION with all capillary retention valves puffs from the inhaler. fitted to MDIs.4 This is because Many believe that other more Over a number of years, patients, conventional MDI valves fill a expensive systemic therapies will practitioners, and regulators have metering chamber immediately after account for an increasing share of the expressed real concerns about the the last dose is fired, and this chamber MDI market in the coming years. As impact of poor regime assurance on may partially empty if the inhaler is pharmaceutical companies consider the successful treatment of illness. inverted or left for some time. For the delivering more expensive drugs via It is becoming clear that in many inhaler to then deliver an optimum MDIs, and generic equivalents cases, patient compliance can be dose, the patient should ideally fire compete with more and more of the better ensured with assistance from one shot into the air to ensure the molecules that have historically been within the device itself. In time, more valve chamber is completely refilled delivered in MDIs, the high wastage and more regime assurance and from the main can reservoir. This issue becomes of greater concern. assistance features will be requirement results in high levels of incorporated into everyday drug wastage and, of course, assumes that A NEW VALVE DESIGN delivery devices. Indeed, as recently the patient has been shown how to use as 2003, the US FDA issued draft the inhaler properly or has read the Bespak, a leading designer, guidance recommending that dose (often ignored) Patient Information developer, and manufacturer of counters be considered for all future Leaflet that came with their specialty medical devices, has pressurized metered dose inhaler medication. Often, this is not the developed a unique MDI valve to (MDI) therapies.1 The FDA and other case, so the only reliable method to eliminate LOP and improve dose regulatory authorities have also ensure a full dose is taken is to content uniformity. The BK361 emphasized the need to produce less recommend a regime based on two Easifill valve is designed to have fast variable MDIs that deliver doses more accurately than the current FIGURE 1 requirement in the United States 2

o 2,3

N Pharmacopoeia (USP). 7

l Many devices in development o V now feature dose counters, but 7 0 0

2 perhaps the most impactful y r a technologies in drug delivery regime u r b e

F assurance are those that provide y

g benefit invisibly that do not require o l o

n the user to consider more information h c e T or learn further steps to gain y r e v i

l advantage. e D

g Loss of prime (LOP) and u r D dose content variability are major Schematic of the Bespak BK361 Easifill Valve 48 patient compliance issues associated

INHALER TECHNOLOGY

FIGURE 2 valve down. The nominal shot weight was established and indicated that the valves were primed. The device was then inverted (valve up) and shots 5 to 9 were fired, without shaking, to empty the metering chamber. The mass of shot 9 was noted to indicate exhaustion of the valve metering chamber. Shots 10, 11, and 12 were fired valve down to establish whether the valve could deliver a full shot from empty. The procedure was repeated at the end of the MDI life (nominal 100 doses). Dose content uniformity (DCU) was assessed for MDIs fitted with a Through Life Shot Weight Data for Salbutamol MDIs Fitted With BK361 Easifill and Conventional BK361 valve at time = 0 and following HFA Valves (n=5) storage at 40°C/75% RH (valve down) for 3 months. DCU was assessed fill/fast drain characteristics that allow study of BK361 and a conventional HFA through the life of 10 units at the the metering chamber to fully refill after valve was performed to assess each beginning (3 shots), middle (4 shots), actuation or storage, eliminating LOP, valve’s ability to re-prime from empty. and end (3 shots) of the unit life reducing dosing variability, and The procedure involved test firing each according to USP methods. Salbutamol therefore helping to improve patient inhaler with 3 shots using a 5-second content was determined using a reverse compliance. The following paragraphs shake between shots. Shot 4 was fired, phase HPLC method. detail the methodology and results of testing the BK361 Easifill valve against FIGURE 3 a conventional capillary retention valve. Figure 1 shows a cross-sectional 2 o

N diagram of the BK361, which has a 7

l larger flow path than the standard o V metering valve and therefore is able to 7 0 0

2 fill and drain easily. y r a u r b

e METHODS F y g o l

o The performance of Easifill 50- l n m h c e

T valves fitted with RB700 EPDM y r e

v elastomers was investigated using a i l e

D model 0.4% salbutamol sulphate HFA g u r D 134a formulation containing 15% ethanol Through Life Dose Content Uniformity for Salbutamol MDIs Fitted With BK361 Easifill Valves at Initial and oleic acid. A comparative priming (Ambient) (Start: 3 Shots, Middle: 4 shots, End: 3 Shots From 10 pMDIs) 50 INHALER TECHNOLOGY

likelihood of more expensive molecules FIGURE 4 being delivered from MDIs, will almost certainly offer a significant economic advantage. Easily incorporated into new MDI designs, the business case for using the Easifill valve is further enhanced when considered in the context of the key benefits of MDIs as a delivery route, ie, the flexibility to deliver to a range of formulations, enhanced delivery to the lungs, and historically a speedier route to market.

REFERENCES Through Life Dose Content Uniformity for Salbutamol MDIs Fitted With BK361 Easifill Valves Following 3 Months’ Storage (40°C/75% RH, Valve Down) (Start: 3 Shots, Middle: 4 Shots, End: 3 Shots From 10 1. Guidance for Industry: Integration of Dose-Counting Mechanisms into MDI Drug Products; Department of Health and Human Services, Food and Drug pMDIs) Administration, Center for Drug Evaluation and Research (CDER), March 2003. 2. Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products – Chemistry, Manufacturing and Controls Documentation; U.S Department of Health and Human Services, Food and Drug Administration, Centre for Drug Evaluation and Research (CDER), October 1998. 3. United States Pharmacopoeia. USP 29 NF 24, Monograph No. 601 Aerosols; RESULTS & DISCUSSION 2006:2617. CONCLUSION 4. Cyr TD, Graham SJ, Li KYR, Lovering EG. 1991. Low first spray content in albuterol metered-dose . Pharm Res. 1991;8:658-660. Figure 2 summarizes the results of The data indicate that the BK361 the priming study and shows that Easifill valve has fast fill/fast drain following exhaustion, shots 10 and 85, characteristics, that LOP has been actuated from MDIs packaged with eliminated, and that MDIs fitted with this BIOGRAPHY Easifill valves, delivered a full dose. In valve do not require priming. DCU John Olley joined the contrast, MDIs fitted with standard HFA results at the start, middle, and end of Engineering Department valves did not deliver a full dose when unit life for the initial and 3 months time

at Bespak in 1974, 2 o

fired from empty. Figures 3 and 4 points indicate that all data were within having completed an N 7

illustrate through life dose content indentured l the specification outlined by the FDA o V uniformity of Salbutamol MDIs apprenticeship in and well within the specification detailed 7 0

injection mould tool making. Mr. Olley 0 packaged with BK361 Easifill valves at in the USP. 2 y

has served in several R&D functions at r a

time = 0 and following 3 months’ storage Because the Easifill valve requires u r

Bespak, where his knowledge and b e at 40°C/75% RH, respectively. The no priming, pharmaceutical partners can experience of Polymer Engineering and F y

results indicate that the DCU remains provide a drug delivery solution that g

tool making has benefited the design and o l o

within the ± 20 % target limits through manufacture of many new products. In n gives a consistently accurate dose with a h c e the life of the product. single actuation, resulting in greater his current role as a Senior Development T y r e

Engineer, he leads a team of engineers v i

regime compliance as patients need only l e

dedicated to delivering innovative design D

take one puff of their inhaler rather than g u

solutions for Bespak’s proprietary next- r D the two usually recommended. This generation projects. reduces waste and, with the growing 51

OCULAR DELIVERY

Nanoparticles & Microparticles: Particle Engineering, Cell Uptake, In Vivo Disposition & Efficacy By: Aniruddha C. Amrite and Uday B. Kompella, PhD

ABSTRACT

Composite nanoparticles and microparticles of drugs, including nucleic acids, are useful in either enhancing or sustaining ocular drug delivery and effects. Eye drops and their ingredients, including particulate systems, can be rapidly cleared due to tear drainage and blinking. Functionalization of nanoparticles is one suitable approach to facilitate rapid uptake of drug into the corneal and conjunctival epithelia. Drug delivery to the retina is more formidable. Periocularly administered particulate systems are offering a safer alternative to systemic and intravitreal modes of administration for retinal drug delivery. Nanoparticles and microparticles > 200 nm are retained in the periocular space for a few months, allowing sustained drug delivery and effects.

INTRODUCTION retina, the dose required to achieve diminished patient compliance. Thus, therapeutic levels is high due to dose sustained delivery systems that deliver Although the eye is a readily dilution throughout the body and the therapeutic concentrations of drugs to the accessible organ for the administration of presence of the blood retinal barrier. Large retina are needed. Our focus is eye drops, the extent of drug delivery to doses needed with systemic dosing may biodegradable sustained-release systems, the anterior segment tissues of the eye to lead to toxicity. To overcome the including nanoparticles, microparticles, treat disorders such as glaucoma is low aforementioned limitations of conventional and implants for this purpose. The following topical drop administration.3 topical and oral modes of administration advantage with the particulate systems is Even for lipophilic solutes < 500 Da, the for retinal delivery, local delivery that they can be injected and do not extent of absorption is estimated to be less approaches are currently being require surgical placement and/or removal than 10%. For macromolecules, the investigated. The intravitreal and as is the case with implants. Nanoparticles absorption is much less or negligible. The periocular routes are alternatives that can can be further tailored to have unique reasons for low drug bioavailability deliver greater dose fraction to the retina, properties for enhanced cellular entry, and include nasolacrimal drainage of applied resulting in dose reduction and reduced hence, gene therapy.4 This manuscript drop aided by blinking, drug binding to systemic toxicity. The intravitreal route summarizes our investigations in particle

2 tear proteins, and poor corneal provides the highest drug levels in the engineering, biopharmaceutics and o N permeability of solutes. Our investigations, retina, but this route is associated with pharmacokinetics of particulate systems, 7 l

o complications such as retinal detachment, and the safety and efficacy of particulate

V as discussed briefly in this manuscript, are cataracts, and hemorrhage. Periocular systems, primarily as they relate to 7 indicating that nanoparticle systems can 0

