March 2007 Vol 7 No 3 www.drugdeliverytech.com IN THIS ISSUE

INTERVIEW WITH DPT’S PRESIDENT MR. PAUL JOHNSON In Situ Gel Systems 30 Mitan Gokulgandhi, BPharm Dharmesh M. Modi, MPharm COX-II Microspheres 38 Lakshmi Sivasubramanian Madhumathi Seshadri Undermining CEO’s 82 John A. Bermingham

FEATURING

Parkinson’s Disease 59 Steven Damon Yogi R. Patel

The science & business of specialty pharma, biotechnology, and drug delivery Specialty Pharma Indices 64 Dr. Barath Christopher Avani Amin, Josef Bossart, PhD Shankar Robinson, PhD Drug Delivery’s PhD Current Status of Clinical Trials Increasing New Ways to Non-Invasive In Asia 68 Importance to Partner With Insulin Delivery Ames Gross, MBA Big Pharma & the Federal Technologies Specialty Pharma Government Momoko Hirose

4 Drug Delivery Technology March 2007 Vol 7 No 3 $15.00, US,Canada,andMe 01923; pho Technology LLC for librariesandotherusersregistered withtheCopywriteClearance, 222RosewoodDrive, Danvers, MA items f Periodicals Postage Paid atMontville, NJ07045-9998andadditionalmailingoffices. Postmaster: Delivery T States, Canada,andMexico. AllsubscriptionsarepayableinUSfunds, drawnonUSbanks. Sendpayment to:Drug Subscription rates:$99.00f October (ISSN 1537-2898)ispublished10timesin2007,January, February, March,April,May, June, July/August, September, responsibility f o All editorialsubmissionsarehandledwithreasonable care, butthepublishersassumenoresponsibilityfor thesafety or inf be reproducedortransmitted inanyform orbyanymeans, electronicormechanical,includingbyphotocopy, recording, the U.S.,Internationaland P address changestoDrugDeliveryT f artwork, photographs ormation storageandretrieval system,withoutwrittenpermissionfromthepublisher or internalpersonaluse , and November/DecemberbyDrugDeliveryT echnology LL ne: (978)750-8400, f or theaccuracyo East &Midwest Mailing ListRental International W C est Coast subscription Department,219ChangebridgeRoad,Montville NJ07045.Singlecopies(prepaid) , or manuscripts or 1yearintheUnitedStates 219 Changebridge Road, Montville, NJ07045 an-American CopyrightConventions xico; $24.00inallothercountries ax: (978)750-4470. f EXECUTIVE EDITORIAL DIRECTOR inf [email protected] , echnology ormation suppliedhereinorfor anyopinionexpressed. Drug DeliveryTechnology or theinternalpersonal useof specificclients, isgrantedbyDrugDelivery Can Ralph Vitaro Warren DeGraff 103 Oronoco Street, Suite200 Cheryl S.Stratos -Account Executive Victoria Geis-Account Executive March 2007 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 Vol 7No 3 [email protected] . en toensureaccuracy . All rightsreserved.Nopart of thispublicationmay on C, 219ChangebridgeRoad,MontvilleNJ07045. Add $5.00perorderfor shippingandhandling. al M an ag er , but publisherscannotaccept . A uthorization tophotocopy please send

6 Drug Delivery Technology MArch 2007 Vol 7 No 3 acquisition targets orlicensing partners.” and specialty pharmaceutical companies as remain the focus of attention of big pharma result, DrugDeliverycompanies are likely to platforms and re-branding products. As a late-stag en “Drug Deliverycompanies are likely to able pharmaceutical companies torevive e pr od u cts byusing drug delivery p.26 30 26 48 38 Delivery: AReview Delivery: I acquisition targets orlicensing partners. attention of big pharma and specialty pharma as companies are likely toremain the focus of branding products. As aresult, drug delivery products byusing drug delivery platforms and re- pharmaceutical companies torevive late-stage says the drug delivery market islikely toenable Frost &SullivanResearch Analyst Barath Shankar Pharma &Specialty to BigPharma Delivery’s IncreasingDrug Importance various non-invasive technologies for insulin. MPharm, PhD;r Jagruti Patel, MPharm,PhD;and Anuradha Gajjar, A TechnologiesDelivery Non-Invasive Insulin Current Status of of the three polymers used. microscopy, and stability studies toprove the best release studies, flowproperty, scanning electron drug content, microencapsulation efficiency, methyl cellulose)and various characterizations like sodium carboxymethylcellulose, hydroxypropyl use three different polymers (ethyl cellulose, Madhumathi Seshadri and LakshmiSivasubramaniam S In Vitro Release & Characterization, f COX-II Inhibitor-Loaded Microspheres necessary. better penetration through the cornea are prolonged contact time withthe cornea surface and optimize topical oculardrug delivery systems, R. Parikh, PhD,explain intheir research thatto Mitan R.Gokulgandhi, Dharmesh M.Modi, and Jolly or Familial Adenomatous Polyposis: n vani Amin,MPharm,PhD;Tejal Shah,MPharm; tability Studies tability S it u Gel Systems Drug for Ocular evi ew th e curr ent statusof the in vitro

59 Addressing Unmet Needs in Management of Parkinson’s Disease Mr. Steven Damon and Mr. Yogi R. Patel discuss the development of a transdermal skin patch to provide continuous delivery of apomorphine for the prevention of “off” periods and an improved option for the symptomatic management of Parkinson’s Disease.

68 Conducting Clinical Trials in Asia Mr. Ames Gross and Ms. Momoko Hirose explain that with steadily increasing drug development costs and significant time spent on clinical trials, outsourcing clinical trials in Asia has rapidly become an appealing option for many firms.

77 R&D Takes Center Stage at DPT Executive Summary: Paul Johnson, President of DPT, tells Specialty Pharma why his company is turning its attention to R&D while still maintaining its focus on dosage forms, as well as its desire to remain privately held.

DEPARTMENTS

Market News & Trends ...... 12 3

o Business Development ...... 20 N 7

l New Ways to Partner With the Federal o V

7 Government: Insights From King 0 0 2 Pharmaceuticals h c r a M Technology Showcase ...... 56 y g o l o n

h Facts & Figures ...... 64 c e T y r

e External Delivery ...... 82 v i l e D On Guard….or is it En Guard? g u r D

8 9 Drug Delivery Technology April 2006 Vol 6 No 4 10 Drug Delivery Technology March 2007 Vol 7 No 3 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 Merck Research Laboratories Biologicals &Vaccines Pharm Associate Director, Marc J.Kirchmeier, PhD D M Vice President, Global Sarath Chandar, MBA S A Development BD enior Director, R&D errigo Company PI Pharma evelopm dvan opharm arketing &Commercial ector o Technology D Director Executive Editorial Dan Marino,MSc ector o or Director, Drug rug Delivery aceutical R&D ced DrugDelivery aceuti f ent e f nt nt Exploratory Busin cs & ess 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, T President &CEO John A.Bermingham Pharm Associate Professor of Uday B.Kompella,PhD Development Pfizer GlobalResearch & Form Director, Research Keith Horspool,PhD Wilm Partner, FDA Department James N.Czaban,JD U M ctinium he Lang Companies axter Healthcare niversity o edi nell Stamoran cal Cen erH ulati aceuticals aceuti ale on s ter f cs N ebr aska Glax S.R. One, Limited, Investment Manager Philip L.Smith,PhD Pharm Brookwood and Chief Scientific Officer Executive Vice President T at Austin University of Texas Pr James W Labor M Director Henry Y. Wu, PhD,MS Corium International President &CTO Phar Gary W. Cleary, PhD, P Investigator, Matthew D.Burke,PhD GlaxoSmithKline Pr Ravi Kiron,PhD,MBA Eur President, North America John Fraher R&K Con om Tice, PhD harmaceutical Development er ofessor of Pharmaceutics esi an ck Resear oSmithKlin d mD, MBA atories d aceuti en t sultin . McGinity, PhD cals ch e g

12 Drug Delivery Technology March 2007 Vol 7 No 3 our f infections. and indicationsfor Amphotericin B.” w such, itcouldha marketing approval,” saidDr. MarkSirgo, PresidentandCEOofBDSI.“As mark ef according totheCentersforDiseaseControlandPre parasitic diseasethataf Amphotericin Bisalsoanimpor patients who arereceiving cancerchemotherapy. esophageal candidiasis,aninfectionprevalent inHIVpatientsandmany potent, broadly active antifungicidalagentfortreatinginfections,suchas isanenchocleatedversion of IND was filed Amphotericin B(CAMB),a deliverycochleate drug technology. The leadBioralproductforwhich the D D B Technology Delivery First INDfor Cochleate Drug Bioral® Amphotericin IND: BDSI Announces FDA Acceptance of of our resources from current projects.”of ourresourcesfrom current they have theknow-how todevelop additionalproductswithout any diversion Biovail’s withthe in-depthfamiliarity AcuForm we platform, areconfident said JohnFara, PhD, Depomed’s President,andCEO. Chairman, “Given our AcuForm technology, validating further thepotentialforitsbroadutility,” commercial salesofany productdeveloped undertheagreement. also stipulatesthatBiovail make royalty payments toDepomedon net approvaland uponreceiptofUSregulatory foreachproduct. The agreement PhaseIIItrialforeachproduct, of thelicenseoption,initiationfirst contingently obligated topay Depomedadditionalfeesrelated totheexercise have nodevelopment obligations undertheagreement. upon listofcompoundsatany timeover thenext 18months.Depomedwill products.Biovailpharmaceutical may selecttheseproductsfromanagreed- Depomed’s AcuForm technology todevelop andcommercializeuptotwo ofBiovail, SRL,asubsidiary Laboratories International anoptiontolicense development ofuptotwo Biovail products. access toDepomed’s proprietary AcuForm delivery drug technology forthe a and cost. Delivery TechnologyDelivery v e fecti ailab Dr. Sirgo continued, “Although we continuetospendthevast majorityof The patentedBioralcochleatetechnolo In additiontothetreatmentofsuchinfectionsasesophagealcandidiasis, Dr. Douglas Squires,CEOofBiovail, added, with “Thisagreement “We pleasedtohave arevery with Biovail enteredinto thisagreement for BiovailIn return, haspaidDepomedanup-frontfeeof$500Kandis Biovail Depomedhasgranted oftheagreement, Under theterms “CAMB w are encouragedb epomed & Biovail Sign License Agreement &Biovail License for AcuForm Sign epomed acceptance by theUSFDA ofBDSI’s INDforthecompany’s first Bioral and ioDelivery Inc.recently thefiling SciencesInternational, reported companies have thatprovides enteredintoanagreement Biovail with epomed, Inc.andBiovail recently announcedthatthe Corporation inancial andotherresourcesonourPhaseIIIBEMA et islimitedb v le e, theuseofcur in ” the ould bethef w v orld, ifclinicaltrialsaresuccessfulandtheproductachieves e y a y the requirementforintra major impactonthetreatmentandproph the potentialfor fects anestimated2millionpeoplew irst broadl rentl y tant dr a v ailab y mulations fortheBioraltechnology ef ug fortreatingLeishmaniasis,a le Amphotericin Bproductsonthe fecti gy hasthepotentialtotransfor v v enous administration,toxicity, e oral antifungicidalagent vention. While highlyvention. While ® F entan orldwide, ylaxis offung yl product, m al dr andtoxic number ofadditionalexisting injectable, difficult-to-formulate, CAMB couldsuppor f andsafetyofCAMBinour volunteers thedistribution normal todetermine no accomplishment fortheBioralcochleatetechnolo potential par adv highl and ChiefScientif period usinganimalmodels, infections andsubstantialsafetyle gastrointestinal tract. gastrointestinal enzymesandacids,orcannotbeabsorbedthroughthe and delivermoleculesthatareeitherbroken down drug certain by substancesandaredesignedtoencapsulate,protect, of naturally occurring injection, intopatientfriendly, orally available products.Cochleatesaremade suchas drugs, Amphotericin B, which available arecurrently only by Infectious Diseases,andNationalInstitutesofHealth(NIH). by inpart theDivisionsupported of AIDS, National Institutes of Allergy and of pharmaceutical productsutilizing advanced deliveryof pharmaceutical drug technologies. clinicaltesting,registration, andcommercialization manufacture, formulation, candidate, GabapentinGR. completed aPhaseIItrialindiabetic peripheralneuropathy withitsproduct neuralgiaandhas The company isconductingaPhaseIIItrialinpostherpetic beingmarketedwith type2diabetesandiscurrently intheUSand Canada. hydrochloride extended-release tablets) hasbeenapproved foruseinadults marketed intheUS.Inaddition, once-daily Glumetza(metformin being tractinfectionsand arecurrently treatment ofuncomplicatedurinary extended-release tablets have beenapproved by theFDA for theonce-daily ProQuinXR(ciprofloxacin hydrochloride) profiles. pharmacokinetic and reducedsideeffects, improving patientconvenience, compliance,and AcuForm-based productsaredesignedtoprovide once-daily administration and improved, ofexisting extended-release oraldrugs. formulations innovative AcuForm delivery technology drug todevelop novel oralproducts negotiation relatedtoany Depomedacquisitiontransactions. first Purchase toeliminateBiovail’sAgreement rightsandrightof Boardobserver development pipeline.” delivery drug technologies deepenitsdrug- complementary tofurther Depomed isanotherexample ofBiovail leveraging with strategic partners irst PhaseIe ugs. w Dr. Manninocontinued, “TheFDA’s acceptanceofthisINDisamajor “CAMB consistently against systemicfungal showed efficacy significant The de Biovail company isaspecialtypharmaceutical engaged inthe Corporation Depomed, company Inc.isaspecialty pharmaceutical utilizingits In addition,DepomedandBiovail have amendedtheirMay 2002Security antageous asw in apositiontopotentiall y ” cost-competitive protocolthatwe manufacturing expect willbe v elopment ofBioralCAMBforfung tnering discussions. v aluation. Inaddition,w ic Of e mo t the e f v icer e through thene xtension oftheBioraltechnolo . ” “In addition,w y stated Dr broaden ourproductof ” vels throughoutthepreclinicaldevelopment e TM . belie Raphael Mannino,BDSI’ xt stageofclinicaltestingand D e v e believe we have developed a al infectionshasbeen rug positi gy andourcompan ve clinicaltrialsof ferings andmo gy toalarge s F ounder y ve into . W e are

14 Drug Delivery Technology March 2007 Vol 7 No 3 delivery technology, including asthmapatchesaswell aspatchesfor treating awidevariety ofdiseases. for alarge numberofcompoundsinarangetherapeuticclasses, for to ofreducedsideeffects when andoffer conjugated efficacy thebenefit pol tissue withhighefficiency. a solubilityandactas therapeutic agents,cangreatly enhancethedrug's biocompatible polymer materialwhich, when linked tocertain Cancer CenterofUCSDtak subsidiaries in24countriesaroundtheworld. member ofNittoDenko GroupcomprisingNittoDenko andits117 includingbiomedicalmaterials.Itisa research invarious fields, University SanDiego (UCSD). ofCalifornia, adding thatthedevelopment hasbeenconductedincollaborationwith biodegradable polymer material,thecompany announcedrecently, technology foranovel delivery system(DDS)usinga drug subsidiar J N "car Nitto Denko possesses a strong portfolio of transdermal drug oftransdermal Nitto Denko possessesastrong portfolio NDTisengaged inhigh-tech Located inOceanside,California, existing drugs. In addition, it has the potential to serve asacarrier Inaddition, ithasthepotentialtoserve existing drugs. Cor apan's leadingdi The technology NDTdeveloped thistimetogether withtheMoores While notpossessingany perse,the therapeuticproperties ymer-based carrier hasshownymer-based carrier thepotentialtoincreasetherapeutic itt rier" withpromisingpotentialtodeliver suchagentstothetarget poration hasde o y Nitto Denko Technical (NDT),aplatform Corporation D e nk v ersif o veloped, atitswholly owned USR&D S ied materialscompan ubsidiary Develops Novel Drug Delivery Technology Novel Delivery Develops Drug ubsidiary Platform es advantage ofabiodegradable and y Nitto Denk o high toxicity or poorsolubility. whosecommitment topromising drugs development was halteddueto exhibit hightoxicity (side-effects) orpoorsolubility;andrenewed chemotherapy; improved that ofexisting drugs therapeuticefficacy reduced sideeffects classes,suchascancer ofexisting drug technology would resultinachievement and ofincreasedefficacy R&Dfromhereon. forfurther and isbeingearmarked DDSassets, inadditiontotheGroup's existing transdermal platform, ne biomedical-related technologies. w a by leveraging NittoDenko's polymer synthesiscapabilities,todevelop engaged inextensive researchintobiomedicalmaterialsapplications delivery industry. Aside fromthis new technology, NDThasalsobeen polymer inthelucrative synthesistoincreasetheirbusiness drug by leveragingplan toincreasetheirprofit-margins in theirexpertise delivery drug patches. selling transdermal expandingand ofmanufacturing engaged thebusiness infurther Deli Ha ischemic hear ell asapolymeric foroligonucleotidesynthesisand solidsupport gene delivery reagentbasedonabiodegradable cationicpolymer, as w It isen Showing promisetoexpand this theGroup'sMedical business, great The technology developed by NDTisconsistentwithNittoDenko's ving addedtoitsMedicalDi very Systems)"inFlorida2003,NittoDenkovery Groupisactively technology isexpected tobecomethecoreofanew technological visaged thatsuccessfulcompletion ofthedevelopment ofthis t disease, withalar vision aUScompany (Aveva Drug ge shareintheJapanesemark et. IOMED Introduces HybresisTM System at American Physical Therapy Association’s CSM

OMED, Inc., a leader in the development of active drug Idelivery systems using iontophoresis, recently introduced the new Hybresis System, a first-of-its-kind integrated mini-controller and patch system that uses no lead wires and can deliver in-clinic treatment in as little as 3 minutes. The product was showcased to attendees of the American Physical Therapy Association's Combined Section Meeting this past February in Boston. The Hybresis System consists of a wireless, miniaturized, rechargeable controller that connects directly to an iontophoresis patch and a charging station with four controller bays. The product combines leading-edge design and function with the efficacy, safety, and quality that embody IOMED products. "The Hybresis System is a quantum leap in iontophoresis technology,” said Robert J. Lollini, IOMED's President and CEO. “For the first time, clinicians have access to a wireless system that offers precise dose control, alternative treatment modes, is easy to set up, and can significantly increase patient throughput due to shortened in-clinic treatment times. Patients who use iontophoresis now have access to a discreet, comfortable system that does not require long wear times." Mr. Lollini said the Hybresis System could also lend itself to applications in new markets outside of physical and occupational therapy and sports medicine markets, which have long used iontophoresis delivery systems. IOMED, currently awaiting 510(k) clearance for the 3 o

Hybresis System from the US FDA, expects to ship the N 7 new product within the next several months pending l o regulatory approval. V 7 0

IOMED is a leader in developing, manufacturing, and 0 2 h c

marketing active drug delivery systems used primarily to r a treat acute local inflammation in the physical and M y g

occupational therapy and sports medicine markets. The o l o n company is pursuing opportunities to advance its position h c e as a provider of quality, innovative non-invasive medical T y r e v i products that improve patient healthcare. IOMED seeks to l e D

accomplish this by expanding its product line, distributing g u r new products, developing strategic partnerships, and D through acquisitions. 15 16 Drug Delivery Technology March 2007 Vol 7 No 3 technology. combination antibiotic/cor withInSite negotiate alicenseagreement Vision for AzaSite Plus,a azithromycin.ingredient Inaddition,Inspirehasanexclusive optionto withDuraSite formulated Canada. azithromycin,AzaSite containsthedrug antibiotic, abroad-spectrum e FDA forthetreatmentofbacterialconjunctivitis. solution), atopicalanti-infective underreview productcurrently by theUS Canadian commercializationof AzaSite (1.0%azithromycin ophthalmic I I for bothsingle-entity andcombinationproducts." ophthalmic anti-infective USprescriptionmarket, which exceeds $600million AzaSite, ifappro organization, andprovides asizable near-termrevenue opportunity. We believe focus inophthalmology, onthecapabilitiesof our commercial builds addition of leveragesAzaSite toour late-stageproductportfolio ourtherapeutic V 2years ofcommercializationand25%thereafter.in thefirst InspireandInSite by authorities. regulatory The royalty ratewillbe20%onnetsalesof AzaSite on netsalesof AzaSite forocularinfectionsintheUSandCanada, ifapproved approvalcontingent uponregulatory by theFDA. Inspirewillalsopay aroyalty license feeof$13millionandanadditional$19milestonepayment AzaSite xclusi ision ha nS licensing ag nspire Phar Christy L.Shaf Under theter The ag v it e v reement pro rights tocommercialize e e also enteredintoasuppl V maceuticals, Inc.recentl reement withInSite Vision fortheUSand Incorporated TM ms of the agreement, InspirehasacquiredfromInSite ms oftheagreement, Vision v ision &I fer ed , , vides thatInspirewillpa could captureameaningful shareoftheg PhD ® , ticosteroid productfor , President andCEOofInspire,commented InSite Vision's delivery vehicle. patenteddrug AzaSite forocularinfectionsintheUSand nspir y y ag announced thesigningofane reement fortheacti e y InSite mulated withDuraSite Pharmaceuticals in$32-Million on LicensingDeal Pharmaceuticals Vision anup-front v e ro pharmaceutical wing , xclusive "The with theDuraSite patents heldb patentfamily throughasub-license fromInSite Pfizer Vision. Incombination Treating EyeInfections primar representati approval, we plan toexpand ourexisting salesforcetoatotalof98 position tolaunchtheproductinsecondhalfof2007.Following an Fee Act (PDUFA). If AzaSite isapproved atthattime,we expect tobeina ND among commonocularpatho conjunctivitis. With theemergence ofandincreasingantibacterialresistance ocularinfections,includingbacterial potential treatmentoptionforexternal of theUniversity ofMiami,addeded, "AzaSiterepresentsanexciting new Rodgers DistinguishedChairinOphthalmology, Bascom Palmer Eye Institute pipeline," Shaf to positionuswell forfuturepotentiallaunchesofotherproductsinour related toourotherpipelineproducts. We expect thesestrategic enhancements patent coverage through2019. acti a representing anattractive combination ofawell-known, effective antibiotic,and agreement with Pfizer Inc. under Pfizer's patentfamily titled Inc.under Pfizer's withPfizer agreement regimen usedfortheseconditions." thanproductscurrently novel delivery system. drug AzaSite hasthepotentialtoprovide robust "W Terrence P. O'Brien,MD, ProfessorofOphthalmology andCharlotteBreyer InSite A vity ag e by theendof by User April 2007,asdetermined thePrescriptionDrug y look forw care pro V ainst themostcommonpatho ision hase ves who willcallontargeted specialistsandselectpediatricians fer concluded. viders, withthepotentialforadditionalphased-ine ard tothecompletionofFD x ecuted aworldwide, exclusive royalty-bearing licensing with Azithromycin. Inspirehasobtainedaccesstothe gens, y InSite AzaSite w gens withamoreconvenient dosing V ision, ould beaw AzaSite ise A's review ofthe AzaSite elcome addition xpected toha Method of xpansion ve New Pharmaceutical Services Company – Senopsys – Makes Pharmaceuticals More Palatable

eff Worthington, a noted expert in pharmaceutical sensory analysis and Jformulation development, recently announced the launch of Senopsys LLC, a specialty services company that partners with pharmaceutical, biotechnology, and drug delivery companies and their CROs to improve the palatability of pharmaceuticals. Headquartered in Massachusetts, Senopsys uses proprietary sensory assessment tools to identify the critical sensory attributes of drug substances, quantify taste-masking challenges, measure the flavor quality or palatability of drug prototypes and competing products, and develop target sensory profiles that result in patient-acceptable pharmaceuticals. The company also works with drug developers to assess the suitability of novel dosage forms for specific drug substances and develop new formulation systems for investigational and approved drugs. “The simple truth is if patients don’t like a medication, they just won’t take it, which can have far-reaching implications on patient health and the widespread acceptance of a drug product,” said Mr. Worthington, Founder of Senopsys. “Many will point to a product’s flavor (orange, grape, chocolate) as the key determinant of patient acceptance; but a drug’s palatability is much more complicated than its flavor. The key to developing palatable pharmaceuticals lies beneath the surface and includes factors, such as balancing the four basic tastes (sweet, sour, salty, and bitter) building blend and body, extending the aftertaste duration, and adding beneficial mouth feel factors.” “Unfortunately, few drug developers have the expertise to effectively evaluate or optimize these factors, which can have such a significant impact on acceptability and sales,” he continued. “This is where Senopsys steps in. We help reduce technical and market risks associated with a product’s aesthetics so that developers can concentrate on other technical aspects of clinical and commercial development.” Senopsys is an independent and objective partner that does not license technology or sell ingredients. The results of the company's work are custom formulations that meet the needs of diverse patient populations. Drug manufacturers continue to introduce new dosage forms, such as fast- dissolving tablets, oral films, and soft chews, that are more convenient, portable, and easier for children, the elderly, and impaired patients to swallow. Most of these dosage forms are based on food technology and each has its own set of unique challenges, such as taste-masking, hardness, texture, stickiness, and ease-of-swallowing, that developers must 3 o

address to create a product patients will find acceptable. Senopsys applies N 7

its knowledge of flavor construction, excipient functionality, and l o processing technology to develop formulations for both traditional and V 7

novel dosage forms of investigational and approved drugs that meet the 0 0 needs of specific patient populations. 2 h c r

“Developing palatable drug formulations for specific patient groups a can be a daunting challenge,” explained Mr. Worthington. “The pediatric M y g

market, for example, is particularly tricky and likely the reason that drug o l o developers have not introduced more pediatric medications despite n h c e regulatory requirements and incentives to do so. Many of the dosage T y r forms that work for adults, such as tablets and capsules that bypass taste e v i l receptors, simply are not age appropriate for children. Senopsys has the e D expertise to develop palatable dosage formulations that are acceptable to g u r any patient group.” D

