* DDT July-Aug 2009 Covers:DDT Cover/Back April 2006.qx 6/30/09 3:33 PM Page 2

July/August 2009 Vol 9 No 7 www.drugdeliverytech.com IN THIS ISSUE

INTERVIEW WITH HENKEL’S GLOBAL TRANSDERMAL BUSINESS DIRECTOR MICHAEL TRISCH

Cartridge Pump System 28 Degenhard Marx, PhD

David vs. Goliath 34 Derek G. Hennecke, MBA Transdermal Innovations 44 Cindy H. Dubin

Drug Delivery Strategy 48 Josef Bossart, PhD

FEATURING

Pharma & Biotech The science & business of drug development in specialty pharma, biotechnology, and drug delivery Outsourcing 66

Thomas M. Sandip B. Galia T. Partnering With Reilly, PhD Tiwari, PhD Krayz, PhD Neurologix 70 Medication Applications of Stable Self- John E. Mordock Management in the Complementary Assembled Elderly: Major Polymers in HPMC Formulations of Opportunity for Hydrophilic Lipophilic Drugs Advances in Drug Extended Release With Improved Delivery & Formulation Matrices Bioperformance Technologies 2-4 DDT Jul-Aug 09 front pages :DDT Frntmttr apr06 06.2-4.qx 6/25/09 3:07 PM Page 2 2-4 DDT Jul-Aug 09 front pages :DDT Frntmttr apr06 06.2-4.qx 6/25/09 3:07 PM Page 3 2-4

4 Drug Delivery Technology July/August 2009 Vol 9 No 7 DDT Jul-Aug Fo industry’s Keep r m and Once Go ore or to 09 abreast e-m i drug t nf c front on o orma lic a il only w th k h ww ti im e delivery on o to pages of we n a publication . t con ou drugde bsit Subscrip rv the r tact it e aro@ eNe :DDT y marketplace and Ra ou w lp sle live dru h ca Frntmttr tt V development. tion n gd it entirely e ryte a r! el a ro lso i ve at r S ch yt subscribe ervices 973-299-1200 ec with .com apr06 h.c devoted om the 06.2-4.qx 6/25/093:07PMPage4 resp of Al ( Del Sta Oc 0192 $15.00, Sub Tec I P i or cha rep tem nte ISSN er l to in a hno r iv io tes ed n sc o onsi r r ber s for ges e tw nati di duc 3; r i r , i to 1944- f y l c pti o or , ma ogy Cana a phone bi Te r r ed onal to US, l k, i and s on al l ti i chno i nte ty P LLC or on p D 818X) submi ostage d r hotogr rug C ates: a, : f Novemb r tr and anad o nal stor l (978) for o r a a gy nsmi De the nd ssi age i l or $99. a P aphs s i Pa l LLC Ea Wes In Mai b i , a ons ver p Me ra ac er tted n- 750- p id ubl and and t s e r 00 /De subsc c A y xi , i ern r t es a ura ar li mer so i c t o Tec t shed o. 8400, in for r e & re n c nal M and M 21 c Co e manusc i hand e g tri y hnol a r ontvi mber a A ca i xi Mi 1 p ny t l o 9 eva 10 l a use, ti n c Li io othe f J E yea o; subsc s o fa o d f i le dmari C uly/ X l Co n nf s gy, t o l tim n l x: b we e han d r r $24. system t r E De r , or m al y or pyr i C Vi 103 Wa R C ADMI i p wi (978) n es use CUTI NJ Ren 219 r mati he a ts. a p D TE i CONTR or st cto i the p th P the Co ar nd r lp ght 00 www. g Ad in rre ti ug Augus r 07045- ry UBLI tm b Ever s E eb o , [email protected] CHNI CR r h on C O y y 2009, r ea ns t r ri Uni i w DI inte hangebr l n v 750- e Fa De e p Shalamar n Nic C al r any T ri i V giste V D nt, a NI so ert ono B onventi y thout S supp o Kathleen J E ar e D Cindy l a ted De D it dg x i d E T . an re rna M na pr r ll ason ver 9998 l: CONTR G ATI e 4470. ebra : Ralph Te Alex Fa E E We Te S 818 Fa E M 219 Te Fa E Te Fa E 219 at rug OR ebbie a m holas I S Ja S S ec is e r b ch ark other e paya - - a - - - EDITORIAL CAL l e ro State BUTING co l ( y ( e o t i TRATIVE l i HER/PRESIDENT Gr t ma ma ma ma ma auti i l: l: l: l: d nuar ed e/E x x x x e w n 97 ans, i 9 r s dge o Ma s n ons Roa T n t a : : : : d Cha r V I r w a c 73 ec t i aff 2009 t a ( ( ( - ar tten Raf t AL S nd e g 5 C he b e i 3) ( ( ( ( p il: il: il: il: il: E on vi ( s 7 4 9 th o hno Newland n H y, l . M t B liv c ha d 70 41 97 70 th , e, er rn Road, rino, e nge e 70 Acc ) re o 03 15 73 re s S d OPERATIONS d lle, l C addi it A 29 OLLER sonal D . Febr DIR e ingham Vitaro untr Carrillo the c i i a i a b a v cs wj rv cb 2 ri pe n , Q. s l l ctr e n ng 3) 5) 3) 3) - e l ogy 3) SUPPORT br nada, ut Kinnie Re o e . Av ge ) ) ) Dubin les Kenny 9 a ryt ta o Mon t U r 9- it or t l, r oni Acc i ri ti de re m uar C 9 i , , i dge Vitaro e S N 2 7 2 r un M es the k ghts opyw gi o en a 5 7 2 5 i E at issi 7 EDITORS - ECTOR en a 1 b use for LLC VA ontvi 1 2 9 s@ S ch e nal CA J fund MSc c . S ro g 79 4 2 9 4 y, agel Vol 06 O l 2 rid on u c 2- 1- 9- t and o o Road, or t u A UPPO r 8 1 9 9 p on 07 to h.c 0 , ff t@ M i @ Off a v any dd ubl s@ u r e ma DIRECTOR Exe 3 - - - - r t o -0 7 0 1 d i 9 0 s a a e ff@ l il g m 219 te 3 0 7 6 e , f n 2 l f ic , 7 e ser rc e rug 0 7 6 2 M 4 r l d e l i ec nsur 7 6 9 0 i t 2 om $5. o 3 9 sp sher dr Su e m l h, ice e 4 opi C 3 4 0 2 9 es ru NJ i d M M c 3 6 3 5 ved. 3 ng hanic xi m 8 , l Roa awn Exe e 5 5 4 0 e 0 0 ru gi u Ch o d 3 5 7 7 00 A 1 d c c a 3 a ite the gd ni e RT N n s 0 1 o ifi 0 t pri r r No o na e 4 a tvi l g anc . o i 7045. u J ac a ffic is nge c l v cu n p e No al, $153. d d on ssume l, i gde p lle cur e e ge 3 v 0 t l cli e ubli e, exp r e Ma i s.c e t br 0 7 l ve s. inc 7 U ents, NJ pa a i o iv ry r 222 1 04 i S v y, l c rd r A she d 00 Po e i y, ludi r r om e e ge ll t v no b t 07045. ssed e y June, e r stma 5 anks. r e r b t r Ro f y o . i ch i o ut ng r e Roa f ghts r s f t A r or esp yt . se ch e uthor gr 1 thi .co p ste D by ch. wo July/ e d ship ub a onsi r Se yea Si .c , ug s ch re nted r o p : nd ngle lishe Mo m o ser iza d p hoto co r ple p bi D .co A ub m i o D e ntvi ugust, ng p ved ti lity utsi r m live b a rs ayme lica ive, c o c y se o m n o lle a p c f de r p un D tio a nd to i o y se y, es D rug nno r nt Sep d Te anve NJ nd the n p the r e (p hand e ho chno r to t co ma D temb a re 07045. the to Uni a eli : d r sa r s, p c d d y D c li c a logy ve ing, fe re op r ng. e ted MA id U ug er b pt ty ss r S e ) y y , 5-9 DDT Jul-Aug 2009 TOC pages:DDT April 06 TOC 5-9.qx 6/25/09 3:08 PM Page 5 5-9 DDT Jul-Aug 2009 TOC pages:DDT April 06 TOC 5-9.qx 6/25/09 3:08 PM Page 6

Optimizing Desired 34 David Versus Goliath: Why the Little Guys Have All the Advantages Derek G. Hennecke, MBA, continues with part 4 of Release this 6-part series covering unique strategies for building lasting competitive advantages.

36 Oral Delivery With Novel Solid Dispersions: Stable Self-Assembled Formulations of Lipophilic Drugs With Improved Bioperformance Galia Temtsin Krayz, PhD; Maryana Averbuch, PhD; Anna Berman, MSc; Amir Zalcenstein, PhD, MBA; and Irene Jaffe, PhD; review a unique solid dispersion technology for significantly improving the bioperformance of poorly soluble drugs.

44 Penetrating the Market With Innovative Transdermal Technologies Contributor Cindy H. Dubin discovers that transdermal delivery developers are making their devices more user-friendly and safer by incorporating innovative technology and delivery methods.

48 Up, Down, Sideways - A Look at Drug Delivery Strategy Josef Bossart, PhD, believes it is a good time to take a look at how the Specialty Pharma model has played out for companies that decided to take this strategic direction, and how it’s worked out for companies that stayed on the traditional Drug Delivery track. 7 o

N “Hydrophilic matrix systems have been widely

9 52 Medication Management in the l

o studied and accepted as an ER approach for oral V Elderly: Major Opportunity for

9 drug delivery, with numerous products in the 0 Advances in Drug Delivery & 0 2

t marketplace. However, there are still some

s Formulation Technologies u g

u challenges associated with hydrophilic matrix Thomas M. Reilly, PhD, MBA, indicates the A / y l

u systems, such as potential burst release with development of effective solutions for medication J

y management problems in the elderly represents major g high-solubility APIs, size limitations for high dose o l o

n market opportunities for drug development companies.

h APIs, potential food effect, and obtaining pH- c e T

y independent release profiles for drugs that show r e v i l

e pH-dependent solubility.” D g u r D

6 p.20 5-9 DDT Jul-Aug 2009 TOC pages:DDT April 06 TOC 5-9.qx 6/25/09 3:08 PM Page 7 5-9 DDT Jul-Aug 2009 TOC pages:DDT April 06 TOC 5-9.qx 6/25/09 3:08 PM Page 8

Outsourcing

58 Henkel: Providing Advanced Adhesive Outlook Solutions for Drug Delivery Systems Drug Delivery Executive: Michael Trisch, Global Business Director of Henkel’s Transdermal Business, discusses Henkel’s unique products, innovations, and business strategy.

66 Pharmaceutical & Biotechnology Outsourcing – Growth Opportunities, Trends & Strategies Frost & Sullivan Analyst Barath Shankar Subramanian says long-term growth fundamentals remain strong for the CRO and CMO markets, which are experiencing two-tiered growth from Big Pharma looking to lower fixed costs, while biotechnology and specialty pharmaceutical companies outsource work due to the lack of infrastructure.

70 Neurologix: Targeted Gene Therapies for Brain & CNS Diseases Executive Summary: CEO John Mordock speaks of the opportunities and challenges presented by gene transfer technologies and why gene therapy offers unique benefits as a strategy for improving the treatment of chronic brain disorders.

DEPARTMENTS

Market News & Trends ...... 12

Excipient Update ...... 20 7

o Applications of Complementary Polymers N 3 9 o l “The total pharmaceutical CMO market, which in HPMC Hydrophilic Extended Release o N V

7 Matrices l

9 includes solid dosage and sterile and non- o 0 V 0 2 7 t sterile semi-solids and liquids, is forecast to s 0 u 0 g 2 Advanced Delivery Devices ...... 28 u h

A grow from $9.29 billion in 2009 to $15.02 c / r y

a A Proactive Approach to Developing the l u M J billion by 2014 at a compound annual growth Cartridge Pump System (CPS) in a y y g g o o l l Pressurized Market Environment

o rate (CAGR) of 10.1% In the short-term o n n h h c c e e T T (2009-2010), we expect the slowdown to y y r r e e v v Technology Showcase ...... 62 i i l

l affect the expansion activities of small-to- e e D D g g u u medium CMOs.” r r D D p.66 External Delivery ...... 74 8 Part-Time Productivity: Your Boss Does Notice! 5-9 DDT Jul-Aug 2009 TOC pages:DDT April 06 TOC 5-9.qx 6/26/09 4:14 PM Page 9 10-19

10 Drug Delivery Technology July/August 2009 Vol 9 No 7 DDT Jul-Aug 09 Market B M Jo Ph Sys 3M Di Ja Genz Te Vi Pe T S B M S De BD De A De S De Ma S Da Di Ph P Ms V Sa MB V ion e ana che PI enio art al ice A dv ce vi chno h c re MS T Dr Di Ex D mes S se te vel li vel vel D SF t rk eo hnic il ra Dru au vi si echnol ems anc . v cto ner um P News:Layout c A y Pre i rin eti gi a rector ecuti P r ug on ery f De p me harma o o o d r P th res P kat l n ng g pme pme pme H ha B be og Di r ed a a ng g- sid c G M Va Vic l rt br os of Del o Del & C id C rm rec rs Pl y Ma re S Di f ners orp o e Drug & h e nt nt nt ent v A f a Li e ogy o ugh sa Deve nt, Bu a i n man rvi rec LLC to en, e an ve u i li fe Com P B te So ora v gh , s rt r, , ce res Edi rino ery ry to in in New da Gl Cyc Ph lu De it an , lo Dru tio P r es me Ma id n, gha h, t o Ph tori pme hD r, li ion ba D, l en s n e v g na rcia MBA P ery D , l s t m h ger nt al 1 l D, 6/25/09 3:13PMPage10 S C P DP M Dir M Be V Co M V M Up De Dev T Fo F Davi Cl P M Der P Ber John P PhD U P Di Kei X D U P Ka Den ol at ro P, P, o h an c r re ro f h av ni BA S ar e v d i re T s e e e rmu u p B i u arma t a c z rn e s h s ff fe S M c l ve a n ay h el id p e t es le ver t i c La i id l A La m e to ek c t de i ge e o di or h ark r el to s o r el r- op ds s n rs n s pm e A a la s b r, n I G o ns i , n t n Sm A. men o ce n ac r, te Ho B. n c i d l or g n, l - e t me G. g t t L r, on t P eu ob P S. io en gh y St t g Res LC a C ha & ha it M. obuc in P & De y Ko Da t n o rs n t of a t t art h , He ori ic amo g mp s C Br rma am t l rma CE & e p E po E vi La a Re C mp a & n O e a l s O ow Bu n a o ds r e s rt b c c q. c ni s S lo ol Pr nec r e o h e me o c i ra si u el e , r r ar o ie n , n, a ad t s n je n i t nt PhD la c n e c & ori k h o ce c a s PhD, , e, s t l o e & s f s U Pha Dep Cha Ph M Pha Su Vi T a U P P Jam L M P Bi Di H M C P P G J M T R D Ph G A E P J C T M niv o a t a e ec rof or o re ur ol ni e re h c lo e o har c o e i opha r rM l ar er- b c r S hn D, ch m s e r e A i N i e dif rma D ar s h iu or h n rmac an s v D hn b ora ck e r es e c u e n ide R ide od e no y P a a n r s tor r tmen m con es il & st te ael Yang rs m r d i Ti re o l y sit DDS o ajab sor c e Re tor W ceu rma ic l n Fr n l i T C n i ra h o d A s In o n c ty Y eu D, echni y o t t, s ide o g W se ss & gi e, . l . F ie a n Re A. of f y, t & t tic o tic e ceu C Del su e o oc e W No arc h i . s Jo M f llo n of - r f l s P R C l er P ea Lee, Mc n S s t me al M R ear i h u & TO r T c hD , ate ha B h i a w, tic th iah e v al i nso s, ep se D , tio Rese s A xas e r r s G P s R ry y mac La H I Di Ame iss P ka, n & n h bo n , & in ea P r a bs rec c. D D, of P arc ip l hD it l eut o hD, thc r e pi tor, i y h sso m c , a ics a i r , r e , 10-19 DDT Jul-Aug 09 Market News:Layout 1 6/25/09 3:13 PM Page 11 10-19

12 Drug Delivery Technology July/August 2009 Vol 9 No 7 DDT a a of li to of agre m and m of of in th proc Endo, represe li term li was Opa m ha P P c M ter a suc im Mi Va nd nd omm chi c c c ile ill cl e ark col s enwe ense ensi ense ro le port rit whi the C$2 o cha h li udes ar xymorphone si ion A$1.1 evi na Va e Jul-Aug C c e ee ant stone "We The "We joi yal s ori e ce la a nwe omm d gned Thi hie t itt of s el ch Opa ng the ds ant le borat ntly ng ER, nts nsing t . Opana mi Opa Opa ty es ke whe Opana o ed ant " P right f the te s are are st are rec a s The pay ea lli reducti t a a outs Ex erci na the gre rms a wo m a are to ddi st sset t devel th Pharm na na gr n ive n on rson, P eived col il ver pleased ecutive regions agreeme e produc s har 09 cert our ement O eem ro exclusiv al li addit achi ide ti com ER ER ER met ER of & t extended- up-f work on l for onal o yal y abor prese oped mace ons p deve Market ain Cha Op sha t pl ent aceut the from i in in eve he whe pa to t n io i the ana ront En ies n ea ts f a lic Office ana, w Cana nies n to Canada terr re upon P s or our l nt. loped irman Aus i nce ment tion U uti s ale e b i m. enwe s in her n c of holder r e ens ic y S." be V a lic e t a Opa do d it c cer The he r nging s als nsing nd ,” alea ea Pe curr We News:Layout the ha this tra als e e or da, w a e ing a mile patent lea ER r s of g c ns V st nwe t ble fir b it ve ies and na payments lia aid a , Co., h of r alea y r nt immediate-releas a h s c ent Gr in e A Aus e se a produc ec one st de gr ontinue of ement . a in Endo. nd stone ag the ER f P ustr to outs w s f gr J I r r ently Chief f eeme one or enwe als t n egula om nt ennife pr the ith in ormulation Endo expiry optimizing re tr ant add and ee Endo of addition, a alia, outs a oduct O ement ide ha gre f lia s d Vale 10% t r or three the pana betwee es nt announ st. Can are s will to tor a Endo. t to Exec , ota r ement ide Pharma the a Opana ulting 1 and a beg s with or L. “As ant share deliv Vale ucc y nd work strong portfolios, reac to l ca unde c e ing the US a ge 6/25/09 3:13PMPage12 utiv Good an ountries, xte nd Valeant New New n ll ess allowing 20% of the ced the Valeant ada neric erables hed with . from Pe e for l US, up equally ER nd to ceuticals, sales e a r Unde ful oxymorphone formulati regulatory t an nwe va ward f the , Off e tha Ze Zea irst to of our in a President in la Valea produc lue this entry. ” the payment , aland. t has C$1 terms ic st net Cana st r s t la other adde we also Endo it ubje A the er of in a y nd, de Pha to nd ear sa nt u a of the on this al da t nd d ct le all of stral to to J. s , rma w succe A curr i appr 2008, doubl m chi bl pharm a se syst m i m com t O quart O opi r Q del pr m speci col f ncl dent he espi ormul i y it ust pana pana adde orphine edi ar anufact ver oduct anal a ear l ivery l h oid fi udes dre abor ke em ent pany oxi De Opa Pe Endo As Va ce ra r cal if an al e er r ssf e- at & ti st ana aceut yi r, og li ago, at nwe n, t . pa t le ly i f ma ory m di ng y s re 2009, ncr r r a ut opport at P ul ng nee qua i pr na ecent te anchi ant l pr ur in on or at gi enw pha , ong- at m drug lge engaged and ions Ne Pha nd chnol ost of pai f st e ely i es, t me chai a whi ar i ER ent i i ds, m a rte ce cal of n Pharm nd si r rma cals sed i br k es f at at n ar s ly com N rm s act or ntr c nt pat uni and et w anyl r a ca e w produc s l e es r pr anded a t n e f de ily e ogi nar of e ed r i r C used w ac i i ceut f i a c al ndida 58% th e drug c anchi i dis i ncr s pr ng t or vel annual ent nal ancer, m par $400 porte y eiv i , m 2008. i a eut es Z curr n Zeal cot b pre n e part ar c a t eases E an y e scr ar opi opi o i s ges t eut nd ed ed t cal e ase a he to t ily a ic i he i de Endo te coc k se r nd x br cs n nd ent candi d e a equi ner and." i al m et oi ng ic FDA pti w h ic t xt ly and vel r t d oaden cl f f re com a by i . ydrom s he es i s l i or ds, al or drug i i n ly gener n re l ended s. ous P t 31% and na on ov l at i pr a h ea opm s usiv r i s C enw C as a Endo, on i fi i dat r dev t br r nher ng oduct suc I $40.3 er pan s a ar he and anada appr r anada cot vol nt r ch, pube of st a oad f spe e our m es i orphone, t t est orm ent ernat e c cont ear h o he t y i per um di l qua ar r i c neur ma opi pre ova te de e under a ci $52.8 e s s t c sor r , k t at i hat ly m rty s pa c om d ul her ange s iod e r al t in velopment, e i while nage om rte i hat epresented ng me ve script nuous, i Lic l t onal a mitochondr ation st f olo onset ty ders l . or li lso i C (CPP) bi de apeutic r r n of pa A0001, nt on se s licensing an pharmaceutical addr million 2009, ned gy i has of velops, June O o pain, veral ny applying is ense time. ion pr for of ada, ns pana in expertis of pharmaceutical and ar oviding a . es net been f the the of ocused moder ound- puberty 2006 multinational s s compar overactive a year cope a s dermatology. f ER o unmet s ale, nervous ial or mar s coenzyme ales xycodone, ame gr to e its s. the the- and and ate-to- o Valeant to k and in on w In f et ed drug in or per ing the fir clock is that w the st iod ith at 10-19 DDT Jul-Aug 09 Market News:Layout 1 6/25/09 3:13 PM Page 13 10-19