0 4 routes are safer compared to the ophthalmic applications. 2 overcome some of these limitations. y r intravitreal routes and we are investigating a A greater challenge is delivery of u r

b the effectiveness and safety of both NANOPARTICLE &

e drugs to the posterior segment of the eye, F which includes tissues such as the choroid, periocular and intravitreal routes in MICROPARTICLE y

g 5-7

o 5 l retina, and vitreous. The topical route delivering drugs to the retina. ENGINEERING METHODS o n

h Several diseases afflicting the c of administration yields low drug e T posterior segment of the eye, including Particulate systems for ophthalmic y bioavailability in the anterior segment, r e v

i diabetic retinopathy and age-related applications can be prepared using a l resulting in little or no drug levels in the e D macular degeneration, require chronic variety of materials, including proteins,

g posterior segment, necessitating the u r

D development of alternative approaches. treatment. Frequent injections either by the lipids, and polymers. We prepared Although (eg, oral intravitreal or periocular routes particulate systems using either proteins, 52 dosing) can provide drug levels in the compromise safety, and also lead to such as albumin, or biodegradable OCULAR DELIVERY

polymers, such as poly(lactide-co-glycolide) (PLGA) and poly(lactide) (PLA). The TABLE 1 approaches for engineering nanoparticles Neural Retina (µm) ONL (µm) INL (µm) and/or microparticles include polymerization, denaturation, or desolvation Controls 304 ± 12 67 ± 4 35 ± 3 of macromolecules, solvent evaporation, Cele-PLGA 67 ± 2 35 ± 2 ionic gelation, nanoprecipitation, milling, Microparticles 302 ± 5 self-assembly, nanolithography, and supercritical fluid technology. The Morphometric analysis of the rat retina. The thicknesses of the neural retina, outer nuclear layer (ONL), and inner nuclear layer (INL) were compared. Data are expressed engineering methods for preparing as mean ± SD for n = 4. particulate systems differ based on the type of carrier and drug materials utilized and the intended application. We prepared of budesonide and hydroxypropyl-b- cellular uptake of particles, with the uptake PLA/PLGA particles using the widely used cyclodextrin.13 To enhance aerosolization and increasing with size reduction (Figure 1). emulsion-solvent evaporation method or reduce cellular uptake, large nanoporous Uptake by these cells is relatively high due unique approaches based on supercritical particles with low bulk density can be to the known phagocytic nature of these fluid technology. Using the emulsion solvent prepared using supercritical fluid technology. cells. While both nanoparticle and evaporation method and a probe sonicator, Such an approach was successful in reducing microparticle composites are capable of we prepared nanoparticles of budesonide and the uptake of deslorelin containing PLGA protecting the entrapped therapeutic agents a vascular endothelial growth factor (VEGF) particles by alveolar macrophages, thereby from enzymatic degradation, nanoparticles antisense oligonucleotide.8,9 A similar sustaining systemic delivery of a peptide can possibly enter the cells better, enabling technique was used in preparing drug from the lungs.11,14 In a supercritical greater drug delivery. We have demonstrated microparticles of celecoxib, budesonide, and fluid process, several parameters, including that PLGA nanoparticles of an antisense a peptide drug.8,10,11 In this method, the concentration of the drug/polymer, the oligonucleotide for VEGF elevate the cell controlling the energy input from the probe flow rates of solute containing or uptake of the oligonucleotide 4-fold.9 sonicator, the duration of sonication, and the supercritical CO , the temperature and In an ex vivo bovine eye model choice of emulsification system allow 2 pressure conditions of the supercritical fluid, (cornea), the uptake of negatively charged particle size control. and the diameters and type of the capillary 20-nm nanoparticles in 5 min is 2.4%.4 This A key problem with the solvent nozzles used for spraying can be varied to uptake of nanoparticles can be further evaporation methods such as the one optimize the particle properties.15,16 Thus, enhanced by functionalizing the nanoparticle described previously is the presence of supercritical fluid process is a versatile surface. We demonstrated that residual organic solvent in the particles process that allows for a finer control of functionalization of nanoparticle surface prepared. We have utilized new supercritical particle properties. with ligands that bind to cell surface fluid extraction-based methods to remove the receptors, such as deslorelin and transferrin, residual organic solvents form the particles.11 2 o

NANOPARTICLE & can increase the corneal uptake of N A 30-minute exposure of supercritical CO 2 7

MICROPARTICLE UPTAKE BY nanoparticles from an to 9% and l o

to PLGA particles formed using the V CELLS & TISSUES 16% within 5 min. Further, using excised emulsion solvent evaporation method 7 0

bovine eye tissues, we observed more 0 reduces the residual organic solvent 2 y

The cellular uptake of nano- and efficient nanoparticle uptake and transport r

(dichloromethane) content form 4500 ppm to a u microparticles can depend on various across the cornea and conjunctiva following r b less than 25 ppm. In addition, supercritical e factors, including the chemical nature of the particle surface functionalization.4 This F

fluid extraction-based methods can be y

particle, its surface modifications, and size. strategy can be utilized to increase the g o l

utilized for the preparation of drug o

We investigated the influence of size on drug levels in the cornea or conjunctiva n h containing nano- and microparticles of c e 12 particle uptake by retinal pigment epithelial and some intraocular tissues after topical T y PLGA. We have recently extended 1 r e

cells (ARPE-19 cell line). Studies using administration. v i supercritical fluid processing to encapsulate l e

negatively charged fluorescent polystyrene D

plasmids in PLGA (unpublished data). Using g u

particles (Fluospheres) ranging in size from r a solvent-free single-step supercritical fluid D 20 nm to 2 µm indicated size-dependent process, we prepared solid-state complexes 53 OCULAR DELIVERY

NANOPARTICLE & rapid clearance. Thus, drug-particulate MICROPARTICLE DISPOSITION systems greater than 200 nm in size, NANOPARTICLES & IN VIVO formulated using biodegradable polymers, MICROPARTICLES FOR can be utilized for sustained drug delivery to THERAPEUTIC APPLICATIONS Knowledge of disposition kinetics is the retina by the transscleral approach. essential in optimal design of delivery Consistent with their ability to elevate systems. Periocular routes are emerging cellular uptake of oligonucleotides, PLGA modes of administration for sustained drug NANOPARTICLES & nanoparticles significantly inhibited the delivery to the retina via the transscleral MICROPARTICLES FOR secretion of VEGF secretion from retinal pathway.5 We have investigated the disposition ENHANCED OR SUSTAINED pigment epithelial cells with efficacy of nanoparticles and microparticles after DRUG DELIVERY comparable to that of Lipofectamine, a periocular administration to rats.2 The rats commonly employed cell transfection received a periocular injection of either 40 µg Sustained delivery is essential for treating reagent.9 On the other hand, the or 400 µg (25 µl) Fluospheres, ranging in size several posterior segment ocular disorders. oligonucleotide alone is ineffective. In our from 20 to 2000 nm. Animals were Periocularly injected biodegradable gene therapy efforts using nanoparticles, euthanized at 0, 1, 7, or 60 days after PLA/PLGA-based microparticulate systems albumin nanoparticles facilitated the cellular treatment. The particles were quantified in the sustain budesonide and celecoxib levels in the delivery and expression of superoxide ocular tissues and the periocular space. The retina for at least 2-months.6,17 The same dismutase 1 gene in retinal cells in vitro as effect of surface sustained effect is not observed with the well as in vivo.18 Thus, nanoparticles are nanoparticles, although the nanoparticles particularly useful in enhancing the delivery properties, including charge and surface sustain better as compared to the un- and effectiveness of macromolecules, such as hydrophilicity, was evaluated using the 20- encapsulated drug.8 This difference can be nucleic acids. and 200-nm particles. attributed to a high burst release followed by Microparticles of PLGA are useful in Subconjunctivally administered 20- to very slow release observed with nanoparticles. sustaining the delivery and effects of 2000-nm particles failed to reach the retina to any significant extent, and the larger particles FIGURE 1 (200 nm and higher) were almost completely retained at the site of administration for at least 2 months. The 20-nm Fluospheres disappeared rapidly from the periocular space with 15 ± 3% and 8 ± 3.5% particles remaining at the end of 1 and 7 days and no detectable levels at 60 days post- 2

o administration. The dose did not affect the N

7 retention behavior of any type of particles. l o

V The surface hydrophilicity did not influence

7 the retention of the 200-nm particles. In 0 0

2 contrast, for the 20-nm particles, the retention y r a was greater for the hydrophobic particles as u r b

e compared to the hydrophilic ones (Figure 2). F

y There is a cut-off size above which the g o l

o particles are retained in the subconjunctival n h

c tissue. The particulate systems at or above e T y

r 200 nm are retained at the site of Size-dependent uptake of fluorescent-polystyrene nanoparticles and microparticles by retinal e v i l administration for at least a period of 2 pigment epithelium (ARPE-19 cells). Confluent ARPE-19 cells grown in 48-well plates were e

D exposed to nanoparticle suspensions of various sized nano- and micro-particles at

g months, and this retention is not affected by u

r concentrations ranging from 50 to 500 µg/ml for 3 hrs. The data are expressed as mean ± SD D dose or surface properties probably because for n = 4. From Aukunuru et al.1 these particles are above the cut-off size for 54 OCULAR DELIVERY

FIGURE 2 celecoxib in a rat model of early diabetic retinopathy. We observed that an ultra-low dose (75 µg) of celecoxib encapsulated into PLGA microparticles alleviates diabetes- induced oxidative stress in the rat retina.10 The rats were made diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). One day following the injection, the development of diabetes was confirmed by measuring the blood sugar levels, and the rats were given a periocular injection of 75 µg of celecoxib solution or equivalent celecoxib encapsulated in microparticles. The rats were sacrificed after 14 days, and the retinas were removed and assessed for oxidative stress markers. The celecoxib- PLGA microparticles significantly reduced diabetes-induced elevations in thio-barbituric acid reactive species (TBARS: a marker of Microparticles and nanoparticles (> 200 nm) are retained in the periocular space for over 60 days oxidative stress) and 4-hydroxynonenal (4- following posterior subconjunctival injection. A) Retention behavior of 20-nm, 200-nm, and 2-µm HNE: a marker of lipid peroxidation). carboxylate-modified polystyrene particles in the periocular space of rats for up to 60 days. B) However, they did not significantly reverse Effect of dose on the retention of 20 nm and 2 µm particles. A dose of either 40 µg or 400 µg was injected and the retention behavior analyzed post 60 days. C) Effect of surface properties on the glutathione depletion observed in this model. retention of 200-nm particles in the periocular space. Carboxylate (negatively charged, In a separate study, using a higher dose, hydrophilic), sulfate (negatively charged, hydrophobic), or amine modified (positively charged, we have demonstrated that celecoxib-PLGA hydrophobic) 200-nm particles were injected into the periocular space of rats, and there retention microparticles have beneficial effects in was followed for a day. D) Effect of surface properties on the retention of 20-nm particles in the subconjunctival space. The data are expressed as mean ± SD for n=3-4. * Significantly different reducing diabetes-induced elevations in from Day 0 (P≤0.05). Based on Amrite and Kompella.2 VEGF (an endogenous vascular permeabilizing and angiogenic agent), prostaglandin E2 (PGE2; an inflammatory leakage (measured as vitreous: plasma diabetic retinopathy. Potentially similar mediator and vascular permeabilizing agent), protein ratio and a 4-kD FITC-dextran particulate systems can be utilized for and vascular leakage for at least 2 months.6,19 leakage assay) were estimated. Diabetes treating other disorders of the back of the Diabetes was induced in rats using elevated PGE2 secretion, VEGF protein, the eye, including choroidal neovascularization intraperitoneal streptozotocin (60 mg/kg). 2 vitreous-plasma protein ratio, and blood- and retinal degenerative disorders. o The animals were divided into 6 groups: N retinal barrier leakage by 3-, 1.7-, 3.1-, and 7 l o normal, diabetic, normal + celecoxib 2.7-fold, and celecoxib-PLGA microparticles SAFETY OF PARTICULATE V microparticles, diabetic + celecoxib significantly reduced these elevations by 7

SYSTEMS 0 0 microparticles, diabetic + celecoxib 40%, 50%, 40%, and 50%, respectively. 2 y r , and diabetic + placebo particles. a Neither the placebo-treated eyes nor the Safety is of paramount importance in u r b