17

in b fold versus thesubcutaneousinfusionprecededby placebo. The infusionpreceded subcutaneous LRinfusionaccelerated theflow rateofLRby approximately four- Ringers (LR)trial,w trial followsto IVmorphine. The INFUSE-Morphine theINFUSE-Lactated phar events forSCinjectionswithHylenex recombinantversus salineplacebo). recombinant-related toxicity was apparentbasedonacomparisonofadverse injection siteredness,rash,s and themostcommonly adverse events reported measuring absorption; were mild administration,as calculatedbasedonthesamplingtimepointsfor morphine Utilizing Subcutaneousl time cur recombinant provided exposure (4-hourareaundertheconcentration- totaldrug withHylenex plasma concentration(p<0.05);SCadministrationofmorphine when injectedwithHylenex recombinant,a33%reductioninthetimetomaximal minutes when injectedsubcutaneously withthesalineplaceboto9.2minutes maximal plasmaconcentration(Tmax)ofmorphine; Tmax was reducedfrom13.8 accelerationintheaveragedemonstrating astatistically timeto significant patients inthetrialinclude:validation ofthehypothesis was achieved by andtoassesssafetytolerability.morphine, thetime tomaximalblooddetermine levels afterintravenous administrationof after subcutaneousadministrationwithandwithoutHylene study, was thetimetomaximalblood designedtodetermine levels ofmorphine for bothintravenous andsubcutaneous administration. Mor andforsubcutaneous(SC)hydration.and dispersionofotherinjecteddrugs is approved by theUSFDA foruseasaspreadingagenttoincreasetheabsorption recombinanthumanhyaluronidase ingredient, (rHuPH20),whichpharmaceutical without theneedforintra such asanalgesia,may beachieved morerapidly by subcutaneousinjection, administered mor tolerated. by withplacebo,andappearedsafewell- 33%versusmorphine morphine (hyaluronidase humaninjection)acceleratedthetimetomaximalblood levels of withHylenex recombinant subcutaneous administrationofmorphine indication of clinical utility observed inthis study."indication ofclinicalutilityobserved tofully testingiswarranted thepromising for thetrial."Further determine Uni Medical DirectoratSanDiego HospiceandPalliative ofthe Care,anaffiliate H Infuse-Morphine Study Hylenex From the Results for theUse of Promising Present Halozyme &Baxter y v These results suggest that SC morphine plusHylenex recombinantprovidesThese resultssuggestthatSCmorphine Key resultsfromanalysis ofthe12evaluable hospiceandpalliative care The doub "The observed shortening ofthetimetomaximalconcentration foraco- shortening "The observed Hylene estig Hylenex by recombinantalsocausedlessedemaandwas both preferred v phine isawidelyapproved forpainmanagementandiscurrently useddrug macokinetic characteristicsthataresuperiortoSCmor ersity ofCalifor presentation ofresultsaPhaseIIIBclinicaltrialshowing that alozyme Therapeutics, Inc.andBaxterHealthcarerecently announcedthe ator (for92%ofsubjects)andstudy subjects(92%). v e, x A recombinant isaliquidinjectab le-b UC) ofmor lind phine withHylenex recombinantimpliesthatclinicaleffects, , nia, SanDie hich sho randomized, crossover, placebo-controlled, INcreasedFlow y-Enab phine anditsacti v enous infusion,"saidJa w w elling, anditching(however, noHylenex ed thattheuseofHylene led Mor go SchoolofMedicineandPrincipalIn phine clinicaltrial,orINFUSE-Mor ve metabolitethatwas comparable toIV le for mulation thatincludestheacti y Thomas, MD, PhD, Clinical x recombinant preceding x phine aloneandcloser recombinant, to vestigator phine v e

19 Drug Delivery Technology March 2007 Vol 7 No 3

20 Drug Delivery Technology March 2007 Vol 7 No 3 y hitpe oisn B,PD andDebraBingham PhD, MBA, ChristopherRobinson, By: King Pharmaceuticals New Ways toPartner InsightsFromWith theFederal Government: insights fromourconversation withtheseexecutives. ner 50 y critical suppliertotheUSDepar andemergencymilitary medicalneeds. This company hasbeena autoinjector dr itself asaworld leaderinthedevelopment of andmanufacture Meridian Medical Technologies, Inc.in2003,Kingestablished atKingPharmaceuticals. experts Through itsacquisitionof delivery forthedrug industry.the opportunities par industry, thishasledtoaresurgence ofnew to opportunities threats topublic health.For andbiotechnology thepharmaceutical address thenation’s vulnerabilitytobiological, chemical,orother AtroPen emer F :Whatare King’s autoinjectorproducts and Q: pralidoxime injection) by emergency responders. Another Autoinjector) b technolo antidotes fromoneinjection,will replacetheMarkIkit. This new technology, which sequentially delivers thetwo agent criticalnerve Mark Ikitisbeingphasedout.King’s new dual-chambered 1” kitsof Atropine/Pralidoxime autoinjectorsintocombat. The 3“Mark agentpoisoning.Soldierswillcarry treatment fornerve produces aPralidoxime Chlorideautoinjector, which isanadjunct agentpoisoning. organophosphorus ornerve The company also injection ofmedications. forces, emer system tomeetthedemandingoperationalneedsofUSar untrained, autoinjectorsprovide a compactandportabledelivery can becumbersome,time-consuming,andintimidatingforthe def A: F v tner withthegovernment. Inthismonth’s we forum, investigate ined asacute-careproducts.Unlike atraditionalsyringe,which King’s autoinjectorproducts(Figure 1)cangenerally be tec ears, andremainstheonly approved supplierofautoinjector e agentantidotes. genc To explore thistopic, Valeo spoke Partners withateamof EpiPen government steppedupitsefforts to hassignificantly Katrina,andthefearofapandemicflu,US hurricane ollowing events suchinfamous as9-11,theanthraxscare, hnologies? ® gy iskno , containingatropine,isusedtocountertheeffects of y treatmentoflife-threateningallergic reactions. ® genc , containingepinephrine,isanautoinjectorforthe ug deli y themilitar y responders,andpatientsrequiringacute/chronic wn as v V ery systems with specific applicationsto systemswithspecific ery aleo willsummarizethek ATNAA (Antidote Treatment Nerve Agent y andDuodote(atropine and tment ofDefenseformorethan e y pointsand med A: products beingusedisprobab de undersevereperform conditions. As anexample, oneofKing’s toensurethatthey can standardsforruggedness field tough military administered inacontrolledsetting. These products mustsatisfy products pharmaceutical requirements thatarenottypicalofnormal is needed. extinguisher, whichis thatofafire noonethinksaboutuntil have theseproducts available incaseofexposure. A goodanalogy A: get inworking itsstart withthegovernment? how didMeridian From ahistoricalperspective, Q: Q: militar key unmettechnology needthatwas asubjectofdebateat drug contentsofan autoinjectorbydrug feel,insteadofby sight, which packaging design featuresallow asoldiertobe able toidentifythe clothing andstilldeliver anintramuscular injection.Special learning tousetheseproducts. learning norneedle,assistsoldiersin units thatcontainneitheradrug forpainmanagement. and onethatcontainsmorphine Trainers, or to alleviate convulsions resultingfrompoisoningby agent nerve autoinjector productcontainsdiazepam,ananti-convulsant, used that was avast improvement over thesyrette(Figure 2). w controlled setting,b have usingthesyrette. difficulty The productworked well ina squeezed. Soldiersexposed agentswould tonerve understandably needle throughwhichsolutioncontainingatropineis thedrug or toothpaste. The tubehadatiny capthatisremoved toexpose a aluminum tubesimilartothatusedforappl W atropine. existing technology calleda“syrette”foradministrationof as able towork withthegovernment todesignanautoinjector ord War II. The syretteproductwas containedinasmall vices isspecif Over 50years ago,oneofMeridian’s respondedtoa founders Perhaps difference thegreatest isthatthechanceofthese Go Ho A seconddifference isthattherearemany uniquedelivery y conferenceheattended. v w ar ernment unique? This deli e pharmaceuticalpr ically designed topenetratethroughseven layers of v er ut it was not ideal for battlefield use.Meridian ut itwas notidealforbattlefield y systemw l y lo as designedintheearly days of The objecti w . Ho oducts f w e ver, to itisimportant ying topicalointments ve was toreplacean or the

might be compromised in a combat day and night that have King’s nerve agent antidotes in them. So, if FIGURE 1 situation (eg, darkness, smoke). there is an attack on the subway in the city, these antidotes are going to Prolonged stability is important, as show up on the scene. the environment in a military or Bioshield and BARDA (Biodefense Advanced Research & emergency setting is not ideal for Development Agency) legislation was just signed into law. The this purpose. government is investing heavily in research and development to address When considering the gaps in our current capabilities to protect not only the warfighter, but government customer, a drug also the civilian, against certain threats. There are now many more delivery system must be able to development opportunities that have gone beyond bioterrorism agents withstand the practical realities on to other health threats, such as pandemic flu. As a result of the the ground. Take the original broadened scope and increased availability of development funding, the syrette example. Now imagine for overall environment could not be more favorable to drug delivery a moment a scared soldier, in the companies with innovative technologies and products. field with thick heavy gloves, a Funding and distribution channels for EMS products have also mask, and body armor, trying to squeeze the contents of a small changed significantly. The Department of Homeland Security (DHS) toothpaste-like tube through several layers of clothing, all the while now allocates funds to the cities and states that can purchase at the suffering the initial effect of a nerve agent. An autoinjector is the best local level. Now a firehouse in any metropolitan area can apply for solution. Technologies, such as these, adapted to emergency use will funding to purchase supplies for first line of defense products and always be attractive to the government. likely not be turned down if they can justify their need. Because this is Lastly, the government has a range of needs, depending on the a local decision, one fire station may have an entire system in place to agency and the product. Biodefense agents (eg, antibiotics, vaccines) obtain multiple sources of preparedness funds, while another may not are well-suited for stockpile because you have some time to administer even be aware that funding is available. Companies must understand treatment once those who have been exposed have been identified. everyone who might buy their product at all levels of government. However, victims of nerve agent exposure need to be treated immediately, as they only have minutes to survive. It is important that local EMS arrives with antidotes already on board their vehicles. Q: What are the challenges in working with the The national stockpile is designed to deliver supplies anywhere in Government as a development partner? the United States within 8 hours. For biodefense agents, this makes perfect sense, but not for chemical agents. In order to help address this A: There are many challenging aspects of partnering with the need, the government developed the CHEMPACK program, which government that differ from the typical experience in the commercial places forward deployments of the national stockpile into key sector. Generally, a company can expect much longer development metropolitan areas. Even these inventories are considered a second line timelines to get products to market. If you look at some of the more of defense. The public still relies on local first responders to have recent Requests for Proposals (RFPs), they are calling for products to access to antidotes in emergency settings, so the buyers and distributors be available in 5 to 15 years. This might be discouraging to emerging may be different depending on the product. or start-up drug delivery companies ready to commercialize their 3

o

N Drug delivery technologies play a critical role in addressing the technologies.

7

l government’s unique needs. Using the chemical defense arena as an The second key issue is that the developer has no influence over o V

example, the major changes in the past 50 years have primarily been in Federal funding priorities. If the political system decided to shift 7 0

0 the delivery systems, not the medicines. Atropine has been around for a funding priorities, or if a new substitute technology were to be invented, 2

h

c long time. However, the delivery systems for it and other treatments there is no guarantee of continued funding. For this reason, managing r a M

will continue to evolve. the inevitable starts and stops of government contracting can be

y

g precarious for a small technology company. You will essentially have to o l o

n figure out how to manage the burn, and losses might never be h c e

T Q: How has the marketplace changed since 9-11? recovered.

y r

e Lastly, doing business with the government has rules that are v i l e

D A: The community has changed considerably since 9-11. There is a far unfamiliar to most pharmaceutical companies. King’s autoinjector

g u

r greater focus on preparedness and self-sufficiency. In major business has unique cost accounting and compliance systems required D metropolitan areas, there are now vehicles that move around the city 22 FIGURE 2 technology with the government’s project management milestones. King has been so successful throughout the years because its leadership understands both sides of the table and how to synchronize its efforts with those of its government customers.

Q: Does the amount of money a company receives for a development contract compensate for the fact there may not be a buyer of the products at the end of the contract?

A: Yes, in many cases you can build in a certain level of profit margin into a contract. Throughout the past several years, agencies such as the Department of Defense and the Department of Homeland Security have gained a deeper appreciation for the complexities of the drug discovery by the government. This is a substantial hurdle for small companies. and development process. People in the government are better trained While the government is willing to allow some flexibility for emerging to recognize the profit-making needs of their commercial partners in products that fill urgent needs, long-term relationships with the the pharmaceutical industry. The government has also started to government will require adoption of these standards. One should expect integrate the knowledge housed in its different agencies and the government to routinely audit these systems to ensure compliance. departments. Every year, the government has become a more educated On the flip side, working with the government can be quite buyer tuned to the needs of the pharmaceutical industry. beneficial. The main benefits include a unique opportunity for funded It is probably best to remember that accomplishing the scope of research and development and the creation of company-owned work is the goal. The smart way to do business with the government is intellectual property. Longer timelines and more government rules are to properly align the scope, milestones, and development plan. If you often outweighed by the potential to receive development funds for try to scope out too much, the unknowns in drug development will technologies, personnel, and intellectual property associated with cripple the program. government projects. The potential for keeping all of the intellectual property arising from a government grant is an enormous benefit to the commercial enterprise. So, not only is research and development funded, but the Q: How can companies address these unique intellectual property is usually available for commercial use. challenges? Lastly, after a company develops a unique product, the government may be able to provide ongoing support in other ways. A: A company is advised to work with another company familiar with King is one of the few companies in the pharmaceutical industry to government contracting or hire such expertise. You need someone who receive an IBMC (Industrial Base Maintenance Contract) with the can walk you through the process from start to finish, as you can stub military. The IBMC came out of operation Desert Storm and Desert Shield, where the military recognized the need to support its industrial 3 your toe easily if you are not careful. The right organizational mindset o

partners so they can always be ready to respond to spikes in demand. N

is essential. When a company contracts with a commercial partner, the 7

The contract supports a warm base of readiness, where appropriate l goal is almost always the commercialization of the technology. In the o V

inventory levels are maintained; trained personnel are available; and case of the government, successfully completing each phase or 7 0

manufacturing is available on demand. Thus, this type of program can 0 deliverable by the date specified in the contract requires a different 2

h

keep a pharmaceutical company engaged, after development is c discipline. While the objective might eventually be deployment, the r a M

completed and production requirements are met.

completion of any given phase of a project cannot be overlooked. The y g o lesson is to approach each government opportunity as a clearly defined, l o n incremental scope of work and focus your company’s development h c e

Q: Who defines the requirements for the Government’s T

around achieving each contract milestone. y r e

needs? v i

In adopting this mindset, it is important to recognize that the l e D

government, in essence, has one of the most sophisticated project g u A: Most of the time, the government determines product or technology r management systems in use today. A successful partnership with the D government will require integrating the development plan for your requirements. As an example, King’s ATNAA/Duodote was a result of the military’s request for smaller, simpler designs and fewer steps. The 23 government defined the basic requirements and then bid out the international and Department of Defense relationships. Moreover, contract in a very public and structured manner where there were King’s managers have significant knowledge of government needs and multiple competitors. This public RFP process is managed through their the acquisition and procurement process. Dr. Jim Stewart, who leads acquisition/procurement site, Federal Business Opportunities research and development for King’s autoinjector business, is a retired (FedBizOpps). US Army Colonel who worked on a number of programs focused on However, there are other instances in which the government pharmacology, development of chemical defense systems, and identifies a technology or product that stands on its own merits. King’s homeland security planning. Dr. Jerry Wannarka, a retired US Army AtroPen® product was originally developed for insecticide poisoning for Colonel, also has both pharmaceutical and government experience. As field workers. When the military saw it, they concluded that it was a former customers, they understand the issues on both sides of the fence. better mousetrap. The technology was drafted by the military so to Having this type of experience on board facilitates doing business with speak. the government. In general, it is very difficult to market products to the If this type of expertise is not feasible to have in-house, an government. Most contracts are awarded under competitive excellent way to approach the issue is to identify a company with circumstances. While there is some negotiation room in the RFP expertise in the area that is willing to team on a specific government process, the rules governing a competitive bidding and award process opportunity. Relying on a proven partner alleviates much of the learning can never be circumvented. curve and resource commitment required to compete.

Q: Who are the key government buyers? Q: What should a pharmaceutical/biotechnology company look for in a partner to help win and do A: There are many potential buyers for drug delivery-based products. business with the Government? Roughly half of King’s autoinjector business is from international or US government supply of nerve agent antidotes and other products for A: Obviously the most critical component is a successful track record emergency preparedness. The domestic government revenue comes in working with the government. A second critical success factor is from more than 30 unique customers, including the Department of landing a partner who can provide value in all phases of a contract. To Defense, CDC’s national strategic stockpile (and forward stockpiles), understand this second point, it is helpful to look through the eyes of the Department of State (to supply embassies around the world), Health the government procurement agent. That is, each new player in a and Human Services for the Metropolitan Medical Response System, proposal constitutes a new risk and another party to track. An and other federal security agencies. King also sells to local stockpiles, established company such as King can do everything (eg, technology, which are cities/municipalities that desire stockpiles for their local first contracting, manufacturing, clinical development, regulatory filing). responders as well as replenishment inventory. Many state, county, and The government will find the one-stop approach with a known supplier public health agencies also purchase products for stockpiling and easier and less risky to manage. For any company seeking to do deployment to EMS personnel. business with the government for the first time, getting a partner who is established and experienced in dealing with the government is probably the best way to start. 3

o

N Q: What advice could you give to companies regarding

7

l government marketing efforts? Q: How does a company do business with King? o V

7 0

0 A: A company might approach the government opportunity like any A: For King’s government business, those products that are (1) suitable 2

h

c new area in which unique expertise is required to effectively compete. to self-administration or (2) essential in time-sensitive medical r a

M In this case, in addition to the prerequisite knowledge of the FDA situations will fit well. In general, we target products and technologies

y

g regulations, it is important for a company to have ready access to that may also have civilian use. Due to the nature of our government o l o

n people who have a working knowledge of the federal acquisition system business, King will only license or acquire products from companies h c e

T and government contracting process. To attempt to win government who respect intellectual property rights and can legally conduct

y r

e business without this second skill set would be the equivalent of business with the US. v i l e

D attempting to develop a novel therapeutic without a sufficient working King offers its partners a well-established track record of

g u

r knowledge of the FDA! Ultimately, companies will need to learn the supplying products and services to the US government. King has D language of the federal acquisition process to be successful. expertise and capabilities in pharmaceutical development, 24 To this point, King’s organization includes a dedicated manager for manufacturing, and commercialization, including drug delivery systems. King is an excellent partner for doing business with the government or for commercializing products outside the government in IOGRAPHIES therapeutic areas such as cardiovascular/metabolics, acute care, and B neuroscience, which may require a large sales force. If interested in discussing partnering or other business development opportunities, Dr. Christopher Robinson is a Partner please contact Ted Marcuccio, King’s Vice President of Business of Valeo Partners, a Washington, DC- based Development and Strategic Planning at consultancy that provides strategic [email protected]. consulting and business development services to life science companies in the Q: Putting it all together, would you see this as an pharmaceutical, biotechnology, medical attractive area for a drug delivery company? device, and drug delivery markets. At Valeo, A: Absolutely. While a new company may not want to focus Dr. Robinson’s primary focus is in helping clients develop exclusively on the government, it can approach the opportunity as it winning business strategies, generate innovative product would approach any new therapeutic area. There is certainly a need concepts, evaluate market opportunities, and optimize portfolio within the government and a role for drug delivery technologies. While strategies. He brings a results-oriented philosophy to traditional each company’s situation will be different, the potential for government strategic consulting, and has extensive experience working with support for research and development funding, and the creation of executive management and cross-divisional project teams to turn intellectual property rights cannot be overlooked. Simply view this as strategy into proven results. Prior to joining Valeo, Dr. Robinson an opportunity to build your platform, improve your technology and was a Management Consultant at a global strategy consultancy capabilities, and satisfy a new customer. N focused on product development strategy, business process optimization, and implementation. He earned his MBA from ACKNOWLEDGEMENTS Cornell University with specialization in venture capital and entrepreneurship and a PhD in Immunology from the University Valeo Partners would like to extend a special thanks to the team at King of Florida where he focused on autoimmune disease and Pharmaceuticals that contributed to this discussion. Without their insight, this article would genomics. He also holds a BS in Molecular Biology from Lehigh not have been possible: Dennis O’Brien, Executive Vice President and President, Meridian University. Medical Technologies; Cristina Derasmo, Vice President, Government Programs; Tom Handel, Vice President, Commercial Pharmaceuticals and Alliance Management; Ted Ms. Debra Bingham is a Partner of Marcuccio, Vice President, Business Development and Strategic Planning; David Robinson, Valeo Partners. She brings clients over a Senior Director, Corporate Affairs; James Stewart, PhD, DVM, (Colonel, US Army decade of specialized expertise in the Retired), Senior Director, Research and Development; Jerry Wannarka, PhD, RPh, (Colonel, US Army Retired), Formerly, Sr. Vice President, Technology pharmaceutical and biotech industries. At Valeo, her primary focus is in helping clients * Meridian Medical Technologies owns the U.S. NDA for EpiPen, but the trademark in the areas of business strategy, business 3

name EpiPen is owned by EMD Chemicals under license to Dey LP. Trademarks o development, growth opportunity N

7

Duodote and AtroPen are owned by Meridian Medical Technologies. assessment, and strategic partnering. Ms. Bingham leads Valeo’s l o V

strategic partnering offering in affiliation with Stonecroft 7 0 0

Capital, a DC-based investment bank, which provides full-service 2

h c r

transactional capabilities from licensing to M&A. She spent the a M

majority of the past 10 years working in the pharmaceutical y g o l

industry assisting companies with strategic business assessment o n h c e

and business development. Ms. Bingham has authored many drug T

y r e

delivery business articles and technology reviews and is a v i l e D

featured speaker at industry trade conferences. g u r D

25

LICENSING STRATEGIES Drug Delivery’s Increasing Importance to Big Pharma & Specialty Pharma By: Barath Shankar, Research Analyst, Pharmaceuticals & Biotechnology, Frost & Sullivan

INTRODUCTION The drug delivery (DD) market, valued at over $55 billion in 2006, is poised to witness rapid expansion owing to major patent expiries, generic competition, increasing focus on life-cycle management, and tightening FDA regulations. DD companies are likely to enable pharmaceutical companies to revive late-stage products by using drug delivery platforms and re-branding products. As a result, DD companies are likely to remain the focus of attention of big pharma and specialty pharmaceutical companies as acquisition targets or licensing partners. Big pharma pipelines are continuing to shrink, while patent expiries continue to threaten the multi-billion dollar blockbuster business model. DD companies are thus perceived as natural partners to big pharma companies and thus an increase in partnerships between pharma and DD companies is already being witnessed.