14 Drug Delivery Technology July/August 2009 Vol 9 No 7 tha a f mil re dise com wor Cha disa phar G cl t and InC re re me a and and E El I InC inte adr inova sa de pat U Me D exte dis A now mor ug dr r g for DDT yi r te inc S re g ce se cor c fe oundbre ve h nC e t dica ent ilta d-to rou thods ng a the is rdi ube a ldw pat a ar ty a r g m ir a e ns iv C c inov mer the es mac lopme la anouc m ha s EL In “O Founde “T InC d se se del re ube al tha Jul-Aug EO ch ed ga ions n n s sci broa tor il prof t ea w e te tha v l equa in at ub o eg ide an he 206, a c the pr nt is N F spe ci moder iv e C devic il tion e ube s n a nd ompri f ed ve plina a s of DA ati L utic at D as of ali por or p genda obl unde & y er aking the deve dapt . a No. i 20 nt r de and es abs c e sua i ntio ci ive 05 nd t- l y an other nclude P on e d ola xpir e c za I is e a e ic f ned of al nCube. reve ompan re e s E ir f pla tha ra d nd y r by ms at , tion C uc sing Tr an sit r lopment 7,52148 int ug dr exper in now of exi at lan L nce co c a t exper Tre . i borat ck t E e e 09 one hie ino st m s ompanies. he te tf ve t . of ion, Mr. genral y it medical LN nti er gnizes indcatos. Alzhei amyloid abs in es an st At cr ms or edical s am, company s des of and ntor f dis of admi United the ing a ie ng, Market roundbeakig g sf os deliver f rof t vation the D05, Executive ion plying “T ora ocus InCube, Imran plc ELND05 s ise in ul at ignato this ciplnar se and T s, i f o have and technol gies T and year l y mer nister dr companies ransit as remnt ag chalengs. rst reating and is wi on Mr. A inovation mne t the t paten beta ugs much c S y o the One in potenial y admins a unprecdt.” may th i laims ’s implantble ti Apr to ta dd n io dab led platfor include 205 its uniqe T News:Layout Imran s blod- we medical y ion di key 195, ng and ransi e brea f purs Of in ue rom team s of il s trademk n expedit for and of eas is are s P icer f s entrd the met 21, pers engir. America’s cylo-inst or aten devices dt ue terd an today’s tion ms for to Th era peu brain ha t Phmaar e. t inovations The I and or he phar Diagnos centrs, h creating he in Wi focused later nC br hods 209. ug-dedr vice hi devices . s tan impor adr onel Fast-rck al and of the T ai cr treamn T US more s and ube cardi therapuic therapis best he compund maceutils n,” heraputics regul os Transito. into rie bar nam ,” due apr th esing j resach for depth oint s-functioal F T company Tr said ha t said 1 recntly DA most o he i on way than e novati an to y ator treaing ademrk to s oach , t supor With EL N dev elopmnt ibrlato . def (ELND05 a and paten a tisue mileston Disor nov el designato 6/25/09 3:13PMPage14 Mir and of exclusi ve, an for Dr. nd an of to sucef to combinat ic prolif 20 y is tis exper ce uit with r Alzheim agent of 14 unmet he do the the tackle Tony evie w I tar ve Imran paten and anouced has nc. focused der Alzheimr’s it icsite-pcf engir patens is f this is ice Off sucef gets this ostering r ms platfor ad tr D0 esarch, a s tiled ade recntly sc cel b eatmn tha ul uz,Cr medical i af vorable of est , ). medical new of n resiag ve ions e iton mter is the Founder er track- and The tha ca the Protein biol gy, ugsdr R on with known and 05 ’s has isued ul dep with it of e utb l we to of ice an Ep x e ve the Alzhe moder Alzhe a dis world. il f their c ra a Tra lea ther ne Alzhe inter a de b c ne deve s func s hig-leve tha exper includg ga mula for A a a c drive s of olv e nd ompa c nd a ne lr ompa a lzhe ndomize e quire rdiov str e li c r ea d c twar k v ns d r kg mia ve a s ape ove e e te iet s ,r ha ous tion. disc Ky e lopments ic ignf ointes ge produc dy It Ela Tra ELND05 InC Unlike n to a f f for tis iton ma ime ime ime ime yr chnol ic f ate n nie ve ound, by is , mile as d utic e, r a y of e , tions tac n y ns dia s iplna ube ply a jor s . the exte l c c With ys r’ r’ r's r’ s long c Alz e e cy c prote The C e ula d, iton 60 ur . e tina ha omited kling lec s s s rious s linc ant ngie be ts te mploy or s c othe As dis dis with for , re gy doub g InC Pa tne t L s s r he linc r m, ha tric the te by tudy pora inc inc roup na r in l, a ntly rev pla a dis unmet expe Cr eates y ins s e e a bs s ime is n into is ve oc dis a l y a a , l ube r or such me . m a te de luding lude a nd s a s olutina gued ’ le- emrgin a e obesity e neds. , a c l, c tion, iaton e e wide ams n l ase, some es in mis ea e ompa petids, dicatng life-thr wil ur r’s to r tabolic and maceutil biophar mechanil, s problems blind and and practil tise ar intramus is to timaed se re aproximately along ils medical ELND05 a disea. s r creating tradionl and are ntly a plc making ion problem, focus developd intrapulmo indcatos raar y T -23 y spanig more nies and , for InCube’s , as r renal eatnig of placebo- y for rently cur disea, is is hematol gy pieln m in with itself raine, mig aproch and Alzheimr’s novel tha cular. tha a medical to on of by neds of than a ugr D neurosci-ba a disea, a Phas develop for and therapuic (AZD-103) Mr. the vacines. demntia, ming transfo I Alzihme er' s dif to tr more develop phar nC phar dr nal inter y contr ue dr condits. 24 I with the fernc bring n of ug-device 340 gastr tha creating deli tisue e ube’s Imran’s ug y therapis aditon merger ov atril milon maceutil maceutils, I company , . , preclina than treamn oled deprsion, mal, transde ver deliy ver la er rohig- wth patiens clina contiue ointesal Disea eD liyver new r c resach ge engir, acording y omes in ibrlaton, f 5 ares, us for , own inovations roundbeakigg of of markets. dose-rangi, milon peol the the combinat technol gies to ing tha biotherapucs, ed the device dev eloping study. ms platfor with maceutilsphar chroni of natiol.Inter and ymultidscpnar ug dr to liv promise includg its biotechnl gy and materil anxiety, resto treamn ailments, diabets. exist es intrasl, worldwie companies to y proieta Americans device mild-to Transito The candite and of inovatio epilsy, InCube’s the in icensdef around patiens of and healt team study ugdr scien and and safet scien, novel central scien of d t ov er ugr tha hen s ce n y 's is have ugdr the is and and is to a 10-19 DDT Jul-Aug 09 Market News:Layout 1 6/25/09 3:13 PM Page 15

3M Introduces New Dry Powder Inhalers

M Drug Delivery Systems introduces the 3M TM Taper Dry 3Powder Inhaler and the 3M ConixTM Dry Powder Inhaler, new technologies that expand its inhalation platform. The 3M Taper DPI was introduced with a workshop at the Respiratory Drug Delivery Conference in Lisbon, Portugal in May, where presenters explained its unique design, which stores APIs on a microstructured carrier tape, enabling it to provide up to 120 pre-metered doses. The Taper DPI uses 3M microreplication and extrusion technology to create a “dimpled” tape upon which one or more APIs are coated. This unique dimple design allows the use of API only, virtually eliminating the need for lactose or complex powder formulations. The device works via a simple mechanical process: upon opening the mouthpiece, a dose is ready for use. The air flow of the patient’s inhalation releases an impactor that strikes the tape and releases API into the airstream. API particles are further deagglomerated as they pass through the device, helping to ensure effective delivery. A number of features help make the device patient friendly and accurate. A ready indicator provides a visual cue to patients that the device is ready to use. An audible click sounds when the dose has been delivered, and a dose counter displays the number of doses remaining. Its breath-actuated delivery helps ensure effectiveness, and the device works in an easy three-step process - patients simply open the inhaler, inhale, and close. With an API dose range of up to 1 milligram and protection against moisture ingress, the Taper DPI brings important new functionalities to DPI systems. In addition to the Taper DPI, the Conix DPI further expands the 3M inhalation portfolio. The Conix DPI uses an innovative reverse- flow cyclone design to offer effective drug delivery and simple operation. The inhaler’s design allows formulation flexibility and 7 o

protection from moisture ingress, and is engineered to increase the N 9 l

effectiveness of energy transfer from the patient’s inhalation to the o V

drug formulation. Available in single-unit disposable and reloadable 9 0 0 2 t

dose designs as well as multi-unit dose designs, the Conix DPI is s u g u

suitable for a variety of applications, including mass immunizations A / y l u

and vaccinations, and treatment of asthma, COPD, and hay fever. J y g

“Companies turn to 3M for its quality portfolio of drug delivery o l o n h

options, especially when it comes to inhalation systems,” said Jim c e T y r

Vaughan, Division Vice President, 3M Drug Delivery Systems. “We e v i l e

are the leader in MDI delivery systems, and now we’re advancing D g u r

full-steam into DPI drug delivery with several significant offerings.” D

15 10-19

16 Drug Delivery Technology July/August 2009 Vol 9 No 7 ag regul col ye paym condu w com the hav re and A ophta s S E B a B Sc ac w unai Mc com pote sube ac kina col broa com ophta tuni opr com one tha and $ pat w proli ra excl uspe DDT il ith il la diothe ti ti a 1 hol xe l nit labor labor t hway Dona r e vity, vite reg c ted us lice i- anof joi of Pha mer monl ntia se monl mon tre d a c fe ola re Sa U In Be "T ator the a no s ents us nsi que mousl lso ombine Bi us ole Jul-Aug iv ra ra at lmic lmic nder se ntly t at ( ting opica to i-a nof of he D si nse PI3K) s. se l at ci at ra e previous nge ix c on) inc bora e, ti ba ld US s ar is y, nt re y y va futr ca h ec ch li ion, on, al, ion r is py of Ex ll i av Me y a , most Ib/ espon ch a ce re c a c and sha & luding y use nce m- ofr em c cli M ag t use anti s is wide . t aus e 0.6% of ent he FDA l t er $140 e tion; o a fr fe iv ve t cte nse Unde dic wel visur e for te D, lixs L ophta nd o on e nica re I Ex f re equ ber ffor s p r r e ba & or ain omb, disc is c bac m r e i ntis c a c r em rovid ooB c s of ine, omercial ed ec 09 FAC linca nd guarnted lin eli man re om the s ba to iblty cterial ra a the t ho a for l, ystemic mil a as ts 208, selctiv val, he ialr r w nd teri omend under clina spon b pr nt xis ov ctivity nge cterial to wil L XL147 is in nt regulator c t mon acteril wev er, il lmic Market in New dis he a e royalties S al act uf ir f lion the t er event Exelixs al, the as reatm oved om , f and w patiens wil par es or trials y st s of trials cov Clinca for licens, st ocular pay orld an iblty pink M admins t treamn tabli ocular col bes York, e he ir f under XL uring ag fluorqin conjuti ey e ticpae us fo tr resi er Exelixs be al and F inhbtors Besiv milest in ent aproval c res st ials. Exelixs , b ai e. colabrtin. ifloxacin DA y y leadr l a onjucti and il e 147 Ca shing and News:Layout , ey e. , on human bor eligble nst pathogens r s and of pathogens," It earch for with I comeri tance ubseqnt of XL765, New s nc. Reice v activit condit P the terd Advis i-a anof a sale of a B manuf a rofes ones inhbt and the sto ne wil nce cane in Besi ti resach only nc e of fers vits. recnt sev i may licens on, an n York. conduti re gag fundig of to vit s tum of bact XL765 of ( ey e to ha vi trai one of cte or eral of es vance ons be anti or broad-s Exelixs act chem opht r Bes venti whic ors fers , a PI s. . ve be y recive Bacteri al any s ors, r over incl of ly A ns eri cl st of healt, ifloxacin 3K. uring Com speci -i , worl For precli sai and ct and ivance. sol ate of res eril i s, i r anouced and halm any nfective P es ni phys al tha s O otherapy i uding ivat ng of 1 produ and promting s d $1 cal w phos e are ponsible pht i-aventis Sanof um pectr conj the e ipe up-front a dw a mi colabrtin. pr Roy i f Marguerit al $21 il responiblty m and pr on activites. developmnt, nical ion op are ic ic FDA ne , 6/25/09 3:13PMPage16 cal y b l r l eclina a te c a ecntly ide. conjutivits o r licens ilon ia goin have almo gy phoins cts unctivits, htalmic rently ur acturingnuf yegulator , those w fluor br ophta ducts Con milon i- sanof of ns the tha li oad topical PI3K and voted dev a the a the f ne antib cash a oquinle most or ce in treas and glo tha arisng lt w anouced an el lmic activites l PI3K t Appr l tide- a orldwie in he proram sg oped ju ov ba ie d drops, v acteril at i w most wil entis E for Phase the er l a NYU xelixs s nict v 3 is fr a for al th om 3- I o va D ge tha XL147 inc Improve e a c de Sa C the inc pote c c The foc to B a inova c ra a B the in the c e pro a t c s e a c M Pha i ole ourc na lia linc a ome ntir a omn nha ntiba omite ra dv linc EO oe a e c ve it s ndomiz r nc PH, ne dic i-a nof fue l us linc e dic t lude ra luding us ble a me s r r al ; hringe stig nce ntia the c e a ma nc e r nc of pe Ex “ The c B " The of us a e e a al al ompa of r bilty, l c T ation, Sa cte h te d tive ted e tion c dic ond ed e us the pa both oda a utics s rc s t c c e ator a s s or deve tria & l me d Ex on l e ve i-a nof a i e lixs patie nd cle inv ria ialz va with of c e d tiens e FDA Ex eliix nc dia a utic pora Nwe the to B c to to r ondit.” d, Lomb f ntis y's g l c e ny of ompunds nts qua ls to fe c s l. nce ris a Inge XL765 pha es a e the r lixs c s w lopme mov e a for the gnos ra doub da . owth , ra nc r found a c omunity e a Its nts nc deve pa tiga hen F T tol-M is fe Inc te tiv e ma ve d ls pa Ac nc te r py a a s te e D with ma r he wil e e nd prov the ly lhe tie , . dis under ’ r lev eragin Vice e ntis tie e A r. a jor is . r B t in “ tional le ica y ff ov c s ne therapis tha nd c loping of a nt. nts is and W under e and ompunds of rentl yCur ausch im, Exelixs coy ver ompar cokinets, nts,” -masked a tha a resig vely of yers Topical treamn er be s the new studie proval nd phar e ha a its izer, Pf al 209. Presidnt Exelixs al may experincg can bacteril beli ve the dev elopmnt-sag of ef s W other a s other XL147 Besivance compunds a of vailble dev elopmnt Squib, said fectively a the quality yeth ma treamn was inovative & the e Coul d new eradic licens and d track-eod Besivance have its and are Besivance Lomb wer ceutial , trials Inc. to of Har customar George licens potenial Exelixs’ ev of and Phar tha ful y has treamn and dev elopmnt its Besivance in comited a conjutivits. and is a utily t-ScoRdin by caner of nd GlaxoSmithKne, sale ," luated design te . or adv deply involving other vehicl. esta mace treamn their phar “At O optins.” said life, clina presciton rated integ XL765 Globa ba in ey e and colabrtin. and A. pieln, was a y cterial blished forces. wil Phase ncig Gte phthalmic in PI3K broad Bausch macodynis of and in uticals, PI y regulator expe and Fleming Scangos, healt optin biotechnl gy colabrtin comited tr base biotechnl gy 3K provides suce thre to e to be P clina resolutin other ating nearly of we tise r resultd residnt, inhbtors. the I, conjuti product realizng tes inhbtors promted straegic In ug dr d vO er whic novel p & and for are ustAntir multi-cenr, in roducts on developmnt Phase clina and PhD, di seriou the Lomb, in US aprovals. nskoOr v, 2,40 this patiens pleasd a Gentch, prorams g vers discoy ver Daich-Snk to comerialzng smal in seri ica yeff is pieln resouc and vits macies phar the is with Presidnt advancig poratecor I, excedingly The companies, primaly a to tha by company we trials, s patiens caners. disea. reat g ubject and microbal ful provi de molecu at both to of with the dat MD, are help , suget its mplatfor of offer eig Phase safety, topical w the a t yo. a ht o with il n the nd in I 10-19 DDT Jul-Aug 09 Market News:Layout 1 6/25/09 3:13 PM Page 17

InSite Vision Announces FDA Approval of New Ophthalmic Product Enabled by InSite’s DuraSite Technology

nSite Vision Incorporated recently announced that Bausch & Lomb Ihas received approval of Besivance (besifloxacin ophthalmic suspension) 0.6% for the treatment of bacterial conjunctivitis (pink eye) in patients 1 year and older from the US FDA. Besivance is formulated with InSite Vision's DuraSite technology, a synthetic polymer delivery vehicle that enhances the retention time of the drug on the surface of the eye. Bausch & Lomb licensed the besifloxacin DuraSite formulation from InSite Vision in 2003 following Phase I clinical studies and continued development of this broad-spectrum, anti- infective drop specifically for ophthalmic use. Based on the terms of the agreement, InSite will receive competitive single-digit royalties on global net sales of the product. Besivance is being launched in the US in the second quarter of 2009. The product will be promoted by the sales forces of both Bausch & Lomb and Pfizer, Inc. under a co- promotion agreement involving both companies’ prescription ophthalmic pharmaceuticals. "We expect this product to offer patients a valuable therapeutic option for one of the most common ocular conditions worldwide," said Louis Drapeau, InSite's Chief Executive Officer. "The launch of Besivance represents the second commercially available product incorporating InSite’s DuraSite platform, in addition to AzaSite. This is an exciting milestone that further demonstrates the clinical value of the technology. We continue to look for new opportunities to utilize DuraSite to develop valuable products that treat unmet eye care needs.” DuraSite is a synthetic polymer of cross-linked polyacrylic acid that stabilizes small molecules in an aqueous matrix, allowing for targeted and sustained administration. By increasing the time that a therapeutic level of medication remains on the eye's surface, DuraSite enables a less-frequent dosing schedule, increases patient compliance, and increases the therapeutic efficacy. InSite Vision is committed to advancing new and superior ophthalmologic products for unmet eye care needs. InSite Vision is recognized for the discovery and development of novel ocular pharmaceutical products based on its DuraSite bioadhesive polymer core technology, an innovative platform that extends the duration of 7 o

drug delivery on the eye’s surface, thereby reducing frequency of N 9

treatment and improving the efficacy of topically delivered drugs. By l o formulating the well-established antibiotic azithromycin in DuraSite, V 9 0

InSite Vision developed the lowest-dosing ocular antibiotic for the 0 2 t

treatment of bacterial conjunctivitis available to the US ophthalmic s u g

market, AzaSite (azithromycin ophthalmic solution) 1%. AzaSite is u A / y marketed by Inspire Pharmaceuticals in the US and Canada and will l u be marketed by international partners in Japan, South Korea, four J y g o countries in South America, Turkey, and China upon approval in those l o n h

countries. c e T

InSite Vision’s ophthalmic product development portfolio also y r e v i includes ISV-502, which is currently in Phase III pivotal trials for the l e D

treatment of eye and eyelid infection and inflammation, and g u r additional product candidates leveraging the company’s core D technologies. 17 10-19

18 Drug Delivery Technology July/August 2009 Vol 9 No 7 pa simulat 3-wek icantly signf a a improvem e B Cont icantly signf hours re sign a of masked, Deliy ver treamn e the Dir during study’s to E S c a te redints ing fe materil dev whic c in ha A DDT t c O Co xposure ye s nd dminst omit ompunds search ful chnol asibl tiens, s scren n y a a adit yeG e poten elopi clina signed two ct t cor roled reatmn In “ The “ as r OctoP In and Jul-Aug s re e proces of or m Thi Ora’s O t cent es ed pat t par t ion he en leas dr the l oP ty O icoster ed erd dose. placebo-ntrd ng gy. ctoPlus dosing, and of was actu manuf System fol and P s ial sympto ent roups. g the ctober vironme on op ient of study’s ate A hase ly a explora to t y Dr top-level l contrled- of tri C of If o w us ome dvers ow its benf s (p impr ne de by used t m for two acute AE qualify anouced the ith al he deve providng and t in t us n t is he E he w velo he un < ing , umbers I Ey a wil s G 208, d 09 top-level ( EyeGat si m a a ugesti clina oved creation contrl ug dr 0.5) The at evaluti 3 ulations client single-ctr, P-437 com ma: har P for pr y tor lopment, sol e gns no-i European s product-ien ring. -wek tal envir pment E Envi two Win tmen Depar eventa in anlysi, work GP-437 ds Market pat of ution this im in compnet, pan and O t deliy ver patiens Phase improved he while nvasive EGP-437 genral ients, ronmet with onmetal Under dose ng ctoPlus pact also tha eas ed-rlas resach ons en y's worked of study. organizto anlysi post-CAE on for sympto (EGP-437) ive pat e has P a acturing, manuf vi improved biotech s EGP-437, dos Oct straegic rapid im on I a levels) are stil version investigators ronmetal clients, played ient News:Layout in this contrl wit technol gy ocul study mulation for proved randomi Nw e anouced sign ing. at l oPlus' (CAE) s sign sucefl, conjuti for wi chalengs delivering sytem, h w of study Ora. onset cont mulati for ar m biophar hic th y dr twice company. recov Thes an thes a of EGP OctoPlus demonstr focus led-ras and adminster dr of m phar O located and Phase y proieta sign a ract, integ zed clina y dr ey compnet, ug ra, evaluted I of include exi ticos cor y er whic s e ug r D over I obser evalution patiens s and eff ymptos action. a deliver Inc., ymptos on devel sting (105 ey s OctoPlus higly the ons aceutil r r and yndrome aceutil straegic I St egular wit al for ects I e This in -4 ated 1 developing N a licensg s r ved r dur contra tudy ed prov a esarch h tha .V. ole A sym 3- opment patiens), mul for pati or er udy thre y we leadi ,” t the dr ndover, I 37 wek 6/25/09 3:13PMPage18 he rel v ant ing icantsignf i oid n by ly recntly tha s s new ther fur in said , ug ents ides was re combine ystem, ptoms adi contra of the EyeGat wil product focus safety aced f CAE. y lir e ve D (DES). com the minzg and ng solut CAE ved obser deliyver ation. DES E m sytem, ugs dr period. remnt. ag l Imp and George also eight in tion, a GP-437 EyeGat globa evalute MA. contrled- ay pany double- after uniqe biostac,” when tingsupor ion on by the improved anouced and exposure clina prores g s during for For vedobser the EGP-437 for maPhar tha D active client Ora’s CAE whic ica yeff ES O clina withn two rovd e studie act the clients, abil usler, the the I are ive the ydr for ity to it Eion valut ade e the b for includg are Lasi estimad acountig ritaon ir los envi of de symptoaic pla few ic scientf and 30 EyeG licensd Deliver therapuics side based de candites mulation for protein balnce L B P ug dr mulate for maceutil phar xci ns Sig y hase octern iole vel velopmnt co-mrbid yed a ophtalmic the encouragd potenial ted v ronmetal solutin k treamn of ef D O E opment ailble The In mulation for x ate’s ysurger . on Ib S fects, ye E ra a T moderat-s ver functio y about therapuics, tephn aditon, than S heraputics' from central gate System, decras O is is clina y qualit a clina tha active transcle is throug ctoPlus' for icant signf a being treamns. of improved to the to & existng m, ir f reli of disea, leading maceutils, Phar tha the Bascom optins as Symptos actors, f products. 1 both From, i y help by nterfo and and longer-a cting, role most ef. phar in many of O prosect and was studie. actured manuf acelrt tSmp y the thes providng ctoPlus early 4 most y proieta rCt ont ac clina bi the blindes. patiens in ot lead maceutil patien i therapis. Presidnt clina-se prevalent otechnl gy quality cur developd ndept iontphres patien the Palm her number such as the This anterio result.” stage advanced rently alph product such 20 agin tha ugs, dr dr developmnt is er resach. as developmnt vis with y no-i vasive to technol gy-based a of conve niec, Eye contrled-as The resach eye diabets. EGP-437 as of Inc., leading ug dr oms and for m for 40 availble Rather and ts for life redint ing poulatin, to and pain, a patiens Loctern, ophtalmic to industre, patiens Instiue milon product the inc safely acturing manuf broad C Biolex was deliy ver for posteri deliy ver of a EO Over vacines treamn denc genral than European light for activites, patien ocular Ther and founde may of primaly of range timelns deliver ug dr who A s. the by who porating incor and at seking EyeGat a m senit vity, and FDA m, platfor technol gies of prove with chambers contrled- ug dr the OctoPlus ericans y r D is Two s past t discomfr on ophtalm gist. suffer conept-m deliy ver a are of DE and the of version no provider betr a in University OctoPlus behalf aprov al vices ser a eye provide w and 30 S chroni and rently cur to 198 cure to increasg focus can ide ma. Phar is from suffe be years, discover disea, the dev red blur ica y/safet eff Eye increasg and improve technol gy of ult ran of fo its a with o of and and o EyeGat leas the r f DES r ytempora ice usefl of imately to focuse its hepatis n ge is technol gy from arket kno DES, of advanced Ora vedunders icult-o diff the more “We ritaon,ir eye. rently cur clients. have technol gy of prevalenc vison, Miam. novel wn and It after the has DES, therapy vicesser is and due are lead has on than I fewer we C. ugdr the the and to is to in 10-19 DDT Jul-Aug 09 Market News:Layout 1 6/30/09 2:53 PM Page 19 20-27-DDT