After ensuring hyperglycemia, phosphate contralateral eyes in celecoxib-PLGA developing injectable, new drug dosage e F

buffer saline (PBS) containing celecoxib- microparticle-treated rats showed significant forms. We investigated the safety of y g o l

PLGA microparticles (750 µg of celecoxib), effects. Further, celecoxib suspension failed periocular celecoxib-PLGA microparticle o n

6 h celecoxib (750 µg) suspension, placebo c

to exert any significant effects. Thus, systems. For the safety studies, non-diabetic e T y microparticles, or vehicle was administered particulate systems sustain drug delivery and Sprague Dawley rats were injected r e v i to one eye by periocular injection. Two l

effects. The effectiveness is mainly due to subconjunctivally with celecoxib-PLGA e D months post-administration, the animals local delivery of celecoxib to the retina in microparticles to one eye under anesthesia. g u r were euthanized, and the retinal PGE2 the dosed eye. Thus, celecoxib-PLGA The non-diabetic rats injected with PBS D secretion, VEGF protein, and vascular microparticles are of therapeutic value for served as controls. The rats were euthanized 55 56

Drug Delivery Technology February 2007 Vol 7 No 2 OCULAR b inflammation ortoxicity when administered be w w no difference intheblood cellcounts,body volume ratioincomparison tothe because oftheirlownanoparticles surface-to- ascomparedto with microparticles delivery, theeffective sustainment is better canbeusedtosustaindrug nanoparticles endocytotic mechanisms. Although penetrate intothecellsprobably through receptors,can with ligands forcellsurface especiallyNanoparticles, thosefunctionalized nanopar to someextent by usingfunctionalized bydrugs theepithelialcells,canbeovercome dosage for systems, suchasrapidclearanceofthe delivery, limitationsoftheconventional release.Intopicalocular sustained drug including enhancedcellularuptake and These systemscanoffer several advantages, anterior aswell astheposteriorsegments. delivery,useful foroculardrug bothinthe Thus, PLGApar comparedtocontrols. PLGA microaprticles the ratsthatw mor e no atrophy ordegeneration oftheretina,as wereThe particles well tolerated. There was periocular celecoxib-PLGA microparticles. rats andthatwere injectedwith betweencollagen stainingpattern thecontrol conjunctiva, revealed nodifference in staining oftheperioculartissue,including the perioculartissues. The Massontrichrome any histopathological damagetotheretinaor Celecoxib-PLGA didnotcause microparticles used toassessany systemictoxicity. body weights, andblood cellcountswere analysis oftheretina. The blood chemistry, toxicity usinghistology andmorphometric p 60-days postadministration,andthe videnced b y eriocular tissuesandretinawere assessedfor eights, ortheb the periocularroute. phometric anal ell toleratedanddonotleadtoan Nano- and microparticulate systemsare Nano- andmicroparticulate ticulate delivery systems. m y CONCLUSIONS and inefficient uptake ofsome and inefficient histolo ere injectedwithceleco DELI lood chemistr ticles ofceleco ysis (T gical picturesand ab le 1). There was y xib appearto prof VERY iles of xib- y o vert 15. Kompella UB,Koushik K.Preparationofdrugdeliverysystems 15. KoushikK,DhandaDS,Cheruvu NP,KompellaUB.Pulmonary 14. 13. Martin TM,BandiN,ShulzR,RobertsCB,KompellaUB. 12. Koushik K,KompellaUB.Preparationoflargeporous 11. 10. 9. Aukunuru JV,AyalasomayajulaSP,KompellaUB.Nanoparticle 8. 7. 6. Raghava S,HammondM,KompellaUB.Periocularroutesfor 5. 4. Lee VH,RobinsonJR.Topicaloculardrugdelivery:recent 3. 2. Amrite AC,KompellaUB.Size-dependentdispositionof 1. Aukunuru JV,KompellaUB.Invitrodeliveryofnano-andmicro- (through EmoryUniversity). DK064172, EY013842,andEY017045 several factors. drug-related considerations, treatmentobjectives, and includingpathophysiologicalfactors, willhoweverdosage form dependonseveral few months. The ultimatechoiceofthe deliveryretinal drug andeffects foratleasta areofvaluemicroparticles insustaining b Fornanoparticles. thisreasonandduetotheir etter retention, nanoparticles >200nmand etter retention,nanoparticles Amrite AC,AyalasomayajulaSP,CheruvuNP,KompellaUB. 2003;55:1199-1206. retinal pigmentepithelialcells.JPharmPharmacol. endothelial growthfactorantisenseoligonucleotideinhuman formulation enhancesthedeliveryandactivityofavascular Ophthalmol VisSci.2003;44:1192-1201. corticosteroid capableofinhibitingVEGFexpression.Invest nano- andmicroparticlessustainretinaldeliveryofbudesonide,a Kompella UB,BandiN,AyalasomayajulaSP.Subconjunctival Invest OphthalmolVisSci.2006;47:2093-2099. Margalit Eetal.Thesafetyofintraocularketorolacinrabbits. vascular leakage.InvestOphthalmolVisSci.2006;47:1149-1160. inhibits diabetes-inducedelevationsinretinalPGE2,VEGF,and Single periocularinjectionofcelecoxib-PLGAmicroparticles retinal drugdelivery.ExpertOpinDrugDeliv.2004;1:99-114. ex vivoeyemodel.MolVis.2006;12:1185-1198. functionalizations enhancenanoparticledeliveryinanovelbovine hormone-releasing hormoneagonistandtransferrin Kompella UB,SundaramS,RaghavaEscobarER.Luteinizing 1986;2:67-108. developments andfuturechallenges.JOculPharmacol. administration. JPharmPharmacol.2005;57:1555-1563. nanoparticles andmicroparticlesfollowingsubconjunctival Drug DeliveryTechnology.2002;2:50-57. particles tohumanretinalpigmentepithelial(ARPE-19)cells. Ayalasomayajula SP,KompellaUB.Subconjunctivally Syst. 2001;18:173-199. using supercriticalfluid technology. CritRevTherDrugCarrier HPbetaCD complexes.PharmRes.21;1119-1126. delivery ofdeslorelin:large-porousPLGAparticles and 2004;23:159-168. organic-solvent-free supercriticalfluidprocess.Eur JPharmSci. beta-cyclodextrin (HPBCD)complexesusingasingle-step, Preparation ofbudesonide-andindomethacin-hydroxypropyl- Bandi N,WeiW,RobertsCB,KotraLP,Kompella UB. PharmSciTech. 2002;3,E18. using supercriticalfluidprecipitationtechnology.AAPS Preparation ofbudesonideandbudesonide-PLAmicroparticles Pharm Res.2004;21:524-535. and cellularuptakeusingasupercriticalcarbondioxideprocess. deslorelin-PLGA microparticleswithreducedresidualsolvent rat model.EurJPharmacol.2005;511:191-198. drug levelsandalleviatediabetes-inducedoxidativestressina administered celecoxib-PLGAmicroparticlessustainretinal This work was supportedbyNIHgrants ACKNOWLEDGMENT REFERENCES 19. 19. Amrite AC,AyalasomayajulaSP,KompellaUB.Sustained 18. Yun M,BarnettME,RaghavaS,TakemotoD,KompellaUB. Escobar ER,CheruvuNP,ZhanG,TorisCB,KompellaUB. 17. Bandi N,RobertsCB,GuptaRB,KompellaUB.Supercritical 16. an related macular degeneration, diabetic retinopathy, delivery for treating corneal angiogenesis, age- Omaha. Hisresearch interests include drug and gene M Regulatory Affairs. He servesasanEditorial Board Pharm K UNMC Distin recognized withanAAPSFellowAward (2005)and a Technologies, Dr. Kompella’s research wasrecently in Pharm 1997 recipient of the AAPSNew Investigator Award positions inseveral professional organizations. A r o PhD inPharmaceutical Sciences from the University earned his BSand MS inPharmacy inIndia and his and ExpertOpinion onDrugDelivery. Dr. Kompella fr Research Forum.In2006,he received atravel award oral presentation atthe 2005Midwest Biomedical UNMC College of Pharmacy firstplaceawards for his Resear his oral presentation inthe 2005Midwest Biomedical was recognized withthe overall firstplaceaward for using nanoparticles and microparticles. Hisresearch Am Sci Pune, India. He earned hisBSinPharmacy from the University of 2006 Chairman of the UNMCAAPSStudent Chapter. Scientists (AAiPS).Mr. Amriteservedasthe 2005- eceived n f Conference oftheControlledReleaseSociety;2006. diabetic retinopathy.TheProceedingsofthe33rdInternational transscleral deliveryofbudesonideandcelecoxibfortreating Symposium oftheControlledReleaseSociety;2006. delivery vector.TheProceedingsofthe33rdInternational Human serumalbuminnanoparticleformulationasagene 2006;47:E-Abstract 4493. opacities intherabbitmodel.InvestOphthalmolVisSci. microparticles donotelevateintraocularpressureorinducelens Subconjunctival budesonideorbudesonide-poly(lactide) York, NY;2004:367-410. Kompella UB,ShekunovB,eds).Marcel&Dekker,Inc.:New Fluid TechnologyforDrugProductDevelopment(YorkP, ompella servesasanEditorf om th ember f d South entists (AAPS)and aresearch award from the eri lun can A aceuti ch Forum.Also,h e g ern Calif aceutics and the Pharmaceutical or th American Association of Pharmaceutical can BIOGRAPHIES umerous grants, and held leadership ssoci cal Research and Clinical Research and guished Scientist Award (2006).Dr. cer e . journ ation of Indian Pharmaceutical orni H Nebraska Medical Center (UNMC) in Sciences atthe University of Departm Dr. UdayB. Kompella Gr of the Pharmaceutical Sciences A A s N d d research focus isthe retinal Dr. Uday B. Kompella. Hiscurrent working under the supervision of e tudent atthe University of rugs aswellm elivery of lowmolecular weight ssoci ebraska Medical Center inOmaha, niruddha C.Amrite ad has beenpublish a. als DrugDeliveryTechnology u ate Pr e ate Pr received the UNMCand ent of Pharmaceutical ogr or th ofessor and Chairman am inthe e acr J ed e ourn omolecules i is an s xtensively, als a graduate ,