SPECIALTY PHARMA & • Strategy 2: In-license and incurring the cost and risk of extended DRUG DELIVERY develop the market for clinical development. products; Specialty pharmaceutical LICENSING STRATEGIES companies focus on different stages • Strategy 3: Develop drug and aspects of drug development and delivery technologies for Expiring patents have always marketing in addition to partnering existing and new products; and been a problem in the branded with large pharmaceutical companies • Strategy 4: Develop and market pharmaceutical segment, and in the life-cycle management of their generic pharmaceuticals. especially the big pharma companies. products. The areas of expertise for The next 5 years are going to be these companies include drug Figure 1 shows the business tougher with more than $70 billion delivery, clinical development, generic model adoption by the top specialty worth of key branded drugs expected drugs, and sales and marketing. pharmaceutical companies in 2005- to go off-patent. Specialty pharmaceutical 2006. The figure also clearly points DD companies have before them 3

o companies typically focus on one or out that the adoption of in-house drug

N several options to decide on the 7

l two of these areas, leveraging their delivery technologies has been strategic direction they need to adopt o V expertise and positioning themselves minimal compared to other strategic with a therapeutic line/company 7 0

0 options that are pursued by top 2 in a niche pharmaceutical market. The portfolio or dosage type. DD h c r business models of specialty specialty pharma companies, opening

a platforms tend to remain highly M pharmaceutical companies can be up the potential for specialized DD customizable and hence offer y g o l companies to take advantage of the o broadly classified into the following pharmaceutical companies flexibility. n h c

e four types: market potential. Because these However, revenue or profit share of T y r

e specialty pharma companies tend to DD companies have remained lower v i l e

D • Strategy 1: Acquire low sales- operate in non-blockbuster product than expected owing to the lesser risk g u r areas, the addition of DD could enable D generating inline branded that they have tended to take. With the products and market them; them to position their products in a pharmaceutical industry expected to 26 better and effective manner without witness lower margin and revenue

LICENSING STRATEGIES

FIGURE 1

growth compared to the first half of acquisition, or corporate acquisition. acquired by big pharma companies. the decade, DD companies will have to The top specialty pharma companies Licensing or acquisition of be more aggressive and retain a higher have been successful in implementing product(s) involves understanding the share of risk to exploit the growth these strategies in a robust manner. clinical and market potential in order to potential the market offers. Hence, a DD-specialty pharma merger have an understanding of the company’s It is not unlikely that DD or acquisition is likely to set the ball theoretical return on investment. The companies with sufficient cash or rolling for a new generation of rapid growth of tier 1 and tier 2 financial backing could acquire companies that are likely to drive the pharmaceutical and biotech companies

3 specialty or niche pharma companies to growth of the market at the tier 2 level. has resulted in increased competition o N

7 develop and market their own product from several companies targeting l o V line. Several large mergers and CONSOLIDATION TO CONTINUE corporate and product acquisition. 7 0

0 acquisitions amongst big pharma have Hence, there is significant pressure on 2 h

c also resulted in products being out- Big pharma has been facing companies to pay a premium, which r a

M licensed or sold off to specialty pharma increasing pressure with thinning often results in dependence on a single y g o

l companies, as they did not fit into the potential blockbuster pipelines, the pull product, or technology and subsequently o n h

c strategic direction of the larger out of several key products, and falling increased risk in the case of failure. e T y

r company. margins. Hence, it is expected that 2007 The mix of business models and e v i l

e Specialty pharma companies adopt is likely to witness significant market licensing strategies adopted by DD D g u

r a combination of licensing and consolidation with several niche companies enables them to limit clinical D acquisition strategies that include single biotech, specialty pharma, and drug risk and absorb commercial risk to a 28 product acquisition/licensing, franchise discovery companies likely to be greater extent. In-licensing and out- LICENSING LICENSING STRATEGIES STRATEGIES

licensing are likely to remain important with outsourced activities, such as BIOGRAPHY concepts in determining the future research and manufacturing. This entity direction of the industry based on current would thus achieve critical mass at a Mr. Barath Shankar trends, and DD technologies are likely significantly lower cost compared to the is a Research to complement these decisions to a big pharma business model. Analyst with the large extent. Overall, the DD business continues Frost & Sullivan to be driven predominantly by investor North American LIFE-CYCLE MANAGEMENT interest in the perceived robustness of the Healthcare & OUTSOURCING business model and the business Practice. He development strategies adopted by focuses on monitoring and analyzing emerging trends, technologies, and As DD companies continue to companies. With the industry moving market behavior in the pharmaceuticals exhibit rapid growth, they tend to forward into a phase of intense and biotechnology industries in North compete more directly with competition and consolidation, we are America. Since joining Frost & Sullivan pharmaceutical companies. However, the likely to witness a more synergistic and in October 2004, Mr. Shankar has DD business offers the advantage of proactive approach by DD companies, completed several research studies and carrying lesser risk compared to its which is likely to augur well for the consulting projects on Pharmaceuticals pharmaceutical counterparts owing to its market. and Biotechnology. Prior to this, Mr. customizable nature – in other words, the Shankar was a Research & Development failure of a DD technology on a product intern at IPCA Laboratories Ltd., A does not limit its application in Mumbai, India. He brings with him product B or C. considerable analytical and quantitative With several major products experience, giving him a keen reaching the end of their patent life perception into the functioning of technology in the healthcare industry. recently, there is an increased interest in Mr. Shankar has received acclaim for product life-cycle management. Life- his research through articles and cycle management has always been a quotes published in various magazines, buzz word in the pharmaceutical including Specialty Pharma and Drug industry, but seems to have found Delivery Technology. increasing focus amongst the specialty 3 o

pharma group. Drug delivery technology N 7

platforms are widely used by specialty l o V pharma companies for LCM of their 7 0 0

products. 2 h c r

There is a large complementary a M

potential between biotechs (which are y g o l

typically innovation engines), DD, and o n h c

specialty pharma companies that focus e T y r

on sales and marketing. The combination e v i l e

of the three could create an integrated D g u r

entity that could leverage the strengths D from all sides and complement it further 29

OCULAR DELIVERY

In Situ Gel Systems for Ocular Drug Delivery: A Review By: Mitan R. Gokulgandhi, BPharm; Dharmesh M. Modi, MPharm; Jolly R. Parikh, PhD

INTRODUCTION absorption in to the anterior chamber, and layer, containing inorganic salts, glucose, Ophthalmic drug delivery is one of the 1% to 5% or less of the drug applied and urea as well as retinal, ascorbic acid, most interesting and challenging endeavors topically as a solution reaches the inner part various proteins lipocalins, facing pharmaceutical scientists. The of eye. Thus, it may be concluded that both immunoglobulins, lysozyme, lactoferrin, anatomy, physiology, and biochemistry of transconjuctival and transnasal absorption and glycoproteins.8-10 the eye render this organ exquisitely after drainage via the nasolacrimal duct are impervious to foreign substances. The generally undesirable, not only because of Conjuctiva challenge to the formulation is to the loss of active ingredient into the The conjuctiva is a transparent mucus systemic circulation, but also because of circumvent the protective barriers of the membrane. The ocular conjunctiva is very possible side-effect.5,6 Therefore, to eye without causing permanent tissue thin, and blood vessels are clearly visible optimize topical ocular drug delivery damage. The primitive ophthalmic solution, beneath it. When the eye is closed, a slit- systems, prolonged contact time with the suspension, and ointment dosage forms are like space occurs between the conjuctiva- clearly no longer sufficient to combat some cornea surface and better penetration 7 covered eyeball and eyelid. This so-called present virulent diseases.1 through the cornea are necessary. conjuctival sac is where a contact lens lies, In spite of active and continued and eye medications are often administered research and frequent introduction of novel in to its interior recess. Although the ophthalmic drugs, ocular drug delivery ANATOMY & PHYSIOLOGY conjuctiva protects the eye by preventing does not seem to progress at the lively pace OF THE EYE typical of oral, transdermal, or foreign objects from penetrating beyond the transmucosal delivery. The vast majority of Lachrimal Apparatus confines of the conjuctival sac, its major existing ocular delivery systems are still The lachrymal apparatus is a group of function is to produce lubricating mucus 8 fairly primitive and inefficient.2 Successful structures that produce and drain lachrymal that prevents the eyes from drying out. delivery of drugs into the eye is extremely fluid or tears. The lachrymal glands, each complicated because the eye is protected by about the size and shape of an almond, Eyelid a series of complex defense mechanisms, secrete lachrymal fluid, drain in to 6 to 12 The eyelid serves a variety of special which make it difficult to achieve an excretory lachrymal ducts that empty tears functions, including protection of the eye effective concentration of the drug within into the surface of eyelid. Lachrymal fluid from mechanical and chemical injuries. In the target area of the eye.3 Poor is a watery solution, containing salts, some human beings, the average blink rate is 15 bioavailability of drugs from ocular dosage mucus, and lysozyme, a protective bacterial to 20 times per minute, which has great forms is mainly due to the tear production, enzyme. After being secreted, lachrymal influence on the bioavailability of drug. The non-productive absorption, transient 3 osmolality of the tear film equals 310 to

o fluid is spread medially over the surface of N residence time, and impermeability of 350 mosm/kg in normal eyes and is

7 4 the eyeball by blinking of the eyelid. l corneal epithelium. + - o adjusted by principal inorganic ions Na , K , V Each gland produces about 1 ml of The drainage of the topically - -

7 Cl , HCO3 , and protein. The mean pH value

0 lachrymal fluid.

0 administered dose via the nasolacrimal

2 of normal tears is about 7.4. The buffer

h system into the nasopharynx and the c r

a capacity of the tear is determined by

M gastrointestinal tract takes place when the Lachrimal System bicarbonate ions, protein, and mucin.8,11 y volume of fluid exceeds lachrymal fluid The lachrimal system consists of g o l

o (lachrymal fluid 7 to 10 µl). Thus, the secretary glandular and excretory ductal n h

c Mucus Layer

e contact time of the drug with ocular tissue elements. A thin fluid film (the so-called T

y The mucus layer is secreted in to the r

e is relatively short (1 to 2 min), mainly due preocular tear film, which is formed and v i l eye surface by goblet cells, intimately e to the spillage of the instilled solution from maintained by the lachrymal apparatus) D

g associated with glycocalyx of the

u the precorneal area. As a consequence of

r covers the conjuctive and cornea. The D these mechanisms and factors, the rate of lachrymal gland and the accessory gland corneal/conjuctival epithelial cell. The 30 the loss of drug from the eye can be 500 to contribute to the formation of the aqueous mucus layer can form a diffusion barrier to 700 times greater than the rate of macromolecules depending on the degree

OCULAR DELIVERY

of network entanglement on the other hand; VARIOUS FORMULATION of cyclodextrins, prodrug approaches, ocular mucus can bind cationic substance because of APPROCHES TO IMPROVE inserts, and the ready-existing drug carrier the negative change of mucin. OCULAR BIOAVAILABILITY systems, along with their application to In 1992, Prydal et al suggested that the ophthalmic delivery, the main focus of this human tear film is composed substantially of A typical time course of drug release in review will be on the phase transition system mucus instead of fluid. A film composed largely the eye from conventional ophthalmic (ie, in situ activated gel-forming systems) to of mucus (40 microns in thickness), mucus solutions follows a pulsed entry, ie, peak and improve ocular bioavailability to a sufficient consists of glyco protein, protein lipid, electrolyte, valley patterns. It initially shows a very high extent that an ocularly delivered drug can enzyme, mucopolysachhride, and water.12-14 drug concentration followed by rapid decline. elicit its biological action. The aim of this Various approaches that have been attempted article is to provide an insight into the to increase the bioavailability and the duration potential applications of the phase transition TRADITIONAL OPHTHALMIC of therapeutic action of ocular drugs can be system for the conception of innovative DOSAGE FORMS divided into two following categories: ophthalmic delivery approaches, to decrease systemic side effects, and to create a more Traditional ophthalmic dosage forms 1. Maximizing corneal drug absorption pronounced effect, which may be achieved include solutions, suspensions, and ointments. and minimizing precorneal drug loss. with lower doses of the drug. Solutions, in spite of their limitations (ie, quick elimination from the precorneal area 2. Drug delivery system to provide the resulting in poor bioavailability), are still given controlled and continuously delivery IN SITU ACTIVATED top priority by formulators because they are of ophthalmic drug to the pre- and GEL-FORMING SYSTEM relatively simple to prepare, filter, sterilize, intra-ocular tissue. and are cost effective. Suspensions, while not A gel is a soft, solid, or solid-like as common as solutions, are widely used for Several new preparations have been material consisting of two or more formulations involving poorly soluble drugs, developed for ophthalmic use, not only to components, one of which is a liquid, present such as anti-inflammatory steroids. prolong the contact time of the vehicle on the in substantial quantity. A gel should, in a time Ocular suspensions, however, have ocular surface but also slow down drug scale of seconds, not flow under the influence several disadvantages. Proper shaking is elimination. Successful results were obtained of its own weight. The solid-like characteristic required, which if not done can lead to with inserts and collagen shields, although of gel can be defined in terms of two inconsistency in the administered dose. A fine preparation involves some disadvantages, dynamic mechanical properties, an elastic sediment may form that can be difficult to such as non-compliance, especially by elderly modules, G ’(w), which exhibit a pronounced disperse with gentle shaking. And seldom people, and many patients sometimes lose the plateau extending to time at least of the order occurring, but of serious consequences, is a device without noticing it.16 A more desirable of second; and a viscous modules, G”(w), polymorphic change in the suspended drug to dosage form would be one that can be which is considerably smaller than G’ (w).18 form a less soluble or insoluble form of the delivered in a drop form, create little to no Gelation occurs via the cross-linking of 3 o

N drug. An important feature of the ointment is refractive index problem for vision, and dosed polymer chains, something that can be

7 17 l that it remains in the conjuctival cul-de sac, no more frequently then once or twice daily. achieved by the following: o V forming a reservoir of the drug. Moreover, the This can be achieved by using an in situ gel- 7 0

0 disappearance from the precorneal area of a forming ophthalmic drug delivery system 1. Covalent bond formation (chemical 2 h

c drug administered in an ointment vehicle is cross-linking)

r prepared from polymers that exhibit reversible a

M very slow (0.5% per min) when compared phase transition (sol-gel-sol) and pseudo-

y 2. Non-covalent bond formation

g with the elimination by the normal lachrymal

o plastic behavior to minimize interference with

l 19

o (physical cross-linking n turnover (about 16 per min). These

h blinking, increase pre-corneal residence of the c e T preparations, however, occupy a position of delivery system, and enhance ocular y r The progress that has been made in gel e

v minor importance because they are ill

i bioavailability. l

e technology is in the development of a D accepted on account of their greasiness, Because much has already been g

u droppable gel. In situ gel-forming systems r vision blurring effects, etc, and are generally D published about the use of viscosity- 15 can be described as low-viscosity solutions used as night medications. enhancing agents, penetration enhancers, use 32 OCULAR DELIVERY OCULAR DELIVERY

FIGURE 1 that were introduced commercially in the early 1950s as food additives and for pharmaceutical preparations. These water-soluble inert surfactants are triblock co-polymers with a central hydrophobic part (Polyoxypropylene) and two identical lateral hydrophilic parts (Polyoxyethyler).28 Poloxamers were employed as solubilizers and proposed as artificial tears. Pluronic® F127 is no more damaging to the mouse or rabbit cornea than a physiological saline.29 The poloxamers are reported to be well tolerated and non-toxic even though large amounts (20% to 30%) of polymers are required to obtained a suitable gel. At concentrations of 20% w/v and higher, aqueous solutions of Poloxamer-407 remain as a liquid at low temperatures [< 15°C] and yield a highly viscous semisolid gel upon instillation into the cul-de-sac. At low temperatures, the that undergo phase transition in the ocular into the conjuctival sac, making it patient poloxamer forms micellar subunits in solution, cul-de-sac to form viscoelastic gels due to convenient and minimizing interference with and swelling gives rise to large micellar conformational changes of polymers in blinking.24 Gel formulation with suitable subunits and the creation of cross-linked response to the physiological environment.20,21,22 rheological properties increases the contact networks. The result of this phenomenon is a The rate of in situ gel formation is time with the mucus at the site of absorption. sharp increase in viscosity upon heating.30 important because between instillation in the The increased contact time is caused by the Miller et al examined a temperature-sensitive eye, and before a strong gel is formed, the mucoadhesive properties of the polymer in the solution of poloxamer used to deliver the solution or weak gel is produced by the fluid gel and by the rheological properties of the miotic pilocarpin.31 mechanism of the eye. Hence, contact times in ocular protective mechanism and hence better An alternative in situ gelling material of humans were measured for a salt-free solution bioavailability. 25,26 natural origin for ocular drug delivery is of Gelrite® preparation with varying This new concept of producing a gel in xyloglucan, a polysaccharide derived from osmolality. The hypotonic samples were non- situ was suggested for the first time in the Tamarind seeds. When partially degraded by irritating whereas the isotonic and hypertonic early 1980s. These methods have been Beta-galactosidase, this gelling material solution caused an increase in lachrymation employed to cause phase transition on the eye

3 exhibits thermally reversible gelation in dilute

o and blurred vision. The high tolerance of the surface. Change in viscosity can be triggered N aqueous solutions, and varying sol-gel 7 hypotonic sample is due to the rapid formation by change in temperature, change in pH, and l

o transition temperatures upon degree of V of a gel residing in the conjuctival sac, thus change in ionic or electrolyte composition.

7 galactose elimination.

0 avoiding any solution spreading over the 0

2 23 Attwood et al has reported enhancement

h sensitive cornea. Temperature c r of the miotic response following sustained a

M Gelling of the solution is triggered by release of Pilocarpin from the 1.5% w/w y change in temperature, and sustained drug g Advantages o

l xyloglucan gel. In order to develop a o The principal advantage of this delivery can be achieved by the use of a n h

c thermosetting gel with a suitable phase

e formulation is the possibility of administering polymer that changes from solution to gel at T

y transition temperature, Wei et al combined r 27

e accurate and reproducible quantities in contrast the temperature of the eye (37°C). v i

l poloxamer (Pluronic F127 and F68) and e

D to already gelled formulations. This type of gel Poloxamers are thermoreversible gels that

g sodium hyaluronan. Gamma scintigraphy u

r combines the advantage of a solution because seem to fulfill the aforementioned conditions. D demonstrated that the clearance of an these are conveniently dropped as a solution Poloxamers are a broad group of compounds optimized formulation containing 21% F127 34 OCULAR OCULAR DELIVERY DELIVERY

and 10% F68 was significantly delayed with Mlynek.41 Polycarbophil is insoluble in water, drops provided better performance because respect to a phosphate buffer solution. A but its high swelling capacity in a neutral they afforded the advantage of faster gelation three-fold increase of the corneal residence medium permits the entanglement of the over a higher surface area in eye, whereas the time was achieved in the rabbits.32 polymer chains with the mucus layer. The results obtained with the gellan-MP film non-ionized carboxylic acid group binds to seemed to indicate that the gelation at the pH the mucin by means of hydrogen bonds.41,42 surface of the film occurred very slowly, and Gelling of the solution is triggered by a the surface of release was not controlled.45 change in the pH. Cellulose acetate phthalate Ionic Strength Maurice and srinivas measured a two-fold (CAP) latex, cross-linked poly acrylic, and Gelling of the instilled solution is also increase in the permeation of the fluoroscein derivatives such as carbomers are used.33 triggered by change in ionic strength. It is in humans when using gellan gum compared Cellulose acetate derivatives are the only assumed that the rate at which electrolytes to isotonic buffer solution.46 polymer known to have a buffer capacity that from the tear fluid is adsorbed by the polymer Schenker et al compared the commercial is low enough to gel effectively in the cul-de- will depend on the osmotic gradient across product Timoptic XE® 0.5% with a timolol sac of the eye. The pH change of about 2.8 the surface of the gel. It is therefore likely maleate gel-forming solution with xanthan units after instillation of the native that the osmolality of the solution might have gum as the gelling polymer (Timolol GFS® formulation (pH 4.4) into the tear film leads an influence on the rate of the sol-gel 0.5% Alcon Research). The xanthan gum to an almost instantaneous transformation of transition occurring in the eye. One example preparation was developed for once-daily the highly fluid latex into viscous gel.34,35,36 is Gelrite®, an anionic extracellular dosing. The reported data indicated equivalent Cellulose acetate phthalate latex is a polymer polysaccharide, low acetyl gellan gum efficacy in the reduction of intraocular with potentially useful properties for secreted by pseudomonas elodia. Gelrite pressure (a maintained reduction during long- sustained drug delivery to the eye because formulations in aqueous solutions form a term use) and consequently therapeutic latex is a free-running solution at a pH of 4.4, clear gel in the presence of the mono or equivalence.47 which undergoes coagulation when the pH is divalent cations typically found in the tear Hartmann and Keipert reported that the raised by the tear fluid to pH 7.4. The use of fluids. The electrolyte of the tear fluid and increase in therapeutic effects (eg, miosis) in pH-sensitive latex nanoparticles has been especially Na+, Ca+, and Mg+2 cations are rabbits could be due to a permeation- described by Gurny.37 But the low pH of the particularly suited to initiate gelation of the enhancing effect of gellan gum comparable to preparation can elicit discomfort in some polymer when instilled as a liquid solution in EDTA. Apart from its in situ gelling property, patients.38 The poly acrylic acid and its lightly to the cul-de-sac. The concentration of gellan gum diminishes drainage after cross-linked commercial forms sodium ion in human tears is 2.6 gm/l, which instillation. (Polycarbophil® and Carbopol®) exhibit the is particularly suitable to cause gelation of The commercial product Timoptol XE® strongest mucoadhesion. In the pioneering Gelrite when topically instilled in to preparation containing Gelrite remains for a paper, Hui and Robinson demonstrated that conjuctival sac. Gelrite has been the most longer period at the eye surface when 3

the use of acrylates for ocular delivery of widely studied and seems to be preferred compared to conventional timolol maleate eye o N

progesterone was based not only on compared to the pH-sensitive or temperature- drops. This resulted in an enhanced drug 7 l o viscosifying but also on bioadhesion setting systems. The polymeric concentration transfer sufficient enough to obtain an intra- V

39 7 properties. Carbopol is a polyacrylic acid is much lower compared to previously ocular pressure reduction after a once-daily 0 0

43 48-50 2

(PAA) polymer, which shows a sol-to-gel described systems. topical instillation. h c r a

transition in aqueous solution as the pH is Rozier et al found an improvement in the M 40 raised above its pka of about 5.5. Different ocular absorption of timolol in albino rabbits y COMBINATION OF g o l o

grades of Carbopol are available. The when administered in Gelrite when compared DIFFERENT APPROACHES n h c e

manufacturer states that Carbopol 934 gel has with an equiviscous solution of hydroxyl- T y

44 r

the lowest cross-linking density, while ethyl cellulose. Most of the systems require the use of a e v i l e

Carbopol 981 intermediate and Carbopol 940 Sanzgiri et al compared various systems high concentration of polymers. In order to D g u

have the highest. of Methyl prednisalone (MP): esters of MP reduce the total polymer content and improve r D Polycarbophil-based in situ gelling with Gelrite eye drops, gellan-MP film, and the gelling properties, Joshi et al first used a systems were developed by Robinson and gellan film with dispersed MP. Gellan eye combination of polymers in an ocular drug 35 36 OCULAR Drug Delivery Technology March 2007 Vol 7 No 3 slow timolol invitrorelease ofincorporated system. This HPMC-PAA combinationshowed deliveryan insitugellingophthalmicdrug cellulose (HPMC),respectively, tobeusedas pol and thermosensitiveof both properties Joshi etalw for Ofloxacin over an8-hourperiod. E50) andobtainedasustained-releasesystem h systembasedonCarbopol940and irritating investigated. viscosity atlo pol material) andcarbomer(pH-inducedgelling methylcellulose (athermally inducedgelling modulating thetherapeuticresponse. release,thereby dissolution rateandpilocarpin F127 solution. This slowed down thegel hydroxypropylmethyl cellulosetoPluronic Blanchard addedmetylcelluloseand outofthepoloxamerdrug network, Desaiand Duetorapidreleaseofhydrophilicproperties. polymers thatexhibit reversible gelation bycan beformed usingacombinationof such aspH,temperature,andionicstrength, variation inatleasttwo physical parameters, reversibly gelledinresponsetosimultaneous main ideaisthataqueouscomposition delivery.mechanisms inophthalmicdrug The p t delivery system.Several researchers explored polymer. adding asuitable viscosity-enhancing rheological behaviors canbe achieved by aswellthe insitugellingproperties asoverall Carbopol concentrationwithoutcompromising systems, itwas foundthatreductionin the hydroxypropylmethyl cellulose.For both combination ofCarbopoland developed asimilardelivery systemusinga Carbopol andmeth delivery systembasedonacombination of he advantage ofusingvarious insitugelling ydro olymers withdifferent phasetransition yacr ymer), w K Kumar etalexpanded ontheinvention of A xypropyl methylcellulose (Methocel umar andHimmelstancombined pH ylic acidandhydroxypropylmethyl physical combinationof 54,55 hich areab 5 ho de 2 w Srividya etalusedanon- DELI er pol veloped anoculardrug ylcellulose. K ymer concentration,w le toachie umar etal ve adesired VERY 53 51 ere strate (PAA/PVP) was proposedasa formulation ultimately toits optimizingdelivery ofthedrug representing anapproach tocontrollingand broadly as whichgeneric term, isdefined blinking. which withstoodtheshearforceduring was following formed thephasetransition, After instillationasane network atthephysiological formed condition. did notdisr the individual polymer solutions.Pilocarpin than exhibits abetterabilitytoretainthedrug 0.3% Carbopol/14%(w/w)Pluronicsolution bioa and Carbopol/poloxamer mixtureonthe Carbopol 934P, poloxamer (PluronicF127), e Pluronic F127gel. fora1.5%xyloglucanobserved gelanda25% rabbits. A similarmioticresponsewas hydrochloridevehicles forpilocarpin in release Pluronic F127assustaineddrug timolol solution. respectively, comparedwithanaqueous and3%MC/15%F127, formulation 2.4-fold for25%PluronicF127gel bioavailability inrabbitsincreasedby 2.5-and with 3%methylcellulose. The ocular obtained froma15%PluronicF127solution cellulose. The slowest releasewas drug methylcellulose andhydroxypropylmethyl adding viscosifyingagents,suchas compromising theinsitugellingcapacityby p maleate. intact. while keeping mucoadhesive properties PAA/PVP systemexhibits alow viscosity the useofhighly viscousmaterials. The x oloxamer concentrationwithout er v ted b Drug deliverytotheeye asitpertains Drug isa Lin andSungstudiedtheinfluence Miyazaki etalevaluated xyloglucan and E gy too ailability of pilocarpin. ailability ofpilocarpin. The combined 61 l-Kamel attemptedtoreducethe 56 60 y The useofthebipolymer system an aqueoussolutioncontaining upt thestrongerthree-dimensional vercome problems associatedwith CONCLUSION 5 7,58 59 y e drop, astronggel 11. 10. Tiffany JM. Tears inhealthanddisease.Eye. 2003;17:1-4. 5 1 19. KaurIP, Devel Kanwar approach. Drug M.Ocularpreparation: theformulation 18. KaurIP, SmithR.Penetration delivery. enhancerandocularophthalmicdrug 17. RobinsonJR,Mlynek GM.Bioadhesive andphase-change polymers forocular 6. Meseguer G,Gurny R,BuriR.Invivo evaluation applicationof ofdosageform: 9. 8. 7. Keistea JC,CooperER,MisselPJ, LongJC,HagerDF. Sci.1991;80:50. JPharm 13. JI, 12. Prydal P,Artal Woon H,CampellFW. tear Studyofthehumanprecorneal little ornoeye ispossible. irritation with and precisesustained-releaseproperties because aswithnon-viscouseye drops, accurate The insitugellingsystemseemspromising corneal/conjuctival epitheliumcouldplay arole. bioavailability isquestionable. Interactionwith responsible foranimprovement in mucus, thus,mucoadhesionasthewhole factor non-covalent bondsbetween polymer and Mucoadhesion isbasedonentanglementor mucoadhesive islimited. performance s s target tissueintheeye. Inliquiddosageform, 23. CarlforsJ, EdsmanK,Peterson R,Jornving K.Rheological evaluation ofGelrite Le BourlaisC, Aear L,ZiaH,SadoPA,22. Needham T, Leverge R.Ophthalmicdrug 21. 20. Joshi A, DingS,HimmelsteinKJ. Reversible gelationcompositionandmethod 16. BalasubramaniamJ, KantS,Pandit JK.Invitroandinvivo evaluation ofthe 15. SaetfoneMF. Progress delivery. andproblems inophthalmicdrug Pharmatech 14. 4. Kaur IP, Devel Kanwar approach. Drug M.Ocularpreparation:theformulation 3. Kaur IP, SmithR.Penetration delivery. enhancerandocularophthalmicdrug 2. . . olution isfully hydrated beforeinstillation,the uch asviscouseye dropsinwhich polymer Curr Eye Res.1999;19:4-11. Curr Mese Saetfone MF g 1 gamma scintigraphy tonon-enteralroutesofadministration.JDrug Target. Nagy 1981;5:84-86. van HaeringenNJ. Ophthalmol. oftears.Surv Clinicalbiochemistry 1994;2:269-288. Indust Phar DevelDrug 2002;28(4):354-355. IndustPharm. 1986;2:67-108. future challenges.JOculPharmacol. Lee VH, RobinsonJR. Topical delivery: oculardrug recentdevelopments and B amma scintig 994;2:269-288. Ba Indust Phar DevelDrug 2002;28(4):356-357. IndustPharm. dr 2003;53:251. 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College of Pharmacy ophthalmic drug delivery system. Drug Dev Ind Pharm. 1995;21:19-59. 39. Hui H-W, Robinson JR. Ocular drug delivery of progesterone using a Ahemedabad. He is a lifetime member of bioadhesion polymer. Int J Pharmaceut Sci. 1985;26:203-213. 40. Davis NM, Farr SJ, Hadgraft J, Kellaway IW. Evaluation of mucoadhesive the IPA and is recognized as a post- polymers in ocular drug delivery: part 1, viscous solution. Pharm Res. graduate teacher by Sardar Patel University, 1991;8(8):1039-1043. 41. Robinson JR, Mlynek GM. Bioadhesive and phase change polymer for ocular Vallabh Vidyanagar. He is a member of the drug delivery. Adv Drug Deliv Rev. 1995;16:147-152. board of studies of Pharmaceutics at Sardar 42. Kaur IP, Smith R. Penetration enhancer and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev Ind Pharm. 2002;28:353-369. Patel University, Vallabh Vidyanagar. He is 43. Bhaskaran S, Lakshmi PK, Harish CG. Topical ocular drug delivery: a review. Ind J Pharm Sci. 2005;64(4):404-408. guiding two students for their MPharm 44. Rozier A, Mazuel C, Grove J, Plaronnet B. Gelrite®: a novel, ton-activated in (Pharmaceutics). situ gelling effect bioavailability of timolol. Int J Pharm. 1989;57:163-168. 45. Sanzgiri YD, Maschi S, Crescenzi V, Callegaro L, Topp EM, Stella VJ. Gellan based system for ophthalmic sustained delivery of methyl prednisolone. J Dr. Jolly R. Parikh is Controlled Rel. 1993;26:195-201. 46. Maurice DM, Srinivas SP. Use of flurometry in assessing the efficacy of a currently working as cationc-sensitive gel as an ophthalmic vehicle: comparison with scintigraphy. J Assistant Professor and Pharm Sci. 1992;81:615-619. 47. Schenkar HI, Silver LH. Long term intraocular pressure lowering efficiency Head, Department of and safety of timolol maleate gel forming solution 0.5% compared with Timoptic XE 0.5% in a 12 month study. Am J Ophtalmol. 2000;13:145-150. Pharmaceutics & 3 o 48. Shedden A, Laurence J, Tipping R. Efficacy and toleratibility of timolol Pharmaceutical Technology, N

maleate gel forming solution in adults with open angle glaucoma or ocular 7 l

hypertension: a six month double masked multicenter study. Clinical Ther. at the A.R. College of o V 2001;23:440-450. Pharmacy, VallabhVidyanagar, Gujarat, 49. Stewart WC, Leland TM, Cate EA, Stewart JA. Efficacy and safety of timolol 7 0

solution once daily versus timolol gel in treating elevated intraocular pressure. India. She is the Chairman of the Board of 0 2