20 Drug Delivery Technology July/August 2009 Vol 9 No 7 Jul-Aug B h p o r Hd y Ap d wi n mo hy fo o b ar co im cl eff ph pr in ap p sa t T f of th f in fu d so omr u l omr u l ev um pp ro ue he in i e sta n di c er r r y: od u lu mme dr th amr a me e t i th e produc t ha e da c c globa ov re ad elo a he sf e ro o c ap eu hat bi to on hal xt xa ber o ca l r con er rt ts , f at i V T For wi ac Sa at i er ily ph s th pr lex di a ce ct li t r e p un di m he t ar te at at i l p eg i rci he le be nde com on t an ed ce ut de ia y nve wh s, on 9- il a of o o I ha l ine se as e n io ti ib io io l x te it dose, if e dva n ma n n ul ng e ic mic al yr p te an al en t t c s, hy y u dev d al e le 4 and r us n n ER s rot ’s il R T N I at d st re l an th se s e of m i b t d Excipient b per ip co th e dec ad c dr ca l p o not o or y ch m s en li at pat al a the y ot y hi a c e ge at th rov f do elopment ea se t fo im o er ap co op fo t a fe nven ag re cl ent and bur em ech no sep yp a f r tribu d to g i ef post .B is c r ice s nc e se s. es . rmu gi of new ur ent h a p av nd hi exper es , i d om c aplicati d , d es cce pt de vel es rov D O is t t st ur cti ve , regulatory st yc eu m li gs evel o s t fo ai sta es AP Is i dis Ti ti o ere d. ti o c ry p an of o la w g an o l ago , le Hatc lif ti c i mr ul at io lo g efct in ed abl drug ble any f an ma a l i l n te ere I T C U w c is ienced ecular n s n o n anc e d op or t e g eff al are us in ha t . ies d re sp e pm en hy an an mainly wi a 1 tri to o mi ni mi ze all y has for m th In i and n h- Update:Layout mu f to e Fr th ic ac pp an ri on dro p ovat ive es irs t d ces aplicat qui c t e off er ha . of en ER h Wa ad d er ap w o on , d ma n In o ma n com ercializ lt ip O a m weig be ve si vary i n ith its bari h t tr u ul Ph of signi y pm utmos ma dm des cri use xman se s t x E hi a nce o N mo do it io at a come a nc e to eu ti c le b f p an f o n ag co-f li nd advntag es ag ent nuf act high in i wi th een D, r sa ge it y an h ons , c st po ER ng o e d n ficant it s t ion e t ist t em en t v r hen ma o bed he sa fe ty. it s , t w wi to ly ormulati on id es ER A fo r si ere d an but si de very i c ater - an me fo rm an o C s tri n mpor d e d n e th , (N ure it s t regulatory olubity g a a d ces d out 1984 rs DA) change of ation s crucial til Al tanc 1 in t n e m e l p m or i brings era, ma x hyd c hyp us po me t sh c f so be e de s hi av mat c dr br a f f is c R. of dr or ol or e. ar ar ha pp on of 6/25/09 3:14PMPage20 abr A st o u throughout ai e o l t l l ug u m m PIs , h and to bo x bo y d ir ad ws g o n ll ER o While l t r r h r la polymers de bl e e i r im aR j ab m ox y o i wi s, e en yr u u yl c ca 1. A oll h c u me me bil d eviated in ovatr mo s relas la la er reg e yd r veloping se ym e F pr excip ents. l um ng ge ti o esolution s e s a e l Re safety tho o and ing or re ti o tio e pr o DA s in H in he wh s ity : r d ll n ro p ovi l o , ula s lu l le ns a multipe P o t d d a lub ns ns w an in nc ugh , it p lo n th a en re se ep ep MC p po as hy -r de c ot e s i- hi l pot ss at os to y be c yl c d e ost hy e c i e ili us e e TC A R T S B A lc st in dro pu l er - mod ulation s [h g oc d new Si ah gi yr t on e framewor th ic p n n ro ncy t he p ur il dr o ent el l ty w he el e is -e wi o an a yd den den (H st ia ro f e companies. sw devlopin g l ta b . ar us e a o phi ly el to g lu l 3- 7 ff er ul i som ted c u a ma r th r years Using i us ph i yp s ia e drug l-d l ER e c extended ox ni n ec so s il e t. t po l ed e w o b no th os lic ll a cur en t e t pH l ve e d t of se ro tr pta H ti at e l he yp oo fo oc wi yl li c s fod r e ub e, y r a n g technolgy of ym e o bl ic ve ug ls , m o pol -d f io it s k, mr en ra i u ume r th th aplication or r- we nc s is e e r s ili . op blends m m el nme H 2 od i e nic od s m l in s a r e from es po which ym ul a p H ab M t e, E el a r os new a P ve ER pp r e y y efct) a en i, o tr i iu m e chaleng es xh nt R i P MC ER um l ea Patent, n ly w ol il xi d n a e, po relas i r t t er MC s c u de , ce io nd ed Ph i ov id e m h u ibi ne se ma ty o fa wh H p matri ces lym hyd rophil c ydr pharmaceutical t a P b n, i e. of mm s , n al g er ed H n as hinde ed le c P , e t pr t , t, th D tr o r tur xt en T platforms s su g - MC pH ER b in l o a oph aproved er s ix in a e i of e a ab lo b y h ob t ng e on l en (ANDA). g c market e c i r e, (ER) a av d r - h ER , fa an le nd at les )] te ur s r ili al f y ai s r e m y e s iv (size a r o . e- , , d of 1 , g c s n form ulation s. r aproval e formulation matrix share ar polymer limta on s The s e excip ents being net protecion, of sytems 3. 2. 4. s new result of may c re for A ma dr D la in H hy wh ne th a of fe le in on dr s for E va pH of pr o a dev n i The o h t c R ye tr i ad P e P st d i e u u for id lub r al ar dr a t ti a a t t ve m il e tri -i n ia a I MC he il f g g he he exc ea ric elopd, dr st hyd bu r. s for l i dmi s s new folwin g t en c to u b be t l lo x le a o is . ti he e (eg se high de ug le lat th e ti 6, ma g b d m te d t o ip ents CM P H on pin 12-14 fo gi e. c m r ons as ur s ur ER and ma or overcom e r the nis pe a . o ed of o b ion su r 15 n y mr u ba ay 500 chemical phi tr n i g po l to to powerful ,1 g g oa nd e p T t ia tr i s aplications. tr oi n e 6 do swa on fa si fr s ra is an r hi s a xh very be b extension T . a f v li t el ym c 8 n la c om of he or e te c t se ct -11 h t a nt es c te ion o outside ca ea ibi e si ll i specif caly ti dr is ER a import nt ic m b la ma st In ve er ow ff o 100 z r of APIs , E us m se eh ug s t al slow t a h bi e n in a he bi ec d R a thes p yr fo as u a s t e ly h av i th e entiy in of l uri of fo ri id o y strategy oa nd e p it 0 te yd pe , od l of s me x s g ro t b y i r exhi ur th d t t m ant ng v or lig di ns h , . pace ee roph ra h once- t rf ma of 5 ve a ove i rgo de he e e b f e ec g) s gh il o o ct c a htl n h This f y s fa yr re l fe t r a a a c bi tr ol ut pe as w t area ub a ma th i e b ive se ra e th e ma s il y do s ix , bl le c it t s of il tin s nding ic o t an l l b to s, ol an a h s e e i l nc e se ught io n y e t , s ge l t pH g y d ub l s en a e i e or of , e 20-27-DDT Jul-Aug 9- Excipient Update:Layout 1 6/25/09 3:14 PM Page 21 20-27-DDT Jul-Aug 9- Excipient Update:Layout 1 6/25/09 3:14 PM Page 22

to be attributed to the difference in the formulation of extreme drug solubilities from the gel layer. In this case, it is critical to hydrodynamic activity of the coupled with a high dose is challenging. Drug have a strong gel layer through which gastrointestinal tract following solubility is an important factor determining diffusion can occur and hence, high viscosity postprandial dosing. the mechanism of drug release from HPMC grades of HPMC (METHOCEL Premium hydrophilic matrices, influencing the choice of K4M, K15M, or K100M) are recommended in There has been a keen interest amongst polymer viscosity, chemistry, and other their formulations. 24 For successful ER of formulation scientists to develop new excipients. 20-23 Use of an appropriate viscosity drugs, either soluble or insoluble, it is polymeric excipients to overcome some or all grade will enable a formulation scientist to essential that polymer hydration and surface of the aforementioned challenges. However, design matrices based on diffusion, diffusion gel layer formation is quick and consistent in due to regulatory constraints, high costs, and and erosion, or via erosion mechanisms. order to prevent immediate tablet time requirements for the development of a Practically insoluble drugs (eg, solubility < disintegration and premature drug release. For new polymeric substance, establishing its 0.01 mg/mL) may dissolve slowly and have this reason, polymers for hydrophilic matrices safety profile, and gaining market acceptance, slow diffusion through the gel layer of a can be supplied with a small particle size there has been very few, if any, new polymeric hydrophilic matrix. 5 Therefore, the main range (eg, METHOCEL CR or Controlled excipients that have been introduced in the mechanism of release would be through Release grades) for rapid polymer hydration pharmaceutical market in recent years. 17-19 surface erosion of the hydrated matrix. In and consistent formation of the gel layer on Therefore, efforts have been focused on these cases, the control over matrix erosion to the surface of the tablet. 5,25 combining approved polymers of different achieve consistent ER throughout the GI tract Depending on drug solubility, it may be viscosities and/or chemistries to circumvent is critical, hence, low viscosity grades of necessary to blend different viscosity and resolve the aforementioned issues and HPMC (eg, METHOCEL Premium K100LV polymers to obtain intermediate viscosity achieve optimized drug release characteristics or E50LV) that provide adequate erosion are grades of HPMC and achieve desired release and product performance. HPMC is typically recommended. For drugs with very high water kinetics. METHOCEL Premium products of used as the primary polymer, and other solubility, the drug dissolves within the gel the same substitution type, but of different approved polymer(s) have been added to layer (even with small amounts of free water) viscosity grades, can be blended to obtain an enhance functionality and as a tool to and diffuses out into the media. Therefore, it is intermediate viscosity grade. The following modulate the drug release profile. Here, important to ensure integrity of the gel layer mathematical relationship (Equation 1), which blends of HPMC with other polymers, after the drug has been dissolved and released is based on the Phillipof equation, can be used including ionic, nonionic, and water-insoluble polymers, are discussed. FIGURE 1

COMBINATIONS OF DIFFERENT HPMC POLYMERS

HPMC is mixed alkyl hydroxyalkyl cellulose ether containing methoxyl and hydroxypropoxyl as substituent groups on the cellulose backbone. HPMC is a nonionic water- 7 o

N soluble polymer, and hence, the possibility of 9

l chemical interaction or complexation with other o V formulation components is greatly reduced, and 9

0 the hydration and gel formation of its matrices 0 2 are pH-independent. HPMC is available t s u

g commercially from Dow Chemical Company u

A TM

/ under the trade name METHOCEL , premium y l 3-5 u

J cellulose ethers. High molecular weight

y METHOCEL Premium K (hypromellose 2208, g o l

o USP) and E (hypromellose 2910 USP) n h

c chemistries are the most widely used in ER TM

e Drug release profile of nifedipine from matrices containing 10% drug, 30% METHOCEL K100 LV CR, T TM ® y matrix formulations and are represented r or combination of METHOCEL K15M CR + E15LV, 59% (Fast-flo lactose or Starch 1500 , partially e v

i pregelantinized maize starch) and 0.5% w/w of Cab-O-Sil and magnesium stearate. Dissolution l worldwide by Colorcon, Inc. e D Drug solubility and dose are the most study was performed using USP apparatus II at 100 (or 150) rpm and 900 ml of simulated gastric g u

r fluid without enzymes containing 0.5% w/v sodium lauryl sulfate.

D important factors to consider in the design of HPMC ER matrices. In general, ER 22 20-27-DDT Jul-Aug 9- Excipient Update:Layout 1 6/25/09 3:14 PM Page 23 20-27-DDT Jul-Aug 9- Excipient Update:Layout 1 6/25/09 3:14 PM Page 24

HPMC & IONIC HYDROPHILIC FIGUR E 2 POLYMERS

Combination of HPMC and polymethacrylates, most notably anionic polymers (Eudragit L100 55) in hydrophilic matrices, has been reported for developing pH-independent release profiles for weakly basic drugs.9,10 The incorporation of anionic polymers in the matrix can influence drug release in basic media by lowering the micro- environmental pH and also retard the drug release in acidic media by forming an insoluble mass, which acts as a barrier to drug diffusion. Moreover, because these enteric polymers have comparatively high molecular weights, they show longer residence time within the matrix gel layer, possibly facilitating their pH modulation effect to last longer compared to “smaller molecular weight” acids, such as citric acid.9,31 In Verapamil hydrochloride release from matrices containing 48% drug, 20% METHOCELTM K100 LV CR, or addition to the control of micro-environmental combination of 20% K100 LV CR + 8% PVAP, qs% Fast-flo lactose and 0.5% w/w each of Cab-O-Sil and pH, anionic polymers may also alter the gel magnesium stearate. Dissolution study was performed using USP apparatus II at 50 RPM, 900 ml of strength and erosion rate of the matrix and simulated gastric fluid (0 to 1 hrs) and intestinal fluid (2 to 8 hrs) without enzymes. therefore, release rate of the drug. Similar to the development of pH-independent matrices for basic drugs, incorporation of cationic for calculating the viscosity of the blend faster dissolution rate resulted when the paddle polymethycrylate polymers in HPMC matrices product.25 speed was increased from 100 to 150 rpm has been reported for developing pH- (Figure 1). Such in vitro behavior may indicate independent ER matrices for weakly acidic Equation 1. a variable in vivo release rate and possibly food drugs. Combining of Eudragit E 100 with effect.16,27,28 The study showed that a blend of HPMC matrices has been shown to result in high-viscosity grade HPMC (METHOCEL pH-independent release for acidic drugs, such K15M Premium CR) to increase the gel as divalproex sodium.31 This effect has been strength, and a low-viscosity grade HPMC attributed to the enhanced solubility and (METHOCEL E15 Premium LV) to allow for hence, release of the drug in acidic media and consistent erosion can be used to achieve the retardation of the drug release in basic media. 7 Where , , and are the solution desired release profile and meet the USP ® o hB h1 h2 Polyvinyl acetate phthalate (Phthalavin , N viscosity in mPas for polymer blend, polymer requirements. Blending of these two viscosity-

9 Colorcon) is another enteric polymer used in l

o one, and polymer two respectively, and X and grade polymers produced matrices with V 1 combination with HPMC to control the micro- X are the weight fractions of polymer one and improved release characteristics that exhibited 9 2 enviornmental pH and enhance matrix 0

0 two, respectively. The influence of blending similar dissolution profiles at agitation speeds 2 properties, such as gel strength and erosion. t

s different polymer viscosity grades on an eroding of 100 and 150 rpm, respectively. u Combining PVAP with HPMC to formulate g

u HPMC matrix of a practically insoluble drug, The strategy of blending high- and low- A matrices containing verapamil hydrochloride / 26 y

l nifedipine is shown in Figure 1. Erosion is the viscosity grades of HPMC has also been 32

u (HCl) has been reported. When the J principal mechanism of drug release for this reported for achieving the zero-order release formulation was subjected to dissolution y g

o formulation, containing a very slightly soluble profile from matrix formulations and for l according to USP 28 (Method 1) in simulated o

n drug and therefore, a low viscosity grade of reducing the drug release variability (low % h gastric fluid (0 to 1 hours) followed by c e T polymer (ie, METHOCEL K100 Premium LV Relative Standard Deviation, % RSD), thereby intestinal fluid (2 to 8 hours), slower drug y r

e CR) was used. It was observed that although providing more uniform clinical levels of the v release was observed for blends of HPMC and i l 29,30 e the dissolution profile of the formulation was drug. D PVAP compositions as compared to the single g

u within the USP requirement, it showed r HPMC polymer matrix (Figure 2). Similar to D dependency on hydrodynamic conditions, ie, a polymethacrylates, PVAP is soluble in 24 20-27-DDT Jul-Aug 9- Excipient Update:Layout 1 7/7/09 1:04 PM Page 25

simulated intestinal fluid as it is expected to behave like a soluble filler and result in a T ABLE 1 faster drug release rate. It has been proposed FDA Registered Oral ER Formulations Containing Commonly Used Hydrophilic or Water-Insoluble that the retardation of drug release is Polymers# attributable to the synergistic interaction between PVAP and HPMC, resulting in the formation of a stronger gel layer and consequent slower diffusion and erosion rates. Sodium alginate has also been used within HPMC matrices to obtain a pH- independent release profile for basic drugs.33,34 It has been reported that at low pH (in gastric environment), sodium alginate precipitates in the hydrated gel layer as alginic acid. This alginic acid then provides a firm structure to the gel and retards rate of erosion. Solubility of basic drugs at this pH is high, hence diffusion through the matrix gel layer predominates as a mechanism of drug release. At higher pH values, the alginate remains as the soluble salt, thus providing less resistance to erosion. Erosion of the matrix facilitates release of the drug substance at these pH values, where drug solubility is reduced due to higher environmental pH. The balance of erosive and diffusive mechanisms at the pH extremes may explain the pH-independent 43 drug release. This balance is required to be polymer and cationic drug also played an formulated with HPMC. 40 optimized for each new drug candidate to be important role. Freely soluble cationic drugs Combination of HPMC with carbomers incorporated, principally ensuring an adequate have been reported to be released slower from has been studied for achieving ER 44,45 erosion rate at higher pH values compensate combinations of HPMC and Na CMC characteristics for various drugs. The for the fall-off in driving force for matrices than when formulated with HPMC reported advantages with the use of this blend diffusion/dissolution-mediated release as drug alone, an effect attributed to drug/polymer composition were the use of low levels of the solubility decreases. There are commercially interaction. However, for less-soluble drugs, total polymer in the matrix, flexibility in drug available ER matrices using the combination which are released principally by erosion, this release modulation, and ability to extend the of HPMC and sodium alginate.35 effect has been reported to be reversed. There release of some cationic drugs. Sodium carboxymethylcellulose (Na are commercially available ER matrices using Recently, the work of our research group 41 7

combinations of HPMC and Na CMC. has shown that combining HPMC with o

CMC) has been reported to have synergistic N 36- hydrogen-bonding interactions with HPMC. Combination of HPMC with xanthan carbomer and polyvinyl acetate phthalate 9 l

38 o Baveja et al reported combining HPMC with gum has been reported to result in greater (PVAP) in a matrix system resulted in slower V

retardation in drug release profile compared to drug release as compared to matrices 9

Na CMC may result into zero-order release 0

12,42 0 profiles for the drugs propranolol single polymer systems. Rapid hydration of comprising single or binary polymer 2 t

46 s

xanthan gum combined with firm gel strength systems. This has been related to a u

hydrochloride, metoprolol tartrate, oxprenolol g 39 u of HPMC have been attributed to slower drug synergistic increase in the viscosity, and A

hydrochloride, and alprenolol hydrochloride. / y l

The authors postulated that the polymers release of high-solubility APIs. In this system, therefore gel strength, of the matrix, possibly u the initial burst release, which is typical of due to stronger hydrogen bonding between - J

showed a synergistic increase in viscosity, y g o which allowed erosion to occur at a rate highly soluble drugs, was controlled by rapid OH groups of HPMC and the carboxylic l o n

hydration of xanthan gum, whereas groups of the carbomer or PVAP. This stronger h

equating to the movement of the front between c e subsequent drug release and matrix integrity hydrogen-bonding between the polymers T

the glassy and the rubbery polymer. However, y r

12 e

were maintained by the firm gel of HPMC. resulted in a more rigid structure through v i

it was later confirmed that enhancement in l e viscosity was not solely responsible for The rapid gel formation property of xanthan which drug diffusion can occur. The influence D g u

gum has also been exploited in gas-generating of combination of carbomer, PVAP, and r

modulating the drug release profile, but that D the complex formation between the anionic gastro-retentive matrices of ciprofloxacin HPMC blend in a matrix formulation of a 25 20-27-DDT