3M DRUG DELIVERY SYSTEMS:PROVIDING CUSTOMER-FOCUSED SOLUTIONS M Drug Delivery Systems is a global leader in inhalation and transdermal drug delivery systems, providing world-class product development, components, and 33manufacturing to pharmaceutical and biotechnical companies. This organization combines the agility of a leading drug delivery company with the extensive resources of a major multinational company. 3M products are manufactured and sold in more James Vaughan General Manager than 60 countries on 6 continents. Business partners benefit from 3M’s in-depth 3M Drug Delivery expertise and wide-ranging resources, including global regulatory affairs, lean Systems Division manufacturing, and 15 core technology platforms that give 3M Drug Delivery Systems “Speed-to- the flexibility to offer customized solutions to meet their customers’ needs. Drug market is Delivery Technology recently interviewed James Vaughan, 3M Drug Delivery Systems important. General Manager, on his organization’s strategic direction. Between drug discovery and commercialization, Q: Can you tell our readers Q: How does your business model our vertical some things about 3M Drug benefit partners? integration helps Delivery Systems they may not our partners know? A: What our pharmaceutical partners value get to market most is the access they have to all of 3M. For sooner.” A: That’s a timely question because there’s example, we have global regulatory expertise. been some confusion in the marketplace 3M has worked closely with the Food and recently. 3M Drug Delivery Systems is part Drug Administration and other regulators

around the globe for many years, and we 2 of 3M Health Care, one of the company’s six o N

understand the challenges and the 7 major businesses. Our mission is to provide l o complexities involved. Also, we have V

world-class innovative products and services 7 0 0 to help healthcare professionals improve the scientists around the world and can tap into 2 y r a u practice and delivery of patient care. This their expertise and knowledge. Our customers r b e past November, we sold one segment of that benefit from our global reach, our world- F y g o l

business – branded pharmaceuticals. But, let renowned technical community, and our o n h c e

me assure you, 3M Drug Delivery Systems manufacturing capabilities. Speed-to-market T y r e v

is important. Between drug discovery and i

is totally separate and continues to be a l e D

commercialization, our vertical integration g

strong strategic fit within 3M. u r helps our partners get to market sooner. D 57 58 Drug Delivery Technology February 2007 Vol 7 No 2 of have accessto3M’s entirerange with innovation. And ourpartners mind. Ournameissynonymous word innovation, 3Mistopof A: technologies addvalue? How do3M’s core Q: MN Inno wepast fall, openedthe 3M this minds behindthem.Infact, reall immersed ininnovation, andit customers. Ourcustomersare result inuniquesolutionsforour uncommon connectionsthat that sho And 3M’ technology we’re developing. applied toane more easily visible isbeing that isusedtomake streetsigns same microreplicationtechnology technolo advantage ofsome15core take solving, ourpartners product development orproblem have withourpartners. thatwe opportunities business de extensively inproduct technolo e and adhesives are also good xamples ofothercore v technologies andthe bright elopment. . So whether we’re focusedon When you thinkaboutthe y v It’ ation CenterinSt.P unlocks thepotential s wcases how we make gies. F gies thatw a s world-renowned films one-of-a-kind f w or e dr xample, the ug delivery e use acility aul, design components tosolv foam tapes. We canmodifyor liners,and thin andflexible films, varieties ofbackings,membranes, components includeman ofourbusiness. part Transdermal application requirements. adapted tomeetapartner’s design, andthetechnology canbe user the ef of molecules,anditcanenhance g market. This new technology has technologytransdermal to tobringthisnewpartner looking foraphar delivery. drug intradermal We’re system fortranscutaneousor a Transdermal SystemorMTS.It’s A: strategy? y into How doesthisfit to themarketplace. inhalation components transdermal and alsoprovideQ:You A: us more aboutit? Canyou tell mentioned. technology you just the newmicroreplication We’re curiousabout Q: reat potentialforawidev our overall business state-of-the-ar -friendly andwell-tolerated Yes, it’s calledMicrostructed Components areanimportant f icac y of vaccines. It’s a t microneedle maceutical y e ariety competitors want tousethem! our products–even our clear reflectionofthequality least one3Mcomponent. That’s a on themarket today containat patches 80% ofthetransdermal unique problems. about Infact, systems. their o companies thataredeveloping also available topharmaceutical available andare toourpartners systems. Ourcomponentsare optimize container/closure andcan properties formulation We thoroughly understand propellants andthecomponents. interactions between CFC-free for chemicalorph propellants. challenges like CFC-free e been ontheforefront,for inhaler components. And we’ve major supplierofmetered-dose metered-dose inhalers. the componentswe provide for Dr particularly evident withinthe strength of3M,andthisis A: What does3Mof manufacturing services. mentioned Q:You xample, ofdealingwith ug Deli The samecanalsobesaidfor Manufacturing isacore Manufacturing wn metered-doseinhaler very SystemsDivision.very There’ ysical s the potential W fer? e’re a We have facilities worldwide, and Q: A lot of drug delivery industry for 50 years, and, as a we can offer a full range of companies eventually company, we bring more than a advanced manufacturing become specialty century of innovation to the resources through the entire life pharmaceutical marketplace. That’s the cycle of a product. We provide companies. Why has 3M unprecedented experience we pilot to full-scale commercial sustained a true drug offer. N manufacturing, including delivery business model? Schedule C-II and C-III capabilities. Our ability to design A: I think we have a clear customized manufacturing vision. We know what we’re good processes is very important at, and we stay focused on that. because some partners come to us We’ve run a successful and stable at the product development stage organization for many years. As a and others already have a fully result, we are very customer- developed product that requires oriented and cost effective. Our production. We have product partners have unique registrations in more than 60 circumstances, so each countries, and all of our work collaboration is also unique to complies with global regulatory meet their needs. We’re in a fast- guidelines, including cGMPs. changing industry and that kind We also use LEAN of flexibility is important. manufacturing principles and There’s a big gap between a tools in our facilities. The focus is concept on paper and a product on eliminating waste in the supply ready for market. We work chain. That’s any activity that closely with partners to doesn’t add value to the customer. incorporate their drug molecules We don’t just reduce material into successful delivery systems. 2 o waste, we look at everything we It’s one thing to hold a patent and N 7 l o do. We’re reducing cycle time and quite another to deliver a real V 7 inventory and improving service 0 product that has met all of the 0 2 y r levels. LEAN manufacturing is a regulatory requirements and can a u r b e logical extension of our sustain itself after F y commitment to Six Sigma. We’ve g commercialization. 3M has a o l o n learned throughout the past 5 or h long-standing reputation of c e T y more years how to be lean r developing practical and e v i l e thinkers, and we can leverage that ingenious solutions that other D g u r experience on behalf of our firms simply can’t provide. We’ve D partners. been global leaders in this 59

LECITHIN ORGANOGELS

Lecithin Organogels as a Drug Delivery System: A Review By: I.M. Shaikh, MPharm; K.R. Jadhav, MPharm; V.J. Kadam, PhD; and S.S. Pisal, PhD

ABSTRACT

For many systemically acting drugs, the oral conditions, soybean lecithin in an apolar, route has been the preferred route of organic solvent forms an entangled, dynamic administration. However, oral administration of network of long and flexible wormlike, many therapeutic agents has been reportedly multimolecular aggregates.1 This so-called subjected to extensive presystemic elimination lecithin organogel is characterized by a by gastrointestinal and hepatic metabolism. considerably high viscosity and by a complete Topical administration of therapeutic agent optical transparency. A number of therapeutic offers many advantages over oral and invasive agents have been formulated as lecithin methods of drug delivery. However, as skin is an organogels for their facilitated transport through exceptionally effective barrier to most chemicals, the dermal and transdermal route with some very very few drugs can permeate it in amounts encouraging results. Lecithin organogels have sufficient to deliver a therapeutic dose. also been tried successfully for the ocular route. Therefore, systems that make the skin locally This review discusses salient features, formation, more permeable and thereby enable transdermal and various applications of lecithin organogels delivery are of great interest. Under certain as drug delivery systems.

FEATURES OF LECITHIN • Lecithin organogels are moisture FIGURE 1 ORGANOGELS insensitive, and being organic in character, resist microbial contamination.1,11,12 Some of the features of lecithin • Spontaneity of organogel formation, by organogels can be characterized by the virtue of self-assemble supramolecular following bullet points: arrangement of surfactant molecules, makes the process very simple and easy • Use of biocompatible, biodegradable, to handle.11 2 and non-immunogenic materials makes o N lecithin organogels suitable for long- • Lecithin organogels, prior to gelling (ie, 7

l 2-4 o

V term use. before the addition of polar phase),

7 exhibit Newtonian behavior but follow Schematic Diagram of Pseudoternary Phase 0

0 • Lecithin organogels can solubilize 2 Maxwell’s rheological (viscoelastic) Diagram (Blue Patch Shows Organogel- y r lipophilic, hydrophilic, and ampiphilic Existing Area)

a 13

u behavior on addition of polar phase. r

b guest molecules, including enzymes (due e F to reverse micelle formation).5-7 lecithin from soya beans. Lecithin is y

g LECITHIN

o mainly a complex mixture of l o

n • Lecithin organogels are thermoreversible h phospholipids, glycolipids, and c

e A Frenchman named Maurice Gobley T in nature. Above 40ºC, they become triglycerides. In chemical terms, lecithin is y r

e observed phosphtides, isolated them from

v solvent, and when the temperature is i a natural mixture of phosphatides that is l e 7 egg yolk in 1846 for the first time, and D decreased, they revert to gel state. phosphatidylcholine (20% to 31%) (PC), g u

r named them lecithin. In the 1920s, the

D phosphotidylethanolamine (PE), and • Lecithin organogels are Bollmann extraction process made it phosphtidylinositol (PI) in combination 60 thermodynamically stable systems possible to obtain large quantities of with fatty acids, carbohydrates, and other and isotropic in nature.8-11 LECITHIN ORGANOGELS

substances. Lecithin is a trivial name for 1, 2- FIGURE 2 diacyl-sn-3-phosphocholine.11 Soya bean lecithin contains 1.7% palmetic, 4% stearic, 8.6% palmitoleic, 9.8% oleic, 5% linolenic,

4% linoleic, and 5.5% C20 and C22 acids. Lecithin is made up of ubiquitous phospholipids that account for more than 50% of the lipid matrix of biological membranes. Lecithin organogels are readily obtained by adding a minimal amount of polar solvent, such as water, to a solution of lecithin in organic solvents.1 It was Scartazzini and Luici who first provided information about lecithin organogels in an article published in 1988.1

FORMATION OF LECITHIN ORGANOGELS

Lecithin organogels are formed by three Formation of Lecithin Organogel different components, including organic solvent, a polar phase, and an organogellator [lecithin]. The composition of these three However, it has been established that glycerol, The latter form the lipid matrix of biological components required for organogel formation formamide, and ethylene glycol (in addition membranes and also play a key role in 15 is determined from a pseudoternary phase to water) have the ability to induce organogel cellular metabolism. As a biocompatible 11 diagram. formation. The ability to promote thickening surfactant, it is widely used in every day life, of lecithin solutions has correlated with the including human and animal food, medicine, Organic Solvent polarity of molecules. The correlation is cosmetics, and manifold industrial 16,17 More than 50 organic solvents have been particularly pronounced in the series of such applications. Synthetic lecithins containing reported to form organogels with water as an structurally related compounds as glycerol, residues of saturated fatty acids failed to form 9,11,18 aqueous phase.1 Among various organic ethylene glycol, and 1, 3-propanediol. It has organogels. The gelling formation was solvents, fatty acid esters, such as Iso Propyl been inferred from the results that the also not observed with hydrogenated soybean difference between gelforming and non-gel- lecithin.11 These studies indicate the

Myristate and Iso propyl palmitate, have been 2 o widely used for lecithin organogel formation, forming polar solvents is caused by their importance of lecithin in the naturally N 7

orientation and localization in the polar occurring form, which contains unsaturated l

but structural investigations have only been o V performed on systems based on moiety of a lecithin molecule. In a proposed fatty acids. Unsaturation in phospholipid 7 0 hydrocarbons, ie, cyclohexane, iso octane, model of the organogel, the solvent molecules molecules is a desired property for the 0 2