J Glaucoma. 1998;7:402-407. h

Studies in Pharmaceutics & Pharmaceutical c 50. Rosenlund EF. The intraocular pressure lowering effects of timolol in gel r a

forming solution. Acta Ophthalmol Sand. 1996;74:160-162. Technology at the Sardar Patel University, M 51. Desai SD, Blanchard J. Evaluation of Pluronic® F127 based sustained release y

Vallabh Vidyanagar. She has almost 20 years g

ocular delivery system for pilocarpin using the albino rabbit eye model. J o l

Pharmaceut Sci. 1998;87:1190-1195. o of teaching experience and is currently n 52. Ding S. Recent advances in ophthalmic drug delivery. Pharmaceut Sci h c e

Technol. Today. 1998;1:228-235. guiding MPharm and PhD students in the T y

53. Srividya B, Cardoza RM, Amin PD. Sustained ophthalmic delivery of r research area of new drug delivery systems. e v

ofloxacin from pH triggered in situ gelling system. J Controlled Rel. i l 2001;73:205-211. e D

54. Joshi A, Ding S, Himmelstein KJ. Reversible gelation composition and g u method of use. US Patent No. 5,252,318; October 12,1993. r D 55. Kumar S, Haglund BO, Hemmelstein KJ. In situ forming gels for ophthalmic drug delivery. J Ocul Pharmaceut. 1994;10(1):47-56. 37

MMICICRROEOENNCAPSULATIONCAPSULATION

COX-II Inhibitor-Loaded Microspheres for Familial Adenomatous Polyposis: Characterization, In Vitro Release & Stability Studies By: Madhumathi Seshadri and Lakshmi Sivasubramanian

ABSTRACT

Familial Adenomatous Polyposis (FAP) is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop. FAP is an inherited condition caused by a mutation in the APC gene that is inherited in an autosomal dominant way. The condition is characterized by the formation of polyps also known as Adenomas (because they are at a precancerous stage where they may or may not develop into cancerous cells). The usual adopted treatment is surgery, which may or may not offer good results. The only other possibility (and a far better option in the authors’ opinion) is chemotherapy. This is achieved by the use of COX-II inhibitors to reduce the recurrence of polyps. But this syndrome requires the release of a drug for a prolonged time. Therefore the formulation of COX-II inhibitors as microspheres was studied. Because COX-II inhibitors are hydrophobic drugs, the best method for the preparation of microspheres was Emulsification-Solvent Evaporation, which produced a better yield in less time, microspheres with good drug content, and high microencapsulation efficiency. In this method, the authors used three different polymers (ethyl cellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose) and various characterization like drug content, microencapsulation efficiency, in vitro release studies, flow property, scanning electron microscopy, and stability studies to prove the best of the three polymers used.

INTRODUCTION basis. This is the reason to result in a microsphere or a formulate the COX-II inhibitors microcapsule, depending on the There are many methods for the (Valdecoxib and Rofecoxib) as amount of loading. The main treatment of FAP, with surgery microspheres in this study. purpose of encapsulating is for being the oldest.1-3 Genetic Microencapsulation is one of the protection and increasing its counseling and radiation therapy most intriguing fields in the area stability. Its release was triggered are also provided to patients with of drug delivery systems.4,5,6 It by major environmental changes 3

o requires the knowledge of pure as going from a dry to wet

N FAP, but there is no relief to the

7 polymer science, emulsion environment or by a physical l development of polyps in the o V colon as it keeps recurring. The technology (it being an trauma caused by chewing or 7 0

0 only long-term treatment for this is interdisciplinary field), and an grinding of capsules 2 h

c understanding of drug and protein To date, there has been a study

r chemotherapy and particularly use a

M of NSAIDs (ie, COX-II inhibitors stabilization. using Celecoxib, another COX-II y

g Microencapsulation is a process inhibitor, which was prepared as o like Celecoxib, Rofecoxib, l o

n by which solids, liquids, or even microspheres in the treatment of h Valdecoxib to name a few). c e T gases may be encapsulated into FAP. Various biodegradable

y FAP requires the use of drug r e v

i microscopic size particles through polymers like ethyl cellulose,

l treatment for more than 24 hours e D the formation of a thin coating of sodium carboxy methyl cellulose, g in a single dose. There has already u r D been lot of research in this area to “wall materials” around the and hydroxy propylmethyl substance being encapsulated. A cellulose were used for the study. 38 formulate a drug for the treatment of this syndrome on a long-term solvent evaporation process may The characterization to check MICROENCAPSULATION

MICROENCAPMICROENCAPSULSULATIONATION

TABLE 1 FIGURE 1 Microsphere Sample Drug Content in mcg/ml (100 mg) EC SCMC HPMC Rofecoxib 0.0219 0.04629 0.03169

Valdecoxib 0.0284 0.0485 0.038 The drug content in the prepared microspheres after a specified time interval

T ABLE 2 Microsphere Sample Microencapsulation Efficiency(%) (100 mg) EC SCMC HPMC Rofecoxib 43.8 92.6 63.4

Valdecoxib 56.8 97 76 The microencapsulation efficiency in the prepared microspheres after a specified time interval.

microsphere formation was done by CEEAL Analytical Labs, Chennai, checking for its release profile, drug India, as gift samples. Solvents used content, and microencapsulation in the preparation of microspheres FTIR overlay spectrum of SCMC loaded with efficiency. The scanning electron included chloroform and 1,2 Valdecoxib microspheres. microscopy Figure 2a and 2b also dichloroethane, which were proves that microspheres were purchased from SDFINE Chem. forming microspheres by slowly formed. Various tests to check for Ltd, Mumbai, India. Liquid paraffin allowing the solvent to evaporate such things like flow properties were (used as an emulsifying agent) was and the newly formed microspheres also performed, which showed the purchased from CDH, Mumbai, to settle. The liquid paraffin was efficiency of formed microspheres. India. Petroleum ether, used for decanted, and the “stickiness” of the The stability studies were also removing the stickiness from the microspheres was washed off performed, further strengthening the microspheres, was purchased from repeatedly with the help of 3 o

N result of the best of the three SDFINE Chem. Ltd, Mumbai, India. petroleum ether. The microspheres 7

l polymers used for the

o were then air dried and stored in V microencapsulation of drugs. Methods airtight containers. 7 0

0 Method A (Preparation of SCMC 2 h c r MATERIALS & METHODS Microspheres): In this method, an Method B (Preparation of HPMC & a M equal amount of the drug and EC Microspheres): All steps for this y g

o Materials polymer (1:1) was used. First, the l method were the same, but a small o n

h Polymers used in the preparation polymer was dissolved in solvent 1,2

c change was made in the use of the e T

y of microspheres included sodium dichloroethane 50 ml and allowed to

r solvent. In this method, chloroform e v i l caroboxymethyl cellulose (MW stir for sometime until the entire was used. There was no change in e D

g 162.14), hydroxy propyl methyl polymer dissolved. Then liquid the rest of the steps. u r D cellulose (MW 162.14), and ethyl paraffin was added for

40 cellulose, which were obtained from emulsification to set in, thus MICROENCAPMICROENCAPSULSULATIONATION

FIGURE 2A CHARACTERIZATION7,8 Assessment of Flow Properties A funnel was fixed in a stand in Determination of Drug Content which the tip of the funnel was about About 100 mg of the prepared 6 cm from the surface. Then the drug-loaded microspheres were microspheres of 30/40-sieve size treated with 100 ml of phosphate were allowed to flow through the buffer saline (pH 6.8) in a clean funnel so that they form a conical conical flask and kept in an incubator heap on the surface. The height (h) with shaker (50 rpm) at 40°C for 24 and radius (r) of the heap were hours [Orbit Shaker Incubator (OSI) measured, and the repose angle was 264]. Then it was filtered and determined by the following formula: analyzed spectrophotometrically at tanı = h/r. Where; 0 = repose angle, 241 nm for Valdecoxib and at 230 nm h = height of the heap, and r = radius Scanning Electron Microscopy (SEM) of SCMC for Rofecoxib (Shimadzu – UV of the heap. The results are shown in loaded with Valdecoxib microspheres. Double Beam Spectrophotometer).9-12 Table 3. The corresponding drug concentrations FIGURE 2B were calculated from a calibration INFRARED SPECTROSCOPY plot generated by regression. The results are shown in Table 1. Infrared spectra of Valdecoxib, Rofecoxib, EC, SCMC, HPMC, and Determination of microspheres loaded with Valdecoxib Microencapsulation Efficiency and Rofecoxib were taken separately Microencapsulation efficiency was by preparing KBr pellets, which were calculated using the following then recorded on a ThermoNicolet formula: Microencapsulation 330 FT-IR spectrometer. The spectra Efficiency = [Estimated Drug are shown in Figure 1, and the values Content/Theoretical Drug Content] X are shown in Tables 4 through 6. 100. The results of the analysis are shown in Table 2. SCANNING ELECTRON Scanning Electron Microscopy (SEM) of SCMC MICROSCOPY loaded with Rpfecoxib microspheres. 3 o

The sample for SEM analysis was N 7

prepared by sprinkling the prepared l o TABLE 3 microspheres on one side of an V 7 0

adhesive stub. The stub was then 0

Microsphere Sample Angle of Repose (0) 2 h

coated with gold using Jeolifine coat c (100 mg) EC SCMC HPMC r a Rofecoxib 47.2 39.8 56.3 ion sputter fc 1100. The microspheres M y g

were viewed at an accelerating o l o n

Valdecoxib 42.5 36.9 53.1 voltage of 20 kV. The results are h c e shown in Figures 2a and 2b. T y

The flow properties in the prepared microspheres after a specified time interval. r e v i l e D g u r D

41 MMICROENCAPICROENCAPSULSULATIONATION

IN VITRO RELEASE STUDIES The sample was then FIGURE 3 mixed in 100 ml of Release of Valdecoxib and phosphate buffer pH 6.8 Rofecoxib from the prepared for 24 hours in a rotary microspheres was studied in shaker at a constant rpm phosphate buffer saline pH 6.8 (900 of 50, and then filtered ml) using a USP Tablet Dissolution and analyzed Apparatus with a basket stirred at a spectrophotometrically constant rpm of 100 and at a at 241 nm for Valdecoxib temperature maintained at 37 ± 1°C and 230 nm for as prescribed for Valdecoxib and Rofecoxib in a Shimadzu Rofecoxib tablets in USP XXIV. UV-1601 Spectrophoto- Comparative cumulative drug release profile of Valdecoxib- A preweighed amount of meter. loaded microspheres. microspheres equivalent to 50 mg of Similarly, it was done for samples at 50°C and Valdecoxib and Rofecoxib was put FIGURE 4 to use in each test. Exactly 1 ml of 60°C, and values were the samples were withdrawn every recorded for EC, SCMC, 0.5 hours for the first 5 hours and and HPMC with drug- the rest at every hour, which were loaded microspheres. then assayed at 241 nm for Further calculations for Valdecoxib and 230 nm for drug content after storing Rofecoxib using a Shimadzu UV- at different temperatures 1601 Spectrophotometer. The same and the results are shown volume of fresh dissolution medium in Table 8a and further in was replenished after each sampling, Figure 5. Also, the percentage decrease in and the sample was withdrawn until Comparative cumulative drug release profile of Rofecoxib- there was a decrease in absorbance the amount of drug loaded microspheres. value. The results are shown in Table 7. The release profile is shown in Figures 3 and 4. T ABLE 4 FTIR peaks Rofecoxib Valdecoxib

3 STABILITY STUDIES o N -1 7 -N-H stretch - 3376.34 cm l o

V At Different Temperatures -1 -1 7

0 A preweighed amount (300 mg) of Aromatic stretch 3092.36 cm 3070.52 cm 0 2

h prepared microspheres was taken in

c -1 r a amber-colored bottles or vials and -C=N stretch - 1621.15 cm M

y was placed at various temperatures

g -1

o -C=O stretch 1747.70 cm - l

o from room temperature (37°C), n h c

e -1 -1 T 50°C, and 60°C for a period of 21 -S=O stretch 1089.67 cm 1073.68 cm y r

e days. During this period, an v i l -1

e -1

D equivalent amount of samples (about -C-O stretch 1035.37 cm 1027.63 cm g u r 100 mg) was withdrawn at a regular D period of 7 days. The characteristic peaks of drugs. 42 MICROENCAPMICROENCAPSULSULATIONATION

FIGURE 5 TABLE 5 FTIR peaks EC SCMC HPMC

-OH stretch 3485.23 cm-1 3440.76 cm-1 3452.81 cm-1

-CH3 stretch 2976.92 cm-1 2923.48 cm-1 2927.45 cm-1

-CH2 stretch 2930.58 cm-1 2155.79 cm-1 -

-C=O stretch - 1630.98 cm-1 -

-C-O stretch - 1115.13 cm-1 -

The characteristic peaks of polymers The decrease in drug content of SCMC Valdecoxib-loaded microspheres at various temperatures. present was also in Tables 9a and 9b and further in calculated, and the results Figures 7 and 8. are shown in Table 8b and FIGURE 6 further in Figure 6. RESULTS & DISCUSSION At Different pH Buffers of varying pH Drug Content from 1 to 10 were The study revealed that SCMC prepared as per the IP- drug-loaded microspheres have a Appendix and then stored. drug content of 0.0485 (Valdecoxib) Accurately, 100 mg of and 0.04629 (Rofecoxib), which is weighed microsphere greater than those of EC and HPMC samples were taken and drug-loaded microspheres (Table 1). placed in 100 ml of phosphate buffer pH 1 to The percentage decrease in drug content of SCMC Valdecoxib- Microencapsulation Efficiency loaded microspheres at various temperatures. 10 and kept in a rotary SCMC drug-loaded microspheres shaker for 24 hours. have a microencapsulation efficiency They were then filtered of 97% (Valdecoxib) and 92.6% FIGURE 7 and analyzed (Rofecoxib), greater than those of EC

spectrophotometrically at and HPMC drug-loaded 3 o

241 nm for Valdecoxib microspheres. N 7 l

and 230 nm for Rofecoxib o V

in a Shimadzu UV-1601 Angle of Repose 7 0 0

Spectrophotometer. The SCMC drug-loaded 2 h c This was similarly done microspheres were found to have a r a for both drug-loaded lesser angle of 36.9 degrees M y g o microspheres with SCMC, (Valdecoxib) and 39.8 degrees l o n h

EC, and HPMC. The (Rofecoxib), showing better flow c e T y

percentage decrease in property than the HPMC and EC r e v i l

drug amount in different drug-loaded microspheres having a e D g

pH was also calculated, larger angle of repose. u The decrease in drug content of Valdecoxib-loaded micros- r D pheres at various pH levels. and the results are shown 43 MMICROENCAPICROENCAPSULSULATIONATION

FIGURE 8 FTIR Studies 13 The FTIR spectrum was interpreted, and there was no chemical interaction taking place between polymer and drug in the drug-loaded microspheres. The various characteristic peaks of polymers and drug were discovered. The result is shown in Figure 1, showing FTIR overlay spectrum of SCMC loaded with Valdecoxib microspheres.

Scanning Electron Microscopy (SEM) Morphological examination using SEM showed spherical Valdecoxib loaded in SCMC microspheres with a main diameter of 3 to 5 µm (Figure 2a) and spherical Rofecoxib loaded in The percentage decrease in drug content of Valdecoxib-loaded SCMC microspheres with a main diameter of 3 to 5 µm (Figure microspheres at various pH levels. 2b). There was no significant differences between the lot.

TABLE 6 Peaks cm-1 FTIR Spectrum EC-R SCMC-R HPMC-R EC-V SCMC-V HPMC-V -OH stretch 3730.34 3654.35 3624.75 3475.61 3376.26 3317.13

-NH stretch - - - 3322.95 3317.32 3317.13

Ar stretch 3091.97 3092.12 3092.74 3251.76 3248.78 3249.13

=CH of alkyl stretch 2929.71 2926.25 2924.78 3042.94 2924.62 2924.08

-S-H stretch 2394.50 2360.07 2359.84 - - -

-C=O stretch 1747.49 1747.68 1747.69 - - -

-S=O stretch 1148.71 1089.38 1089.44 1098.41 1096.95 1097.23 3 o N

7 -C-O stretch 1035.24 1035.09 1035.11 1238.65 1240.19 1239.60 l o V 7

0 Ar C=C stretch 1595.02 1594.70 1594.80 1595.41 1594.38 1594.60 0 2 h c r

a -C=N stretch - - - 1547.85 1547.97 1547.85 M y g o

l -C-S stretch 552.96 553.09 553.11 571.55 572.28 572.41 o n h c e T -C-N stretch 847.30 847.50 847.08 842.38 842.87 842.74 y r e v i l e D The characteristic peaks of drug-loaded microspheres. g u r D

44 MICROENCAMICROENCAP In Sta In Vitro ReleaseStudies shown inFigures 3and4. formulations. The resultsarefurther suitab microspheres arefoundtobemore Thus, SCMCdrug-loaded showed two extremes ofrelease. microspheres and ECdrug-loaded microspheres. Incontrast,theHPMC extended) fromSCMCdrug-loaded release was 30hours (slow and percentage decrease in drug content percentage decrease indrug 60 contentat50°C and decrease indrug decreaseinpercentage gradual a microspheresat37°C for drug-loaded contentinSCMC decrease indrug signif shown inFigure 5. Also therewas no loaded microsphereswas as observed content inHPMCandECdr 60°C, whereas indrug asteepfall decrease indr 21 days, therewas but agradual microspheres at37°Cforaperiodof content inSCMCdrug-loaded changeinthedrug no significant The Polymer +DruginMicrospheres EC HPMC SCMC period of21days, therewas but a The studiesshowed thatdrug ° V C, whereas in asteepfall bility Studies in vitro ar icant changeinthepercentage le forcontrolled-release ying release profileinthepreparedmicrospheresafteraspecifiedtimeinterval. T emperature: ug contentat50°Cand There was TABLE 7 ug- Time (hrs) 20-21 26-27 30 more asshown inFigures 7and8. thus prolongingthereleasee evendrug moreslowly and gradually, And inhighly alkaline pH,itreleases rather releasingitgradually atpH7. pH (notreleasingdr pol in theacidicpH,sho content was foundto decrease slowly alkaline pH(7to10). The drug in theacidicpH(1to7)than microspheres were foundtobestable chemotherapy isthebestway forits adenomas in the colon,and which isknown toproducepolyps or FamilialPolyposis, Adenomatous other NSAIDsareusedto treat Valdecoxib). andvariousThese drugs inhibitors (Rofecoxib and a microspheres w in HPMCandECdrug-loaded meth methylcellulose, andhydroxy propyl cellulose, sodiumcarbo three dif In in Figure 6. coating materialforCOX-II This work investigated theuseof PSUL V ymer de ar ylcellulose), w ying pH: SULATION ferent polymers (ethyl CONCLUSION g rades lesserintheacidic Type Fast &Short Fast Slow &Extended The drug-loaded as obser hich w ug allatonce), wing thatthe ATION xy v ed assho ere usedas v en wn inhibitors studied. sustained release fortheCOX-II to make microspheresand obtain is oneofthebestchoices polymers content. Soitisconcludethat SCMC was only aslight decreaseinthedrug carbo w different temperatures,andtheresults also car release. The stabilitystudieswere found tobesuitable forcontrolled extended release. Thus, they were flow property, andaslow and microencapsulation efficiency, good content,high good drug character, highpercentageofyield, showed goodmorphological sodium carboxymethylcellulose that themicrospherescoatedwith stability studies. All theseshowed FTIR studies,andSEM,DSC, time consuming. ease oftheprocedure,andisless the methodbecauseofitshighyield, which was decidedafteroptimizing production ofthemicrospheres, Ev them. comparitive studywas donebetween almostequalto1. coefficient A linearity by showing acorrelation they obey Beer’s concentrationof wasdrugs decidedbased on thefact these two drugs. The useofthesetwo effective andidealmicrospheres of hence thiswork aimedatproducing the prolongedadministrationofdrug, polyps incolon. This diseaserequires treatment toavoid of therecurrence microencapsulation efficiency, characterized fortheirdr vitr ere sho These microspheresw aporation methodw o release studies,reposeangle, xymeth The Emulsification-Solvent ried outinvarious pHand wn tof ylcellulose becausethere a vor sodium as usedinthe ere fur ug content, ther in

45 Drug Delivery Technology March 2007 Vol 7 No 3 MMICROENCAPICROENCAPSULSULATIONATION

REFERENCES TABLE 8A

1. Giardiello FN, Brensinger JD, Petersen At 37°C GM. The use and interpretation of Drug Content in mcg/ml commercial APC gene testing for familial adenomatous polyposis. N Engl Days EC-R SCMC-R HPMC-R EC-V SCMC-V HPMC-V J Med. 1997;336(12):823-8277. 2. Powell SM, Petersen GM, Krush AJ. 7 0.02187 0.04629 0.03169 0.02836 0.0485 0.0379 Molecular diagnosis of familial adenomatous polyposis. N Engl J Med. 14 0.02160 0.04623 0.03165 0.02160 0.04843 0.03788 1993;329(27):1982-1987. 3. Bulow S, Faurschou NT. The incidence rate of familial adenomatous polyposis. 21 0.02160 0.04623 0.03165 0.02160 0.04843 0.03788 Int J Colorectal Dis. 1996;11:88-91. 4. Encyclopedia of Novel Drug Delivery At 50°C Systems. New York, NY: Dekker; 1999;493-495, 528, 541-543. 7 0.01988 0.0441 0.02878 0.02231 0.03354 0.046 5. Ansel HC, Allen LV, Jr., Popovich NG. Pharmaceutical dosage forms and drug 14 0.01972 0.0440 0.02806 0.02189 0.04519 0.0321 delivery systems, 7th ed. New York, NY: Lippincotts Williams and Wilkins; 2005;233-234. 21 0.0179 0.04215 0.0591 0.01935 0.0450 0.02908 6. Ministry of Health and Welfare At 60°C Committee. Indian Pharmacopoeia, Vol. 1. Delhi, India: Controller of 7 0.01646 0.04088 0.02309 0.01796 0.0438 0.02789 Publications; 1996:382. 7. Waterman KC, Sutton SC. A computational model for particle size 14 0.01486 0.03906 0.02187 0.01595 0.04189 0.02527 influence on drug controlled release colonic delivery. J Cont Rel. 21 0.01187 0.0385 0.01784 0.01252 0.04061 0.02116 2003;86:293-304. 8. Zahirul IK, Preberg Z, Kurjakoric N. A pH-dependent colon-targeted oral drug The drug content in the prepared microspheres after a specified time interval. delivery system using methacrylic acid copolymers: manipulation of drug release using Eudragit® L 900 and T ABLE 8B Eudragit® S-100 combinations. J Cont Rel. 1999; 58:215-222. At 37°C 9. Jain SK, Rawat S. Spectrophotometric Drug Content in mcg/ml determination of Rofecoxib in Pharmaceutical dosage forms. Indian J Days EC-R SCMC-R HPMC-R EC-V SCMC-V HPMC-V Pharm Sci. 2002;64:500-501. 10. Seedher N, Garg A, Bhatia S. 7 99.68 100 100 99.85 100 99.71 Spectrophotometic method for estimation of some COX-II inhibitors in pure form and in pharmaceutical 14 98.6 99.8 99.87 99.68 99.8 99.68 formulations. Ind J Pharm Sci. 2003;65:655-658. 21 98.6 99.8 99.87 99.68 99.8 99.68 11. United States Pharmacopoeia, 26th ed.