26 Drug Delivery Technology July/August 2009 Vol 9 No 7 t m 3 o r so T f si p p p a l p P b e st st l t m u t he ay ar he ab el omr lon nvi . f ro ol ol hen ene se VA CR, Drug-elas lactose aprtus hi gn r abi 47 at at l eng ger eas th ub er let ym ym il f s ma ov ri ri It of i if ro e P e li ic f ome ul a or T ma y ces ces le ( Jul-Aug e , e w ty er mat th w nme er er mi dose ma t ca n he t tr and his th a combinat ial p as dur ei ti al ix and of com ro wa b cr at co non on ght r l r tly i le n ri . ob s t es u nta f ix: nd i il f o- b cost g, I H som or nta S o t x s was len o wh e 0.5% ve s uc at envi par PMC d sl ow e u c l bl Gu profile lt ca t 7 evr ed im b t ini se d. an pH in ra re su o s .4 d h 10 en d e e o ed si m 9- n e ai sh provin ll f be ng ron also p acc b w/ vi er to im ) oly a th t f asic (3. l ow rpm t lt ed he of en t ower f p o il ar ac t of ro the th si 8. p me at Excipient o ommod h ro 5 mer METHOCL ro es in , HPMC re mr u ed mi la r at Cab-OSil 2 an f hieved, guaifens o similar d d g ina to and ) ntal ve in sulted to b n , ur g uc th th the p len th e wh 4 la ti o o a l oly e 3 p ed at is . e ca n 90 r d s. 0% 5) ro le pH dur d di ss o ated ic e so osa H 1 sh s mer ve matric h cessin x and Moreo h n in within to 5 PM C igh lub (c cipien ml TM ac h g and ow n o HP MC % l ge may w f low arbo or HPMC o K4M re le as e lu ti o from as of in Update:Layout er ility can HPMC f o ieve fo magnesiu f lower g, es, clusion to deionz in er ver, gel b t-sparing mr . t mer, th CR n ta l h re e matrices allow or F micro- I F e they e a al on e. p duce ig ur e as + to ta l ro f gel The dur g carbome E R U G the in i le water. stear. contaig HP c w/ sy a Wh li p poin c vari pro ot he me tf th e rg an c ma tr sh ex c on lc on on on and s o h w o o 1 te M ce w c c c ib il e d po ed p h r ts, u or ix e e e Disolutn it ms o h Co n o C s i la so nt nt nt 3 yl polyvin s r t i il ic sin ls mi n, o d 69% ed o p 6/25/09 3:14PMPage26 b s L A fa M P H tio mo r ra tio ratio ra tio w u n e mb ib n , o le to rg rc e e tty g s. or t it h le s il i n. nd s. ma e r C 48 p e i o nt drug, e a es e 51 nat t s ns ns, ns w es r f a y s O H O l o te r ia to ip hi ci ha C HP a 49 vi s o acet io ar c o l h ( x e d op study g bec i f ≤ How t ve de es f a in a n s 15% h ai n & MC v ni ls si su hi 7. l he s o lo e y a ha sh aus , S L E ch tiv r o 5% b li cce ch F pr r r so ev R. f w le was c ve or ow e AY T T f su t it y phtale, od u i e HP or h l a nd ma er, 6,50 e ss. ub ap p 30% w e xes gg e vi of b n mu O t ed perfomd ee dr /w M 49, Wh il o ng t co m ce th e t R li e 50 he st n ug m r h l C e ) METHOCL at d ca a i ac yd r t Lo ed al e r wi ti ay A f h ir WE X A mi a b e ti n a l re l o s e ti nd o por qs% i il D I C on w- th low l n na od y u ve w e at xed E ev u ea s s na s r R f me ed t HP , t b h e el i at using ed se fo on su g bl Fast-flo na y ig m of of s S re s ty lt at MC e r TM m S h el pr s w mi c of , in ge su er su c a u K4M hi of t el it of ci in g USP l 2 h ch t st t gh ha s 0% ds, il g h . in e v , g e in re mat io th s per pol re th s c re an in dos re new s re mat co A has A c m to nu me a s s l H a w re av H th re a tr a ho uc ol ha a s pp ye P P o id P ta ta g l l s t ni e a de a e fe so a pac d mp at h pr ea ea en ul ub i we tr t yme u fo I I MC il h w l ag r r r c up p ric ric e ydr c r be ty s s l e egy pe c la b da da oa i a ev p ha se se eng tin l ti o . , Co H H x Y H a r r o ia a y ro l 52 a i ve b e p o o li t ma t en po t en s t e e r f a nd t t nd c ,5 3 or P yd en le s y oph H- l te s lym e io io s ri g er s s pr ch n fo us nd and l h y m po th r y i MC tu d . es to en ds , on c of d y In to ent s nc D n n t in u r p en a P H T i of mr de f e b AP n ar th p te o t d t pr o n se o th ro ex ili m ges w c o er a he i in ha oni e re R ar p o e. ie d re PE a na ti ad m ac d r e r er o PE pe ch nt i . le e d it hi du at f c s ar re and c ci ic C nh ma 53 Is a O ns t o s s M t in s du c e hie Co te h t a dit ph l h o b ha nde ul e ie f r O of li c m io el e ke le pie O ob al , T O a be an dd c P or al tr exc e an ni urs g f a ri C hyd nd in s c ve t ts h oo d as n a s ar ion re m le N ve a an L I H t ha iz pol dr h en b sti s ga ts t c d c er tr iti ma nt d ce nt i s o m be e a o ar u e t us ma tiv nts bin & i e C ur ic p a t ove po u s vr s ac cc pi e ro cs f st li in s on r ex , r ac d odu at y ti nd a pr o g ma en s s li el U L tr i e ing es m b H e the g r a ha c en ed ol t , l ll ph i ce ep ce ly a ff t g mi CI N O I N O N pa oi (e ym h e C I t r an of r t ea r rc c P of r d x he it t de el er a e i e ubi i opt r e tr me ve s to ion e ts la pt ut o bu ta n t e el MC ep st ed nde w n om c ile ta om e t d SN O I S h se l l e hi sy s i c i v st te he e li ic e ti x, ion st t e bil ic yl ase ro- iv m t om m it , e u ti r t LO P ort be prod as li rs i ve o gh-s , s d ng st s ed i mi du of al s h a e on s er en sy cs ar m t d te r a e odul c it of ed y. e ov in f a n ic a r ed e yr h n nha ed m ly om or s h c e p y y. n ms e ke a s z sw d ste n t dur e hi av w d ome o al h ydro o te ro , D tr d w e e u uc H p e a t i of f f ob ta R E M Y o a a al I ghl r t to w it dr o n rc c e oly ix n e a el n at bin ms. or el e de nc pl a HP t f com P ppr t x t ha v in g s t h pow le r t ve i he i the HP wa i str be id l ugs M t e ta io l l E a th p a i s he si e ed i y phi g re hi o ng e hi g me c ng a c ng r C ll ys t R 5 lop i t b s e) ove n C e o r 5- o t re ge ni he e t e. s s di e l y gh M l . io 57 n e v n e 5 is ol d a g , o i lic tha rs b 3,54 h- d s ng [PE rf e n w t ff id a s l g ing l r a T n f C us ho he hin d S e l ub m se ug er l do st ul u dr i t e h e the a ha o o th h t si e pH - s se y w n r is le f O] f e ug ge a g , d o- se er t o s n nd o n . l 20-27-DDT whi drug envi 1. re bee 2. 3. 4. 5 6 7. 8. 9. 26 10 11 1 25 1 14 15 16 17 18 20 27 19 21 24 22 23 . . 2 3 ...... H 1963 r I w A 2 c Li de T Vo te T f ma Ra S pa H S Re we Ta e 2 lea at na orm ontr nha 009 006 w tm w G Ta a s G 1992 f G nif D f xa D r e S H U 136. ma c D in 294, S Ta pha P U 1) pr gui Expo S A me dru Ba 1999 ba S 1756 "s 2001 M D im S H tru tr iwar iwar c iguc ww lde PM ro orm el us li rt cr ff ompo ta e ci te ha ie ie ie l. ja le a C hnol e n tr ww otho ww ab ow ohe ia ua S av ch br ev og ve ct e :14 e ch ETH nth s ve ta mul e . pr kl ec ube e ld v m ctur tr c ro yli que of sen e inb ta pma da pma pma L, i bi a 4, ed g 43 nc rm s rm ulat ive as ;52: . ;95( rmac ol s. di P ah D .a x arti is v st r ng iya ha C se a nti 315. s i i y i ry. ri oved Jul-Aug I hi t ulat ine ;38( ;33( . ;48( V, .c .do - s at x- 9. si deli arti n e. l Ex in an nc . nd cc K c at le e e pine ig s re S S s 7. Si og M c am sk ina l on erg J, an ac bas te tab nis nt M e nm si tud ys P me st ti olor hown en O ma J. B, B, i T. co k X ion er a . nn nn nn e A d- f 1145 ma Go ate 7) 200 l e e. J A ng d a w.com ape ci d on. art r ar ti H ea ie Bu s a gu ci ion ia eu E Ph e CEL ve s 6) 1) 2- , te , pr A om hboom P s ac s , H t J m t D lets hyd P r nd ntr , ic : on Mec ut r s nt ie pie A m R M M, a . so s uma Regul ff P d l Br e 1459- red S J, J, J, s N e ( thos s m. da A har c M tic C, ini , H P m. : : 3) . ydr o : ry: th t s arm. rto 0;67 P c le a e a r 199- 27- us l s ic aja le nnu ec V on. ie a dr A pol M ur har ol f ay o n o. o ent -1 mo e t , r K Pe Pe oag be ofil harm a f y a nt hy : the p . ro e ta a pr he of of a ikh a us a ie TM Borzelleca ie f s f r 139- pmann Wei t A tai D z t nd m A n LG, hani ug le B, re se R o thy e l ran na r ee 149. e se l /do bi-Siahb r a s kar s. e .f 32. 6, co el ppas ppas ha xyp m a ym a of nna am nt pr e al ht m xypropyl e r A noli i ias (1 ex 1989; A Exc ff egulat d J, wat i s ma Ce 1 20 s Cont ne e da ng ne ct " vie T d: P 368,6 w Techn S. oli e d Ro pr ent AR, R vi hydroph m. o f 4 a omell PS C. P e z P ne wexci ) t al M dr oxi aceut search har TK, organ ci Co S mo toprol ic rom 157 osage nha adol sm ers A f c 68. d eakly 2 w : .go Ford ro ll ress: , , V S o t e, K, ed May or 101-11 H, w thi ci. NMR er d Mi t ical i pient . all r ug Austria; os foo eet e ulo Nagori NA NA , , O pient release Date pyl Phar nnor col roll of Phar m J, mac d del). REF 15(6): M. dr icti Rajabi F v/scri of in . B or o of c m Augsburg n pH y 28. B not croenvi 2 Pai eg water-i ical K, oomi ing ose odel ical del at Dashevsky n hy se d pient but ugs ic owt . . 009; food matri T mo JL, ol obi 9- y odm the i 31, methy ed hydrop f cel m b ng Phar nce sust s. J, A nsolu for M Hydroph ely the ot effect o s o mSciTech. il the mSci drochlori asi i accessed: Sj statu aci A, E Seth iver 0. M Phar ethyl magin l su rm an i En The Coun (HPM p Present owa, del lit odeli el . ne exci lul Release 975-999 c the d Rober S, im th com -Si ogren m 20 98(4):15 ts/cder/ s/resources/p ap ei 20 ained-action c AR R, 2006. K, cci rel ds ispersed c on l x MacR d American y macol. mat o s. w ters nsol e ro y atrix ose bl er dru also RW por Jena lcellu 09. r s Tech ER proved ; to ah on system m 05;5 Expo and P Excipient cel ease s Saf pient hil release M nly nate Int on R er systems. nment ap . so e a . ng 200 bini of NJ;2 c g. R rices. ( boomi C) Ext pred Sust ajabi-Si i Res. g , tance ehta ili ts uble E, Cont dru HPMC ethers ic l. lul J. proa atio L, A, , de et t Ma excip J t ae Pharm of trol di 7(5):5 D. i fro he . Pepp So abl c May 2. lose lu ng . R M. ig/ sit per matr Inve usi y mat 200 2 Kin 68- Pharm end ose deve 008 g) Ho EN ffusi 20 B ma aine in usin egu ict s. 000 drug ns. al R drug nsfie mod Co Fa ciety m PR 20 re i ro an allow c ets. in J k d od on ng Asso fo b Th an , h 09 u 15 A In rix i 3 a soli ie e osh iff p lea in P su stigat tri as br lle :2 d ( ne ice th Wild J 31 d- 00 hy ah sin ro mmitt l g me d 3 Web ; rm ;3 lo , HPMC) mod mei ility H on to . d g . h d ex nts : 4 e ;1 Res. 7 hyd To Co - 3- 1 o usi ica E sta ces e Ch San sol Co hyd d a ld tics. S d re N ( se p bo Jai d r 2 , pme ;1 sust 6. r hy Te s: ita d m 3 7 u g CE 3 mo 0( rm ele . ur an th cia d e uc r . ro ro ( 54 2 co c f xic Re A. 3 - lea se esu er ) 7( ntr 2) ine on le i tio ic ma ow in ech P, site om I 2 ub ion hy f 0 n ifie sup r p ch dr n e :E n 1) ify r f ce du nf ph ro m. t/me F, o J ase d 6. 4 e ef 0 tro tio An a a d 1 ain or atio 10 :2 th g S nt lea Ph o R sa ol se , Dav xy K HPMC op Ja ol n e :6 pr le 3. tte 3 se 9 d u 99 Ph da ltin tri lue ph An ficie i Pr c cts. f an Lo ilic s d 10 . p o I micro- . 1 : . o la n K, visi ): llin D o o fet o co i. we pa 2- A. to S . om ed r arm p P A h se) hy ressi f f Rele ma rns . ces. p o f ry th e 6; n p tho ele a f ili od r f 12 isms ro t S o nc ro a ilic . g n p h ie H- 2 ele r nio w r io 68 rm : h dv the p nt n. y t m te e ed f mat a 13 llin cin p We ua er a g c Mo 00 re he ted . nt ello m arma th ran P pyl tri d s 90 eak l e ase n gel rmac ro ce ro Mfr. P a o n Web ind . od stab ase Dru R ma rug the B. -ma on . ase J a lea , d s MC (3 l Dru Update:Layout eo ssessme A an Bio f ha 4; o eed x tigr b de bsi g, mell - cc In lled : T l/me Me r ric o es. d d Meet Ph in f 1 ified se we ased ly , u ):3 m 93 ta ep tec ret f d Con X; ula ial tr rm se of . 2 tern liv me essed ceu Mit g an r f g d tric re te site es. ol , p 1 g b ap ethy arm ic e ormu t ble 98 2 tho b hy m fo 1 ak en (9 7 he ica ha Me 9 de ur lea ose d hn layer, I d th 00 ace lea tio ery th a d 2 e . ru 9 D e 6- v th nf hi 8 atr ing ru ili tic r tr . osa sic ch dr es ):2 ff atio re 00 ly s 1 9 re d J ts. st isite _p rm e d liv disso 4 eli v ol ge l 1 a p 38 nt se n oll lc 9 or c 9 e e se l : f S g Ph s ut lea op ; le isit ice al e ia c ;73 in an in re 6 n o syste la 9 c ba ;1 f 3 5( g re og May re ge e ery ci. stu o v J dru l ty ll ry . an or Mo 0. n de ts . t r o ica 6 ed a 19 o J. llu k itia tio cli f h a d: 6( lea laye CD al 3) Con se sen al o sic se s. f Re ;24 ed r f y or D (2 lic in rm ob lu d d e on liv dy f ra co . -2 ysis gs 11 l lo :1- nic rel o n l , le rug Pa al etic l : se ms -3 D tio ta v of . 31 l rm tati ic (2 Bi d 33 ery: ntr a r se . bu a o tr Sc ): to ru d f ease b 9. ): rug pe n al se f o in n ro , ol , 17 ol. le ru 1 d o s s: 1 ol rst on f an g i. U Pt r . f 2 m t (th o g s an 48 led K- 1 d s.h f - e a - 5 5 5 5 4 5 4 4 4 4 3 4 4 4 3 4 3 4 5 3 5 5 3 3 3 3 3 3 2 2 3. 2. 1. 4. 1. 0. 9. 0. 7. 6. 9. 5. 8. 4. 8. 3. 7. 7. 2. 6. 6. 5. 4. 5. 3. 2. 1. 0. 9. 8. O U M G s U G Bi k H W L D b T Ba M T 2 c Re P b p S M 5 w h 2 1 io c E w a c o D P me r U Co T M c E 2 A f V p 3 Co M 3 w e Vu f h U a T Ca in 1 U 1 m Re U Ra W J H U 2 ta me S h 1 ele or or u o a o t o h th c y y len in e 0 ro S 0 9 f 0 o 1 1 ttp 9 9 0 ec ec h a h c iwa imm o x bu ar bl pt S lu S lu os ab ww ww ev S AP ww S S S PM S n d a r c s s a o a a a O/2 O/2 ta- n n a ol d d th m 0 0 8 0 ly , , h 8 9 0 ar an ar v g o h le p la o e n n m m b er c tr th tai e ic e hi e f cr rt tric tric sh r h h d d t ro e ro a ima me c 3; 9. 9; 5; o 8. 7; 3; 2 2 :/ P P P P P P P ej x b e s ra os b i ha b ti ti d ox ac tic ro pe ile m e ss an as ic n V, ma ma n n u ts s o it in u u Sc ad ri a d o lz S 0 0 p . . . a /p a a a a a a a a e ag C; K s p a n o 55 6( 31 2( 55 a ch p P e M ® ex lu med y ol ol l 0 0 Am i p in la la S, S, io it ip d 0 0 e t t t t t t t e lle e e re . te n e e e n ati ns y n s . s t i o e s hi M e e e e e e e NK P f ac S, E 0 0 P r A h 6/25/09 3:14PMPage27 r S d i. s S l za L 9 9 o io We c c s s 4 1 br is h B, az d . . o tio tio me d d , Dr lo nt nt nt nt nt nt nt ly c en n R. S b Ti ( ( ( , ri n o o o ; h 19 5/ 7/ a n M : . . e e f d R. p , M M lic r 3) ):3 7) ):2 4) , , on en r 19 19 ip L Ga k co co s e m 2 n R , P o f f f M ® g a ati 2 z e iz M u u n re g mer r M o ia Ra Tiw w ac Ko 12 01 e T n n , ag . a 0 , u No No No No No No No d J , . r M o lo b at ri , e 9 0 o t :3 :6 :4 P a a tic tic ib d p o ie u h ao ly t , rg o 9 9 mS hy We n n 1 5 ci l We D . 0 A, g H i ru a s ® L ma S a t s o, 1 Ras t gg gg 0 n a o ic r ca n s o o h et p e w io Ta hi l e l 3 0 o 9 7 n e ta ta 5 3 5 -3 4 . tu o up it K, riCo 4; r mer op y s e a . 6. .c f di G, . a a ic as -io el f f ar fi ...... ik s co x t ar in g lc hy 1 3 lo ;4 ;2 A. v t W 1 -3 3 3 K a n te a e d n n n az l l i i in p in in KR, f d bs F c d 1 2 5 6 5 4 2 5 v bs 7( trix te su c 31 o mi er 3 6 ze a c - - - r o t r e e a r m . e h i o s d V, Sc p wi b L, L, fe (3 (2 iT y Qi v mp as ak o r 3 1 6 . 4 e 0 4 2 9 7 0 0 eb i o As n to Die m/ a d r 4 9 M in in n st l id n e llu I it 5 u i . l d lo e Ba it ol L ap S g f s d is rd 55 7. 65 51 03 03 61 48 lo 92 07 09 r. f n ic a S , mix ro y d . . n n A no r e ): ): de a e liv ta ):7 g .n en In r e ie c o y g g B e s ib u o , ce e , S S o e co ts 2 re . me it P ym s t c c t ac clo u ri o r D lo ite z a 3 1 M l H c ab s Ra h g . . . /0 5 6 4 4 /0 8 tis p oc lo Ra i A 0 J e e v ke h. a e co r n A, Y. v ed i h p d Na Na J t . ex g u s mil n er 1 6 a p h u e 7 bm L ta m/ o 9 0 4 5 9 ve g g o t ev E f 0 is s tis H t i , is ar h -r s. p N, J 1 0 g , l ed /a r s 3 1 P re let lo t le ro u tio e ta r 2 ia e , 3 1 0 2 5 a a ly r n c 9 , v jab 2 : y Wy ic ja te , en ro o D it 0 4 e it Ho , h -3 -1 ele s CM CM H r P r ha ja -7 l le le i S. ma . . . . . CA; o me an ts . fi . is a Ru 0 I A se r tio s a o d m es s. . - mer 4 8 pd ed y s. ed Ka al b n hy s d K n A n h Ta es id K n f Ro Ho L se fe re ow 0 n 2 7 les a iu ite In 7 0 3 y i- d o br r fo i- d c f An S e L L t s n ar d an tr a s S 6 u d d h 4 0 r ce m. P ro n : e D ric 6. bi 5 7 st H f ig : o ro n f r fo l d ed Si s C C l se t Si , J m o ze , , t u o ;7 co . . i eas CLA, yce f in or eir wa . . a r ms; w d c m. ard 3 7 m/p /p a s w ro h em 2 d wi ro r Fa in o P ra n m M M n u rel sta lle h D J Z n c Ph C. r e . : ah in . o ahb a u an an y (1 a mi g, 0 t A 2 f mu st hy f nt MC ww. re ro t h a pha ua c ol P A s e g -v r Ph m r g of rd a i dr rom e t 07 t a a C 00 20 J, ms l d Ph a he hl / c e b r i e h 1 a ): h A. A. a ap J t d d a l S ori i 1 ch ch pre duc N p a 1. n a dro o-o l e a a l Dev iv m ea . / i r M A oo s i . ox oo i la 1 a m re nd J 99 or pi ust n h rov p J, . e sw 7; m l/ s n 0 t l HP HP t s V , M O a gl Ra e Gu so M, a a r 68 e o i i e r a b . e d i H-i de M Eff ol s t in 7 , B r s s a S l m r se mi _g MH ic yp ei i c T i m m ro 3 x . i t p rde t pt Th e 5. a e u m F n de t t e ; e B o a t h ri n f s/ c c R e i r p id 33 in e e 2 im j -1 g 3 s h r a MC MC e . . ga m sl ro e d ll n In i i a oc ns yd ge a o h e n im R re f i l ro x ec e ac e re G, nd us n s 0 lt 33 il e B t U 198 c A. u e t in EO EO rom t A. b i ; s y c -a e r 7 d e e in re e r (1 a m e l d 0 , ng ot d m es ic H, se t . c t hu n p se i on , r rod e pro 1 i t e r g s F 4. tz pi i e e t re d a g e osa 3; -S ( Hog c ct d op : : su g z 1 yl l io S as e e D u , 9 h - P ffe Th i 1 ra G, o n Th b p DC e d , , e m nt m a e a n 2) 7; _c o 99 pa pa c le re re t t t e 25 S i a 99 S -2 f ti h le ia a e a of s. m ns/ : re ro C C e s x ve i l e t M. m y h m s nu o us n n ca i a e io g o se n a a nd v ta 3 a c t m w e : le s. e M r v a B na t a hb r r n 7; o o ):1 a a d 13 e ssm F tr d 2 P . .c t r , e l us E de s t e a s e 9 t t H la h ge e ri n l h n la E i s a m n i . nt nt t a l i on po e o e (1- t m l Mi ix e of ne ( a WO n fro h u Z r o nf e yd 2, 1, i of a m fo t r xy l oo tm i se Ex x C . r a 6-1 1-2 S F n rm 4 s n y d y t ab an o fo ix yl J . ro fl e e h r t _ m n e a e t A17 Mo r _ 3 c t a E, l i d ont rm s t y 2): JJ t i 1 x d p r l th sw di r t ue d er a J 3 re u c m sy m tr U U l a c rt a n wit i n s po e si / le l - d ri o co o m ul dro . 99 t r. r o l en s p e 4 ): / 1, e 15 r ble r e , bl P g am a e ss , , c ph h 1 ug l -o i .p x ? o e R Da ma n t s r l pdf s. J. 8 n re a 2. c e l B d ro e at h P a 3 b y si s; o h nt Gre Gre 9 l A, t l A- e n Ame t 9 c n of h ha l 1 c ol a LG, 2 t 1. J. i a y u J df e l ea 9- t r i i , m p m a l sc t i 97 C t. e W i f t et e ; a ll a e d na s se de - rol ja in s. m 009 l r te dro l on i 2 t c rm 2 hi C h i P ri . ut 86 i t d bl os e Ora on ra ric . 45 e a er s p e h F s o o ri P c s 00 of eb 5 sp i b n n g / Da h l o a ha e d n r d Dr Da l gh osi y a i 01 hy e f n f e l e h ME (6) c b A i e. ic c i i a l . na o l ri o ed J . phi or . e ge - c dr r b e e ts . a a B s tro m a si te 1 a r t o h i re a rm o u S n e At f hy l s. nnu c c h t ng r r e se l nd ug t p 88 r t . t y ly n n P : m on e i t a e te ne le i : op ri at i e e a Al io le l m e l o m u rom P P M, a r 7 pe ah dro . l i y ta l. n nd i h e P ss . n dro la e z ac ic on _i , , a a ph nf l ra 1 ri a 6 P a US Ro a a d n s a vi r De e P h a l a i pra a Ve Ve se K t P Dev t c r As 4. c n s b ed e 5-7 d e se ni x r h s s rix n t he p l AB t c il l l fo ha m ic low e c d P o a for s h l m a ta o i u mi e , ch a fo e e ea g le fo on on i Me i e v n P r t y rg rg n se a a : f l om Yo e rm c soc z te for rm s a r a m , m rm u l s or 7 po g d r re na t nc .a M Dev t s ol lo os t bl ni r . mi In s se p rol na na GA; m pr of m T po a d 1 r ua e a e . m re of u v S so mu e sp l ic a ad p bl a e mu i a ri : mi . d e l st t a i e e d e d: s e ng y t is c r D u u n u a nc re c m; AR ly t R ; y a l : c i a e d ix et s d e A . . o e m ti of d a ng l l . hno s in P tr co e se s 2 ev Ma c e e l t t es pa re i me May a t l 31 Da l. P l e on 2 a s 200 l ha . um a a 0 n C ix . p e e G. G. s u l 2 a t . 0 si d in ul t . r 01 te o H- e io ri a s , io k , 00 s l 0 y r te r f n t i o . n e os m. d y n n 5; 8. on n; J . d f d g 7. g e delivery patents. articles, technology pharmaceutics positions Rajabi-Siahboomi a interests Middle Colorcon Liverpool nanotechnology. non-invasive the University, throughout various pharmaceutical an Zydus diagnostics. University, publications chapters PhD He Department nanotechnology investigated Senior Associate has areas Pharmaceutical Research I B East, over stages systems. book Scientist and as are (7 JM of India. Boston, with his Technical of H P A R G O 10 Dr. controlled-release years) and and the in Research Universities drug contributed chapters, of and Novel career. Center, field years the Tiwari in emphasis application conference Africa). drug He He has and delivery, drug pharmaceutical in MA, area Sciences and has Drug has experience Director Nottingham University PhD earned Affairs Director Siahboomi Dr. fellow was to West at Product Senior Dr. held Nottingham Head Scientist also development Dr. Ahmedabad, abstracts, where delivery of Colorcon joining published has His written before Ali to Sandip Tiwari Delivery a in on various worked solid Point, and of post-doctoral presentations over of at Manager, main at participated from Rajabi- Pharmacy his oral Development (Europe, of he technology, the Northeastern I and Colorcon. joining of Colorcon, in and earned dosage BPharm three Scientific B. 75 is S E PA. Inc. and (UK). drug and Mangalore research academic at Systems. over the India, Senior then Tiwari research the Prior in book from his 150 Dr. form and as He in in as he is 27 Drug Delivery Technology July/August 2009 Vol 9 No 7 28-33-DDT

28 Drug Delivery Technology July/August 2009 Vol 9 No 7 - Jul-Aug 09-AdvancedDelivery:Layout16/25/093:16PMPage28 B A S i t r a de f c de s i a pr Ma t de o f pr T t yea a c pr C i wi s s fo co pr ro f ndu s im im nt im s T e or afety ys pra ddi l n dm ha y CS osu r qui od o ocedur mr es vi yt v l r a mp ou : t m e t s y r mul iv vi ho ut tem e e nu e-c r rs. el od ne y ne ce hin e a t De in uct Th e e c a o r P ion ul and to r di n opm vr a ct tr en s fac em ry uce e pat is t w s, and ons wl Wor at y at , e g genh . ma sys te al nd s r g c th ra ti ion suc sys te i now Due tu dur g ur ent y e i t Ca tha m d on ha ze ent enr . ve uming de s he hi gh e ti c eficf a rket re ld has de es ubs oney ne ha s, on rac d, h s. rt ard us e -fr t velo a flow rs m wide pr velo pro ri nd ca w m t ha mi a dru lle Co a ap o The -p e equ ee b s d te dg o is oc ( nd n s g CC ec ev Ma th a c of f n cr sp pr c to p al riz S P C ( mp bu g y. uid re d e p to ge e s , b rf e v i t ess CC p me is e o ic ob r s low s y e ray o ss ed e c ag ol a rx P e m or nt T ed S) me s sir able . i v ste s, on d spe n es are d th li able co eli n nte u do in he ia ig nt a S eet el e of mi n and , mp m a as l an p Ph nc b str ess m. mp l ca n s a od pp ivered n and a gral um y a p ul i nd es in dr e hav ts d d th nd th ie D h uc wit to g y a ro sh S ti- lex terg i t to ar ug i d , th mu ese s na e to ps, u co y n u a Ap me ti va ev well - or to t do e se mac h re st gh e ) co smo he ity on re c mi n in ch by ic es . ten l em on or d p spo tr ib ta th se nta in ce as , cre ase y ru res ent a c i o al e l- e sis te m nd ot sp nt pu f uti n g p th a (C nsi fre ut dr or h t eci al e he er e mp ca PS u h c a o r the e bl e n g by a l t e ) P R l one engt Comparisn pum High-sped ar s s e r O C ely or Dev hy E H T PM A and o t mor is and el e z i r u a a opi e camer f F of CPS Y T I L I B I T H T mul or e v e D chal a M R O ng materils ct E nasl, ive l a engi SY pictures at m for AL U i i ng using d ME T S on ng used r l ul edi B N O I T j n i p o r Ma ust of pr at deionz T E in ent the oces i on the a W s thre s E i w convetial & s. i m s E R U G I F E R U G I F N E i t water a pl t e k h g phase e t as e h folwing mediu. n e m n o r i Env pum w compunds for avai sta When pr a e bil t vent e e l C r- xam abl and 1 2 i t based t the y, he r a e, m the pl t actuion o i t i f cr he e, CPS. i nal of t ncr s obi t ol ne o i r t en ut ea f al enhac xt mulation or i of e g d s ha on. contami. step e a ve vis convetial yAuxilar to is cosity, s olubity to be pm u P t is ensur ade or nasl to e , and the 28-33-DDT - Jul-Aug 09 - Advanced Delivery:Layout 1 6/25/09 3:16 PM Page 29 28-33-DDT - Jul-Aug 09 - Advanced Delivery:Layout 1 6/25/09 3:17 PM Page 30

ingredients do not affect the function TABLE 1 and integrity of the CCS. According to EU and FDA guidelines, relevant Test System n Short Test Description Results information should be provided on the Artificial dust Repeated actuations until Venting System contaminated with 20 half the bottle volume was No bacterial contamination characteristics of each of the critical B. subtilis dispensed Repeated actuation of the 1,2 components of the CCS. Critical Suspension primed pump with the tip Tip Seal containing 20 dipped into the No bacterial contamination components are defined as: (1) those P. aeruginosa contaminated suspension over 5 days that come into contact with the patient’s Summarized Results From Microbial-Integrity Testing mouth or nose or with the formulation,