11,13,14 y bridge phosphate groups of neighboring lipid formation of lecithin organogels. This may be r

and decane. a u molecules, thus allow their association into attributed to its impact on the nature of self- r b e Polar Solvent tubular aggregates through an extensive assembly in which the phospholipid F y

11 g

ribbon-like hydrogen bonding network. molecules associate and form the o A series of polar solvents have been l o n

microstructures. The unsaturation contributes h studied in order to reveal those capable of c e to the volume factor of the non-polar region T

Organogellator-Lecithin y

producing the thickening effect on r e v

Organogellator-lecithin is a trivial name for of phospholipid molecules and may alter the i hydrocarbon and fatty acid ester solutions of l e 1, 2-diacyl-sn-3-phosphocholine. It belongs to value of critical packing parameter (CPP), D lecithin. Water has been used extensively as a g u r polar solvent for organogel formation. a biologically essential class of substances favoring the formation of reverse micellar D termed phosphoglycerides or phospholipids. structures. And most likely, the size of such 61 LECITHIN ORGANOGELS

FIGURE 3 water, the thickening effect is observed at a certain specific molar ratio of water to lecithin. After this threshold concentration, further addition of water leads to a sharp increase in the viscosity and the formation of an organogel. For lecithin organogels prepared using isopropyl palmitate as the organic solvent, this sharp increase in viscosity is observed at nw = 3.28 The organogel state is maintained up to a particular molar ratio of water to lecithin, designated as ncr. At the state in which nw is equal to ncr, the maximum viscosity of organogel is achieved. On continuing the water addition above the ncr, ie, at nw > ncr, the three-dimensional network collapses, and separation of the homogenous Transformation of Spherical Micelles to Cylindrical Micellar Aggregates organogel takes place via a two-phase system consisting of low viscous liquid and a compact structures is also one of the crucial factors that It has been shown that the inclusion of organogel or jelly-like phase. For lecithin play an important role in the gelling process. pluronics as a cosurfactant makes the organogels prepared using isopropyl palmitate In addition to the effect on CPP and size of the organogelling feasible with lecithin of as the organic solvent, this stage is observed at microstructures, the property of unsaturation relatively lesser purity.22 The term “pluronic” nw = 5-6.28 A schematic of the pseudo ternary can also be interpreted in terms of degree of refers to a series of non-ionic closely related phase diagram for lecithin organogels is hydration of phospholipid molecules that it block copolymers of ethylene oxide and depicted in Figure 1. provides. In contrast to the saturated propylene oxide.23 Also known as poloxamers, hydrogenated phospholipids, unsaturation in poloxamer polyols, or Lutrols®, these are MECHANISM OF GEL FORMATION phospholipid molecules would result in better primarily used in pharmaceutical formulations hydration of the polar head group, thereby as co-surfactants, emulsifiers, solubilizers, The first prerequisite for gel formation is the increasing the area per lipid polar head group. suspending agents, and stabilizers. These balance of intermolecular interaction amongst Consequently, a larger area and relatively pluronic-containing LOs have been termed the gelator molecules (eg, Hbonding, vander smaller volume would favorably alter the “pluronic lecithin organogels.” Waals interactions, etc) and between gelator spontaneous curvature of lipid monomers for and solvent molecules. The latter helps in the 2

o the formation of micelles and subsequently formation of a continuous three-dimensional N

7 their self-assembly to form a micellar network. PHASE-BEHAVIOR OF network. The simplest mechanism of gel l o V Additionally, the purity of lecithin also plays a ORGANOGELS formation involves shifting the balance of 7

0 critical role in the organogel formation. Poorly intermolecular and intramolecular attractions 0 2

y purified lecithin does not possess gel-forming The phase-behavior of a ternary system of of the gelator molecules and organic solvent. r a u

r properties, and it has been demonstrated that lecithin/organic solvent/polar solvent is mainly This should result in a comparative increase in b e F lecithin should contain at least 95% governed by the concentration of polar solvent the intermolecular attraction amongst the y

g gelator molecules and a comparative decrease

o phosphatidylcholine content for the preparation and lecithin; the same is defined in terms l

o 1,11,13 n in the interaction between the gelator

h of organogels. The high-purity grade of the parameter, nw, ie, the molar ratio of c e T lecithin is not only expensive but also difficult polar solvent to lecithin (nw = polar molecules and solvent (eg, by addition of y r

e 1,11-13,24,25

v critical amount of water). This leads to the

i to obtain in large quantities. However, recent solvent/lecithin). It is noted that the l e

D reports indicate the incorporation of synthetic organogel as a homogenous phase exists over a formation of a molecular dispersion that g u r further results in the formation of a three- D polymers, ie, pluronics in LOs, for their very narrow range of polar solvent usefulness as cosurfactants and stabilizers.19-22 concentration.24,27 Initially, with the addition of dimensional network in which the organic 62 LECITHIN ORGANOGELS

solvent molecules are trapped (Figure 2). The • They have the ability to disperse the that both lipases keep their catalytic function gelation of the lecithin solutions in organic biocatalyst at a molecular level. after entrapment in the , catalyzing the solvents is induced as a result of the esterification reaction of 1-propanol with • It is possible to incorporate regenerable incorporation of a polar solvent. Lecithin, fatty acids in non-polar hydrocarbons at room cofactors. when being dissolved in non-polar media temperature.35 Stamatis and Xenakis have alone, self-assembles into reverse spherical immobilized Pseudomonas cepacia lipase in micelles at a concentration of about 0.01 • They are efficient in that they can be reused. lecithin organogels using gelatin, agar, and 29 mM. The enormous uniaxial growth of these • They are suitable to larger-scale synthesis. carrageenan as gelling agents. Gels prepared spherical-reverse micelles and subsequent from gelatin and agar are found to be most transformation into tubular or cylindrical • Organogels are stable when in contact with suitable for the esterification of 1-propanol micellar aggregates (sphere-to cylinder organic solvents as an external phase. with lauric acid in hydrocarbon solvents. transformation) is triggered by the addition of These gels have excellent operational stability • Enzymes immobilized in organogels also small and critical amounts of polar additive as in addition to being biocompatible.36 tolerate high substrate concentrations. shown in Figure 3. The molecules of polar solvent, on addition, bind in stochiometric • Enzymes immobilized in organogels are PHARMACEUTICAL ratios to the hydrophilic head portion of the also useful in conducting the reactions at APPLICATIONS lecithin molecules in such a way that two sub-zero temperatures. Temperature- adjacent lecithin molecules are bridged sensitive compounds and rearrangements or Lecithin Organogels as a Topical together by one polar molecule.9,13 This leads racemization can be avoided by conducting Drug Delivery System to the formation of linear networks, from reactions at low temperatures. Lecithin-based organogels have been hydrogen bonds formed by the polar proposed as a matrix for topical delivery of molecules and phosphate groups of lecithin • Enzymes immobilized in organogels also drugs. The mechanism, which is offered for molecules, and in turn, to the one- tolerate high-substrate concentrations. enhanced penetration, is that lecithin dimensional uniaxial growth of lecithin- disorganizes the structure of the skin slightly reverses micelles. Further increase in the Pastou et al have immobilized lipases from and thus increases the penetration of various amount of polar additive results in the Rhizomucor miehei and Candida antarctica in drugs. This may be due to the interaction formation of flexible, long tubular micelles lecithin organogels formed with agar and between the skin lipids and the phospholipids with a 2.0- to 2.5-nm radius and hundreds to hydroxypropylmethyl cellulose.35 It was found in the gels. Topical administration of a thousands of nanometers in length.24,25 After reaching a critical length, these extended FIGURE 4 micelles begin to overlap, entangle themselves, and build up a transient three-

10,11,30-34 2

dimensional network. o N 7 l o BIOTECNOLOGICAL V 7

APPLICATIONS 0 0 2 y r a u

Organogels in Enzyme r b e Immobilization F y

There are various enzymes that are g o l

35 o pharmaceutically important (Table1). n h c e

Enzymes immobilized in organogels offer T y r e

considerable potential for use in organic v i l e synthesis. The following are advantages of D g u enzymes immobilized in organogels: r Solubilization of Hydrophobic & Ampiphilic Guest Molecules in Reverse Micelles D