3 The US Pharmacopoeial Convention At 50°C o

N Inc., Rockville, MD; 2003.

7 12. Budavari S. The Merck Index, 13th ed. 7 90.8 95.3 90.8 78.5 94.8 88.3 l o

V White House Station, NJ: Merck & Co. Inc; 2001:308, 673, 1481. 7 14 90.0 95 88.5 77 93.1 84.5 0

0 13. Willard HH, Merritt LM, Jr., Dean JA, 2 Settle FR, Jr., eds. Instrumental h c r Methods of Analysis, 7th ed. Delhi, 21 81.7 91 81.8 68.1 92.8 76.5 a

M India:CBS Publishers;1986:309-316.

y At 60°C g o l o

n 7 75.2 88.5 72.9 63.2 90.30 73.4 h c e T y r 14 84.4 69 56.2 86.4 66.5

e 67.8 v i l e D

g 21 54.2 83.2 56.3 44.1 83.7 55.7 u r D The percentage decrease in drug content in the prepared microspheres after a specified time 46 interval at various temperatures. MMICROENCAPICROENCAPSULSULATIONATION

TABLE 9A BIOGRAPHIES

Drug Content in mcg/ml Lakshmi Sivasubramanian pH EC-R SCMC-R HPMC-R EC-V SCMC-V HPMC-V has 6 years of 1.2 0.07237 0.1570 0.08011 0.09370 0.392 0.0934 teaching experience. Her research interest includes 2 0.05723 - 0.07911 0.08025 0.1892 0.08570 analytical method development for single and combined dosage 4 0.03828 0.07077 0.07723 0.06271 0.1760 0.08140 forms using various analytical tools as well as synthesis and 5 0.03574 0.06165 0.06419 0.05489 0.1711 0.07510 characterization of targeted drug delivery systems. She is a 6 0.03154 0.05386 0.06232 0.04512 0.1287 0.04461 member of the Indian Pharmaceutical Association and 7 0.01895 0.03508 0.04762 0.04003 0.1222 0.04312 Association for Pharmacy Teachers of India. She has 8 0.01729 0.02944 0.04486 0.03077 0.1102 0.03144 published 12 articles in national and international 9 0.01342 0.02911 0.03121 0.01992 0.04914 0.03130 journals and more than 20 articles at national and 10 0.00878 0.02790 0.02220 0.01548 0.03673 0.02032 international conferences. The drug content in the prepared microspheres after a specified time interval at various pH. Madhumathi Seshadri has just TABLE 9B completed her PG in Pharmacy and is % Decrease in Drug Content planning to move to Australia to begin her PhD HPMC-V pH EC-R SCMC-R HPMC-R EC-V SCMC-V Programme. She has authored 1.2 40.1 60.3 70 54.5 75.7 53.5 an estimated 8 e-articles at pharmainfo.net. She has also 2 61.3 62.8 82.1 70.1 101.3 82.4 presented 4 articles at national and international conferences. 4 78.9 63.6 141.6 108.3 227.2 82.7

5 86.5 75.8 150.3 140.9 251.9 113.5 3 o N

6 144 116.35 196.7 158.9 265.3 117.4 7 l o V

7 163.2 133.1 202.6 193.3 352.8 197.6 7 0 0 2 h c

8 174.8 152.9 243.7 220.8 362.9 214.2 r a M y

9 261.3 166 249.6 282.6 390.1 225.5 g o l o n h c e

10 330.4 339.1 252.8 330 808.2 245.8 T y r e v i The percentage decrease in drug content in the prepared microspheres after a specified time l e interval at various pH. D g u r D

47

NON-INVASIVE INSULIN UPDATE

Current Status of Non-Invasive Insulin Delivery Technologies By: Avani Amin, MPharm, PhD; Tejal Shah, MPharm; Jagruti Patel, MPharm, PhD; and Anuradha Gajjar, MPharm, PhD

ABSTRACT The discovery of insulin is one of the greatest milestones in medical history that revolutionized the use of peptides and proteins as therapeutic agents. Patients with Insulin-Dependent Diabetes Mellitus need to use insulin in the form of multiple subcutaneous injections to achieve adequate glycemic control. This is a heavy burden for them and it involves a lot of discomfort. Significant efforts are currently focused toward developing non-invasive insulin delivery systems, and there are several competing technologies at different stages of development. Innovative, non-invasive methods to deliver insulin are poised to transform diabetes management. Major breakthroughs have been observed regarding the pulmonary/inhaled insulins with the FDA approval and launch of the first inhaled insulin Exubera® by Pfizer and Netkar in 2006. Novo Nordisk is also in the final stages of clinical studies on AERx, and it may be launched by 2008. This article is an update to review the current status of the various non-invasive insulin technologies. Review on the market and research status of inhaled and oral insulin has been provided. Current developments in alternative routes of insulin delivery have also been appraised.

INTRODUCTION cell transplantation, and diabetes vaccine.1 diabetes mellitus population worldwide is An article has been presented earlier by us projected to grow from 39.4 to 49.4 million The discovery of insulin is one of the on the Non-Invasive Insulin Delivery from 2003 to 2010. With the greatest milestones in medical history that Technologies, which gives a detailed aforementioned new treatments in late- revolutionized the use of peptides and description about the various routes of stage development, diabetes disease proteins as therapeutic agents. In the past insulin.2 In the near future, several novel management is on the brink of a therapeutic several decades, insulin from different approaches that mimic the endogenous revolution. In the $4-billion insulin market, animal sources was used, until the release and kinetics of insulin shall be the arrival of inhaled and oral insulins will breakthrough in biotechnology made it designed to achieve better control and offer greater flexibility and options for both possible to produce human insulin. Insulin, effective treatment of diabetes.3 type 1 and type 2 patients.5-7 a pancreatic hormone, helps to lower the The aim of this update is to review the blood sugar levels. An intensive treatment current status of the various non-invasive PULMONARY ROUTE that mimics the physiologic secretion of technologies for insulin. As previously insulin secretions would be ideal. Patients stated, major breakthroughs have been Pulmonary insulin delivery is the most with Insulin-Dependent Diabetes Mellitus observed regarding pulmonary/inhaled promising alternative with several inhaled 3

o need to use insulin in the form of multiple insulins with the FDA approval and launch insulin systems in the process of N

7 subcutaneous injections to achieve adequate of the first inhaled insulin (Exubera) in development and approval for the treatment l o V glycemic control. Significant efforts are 2006. Novo Nordisk is also in the final of adult patients with type 1 or type 2 8 7 stages of clinical studies on its AERx. diabetes. They deliver insulin into the 0 currently focused toward developing non- 0 2 Numerous developments have also been lungs, which can be a powder formulation

h invasive insulin delivery systems, and there c r a are several competing technologies at observed for oral insulin with Biocon being or a solution. The first inhaled human M the brand leader in the supply of oral insulin, a product of a joint development

y different stages of development. Innovative, g o

l insulin. Current developments in alternative program initially between Aventis, Pfizer,

o non-invasive methods to deliver insulin are n

h routes of insulin delivery (buccal, ocular, and Nektar (Exubera), was approved in the c poised to transform diabetes management. e T

y nasal, colon, vaginal, and transdermal) have United States and the European Union on

r Investigators have contemplated every e v i l possible route of drug delivery for insulin. also been appraised. In addition, application January 27, 2006, for the treatment of adult e D of nanotechnology for designing insulin patients with type 1 or type 2 diabetes. g The non-invasive methods in insulin u r D therapy include oral, pulmonary, drug delivery systems has also been Exubera is a rapid-acting, fine powder form transmucosal, buccal, nasal, transdermal, reviewed.4 of insulin. This system delivers a fine dry- 48 rectal, ocular, vaginal, gene therapy, islet The combined type 1 and type 2 powder formulation (< 5 microns) in

NON-INVASIVE INSULIN UPDATE

diameter of regular short-acting human insulin TABLE 1 to the deep lung in a reproducible and efficient manner. The number of individual blister Serial No. Product Name Pharmaceutical Regulatory Year Status packs inhaled controls the dose. The insulin Company dry powder is packaged into a single-dose 1 Exubera Pfizer Inc. Approved Jan. 2006* blister containing 1 or 3 mg, with a 1-mg blister corresponding to ~3 units of insulin.9 2 AERx (iDMS) Novo-Nordisk & Phase III 2002** Aradigm The bioavailability of this product is about 10% compared to regular human insulin given 3 AIR (HIIP) Eli Lilly & Alkermes Phase III July 2005 by subcutaneous route.10 The safety and efficacy of Exubera have been studied in 4 Technosphere Mannkind Phase III 2004 about 2,500 adult patients with type 1 and KOS Pharmaceuticals Phase II 2004 type 2 diabetes. In clinical studies, Exubera 5 BAI reached peak insulin concentrations more Regulatory Status of Various Inhaled Insulin Delivery Devices quickly than regular insulin, administered by * USA and European Union an injection. Peak insulin levels were achieved ** Put on hold in 2005 for examination of its dosing issues. in about 50 minutes (range 30 to 90 minutes) with Exubera inhaled insulin compared with 105 minutes (range 60 to 240 minutes) with thereafter.11 regular insulin. For patients with type 1 The traditional study designs cannot device to guide the correct rate and depth of diabetes, inhaled insulin can be added to provide answers to important and practical breathing for triggering insulin at the longer-acting insulin taken with meals. questions regarding real-world effectiveness, optimum movement in the inspiration- Whereas for patients with type 2 diabetes, which is influenced by psychological or other expiration cycle. This aims at consistent inhaled insulin can be used alone, along with access barriers. To overcome these delivery of insulin, regardless of a patient’s oral medication that controls blood sugar, or limitations, a real-world randomized clinical breathing ability. However, liquid with longer-acting insulins. trial has been undertaken (protocol No. formulations carry the risk of microbial 13 The major problems with the inhaled A21710187, registered with Clinicaltrials.gov, growth and thus require refrigeration. The insulin are loss of drug within the inhaler and Registration ID. NCT00134147) with bioavailability of this liquid formulation is 10 mouth during inhalation, variations in approximately 700 patients from Canada, shown to be about 13% to 17%. absorption due to age-related differences, France, Germany, Italy, Spain, United Compared to Exubera, the dry-powder respiratory tract infections, and smoking. The Kingdom, and the United States with type 2 AIR-(HIIP) (Human Insulin Inhalation long-term effects of the inhaled insulin diabetes mellitus poorly controlled by oral Powder) formulation developed by Lilly and deposited in the lungs are not known. There is agent therapy. This trial has been designed to Alkermes apparently has much larger also the risk of production of anti-insulin estimate the effect of the availability of individual particles (10 to 20 microns) that antibodies against inhaled insulin. Because Exubera as a treatment option for glycemic contain both insulin and excipients. Despite the bioavailability of inhaled insulin is control in the global population.12 larger geometric diameter of the particles, the relatively low, very high doses of insulin The other pulmonary insulin delivery company claims that the mass mean

3 (about 8 times that of subcutaneous dose) systems under investigation are ProMaxx, aerodynamic diameter remains within the o N may be needed to achieve the same glycemic AIR, Spiros, and Technosphere. However, range (ie, < 5µm) for optimal delivery to the 7

l control, which can increase the financial deep lung because of the particle’s porous, o

V much information is not available on their burden on patients.10 low-density properties.13

7 status. The AERx (iDMS) is the only inhaled 0

0 Some of the reported side effects The dry-powder insulin utilized by 2 insulin system currently in clinical trials to h

c associated with Exubera therapy are low Mannkind is the microencapsulated form of r investigate the use of a liquid (water-based) a M blood sugar, cough, shortness of breath, sore insulin formulation. The AERx (iDMS) insulin entrapped within a small (2 microns) y

g throat, and dry mouth. Exubera is not organic particle known as Technosphere,

o device creates an inhalable aerosol of liquid l o

n recommended for active smokers or by those which self-assembles around insulin during

h insulin droplets (1 to 3 microns) by c 13 e T who have quit smoking within the past 6 compressing the liquid insulin formulation the manufacturing process. The y r

e months. Exubera is contraindicated for Technosphere contains 90% excipient and v

i through an array of hundreds of precisely l

e patients with asthma, bronchitis, or hence may constitute an increased powder D laser-drilled holes. In this, single-use insulin g

u emphysema. Baseline lung function tests are burden for the lungs of patients compared r strips are combined with a hand-held, D recommended before starting the treatment breath-activated, microprocessor-controlled with other insulin delivery systems. 50 and should be repeated every 6 to 12 months The KOS insulin is an excipient-free NON-INVASIVE INSULIN UPDATE

TABLE 2 Type DosageForm/ Reference Name of Agent Delivery of Insulin BBI (Bowman-Birk-Inhibitor) Protease Thiolated chitosan- 18 Inhibitor insulin tablets Ovomucoid- glycoprotein inhibitor Protease Polymeric 19 Inhibitor hydrogel Wheat germ agglutinin Protease Liposomes and solid- 20 Inhibitor lipid Nanoparticles Camostat mesilate Protease Azopolymer-coated 21 Inhibitor pellets for colon targeting Eudragit S-100 Protease Eudragit 22 Inhibitor Micropsheres Sodium salicylate Permeation Eudragit S100- 23 Enhancer coated insulin HGC 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD), lauric acid (C12), or Absorption Acrylic hydrogel 24 of insulin the sodium salt of C12 (C12Na) Enhancers

Lysalbinic acid Absorption Buccal 25 Promoters Sodium glycocholate Absorption Colon targeted 26 Promoters Capric acid, glycyrrhizic acid, deoxycholic acid, hydroxypropyl-beta- Absorption Insulin-loaded poly 27 Enhancers (ethylcyano acrylate) cyclodextrin (HPbetaCD) cholic acid nanospheres Hydroxylpropyl-beta-cyclodextrin (HP-beta-CD), chitosan, polyethylene- Absorption Sublingual insulin 28 polypropylene glycol, polyoxyethylene lauryl ether, polysorbate 80, egg Enhancers lecithin, or oleic acid

Mucoadhesive Liposomal insulin 29 Methyl cellulose Agent Cross-linked poly(methacrylic acid) and poly(ethylene glycol) Complexing Microparticles 30 Agent

Various Types of Agents Used in Insulin Drug Delivery

crystalline recombinant human insulin • Formulation is stable at room ORAL ROUTE delivered by the company’s BAI (Breath temperature, less susceptible to Actuated Inhaler) device. The bioavailability of microbial growth, and environmental Considerable research efforts have also the KOS formulation has been found to range degradation. been devoted to the development of oral forms

from 10% to 15% of subcutaneous regular • Long-term chemical stability (prepared 3 of insulin that can be delivered safely and o insulin. by glass stabilization process). N effectively without the need for injection. In 7 l

The following are advantages of dry- o • Available as individual unit-dose contrast to the inconvenient and potentially V

powder insulin formulations and delivery packaging in aluminium foil blister problematic method of parenteral insulin 7 0 0

devices: packs, which provides strong barrier administration, the oral route offers the 2 h c r

against moisture. advantages of self-administration with a high a • Reusable, durable, and simple for the • No chemical propellant to dispense the degree of patient acceptability and compliance. M y g

patients to use. o insulin. Instead, it uses patient-activated This route also closely replicates the natural l o n

• Convenient to store, carry, and use by secretion pathway of insulin from the pancreas h pressurized air as the energy source. c e the patients. T

to the liver. Due to the directness of this route, y r e v

• Works without the use of electronics, many of the major insulin-related side effects i The regulatory status of various inhaled l e batteries, and microchips. that diabetics suffer from could possibly be D

insulin delivery devices has been summarized g u r

in Table 1. avoided. However, there are several limitations D of the oral route. These include low oral 51 NON-INVASIVE INSULIN UPDATE

bioavailability due to degradation in the Complexing agents also display enzyme Emisphere is currently putting together a stomach, inactivation and digestion by inhibitory activity. Drawbacks of these agents, Scientific Advisory Board (SAB), composed proteolytic enzymes in the luminal cavity, such as risk of toxic side effects or high of leading clinicians, endocrine, and poor permeability across intestinal epithelium production costs, might be excluded by the metabolic experts. With the SAB, Emisphere because of its high molecular weight, and development of advanced drug delivery will be in a strong position to continue and lack of lipophilicity.14 Scientists developed systems.15-17 Various types of agents used by move its oral insulin program ahead. various approaches to overcome these scientists in insulin formulations are shown in Apollo Life Sciences announced the enzymatic and diffusional barriers. Table 2. successful completion of data gathering in Furthermore, the results of in vivo studies on Several companies across the globe are independent Phase I toxicology trials for oral different animals in the past decade have solely concerned with the creation of effective insulin and its oral delivery device, Oradel, in suggested that protection of insulin by oral insulin delivery in the form of buccal December 2006. Oramed Pharmaceuticals is adopting a suitable means improve the sprays, enteric-coated tablets, gel capsules, focused on the development of oral delivery absorption. These include enteric polymer etc. Some companies are market leaders in solutions based on proprietary technology. coatings to protect the drug as well as carrier the field of oral insulin, including Biocon in Oramed is currently developing an orally systems from digestion in the stomach, India (which acquired the IP rights to its ingestible soft gel insulin capsule for the incorporation of penetration enhancers, use of collaborator Nobex in 2006), Emisphere treatment of type 1 and 2 diabetes. The protease inhibitors in the system to prevent Technologies in the United States, Generex in preclinical studies were completed and insulin from intestinal enzymatic digestion, South America, and numerous other presently it is under Phase I trials.32 incorporation of insulin into bioadhesive companies throughout the world. These Diabetology, a UK clinical research and polymeric carriers, or a combination of these companies are at various stages of putting development company, has an oral insulin approaches for increasing bioavailability. The oral insulin through clinical trials. capsule (Capsulin), which is currently in agents used for increasing bioavailability of Biocon completed Phase-IV trials for Phase II).33 However, extensive studies of insulin formulations can be classified as the insulin and marketed it as Insugen in the insulin products on humans are necessary. following: Indian market. Biocon plans to launch The results of such clinical trials can only Insugen in Europe in 2007 and in the US predict the future of oral insulin drug delivery. • Enzyme inhibitory agents some time in 2008. Under development by • Inhibitors that are not based on amino the Canadian company Generex NANOPARTICLES FOR acids, such as p-aminobenzamidine, Biotechnology, Oral-Lyn is developed. It is a INSULIN DELIVERY FK-448, and camostat mesilate liquid formulation of human insulin that is • Amino acids and modified amino sprayed into the mouth using its proprietary Nanoparticles can be used as carriers for acids, such as acid derivatives RapidMist device. The liquid spray is delivering proteins and peptides and thus have • Peptides and modified peptides (eg, absorbed by the buccal mucosa. It is approved enormous significance in insulin drug bacitracin, antipain, chymostatin, and for use in Ecuador.31 NIN-058 (oral insulin delivery. Li MG, Lu WL, and co-workers amastatin) analogue) is a GlaxoSmithKline/Nobex investigated distribution, transition, • Polypeptide protease inhibitors (eg, product that is a pill form of insulin. The bioadhesion, and release behaviors of insulin- aprotinin, Bowman-Birk inhibitor, and product has completed Phase-I trials. This loaded pH-sensitive nanoparticles in the gut chymotrypsin inhibitor, soybean milestone is important in the development of of rats, as well as the effects of viscosity trypsin inhibitor, chicken, and duck oral insulin. However, major pharmaceutical agents on them. It was observed that the

3 ovomucoid companies are in mid stage of clinical release profile of insulin from the o N • Absorption enhancers and promoters development. nanoparticles was S-shaped, and addition of 7 l

o (eg, bile salts, sodium cholate, long- In October 2006, Emisphere announced HPMC was found to be favorable to the V results of a 90-day, Phase II multi-center, absorption of the drug loaded.34

7 chain fatty acids, salicylates, 0

0 randomized trial for its oral insulin tablet Attivi et al formulated insulin-loaded

2 cyclodextrins, chelating agents, and

h ®

c using its propriety (eligen ) technology. The polymeric nanoparticles using response r surfactants) a M • Mucoadhesive polymers four-arm study evaluated the safety and surface methodology. The nanoparticles were y

g efficacy of low and high fixed doses of oral prepared by water-in-oil-in-water

o • Natural polymers (eg, alginate, pectin, l o

n insulin tablets versus placebo in patients with emulsification and evaporation methods using

h chitosan, lectin, and gelatin) c e T • Synthetic polymers (eg, type 2 diabetes mellitus on existing oral blends of biodegradable poly-epsilon- y r

e metformin monotherapy. One focus of the caprolactone (PCL) and positively charged, v sodiumcarboxymethylcellulose, i l e trial was to confirm that insulin delivered nonbiodegradable polymers (Eudragit RS). D hydroxypropylmethylcellulose, g u r polyacrylic acid) orally could be administered as a fixed-dose An interesting formulation exhibited 25 D product without the need to conduct glucose IU/100 mg of polymer entrapment, 350 nm 52 monitoring or titrate the insulin dose. particle size, +44 mV zeta potential with a NON- I NSUL INV IN ASI UPDATE VE NON- I dependent onthepHofmedium. efficiency, was greatly andreleaseprofile prof displa been copol le study indicatedreductioninb stability indistinctpHenvironments. The e deli characterized b pol absor impor nanopar solution ofinsulin. and duodenum>ileumjejunumforaqueous duodenum forinsulincontainingliposomes containing SLNs;ileum>jejunum insulin jejunum >ileumfor WGA-modified liposomesandduodenum > WGA-modified order: duodenum>ileumjejunumfor sitesinthefollowingin different absorption was foundtobedecreasedfortheformulations rats.Insulinconcentration and ileumonfasted w Formulations containing100IU/kginsulin and SLNsinaperfusedratintestinalmodel. insulin-liposomes agglutinin (WGA)-modified characteristicsofwheat-germ transport In vivo (WGA)-N-glutaryl-phosphatidylethanolamine. usingwheatagglutinin germ were modified and co-workers. Someinsulin-loadedSLNs deliverycharacterized fororaldrug by Zhang (SLN) containinginsulinwere designedand insulin releaseafter7hours. polydispersity of0.21,and4.8IU/100mg on h insulin. of demonstrated increaseinoralabsorption SLNs inSLNsand observed WGA-modified alone. However, thehigherbioavailability SLNsthan effect of WGA-modified (pol polymethacrylic acid-chitosan-polyether (HpbetaCD-I) comple v v ere administeredtotheduodenum,jejunum, en afterloadingwithinsulin,and therelease el inadiabeticrat model. y(&gg very. remainedspherical Nanoparticles y iles w ydro Nanopar Zhang andco-w solidlipidnanoparticles Lectin-modified eth developed. PMCPnanoparticles ption. ymer, have PMCP)nanoparticles also y tant f ed goodinsulinencapsulation 3 studies indicated greater stabilizing studies indicatedgreater 6 ticle typeanddelivery sitewere ylene gl xyprop An oralinsulindelivery systembased r;-glutamic acid)w ere signif 20 actors forintestinalmucosal ticles composedofchitosanand y yl betac ycol-pol Lin etalfororalinsulin This indicatedthat NSUL icantl ork x encapsulated in ypropylene glycol yclode ers alsoe y af INV 35 38 ere preparedand fected b lood glucose xtrin-insulin v aluated the y 3 7 their IN ASI like insulin. animals usingthetransder glucose le demonstrated signif potential forfur transmucosal routemightsho that useofnanopar diabetes mellitus. subcutaneous administrationusedfortypeI comparable tothatachieved usingthestandard suitab carriers. wereThese nanoparticles foundtobe initiator affected ofthe theperformance pol conditions. The amountofmucoadhesive found tobestab de have openednew avenues forthe feasibilityof human applications. CaCo deli sho theintranasaladministration Furthermore, was delivered usingthegoldnanoparticles. hyperglycemia) was when observed insulin reduction ofblood glucoselevels (postprandial orally andintranasally torats. A significant andadministered capped goldnanoparticles Insulin w fortransmucosaldelivery ofinsulin. carriers Joshi etal,goldnanopar pol polymerization processusingchitosan, nanocar nanopar have preparedmucoadhesive polymer-coated pulmonary, nasal,andoral).Cuiworkers insulin throughthetransmucosalroutes(ie, deliverypromising drug systemfordelivering mucoadhesive polymers have proved a preparedusing nanoparticles recent finding, in delivering insulinthroughotherroutes.Ina reducing blood glucoselevels. PHNP was foundasaneffective methodfor for oralinsulindelivery. Useofinsulin-loaded (PHNP)ascarriers PLGA-Hp55 nanoparticles (PNP)and potential ofPLGAnanoparticles v ymers andconcentrationoftheradical y(acr w eloping nanopar v ering insulintransder ed controlofpostprandialhyperglycemia Nanopar In anotherlatestdiscovery by reported haveNanoparticles alsofoundapplication Cui FDandco-workers investigated the UPDATE 3 le forcar nanopar riers w ticles colloidalcar ylic acid)andcarbopol. as loadedintobareandaspar v els indiabeticmice. 40 VE ticles have also beenusedfor ere preparedusingtheemulsion r ticles. ther de ying proteinorpeptidedr le underphysiological pH Thus, itcouldbeobser ticles throughthe ticles transder icant decreaseintheb 42 A v elopments. study conductedin ticles w mall mal nanoinsulin riers. w 39 y The results considerab These ere preparedas using no The mally for 41 y w tic-acid- ere vel v ugs lood ed le ner fromthenasalcavitytransport tothecentral administration resultedindirectinsulin administration. Intranasalinsulin as comparedtoperipheralinsulin Craft, the insulin. Inastudyconductedby Reger and of transpor the nasalmucosaf a the methodofpreparationwere foundtohave buccal route. buccal improved delivery ofinsulinthroughthe also showed improvement intastealongwith promoter was effects freefromany and irritant Dube le subcutaneous routeinlowering blood glucose for that insulinadministeredviatheb versus spray buccal insulin.Itwas concluded measured afteradministrationofsubcutaneous glucose, insulin,orC-peptidele difference in No statistically significant regularpatients withtype1diabetes. insulinin insulin spray was comparedwithsubcutaneous co-workers, themetaboliceffect ofabuccal In abiokineticstudyconductedby Pozzilli and insulin hasalsosightedmany new approaches. Buccal lar forthedeliveryopportunities ofinsulin. The insulin. ne administration, thenasalrouteseemstobe Nasal deli acid homo ultrasonic, high-speedshearandhigh-pressure route. the buccal The vesicles were preparedby per soybean lecithin-basedvesicles toimprove the v signif xt routethatpro ge surf els. mulation was aseffective asthe v meation-enhancing ef v , ous systemviaintraneuronal and ALTERNATIVE ROUTESFOR ery ofinsulinbyery Starokadomskyy and T In additiontopulmonar A Zhu andhisresearchteamhave prepared w y. They have thatthenew reported genization methods. 43 he buccal routeforthedeliveryhe buccal of as usedforimpro 44 icant ef new absorption promoter,new absorption lysalbinic y ace areaandthehighv INSULIN DELIVERY t ha of insulinthroughthenasalroute 25 ve demonstratedthesuperiority fect ontheb vides awidear a v or thef ving theb fect ofinsulinthrough The par uccal deli ast absor y insulin vels was ascularity of ra uccal spra ticle sizeand uccal y v ption of of er y of y