(2) those that affect the overall and efficacy, authorities request a phase is the most important because the performance of the device, and (3) any detailed description of the spray. The formulation will be delivered with the 1 additional protective packaging. Parts events that follow the pump actuation optimum droplet size. During the with metal balls and springs are prone to can be described as the spray formation formation and dissipation phases, larger cause problems. Even if they are made phase, fully developed phase, and droplets are formed. Figure 2 compares of non-corrosive material, the surface dissipation phase. 1 The fully developed the three phases in a conventional nasal can rust or discolor the formulation due to impurities or contamination with FIGURE 3 lower grade material during the manufacturing process. A unique property of the CPS is that there are no metal parts in the fluid path. All other components of the pump are made solely of medical- or pharmaceutical-grade polyolefines. The materials used in the conventional 7 o

N pump and the CPS are compared in 9 l

o Figure 1. V 9 0 0 2

t OPTIMUM SPRAY s u g

u PERFORMANCE A / y l

u Technical performance of the J y

g device is very important for sprays o l o n h

c intended to deliver the drug substance e T y r

e into the lungs or to the nasal mucosa. v i l e D For multi-dose systems, dose g u r Delivered dose following actuation of a conventional nasal pump and a CPS nasal, using deionized water D uniformity during the lifetime of the as medium. Spray intensity versus time was assessed 30 mm away from the orifice using Proveris’ 30 device is mandatory. To ensure safety SprayVIEW NSP equipment. 28-33-DDT - Jul-Aug 09 - Advanced Delivery:Layout 1 6/25/09 3:17 PM Page 31

THE ROLE OF PARTICLE SIZE FIGURE 4 DISTRIBUTION Two important features of spray pumps are the size range and distribution of the delivered droplet. The size of the particles or droplets depends on the intended use. If the spray is for oral inhalation of beta-agonists, for example, the majority of droplets should be from 1.5 to 6 microns in order to reach the middle and lower airways. Larger particles will be deposited in the pharynx. For nasal sprays, much larger droplets are required to get a good distribution and deposition in the nasal cavity. During the formation and dissipation phases, very large droplets (> 300 microns) can be formed, which may irritate the nasal mucosa and induce Spray pattern of a conventional nasal pump compared with a CPS nasal, using deionized water as medium. Spray geometry was assessed 30 mm away from the orifice using Proveris’ SprayVIEW NSP discomfort. At the other end of the size equipment. range, particles with less than a 10- micron median aerodynamic diameter pump and a CPS nasal. illustrates the amount of delivered dose can reach the lower airways during nasal To improve the spray performance of during the three phases of the actuation breathing. 4 The authorities therefore a device, technical measures should be of a nasal spray pump. In a conventional consider that droplets less than 10 taken to keep the formation and system, only 30% to 40% of a dose is microns in diameter in the spray should

dissipation phases as short as possible. delivered during the fully developed 7

1 o be characterized. Depending on the N

The majority of the dose should be phase, compared with 80% in the CPS 9 l o

active ingredient, any auxiliary V delivered during the fully developed nasal. 9

compounds, and the total amount 0 0

phase, which is reached when the pump The technical measures already 2 t s

delivered, this fine particle fraction may u mechanism secures a certain pressure mentioned and the design of the swirling g u A cause side effects. / y l

within the system. In the CPS, a spring- chamber have a positive effect on spray- u When using deionized water, the J y

loaded tip seal keeps the system closed pattern geometry (Figure 4). As a result, g o l

number of droplets less than 10 microns o n

until a predefined pressure is reached, at the CPS delivers a very consistent and h c e in diameter is significantly lower in the T y

which point the formulation is forced regular spray pattern. r e v i CPS nasal, compared with a conventional l e

through the orifice with a well-controlled D g u

pump, and no droplets larger than 300 r pressure. When the pressure drops at the D microns are created (Figure 5), so it is end of the process, the tip seal 31 less likely to cause problems. immediately closes the orifice. Figure 3 28-33-DDT - Jul-Aug 09 - Advanced Delivery:Layout 1 6/25/09 3:17 PM Page 32

MICROBIAL INTEGRITY FIGURE 5 During the manufacturing process, microbial contamination of the formulation will affect the product’s quality and shelf-life. Depending on the product’s intended use, microorganisms should be absent (products for inhalation) or as low in number as possible. Depending on the drug, the formulation may be manufactured under sterile conditions or treated using autoclaving or radiation to ensure inactivation of microbial contamination. These approaches are not always viable, however, and preservatives such as benzalkonium chloride may need to be

added. The use of preservatives is Droplet size distribution of the full spray of a conventional nasal pump compared with a CPS nasal, controversial and has to be justified to using deionized water as medium. Droplet size distribution was assessed 30 mm away from the orifice using Malvern’s Spraytec RTsizer. the authorities. 1,2,5 For multiple-dose

systems, preservatives may also be used pore size) to prevent microorganisms To support this claim and to provide to control microbial contamination from entering. The principle of sterile data on the microbial integrity of the during the regular use of the product. filtration is well recognized and widely CPS, challenging test procedures for the Microorganisms can enter the system via used. To prevent contamination via the venting system and the tip seal were

the venting air or through the orifice. In 6 7 orifice, a pure mechanical approach is developed and used. The tests were o N preserved formulations, the added

9 applied. The CPS’ spring-loaded tip seal carried out at Qualis Laboratorium in l o V preservative just controls microbial keeps the system closed until a defined Constance, Germany, using sterilized 9 0

0 growth, and no measures need to be 2 pressure is reached, then the formulation (gamma-radiated) pumps and glass t s u

g taken to prevent the microbial

u is forced through the orifice. When the bottles. A / y

l occupation in a conventional system. If

u pressure drops at the end of the process, J

y the formulation cannot contain MICROBIAL INTEGRITY TESTS

g the tip seal immediately closes the orifice o l

o ON THE CPS

n preservatives, the pump must be able to h and no back-flow of contaminated c e

T For both test series, glass bottles

y keep microorganisms out of the system. r particles is possible. This mechanism e v

i were filled with sterile bacterial culture l

e The CPS uses a sterile filter in the D should therefore provide sufficient g

u medium, and the CPS nasal was r D venting system (0.2 micron nominal protection from microbial occupation. mounted under sterile conditions. 32 28-33-DDT T coul kept up the hars of the of inc vol bo Th sp 25 up wa Th pu 10 sp Pse bac wrape V the wa a pu we the the of pr nd IP E ev ores ac si tl 0 mps 7 mp m t m is e re s s n ubat NTI ume a he il udomna bot c bot e c de S nd the d ent e f di nas e ic ic xperi hal lus oln - out c proce inc il EAL r hal te be be w w NG ped expe robia robia -down pm le tle tle of Jul-Aug 09-AdvancedDelivery:Layout16/25/093:17PMPage33 we d ed ed . upsi st le t as a spore uba tw d ips Ne of l le s de i m y-for : nge B S me n wa wa re condi a for the and wi dure A em a nged e rim Y ct ac the xt, te de l l a c in te wer ST s then s s nt, rog wth. rog wth. tuaed th n uat c cted posi uber r i d pti to 7 procedu ent l uginos aer ul anlyzed anlyzed ent, down) act t EM t sy per he t ar w us t he at days t ing or ture t ions, thi ed he wice rance as ti uated not vte or : ins 35° if tem, sy subtil pum the on. of s ram). g The to and cultr ica uni r su m sea at epa ide The Ev for wiped. te C. a a ha a The cultr xed edi l of ts and 30°C. ms pr l se s, pum pens en f f l a r da lf A ing, the or or ela dus s 3 a (CFU te ime ve tip e um was CFU por the nd t The ( y it twic under s wer s 10 d mediu the the the no ra ec s ys ps t e for ion, s se Betwen se and until e d the yste c ilngf A c 8 s l m onds pre te s e ontaig yste ontaig ba d pr al t w ) e times sy pr pr end into t o 5 wer ms e pe in er the the (tops i s dium c thes es es the m. par 10 me days ea ter tem the ms e r enc enc an a e of wer n the 9 in ling ml . e ed. t d ia e dr nd the ide , in e y 1. benf cont th CP ex huma si deve sy to produc mi m phar chal 2. 3. 4. 6. 5. in sy ug Dr Spr G Doc C Rockvi br pha U Res Medi S B The Per Inf de gni is si tua per om om uida sm c nim onc li S, ma or te te spe ay ma r ve pir de ume ome t r J ani l c pr inu ap hodila A I lopm y r nc i D engs i f c BO ms m, it er ne C l t dm c t. ie n tion, it ug r Pf O e nta e, e s r e ne R s ov ace 1984; i ut ys i cant the . i for S, t ts i s A MD , ze se nce D nis tion. s ic r C f tor t P Ke or e e genc . Bi ng epos a Cha es ar a r m I ar P en t t oduct l ndust l i ra ; n r disc w 5:369- me e r If nd m har o s qua e ent i uti ffe 20. U . ti t M pte spone y; syt ourc k it e M J, ly on, he dic S i ion and e to cust lit w s 206. y: r ely ma H ed a l r d. D ombe a O C higl ina ca y - r c no 12, e C F E R e pr opei a 205; nes 390. C re i De t par N of act ent nd t only l th pr i a hem em a P i pr s l s vi ac nuf i es sa M er nhal re duce m c me t omer a th odu N c bact K le a, l m 172:49- hat ovi s F, oa is e fun c f ivi t S e , a or n t T F r e he ra pr ati Ba Zw E R E y yr , e om t c U L C ned va te our e act anuf c af t D of c nc ay s t on ch ne r t hnol ion inc t t M is ug r i de f ens pr v e He or y, o re a le er t e a a e t dev s of nd s s- t er m nuf nd r of nt ur a huma . Eva 1504. P he oact Effe W lth t ma gul 204;15:- inha h i J. I re t E C N and be m na o a nha . a uing i NO I S he Editon, c R lua er P and 5 t ta d. tur s c egi n r el le ase al t easur ti la f e 2- coul i f tion r ed us d se v ing, a y s ut ti pr da ona ur agoni Hum e k ive opme pa on vr a e ne t B naci oduct pa yor of et ( a tic r ca ur S l a Engli s CH S er nd ti ys. a nd pr t lung 16,8. in an olutin, v st T o le d e sed ti MP R s. e e n f i - C pa s Se ab di s. st f esur e sh n or r ont Lond: ent de a se t tic r e be vic r En ) s , to e he . nt v spen a al plying posi pa rol l G t yst e na r vir le S c e r hei e uide ge on new sion, h uspe s s s s. on s t f al , of i ( and ion y z 132. F CD ound Eur e. em l ugdr e od H i nsi ear ne G r e a A i ER) a nd e ope t ts on, on m i l ne on a he th ng nd s, . J r a s a al t n he nd Man Pharm G resarch joi Folwi v L apoin drugs Pharm tok Dresden/ suces coletd infl th posit th pharm et ei er e esi n pzig, erin man am ed ager drug ion over . a a/N aceut at ted In ary t ng f y. B h atory ul Div Dr. A at in at e d t ample Duri y I 208, st a t h evl m com Busi comed Arzn h is H P A R G O e ical Alt 192. Ing. a Senio e edicin Degnhard ion. U ng an M stud opmen an pletion niver n eim edica i e d he exper nd E. a thi s r i In cardi ovasculr e y n ustr itelwr Resarch Pf was sity s Devlopmen t and of Constan t 201, ei co-perate time ien ces o of y, f f o Y er, th he his f anti Marx ke e in h ce, i e - n th e

3 Drug Delivery Technology July/August 2009 Vol 9 No 7 34-35- DDT jul-Aug 09 Molecular Responsibility:Layout 1 6/25/09 3:18 PM Page 34

David Versus Goliath: Why the Little Guys Have All the Advantages Part IV of a Six-Part Series By: Derek G. Hennecke, MBA

hen you’re in the mood for backroom. He threw a bunch a burger, there are of oil-soaked cloths over it, and Wprobably several rushed back out, ordering us to megachains you know you can go to down our cones. Apparently the for a reasonably good, reliably franchise owner was coming by, and consistent burger. But what if you’re in the because the ice cream wasn’t mood for a really juicy, hedonistic kind of “officially” part of the franchise formula, he burger? I mean the kind of burger that changes lives - that stimulates wasn’t allowed to sell it. Once the owner left, the manager returned and invigorates all of your senses, and makes you believe that man the much-loved machine to its regular spot, plugged it back in,

7 truly is a spiritual being. Is that megachain where you go? cleaned it out, and was back in business. o

N My favorite burger is from a little local restaurant called Catch I returned to the restaurant many years later and noticed the 9

l 23. Unpredictably, Catch 23 is a latin-infused seafood restaurant in machine was no longer there. The story is that the manager got caught o V Tampa, Florida, and its seafood really is quite exquisite. But everyone off-guard one time, and our beloved ice cream machine was history. 9

0 around here knows it also makes a breathtakingly fabulous burger. On So, coincidentally, was the restaurant’s status as a youth hangout, and 0 2 $2.99 burger night, you’ll be hard-pressed to get a seat after 5 PM. the place has never truly prospered since. t s u

g If Catch 23 were a megachain, do you believe they would have a When David challenged Goliath, many people assumed that u A

/ burger night? Not a chance. It wouldn’t fit their strategic mandate as a David’s win was kind of an exception to the rule. I mean really, the y l

u latin-infused seafood chain. But Catch 23 knows its market. The little odds were in Goliath’s favor, right? Malcolm Gladwell wrote an J

y guys generally do. article in the May New Yorker called, How David Beats Goliath that g o l In the Canadian town I grew up in, there is a fast-food restaurant throws things into a completely different light. o n h

c (I won’t name it because it’s still in business) that always sold soft ice Mr. Gladwell points to research by political scientist Arreguín- e T cream and made a killing on it all summer long. We kids headed over Toft. Apparently, in every war fought in the past 200 years between y r e v

i there on a regular basis because there was no other soft ice cream in strong and weak combatants, the David’s won almost one-third of the l e

D town. We often had a burger or two as well while we were there. time. This is particularly exceptional when you consider that he only g u

r One day, I was in the shop when the manager flew out of his looked at those wars where one side was at least 10 times more D office, unplugged the soft ice cream machine, and raced it into the powerful than the other in terms of weaponry and population. 34 34-35- DDT Q s s ne li de a innov D de ha ma ta c kno a innov w innov y of c ba pr b po y po e 28.5% r A br unde s r H li thos us w he c oppone c he G T r or in be the f ma te e- es ight as hould hould tra v bout us rgue our onv ou’ hos onv uilt k k HE e k a ill rr e olia st ve U ga ea oce e eryt w v ma ppen. tc lme com wde we e e doing ana vids. ar t ter jul-Aug e re r na tom d ing elopm eguín- pi tegy. wn IC l la ke hes, e st re is k y niz D t e enti enti ing way the rdo turne I T E T W r fav to urn -A up at nd. geme d at at at cke tes sse th, c t, hing avi t the fiv lyz drug t t KE w in his ve his r hist e indi wil o as o t titude er. ion ion. ion. or be: hav nt hen thi ati that nee o it. RT mi and g’s ould We t or. onal the indust onal time d all n a he pi Under d fi thi e W C es d, ed on to innova ent 63.6% Toft nd onal c ling on s R per c g d And ory. more So ca in ght cr aps nt. e s ck up ds onve lea hang e , we a winn dev to ngs, D truth T David It’ that m w i in win ar firs those v a T a n cl in o-dos te c our the sua a put a mea ECH i wis ore me e 09 to ooth s up he or O e B fi de uge ontinue ndus sw follo dime ai vid b w to Goliath ry-le s s be s e it’ w Ar i not ummarized, t ve ec us nt the iz thos ts es ming lopment, ! gea hic they figure tions tha the . ADOPT rs ing the ding a wa dom ord. ildly fiel dr s Nor t ins go lieve it a ns Molecular When e iona ns l’ Small hose a reguín- ines ing same . pocket. wa is rarely smoot w ev NO rocks tr s opped use coat this ading h the n combined W nts change r to tr e odds battl beyond d percentage y, of Xcelodos that our th er lked becaus s the an This 30 ument e’re lev and circumst without he s, uneven l s houldn’t of to , LOG keep/ear we on CROs r ys our ything. meg out meeting r American way and ocks battles of b we ules, the uncon APIs els e. h s push a unde couldn’t we bat Tof Goli tem usines of exper we the ource STAT his by Your kno out find was s good mail, what clients ’ve Let achains mas . tones, s e “even li m tle. Y: of t winning t can In he . far and were ttle ar are o gear ath they battle w he r paus e with t ake and months No the ventional ances .” wn dogs o It al a Responsibility:Layout 16/25/093:18PMPage35 the n ® tis m looki Sma ters e CRO the s went But E-O an of about CR a ways the a meet take pre new was m a e in the w, guys who driv define e walk CRO en i local wanted and 100 brass t when e. and win, able t tell ight , e the drug having , that ll O s c , chose, we’v r then the mos velope ng F- n’t i teady He ar is ms. the fr e f way on of wi s the ion you om e to be for to t a ll in e liquid-in-c a PR of p Xc by s time a ROUT s been me s s a bl who s you dedi proje OFFE outs a – ta vir de prog s a c c This Xc I imple tha What man real man hi c c the s ha wan kno a Xc COM B M DE gia t cient m olel tudy plitte cie va ddre re nd pproa ommunic ompanie ustomiz re llows ote am andar OX ke o s/ onc dica ppening ANA this tua all elodos elie elie as ati etings t nt cks expanding OVI ilab DICA her w ly re ntific t ide cated agem agem pia ncy do we ra y a cares looking a , c ta to er access ve e ss a c men ifi l S n t not a M r s pproa t . !) suc m nc nc te by , R his lly a ch , le lki for d I ho nd an ld OL no s GE ma for Still, DE unc rgo the th c w c an N unme d pecial U s c y , e e ed f a or S e olutions T d ent ent, uld. ompounds, ng tha s the he h to b or or e our just E t s c we advocat nnot exte NI means a . d wire PE a a abo fe re na quic UT olutions y M ool a into E e thos on la LY sch bo ps tion. a B s de c PE b n s wh t proje quall t th e s t s hip a man D, compa ge h CAT o uita we echnical is us rge ut a e E ide ma l t E acces ule ve when At bout a x? your a our ut dic ns I lo is he quipment teachers ool? . a t k things like c NT: RSONALIZED, ddre only o ONS: r D FI e ine centr hem more c PR s llo ntional us Ho w-weight ion will de tur you ap Our b a a us a ometimes Xcel y phar al is a unde s y . c te e & ND nd d nd ION: le exper olutions ted tomer s ws At ts so cl lo tomer proach s w’s OJECT child’ well. chnology a wi ning s that rator ss to one A S it to find r of al machine al EASE ien t w-cost involves weekly o solutions r never small, while “team o challenging t maceutical ience, about Xcelience, f pro works th Eve egula us e resour r OUT-OF-THE- project do l. new acilit to s it that the quipment all and one tise approach ts in you c out All Is on we s W needs. to product hool, is but ject just proj needed r n’t t t fills our i our hat e client eacher, on n mar be hea we r with at for ser ates a OF p with of roof, flexible, de be assignment” o pr hav as ces. the are client also our rincipal is wn. t as ect dime? wasn’t that. status. a the hat a oject pa ing defined org we other ve plexiglass rd y need like or well thinking ke an e Adopting dedicated dime. ou ( much way willing pr We r not indus su we facility. that blinding a which a both ts a tme if anizatio eas same high- technical set sma oject b bout example One tablet wa s ccess. an needed ut tha as ingle, Not hav . of This it ier nts t You make nt he And ll as FTE try al fer t of a e to t so is to he a . n t tha wor F Da sam tr a Se st we fo much We p a pr the Becaus ev oper advan We dedi When FL ls r A adition udies, “ r o o en e o vid be CI US. various operations Rotterdam, MBA University and Roche’s and DSM development MDS, ointments, solutions, modified-release capsule formulation business capacity, MDS Pharmaceutics President t vider, E j coul long ms next th mov turn ect e cated ati we ha XI I’ keepin s y L comp tage more t-in-indus you m a Mr. onal Canada. Mexico. s e kind Pharma I in enab B Da at d mongs ed little e and Mr. al T pr perio be we’ not L ou co AT project R G O I B Canada, Hennecke drug ro the research development, vids by oject for thi ar E e o and he Hennecke and desig g r quickl mplete l oms, n r of t suppositories, und of ing e E hen or e s guys OPE and pr s (The ds adopti equip mulat Erasmus was development, c a In Sciences, t a He products not unfa di management ying ite Alberta operations out F ojects General businesses C tr – and s of speed ASTER, s ev n, sadvant these m gels. mal y” ROs. you Egypt, d earned responsible cap y Netherlands). t RATIONAL activities tablets, ha a hrough en there. ment o tim ion an has sch ir, by ng and Biopharmaceuticals Xc ve commer strength. held v l Mr. Xcelience President He De served 2004 of is acity University tend ha e wit Prior API does compan (Canada) Manager, e. roles, numerous edu t Inc. a T also for de tablet a e v Xcelience. o rek P A n all The ve then lience Derek his age ery h flex on founding So nec hin various of vel I’m fi creams, ere to suspensions, -int MORE to Europe li our to n’t including i In the to to positions rs in worked as , s n G. BSc MDS’ Netherlands, wh he for quickl opm introduce i ci in ke, 2006, fo g t- the move formulation, n ble be Y H are this o-caps joining get G. jus & Germany V y it? al-s ever in-h to sys advantages. mo r eel is and built ice in the from CEO with DESI Hennecke e s drug MBA t CRO s ent and an From other the clients maller. N creativ x member ame s. tems cale del, s uman for y he ample, aying his on tied the for ule in f the only the fewer or of GN: t to and year. o up e. t as he

35 Drug Delivery Technology July/August 2009 Vol 9 No 7 36-43 Tech DDT Jul-Aug 09- Solid Dispersion:Layout 1 6/25/09 3:37 PM Page 36

SOLID DISPERSION TECHNOLOGY Oral Delivery With Novel Solid Dispersions: Stable Self-Assembled Formulations of Lipophilic Drugs With Improved Bioperformance By: Galia Temtsin Krayz, PhD; Maryana Averbuch, PhD; Anna Berman, MSc; Amir Zalcenstein, PhD, MBA; and Irene Jaffe, PhD