63 64

Drug Delivery Technology February 2007 Vol 7 No 2 LECITHIN lecithin organogels hasbeenreported. hydrochloride in amitryptiline formulated analgesic actionofketamine hydrochloride and one suchstudy, improvement significant inthe onset ofactionwithlow In side-effect profile. administration ofdr more adv andchronic,lecithinorganogelssurface, are orof gels hasbeenreported. peripheral orneuropathicpain. muscle spasmaswell asinthemanagementof been foundtobeeffective forthetreatmentof therapeutically effective amountofdigoxin has lecithin organogel containinga formulation transport ofdrugs. transport organogels asmatrixsystems fortransdermal and Luisiw of transport been usedasamatrixfortransdermal in inflammator oranyin psoriasis,psoriaticarthritis, other scars.Itwasor burn alsoshown tobeeffective topical treatmentofk and mucocutaneousjunction,thususefulinthe effectively inhibitthePKCactivity intheskin or lecithin organogels astopicalvehicles. cyclobenzaprin, amusclerelaxant,using repor 33000 daltons. macromolecules withamolecular weight of an excellent matrixfor the delivery ofa Lecithin or properties. penetration andpartitioning is otherwiselimitedduetotheirpoorskin use ofthesecompoundsfortopicalpainrelief inhibitor sphingosine, aProteinKinaseC(PKC) high skinpenetrationofphytosphingosine or g (tooth relief ofpainresultingfrombruxism organogels isshown toprovide immediate muscle relaxantadministeredinlecithin-IPM rinding) andtoothclenching.Remarkably v g dif olves PKC. It is inferred thatforthose olves PKC.Itisinferred anogel-based was formulation foundto acial disordersthatareregional, nearthe ted thesubcutaneousdelivery of ferent therapeuticcompounds. , antageous o incor ganogels have alsobeenfoundtobe ORGANO ere thef y condition oftheskinthat 41 porated inlecithinor Organogel systemshave also 42 ugs becauseoftherapid irst tostudylecithin The authorsinvestigated ver systemic eloids andh 3 9 The prepared 37 Friedman has yper g Willimann anogel 40 trophic 3 8 The The GELS organogel compounds: and diclofenacin lecithinorganogels [IPP(10 estradiol 17-enanthate, solubility datare lecithin or in obtained withbroxaterol incorporated aqueous solution. in incomparisontothatofdrug observed flux ofscopolamineinlecithin-IPPgelwas respectively. highertransdermal Significantly concentration of40mg/mland75mg/ml, broxaterol were solubilizedinthegeluptoa tw of lecithininabiocompatible solvent IPP, in employing lecithingelcomposedof200mM broxaterol agent) (abronchodilatory active against motionsickness)and drug deliverythe transdermal ofscopolamine(an and w propranolol hydrochloride, apoorly permeable in value. found topossessaremarkab no andthis with mild-tomoderateosteoarthritis, organogels inthetreatmentofpainassociated andsafetyof2%diclofenacinlecithin efficacy investigated. Graceetalhave assessedthe for ofvariousdelivery andefficacy NSAIDs inpetroleumjelly.emulsified The transdermal to thatofpuredr octane/water organogel systemincomparison employing ina200-mMlecithin/iso- drug acrossthehumanskinwasdrug observed ofmicellar-borne times higher)permeability enhanced(approximatelySignificantly 10 b clonidine. cypionate, isosorbidedinitrate,nifedipine,and molecules (F h micelles, which have abilitytosolubilize tothepresenceoflecithin-reverseattributed or ydrophilic, h -estradiol diacetate, vestigated of thetrans-skinpermeability g v o mulated inlecithinorganogels hasalsobeen anogels, acrosshumancadaver skin. el topical formulation ofdiclofenacwasel topicalformulation separate studies.Scopolamineand 44 ater Dreher et al incorporated indomethacin Dreher etalincorporated -soluble drug incorporated inlecithin -soluble incorporated drug 42 ganogels. Likewise, thereisgood This increaseinsolubilityis igure 4). ydrophobic, andampiphilicguest g ug insolutionfor arding thefollo Analogous resultswere b 33 -estradiol 17-v Bhatnag b b -estradiol 17- -estradiol 17-acetate, le therapeutic ar etalha wing lecithin m or alerate, 43 ve b - incor deliverytransdermal ofprogesterone in KTrelease.Shippenetalhave studied reports onthevariedreports fundamental aspectsof Thus, withtheinflow ofseveral research mark of theor Increasingthewaterw/w ofthedrug. content w/w ofKTcomparedtothosecontaining1% also obser A k for from 40%to50%andthen60%w/win that asthelecithinconcentrationincreased experimentally.determined Itwas observed membraneswas then various artificial from MBGsthroughintactguineapigskinand ofthedrug variables onthereleaseprofile or rat paw oedemawas withan observed inhibitionofcarrageenan-induced significant in aLOconsistingoflecithin/IPM/water. thedrug also beenattemptedby incorporating increase itstransder erythema. The solubilizationofpiroxicam, to persistence ofmethyl nicotinate-induced results sho vehicle. organogels inIPPaloneasthe vis-à-visdrug were foundtobehigherusinglecithin deliverythe transdermal ofbothdrugs ml), soy lecithin(1.9g),water (135 because ofitslo topical route. achie incor metabolism,hasbeen extensive first-pass Nicardipine, acalciumchannelb tested theminvivo withhumansubjects. methyl nicotinatelecithin-IPMorganogels and delivery, Boninaandcoworkers formulated potential oflecithinorganogels intransdermal tromethamine. lecithin or etorolac tromethaminereleasew g remarkable releasewas increaseinthedrug mulations, a significant decreasein mulations, asignificant anogel ofpiroxicam formulation vis-à-vis eted transder porated inlecithinor porated inanLOsystemorderto v e 2 systemic absorption throughthe systemic absorption g Aboofazeli etalhaveAboofazeli formulated ano v ganogels containingketorolac w ed in formulations containing6.5% ed informulations ed rapidinductionandintense 47 gels alsoresultedinanincrease 45 In anotherstudyonthe w The effect offormulation mal productafter3hours. dose, short half-life,and dose, short mal permeation rate,has mal permeation g ano gels. lock as obtained. 46 m er, l)], and 48 49 The A LECITHIN ORGANOGELS

TABLE 1 • because of their high viscosity and organic solvent as a continuous phase, are difficult to wash off.

Three formulations of organogels have been prepared by Fresta et al using lecithin as a gelator and organic solvents (paraffin, isopropyl palmitate, and cyclooctane).50 Cyclooctane gels have been found to be toxic, and paraffin-based gels have been found to be the safest, whereas isopropyl palmitate gels cause mild morphological changes. Hence, lecithin-based organogels hold good potential as ophthalmic drug delivery systems owing to their very low toxic potential, coupled with their unique ability to incorporate lipophilic, hydrophilic, as well as amphoteric compounds. In the case of drug delivery, the presence of stable barriers permits a slow Enzymes of Pharmaceutical Importance delivery of pharmaceuticals. This is likely the rationale for the performance of lecithin LOs, along with some promising results on Suspensions have a disadvantage in that the organogels made of isopropylmyristate as a the front of drug delivery, these systems can rate of drug release is dependent on the rate carrier of timolol maleate in glaucoma be seen as potential tools in the field of of dissolution of drug particles, which vary therapy. On contact with the lachrymal fluid, topical drug delivery applications. due to constant change in composition and a stable emulsion forms, leading to a outflow of lachrymal fluid. In order to controlled release of timolol maleate. increase the therapeutic efficacy, one of the Lecithin Organogels as an methods suggested is to increase the viscosity CONCLUSION Ophthalmic Drug Delivery so as to prolong the contact period. But, the System addition of viscosity builders, such as CMC, Lecithin organogels are emerging as novel Most ocular treatments call for the topical did not improve the situation much and in the drug carrier systems for drug molecules with diverse physico-chemical properties and

administration of drugs in the tissues around case of water-insoluble ointments, immediate 2 o the ocular cavity. Various types of dosage vision was affected. Lecithin-based macromolecules like proteins and peptides. N 7 forms have been developed for ocular drug organogels offer a potential ophthalmic drug The discovery of biocompatible substances, l o V delivery, which include drops, suspensions, delivery system that may overcome the such as lecithins capable of gelling various 7 0 ointments, ocuserts, more recently, eyelid skin aforementioned difficulties. These gels: organic solvents, has opened a new area in the 0 2 y development of novel drug delivery systems. r delivery systems. Eye drops are the most • present a unique feature of being able to a u r widely used and most popular but suffers These exhibit pharmaceutically useful b incorporate lipophilic, hydrophilic, as well e from the drawback that a majority of the properties like thermo reversibility, ability to F

as amphoteric bioactive compounds; y g o medication is immediately diluted by tears incorporate all types of drug molecules, l o n

• are transparent and hence even their long- h and is rapidly drained out by the constant tear increased resistance to microbial c e term presence in the ophthalmic cavity T contamination, and reduced risk of irritation. y flow. Therefore, only a fraction of r e v

does not affect vision; i administered drug is absorbed to target tissue The concept of drug delivery through l e D and thus, repeated administration of eye drops lecithin-based organogel systems has been g u

• released drug at a steady rate because of the r becomes essential, leading to poor patient studied extensively for various routes of drug D three-dimensional network of the gel; and administration, such as dermal, transdermal, compliance and undesirable side effects. 65 66