53 Drug Delivery Technology March 2007 Vol 7 No 2 NON-INVASIVE INSULIN UPDATE

extraneuronal pathways and suggests that the the rectal and vaginal mucosa was found to anionic lipids to achieve therapeutic levels intranasal insulin administration is safe in increase further with the incorporation of through the epidermis.54 Rastogi and Singh humans. Thus, they have concluded that dimethyl-beta-cyclodextrin (DM-betaCD) as a have investigated the effect of various intranasal insulin administration offers a novel penetration enhancer.49 chemical enhancers, such as fatty acids and treatment strategy for disorders associated Ning et al have encapsulated insulin in limonene and cathodal iontophoresis, on with central insulin abnormalities, such as niosomes using Span 60 and Span 40 for the percutaneous absorption of insulin. It has diabetes and neurodegenerative diseases.45 penetration of the vaginally administered been reported that linolenic acid produced niosomes. Insulin-sorbitan monoester greater permeability of insulin when Chitosan as a polymer for nasal niosomes were therapeutically effective on compared with other fatty acids.55 delivery: To increase the nasal absorption of vaginal administration. This study opens up Recent studies have also demonstrated insulin, permeation enhancers or avenues for the use of niosomes as carriers of the use of ultrasound-mediated transdermal mucoadhesive polymers are used in the drug proteinaceous drugs for vaginal delivery.50 insulin delivery with the use of cymbal delivery systems. Chitosan represents a array.56 An Erbium:yttrium-aluminium-garnet multifunctional polymer possessing both Ocular Route (Er:YAG) laser can be effectively utilized for mucoadhesive and permeation-enhancing The ocular route has also been suggested transdermal delivery of macromolecules and properties. It is thus a promising polymer for as an alternative to subcutaneous protein-based drugs like insulin.57 nasal delivery of insulin. Thiolated chitosan administration of insulin using polymeric has been used by Krauland et al for the systems, such as nanoparticles, liposomes, SUMMARY preparation of insulin microparticles that were ocular inserts, gels, etc. However, its use is evaluated in vivo. They reported that the limited due to the amount of insulin absorbed Non-invasive insulin delivery thiolated chitosan microparticles systemically via eyes. Xuan et al used insulin technologies are poised to change the status demonstrated better glucose reduction eye drops and studied the effects of pH and of disease management. Much progress has capacity and pharmacological effect than the absorption enhancers, such as glycocholate been made since several decades in the unmodified chitosan.46 In another study and fusidic acid in rabbits. Systemic development of non-invasive techniques. conducted by Varshosaz and co-workers, absorption was higher at increased pH (8.0), Various delivery strategies and specialized chitosan was used as a bioadhesive gel. The and both the absorption enhancers further companies have evolved throughout the past authors reported that the use of permeation increased the insulin absorption.51 few years to improve the delivery of insulin. enhancers, such as saponins, sodiume Among all the approaches, pulmonary decxycholate, EDTA, and lecithin, improved Transdermal Route administration of insulin has achieved much the nasal absorption of insulin. They also The human skin presents itself as a clinical significance. The oral route is also concluded that the in vivo studies of the rather thick barrier to allow permeation of booming to enter the market and has EDTA-chitosan gels showed reduction of large molecules like insulin. However, the undergone considerable market research, and glucose levels as much as 46% as compared significant advantage offered by transdermal other delivery routes are chasing closely to the intravenous route.47 Yu et al have delivery of drugs is the complete lack of behind. However, delivery via the non- studied the delivery of insulin through the degrading enzymes, which has attracted a invasive route yet remains a challenge due to nasal route using chitosan solution. Chitosan good amount of investigations for this poor absorption and enzymatic instability. solutions containing absorption enhancers, alternative route. Iontophoresis increases the Long-term studies to ensure the safety of the such as Tween 80, EDTA, beta cyclodextrin, transdermal permeation of charged and alternative routes of insulin are yet necessary and hydroxylpropyl betacyclodextrin, have neutral compounds by the process of electro- before recommending its extended use. 3

o been studied to improve the nasal delivery of migration and electro-osmosis. Tokumoto et Although as these technologies become N 48 7 insulin. al reported from their in vivo study on feasible in the near future, they could offer l o V percutaneous absorption of human insulin in non-invasive, efficacious, and a more 7

0 Vaginal/Uterine Route rats that synergistic application of physiological way of insulin administration to 0 2 The polypeptide insulin, which is electroporation (EP) and iontophoresis (IP) patients with diabetes. h c

r 52 a extensively degraded by proteolytic enzymes enhanced the percutaneous absorption. M

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g Degim et al showed that chitosan gel (CH- of electro-osmosis (anodal iontophoresis) Expert Opin Drug Deliv. 2006;3(6):763-770. u r 4. Shaikh IM, Jadhav KR, Ganga S, Kadam VJ, Pisal SS. Advanced approaches in D gel) could be used for effective administration subsequent to electroporation in the presence insulin delivery. Curr Pharm Biotechnol. 2005;6(5):387-395. of insulin. The penetration of insulin through of 1,2-dimyristoylphosphatidylserine or other 54 N I ON- NSUL INV IN ASI UPDATE VE NON- I 35. 34. LiMG,Lu WL, Wang JC,Zhnag, Wang XQ,Zheng AP. Distribution, 33. 32. Appolo OralInsulinUpdate-PhaseI Toxicology Trials forOralInsulinandits 31. 30. MorishitaM,Goto T, NakamuraK,Lowman Am, Takayama K,Peppas NA. 29. 28. 27. Radwant MA, Aboul-Enein HY. enhancersonthe The effect of oralabsorption 26. KatsumaM, Watanabe S,Kawai H, Takemura S,Sako K.Effect ofabsorption 17. 16. Narayani R.Oraldelivery ofinsulin-makingneedlesneedles. Trends Biomater 1 14. 13. Patton J. MedRes&Opin.2006;22:S5- delivery ofinsulin.Curr Pulmonary 22. 25. 24. Uchida T, Toida Y, SakakibaraS,Miyanaga Y, Tanaka H,NishikataM, Tazuya 23. 1 11. www.fda.gov. FDA ConsumerMagazine. First Inhaled InsulinProduct 10. GirishC,ManikandanS,Jayanthi M.Newer insulinanalogues andinhaled 9 8. Fabbri safetyofinhaledinsulin:areview data. L.Pulmonary ofthecurrent 7. Gomez-Perez FJ, RullJA. Insulintherapy:alternatives. current Arch Med.Res. 6. oftightglycaemicPatton JS.Unlockingtheopportunity control:innovative 5. Scherbaum WA. oftightglycaemic Unlockingtheopportunity control:inhaled 21. Tozaki H,NishiokaJ, Komoike J, OkadaN, Fujita T, MuranishiS,KimSI, 20. ZhangN, PingQ,HuangG,HanX,Cheng Y, Xu W. Transport characteristics 1 18. 5. Bernkop-Schnurch 5. Bernkop-Schnurch A. agentstoovercomeThe useofinhibitory theenzymatic 2. Freemantle N, Strack TR. The real-world trialists:willavailability ofinhaled . 9. Valuev IL,Sytov GA, Valuev LI, Valueva TA, Ul'ianova MV, PlateNA. Diabetes Care.2004;27:239-245. Cefalu WT. Concept,strategies, andfeasibilityofNon-invasive insulindelivery. d i nsulin: clinicalefficacy. DiabetesObesMetab. 2005;7(suppl1:S9-S13). C Med ResOpin.2006;22:21-28. Atti W W elivery ofinsulinviathelung.DiabetesObesMetab. 2005;7(suppl1:S5-S8). methodolo Formulation ofinslin-loaded polymeric usingresponse surface nanoparticles 2007;329(1-2):182-191. rats. IntJPharm. inthegutof transition, adhesion,andreleaseofinsulinloadednanoparticles Oral Delivery Device, Oradel.DiabetesNews. December 14,2006. Controlled Release.2006;110(3):587-594. single andmultipleadministrationstudiesintype12diabetic rats.J Novel oralinsulindelivery systemsbasedoncomplexation polymer hydrogels: 10):2945-2949. administration ofliposomalinsulin.JNanosciNanotechnol.2006;6(9- Degim IT, GumuselB, Degim Z,Ozcelikay T, Tay A, GunerS.Oral hypoglycemic activity. Bull.2005;28(12):2279-2288. BiolPharm mucosal lipidfluidityandproteinconfor Zhang X,Q. Sublingual delivery ofinsulin:effects ofenhancersonthe Cui CY diabetic rats.JMicroencapsul.2002;19(2):225-235. in vivo ofinsulin-loadedpoly(ethylcyanoacrylate) performance nanospheresin 2006;307(2):156-162. throughcolon-targeted delivery.promoters oninsulinabsorption IntJPharm. 2006;308(1-2):149-154. delivery: preparationandcharacterizationoflysalbinic acid.IntJPharm. K A Release. 1998;52(1-2):1-16. toperorally administeredtherapeuticproteinsandpeptides.JControl. barrier and de Hamman JH,EnslinGM,K S11. of thereal-world trial. Trials. 2006;7:25. Jain D Starokadomsk 2001;49(10):1261-1266. hydrogels Bull. acrylic enhancers.ChemPharm containingabsorption K, Yasuda N, MatsuyamaK.Preparationandcharacterization ofinsulin-loaded of diabeticbeagledogs. 2002;237:71-76. IntJPharm. coated capsulescontainingsodiumsalic Hosny EA, Al-Shora HI,ElmazarMA.Oraldelivery ofinsulinfromenteric microspheres fororaldelivery. 16. 2005;6(1):Article AAPS Pharmscitech. deli calcitonin usingnovel azopolymer-coated pelletsforcolon-specifcdrug human insulin(Exubera A insulin. IndJMedSci.2006;60:117-123. T 2006;6(9-10):2959-2966. nanopar o Med Khim.2001;47(1):132-139. Inhibitors ofproteolytic enzymesinthetreatmentofdibetesmellitus. Vopr 2004;95(3):547-555. p Krauland a 2005;36(3):258-272. urr urr bsorption enhancers, and protease inhibitors. Pharm enhancers,andproteaseinhibitors.Pharm bsorption Technol. April, 2006. f otential ofthiolatedchitosan-inslintablets ondiabeticrats.JControlRelease. erashima H, rtif Organs.rtif 2001;15(1):12-16. han NM.Oralinsulindeli pproved. March-April2006. ebsite: www ebsite: www.generex.com w v vi D, Wehrle P, UbrichN, DamageC,Hoffman M,MaincentP. heat ger er , v y , P elopments. BioDrugs. 2005;1(3):165-177. elopments. BioDrugs. . ticles inaperfusedratintestinalmodel.JNanosciNanotechnol. Lu anda J A gy. Dev 2005;31(2):179-189. Drug IndPharm. Phar H, GuggiD, Bernkop-Schnurch A. Oralinsulindelivery: the WL, XiaoL,ZhangSQ,Huang m Y AK, MajumdarDK.EudragitS100entrappedinsulin yy PL,Dube .diabetolo agglutinin-modif amamoto m Sci. 2001;90(1):89-97. ® gy ) A .co.uk. improve managementoftype2diabetes? The design . y v otze Enhanced absor NSUL er IY y . ied insulin-liposomesandsolidlipid New absorption promoterforthebuccal New absorption A strate F. barriers Oraldelivery ofpeptidedrugs: gies using absorption promoters, gies usingabsorption ylate:effect onrelative hypoglycemia mation, transpor INV ption ofinsulinand(Asu(1,7))eel- YB, LiSL,ZhangRJ, Wang GL, t, andinvivo IN ASI 41. JoshiHM,BhumkarDR,K,Pokharkar V, M.Goldnanoparticles Sastry 40. CuiF, QianF, Yin C.Preparationandcharacterizationofmucoadhesive 3 38. Lin YH, MiFL,ChenCT, Chang WC, Peng SF, LiangHF, SungHW. 3 36. ZhangN, PingQ,HuangG,Xu W, Cheng Y, solid- HanX.Lectinmodified 57. 56. 55. Rastogi SK,SinghJ. Effect ofchemicalpenetrationenhancerand 54. Murthy SN, Zhao YL, MarianK,HuiSW, Kazim AL, Sen A. Lipidandelectro 53. 52. 51. XuanB, McClellanDA, MooreR,ChiouGC. Alternative delivery ofinsulin 50. NingM,Guo Y, Pan H, Yu H,GuZ.Niosomeswithsorbitanmonoesterasa 43. Pozzilli P, ManfriniS,CostanzaF, CoppolinoG,Cavallo MG,Fioriti E,Modi 42. Higaki M,Kameyama M,Udagawa M,Ueno Y, Yamaguchi Y, Igarashi R, 46. 45. Reger MA,CraftS.Intranasalinsulinadministration:amethodfordissociating 4 49. Degim Z,Degim T, F,Acarturk Erdogan D, Ozogul C,Koksal M.Rectaland 4 4 9. CuiFD, Tao AJ, CunDM,ZhangLQ,ShiK.Preparationofinsulinloaded CP.7. SajeeshS,Sharma Cyclodextrin-insulin complex encapsulated 4. ZhuDD, ChenHB, ZhengJN, DuDR,MouDS, Yang XL.Preparationand 8. Yu S,Zhao Y, Wu F, ZhangX,Lu W, ZhangH,Q. Nasalinsulin 7. Varshosaz J, SadraiH,Heidari A. Nasaldelivery ofinsulinusingbioadhesive Tokumoto S,HigoN, Sugibayashi K.Effect ofelectroporationandpHonthe a polymer-coated 2006;316(1-2):154-161. IntJPharm. nanoparticles. fororaldelivery.PLGA-Hp55 nanoparticles Sci.2007;96(2):421-427. JPharm delivery.drug Biomacromolecules.2007;8(1):146-152. P 2006;325(1- 2):147-154. polymethacrylic acid-basednanopaticlesfororalinsulindelivery. IntJPharm. 2006;327(1-2):153-159. l F Diabetes TechnolTher. 2004;6(6):808-815. insulindelivery inrabbitsusingthelight-weighttransdermal cymbal array. Lee S,Sn Dev Pharm through porcineepidermis. Technol. 2005;10(1):97-104. iontophoresis ontheinvitropercutaneousabsor Sci. 2006;95(9):2041-2050. delivery ofinsulinbyosmosis enhancedtransdermal electroporation.JPharm 2):13-19. iontophoretic transder Deliv.Drug 2006;3(1):127-138. Batheja P 2 2004;100(1):75-85. delivery ofmacromoleculesby erbium:YAG laser. JControlledRelease. via e 2 forvaginal Delivery. deliverycarrier ofinsulin:studiesinrats.Drug P containing insulin.Diabetes Technol Ther. 2006;8(3):369-377. Ishihara T, Mizushima Y. Transdermal delivery ofCaCO3-nanoparticles in rabbits.JDr K c Xue Yuan XueBao.2006;28(4):492-496. studiesofsoybeanpermeation lecithin-basedvesicles. Zhongguo Yi XueKe Metabolism. 2005;54(7):930-934. v 2004;281(1-2):11-23. delivery inthechitosansolution:vitroandvivo studies.IntJPharm. Deliv.chitosan gels.Drug 2006;13(1):31-38. Phar e ipid nanoparticles as carriers fororaladministrationofinsulin.IntJPharm. ascarriers ipid nanoparticles . valuation ofanasalinsulindelivery systembasedonthiolatedchitosan.J s entral andperipheraleffects ofinsulin.Drugs Today. 2006;42(11):729-739. aginal administrationofinsulin-chitosanfor ang JY 005;12(6):399-407. 006;22(1):300 305. reparation and characterization of nanoparticles shelledwithchitosanfororal reparation andcharacterizationofnanoparticles rauland Biokinetics ofb carriers for efficient transmucosalinsulindelivery. forefficient carriers Langmuir. m UPDATE y e Sci. 2006:95(11):2463-2472. drops. Diabetes , Lee , yder B A Thakur R,MichniakB H, Leitner WR, ShenSC, ug , Newnham RE,SmithNB. Noninvasive ultrasonic T uccal spra VE arget. 2005;13(10):563-572. mal delivery of human insulin. Int J Pharm. 2006;326(1- mal delivery ofhumaninsulin.IntJPharm. VM, Grabo T echnol y W insulin inpatientswithtype1diabetes. ang HY T . her v Transdermal iontophoresis. Expert Opin Transdermal iontophoresis.Expert ac V, Bernkop-Schnurch A. Invivo . 2005;7(5):695-698. , Fang CL,HuCH. Transdermal mulations: ane ption enhancementofinsulin xperimental study state levelprizes Pharm Pharm Pharmacology. publications. She earned her MPharmand PhDin University, and several other prizesfor her research of India, the Hari OmAshram Prizeof Sardar Patel the Association of Physiologists and Pharmacologists She hasalsobeenawarded the C.L.Malhotra prizeof review articles inIndian and international journals. experience. She haspublished 10research papersand Pharm t presented papersatvarious conferences. Dr. Aminis and national pharmaceutical journals. She hasalso more than25research publications ininternational has submittedh Gujar Drug DeliverySystem Pharm PhD atSar he recipient of the Motan DeviDandiya Prizein at U aceuti aceuti acy aceuti , niversity d th BIOGRAPHIES ar P cs cs cs an e . , Pr atel U th er PhDth o . d . e f. M.L.Kh Sh is activelyworkin G. P e s professional and research teaching and 7 years of which 6yearsof regular than 14yearsof experience of Technology. Dr. Patel hasmore Nirma University of Science & Pr workin Dr Nirm Pr workin Ms T m chapter writtenbyh years o Sh Pharm A curr Ms. Anuradha Gajjar Pharm earn years e T U niversity Dr. Avani F. Amin of industrial experience. She has r years asavisiting faculty and years of regular teaching, 6 Technology. Dr. Aminhas5 Nirma University of Science & P working asanAssistant . esearch scientist, and 2years echn echn earn rofessor inPharmaceutics, ssistan niversity o ulti-auth ofessor inPharmacology, o . Sh . e . fessor inPharm Jagruti A.P N en T esis atth has 5publi ed h e a air IDMAawar ejal Shah ed h ology ology tly workin aceuti aceuti earn g U g xperi f ur niversity o t . as anAssistant as anA teachin er MPharmin an Pr er MPharman or ed h . . a o en f cal Ch cal Ch Ms ed bookonN Ms fessor in M Sci e ce teaching. She . emorial Prizein er MPharmin . cati g Hem. North atel ssistan g g is curr en Shah has8 Gajjar has9 towar e as an emistry emistry and f aceuti ce & is currently d on xperi Sci , er ina is curr s is an en t en d an d en d cs tly h ce & , d PhD in ovel other er ce , Nirma en a . tly

55 Drug Delivery Technology March 2007 Vol 7 No 3 56 Drug Delivery Technology March 2007 Vol 7 No 3 Abeille Pharmaceuticalsa contact For moreinformation, millions ofdollarsinpotentialsales. by accountforseveraltensof Abeille seektofillmarketnichesthat Theproductsbeingdeveloped tothepipelineproducts. rights related through theacquisitionand/orin-licensingofintellectualproperty achieved throughinternaleffortsandisfurthercomplimented whichis positionaroundeachoftheproductsitpursues, proprietary astrong Abeillecreates andoralcontrolled-releasesystems. delivery metabolicdisordersbasedontransdermal andrelated diabetes, initial focusisondevelopingproductsinoncolog Thecompany’s side-effects. and/orameliorate improve compliance, on improvingadrug'sadministra www e-mail call(866)720-3148 or oftheproductlife cycle, through allstages can helpexpediteyourproductfrom conceptandfeasibilitystudies P ULMONARY .abeillepharma.com. [email protected]. P RODUCT & t (609) 951-2204orvisit N D ASAL EVELOPMENT tion toenhanceconvenience, explore how Cardinal’sexplore how services To nebulizers andliquidinhalers. and suspensions forinhalation, sprays andsolutions/ po dry dose inhalers(pMDIs), including pressurizedmetered- forms, and nasaldosage experience withallpulmonar extensive divisions have nasal developmentservices and comprehensive pulmonary Its industries. biotechnology pharmaceutical and the serving packaging, and contract manufacturing, technologies, drug delivery global leaderindevelopment, Group ofCardinalHealthisthe Technologies andServices The Pharmaceutical D drihlr DI) nasal wder inhalers(DPIs), EVELOPMENT y products that focus products that pharmaceutical mission todevelop compan development product pharmaceutical isa Inc., Pharmaceuticals, Abeille supportive care, y with a y Senopsys a contact For moreinformation, drugs. andapproved investigational for specificdrugsubstancesanddevelopnewformula technologies formsanddelivery assess thesuitabilityofnoveldosage acceptable drugproducts. resultinpatient- profilesthat anddeveloptargetsensory products, challenges, quantifytaste-masking ofdrugsubstances, attributes sensory assessmenttoolstoidentifythecritical sensory uses proprietary to optimizethesensor partners withpharmaceutical, effect oncompliance, DDS at DDS at visit Aveva For moreinformation, transdermalproducts. innovative proprietar whereituses its FL, Aveva DDSisbasedinMiramar, costs. production streamlines itsabilitytomeetR&Dtimelines andlower control. optimiza increasingefficiency forprocess development, transdermal systems, real-timeprocess analyzersinitsmanufacturingof on-line, Aveva DDSisa a gencies worldwidetoimproveproductqualityinthe21stcentur www.avevadds.com. vv’ ult oioig usingin-process PAT technology, Aveva’s qualitymonitoring, tion, y t measure thepala drug-enabling technologies todevelopandcommercialize [email protected] orvisit scale-up, T pyn A,sc sna nrrdrddtcin with suchasnearinfraredreddetection, pplying PAT, RANSDERMAL D health outcomes, y RUG characteristics ofmedica technology transfer, and ultimate finalproduct andultimate transfer, technology Senopsys alsoworkswithdevelopersto tability ofdrugprototypesandcompeting biotechnolog P ALATABILITY and productsales. www Q ,du eiey andCROs drugdelivery, y, can have adramatic can have and ease-of-swallowing) mouthfeel, texture, flavor, aroma, (appearance, product's aesthetics drug A pharmaceuticals. development ofpalatable tothe dedicated firm specialty services Senopsys LLCisa UALITY .senopsys.com. a Technology (PAT) is Process and regula embraced bytheFDA Theconceptis quality. ensuring finalproduct with thegoalof performance attributes of criticalqualityand timely measurements manufacturing through and controlling analyzing, designing, tions. system for tion systemsfor The compan Analytical tor Senopsys y y y . C www.dptlabs.com. F forbothconventionalandspecializedpackaging. resources necessary P andcompletesupplychainmanagement. ClassII-IV, registration trial ma clinical includeSpecialized productioncapabilities fourcGMPfacilities, analytical developmentandvalida www.dsmpharmaceuticals.com. (973)257-8011 orvisit contactDSMPharmaceuticalsat information, solutions tosa the highestlevelofser DSMfocusestherightresourcesonproviding commercial services, From clinical to services. III; fillfinishmanufacturing;andlypholization manufacturing; scheduleddrugs;c areas ofsteriles, Pharmaceuticals providesabreadthofmanufacturingser DSM pharmaceutical andbiopharmaceuticalindustries. 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S ERVICES pplying innova controlled substance S ER VICES vices inthe tive the industr developmentandmanufacturingassetstomajormarketswithin dosage itsconsiderablesolid isuniquelypositionedtoapply Glatt Switzerland, and Germany, facilitiesinNewJersey, With products. solid dosage development throughprocessscale-uptocommercialmanufacturingof solutions topartnersfromtheinitialconceptsinproductandformula usesthisextensiveexperiencetoprovide Glatt commitment possible. for thepast50yearsalongwithhighestlevelofsupportand a 800-310-4445 or visit contactBilcareat For moreinformation, and focusedorganization. an comprehensive andbest-in-c first time, For the fordrugproducts. materials engineering arangeofinnovative andsystemsexpertisefordesigning material well aspackaging as andIVRSplatforms, globalclinical suppliesmanagement, services, including andanalytical formulation rangeofsupport, integrated offersabroadbut Thecompany andvalue. highest degreeofservice andprovidingthe processimprovement, commitment toquality, andotherspecialistswitha projectmanagers, engineers, scientists, Bilcare’s Research Team iscomposedofexperienced organization. kno andtechnological plannedgrowth, Through auniquebusinessmodel, t (201) 825-8700orvisit ywhere in P w-how, Bilcare has built a quality and innovation-driven global Bilcarehasbuiltaqualityandinnovation-driven w-how, HARMA y global pharmaceuticalcompaniescan enjo . F or moreinforma Asia, C America, LINICAL D www.bilcare.com. EVELOPMENT www rErp rmoeeprecd reputed, or Europefromoneexperienced, tion, lass mana .glattpharmaceuticals.com. contact Gla S ERVICES gement ofc global pharmaceuticalindustry processing expertisetothe and systems, integrated equipment, technology, been supplyingsoliddosage Grouphas TheGlatt world. throughoutthe capabilities first-class expertiseand of projectsandofferclients andtimingdemands financial, provider tomeetthetechnical, It iscriticalforaservice tt PharmaceuticalSer S ERVICES linical trials y vices tion

57 Drug Delivery Technology March 2007 Vol 7 No 3

TherapeuticTherapeutic Focus

Addressing Unmet Needs in Management of Parkinson’s Disease

By: Steven Damon, Vice President, Business Development, and Yogi R. Patel, Manager, Business Development, Altea Therapeutics 3 o 3 N

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xx 59 Altea Therapeutics is currently in include rigidity or stiffness of the limbs progresses and deterioration increases, it clinical development of a transdermal and trunk, bradykinesia or slowness of usually has a negative impact on the patch designed to address a major unmet movement, and postural instability or entire family’s quality of life and need by preventing “off ” periods and impaired balance and coordination. In financial status. provide an improved therapeutic option for severe cases, Parkinson’s can lead to In the United States alone, combined managing Parkinson’s disease. dementia, memory loss, and other direct and indirect costs for Parkinson’s cognitive disturbances. Common disease is estimated to exceed $5.6 Introduction complications of the disease include billion per year. Medication costs for an depression, difficulty chewing and individual patient average $2,500 a year, Parkinson’s disease is a progressive swallowing, urinary problems, and therapeutic surgery can cost up to neurodegenerative disorder of the central sleeplessness, injuries from falls, side $100,000 per patient. The greatest nervous system that has a terrible impact effects of medications, and difficulty financial costs associated with on the quality of life of many of the 4 performing general activities of daily Parkinson's disease can be attributed to million sufferers worldwide. The disease living. Medications for Parkinson’s loss of productivity followed closely by tends to affect both genders equally, and disease may also cause a number of homecare and direct healthcare costs. the initial symptoms typically appear when complications, including involuntary people are in their late 50s or early 60s. twitching or jerking movements of the Current Treatments Because there is no cure for the disease, arms or legs (dyskinesia), hallucinations, patients are prescribed medications mainly sleepiness, and a drop in blood pressure Currently, no treatment has been to alleviate their symptoms, which is when standing up (orthostatic shown to slow or stop the progression of difficult to accomplish in later stages. hypotension). Parkinson’s disease. Instead, therapy is Parkinson’s disease is associated Parkinson’s disease causes a severe directed at treating the symptoms that are with the part of the brain responsible for burden not only on the patients, but also most troublesome to a patient. Treatment coordinated movements and is caused by on their family and loved ones. Patients approaches include medication and a loss of dopamine-producing cells in often suffer disrupted family and surgical therapy. Surgery is an option for these areas. Often, the first symptom of personal relationships, withdraw from patients who have severe, fast- Parkinson’s disease is tremor (trembling social activities, and frequently suffer progressing disease and have failed on or shaking) of the hands, arms, legs, jaw, from depression (even from the earliest other therapies. Other treatment and/or face. Other common symptoms stages of the disorder). As the disease approaches include general lifestyle modifications, physical therapy, and speech therapy. The most effective therapy currently available for Parkinson’s is levodopa, which remains the cornerstone of 3

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Parkinson’s treatment. Nevertheless, the

7

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o effectiveness of levodopa tends to V diminish over time. After 2 to 5 years, 60% to 80% of Parkinson’s disease patients on levodopa experience 7 0 0

2 fluctuations in response to their therapy.