INTRODUCTION Overcoming solubility limitations remains one of the most challenging aspects of pharmaceutical formulation development. Traditional solutions to this problem, such as pro-drug synthesis, salt formation, and use of co- solvents have been augmented by more recent approaches. These methodologies include: (1) improvement of water miscibility by employing self-emulsification, lipid-based techniques, solubilization into micellar cores, or alternatively complexation with cyclodextrins; (2) reduction of particle size to nano-scale via mechanical milling or high-pressure homogenization accompanied by particle stabilization; and (3) impacting crystal lattice energy using polymorphs or co-crystals, or through the creation of solid dispersions of drug in inert carriers or matrices.1-10 Solid dispersions have inherent advantages over other approaches. Presence of an active compound as a molecular or nano-particle dispersion combines the benefits of decreasing crystal lattice energy and surface area maximization, thus facilitating better contact with dissolution media. Advantageously, many of the carriers that can be employed for the production of solid dispersions are already extensively used as excipients, easing the regulatory process. In spite of these advantages, only very few solid dispersions have reached the market to date. This is due to a number of reasons, including the absence of sufficient in vivo validation, laborious preparation, lack of reproducibility of physico-chemical analytics, cumbersome incorporation into suitable dosage forms, unsuccessful manufacturing scale-up, and instability of the drugs and their vehicles.11-12 Thus, technologies that can effectively overcome these challenges are highly desirable. SoluBest has developed a unique solid dispersion technology for significantly improving the bioperformance of poorly soluble drugs. This robust and versatile technological platform, referred to as SolumerTM, can be applied toward a wide range of marketed drugs and molecules in development. 7

o 13 N TECHNOLOGICAL CONCEPT drug-polymer solid dispersions in facilitating their selection. Specific 9

l which the lipophilic drug is amphiphilic and hydrophilic polymers o & METHODOLOGY V homogeneously interwoven within a at optimal ratios yield solid dispersions 9 0 0

2 Solumerization is based on the multi-polymer matrix. Moreover, due to with a unique built-in hydrophobic- t s

u interaction with the amphiphilic hydrophilic gradient. This gradient g self-assembly of selected components, u A

/ polymer, Solumerized drugs exhibit enables the rapid disintegration of the

y enabling the design of new polymer- l u J drug constructs with well-defined modified physico-chemical properties powder in aqueous media, generating y

g (eg, decreased enthalpy and easily measurable colloidal nano- o

l physical-chemical properties. o n

h temperature of melting) compared to dispersions.

c Leveraging the thermodynamic e T the crystalline lipophilic APIs. In the context of the Solumer y

r behavior of amphiphilic and e v i

l Solubility parameters can be used technology, amphiphilic polymers are

e hydrophilic polymers in mixed D

g as a semi-empirical tool for the defined as soluble both in organic

u solvents, SoluBest has developed a r D proprietary platform for the creation of prediction of component interactions, solvents and in water. Examples of 36 36-43 Tech DDT Jul-Aug 09- Solid Dispersion:Layout 1 6/25/09 3:37 PM Page 37 36-43 Tech DDT Jul-Aug 09- Solid Dispersion:Layout 1 6/25/09 3:37 PM Page 38

amphiphilic polymers suitable for use with F IGU RE 1 Solumer include but are not limited to polyethylene oxides (PEO, also commonly referred to as polyethylene glycol or PEG), PEO derivatives, PEO copolymers such as PEO/polypropylene glycol (PPG) copolymers, PEG-modified starches, poloxamers, poloxamines, polyvinylpyrrolidones, hydroxypropyl cellulose, hypromellose and esters thereof, vinyl acetate/vinylpyrrolidone random copolymers, polyacrylic acid, and polyacrylates. Hydrophilic polymers are defined as those soluble in water or in a mixture of organic solvent and water, but not soluble in organic solvent alone. Examples of hydrophilic polymers include but are not limited to starch, sodium carboxymethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, sodium alginate, chitosan, and carrageenan. Notably, SoluBest formulations utilize only FDA-approved polymers. The use of hydrophilic polymers that ionize at different pH allows for the design of formulations targeted either to the stomach or the intestine. For example, chitosan, which is ionized at low pH, promotes drug release in the stomach, while sodium carboxymethyl cellulose and sodium alginate, ionized at neutral conditions, facilitate release in the small intestine. The Solumer process is an easily scalable two-step preparation. The first step involves the preparation of a liquid feed, which is a homogeneous solution of the lipophilic drug and at least two polymers in Overview of Solumer™ process and product characterization a mixed solvent (organic/water). The second step involves spray-drying of the solution to obtain a well-characterized powder. In availability of spray-drying equipment G Solubilized drug homogeneously 7

o enables the process to be easily interwoven into a polymer matrix, N contrast with other technologies, there are 9

l no intermediate steps including formation implemented without an increase in the o V and separation of nano-particles in the manufacturing footprint. Furthermore, the G Modified thermal behavior 9 0

0 Solumer platform is applicable to a wide demonstrating depressed melting 2 liquid media. Thus, drawbacks inherent to t s

u other nano-technologies (eg, milling, range of products, including those that are temperature and enthalpy of melting g u A

/ homogenization), such as the agglomeration toxic, aseptic and heat sensitive. An of the drug, y l u

J of nanoparticles or chemical degradation illustration of a typical SoluDrug y

g preparation and its physico-chemical G Spontaneous formation of nano-

o upon application of shear force, are not l o

n 14 characterization is demonstrated in Figure 1. colloidal dispersions upon contact h relevant to the Solumer platform. c e T The resultant spray-dried powder is with aqueous media,

y Solumer feed solution amenability to r e v i

l spray-drying results in an attractive well-defined and exhibits the following e D

g industrial process. Spray-drying allows for collective unique “fingerprints” of a u r D flexible capacity and continuous and Solumer solid dispersion: 38 automatic production. The widespread 36-43 Tech DDT Jul-Aug 09- Solid Dispersion:Layout 1 6/25/09 3:37 PM Page 39

TABLES 1 & 2 the effective crystallite size of formulated albendazole is 33 nm. 15 Laser Diffraction and Dynamic Light Scattering analysis TABLE 1 Fenofibric Acid show that disintegration of formulated Formulation Cmax AUCt Tmax powder in water results in colloidal (µg/ml) (µg hr/ml) (hrs) dispersion with a mean particle size of 419 7.06 ± 1.16 109.20 ± 37.45 3.0 ± 0.8 SoluFeno nm. All these properties lead to a high TriCor 145 8.10 ± 1.63 113.9 ± 38.70 2.0 ± 0.8 Test / Reference 0.87 0.98 - dissolution rate for solubilized albendazole 90 % Confidence Intervals 0.76 – 1.01 0.91 – 1.01 - (SoluAlbendazole or SoluABZ) versus raw Pharmacokinetics of fenofibric acid in the plasma of volunteers (n=12) following oral administration of bulk material in a sodium lauryl sulfate, a SoluFenofibrate versus Tricor 145. surfactant that is a typical medium for dissolution of insoluble drugs (Figure 2A). TABLE 2 Supersaturation is shown in physiological media, exemplified by fast state simulating Resveratrol Resveratrol Total Metabolites intestinal fluid (FaSSIF) (Figure 2B). Formulation Mean Mean Median Mean Mean Mean Median The correlation between physico- AUCt Cmax Tmax AUCinf AUCt Cmax Tmax (ng hr/ml) (ng/ml) (hrs) (ng hr/ml) (ng hr/ml) (ng/ml) (hrs) chemical properties, demonstrated through in vitro tests, and bioavailability was studied SoluResveratrol 504 330 0.50 28410 27600 8820 1.00 using a pig model. A comparative evaluation of the bioavailability and therapeutic Raw Resveratrol 331 111 2.00 23960 22430 4160 1.50 efficacy of an orally administered Solu- Test/Reference 1.52 2.97 - 1.19 1.23 2.12 - Albendazole (test) formulation and a commercial formulation of Albazen 90% Confidence 0.90-2.58 1.95-4.54 - 0.95-1.48 0.97-1.56 1.58-2.83 - Intervals (reference) was carried out at Rubikon Ltd. under supervision of its Chief Statistical Significance NS* <0.00009 <0.0013 NS* NS* <0.0009 <0.003 Pharmacologist, Prof. Vasil Piatrou. Albazen, * NS – No statistically significant difference which is manufactured by Rubikon, is the generic version of Pfizer’s Valbazen. A total Pharmacokinetics of resveratrol and metabolites in the plasma of volunteers (n=12) following oral of 40 pigs (aged 75 days) spontaneously administration of SoluResveratrol versus raw resveratrol. infected by nematodes were treated with water suspensions of the test and reference G Enhanced dissolution rate/solubility pharmaceutical development process, due formulations at doses of 5 and 10 mg/kg. of the drug in aqueous media as well to the rapid screening times possible for Both formulations were administered orally as prolonged supersaturation in determination of candidate suitability (up to through a pig-dozator under fasted relevant biological fluids, and 4 weeks) as well as the short time required conditions with free access to water. for product formulation. SoluBest can For pharmacokinetic studies, blood G GI site-targeted release of the drug. proceed from feasibility studies to clinical samples were collected at 0, 3, 9, and 24 studies in less than 6 months. hours after oral administration. The Solumer platform was validated Concentrations of the therapeutically active for a number of marketed compounds. metabolite of Albendazole, Albendazole Collectively, these formulations have ALBENDAZOLE

sulfoxide (ABZSO), in pig plasma were 7

repeatedly demonstrated the platform’s key o determined using an HPLC method with N 9

properties: stability (measured up to 2 Albendazole is an anti-helmintic or l o

UV detection. V years), batch-to-batch consistency, anti-worm medication that prevents newly In order to estimate therapeutic 9 0 0

commercial scalability, and clinically hatched insect larvae from growing and 2

efficacy of the test and reference t s

proven increased bioavailability compared multiplying in the body. Albendazole is u g

formulations, feces samples were collected u A

to API (or bioequivalence to marketed insoluble in water with MW = 265 Daltons; / y

for coproscopy on days 0, 1, 3, 5, 10, and l u

nano-pharmaceuticals). Clinical and log P = 3.0; T = 215°C, and ∆H = J melt melt 15 following administration. Hematological y

preclinical studies on Solumerized 210 J/g. The Solumer formulation of this g o and biochemical blood tests were carried l o n

molecules demonstrate a direct correlation drug with poloxamer 407 and sodium h

out to identify the safety of the formulation. c e between their increased solubility and carboxymethyl cellulose yields a T y Pharmacokinetic study results are presented r e v i

bioperformance (Figures 2 through 4 and composition with decreased albendazole l in Figure 2C. e D

Tables 1 and 2). melting temperature and enthalpy (161°C g u

As is evident from the PK data, oral r Lastly, the Solumer platform has and 31 J/g, respectively, according to DSC D absorption of Albendazole from Solu- distinct advantages in the context of the analysis). As evidenced by X-ray analysis, 39 36-43 Tech DDT Jul-Aug 09- Solid Dispersion:Layout 1 6/25/09 3:37 PM Page 40

FIGURES 2A-2D

Correlation between in-vitro release profiles and bioperformance for SoluAlbendazole vs Albazene

Albendazole is significantly higher (two- to Thus, this study demonstrated a good according to a DSC analysis). As exhibited three-fold) than the absorption from a correlation between the in vitro and in vivo by X-ray analysis, the effective crystallite size commercial Albazen suspension. Solu- behavior of Solumerized Albendazole. of formulated fenofibrate is about 40 nm. Albendazole exhibits a clear dose Furthermore, the increased bioavailability Disintegration of formulated powder in water dependence, while Albazen does not. exhibited by this product resulted in results in a colloidal dispersion with a mean Evaluation of hematological and increased efficacy. particle size of 774 nm as measured by biochemical data demonstrate that increased Dynamic Light Scattering. These collective 7 o

N drug absorption observed subsequent to properties result in a higher dissolution rate 9

l Solu-Albendazole administration does not FENOFIBRATE of solubilized fenofibrate as compared to raw o V cause abnormal changes in blood API and commercial micronized fenofibrate. 9 0 0

2 parameters; the formulation can therefore be Fenofibrate, a cardiovascular drug used The dissolution profile of SoluFenofibrate t s

u considered safe. to lower triglycerides and cholesterol, is appears to be similar to that of the leading g u A

/ A comparison of anti-helminitic activity practically insoluble in water. It is a market nano-formulation TriCor 145, which y l u

J of the reference and the test formulations lipophilic, crystalline substance with MW = is manufactured by Abbott using Elan’s y

g (Figure 2D) clearly favors Solu-Albendazole. 360.8 D; log P = 4.8; T = 82°C, and NanoCrystal milling technology (Figure 3A). o melt l o n

h Solu-Albendazole exhibits higher efficacy at ∆Hmelt = 74.3 J/g. The Solumerized To determine SoluFenofibrate c e T a lower dose. Complete dehelmintization is formulation of this drug with poloxamer bioavailability in comparison to a reference y r e v i

l achieved in ten days after administration of 5 407 and sodium carboxymethyl cellulose product (TriCor 145 tablet), a randomized e D

g mg/kg of SoluABZ while Albazene does not yields a composition with decreased cross-over study was conducted in 12 u r D result in complete dehelmintization even at a temperature and enthalpy of fenofibrate healthy volunteers. A single oral fenofibrate 40 higher dose. melting (64.4°C and 9.3 J/g, respectively, dose of 145 mg was administered under 36-43 fe f ac id, Mo n w ch em up stud m Ta fall as t Tech as n ea n bl on Corelatin i of ed we ie e p Th i were is to st erf s b tes 1 c ll t u rat . r e DDT ar on yr , in As omr dy t wit res e /r e g di a h efer pr ac t ter na l s o h u t em betwn Jul-Aug ed io h f in es e lt ow n mi iv a s ns yz en ato fo dv th of e nt . na ed ce r e m Pla l er ed og in th al tio ac in-vtro r eta us se at l es y, s i Tab ce n. n s in ma 09- ios e bo e ub a pt F f g nd fe p le igu lit j ed c ha HPLC fo ec relas c on c Solid e, 1, ts, u r mr re ts lim r AU C F fe ine th c e p 3B ac no l ntr U G I e ri its i -UV. profiles nic ok or an g i f a a eo Dispersion:Layout 16/25/093:37PMPage41 f va tio nd br ine o al a t o r l me ys i lues ic ns S E R a ti and nd c tric s of bioperfmanc A 3 in wo u va mus bioe g vol invol t Ad mi te b h ioe re st e lue a se un te a /re t l qu i qu i te f d ve or s be nis r f r & eq ui be er f d ma va l va l e nu or rs no te tra e a f nc e for mbe 3 , en en l i ou nd re r ti nd ivi it bi e on B ce ce me d SoluFenofibrat l at i oe q ra s r th . ivel re o nts o a tio Th du al w at f ntic f uiv al qu irem ithin th v . e y so m for ol A e ge ipate s vo s un te mall en ce S C ometr e t the oluF luntee he m en ts t d ax es ers vs nu mb e req pilo s tha a t e tudy /re ; Trico lso ic . n rs ho we uired of t t fere mean th fe s mee i tudy brate ha r es 145 l l nc e ve of ving e lim ou ts ts r va , C i it lues ts ide a m a x he ina f howe r is of ve ins S ac t oral to wit me th da ma decr is c tes f prote co nc res res com pr co ntr eff As o st ma an d eff mol ec of in cand sm mell meta re s T de cr co mpa ound e omr irc rga o me ome ome r. atus s er clu yr a be lum er ec ts ec ti unc res ted ve olub iva tor ve pec ve all y c ta h lt t, e ula a tive urine eas ea s nis itus xhi b nut = Re R R The en tra ida bolis bo lic ulatio pot peut de l pol o ction ol ve ra r r or ge , a ver ow rs atr at r molec ular ve ha i tive is es es to in 267. 4 tion. re d n n trol le or ms r; ed e sv : r a te Th t , e o entia c ver ver itiona n ol ol ef he atrol ge -r a it b c i the for s c of in xyge ic phy e bioa is xa s only m in e tio n ge a ly pa r is e yr s e tc. s tem t fec n is w r numbe an d only an d -i 2 bn omr a is for o me is d yn drome a atr atr , inc -r a e 2 m th e s biolo gi mul a R ul re d a °C, n, eigh t did s tr ol clini 1 elat ging ffe lly fomr ac s itr uin th e ame que e by d ta l om va 6 tive 45 er ic ar S E n. s re es l ol ol pera lti ng sve the e rea S in R u as cord in cts s am oun rg a o-ch ila the li te 21 e s e olumer , and lting n ed 407 X uppleme es e exis nm , is is ra ous ve t c. le V te ne which r ot r s si r ion hu ma ns a ula ag en proc e is Re bili t -ra at tur e w im ver l ra de ca n a vate of en z a c r w ra E ng d (19 9.1°C a ing I s urod e s r c emical re ol ur 22 , f ∆ ts c iz is ns- s an ti- a tio n e s me y he . AR l tr ma d ha nge an d ila in ty, of type ve ly tive the atr mall suc nd H s or t r e ymes nitr t ol being a 8 a analy s an ult o ization. e n to ss res of re r m nd in s d o ra are of te a ntly r thi s a de rs o D; r O R T elt s nt. i e ia nly ces t c ca nc pos , d ge ner nd it . t ape s l c n tr o ic ri al . DS tr odi um wo x in tiv cyr s r II ve ve ob es Thes = on fomr ul a , molecu le tr wa s en ev ers ol char pos ans s the , other typica log de H s o a how ra c ma of se e e ra diab e 253. 6 ra tra an y whic utic is in C ve a ful, ns xide th omp ound ge s er xten i . owe nd L pi mons s ta , t tro -re ss e ative T Its ity, sys r c e als tr e ana the alp P acte -r va r rk d the ome p ol d, ll in ing dur g. ra e s e a ad ve dis thes e ra ie f 14 l sv lipophilic = h eted t s l ver d sive lgi nate tes o a a n s te o y ex w te d ious to lysi s J b c v mo s ris it y ma erat r 3.1; tr to 55 % /g. orde r f lds mic atr e tr tic ligh lood of a - e J t ou nd , a e d s e /g, r 17 rs ic ly tics its t a u the as y ns ur g a . es tria - T ). e tr 2 nts lly rial t, ol 0 he ive o a s l; ls n

41 Drug Delivery Technology July/August 2009 Vol 9 No 7 36-43

42 Drug Delivery Technology July/August 2009 Vol 9 No 7 met co n po fo un adm 12 In was Re the sim u Dis wat mean Las sa prop re Tech sv mr t wd er de r a ur sv h in er ce n er ab e SoluResvrat profiles Corelatin er in eal sh t etr Th nh ati lat u era wo te oli at par la res Di i fas o st tr rg at ies o t an ed e DDT ro wn ti tr hy di -way n at i rat te ffr ul ti in on ti ol ced l s in s s ng im cl and pe r t o i v act i v o i s on s on v we co ns t n o ers e Jul-Aug lu est it i p we lu betwn cro co bi n io s a si bioperfmanc mp ro act bi re of of ed o n u nt in oa a ze n nd re f l s s it da ex a ee vs al th ar c An 50 so re va a i r na y it oll o n a aw p e ta ed rs sv s ve dm raw io n f fl 0 il f wa ly z al lor ign in-vtro or f o 12 ui a e co wi or m r AP ysi 09- to id bil ra in s, d a t e Resvratol r 44 if So g er mul r r an th al to d tr is te ra ity s. te ( I ic . of e Fi ol yr by l dom dis w i a n Th e la st um an The Solid n relas for at gur m r o r sin te an e c r a es a HPLC tl f pe ed es d li er nd s as y iz s S f d e ve pl a gle nic r a e as ve wel iz ol powd i s ed 4A) it s st nc sh r ra i c e e u- ra on sm a a Dispersion:Layout 16/25/093:37PMPage42 oll d or fe st l tr l o r -UV t tr r ea wn . wit stu at ol a ia r a ec wi ol e e l sed e , l r nc e ti dy. th h as in by in ve a ad f r wit pr pr bioa f th e e mod “ dis te es or or nha if nge c e e min i hnol pe ults h se se s r t va he iif e e ol nc As So r com nte nte sve si r ub il i in pr str ogy of l lu m t ons d abi ota c d d, F g ra int a ple t a t it he in G I n the he tio n a tr lit e l is y pos ” r ol r b me r s F se y of fe ma es ba i ig is e r ig s R U i M U S a wa of ver b c n nif ph es ts se li a ur tu l lea io ta po elf n be s d s r S e ar ic yr a i atr ol ov es ng s olu -R p va rly on d ha S E ma a s hi , e 4B el LC ntly M ubs il ex vi mons a l va s ab ic c t o met R A e e u e okine and -MS st c r en es mp eque nt ni i d 4 , h li h l r na y q igher t ver no tra ug abol it ie Y 4 - A from ue l 4C i iif n mp s a l tic s t og o atr ol . ed na , ed c Th - he ol a co to r y s lys es ov nd the not t by l e n i udi ll ec C . oral m ce ed o is. but T ti p id dat o e a o r so The s bl al nly ov n als are a l e of id i n 2. o g 1 2 pl al aq as I di s ha it bi ob ch . . nv p s b at s o G ( Ph H K b r v el ue ar t SED w ioa pe e ay ai av es einr ur au e f amr a f n ac e o soy ou ss v ne r t s - ai d e a l D s rm ig s dr h ila l D t a az JJ. S) io c la e RN, s d own as J, s oth a b y r ility f i Lip m o bi ti ns F is o b al ly i o e r l n Be o fo et r. g t e l ed imp id lo a i g i ns a 2 f to , nita cs l ty - w r nd t 0 o b ws SE, h f mu i p 0 r a E R . r a, en een ove , 4 se at in ly i r m S. ;5 n F d oc mp d F v a 8 d oif f d l ur ic Self is a a d ( o at nd ol o 3 u E F o eli ha es n t ph s r r ) r i t a s i :1 illi - on o b tic v he v l on e e s t r e 7 mu d lu r r G in y ap yr i x 3 R JV, e tr a i n r -1 si liv a c a u t te I lsify g mo syste g d n i i l 8 N E el co Pr e p o d sp s 2. . e , yr s t i o n ice l ve h T o in c a t c e ms re -ch tr o n e e al nd g h an n p f C -s C l o , d lipo e t co o f i ro f e A, o r n S e p E d u a p co -u r S res g s mi if e Ro id o p p impr n m S o ol o h d c p l t rrel le o ilic e y l at u act i en ev , live r ca ub u if ly T, o m s e e vin m d , c e t wa Ja l m yr at ur l e . an s wi rat e g er y re r g c te sy i pl a s. th o r d re r le d a stems th -so l rol e n B oy j rug eas e AA, nd io or a lu was n me i ble ng i e s s, n d l . g & 36-43 22. 21. 20. 19. 18. 17. 16. 15. 1 13. 12. 11. 10. 8. 9 7. 6. 5. 4. 3 4. . . Tech Si p Goo 347 des n b Mül 200 devel Kes App Sz c Jon d Ran LTB ol ha an i r hum abs Wal 200 ju RB. Wan Age che Res Cal 200 i Jan hype and Zo 1 pr pl T Pac v Bau Ph Li New Par pr com Te te al Kar s c Di usi Le ot n ng ugs up om ej 99 ivo h l ch te ic duc at ig ot ep es ps r opa mt oi . 7; Nun is ech un ot gel u e ng l t d l m 4 i hal orpti g mo er e- rn er li e, e a 2; ver 3; 5; kh l n: ect op r C, ni nt og wi pr . po da C 39(7 An on ar a g r og e JG r le nt M DJ, ev si Y er i ac JH e sa As J ed ns. J ch 50(3 34(8 235 ative J. - nh rti so he ca s. c RH Y T, ati A, i d me or a t Yag lo n imm dr l ne h si zio a i D, rap si Ga D C, ran Ph id eu tr , on H , C, DDT Pas ol ag tro , on d LC c ci l li ib 2 p w m. tio u ox K k, W H ng on u Hs Ro M. ): C u Dr e l S ru H, (2 Si nt 00 ra re d , ti po a es e C rb ak g Le in h ): ): it ra n gr b G, ui 63 F , J a D ur l a a Kr rm i s n ca ap M t, b un . s - g s C, ):2 nc ct , c p d or. u err ie 20 d 43 11 u tan d Sh gai lo ter n . an a 3 e an M tio ly s Wo egat . H ut re Pate e. h ro or is Pa r a 1 - g CO rig CR nd p g l ic ;3 Ave ar c h p ec a N. o p la p t J tive 0 ph -6 1 0 0 an S ss en M p re Y a a P y d ol o c ro n t a J ux ns M t. se op N al ver H, Z h (2 n ce F 4; o -4 0- 7- rrie Bi ir er oc u k os ha Jul-Aug . F. rev J. 4 ma c se , , en , j b Ph m em io mai a F, d en R ill l ac oy nt at Ph ez n t ui eta rb D 76 ):7 o an k 4 h 3 1 2 pe si ch D Pe io Ha CM M. D bo ot J te ry J rma y si PC1 , Pro et c n n ur Yan er . o ili 5 1 1 he C. o ce rs a ru az -H W. on u iew n D No eL ar o ic A. ph Hu t, V r c ( ec rs ti i li b . 10 9. 7- ss r l ho st l a o ch h 10 ev e ro c . ow er S m WA e , g M z s DA J. i c n m S, r k . a p s te a n or Po & ra o r h a e c 9 E , kke i e s . R g T a D . a 2 a d d . n : n e Ch e ec in ls n ) D gg rm eu a . 3. I ac Wu sv o M, o c n u Sc WO c ng S b :1 h n d E h ar t S ev. M Y, ch mp ru g ly b ce D . f 2 e ti e f r f ti , d A r e . t bi , i ed er o c u t t an e e m i i n a iv 8 0 Cr r f ve a y li ve Mc i he Th a Ph d me i J co ur A o g Di e i r J, YZ : u l r i ra . ll Sc Ro ha s G t 25 04 c a c ve l r 2 MH Y. n ru o e. mo il ava s. Te s he tu p P N 2 a e , ovi J e pe po y 20 ti t T 0 t s d it a -r a e l e c hy m . n Ye u r ng wi 0 ro n ha i G N. – ; g st r an an vi d ew A P r 0 av I rm e ma , ff . ic om ch N i 11 a al y 2 ev ti 00 ce u e In nt p 18 ly s 0 ia e at 6 a in ha n Ca 2 rt l , na e t dv r 0 h e n ti c G an o r 9 a 09- r yz n RR Te ie ;5 o S L . g 0 m m & m ct b 3 Oa e on a d t e h s i al 04 n e. ; Yo i c re id 4 p / J erpretation u r d ck C, f ro 87 20 ty 0 ra o n ce ve il :1 , o s . dis : o d m i i 5. a ou orphism ch 0 or fa D is 49 pote Mo . 5 l oc s of cyclodextrin celles & ng Co Zelkind i F ev J ; sizing . ti nd rug wt r t ubility s 5 e 40 K ty utical 32 n ( 0 ; C JW, ro e k ru Mizut c R, r a LC. yn Industr Ag 8( s n nd 2) n & 1- ti r 3 7; ee as aluatio t J, , Biopharm. E l resver u h . ol d ystal t 8 u l l o JE ( -506. g o : solution otal 2):147-16 NY;1997:7 :164-169. 170. b rr ntial t P 7( 12):1377 othelial s Richard e. 18. Biopharm. solubilit r Wu f Med. and hesis: n ric Des. New ogy. Solid , Radic ioav e W Del , an Micellar oral 4):87. - Med Soleas , Clin - Gr of Walle ani illiams advant a ap Food res and d oral technol I. iall atrol JM. querc of n. ailabi ne anula Re 20 of solid York 2009; meth optos 200 Com resv Y, im verat A Ch Bi y Chim resv w 08 for f v. X-r dos y f B re u - Ef d U G, Bo 3 fe p or C on 1 ol 1 3; a ge e n f , em- v 2 ;8( e , 7- li . s l R tio s 999 od 38 d or K. g po hem fec t asi ic ct 9(5 o is, 2 the ra v ea m 0 ay era age r NY; o 11( in t n D isp O. e M Gol ner ol y 7 g 000 an b 0 Dispersion:Layout 16/25/093:37PMPage43 lu ati 9): ion n av tro 2. u Act s r ora 8 y eta b ru o f 4; H An t and blo th Dif e ch. ;48 i tro ): la or bil Te . in er 3): del le ti Fo f . a ons of d. id Bre an 19 for 24- i 56: dbe g l 2 rou ;50 tio gh on ti -am l in s a. t l: 2 ch in iza a ck t g :10 rm fra i 317 on i De d Pur iv de 6 hei red -C on 52 m rap n 33 335 em B t 1 :4 rg for gh n li e h tio cti ula li yl h . 1-1 . l anc olo ry o s: -22 r e pid 7 -3 e . uma ver wi e Re e DM f oid - - on n i n a 60 tin 2 n of gy 11. er 64. n 0 of v. y e . . n g . . e re D in a e c s En An ha Sol comm Dr Sol man Ch Ch an met a D C s s S a D G t W s e yst h xper nh nd he ca ynt ci na he he nd nt r. en r. r. spon s ei emi . gin e e d vin ti e n uBe uBe l a Ma an mis mis zm l mis em I a Ga Am e e- nc Tec a a c tut yti h ha compl il pl r ll ti t ol ge en g es e c s erc c up. is B e i an s an l r c s. al er s s s c, c e tr tr t ia loi i in ya ibl h s, wor er bus is men e t t al ry r e d s n bot i y y n i n e g proper ng, a al es dire . in na Za da ma e i Tems S compl G O I B an Ja in dr ct e me on nd from f I in h ke He a rom s te n t for h l an lc g ug or e n f th d en n A es st , c f d St th a s d d r en pol . ac a e ea ts ver a ys proc e Isra n it t ea s t t s pre . sol d od lyt eva post t ia d t e B i h a c s ute ph t ie r eve he n d S Pe R yme t r ie n en e de t a bu l e e ne e ol i ubi &D el s ein vi ms. ed P A R s e deve ca K ys l e va d n ve te ua mic s uB We l a xpe c ousl ti r d bee of Gur opmen d s I r ic l h a h r nd lu li lopm h ns fi a oc t sburg, y i h l i c e , de o- Sh za iz i er nd a at s s S c l n z h ri e st i n t opme an S t borat y c ma bi on , g ch emi r t it post in vel e e ora ion e ol S E I H ie . PhD ion i dire nc for en xpe I ologi M d ut nvol c vol br He e uBe t n P nn opme or Un S l mic st ce e in e t a R in in c - s nt or re c t r re ved c n doc us r t a dus i i e o ie , i wo In on st gs ts ve f y n n rat d ve c ie n , s a f a l rom t a n a si al e ’s d h rn l s a proc t Orga n c n d s Te i r ti ce Sol a tr ti egy e va mpl a. he s . in of ept s prope i t d publ e rc Ch n ac on it i c tut i w biom d n al of l t h re spa h uBe Sh y ua busi Is N . h bioa t e ie el s eme ni n h te ivi e be c ss . e anotech expe a i S ra A ology. e i f bl l is n ei c c t he rti ns S ch PIs. of Institute s t a Te e tw edi h e nes he op ved t y a M nalyti B relati n PhD s l’ es as n n chn e organ ta s expe Formulati e Sci IT’s ee ri of ma ti ologi cal d e arn h s en lea i of r miz brought n h on as Hi Mate en drug deve ology i teri n S ons i ce n cal ed D se s ph ri din ology polyme he s ce e ic, c a ept. of e Ca M ct xten a e ti a of in ys n va h ria fie lopme g xperi l BA i ls in on de ce nce or polyme n orga e i on , O co- C orga r l , ld res of li the to i from s ffice Isra Is i from Ph vil a a r ive rs very n en R nd rae nd a n ea nt &D D fter ni o- el. li ce r rch. r l c fe i at the , n i s