Drug Delivery Technology February 2007 Vol 7 No 2 LECITHIN 24. Shchipunov YuA, SchmiedelP.Phasebehavioroflecithinatthe 24. Collett JH,PopliHP.In:KibbeAH,ed.Handbookof 23. Crandall WT. Topicalmoisturizingcompositionandmethod.US 22. Giordano J,DaleoC, SacksSM.Topicalondansetroneattenuates 21. Burnham R,GreggHealyP,SteadwardR.Theeffectiveness of 20. Berti JJ,LipskysJJ.Transcutaneousdrugdelivery:apractical 19. Shumilina EV,KhromovaYuL,ShchipunovYuA.Lecithin 18. 17. SchneiderM.Industrialproductionofphospholipids-lecithin Wendel A.Kirk-OthmerEncyclopediaofChemicalTechnology. 16. Hanahan DJ.AGuidetoPhospholipidChemistry.Oxford 15. Pallazzo G,AngelicoR,CeglieA,OlssonU.Lecithinorganogels: 14. Shchipunov YA,ShumilinaEV.Lecithinbridgingbyhydrogen 13. Schurtenberger P,ScartazziniR,MagidLJ,LeserME,LuisiPL. 12. Shchipunov YuA.Lecithinorganogel:amicellarsystemwith 11. Shumilina EV,KhromovaYuL,ShchipunovYuA.Astudyofthe 10. 9. Walde P,GiulianiAM,BoicelliCA,LuisiPL.Phospholipid-based Capitani D,SegreAL,DreherF,WaldeP,LuisiPL.Multinuclear 8. 7. Willimann H,WaldeP,LuisiPL,GazzanigaA,StroppoloF. MitchellDJ,WinhamBW.Micelles,vesicles,andmicroemulsions. 6. 5. 4. 3. 2. 1. Scartazzini R,LuisiPL.Organogelsfromlecithins.JPhysChem. unco and theirpotentialfortheseremainstobe systems fortheotherroutesofadministration, has beendoneontheusefulnessofthese diffusion process.However, notmuchwork the organogel systemsiscontrolledby asimple a nd ophthalmic. releasefrommostof The drug reverse micelles.ChemPhysLipids.1990;53:265-288. Chem. 1996;100(37):15211-15217. NMR investigationofphosphatidylcholineorganogels.JPhys Pharm Sci.1992;81:871-874. Lecithin organogelsasmatrixfortransdermaltransportofdrugs.J J transdermal drugdelivery.IntJPharm.1999;184:1-6. Hadgraft J.Passiveenhancementstrategiesintopicaland 1996;9:124-129. of alecithinmicroemulsiongelandliposomes.SkinPharmacol. Dreher F,WaldeP,LuisiPL,ElsnerP.Humanskinirritationstudies Symp ControlRelBioactMater22Langmuir.1995:640-641. soybean lecithinmicroemulsiongelandofliposomes.ProcInt Dreher F,WaldeP,LuisiPL,ElsnerP.Humanskinirritationofa transdermal transport.JControlRelease.1997;45:131-140. microemulsion gelwithhumanstratumcorneumanditseffecton Dreher F,WaldeP,WaltherWehrliE.Interactionofalecithin 1988;92:829-833. oil/water interface.Langmuir. 1996;12(26):6443-6445. UK;2000:386-388. Pharmaceutical Excipients.3rded. Press:London, Patent No.6316428;2001. humans. EurJPharmacol.1998;31:13-14. nociceptive andinflammatoryeffectsofintradermal capsaicinin 1998;8:78-81. topical diclofenacforlateralepicondylitis.ClinJ Sports Med. review. MayoClinProc.1995;70:581-586. Colloid Journal.1997;59(4):514-518. organogels: theeffectofphosphatidylethanolamineadditives. processing. LipidTechnol.1997;9:109-116. Vol. 15.JohnWiley&Sons:NewYork,NY;1995:192-193. University Press:NewYork,NY;1997. Self-Assembly. IOSPress:Burke,VA;2003:318. structure, dynamics,andphasebehavior.In:RobinsomB,ed. 1995:43-50. bonds intheorganogel.MaterialsScience&EngineeringC3. micelles. JPhysChem.1990;94:3695-3701. Structural anddynamicpropertiesofpolymerlikereverse Engineering Aspects.2001;183-185:541-554. unique properties.ColloidsSurfAPhysicochemical& spectroscopy. ZhurnalFizicheskoiKhimii.2000;74(7):1210-1219. structure oflecithinorganicgelsbyFourier-transformIR Chem SocFaradayTransII.1981;77:601-629. vered. ORGANO REFERENCES GELS 50. Mackeben S,MullerM,Muller-Goymann CC.ColloidsSurfA. 50. Fresta M,Puglisi G.VenturaCA,PanicoAM,MazzoneMG, 49. 48. Agrawal GP,JunejaM,S,JainSK,PancholiSS. 47. 46. Shippen E.Progestroneorganogelforpremenstrualdysphoric 45. 44. 43. 42. 41. Crandall WT.Transdermaltransportofpharmaceuticals.PCTInt 40. Ford PR.Topicalanalgesiccompositionscontainingcream-type 39. Crandall WT.Methodfortopicaltreatmentofscarswithprotein 38. Friedman M.Treatmentofbruxism.USPatentNo.6632843;2003. 37. Charles L,MatthewD.Cardiacglycosidesfortreatingmuscle 36. Stamatis H,XenakisAJ.Biocatalysisusingmicroemulsion-based 35. Pastou A,StamatisH,XenakisA.Microemulsion-based 34. 3 Voit AV,ShchipunovYuA.Dynamicsofpolymer-likelecithin 32. Shchipunov YuA,HoffmannH.Thinningandthickeningeffects 31. Shchipunov YuA,ShumilinaEV,HoffmannH.Lecithin 30. Shchipunov YuA,ShumilinaEV,HoffmannH.Lecithin 29. Shchipunov YuA,DurrschmidtT,HoffmannH.Electrorheological 28. 27. Angelico R,CeglieA,ColafemminaG,LopezF,MurgiaS, Shchipunov YuA,ShumilinaEV.Lecithinorganogels:roleofpolar 26. Shchipunov YuA,SchmiedelP.Electrorheologicalphenomenain 25. 3. Shchipunov YuA,MezzasalmaSA,KoperGJM,HoffmannH. 3. Aboofazeli RZ,HosseinN,ThomasE.Transdermaldeliveryof Aboofazeli RZ,NasseriAA,HosseinZ,ThomasEN.Lecithin Willimann H,LuisiPL.Lecithinorganogelsasmatrixfor 2001;183/185:699. 1997;48:328-329. delivery systems:atoxicologicalstudy.JControl Release. Moschetti V.Lecithinorganogelsaspotentialophthalmic drug organogels ofpiroxicam.Pharmazie.2004;59(3):191-193. Preparation andcharacterizationofreversemicellebased methyl nicotinate.JControlRelease.1995:34:53-63. formulations oninvitroandvivopercutaneousabsorptionof Menegatti C,NastruzziC.Effectsofphospholipidsbased Bonina FP,MontenegroL,ScrofaniN,EspositoE,CortesiR, Drug Deliv.2002;9(4):239-247. nicardipine: anapproachtoinvitropermeationenhancement. disorder. JAmAcadChildAdolescPsychiatry.2001;40:262-263. Pharma Res.2003;117-124. of ketorolactromethamine.II.invitroreleasestudy.IranianJ stabilized microemulsionbasedorganogelsfortopicalapplication 1999;26:2659-2663. patients withosteoarthritisoftheknee.JRheumatol. versus placebo:adoubleblind,randomized,clinicaltrialin Grace D,RogersJ,SkeithK,AndersonK.Topicaldiclofenac delivery ofpropanaolol.JMicroencapsul.1994:2:431-438. Bhatnagar S,VyasSP.Organogel-basedsystemsfortransdermal 1991;177:897-900. transdermal transportofdrugs.BiochemBiophyResCommun. Appl. WO9803641;1998. carriers. USPatentApplNo.2002028789;2002. kinase Cinhibitors.USPatentNo.6306383;2001. pain andspasmUSPatApplicationNo.20030229029;2003. 1999;6:399-406. polymer gelscontaininglipase.JMolCatalBEnzym. Prog ColloidPolymSci.2000;115:192-195. organogels containinglipase:applicationinthesynthesisofesters. P L 2 m Rheologica Acta.2000;39(6):542-553. induced byshearinginlecithinsolutionsofpolymer-likemicelles. lactobionamide. ColloidPolymerSci.1998;276(4):368-372. organogels withnalkyl-D-glucosidesandn-alkyl-D- 1998;199(2):218-221. organogels withalkylglucosides.JColloidInterfaceSci. Interface Sci.1999;212(2):390-401. effects inlecithinorganogelswithwaterandglycerol.JColloid and phaseequilibria.Langmuir.2005;21:140-148. Olsson U,PalazzoG.Biocompatiblelecithinorganogels:structure 1996;58(1):117-125. solvent andnatureofintermolecularinteractions.ColloidJournal. 1996;179(1):201-206. lecithindecane-water mixtures.JColloidInterfaceSci. 000;62(4):424-430. hys ChemB.2001;105(43):10484-10488. ecithin organogelwithnewrheologicalandscalingbehavior.J icelles rheologicalmeasurements.ColloidJournal. Award for Young Teachers. recipient of the prestigious 2002Career Center, Pune-411 038,India. He isa Cen Sandoz Pharmaceutical Development currently working as Researcher at o f Pharm ter (In BIOGRAPHIES acy, Navi-Mumbai, India. di a). India. Pharmacy, Navi-Mumbai, Dr. V.J. Kadam, an Professor of Pharmaceutics Vidyapeeth College of Bharati Vidyapeeth College Pharmaceutics atthe Assistant Professor of MPharm, isworking asan Pr Mumbai, India, and is of Pharmacy, Navi- Bharati Vidyapeeth College Pharmaceutics from the earned hisMPharmin Mr. ShaikhM.Ishaque Pharmacy and Research BVDU, Poona College of Bi and Head, Pharmaceutical Dr o d otechn . fessor K.R.Jadav, S.S. Pisal, Prin cipal of Bharati ology (PG), is Pr is o fessor

XCELIENCE:EXCELLING & ACCELERATING ITS PARTNERS’SCIENCE celience is a Tampa-based formulations company that’s making waves in the biotech and pharmaceutical industries by formulating and manufacturing products with XXunprecedented speed. The small but rapidly-growing company produces solid, semi- solid, and liquid dosage forms, manufactures batches for stability testing, scales up and Derek Hennecke produces pilot batches, and manufactures clinical trial supplies from Phase I through to Phase Chief Executive Officer IIb. It has a clean compliance record in North America, and several European QP reviews Xcelience under its belt. Drug Development Technology recently spoke to Derek Hennecke, Chief “Our values are Executive Officer of Xcelience, to learn more about the company as well as its drug quality and speed. development and manufacturing solutions. I say it in that order for a reason. Q: Xcelience is an unusual Our experienced scientists continue to be our We are passionate name. Can you tell our readers core strength. about getting our more about it? In fact, we are very proud of our sponsors’ products compliance record and multiple European QP to the clinic, but A: We wanted a name that reflected our reviews. Xcelience is a privately held we don’t cut values. Our core values are quality and company with no private equity funding, no corners with quality. Our people speed. We want to provide top-quality debt, and a strong cash position. This is give us confidence custom-made products for clients who need different from our competitors, many of whom in our quality. them, yesterday. The first half of the name are on an acquisition spree or have recently But for speed, should make you think of excellence, or been put on the selling block. Xcelience’s well, that’s where

excelling; but also of accelerating. The latter investors are long-time devotees of this 2 o

technology comes in.” N half is from the word science. Thus, business. They’re not going anywhere. 7 l o Xcelience is about excelling and accelerating Our management brings years of experience as V 7 0

science. well. Take Vice President Randall Guthrie, for 0 2 y r

example, who received a Presidential Citation a u r b e Q: Is your company new to the at this year’s 20th anniversary meeting for his F y g

longevity and dedication to the AAPS o market? l o n h

(American Association of Pharmaceutical c e T y A: Not at all. The company was formed in r

Scientists). Randall has 30 years of experience e v i l e

1997. In 2006, we changed ownership and in the Pharmaceutical Service Industry. D g u r

launched a new name and a stronger focus. D

67 68 Drug Delivery Technology February 2007 Vol 7 No 2 Xcelodose I’m goingtotalkaboutthe having thebesttechnology, and sa values are qualityandspeed.I secret toquality. scientists, simply put,arethe do going toletthewhole team because ifthey can’t, they’re A: do you dothis? How drugs first-in-man. companies get their else athelping be faster thananyone Xcelienceclaimsto Q: y machine aloneisn’t goingtogive one pieceofthepicture. A me tellyou thattechnology isjust w afford tohave peopleonstaff we keep looking. We justcan’t minds, of themanagementteams’ offer. Ifthereisany doubtinany before they arepresented withan meeting every seriouscandidate interviews, andIinsiston There areseveral roundsof checksare. and background on ho the best.Jobapplicantscomment experienced scientists. We hire the rightpeople. speed together. For thatyou need going togi ou speed ho can’ y wn. it inthatorder forareason. As Imentionedearlier, our It reall Part of being the fastest is ofbeingthefastest Part w T op-rated tough ourinter t , TM pull y and certainly isn’t and certainly ve you qualityand star later on. But first, let later on.Butfirst, their own weight, , ts withha e xperienced vie ving wing is theXcelodosetechnology. certainlybut thegeminfield the latestandbesttechnologies, make apointofalways having technology comesin.For this,we speed, well, that’s where inourquality.confidence Butfor with quality. Ourpeoplegive us weclinic, but don’t cutcorners productstothe our sponsors’ We arepassionateaboutgetting Nor A: Xcelodose. readers more aboutthe Pleasetellour Q: need fore alone, thereby eliminating the substances capsules withdrug technology allows ustofill Capsugel BVBA). This unique (Xcelodose isatrademarkof Capsugel’s Xcelodosetechnology de candidate compoundsfor increase inthroughputof decision point,w the f reduces thetimetaken toreach it Inturn, with hand-filling. possible inaccuraciesassociated and time-consuming formulation reducing theneedforcostly and developmentthe drug processby and prefor v elopment. th This substantially abbreviates The Xcelodose isaprecision We CRO were in thefirst irst-in-man clinicaltrial America tointroduce xcipient compatibility mulation acti hich allo vities. ws an lo For example, asponsorgave usa throughout thecompany’s history. regularlyrelease formulations A: formulations? controlled-release experience with Tell usaboutyour Q: used tomak process wasAn API densification water andhadlot-to-lotvariation. also unstable inthepresenceof API. Ifthatwasn’t enough, itwas deviation. accuracy of2%standard quality asw endears ittome)impro and (somethingthatparticularly This reducestimelineslippage material foruseinclinicaltrials. to producingclinicaltrial Obviously, it’s particularly suited hundred capsulesperhour. excipients) atarateofseveral (APIs) intocapsules(without ingredients pharmaceutical activedirectly fills It than100milligrams. greater rangeof100micrograms to fill automated encapsulatorwitha powder micro-doserand of the API, throughdetermination prefor studies. for PhaseIpharmacokinetics intohardcapsules filling uniform w density We’ve been doingcontrolled- mulation characterization The PKdataand , ell, withimproved e lo the w melting point API suitab v es le for of pKa, solubility in various discovery that one of the spearheaded by our Scientific solvents, moisture uptake, DSC, components in the drug product Director, Dr. Steve Bannister. His and TGA was used to design and was deteriorating the HPLC 23 years of experience in develop a controlled-release column and needed to be managing and consulting in the tablet for continued clinical study. removed prior to analysis. We pharmaceutical industry will help In the end, a suitable developed an extraction method our growing client base to plan, was developed, and the sponsor and included a step to precipitate execute, and evaluate the filed a patent to protect its out the interfering excipient. The development of drug products. intellectual property. supernatant was collected, rinsed, And the one thing we won’t do? and evaporated before being Xcelience will not be developing brought to a total volume of 5 its own NDAs. We believe that Q: Where do you see mL. This low total volume was would be a disservice to our the drug delivery necessary for analysis of related clients. Once a CRO starts to challenges coming in compounds at a very low level. In pursue an NDA, there are only the future? the end, we recovered 100% of two possible outcomes, neither of the NME from the drug product, which serves the sponsor. Either A: Our new ads use the slogan and the method has been the NDA is successful and the “send us your biggest challenge.” validated for use in routine company starts diverting its top The increasing complexity of testing of clinical supplies. talent and resources to it and drug development means, simply putting sponsors next in line; or put, that there are fewer and the NDA fails, creating a cash fewer simple cases. Q: Does your company pit. This ultimately leads to For example, many people have any new plans for cutbacks and shuffling of have reported the difficulty of the coming year? resources to cover shortfalls. formulating low soluble and/or Given the loyalty our sponsors low permeable drugs in our A: Always! I can tell you two have shown us throughout the collective futures (classes II to IV things we plan to implement right years, we feel no temptation to of the BCS). Even after the away, and one we won’t pursue NDAs. If we do our job development of a suitable implement at all. We plan to right and our sponsors are 2 o formulation, it is important to N

extend our services via our successful, they return to us and 7 l o develop the analytical methods. website, www.xcelience.com, we ride along on their success. V 7 0