H C Also, the most common side effect of R A

M levodopa is dyskinesias, which are abnormal and involuntary muscle movements. A

M Other common drugs used to R A

H manage the symptoms of Parkinson’s P

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T disease include Catechol-O-methyl L A I

C transferase (COMT) inhibitors, E P S anticholinergic agents, and monoamine oxidase (MAO-B) inhibitors. Another class of drugs, known as Figure 1. The Company’s Development Pipeline Attests to the Ability of the PassPortTM dopamine receptor agonists, mimic the 60 System to Deliver a Wide Variety of Drugs and Vaccines Transdermally

Figure 2. The PassPortTM System is simple and easy to use.

action of dopamine in the body. mechanisms and formulations will patch. The PassPort System enables the Dopamine agonists currently become an increasingly important affordable, non-invasive, painless, and dominate the Parkinson’s disease market product-differentiating strategy. controllable delivery of a wide range of due to the lack of efficacy of marketed Using its proprietary PassPort™ drugs (Figure 1) via the skin that cannot brands from other drug classes, which System, Altea Therapeutics is developing be delivered using conventional patches. fail to provide long-lasting symptomatic a transdermal skin patch to provide In addition to PassPort™ Apomorphine, relief. In addition, although levodopa continuous delivery of apomorphine for Altea Therapeutics is developing a (and other dopaminergics) have been the prevention of “off ” periods and fentanyl citrate patch for management of widely used, recent studies suggest that provide an improved option for the moderate-to-severe pain. The fentanyl dopamine agonists are a useful symptomatic management of Parkinson’s citrate patch is designed to incorporate symptomatic long-term treatment for disease. layers of potential deterrents against Parkinson’s disease and that the early use product abuse, misuse, and diversion, TM of dopamine agonists reduces the The PassPort System and provides rapid and sustained delivery incidence of motor complications as of a highly effective opioid. The compared to levodopa. Altea Therapeutics new transdermal company is also developing a basal The various dopamine agonists technology enables the sustained insulin patch for treatment of diabetes, a differ in several respects, including transdermal delivery of water-soluble low molecular weight heparin patch for chemical structure, duration of action, drugs, peptides, proteins, and nucleotides prevention and acute treatment of and side effects. The response to a from a painless and cost-effective skin thrombosis, an atypical antipsychotic particular dopamine agonist varies considerably between individuals, so that 3 if one dopamine agonist does not offer o N

7 benefit or causes bothersome side

l o V effects, another agonist may be tried. Emerging Treatments 7 0 0 2 Despite the enormous efforts toward H C R

A finding a cure, symptomatic relief using M various drugs remains the therapeutic cornerstone. These drugs, although effective, do not provide complete A M

R resolution of symptoms. In fact, some A H P

medications result in side effects that are

Y T L further debilitating for patients. The A I C E

P major unmet need in the treatment of S advanced Parkinson’s disease is the reduction of “off ” periods — frequent, prolonged, and/or unpredictable periods Figure 3. of hypomobility. Novel drug delivery Apomorphine Concentration (Plasma) Versus Time in Hairless Rats by (i) 62 Transdermal Administration Using the PassPortTM System and (ii) Subcutaneous Infusion patch for schizophrenia and related convenient skin patch. With the potential to provide a major increase in the disorders, and an influenza vaccine patch. quality of life of Parkinson patients, Altea expects to grow and capture a The PassPort System (Figure 2) is significant share of the market for Parkinson’s disease therapy. The market for painless and easy to use: Step 1: Clip a drugs for the treatment of Parkinson’s disease was $2.7 billion in 2005. PassPort Patch into the applicator and Throughout the previous 5 years, the market has reported a growth rate of place against the skin. Step 2: Press the 12.9%. Dopamine agonists currently dominate the Parkinson’s market; six out of activation button of the applicator. Step 3: the top nine marketed brands are dopamine agonists. Remove the applicator, thereby leaving the Altea is actively looking for a development and commercialization partner drug patch on the skin. Secure patch and who has the capability to support development and effectively market this commence drug delivery. exciting new therapy in the CNS/Parkinson’s market. I PassPort Apomorphine is designed to deliver continuous levels of apomorphine over a sustained period of time from a skin patch ranging from 2 cm2 to 8 cm2. Currently, the PassPort Apomorphine Patch is undergoing Phase I clinical development. An initial Phase I pharmacokinetic study has demonstrated Steven Damon steady delivery of apomorphine over an 8- Vice President, Business Development hour application period with rapid rise to Altea Therapeutics steady plasma levels and rapid elimination after patch removal. Preclinical studies have demonstrated transdermal delivery of apomorphine in hairless rats comparable Mr. Steven Damon leads the Business Development Team for Altea to subcutaneous infusion (Figure 3). The Therapeutics and has over 17 years of experience with various business roles patch provides constant therapeutic effect in the medical and pharmaceutical industries. His experience includes without interruption and thereby serves to business development, commercial development, and mergers and completely replace injections. acquisitions. Prior to joining Altea Therapeutics, Mr. Damon was at Durect The applicator facilitates intuitive, Corporation, where, as Executive Director, he completed several product accurate, and easy patch application. In partnership agreements with major pharmaceutical companies, was addition, the applicator stores verifiable responsible for other commercial activities (including the Alzet brand drug dosing information, including a record of delivery pumps for animal research), and was President of a wholly owned time and date for each successful patch subsidiary - Absorbable Polymers International. He was previously at Kimberly- Clark Professional Healthcare with lead responsibilities for commercial 3 application by the patient. This o

development of the healthcare business in Europe and key responsibilities for N

information may be accessed by the 7

a number of major acquisition deals. l o

physician to monitor compliance — a V critical tool in the management of Parkinson’s disease since only 10% of all

patients are fully compliant with their 7 0 0 2 prescribed therapy. H C R A

Yogi R. Patel, PharmD M Market Potential & Manager, Business Development Partnership Opportunity Altea Therapeutics A M R A

Altea Therapeutics PassPort H P

Apomorphine represents an important Y T

Mr. Yogi R. Patel is currently the Manager of Business Development for Altea L A opportunity in the management of I C

Therapeutics. His experience at the company also includes supportive roles E P

Parkinson’s Disease as it addresses the S working in pharmaceutical research and development. Prior to joining Altea most significant unmet market need in Therapeutics, Mr. Patel completed a Medical Information Residency with managing the symptoms — the prevention AstraZeneca Pharmaceuticals in Wilmington, DE. He earned his PharmD from of “off ” periods by a small, painless, and Mercer University in 2003. 63

Facts & Figures

Bionumbers: A Resource for Plans, Forecasts & Budgets

strength in the market or whether it is a River has agreed to be acquired by Shire Specialty Pharma rebound from 2006 where these at a premium of 14.4% over its closing Index Trends companies all showed cumulative losses price; about the same premium relative to Both markets seem to have reversed in market capitalization. Among the its end of January 2007 close). Only four themselves in the early part of 2007 market cap leaders only Abraxis was companies in this 20-company index (www.bionumbers.com). Following a down, continuing its slide of 2006. showed an increase for the month. The strong 2006 (up 22%), the Emerging Among the five leading laggards, there laggards were led by Nektar, Alexza, and Stage Specialty Pharma Index (ESPI) has was a mixture of trends. Several Penwest, among the biggest market cap given back a large part of its gains (down companies showed big losses in January contributors to the index. Capitalization 6%) through the end of January 2007. 2007 after strong gains in 2006 for the index dropped to $6.9 billion The Commercial Stage Specialty Pharma (Advancis +118%, Santarus +60%, and from $7.3 billion at the end of December Index (CSPI) in contrast was up nicely, a Columbia +30% in 2006), while for the 2006. Only a little more than one-tenth little more than 5% in January 2007 after other companies, it was more of 2006 the size of the Commercial Stage Index, 3

(Encysive -46% and Bentley -11% in the Emerging Stage Index capitalization o posting only a 4% increase in all of N

2006). Overall, the index capitalization will take a huge hit later in the year when 7

2006. The largest fluctuations in l o V valuations through January are to be was up only $500 million despite a 5% the New River acquisition is completed. I found in the smaller members of the two index growth because of the departure of Kos from the index following its year- Editor’s Note: These indices are intended to indexes. With share prices in the single provide information on the macro trends within

7 end acquisition by Abbott. 0 digits and teens, even a $1 change in each covered sector. These indices have no value 0 2 for investment purposes. Given the fluid nature of

H price can cause a large percentage C

R market prices, public company information

A change. M Emerging Stage updates, and a once-monthly index revision, the information will at best be of historical value. Commercial Stage Index Trends The ESP Index showed a significant A M R

A Index Trends reversal in growth following a very good H P

The CSP Index moved up on good

2006 (up 22%). Almost all of the larger Y T

L gains by the larger market cap

A cap companies (larger being strictly I C

E companies. While Shire was up a solid P relative) showed a major drop in January S 3% for the month, it was King, Hospira, 2007 that weighed heavily on the index. and Endo all up by double digits that The exception was New River, which drove the index growth. It’s not clear basically held it’s own with a 2% whether this is an indication of renewed increase in January. (Since then, New 64

Bionumbers Commercial Stage Specialty Pharma Index DECEMBER

2006 r 1,350 JANUARYDECEMBER a e 1,3001,350

20072006 Y 1,250 r / 1,300

a h e 1,200

t 1,250 Y

n /

1,150

o 1,200 h t

M 1,100

n 1,150 o 1,050

M 1,100

1,0001,050 2005-DEC 2006-JUN 2006-OCT 2006-NOV 2006-DEC 2007-JAN Index1,000 1,104 1,078 1,047 1,128 1145 1203 2005-DEC 2006-JUN 2006-OCTIndex Value2006-NOV 2006-DEC 2007-JAN Index 1,104 1,078 1,047 1,128 1145 1203 Index Value

Key Figures January 2007 Top 5 Gainers YTD Change Top 5 Laggards YTD Change Top 5 Capitalizations YTD Change Index Value: 1203 Savient +33% Advancis -25% Shire $10.8 Billion 3% Change YTD: +5.1% Pharmion +24% Encysive -20% Hospira $5.8 Billion 10% Total Index Vivus +22% Santarus -11% King $4.4 Billion 12% Capitalization: -$59.7 Billion Salix +17% Bentley -11% Abraxis $4.2 Billion -4% InterMune +14% Columbia Labs -9% Endo $4.1 Billion 11%

Bionumbers Emerging Specialty Pharma Index

JANUARDECEMBERY 2,000

2006 r 2007 1,900 DECEMBER a 2,000 e 1,800 2006 Y 1,900

r / 1,700

a

3 1,800

h o e N t

Y 1,600 7 1,700

l n / o

V

o 1,500 h 1,600 t M n 1,4001,500 o 7 0 M 1,300 0 1,400 2

H C

R 1,200

A 1,300 2005-DEC 2006-JUN 2006-OCT 2006-NOV 2006-DEC 2007-JAN M 1,339 1,538 1,559 1,609 1,655 Index1,200 1,564 2005-DEC 2006-JUN 2006-OCTIndex Value2006-NOV 2006-DEC 2007-JAN Index 1,339 1,538 1,559 1,609 1,655 1,564 A M

R Key Figures January 2007 Top 5 Gainers YTD Change Top 5 LaggarIndex dsValue YTD Change Top 5 Capitalizations YTD Change A H P

Index Value: 1564 Catalyst +32% Nektar -16% New River $2002 Million 2% Y T L A

I Change YTD: -5.5% Spectrum +16% Alexza -15% Nektar $1143 Million -16% C E P S Total Index Acusphere +11% Penwest -14% Aspreva $716 Million -3% Capitalization: $6.9 Billion New River +2% Keryx -14% Keryx $493 Million -14% All Others -ve Scolr -12% Cadence $343 Million -1%

66

Clinical Trials

parts of the body are permitted for Conducting Clinical Trials in Asia testing. Some countries may also have less complicated regulatory regimes, allowing for faster approval times. By: Ames Gross, MBA, President & Founder; and Asia also boasts a genetically diverse Momoko Hirose, Associate, Pacific Bridge Medical population with more than 4 billion people, many of whom have never received medication to treat their conditions. With such large numbers of new candidates, pharmaceutical Introduction Why Go to Asian CROs? companies can assess the success of their drug more accurately. With steadily increasing drug The major incentive for moving Finally, many of these Asian people development costs and significant time clinical trials overseas is cost. Often, the may be willing to undergo testing for the spent on clinical trials, outsourcing cost of the hospitals, clinical evaluations, access to medication and care they clinical trials in Asia has rapidly become and data analysis are cheaper in Asia otherwise would not be able to afford. an appealing option for many firms than in the US or Europe. One of the For example, India provides free main factors contributing to lower costs medication and, in many cases, better

3 (Figure 1). As developing a single drug

o N

with outsourcing clinical trials in Asia is can cost more than $200 million and take 7 Table 1.

l

o that patient recruitment is generally V at least 10 years, Asia (except Japan) offers a less expensive, less time- easier and faster. Recruitment is a time- Country Pharmaceutical consuming process for clinical trials. consuming task and sometimes accounts Market Size 7

0 for about half of the time required for 0 Simultaneously, increased demand and China $20 billion 2

H the clinical trial. In fact, almost 90% of C awareness for various medical drugs and Hong Kong $1.5 billion R A

M health services (Tables 1 and 2) have clinical trials experience an unexpected Philippines $300 million encouraged many of these countries to delay of some sort, and problems with Indonesia $350 million Japan $60 billion develop their own Contract Research recruiting patients are generally the A Malaysia $210 million M

R Organizations (CROs), and many US number one reason for these delays. A

H Singapore $400 million P

Other incentives include lower costs firms have eagerly turned to these Y

T Korea $6.5 billion L

A due to looser regulations in some of the

I options to survive in a growing

C Taiwan $2.5 billion E P S competitive global market. Asian countries, excluding Japan. For India $6 billion example, governments in some Asian Thailand $1.5 billion countries may have a less conservative stance on what population segments or Source: Pacific Bridge Medical 68

medical attention to clinical trial patients such concerns. Now, with the World the facilities and quality control of the than the average Indian hospital would Trade Organization’s agreement on Trade trials are comparable to Western provide. Related Aspects of Intellectual Property standards. Rights, member countries are required to There is also concern about establish minimum standards concerning unethical treatment of patients in What to Watch Out For the scope and use of IP rights and the countries without specific laws procedures for enforcing them. Contract protecting participants. Some countries Despite all of the advantages of research organizations in Asia are also may not get the “informed consent” of outsourcing clinical trials, there are also enforcing stricter IP procedures. At the subjects in the trial beforehand. Also, concerns and potential pitfalls that WuXi PharmaTech in Shanghai, China, many CROs purport to run facilities that should be addressed. One concern is the workers who fail to follow IP protection are compliant with the International lax enforcement of intellectual property procedures are fired after two warnings. Committee on Harmonization (ICH) laws or complete lack of intellectual Of course, by then it may be too late. standards of Good Clinical Practice property laws at all. For example, it may Another concern of pharmaceutical (GCP), but in practice they do not do so. be difficult for a foreign pharmaceutical companies working with foreign CROs is company doing trials in China to ensure that the research and clinical trial data that the formula for its new drug will be will be of low quality. This is certainly a How to Choose a CRO kept strictly confidential when utilized legitimate issue as in some developing by a Chinese CRO. Confidentiality countries, the quality of facilities, Understandably, it can be daunting agreements, which in theory are binding infrastructure, and data collection may to find an appropriate, qualified CRO in in the West, may not be so “confidential” not be as high as one might expect in a an Asian (or any foreign) country. The in Asia. In addition, enforcement of typically modern, high-tech hospital in conventional choice is to pick one of the intellectual property is not uniform the US, Europe, or Japan. However, large global CROs that has offices throughout the Asian region. quality is constantly improving, and in around the world and an excellent Measures have been taken to address places like Singapore and Hong Kong, reputation. However, this may not always be the best choice for every company. A CRO may have done excellent work in the US or Europe, but its offices in farther-off locales like Asia may not be

3 staffed with the same quality of

o N

personnel as its headquarters. A local 7

l o

V CRO may be better suited for certain clinical studies because it can devote more attention to smaller projects, and 7 0

0 because it may value that client more 2

H

C than a large global CRO would. Local R A M CROs may also have more expertise on the local regulations, as well as closer ties to the local regulatory authorities. In A M R addition, a global CRO may be more A H P

concerned about keeping its large Y T L A

I pharmaceutical clients, with their large, C E P S multi-site studies with hundreds of patients, happy. Figure 1. Once a CRO is chosen, it may also be a good idea to have a local 70

Table 2. Tier 1: Japan Country Health Health Physicians Hospital Beds Expenditure Expenditure Per 1,000 Per 1,000 Japan’s medical business is very Per Capita as % of GDP People People sophisticated and comparable to Western China $61 5.60% 1.6 2.5 standards. Western companies looking to India $27 4.80% 0.6 0.9 outsource clinical trials to save money Indonesia $30 3.10% 0.1 6 and time should NOT go to Japan. Japan $2,662 7.90% 2 14.3 However, in almost all cases, Western Korea $705 5.60% 1.6 7.1 Malaysia $163 3.80% 0.7 1.9 companies that wish to sell drugs or Philippines $31 3.20% 1.2 1 more risky medical devices in the Singapore $964 4.50% 1.4 2.9 Japanese market will need to do at least Thailand $76 3.30% 0.4 2.2 some clinical trials in Japan in order to Taiwan $743 5.60% 7.4 5.7 get product approval. Vietnam $26 5.40% 0.5 2.4 In Japan, the Ministry of Health, Source: World Bank, World Development Indicators 2006. Labor, and Welfare (MHLW) oversees the regulation and safety of independent regulatory person or one of Clinical trials in Japan are normally more pharmaceuticals, medical devices, your employees move abroad to help expensive than comparable trials in the cosmetics, and food. It is comparable to oversee the trials. CROs that are West, and the quality of the clinical the US FDA. The Pharmaceuticals and monitored locally often provide their research is generally just as high. As Medical Devices Agency (PMDA), services in a timelier manner and at a more medical companies enter Japan, the established in April 2004 under the higher level of quality. need for at least some local clinical trials revised Pharmaceutical Affairs Law has increased. (PAL) in 2002, oversees regulatory The second tier includes Taiwan, affairs for drugs and medical devices. Which Countries? Korea, Singapore, and Hong Kong. These Though both have websites in English countries provide clinical trial services at (www.mhlw.go.jp/english/index.html and Aside from differences in cost, one a relatively high level of quality and www.pmda.go.jp/index-e.html), they are should look at other attributes, such as generally at lower cost than in Japan or not updated as regularly as the Japanese

3 sites.

each country’s regulatory and healthcare the West. o N

Currently, there are no base

7 environment. Ease of regulatory approval The third tier includes India, China,

l o V can vary significantly depending on each and Southeast Asian countries, such as guidelines or specific laws about what government’s regulations and laws on Indonesia, Malaysia, the Philippines, and types of foreign clinical data are drugs and clinical research. Some Thailand. Clinical trials in these acceptable for each product. In many 7 0

0 countries may be able to provide large countries can be of decent quality and cases, the PMDA must work on a case- 2

H

C by-case basis for each medical product

R numbers of patients that suffer from a normally offer significantly lower costs A M particular disease or illness, while other than places like Taiwan, Singapore, and with independent Japanese experts to countries may not have such patient Hong Kong. However, issues such as the determine specific logistical issues, such populations. Sometimes you may be quality of the trials and intellectual as number of participants, what data is A M

R required, and how the study should be

A willing to do the trials in a foreign property protection are generally real H P

conducted. However, the PMDA is

Y language, while in other cases, English is concerns in these locations. The T L A I required. information below gives some currently working with experts in C E P S Clinical trial locations in Asia can be background on most of these Asian specific fields to establish clinical trial divided into three tiers. The first tier is countries and outlines how to get started guidelines for different product types. Japan, which has a very high-quality, with clinical trials. Before making a clinical trial very conservative medical community. request, an applicant submits a Clinical 72

Trial Notification (CTN) to the PMDA. individual IRB approval from each devices. The Centre for Drug The notification mainly consists of hospital. More than 40 hospitals have Administration (CDA), a division of the description and product summary, pre- participated in the joint IRB, and JIRB HSA, regulates and evaluates drugs and clinical data, clinical trial protocol, has helped Taiwan attract more multi- medical devices, including clinical trials. analysis plan, SOPs, contact person, and center trials. All clinical drug trials in Singapore appropriate research institution. Also, In addition to IRB approval, the require regulatory approval in the form compliance with Good Clinical Practice clinical trial protocol must also be of a Clinical Trial Certificate (CTC), (GCP) often requires an Institutional reviewed and approved by the Bureau of granted by the CDA before the trial can Review Board (IRB) to review the Pharmaceutical Affairs at the DOH. The proceed. clinical trial protocol, written informed Center for Drug Evaluation (CDE), a The Medical Clinical Research consent forms for participants, and non-governmental, non-profit Committee (MCRC) reviews applications adverse event reporting. For those who organization, assists in reviewing all for CTCs, in addition to conducting require further specific guidance on their clinical trial protocols submitted to the continuing reviews of the clinical trial product, the PMDA also provides more DOH. In addition, it also provides and monitoring adverse events. The in-depth consultation sessions. regulatory consultation, reviews entire approval process to start clinical informed consent documents, and trials takes about 2 to 3 months, Tier Two: Taiwan, facilitates the drug development process including IRB/EC approval. All clinical in Taiwan. Regulatory approval to start trials conducted in Singapore must Singapore, Hong Kong, clinical trials also takes 2 to 3 months. comply with the Singapore Guidelines Korea for Good Clinical Practice (GCP), which Singapore: Singapore is a good were adapted from ICH-GCP standards Taiwan: Taiwan is a country in which location for conducting clinical trials and implemented in 1998. CROs are already very active. Quality because it boasts the second-best standards for clinical trials in Taiwan healthcare system in Asia (after Japan). Hong Kong: This country is an adhere to the accepted international Singapore has 4.3 million people, high- emerging market for clinical trials. The standards of ICH GCP. GCP guidelines quality facilities, and highly educated country has advanced medical care, were implemented by the Department of doctors, many of whom went to school in along with developed infrastructure, Health (DOH; www.doh.gov.tw/EN/ the US or Europe (especially England). strong presence of academic institutions, Webpage/index.aspx) in 1997 and then However, one of the drawbacks of doing and high-quality investigators. Doctors 3

o

N clinical trials there is its small are highly educated and have studied further revised in 2002 to be consistent