43 Drug Delivery Technology July/August 2009 Vol 9 No 7 44-47- DDT Jul-Aug 2009 - Special Feature :Layout 1 6/25/09 3:21 PM Page 44

By: Cindy H. Dubin, Contributor

ed by innovative market entries of promising new APIs, SURVIVING THE ECONOMY prescription transdermal patches and gels for pain management are Lpositioned for double-digit growth throughout the next 4 years, The economic downturn has affected the drug delivery industry. according to Applied Data Research (ADR). Responding to the desires for Budgets are tight, and funding is harder to come by. As a result, it is even simplified dosing, reduced side effects, and improved safety of more important than ever for companies to be focused and control costs, transdermal pain patches and gels, drug developers are investing in the as well as concentrate their efforts on programs that add real value to clinical development of a range of pain drugs that can be delivered via the patients and the healthcare system. Companies are evaluating programs skin. Pipeline pain patches that will enter the market within the next 3 and ensuring they are applying resources to the highest-priority years include products based on bupivacaine, desamethasone, ketoprofen, opportunities, says Peter Staple, President and CEO of Corium. and capsaicin. “We are seeing that investors are more careful with their money; Narcotic pain drugs now account for more than half of all therefore, it is wise to plan ahead long enough for financing rounds,” says transdermal pain products worldwide. Increasing demand in existing Dr. Christof Boehler, CEO of Pantec Biosolutions. markets and greater emphasis on under-developed regional markets will Planning for some drug delivery firms includes deal-making and drive the total value of the pain mangement sector beyond $8 billion by partnerships. Consider Altea’s partnerships with Lilly/Amylin and 2012. For example, Alpharma’s Flector diclofenac patch exceeded Hospira, as well as Intercell’s acquisition of Iomai for its transdermal analysts’ estimates in 2008, its first full year of FDA approval, vaccine technology and Lilly’s agreement with TransPharma Medical for a demonstrating the potential of non-opioid drugs for the treatment of transdermal PTH product. neuropathic pain. In Latin America, Amarin’s diclofenac TDS is becoming Proper planning and continuous influx of funding should help the available in a growing list of countries. Sales of buprenorphine patches $7.1-billion transdermal and topical drug delivery market reach an are growing 16% annually in Europe; German-based Grunenthal’s Versatis estimated $8.2 billion by 2010, according to ADR. But, given the current is the only approved topical anesthetic patch. And in Australia, a jewelry economic climate, 2009 will remain relatively flat. What could help is the designer is working on a silver vial necklace that would not only carry a emergence of the active marketplace in the coming years. Industry sources 8 7 supply of tiny insulin patches but act as an applicator as well. estimate the active market will represent 10% of the total transdermal o N N Fentanyl will remain the drug of choice for breakthrough pain drug delivery market by the end of this year. 6 9 associated with cancer; Teva’s fentanyl patch won FDA approval in l l “After a decade of basic research and development, active o V V October. However, there was the recall of the Johnson & Johnson (Alza transdermal technologies are now emerging as promising new ways to 6 9 Corp.) Duragesic Pain Patch in which approximately 32 million of these 0 0 deliver large molecules through the skin,” says Mr. Staple. “There are now 0 0 2 2 fentanyl-containing transdermal patches were recalled due to defects that t s could lead to accidental overdoses. b u g

u Issues of patient compliance and safety also permeate delivery A FIGURE 1 t /

y methods for CNS drugs, as these patients’ cognitive abilities are often l S u ® J compromised by the nature of their diseases. Drug developers are Altea’s PassPort y

g increasingly turning to transdermal formulations of CNS drugs to Transdermal System l o l

o overcome patient compliance issues. According to ADR, the ability of h n h c

transdermal CNS therapeutics to respond to the growing unmet need for T e T

y patient-friendly administration has analysts predicting the total value of r e i l v

i transdermal CNS drug products exceeding $1 billion in 2012. l D e D g u D r D

3 44 44-47- DDT Jul-Aug 2009 - Special Feature :Layout 1 6/30/09 3:01 PM Page 45

real options for the delivery of biotech-based large conventional patches, and even oral agents.” molecules, such as proteins, peptides, and vaccines Altea’s business model relies on partnering its FIGUR E 2 without using the traditional syringe and needle.” products with the pharmaceutical industry. Its current product portfolio includes two partnered products: a transdermal version of exenatide MARKETPLACE HAPPENINGS (currently available on the market as Byetta® injection) with Lilly/Amylin and a transdermal Transdermal delivery systems are based on product with Hospira. Further, Altea is in clinical passive or active transport. Passive patches utilize a development for a Transdermal Basal Insulin Patch one-size-fits-all approach. Drug is preloaded into that provides continuous delivery of insulin for the adhesive on the patch, and all the patient has to people with type 1 and type 2 diabetes, and for a TM do is peel and stick the patch on the body, and the Transdermal Fentanyl Citrate Patch that enables Corium’s proprietary MicroCor active drug will passively transport across the skin barrier. rapid and safe management of moderate-to-severe transdermal technology uses mechanical energy These patches fill the need for delivery of drugs pain. The company is in preclinical development to deliver the active therapeutic agent. (ie, nicotine, contraceptives) with small molecular with several product candidates, including a weight that are fairly stable and do not require any Parathyroid Hormone Transdermal Patch for the development projects, says Mr. Bloder. customization of delivery. prevention and management of osteoporosis. The company’s crystal reservoir technology For drugs with a larger molecular weight, “Altea’s partnerships with Lilly/Amylin and has resulted in the development of smaller patches active patches transport the drug through the with Hospira were significant events that both with a more controlled and sustained drug release. stratum corneum through a variety of modalities, validate our transdermal PassPort System technology Drug release is based on the oversaturation of an such as heat, microporation, or iontophoresis. The and provide us with enormous business adhesive polymer with API forcing a partial following highlights what some of the players in the opportunities,” says Dr. Tomlinson. “Both our crystallization of the drug. The presence of active and passive markets have in their pipelines. partnerships and our broadly applicable technology molecular solute and solid crystal forms allow for a Featured companies include Altea Therapeutics, platform have enabled us to insulate ourselves from considerably higher concentration and consistent Aveva, Corium, Isis Biopolymer, LTS Lohmann, the travails of capital formation that private and supply of drug in each patch, explains Mr. Bloder. Pantec Biosolutions, and Transpharma Medical. publicly traded companies are currently experiencing. This technology is employed in the commercial There is no doubt though that a continued weakness production of an Asthma Patch currently sold in in the economy could begin to impact our future China and Japan. ALTEA THERAPEUTICS — ability to raise significant capital to grow the Nitto Denko's asthma patch is the world's first PARTNERSHIPS PROPEL business faster than our corporate deals permit.” and only asthma patch, also indicated for PASSPORT® PLATFORM emphysema as well as acute and chronic bronchitis. The product's delivery profile is designed to peak Altea Therapeutics is a clinical-stage specialty AVEVA DRUG DELIVERY SYSTEMS in the early morning when patients most need the pharmaceutical company with a proprietary — DELIVERING DRUGS drug to prevent coughing related to broncho- platform technology, The PassPort System is WHEN NEEDED constriction, says Mr. Bloder. broadly applicable to the transdermal delivery of As far as where Aveva and the transdermal biological drugs (proteins and carbohydrates) that Despite an economy that is forcing many industry are headed, Mr. Bloder states, “I believe otherwise would be administered by needle companies to do more with less, Aveva Drug we will begin to see how passive delivery can be injection or infusion. The PassPort Transdermal Delivery Systems is experiencing explosive growth, maximized with new and unique enhancers, System (Figure 1) is also suited for delivering which is attributable to global expansion, a healthy excipients, and alternative occluding technologies. highly water-soluble, low-molecular weight drugs pipeline, as well as Aveva’s new product approvals We may also have the opportunity to assess the that otherwise could not be delivered transdermally. and commercial launches, explains Robert J. receptivity of patients and learned-intermediaries to These include ionic salt forms of drugs, eg, Bloder, Vice President Business Development at disruptive skin technologies, including fentanyl citrate, that can be delivered more safely Aveva, which is part of the $7 billion Nitto Denko microneedles and other active patch platforms, and effectively than by the existing transdermal Group. Recent product approvals in the US and which through various modalities, alter the stratum product, and other low molecular weight drugs with Canada include Aveva’s Fentanyl patch marketed by corneum to increase drug delivery.” potencies too low to be delivered using Teva and its Nicotine patch marketed by Watson in conventional transdermal patches, says Eric the US and Perrigo in Canada. Aveva is also Tomlinson, DSc, PhD, President and CEO of Altea. manufacturing the 7-day Sancuso Patch for “The Altea Therapeutics PassPort Transdermal ProStrakan. Sancuso is the first patch indicated for FI GUR E 3 System can alter the way several diseases are the treatment of chemotherapy-induced nausea and currently managed by enabling the efficient

8 vomiting. Aveva also has many products in various 7 o transdermal delivery of biologicals and water- N

stages of development available for licensing and o N 6 soluble low molecular weight drugs,” he adds. “This manufactures the Onsolis product (awaiting FDA l 9 o l

V technology has the potential to grow the current

approval) for BioDelivery Sciences Incorporated. o market of transdermal patches by replacing V 6 Onsolis is a bioerodible, mucoadhesive indicated 0 9 0

injections, and in some cases, even oral agents.” 0 2

for breakthrough pain associated with cancer pain. 0 r By enabling transdermal delivery of 2 e

Aveva and Nitto Denko provide patches t b s u m medications currently administered via injection, g

e designed to exceed industry performance standards. t u p the PassPort System offer benefits related to A e Whether the transdermal platform is active or / S y convenient drug administration and compliance. l passive, patch comfort and wear are important u J y

g “Patient compliance is a critical issue for

o features. The Gel Matrix adhesive system provides l y o patients on insulin who are uncomfortable with g n o

the perfect balance of gentleness and reliability. It l h o c

needles or have lifestyle concerns surrounding the n e

T is one of the many performance adhesives utilized h c y

need to self-administer one or more injections per e r

in our matrix systems that have met or exceeded T e v y i

day, as is the case with many type 2 diabetes r l

market expectations over the years. Unlike e e v D i

patients,” says Dr. Tomlinson. “The unique l e

g conventional adhesives, the gel matrix adhesive D u

r attributes of our transdermal technology provide g D causes little disruption of the stratum corneum Isis Biopolymer’s Isis Patch has the ability to u substantial benefits, such as improvements in r during removal, which greatly diminishes skin transport up to three drugs per patch and is D quality of life, greater compliance, better efficacy, 34 irritation. Thusly achieving a desirable patient fully programmable for customized delivery. and safety, mostly by replacing injections, some experience that is mindfully present in all product 45 44-47- DDT Jul-Aug 2009 - Special Feature :Layout 1 6/30/09 3:01 PM Page 46

FIGURE 4 CORIUM — NIXING THE NEEDLE approach by combining aspects of our technologies IN THE NAME OF PATIENT into a detect-measure-deliver process with COMPLIANCE integrated feedback to ensure the correct dose for an individual patient’s needs.” Corium focuses on product opportunities in which a transdermal dosage form can reduce or eliminate side effects, improve efficacy, or access a ISIS BIOPOLYMER — patient population that has problems with existing TRANSDERMAL GOES WIRELESS dosage forms. For example, in some disease categories and in an elderly population, swallowing Isis Biopolymer has developed technology to difficulties present challenges for oral dosage prevent inadvertent or over delivery that results forms. Additionally, for certain applications, the from changes in the skin, such as temperature, use of subcutaneous injections for chronically moisture, and movement. Its proprietary single administered therapies can cause patients to electrode design removes the variability of these discontinue their medication. changes in the skin, while the selective barrier With its MicroCorTM active transdermal membrane facilitates transport or complete technology, Corium replaces the needle and syringe cessation of drug delivery. and offers improved convenience and compliance The single-use, band-aid-like active patch for subcutaneous, intramuscular, and intravenous controls and monitors transdermal drug delivery, drug delivery (Figure 2). ensuring safe and accurate administration through Corium’s proprietary MicroCor active the skin using iontophoresis. The Isis Patch has the transdermal technology uses mechanical energy to ability to transport up to three drugs per patch and deliver the active therapeutic agent via is fully programmable for customized delivery microstructures that are incorporated into a very and monitoring via an integrated wireless small patch. The patch is worn for a very short communication platform (Figure 3). period of time, and its drug-sparing design enables “The shift to fewer healthcare providers and a delivery of nearly 100% of the drug. The stronger focus on home and self-care requires biodegradable nature of the microstructures transdermal devices with this technology and is enhances safety by leaving no residual sharps and ideal for this trend,” says Emma Durand, President reduces any abuse potential. This technology also and CTO of Isis. “We have the ability to wirelessly eliminates the need for cold storage, which is program the Isis Patch, which will have important common with most large molecules. implications in the future.” In the passive transdermal field, Corium’s The Isis Patch is also a biosensor, which can CorplexTM technology presents opportunities for detect skin emanations that may be indications of never-before transdermally delivered drugs, says medical events, such as heart attack, shock, or Mr. Staple of Corium. Corplex is a flexible diabetic reactions. “In addition to being intelligent polymer system that encompasses a new class of and highly reliable, the Isis Biopolymer patch is biocompatible hydrophilic pressure-sensitive very safe,” adds Ms. Durand. adhesives that can adhere to wet or dry surfaces The company’s target audience is primarily over a range of wear times. The highlight of this pharmaceutical companies that have a current system, says Mr. Staple, is its ability to hold large unmet patient need for drug delivery. “We are amounts of drug and enhancers in a small, solid- focused on working with organizations that have state matrix patch. This allows for greater flux approved drugs, as well as pipeline products or through the skin and improved adhesion for 7 days drugs in development that have challenging or more. There are many opportunities in the CNS delivery issues where active transdermal delivery arena to exploit the Corplex advantages. offers a solution,” she says. “Whether delivered actively with MicroCor Therapeutic areas of interest are both chronic or passively with Corplex, our technologies look to and acute, such as pain management, oncology, offer the patient a painless and user-friendly way of neurology, women’s health, endocrinology, and taking medication and delivering small and large cardiovascular. molecules through the skin,” says Mr. Staple. For Founded a little more than 2 years ago, Isis example, Corium is developing a multi-day Biopolymer has successfully completed animal trials 7 and has recently initiated its first human clinical o transdermal system for delivery of Tamsulosin, a N drug used for the treatment of benign prostate trials, as well as filed a 510k for FDA approval. 9 l

o hyperplasia that has not previously been delivered “This year was very busy for us, building our V through the skin. patent protection portfolio as well as fueling our 9

0 R&D projects. We are also engaged in ongoing

0 Corium’s partnering efforts are underway as 2

t well. Corium is looking at significant growth in discussions with several pharmaceutical and s u

g demand for products it has already developed for biotech companies,” says Ms. Durand. u

A Isis Biopolymer’s business model was / partners. As a result, its revenues are expected to y l

u increase two-fold throughout the next year, originally designed to make it capital efficient and J explains Mr. Staple. to generate profit within the first 3 years, she y g

o explains. “The strategy has been to raise enough l “Like all companies, we have to be o

n funds to get us quickly and successfully through

h thoughtful about product selection and c e

T commercialization strategies, and not just follow- our initial milestones, such as R&D, intellectual y r property, and commercialization, that will e Pantec’s P.L.E.A.S.E. hand-held laser device the-technology. Transdermal companies must v i l ultimately lead to licensing agreements and e creates aqueous micropores in the epidermis choose products with a market need and a D

g consumer advantage in order to succeed. As we manufacturing. In essence, our goal is to do more

u to deliver drugs painlessly. r

D look into the future, we also see opportunities to with less.” address the need for a personalized medicine 46 44-47- DDT Jul-Aug 2009 - Special Feature :Layout 1 6/30/09 3:01 PM Page 47