In one case, a sponsor requested 0

through two major projects. We’ll Everybody is happy. N 2 y r

a formulation of an NME below a

launch an online pharmaceutical u r b e 10 µg/gram for a topical forum, which will open the F y

application. A suitable semi-solid g o

dialogue of drug development l o n h

dosage form was found, but it c

and where we can answer e T y was difficult to extract the NME r e

questions and provide advice on v i l e from the drug product. A series line. 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DrugDelivery oneofthe ofthe$5.3-billionNittoDenkoCorporation, subsidiary Avevaisawhollyowned Transdermal technologies. DrugDelivery throughtheuseofitsproprietary populations patient underserved focusedon Systemsisadrug-enablingcompany Aveva DrugDelivery Brian Guy (Director, Business Development) at (954) 624-1271 or visit or 624-1271 (954) BusinessDevelopment)at Brian Guy(Director, collabora Avevaiscurrentlylookingforapartnerto 2005. in billion $12.5 845 9521orvisit projects. totakeonyourtoughest staffisready andinnovative creative Our andhotmeltformulations. aqueous, Our facilitiesprocesssolvent, andcontrolledsubstanceproducts. OTC, forRx, masking applications moistureoroxygenbarrierandtaste- orsustainedrelease, delayed, suchasenteric, include Applications controlledoraldelivery, support. and commercialmanufacturinginaGMPenvironmentwithanalytical tment ofasthma, D .avev EVELOPMENT te onthedevelopmentofthisnovela For more information, contact Coating Place, Inc. at (608) at Inc. Place, contactCoating For moreinformation, adds.com L ICENSING www a . market whichhadglobalrevenuesexceeding .encap .com & O tion endpointcriterion. . PPORTUNITY M The productsuccessfullymet ehooytase,scale-up, transfer, technology development, formulation includeOur services contract andtablets. hard shellcapsules, includecapabilities , Othercoating beads. and crystals, granules, powders, of fluid bedmicroencapsulation specializingin company Wurster development andmanufacturing systems drugdelivery owned Coa ANUFACTURING ting Place, pplica tion. n.isaprivately Inc. Aveva’ Please contact s visit SCOLRPharmaa protection (fullpa andstrongpatent payload (whencomparedtoothertechnologies), higher costeffective(utilizesstandardtabletingexcipients), equipment), conventionalmanufacturing easytomanufacture(employs profiles), including ofawiderangerelease highlyprogrammable(capable arrangements. uponfinancial orothermutuallyagreed manufacturingcontracts, royalties, companies undercontractualarrangementstha SCOLRPharmapartnerswith conventional productionequipment. Lablabo a visit For moreinformation, fortransdermal applications. packaging anideal astandstillposition, or containmentofthepouchat delivery, precisedosage thebottle couldbeusedupside-down, restitution, 100.000 cps)andthemostfluid(alcohol) andoffersexcellent EasyFoil acceptsthemostviscousproducts(> oxygenorUV. against C ONTROLLED t www SCOLR Pharma'sCDT tent lifeandeasyenforcement). .lablabo.com A t www IRLESS .scolr D , rvd efc are,especially provide aperfectbarrier, withasufficientthicknessto material cup beingproducedinthesame choice willbePPorPE, theinternallayer the productused, of Dependingonthenature thickness. aluminum layerof12micronsin PP orPElayerwra of anexteriorPETlayerandinterior Thefilmiscomposed plastic material. inferior cup, welded aroundasuperiorringandan aluminum multilayerfilmrolledupand fitted withapouchconsistingofan LABLABO’s newEasyFoil bottleis or [email protected]. ELIVERY .com B ® CDT itspatented SCOLR Pharmaapplies a be manufacturedusingreadily periods forupto24hoursandcan be usedforcontrolled-release elegantly simpletechnologiescan These nutraceutical products. and OTC, pharmaceutical, forcompanieswith formulations Technologies todevelop has theman vailable standardma . OTTLE ® Controlled Delivery both producedinathick t inc F P or moreinforma y lude licensingfees, pping acentral LATFORM distinct advantages, the ringand terials and tion,

71 Drug Delivery Technology February 2007 Vol 7 No 2

Company Pg Phone Web Site

3M Drug Delivery Systems 5 800-643-8086 www.3m.com/dds

Baxter BioPharma Solutions 13 800-422-9837 www.baxterbiopharmasolutions.com

BD 23 800-225-3310 www.bdpharma.com

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

Coating Place Inc. 2 608-854-9521 www.encap.com

Controlled Release Society 65 651-994-3817 www.controlledrelease.org

Davidson, Davidson & Koppel 29 212-736-1940 www.ddkpatent.com

Drug Delivery Technology 71 973-299-1200 www.drugdeliverytech.com

Dow Chemical Company 19 1-800-447-4369 www.dowexcipients.com

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

ExcipientFest 41 787-746-5080 www.exceipientfest.com

2 InnerCap Technologies 3 813-837-0796 www.innercap.com o N 7 l o V PharmaCircle 15 847-729-2960 www.pharmacircle.com 7 0 0 2 y r a RDD Europe 49 www.rddonline.com u r b e F y g o

l Scolr Pharma, Inc 9 425-373-0171 www.scolr.com o n h c e T y r

e Specialty Pharma 4 www.specialtypharma.com v i l e D g u r D Weiler Engineering 7 847-697-4900 www.weilerengineering.com

72

Why CEOs Are Underpaid! By: John A. Bermingham

he departure of Bob Nardelli from Home Depot has demanding hours and travel requirements, but does the job really fired up a lot of people recently. Not because he security of thousands and retirement plans of millions rely on TTwas asked to leave Home Depot by the Board of your decisions? People who save lives for a living are excluded Directors, but because he left with a $210-million dollar as their services are priceless. There is much more, but I don’t severance package. Sheesh! A $210-million package for want you to think that I’m whining. Well maybe a little. failing in your job and getting fired? We should all be so Now if you look at what a CEO does for a living, what is lucky. The guy was really overpaid, right? Well, maybe not. that person’s worth to the company to make those sacrifices? When Bob Nardelli was passed over for the CEO position What does it take financially to keep them motivated and hard at G.E. by Jack Welch, Mr. Nardelli became a hot property to working? What should it cost to have a person successfully lead another company. I am certain that Bob Nardelli was not lead a company that makes billions? What about just looking at Home Depot but was instead being courted by compensation for the hours worked? Most CEOs work 70 to several companies to become their CEO. So what did it take 80 hours per week to include weekends. What is that worth? to convince Mr. Nardelli to take the Home Depot position So here is the final issue on CEO compensation. Question: instead of going to another company? How about a $210- How much should you pay a CEO to lead the company to million severance package negotiated up-front, amongst other success? Answer: Whatever it takes. Okay, back to Mr. perks, before he took the position. Nardelli and Home Depot. So looking at the supply/demand ratio, Mr. Nardelli being I think that the Home Depot compensation committee the supply of one and many companies competing in the should have pegged Bob Nardelli’s severance agreement to demand column for his services, the cost was very high to performance-based metrics. If the Board chose to release him land him. I don’t know of any CEO who thinks he or she is without cause, then there should have been a much lower over paid, me included. I said in a previous article that being a guaranteed minimum with upside depending on his CEO is the best job in the world and the worst job in the performance against those metrics over the duration of his world. Just depends on the day. May I now include the most time with the company. But then again, Home Depot may not underpaid job in the world? have landed him with that kind of deal. So was the $210- I think that pressure is the number one issue that every million dollar severance package worth it? Ask the CEO faces because the ultimate responsibility for the shareholders! N company rests with the CEO, and every move made is put under a microscope and can make or break an empire. As Harry Truman said, “The buck stops here,” and every CEO B IOGRAPHY faces the same issue. The final decision, right or wrong, rests with the CEO. John A. Bermingham is currently the CEO of The Lang Companies, an innovative leader in the social Adding to the pressure are the time demands, both personal sentiment and home décor industries. He was and professional. CEOs are on call 24/7, and their days are not previously the President, Chairman, and CEO during the

2 necessarily under their control. Early morning (7 AM) arrivals successful turnaround and sale of Ampad, a leading o N at the office are commonplace, and late-evening departures manufacturer and distributor of office products. With 7

l more than 20 years of experience in guiding enterprises o are as well. Most CEOs eat lunch on the run. Attendance at V to new levels of performance, Mr. Bermingham also held the positions of

7 special events, charities, etc is expected. And being at home

0 Chairman, President, and CEO of Centis, Inc., a diverse multinational 0

2 does not relieve you from your company responsibility. You manufacturer and marketer of office, storage, and human resources y

r still have complicated financial and strategic documents to

a products. Among many career highlights in the role of President and CEO, u r

b read that you could not accomplish at the office, conference he also successfully reorganized Smith Corona Corporation and refocused e F calls, e-mails, and telephonic Board Meetings are some of the operations and a strategic vision for a dramatic turnaround for Rolodex y

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

o at-home issues a CEO faces. l

o giants, such as AT&T Consumer Products Group, and by having served as the n Then there is the travel (several trips a month). Very early h

c EVP of the Electronics Group and President of the Magnetic Products Group, e

T morning wake-ups, hassles at the airport, delayed flights,

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

v dinners consisting of a bag of pretzels on board, late arrivals at

i Army Signal Corps with responsibility for Top Secret Cryptographic Codes l e

D the hotel to find that they do not have your reservation, etc. and Top Secret Nuclear Release Codes, earned his BA in Business g u

r Don’t forget the missed anniversaries, birthdays, special Administration from Saint Leo University, and completed the Harvard D family events, you name it. University Graduate School of Business Advanced Management Program. 74 Yes, it is true that many professions face the same