7

l

o population; sometimes trials in Singapore abroad, particularly in the US and Europe

V with ICH standards. The DOH conducts GCP inspections on nearly all clinical can encounter difficulty recruiting (ie, England). The majority of clinical trials to ensure their quality and credibility enough patients. trials conducted in Hong Kong are in 7

0 and is equivalent to the US FDA. Singapore is also strong in Phases II to IV, and clinical trials are 0 2

H intellectual property (IP) protection, regulated by the Department of Health

C Before a clinical trial in Taiwan can R A being ranked the top Asian country for IP (www.dh.gov.hk/eindex.html). M begin, approval of the clinical trial protocol must be obtained from both the protection for 3 years (2002-2004) by the Under Regulation 36B of the IRB and the DOH. The IRB or ethics Institute for Management Development Pharmacy and Poisons Regulations, a A

M (IMD), the World Economic Forum certificate for Clinical Trial/Medicinal

R committee of the individual hospitals A H

P (WEF), and the Political Economic Risk Test (CTC) is required before conducting will review the protocol for any ethics

Y T

L Consultancy (PERC). a clinical trial. Before applying for a A concerns. Approval takes about 2 to 3 I C E

P The Health Sciences Authority CTC, an applicant should first receive

S months. Taiwan also offers the option of joint (HSA) (www.has.gov.sg/), established in approval from the hospital’s Ethics IRB (JIRB) approval, which allows for 2001, is generally responsible for the Committee (EC). Obtaining EC approval multi-center approval as opposed to quality, safety, and efficacy of drugs and generally takes 4 to 6 weeks. 74 The CTC submission will include while the IRB approval also takes about existing presence of pharmaceutical the protocol, investigator’s brochure, pre- 30 days. Both these processes can be know-how and capacity. Add to that the clinical study results, drug samples, the done in parallel. tremendous diversity of its population, EC approval letter, an informed consent huge geographic expanse, the number of form, and an endorsement letter from the Tier Three: India, China, foreign-educated doctors, and the fact principal investigator. The CTC is that English is a spoken language; it is granted to the principal investigator, and Southeast Asia no surprise, then, that India has become a usually takes an additional 4 to 6 weeks. prime spot for clinical research activity. The sponsor must also apply for an The third tier of clinical research India’s recent changes in patent import license at the Trade and Industry includes countries whose healthcare regulations have also encouraged more Department for permission to import infrastructures may not be as highly international business in the past 10 samples of the drug for the purpose of developed as in wealthier Asian years. The Indian Patents Act (1970) did obtaining the CTC. This will generally be countries. However, clinical trial services not recognize pharmaceutical product available within a week. A copy of the offered here are often significantly less patents as only manufacturing process CTC will be required when the drugs are expensive than in the second-tier patents were recognized. However, in actually imported for clinical testing. The countries and can be of decent quality. 1995, India agreed to uphold the WTO total approval time will be about 2 to 4 Even amongst these countries there is Trade-Related Intellectual Property months. some variation. For example, India has a Rights (TRIPS) in which India would highly educated human resource pool recognize and enforce pharmaceutical Korea: The Korea Food and Drug and existing infrastructure for drug product patents, in addition to other Administration (KFDA; production, which has made it easier for product patents. www.kfda.go.kr/), established in 1996, is Indian companies to transition into Drug registrations and approvals fall the main regulatory body for drugs, clinical research. There are many local under the responsibility of the Central medical devices, food, and cosmetic CROs that are headquartered in India, Drug Standards Control Organization products. To conduct a clinical trial in along with many satellite offices of (CDSCO). A key official within this Korea, the sponsor must obtain both global CROs. Recently, China too has organization is the Drug Controller regulatory approval and IRB approval. become a target location for many General India (DCGI), and both work The KFDA provides optional pre-IND clinical trials. In the Southeast Asian together on regulations for clinical trials. (Investigational New Drug) consultation countries, however, there are not many Legislative requirements on clinical trials 3 services, and it is generally local “homegrown” CROs and only a few are guided by specifications of Schedule o N recommended that the sponsor engage in Y of the Drug & Cosmetics Act, 1940. 7

branch offices of large global or regional l o these consultations. The sponsor will CROs. As of today, not many foreign Schedule Y contains detailed information V then submit the clinical trial application medical companies focus on Southeast for each trial phase, including dossier with the appropriate supporting Asia (Malaysia, Philippines, Indonesia, requirements for Ethics Committees, 7 0 documents (such as the protocol, informed consent, animal pharmacology, 0 2

and Thailand) when looking to do H C

Chemistry, Manufacturing and Control clinical trials in the region. and other details. R A data, etc.) to the KFDA. The full clinical The CDSCO has recently passed M trial application must be translated into India: For a number of reasons, India’s new regulations on global clinical trials Korean. All trials must follow KGCP based on a meeting held in October

clinical trial business has grown rapidly A M R (which was revised in 2001 to harmonize throughout the past few years. Perhaps 2006. For the purpose of granting A H P

with ICH guidelines) and can only take permission, clinical trials are to be Y

the major factor for such growth is the T L A place at accredited sites. The KFDA will classified into Category A and B. I fact that clinical trials in India are C E P consult with the Central Pharmaceutical significantly cheaper than in the West. Category A will include those trials S Affairs Committee in making its decision Another factor spurring growth in the whose protocols are approved by the US, on approving the clinical trial. Indian market is the large, already- UK, Switzerland, Australia, Canada, Regulatory approval takes about 30 days Germany, South Africa, Japan, and 75 EMEA (European Medicines Agency). drugs that treat serious or life-threatening Because permission will be granted illness, or for drugs that are the same accepting the approvals of the protocols kind of drug as one that has already been from these countries, the CDSCO approved. Mr. Ames Gross, estimates that approval time for clinical MBA trials will take 2 to 4 weeks. However, all Southeast Asia: Each country has a President & Founder other applicants will fall under Category specific governmental health Pacific Bridge Medical B, which will require protocol organization that oversees clinical trials verification and take 3 to 4 months and pharmaceutical regulations. Approval approval time. processes can be relatively quick in these Mr. Ames Gross is President and The CDSCO (http://cdsco.nic.in/ countries, taking only 3 to 4 months. The Founder of Pacific Bridge Medical index.html) has also categorized protocol most popular location for clinical trials in (PBM), and is recognized nationally and internationally as a leader in the amendments into three groups: those not Southeast Asia (not including Singapore) Asian medical markets. Established in requiring any notification or permission, is Malaysia for its relatively developed 1988, PBM is a consulting firm that those that require notification but no hospital infrastructure and advanced assists medical companies with permission, and those requiring prior regulatory environment for drugs. business development and regulatory permission from the CDSCO before issues in Asia. PBM has helped more implementation of clinical trial protocol Summary than 200 medical companies over the years. Mr. Gross earned his BA, Phi amendments. Beta Kappa, from the University of Outsourcing clinical trials in Asia Pennsylvania and his MBA from China: The State Food and Drug provides a way for US and European Columbia University. Administration (SFDA; medical companies to reduce cost and www.sfda.gov/cn/eng/) is the Chinese increase productivity and efficiency. equivalent of the US FDA and is the Currently, about 25% of US medical national authority that approves and companies outsource overseas to some reviews clinical research. The regulation extent. Although IP protection issues still Ms. Momoko Hirose of drugs and clinical trials is outlined by linger, some US companies are now Associate the Drug Administration Law of the outsourcing all phases of product Pacific Bridge Medical People’s Republic of China, which went development, including drug discovery, 3

into effect in December 2001, and the research and development, clinical trials, o N

7 Drug Registration Regulation of 2002. and manufacturing. American companies

l Ms. Momoko Hirose is an Associate of o V Before a clinical trial may be carried will continue to outsource in Asia as the PBM. She works on research, writing, out in China, it must first be approved by medical communities in Asian countries and consulting projects and is a the SFDA. The sponsor should prepare continue to become more sophisticated graduate of Brown University. 7 0 0

2 and submit the dossier and drug samples and cost reduction can be more clearly

H C

R to the SFDA, which will consult with the defined. I A M Center for Drug Evaluation before issuing a clinical trial approval letter. To purchase Pacific Bridge Medical’s Other drug institutes, such as the complete report on clinical A M R

A National Institute for the Control of trials/contract research organizations H P

Y Pharmaceutical and Biological Products, in Asia, please visit our website at T L A I

C will also aide the SFDA in screening www.pacificbridgemedical.com. E P S applications. The entire process for clinical trial approval takes approximately 7 to 9 months. Fast-track review is available for clinical trials of 76

Executive Paul Johnson President, Summary DPT Laboratories, Ltd.

R&D Takes Center Q: Why does DPT invest in research and development? A: While maintaining our focus on semi-solids and liquids, we are spending more in research and development, especially in drug Stage at DPT delivery technology. It is an essential part of our emphasis on being a contract development and manufacturing organization, or CDMO. A By: Cindy H. Dubin, Contributor lot of companies strictly do work for hire. We take a certain amount of our profit and invest it in research. It’s done primarily because there is tremendous market need for companies to differentiate themselves. We can add value to our customers through novel drug delivery or package and delivery systems. We are investing more and more into those areas as a way to continue bringing greater value to our customers. For example, some time ago, we launched MVE PT Laboratories, Ltd. is a contract technology (Multi-Vesicular Emulsion) system, which we patented. development and manufacturing We offer this technology to our customers as a potential way of D maintaining efficacy but decreasing irritation of actives that have a organization (CDMO), specializing in semi- tendency to be irritating. In addition, we built continuous spray system solid and liquid dosage forms. Recognized capability at DPT with the help of a customer. Using this system, we globally for technical expertise and recently launched a prescription wound care product that was only available in a tube. This spray system makes the product easier to use manufacturing capabilities, the company is for caregivers. 3 3

turning its attention to R&D, while still o o

Q: N N

What is the value of being and remaining privately held?

7 7 maintaining its focus on dosage forms. Paul

l l o o V V Johnson, President, tells Specialty Pharma that A: We’ve been private since 1990. I think that has allowed us to focus on mid- to long-term and not quarter-to-quarter results, allowing us to this is done to help the company differentiate make investments that do not have an immediate payoff. We can also 7 7

itself in the market. He also shares with SP 0 0 make quicker decisions, there are fewer people to get buy-in from, 0 0 2 2 and, ultimately, our ability to adapt is better so we can adjust to H H readers about the company’s desire to remain C C R R changing market dynamics that may come at us. In many ways, we A A M M privately held and its success in Texas. have always operated with the financial discipline of a publicly held company. However, being privately held allows us to make decisions that are not based on quarter-to-quarter results, but decisions that are A A based on whether they are right for the business. M M R R A A H H P P

Q: Y Y Why have you kept DPT in San Antonio all these T T L L A A I I years instead of moving it to the northeastern C C E E P P

United States? S S

A: We certainly have a very strong northeast presence, and it’s important to note that we have 1 million square feet of infrastructure between San Antonio and our Lakewood, New Jersey, site. We now have sites xx 77 that give customers the confidence — the assurance — that they value-added proposition that we provide is comprehensive services have a back-up plant versus a single-source site. That being said, for our focus, and our market segment, from early development San Antonio offers a great quality of life to a great number of through commercialization. Customers need to have confidence in people, and we have no difficulty attracting top talent — and the people they will be working with. They are handing off, in customers — to the site. San Antonio is also becoming better many ways, their baby, to someone. And they have to have the known for its biotech emphasis, and this city has a very strong trust and confidence that you are going to nurture and take care of commitment to the biotech industry. There are very good that child and bring it to fruition and growth. They’ll talk to your resources and synergies that we utilize in San Antonio, where, quality people. They’ll talk to your R&D people, operations if necessary, we can draw on their expertise. We also receive people, and engineering. And it’s really an entire team approach to very strong support from the city of San Antonio, which considers get comfortable with the company before the customer makes that DPT a preferred employer. And Texas is, on the whole, friendly decision. The customer’s career depends on your ability to do what to business. you say you’re going to do. In the case of Specialty Pharma or virtual pharma, it may not just be their career, but their whole Q: What makes the company’s business model company. A lot of trust is required in this business. We have some unique? customers with whom we have such a strategic relationship that if we don’t deliver, they cease to be. They are 100% dependent on us A: It is the concept of a CDMO. Often in our industry, you’re either for their entire supply chain. known for your development or you’re known for your manufacturing. So a customer might source from a development Q: How is your work today different from in years organization and separate manufacturing organization. We put past? equal emphasis on both of those capabilities so that we can get involved very early in the development process, from A: We are finding ourselves doing earlier and earlier development preformulation all the way through FDA approval. Once the work, a greater need for Phase II and Phase III development work. product is approved, we have excellence and strength in the That whole CDMO concept, we’re seeing more and more of our manufacturing and supply chain piece, as well. And very, very few work shifting to development services. That is becoming a larger could ever make that claim. I think DPT is in a unique position to percentage of the overall scope of the company. The need to launch be able to claim that we have strength in both of those domains. new products has never been greater for most of our customers, and The reason that we execute the CDMO concept very well is our they just don’t have the internal resources to do it, so they are emphasis on semi-solids and liquids. We’re focused. We’re not seeking companies that can fulfill that need for them. For these trying to be all things to all people. Our expertise in semi-solids customers, it used to be all in-house, so that’s a huge shift. A lot of and liquids gives us the ability to excel in both development and products are coming off patent, and we’re finding that we can go to manufacturing. our customers and give them suggestions on how to differentiate their product and possibly extend its life cycle. We recently met Q: What makes the company attractive as a partner with one that has a several-hundred-million-dollar brand coming off to pharma companies? patent in a couple of years. We have no problem getting meetings with top executives when we can talk about that. The majority of A: I think the first thing a pharma company looks for is a stellar work we are doing today is assisting clients with their development 3

o regulatory compliance record. Our size and critical mass are also programs, but also taking it and launching it into a commercial, N

7

keys. This is a very fragmented industry and for our area of viable product, which is different from what we did in the past. In l o V specialty, we really are the leader. We are the industry choice when the past, it was more opportunistic: “I don’t have enough capacity it comes to outsourcing services for semi-solid and liquid dosage in my plant. I’ll give you my leftovers.” Or tactical: “I have a surge products. I believe our expertise is another area that makes us in demand. Can you handle that for me?” The industry has now

7 attractive. And ultimately, our track record, the number of products recognized that what pharma does particularly well is research, and 0 0 2

that we have successfully launched for our customers. I think those what they do particularly well is sales and marketing. They also H C

R are all things that a pharma company would look at in selecting don’t want to tie their money up in the development, manufacturing A

M someone for the first time. We are not so big that our customers piece. They prefer to spend their money on research and on sales get lost in trying to do business with us; nor do we have the and marketing. Therefore, you better find the right partner, because limitations of a one-person shop. We have enough infrastructure this is a strategic decision. It’s not only this one opportunity, but

A and enough talent that we can do multiple projects at the same making sure their partner can handle opportunity two, three, four, M R

A time. That infrastructure encompasses everything from quality to or five. So that’s the shift that we’re seeing in the industry, and I H P

research and development, to engineering. We have the balance think the pendulum is still shifting. What used to happen, too, is Y T L

A and the flexibility with the critical mass. Customers first want to they’d go out and find a development company, do formulation I C

E make sure of your regulatory compliance. Once they have that, development, find a method development company, and then P S they want to know that you can deliver a product on time, every they’d find a clinical trial manufacturer, and then they would time. Thirdly, they’re going to find out if you are competitive transfer it to a contract manufacturing organization. Today, as a price-wise. But if you don’t get No. 1, then you don’t really get to world-class CDMO, we have the expertise to offer all of those talk about No. 2 or No. 3. Once we get past those three, I think the services together to our customers. 78 Q: What are some of the business strategies that that we handle, we are in a unique position. Sometimes plants are have contributed to your success? running only run a few products at a time — two, three, four. We run hundreds of product formulas and have seen hundreds, so we A: The first would be our proactive approach to extend product life have a unique way of looking at the world because of what we’ve cycles. We’ve focused on new technologies and innovation, with been exposed to. So when we take on that assignment, we can say, more emphasis on development to bring continued value to our “Why are you doing things this way? Why is it being done this customers. Number two is operational excellence. There is huge way?” We can incorporate our experience and expertise and pressure in the marketplace to lower costs. So we’re expending a change things when it makes sense. We’re able to learn best lot of effort in our strategy to achieve operational excellence, and practices from the amount of projects we do and then we’re able to taking non-value-added steps out of the process to become more apply those practices to certain situations. competitive than our customers could be within their own Q: facilities. The third contribution to our success that I believe is What’s the mistake you have to avoid going really key is that we have been very successful in recruiting and forward? retaining top talent. It is amazing the transition throughout the past A: 4 years if you look at the management team and the individuals We can’t allow complacency to creep in. We have an outstanding, we’ve been able to bring on board, not only from a technical stellar regulatory compliance record, and our service levels are standpoint, but also our emphasis on our value system. We have a very good. We’ve had strong growth, but this is an extremely huge initiative to continue focusing on our value system, so we challenging business and you’re only as good as the last product really believe that it is not only what you get done, but how you go you helped bring to market, last order you shipped, and last audit. about doing it that’s really a sustainable model for the long haul. We can never allow ourselves to be satisfied or complacent That is really the differentiating point with pharmaceutical because this market is a tough market and it’s ever-changing. So, companies. They want to know who the people are, and that we can’t make the mistake of resting on our past success, because they have a common, shared value system. Overall, the it does not guarantee your future success. pharmaceutical industry is a very ethical industry, and it attracts Q: individuals of like mind. The talent that we’ve brought to DPT What are the goals and objectives going forward has a strong value system. for the company in the next 5 years? A: Q: What was one thing that happened in the past Our vision is to focus on service, innovation, and technology. year that you were not expecting? We’ll have tremendous focus on our core business, which is semi- solids and liquids, in both development and manufacturing. We’ll A: In March 2006, a strategic partner and Specialty Pharma also be expanding into what we call adjacent technologies that organization asked us to take over the management of its entire we’ll bring to our customers. Our strategy isn’t necessarily to supply chain for an acquisition that had just taken place. That become the biggest, but our goal is to be the best at whatever we included the active pharmaceutical ingredient, or API, through take on. processing of the API, to the manufacture of that product. We not only had supply chain issues associated with it, but also had some

Q: 3 What keeps you awake at night? serious regulatory issues. We were given very little notice. We met o N

and agreed to this, and here we are now, and the supply services 7

l

A: Finding and retaining the talent to execute DPT’s vision. I’m o are excellent, and the regulatory issues have been dealt with, all in V a very timely manner. That really speaks to the talent and the convinced the market dynamics are there. The industry trend is depth we have in our organization because the API part of the there. The only thing that’s going to stop us from getting there is being able to bring the talent to sustain this growth throughout the

supply chain was an area that wasn’t particularly in our core. But it 7 0

next 5 years. We plan to double in size, so every hire is key to us. 0

demonstrates that customers are looking at us in a very different 2

DPT has a very rigorous interview process, and it’s not just with H light and trust us to bring the expertise to handle difficult projects. C R

the hiring manager. It is a cross-functional team that has to agree A

This company didn’t have the expertise or the resources to resolve M its compliance issues and supply chain issues. Therefore, it sought on this individual, not only the experience and technical expertise, out a strategic partner. DPT is the partner that has resolved those but the shared values, as well, that allow this person the issues, and the client now can focus its expertise, generating more opportunity to be successful in this organization. We have found A

that if you don’t have the right fit, it doesn’t matter if that M sales. Because we’ve helped resolve these issues, the customer R A

individual is good or bad. It’s not a good fit if you don’t share the H P

generated more sales and the price it paid for this acquisition

Y

same values. We call our values system “IDPT,” for “Integrity, T compared to what it is worth today is astounding. We think there’s L A I

Dignity, Perseverance, Trust,” and we really try to live by it. I C

going to be more of this, where companies will say, “You guys are E P good at running plants and factories. Can you take over the believe if you model those values at the top, then you have a right S management of our plant?” Or, “We have three plants, but we only to expect it at the director level, the managerial level, the need two. Can you take that project on for us?” We probably supervisory level, and on the production line. Come to think of it, couldn’t have pulled this off 3 or 4 years ago, but now we can look our success in finding talented employees who share our core values is helping me sleep pretty well these days. at the world a little differently. With the vast number of products I 79

Company Pg Phone Web Site

3M Drug Delivery Systems 5 800-643-8086 www.3m.com/dds Abeille Pharmaceuticals 61 609-951-2204 www.abeillepharma.com Aveva Drug Delivery Systems 67 954-624-1374 www.avevaDDS.com Azopharma 17 954-433-7480 www.azopharma.com Baxter BioPharma Solutions 13 800-422-9837 www.baxterbiopharmasolutions.com Bespak 15 +44 (0) 1553 691000 www.bespak.com BD 11 800-225-3310 www.bdpharma.com Bilcare 69 800-310-4445 www.bilcare.com Cardinal Health 84 866-720-3148 www.cardinal.com/pts Controlled Release Society 39 651-994-3817 www.controlledrelease.org Davidson, Davidson & Koppel 27 212-736-1940 www.ddkpatent.com DPT Laboratories 2, 65 866-CALL-DPT www.dptlabs.com DSM 71 973-257-8011 www.dsmpharmaceuticals.com Eurand 7 937-898-9669 www.eurand.com ExcipientFest 33 787-746-5080 www.exceipientfest.com Frost & Sullivan 18 www.frost.com Glatt Pharmaceutical Services 21 201-825-8700 www.glattpharmaceuticals.com InnerCap Technologies 3 813-837-0796 www.innercap.com Iomed 31 801-975-1191 www.iomed.com Lipocine Incorporated 73 801-994-7383 www.lipocine.com Lablabo 19 www.lablabo.com Nektar Therapeutics 58 www.nektar.com 3 o Pacific Bridge Medical 14 301-469-3400 www.pacificbridgemedical.com N 7 l o PharmaCircle 16 847-729-2960 www.pharmacircle.com V 7 0 0

Radius Product Development 8 978-368-3200 www.radiusmedical.com 2 h c r a

RDD Europe 49 www.rddonline.com M y g

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

Specialty Pharma Business 80 888-670-8200 www.iirusa.com/specialtypharma.com e T y r e

Texmac 17 www.texmac.com v i l e D

Valeo Partners 83 202-722-1864 www.valeopartners.com g u r D Xcelience 4 608-592-5535 www.xcelience.com 81 On Guard….or is it En Guard? By: John A. Bermingham

couldn’t figure out exactly what to name this article, stronger one make his/her own decision as to how to act so I went for two names, one defensive and one going forward. The other one quickly saw the light and IIoffensive. The reason is that all people who work with conformed Thanks Tony! others have to remain “on guard” at all times and “en So what if you are not the CEO? Well, the very first guard” when necessary. What is this guy talking about, time it happens to you, do not ever ignore it. When you you ask? discover a back-channeling, back-stabbing, lying, low life I’m talking about those people around you that reprobate doing this to you, it probably has been going on continually undermine you and stab you in the back. Even for some time. I suggest that you confront the person with CEOs have to constantly watch out for this. So you always the facts or suspicion and let them know in no uncertain have to play defense and sometimes offense. The terms that you will not tolerate this conduct. I would then following is one example that happened to me. bring your boss into the loop quickly. If it happens again, Prior to my taking over a previous company to turn it file a complaint with human resources, your boss, and the around, the CEO in place before me had led the company person’s boss. downward in revenue and profit for 3 straight years. I have always believed that there are two types of During that time, the CEO was not necessarily giving the people in a company; those who are competent and Private Equity firm that owned the company accurate compete fairly for advancement, and those who are information, or he was promising things that he absolutely incompetent and compete in an underground behind your could not deliver. Two senior executives in this company back manner. You cannot escape the second type of took it upon themselves to back channel information to person, so you must deal with them like Tony Soprano the Private Equity firm around the CEO with the “real would: quickly, directly, and aggressively. truth,” which differed completely from what the CEO was So I always try to keep in mind that I have to be on reporting. So the Private Equity firm’s management chose guard all of the time and resort to en guard whenever it to believe the two back-channeling executives due to the becomes necessary. And just like in the en guard fencing credibility issue they had with the CEO. The back move, hesitation means defeat. N channelers cost the CEO his job. Enter me as the new CEO. B IOGRAPHY So these two executives decided that because they had John A. Bermingham is currently the CEO of The ingratiated themselves so well with the Private Equity Lang Companies, an innovative leader in the social firm’s management, they would continue on doing it to me sentiment and home décor industries. He was so as to strengthen their position even more so with the previously the President, Chairman, and CEO during the successful turnaround and sale of Ampad, a leading

3 Private Equity firm’s management. Once I found out that

o manufacturer and distributor of office products. With N this was happening, I did what any CEO would do. I spoke more than 20 years of experience in guiding enterprises 7 l

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

V to them individually and reconfirmed to them the new Chairman, President, and CEO of Centis, Inc., a diverse multinational 7 ground rules, making certain that there was no confusion 0 manufacturer and marketer of office, storage, and human resources 0 2 on their part. I explained that undermining anyone in the products. Among many career highlights in the role of President and CEO, h c r he also successfully reorganized Smith Corona Corporation and refocused

a company was a real no-no, particularly the CEO, and that M it would not be tolerated going forward. I also told them 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 l that if it happened again, it would be dealt with quickly o giants, such as AT&T Consumer Products Group, and by having served as the n h

c and severely. I wanted them to understand the disruption EVP of the Electronics Group and President of the Magnetic Products Group, e T

y Sony Corporation of America. Mr. Bermingham served three years in the U.S. r and harm they were causing the company. e v

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

e They both continued on so I did what any CEO would D and Top Secret Nuclear Release Codes, earned his BA in Business g u

r do. I pulled a Tony Soprano. I whacked the weaker of the Administration from Saint Leo University, and completed the Harvard D two of them (fired for insubordinate conduct) and let the University Graduate School of Business Advanced Management Program. 82