LTS LOHMANN — DEVELOPING period of time, something a patch can do because it FI GUR E 5 PATCHES FOR TODAY’S releases drug continuously over several hours and TRANSDERMAL REQUIREMENTS days, if it is well designed, he says. “With our clinical data, we can now work toward pivotal studies and leverage the results in This past year, LTS launched its first other applications in the biopharmaceuticals Alzheimer transdermal patch manufactured for one market, which has a size of $80 billion and of its customers. This patch is an alternative to the growing at 10%. Several discussions currently held capsules that have been on the market with the with pharmaceutical companies might lead into same active ingredient. Additionally, the company partnering deals.” has developed a Parkinson patch, which is the first P.L.E.A.S.E. is designed to deliver high patch including an NCE. Smoking cessation, pain molecular weight drugs. The hand-held laser management, CNS, contraception, and hormone device creates controlled aqueous micropores in replacement therapy make up LTS’ therapeutic TransPharma’s ViaDerm system is clinically the epidermis (Figure 4). The laser procedure lasts focus areas. proven to deliver peptides and proteins. only a few seconds, followed by attaching the “Our technology relies on state-of-the-art drug-containing patch over the microporated area historical techniques of medical product projected to be the fastest growing segment in the on the skin. Due to the special features of the manufacturing,” explains Yvonne Müller, US osteoporosis market, which is expected to device, the micropores do not reach the dermis Marketing Manager at LTS. “Technologies of reach $1.24 billion by 2010. “Our proprietary where nerves and blood vessels reside. A graphical coating and drying have been applied by scientists products in development enable transdermal user interface guarantees simple and safe use by and developers into a unique pharmaceutical delivery of large, hydrophilic molecules by the medical personnel or the patient, who can use technology for all forms of application with thin- creating temporary, shallow aqueous the device without supervision. film elements.” microchannels in the skin,” says Dr. Heffetz. “The Transdermal system concepts usually are ability to efficiently deliver protein drugs by divided between matrix systems and TRANSPHARMA MEDICAL — SAFELY methods that are safe and appealing to patients is reservoir/membrane types. This separation is no one of the greatest unmet needs of the drug longer sustainable with today’s transdermal DELIVERING PROTEIN DRUGS delivery field.” products, she says. Multiple types of different system designs exist. The main functionalities TransPharma Medical successfully completed (adhesion, reservoir function, driving force, and a Phase I clinical study that included a 7-day SUMMARY rate control) can be assigned to different repeated application of its ViaDerm-hPTH (1-34) substructures of the patch, but are also influenced and subsequently entered into a Phase II trial. In Transdermal drug delivery offers compelling by the human skin. LTS supports all different parallel, TransPharma has advanced the opportunities to address unmet needs in the market system variations, from both a development and development and design of its commercial for safety, convenience, and compliance. Novel manufacturing capability.” prototype product and accomplished building approaches to transdermal drug delivery have The company’s Estradiol Matrix Patches deploy scaled-up manufacturing lines for its ViaDerm significantly expanded the platform of molecules the concept of mono-layered drug matrices, allowing system, explains Dr. Daphna Heffetz, that can be delivered via the skin. efficient manufacturing, but more comfortable TransPharma's CEO. “In 3 to 5 years, we will see more wearing properties to the consumer as well. “In the past year, we have demonstrated transdermal patches in the market than ever,” “Estradiol is the most important natural through advanced clinical trials that our system is insists Dr. Boehler of Pantec Biosolutions. estrogen that can be delivered transdermally offering patients a safe and therapeutically In addition to passive transdermal patches efficiently and devoid of sudden changes in blood effective method for administering drugs,” says Dr. containing small molecular weight drugs, a handful level,” Ms. Müller says. Heffetz. “More than 450 patients have been treated of active transdermal systems that consist of with our ViaDerm system in various clinical trials, devices that either pretreat the askin to make it and we are seeing not only promising clinical temporarily more permeable or patches that force PANTEC BIOSOLUTIONS — results, but also patients’ and caregivers’ drug molecules to enter the skin mechanically, A P.L.E.A.S.E.ING enthusiasm toward the ViaDerm system.” electrically, or thermodynamically, will also be SOLUTION FOR INFERTILITY The ViaDerm transdermal system is intended available. Active systems will offer greater for patients who require chronic treatment of flexibility in dose sizes, frequency, and controlled therapeutic compounds (Figure 5). Transdermal Pantec has recently completed major clinical release. In general, transdermal systems will delivery here can improve the compliance, safety, milestones for peptides and proteins with its become more user friendly. and ease of their administration, adds Dr. Heffetz. P.L.E.A.S.E. (Painless Laser Epidermal System) in “We cannot ignore the fact that 40% of “We have further established that ViaDerm’s patients do not follow their prescribed regimen,” its key focus area of infertility, which represents a 7 system is designed for delivering peptides and says Ms. Durand. “The companies that will thrive o hormone drug market of about $1.5 billion. N

proteins and that the system’s patch component in the future will provide products and services 9

“We have chosen infertility as our first target l allows for a stable drug product at room o area as it is an ideal market to introduce such a that help to obtain better compliance.” V temperature, which adds to the convenience of the

“The skin is our largest organ, and in addition 9

new technology,” says Dr. Christof Boehler, CEO 0

product supply and handling.” to performing as a protective barrier, it is also one 0 of Pantec. “The most widely used method to treat 2 In June 2008, TransPharma Medical and Eli t of the most direct routes to our blood system,” s

infertility globally is In Vitro Fertilization, which u Lilly entered into a licensing agreement for the g

adds Isis Biopolymer’s Dr. Heffetz. “Passive u

forces women to apply 50 hormone injections or A

development and marketing of ViaDerm-hPTH (1- /

transdermal delivery has already become a widely y more. The industry’s current hormone therapy is l 34) for treating osteoporosis. u very complex and complicated for patients as they acceptable route for delivering small molecules, J

“This validates the product potential and such as hormone-replacement therapies, pain y frequently have to self-inject up to three hormones g o

ViaDerm’s clinical and manufacturing process l all coming in different application forms, suvch as management therapeutics, anti-emetics, etc. o n

achievements,” says Dr. Heffetz. h

Innovative technologies for transdermal delivery c

syringes, needles, prefilled syringes, and pens. e TransPharma’s ViaDerm hPTH (1-34) is will undoubtedly extend the use of transdermal T y

Pantec Biosolutions has already indentified several r

intended for osteoporosis patients who require e

delivery to a wider variety of drugs, which is why v i

private infertility clinics confirming strong interest l

daily painful injections of hPTH (1-34). “Currently, e in adopting P.L.E.A.S.E.” we believe that transdermal delivery will become D

hPTH (1-34) is the only osteoporosis drug with g

the leading alternative delivery route.” u And, it’s not just the women who benefit N r anabolic properties, stimulating new bone growth D from the P.L.E.A.S.E. system. Doctors want to that results in increased bone strength and a achieve drug serum concentration over a certain decrease in fracture risk. Anabolic agents are 47 48-51 DDT Jul-Aug 09- Business Analysis:Layout 1 6/25/09 3:23 PM Page 48

BUSINESS ANALYSIS Up, Down, Sideways - A Look at Drug Delivery Strategy By: Josef Bossart, PhD

ABSTRACT If you attended drug delivery meetings in the past decade, you surely remember the prescription offered for Drug Delivery company success was to be found in transitioning to the Specialty Pharma model. Margins in the drug delivery business were seen as tight, and Big Pharma seemed to have little respect for technology-only Drug Delivery companies when negotiating deals. In contrast, Specialty Pharma companies were by any measure masters of the universe, capable of launching and selling their own products at high margins and earning consistent profits. This mastery not only provided for high stock prices, it also allowed access to the capital necessary to be successful. And of course, if a Specialty Pharma company were too successful, Big Pharma would acquire it at a very attractive premium. All one needed to do was make the move and soon enough the market would recognize the wisdom of the strategic decision and reward the company with greater market capitalization and funding. That was the best thinking of industry minds in the middle of this decade, and a number of companies moved in this direction. After all, hadn’t Alza, Biovail, and Elan moved their valuations into the stratosphere by adopting the Specialty Pharma model? It seems a good time to take a look at how this strategy has played out for companies that decided to take this strategic direction, and how it’s worked out for companies that stayed on the traditional Drug Delivery track. A word of caution; this is not a discussion for those who like everything neat and tidy. The analysis is a little messy because many companies keep one foot in Drug Delivery while placing the other in Specialty Pharma. We will handle this by looking at groups of companies, an average effect, rather than focusing on specific companies. The net/net will be insights on how the strategic move from Drug Delivery to Specialty Pharma might play out for companies already on that path or thinking of heading in that direction.

WHAT IS A SPECIALTY purpose of this article, we’ll use the A Drug Delivery company is a PHARMA COMPANY? following definition: biopharmaceutical company with no 7

o We toss around the expression Drug A Specialty Pharma company is a discovery operations primarily focused on N

9 biopharmaceutical company with no developing and validating drug delivery l Delivery very casually in our discussions o V with a sense of confidence about what we discovery operations primarily focused on technologies and products for 9 0

0 mean. But what about Specialty Pharma? developing and commercializing validated commercialization by other companies. 2 t

s actives in a very limited number of u What defines a Specialty Pharma g u

A therapeutic areas. These two definitions provide a

/ company? While open to opinion, my y l

u reasonably good distinction between the J sense is that a Specialty Pharma company

y WHAT IS A DRUG two companies. For a Drug Delivery g is not a company that simply focuses on o l o

n one or two therapeutic areas. If that were DELIVERY COMPANY? company to become a Specialty Pharma h c e T the case, then all Biotech companies company, it would need to retain its y r e

v This should be pretty obvious to the portfolio products through to

i developing kinase inhibitors to treat cancer l e D or new agents to treat neurological readers of this magazine, but it’s worth commercialization. Simply taking products g u r

D diseases would be considered Specialty defining Drug Delivery companies as will through approval and then licensing them Pharma companies, but they’re not. For the be used in this article: out does not reclassify a Drug Delivery 48 48-51 DDT Jul-Aug 09- Business Analysis:Layout 1 6/25/09 3:23 PM Page 49

BUSINESS ANALYSIS

company as a Specialty Pharma company F IGU RE 1 based on our definitions.

THE BIONUMBERS INDEXES

The Bionumbers indexes have been presented on occasion in this magazine and track the market capitalization of Drug Delivery and Specialty Pharma companies as defined earlier. Details on these indexes can be found at www.bionumbers.com. In summary:

1. The indexes are based on the market capitalization value of individual companies summed to create a total value. Market capitalization is stock price multiplied by shares outstanding as reported by the companies.

2. Market capitalization is followed Bionumbers Market Index Summary, December 2004 to April 2009 month by month for three separate groups of companies: 4. The companies included in each of the This is followed by the DDI, which has lost G Commercial Specialty Pharma indexes are listed at the Bionumbers 40% of its capitalization value. The ESPI has Index (CSPI) - includes Specialty website. Note that some companies are done the worst of the bunch, losing a little less Pharma companies as defined included in both the ESPI and DDI than half of its value. earlier that have active commercial because, as noted earlier, they have one It’s worth noting, but not obvious from operations. foot in each business. Figure 1 and Table 1, that there has been considerable acquisition activity in the G Emerging Specialty Pharma Index MARKET CAPITALIZATION Commercial Specialty Pharma group. Of the (ESPI) - includes Specialty Pharma PERFORMANCE 43 companies initially included in the CSPI, 16 companies that have expressed an have been acquired in the 4+ year period the intent to market their own products Figure 1 and Table 1 provide a summary index covers. By contrast, the DDI and ESPI but have not yet reached the stage of the performance of the three indexes (CSPI, have seen almost no merger and acquisition 7

of commercialization. o

ESPI, and DDI) plus the NASDAQ Composite activity in this same period. N 9

since the end of 2004, a period of about 4.5 All of the indexes have a very similar l o V G Drug Delivery Index (DDI) - years. Figure 1 summarizes the closing values shape, up in the 2004 to 2006 period (when 9 0

includes Drug Delivery companies 0

on the last day of the year for 2004 though Specialty Pharma was THE model) followed by 2 t s

that have expressed no intent to 2008, and for the last day of April 2009. a severe dip that started in 2007 and 2008. u g u

move to product commercialization A A quick look at Figure 1 reveals a For all practical purposes, it seems there is / y l

activities. u troubling trend. All of the companies in the little difference in market capitalization J y

index have lost market capitalization value over performance between companies that pursued a g o l o

3. All indexes are normalized at a value n

the past 4.5 years. Even NASDAQ Drug Delivery strategy and those that went off h c e of 1,000 based on the closing market performance, which uses other methodology, in search of Specialty Pharma riches. And T y r e

capitalizations on the last day of 2004. v i

shows a drop in value of 20% over this same given the reasonably large sample size, 50 l e The indexes cover the period from the D

period. public Drug Delivery and 20 Emerging g u r end of 2004 through to the present and The CSPI has done the best over this Specialty Pharma companies, the observations D are updated monthly. period, losing a little over 10% of its value. are reasonably robust. 49 48-51 DDT Jul-Aug 09- Business Analysis:Layout 1 6/25/09 3:23 PM Page 50

BUSINESS ANALYSIS

TA BL E 1 companies, and the resulting average is not pretty. As we’ll see in the next section, the loss End End End End End End in market capitalization is exceeded by the loss Index/Companies April 2004 2005 2006 2007 2008 in share price, the factor of most interest to 2009 Specialty Pharma investors. -Commercial Stage 1,000 1,104 1,145 1,290 1,043 889 - Emerging Stage 1,000 1,174 1,277 968 500 529 SHARE PRICE PERFORMANCE Drug Delivery 1,000 1,264 1,279 968 595 596 NASDAQ Index 1,000 1,014 1,110 1,219 725 789 Bionumbers Market Index Summary, December 2004 to April 2009 Another measure of a company’s performance and its ability to attract investors, new capital, and employees is the performance Ah, but you say the pay-off for an the six-fold increase in valuation has come 3 to of its stock price. A doubling in market Emerging Specialty Pharma company is still a 4 years after Testim’s approval, which implies capitalization at the expense of a 100% dilution few years off. It takes time to develop a product the interval between the start of clinicals to real is not very attractive to an investor, although it and bring it to market. Good point. According market value creation is perhaps 9 years (6 is better than a loss in market capitalization and to the Bionumbers 2009 Drug Delivery report years for clinicals and approval, and 3 years for a drop in stock price. There are many ways to issued in June, the average time to take a drug substantial market penetration). calculate stock price performance for a group delivery product from the start of Phase I trials A less happy example is Alkermes, one of of companies. For our purposes, we’ll use the to approval is 5.8 years. So for those the model Drug Delivery companies that has December 30, 2004, closing price as our base, companies that jumped on the Specialty taken on a Specialty Pharma identity. Despite and apportion our price index as a function of Pharma bandwagon in 2003, 2004, and 2005, the approval of their first internal portfolio each company’s market capitalization share of the pay-off in terms of commercial rewards is product (Vivitrol in April 2006), which they co- the total index on that date. This means if a not going to arrive before 2010 if they had promoted with Cephalon, their market company accounted for 10% of a group’s nothing already in their clinical pipeline. But capitalization has dropped from about $1.3 capitalization at the end of 2004, it will account just how much and how soon does a marketed billion at the end of 2004 to $1 billion by the for 10% of the index stock price performance. product impact the market capitalization of a end of 2008, and to $720 million by the end of See the Bionumbers website for additional company? April 2009. Shouldn’t its valuation have explanation and examples. Auxilium Pharma may be a reasonable increased? Having a product on the market If the market capitalization figures were success model to consider. The company’s doesn’t have the same value as having a discouraging, the share price performance for capitalization has grown from about $180 successful product on the market. all of the groups is even more disappointing million in 2004 to $1.2 billion by the end of These companies are examples of how the (Table 2). These figures represent the ongoing 2008. It now sits at around $970 million. This market has treated those that have adopted a value of a portfolio that invested $1,000 on growth has largely paralleled the growth of Specialty Pharma approach. The Bionumbers 7 December 31, 2004, in each of the indexes, and o

N their first product (Testim), a second-to-market indexes average out these extremes by

9 held the shares through to the end of April

l testosterone gel approved in October 2004. But aggregating the performance of multiple o

V 2009. This $1,000 base allows us to roughly 9

0 compare performance with the market 0 2 t

s TA BL E 2 capitalization figures presented in Table 1. u g

u The greatest difference between market A / End y l End End End End End capitalization and stock price performance is u

J Index/Companies April 2004 2005 2006 2007 2008

y 2009 seen with the ESPI. On a stock price basis, the g o l

o Specialty Pharma market has hammered Emerging Specialty n

h - Commercial Stage c $1,000 $1,111 $1,208 $1,220 $865 $785

e Pharma companies. The reason of course is T - Emerging Stage y $1,000 $959 $942 $560 $218 $214 r

e that to pursue the Specialty Pharma model, v

i Drug Delivery $1,000 $1,164 $1,078 $815 $503 $496 l e

D these pre-commercial companies have been g u r Share Price Performance Index, 2004 to Present forced to go to the market for funds to finance D clinical development and premarketing 50 48-51 DDT Jul-Aug 09- Business Analysis:Layout 1 6/25/09 3:23 PM Page 51

BUSINESS ANALYSIS

expenses. This financing has come by diluting With these figures in hand, the question is BIOG RAPHY existing shareholders with the issuance of why would a Drug Delivery company jump additional stock. This effect is largely hidden onto the Specialty Pharma track? Well, because when looking at market capitalization, but if you can get to the stage of being a successful shows up glaringly with stock price. Commercial Specialty Pharma company, the In contrast, the Commercial Specialty outlook is rather good; market capitalization Pharma and Drug Delivery companies seem and stock price are sure to jump, and there is able to support expenses through income from the possibility for an acquisition premium. The commercial sales of products, technology, challenge is getting through the very lean years and/or services. Yes, there is some loss of share of being an Emerging Specialty Pharma price consistent with a drop of market company, a period that can last on the order of capitalization, but much less than those a decade, depending on the product and companies with no access to cash except that development strategy chosen. For Emerging provided by issuing additional stock. Specialty Pharma companies, it seems as Dr. Josef Bossart is Managing Director of Oh, and what about Auxilium and important to have a successful financing Pharmanumbers, a boutique research Alkermes? How has their stock done? Well strategy as it is to choose a winning product group analyzing the parameters and Auxilium’s share price has almost tripled, from and development strategy. numbers that drive biopharma success $8.85 to $22.90, much to the delight of Up, down, sideways. Well it seems that and profitability, with a focus on Drug investors, option holders, and employees’ 401k after a short upward trend for the first couple Delivery. In addition to issuing industry plans. Alkermes’ stock price in stark contrast of years, it’s been mostly down for Drug reports, such as the recently released has sagged from $14.09 to $7.65. Delivery and Specialty Pharma company Drug Delivery 2009 report, Bionumbers Taking on product development activities stocks. This period has seen some strong provides emerging companies with as- requires major planning and provisioning, in successes, but they are far outnumbered by needed business development resources, this case, provisioning cash for development companies in distress. Does it make sense for a including transaction support, product expenses. And like a major expedition into Drug Delivery company to consider adopting a uncharted territory, you need to be provisioned Specialty Pharma strategy? My sense is yes, forecasting, and strategy development. to handle all situations and delays, or you need but with a few provisos. It’s hard to imagine Dr. Bossart has held senior sales, to be able to “live off the land” as you go any Drug Delivery company being able to load marketing, operational, and/or business forward. Having supplies airlifted in, if even a up enough cash to take it through to early development positions within the possibility, is bound to be horribly expensive. commercialization, so it must be able to biopharmaceutical industry with Enzon survive by leveraging its technology base to Pharmaceuticals, GeneMedicine, and REFLECTIONS bring in service and licensing income. This Rhône-Poulenc Rorer. He regularly 7

needs to be complemented by a product publishes articles providing strategic and o N

Well, the overall numbers probably won’t candidate selection and development strategy tactical analyses in the areas of Drug 9 l o surprise anyone. The market has been in a deep that can get through development and approval Delivery and Specialty Pharma. Dr. V 9 0

funk for more than 18 months, and there is no in less than the average 6-year development Bossart earned his PhD in Medicinal 0 2 t

reason why the Biopharma industry should be and approval cycle. It’s possible but not always s Chemistry from The Ohio State University. u g u

immune. What is surprising is how poor the obvious. A / y l

return has been for companies starting on the Up, down, sideways. Let’s hope the path is u J

Specialty Pharma trail. One dollar invested in all up from here. But hope is not as important y g o l

these companies at the end of 2004 is worth a as a good strategic and tactical plan; plus a o n h c e

little more than 20¢ today. That’s not a great boatload of cash in the bank and very T y r e

way to win friends and influence people. The supportive investors. v i l e

performance of Drug Delivery companies is D g u r

better but not great; that same dollar is worth a D little less than 50¢. 51 52-57 -DDT Jul-Aug 09 - Opportunity Report:Layout 1 6/25/09 3:24 PM Page 52

OPPORTUNITY REPORT

Medication Management in the Elderly: Major Opportunity for Advances in Drug Delivery & Formulation Technologies By: Thomas M. Reilly, PhD, MBA

INTRODUCTION Geriatrics is a growing area of critical importance in our national healthcare system. The number of American citizens over the age of 65 is already a major segment of the US population and is projected to reach 70 million by 2030.1 Compared with younger Americans, the elderly population also fills a disproportionate number of drug prescriptions. By age 65, two-thirds of all seniors have two or more chronic conditions requiring prescription medications. Each additional chronic diagnosis adds a medication or two. Medication mismanagement, including non-compliance, under- and over-medicating, is a serious problem in the elderly population.2 For example, up to 35% of hospital admissions of the elderly and over 125,000 deaths each year are attributable to medication mismanagement. A myriad of reasons exist why elderly patients are especially vulnerable to incorrect uses of medications. These include cognitive impairment, vision loss, increased adverse drug reactions, dysphagia (difficulty in swallowing), and increased gastric stasis, which impacts drug absorption. These problems are often compounded with traditional oral formulations. The development of effective solutions for medication management problems in the elderly represents major market opportunities for drug development companies. One important strategy for addressing these issues is the development of user-friendly and effective drug delivery and formulation modes. The following will highlight the significance of this opportunity by reviewing just a few of the leading diseases affecting the geriatric population (Table 1) and identifying specific advances in drug delivery and formulation 7 o

N technologies that have been, or will be applied, to aid this population and their caretakers with medication 9 l

o management. V 9 0 0 2 t

s ALZHEIMER’S DISEASE FDA has approved two types of multitude of risk factors in the AD u g u

A medications to treat cognitive population, including memory loss / y l u J Alzheimer’s Disease (AD) is the symptoms of AD: cholinesterase and high incidences of dysphagia, y g

o inhibitors such as Rivastgimine compliance to conventional oral

l most common cause of dementia and o

n 4 h

c the fourth leading cause of death after (Exelon), Donepezil (Aricept), and formulations has been poor. e T y r

e heart disease, cancer, and stroke. Galantamine (Razadyne), and Eisai and Pfizer introduced a new v i l e

D Approximately 10% of people over Memantine (Namenda), which works formulation of Aricept, Aricept ODT g u r 3 D the age of 65 may develop AD. by regulating the activity of glutamate. orally disintegrating tablets, in

52 Although currently no treatments can These drugs are widely available in October 2004 for patients with stop the progression of AD, the US oral formulations. However, due to a swallowing problems. Aricept ODT 52-57 -DDT Jul-Aug 09 - Opportunity Report:Layout 1 6/25/09 3:24 PM Page 53 52-57 -DDT Jul-Aug 09 - Opportunity Report:Layout 1 6/25/09 3:24 PM Page 54

OPPORTUNITY REPORT

disintegrates in the mouth within T ABLE 1 seconds, and dosing is followed by drinking a glass of water. Applied US Patient Percentage of Indication Population Patients 65 or Pharma Research of Switzerland and (Millions) Older Labtec Gmbii of Germany are also Alzheimer’s developing an ODT formulation generic Disease 5.3 94 to Aricept ODT using Labtec’s Parkinson’s proprietary Rapid Film technology. Its Disease 1.5 87 potential advantage is that no water Urinary intake after dosing is needed. Aricept’s Incontinence 19 50 base patent expires in 2010. Macular Degeneration The many challenges facing 10 75 (Wet & Dry) caretakers who supervise the dosing of Indications With a High Percentage of Geriatric Patients medications to AD patients prompted Novartis to introduce the Exelon Patch capsules, well-known side effects of with the program. in 2007, the first transdermal therapy cholinesterase inhibitors. Local skin for AD. Transdermal patches are tolerability was good, as was skin PARKINSON’S DISEASE designed to provide controlled, adhesion of the patch over a 24-hour continuous delivery of drug through the period in a range of everyday situations Parkinson’s Disease (PD) is the skin. This maintains steady drug levels such as bathing. In addition, according second most common neurodegenerative in the bloodstream, avoiding the peak to a questionnaire, over 70% of disorder following Alzheimer’s disease. and trough drug levels often associated caregivers in the IDEAL study preferred Approximately 60,000 new cases are with side effects from oral dosing. the patch to capsules as a method of diagnosed each year in the US, adding Transdermal administration also avoids drug delivery for reasons including to the 1.5 million Americans who 6 first-pass metabolism of drugs overall ease of use, advantages in already have the disease. The average following oral administration. Finally, keeping to the treatment schedule, and age of onset is 60, and significant 7

o prevalence growth is expected over the N transdermal delivery overcomes the less interference with daily life. The 9

l next 25 years due to the increase in the o problem of swallowing oral capsules in

V Exelon patch, with its clinical efficacy,

9 patients with dysphagia, common in the elderly population. Currently, there is no 0 patient acceptability, and caretaker 0 2

t AD patient population. cure for PD; however, a number of s preference, represents a significant u g u The 6-month IDEAL trial of 1,195 drugs are available to provide either A advance for patients with AD. Eisai was / y l

u neuroprotection and/or symptomatic J AD patients showed that the Exelon collaborating with Nitto Denko y

g patch provided benefits across a range relief. The challenges of medication o Corporation in developing a transdermal l o n

h of symptoms, achieving efficacy management in Parkinson’s patients, c patch for its cholinesterase inhibitor, e T y

r comparable to that observed with the particularly the elderly, have triggered a

e Aricept. However, this agreement was v i l 5 e number of developments in drug D highest dose of capsules. The patch was terminated in early 2009, apparently g u r delivery and formulation products. D associated with three times fewer because of lack of technical progress reports of nausea and vomiting than the Levodopa, a precursor to dopamine, 54 52-57 of a be (S (C daily le reduce Si Thi reduce exposure of le that le episode trem (on-of effe contri and incon num a le of periphe le d and sti pro So Duodopa syst OPPO REPORT -DDT nd eca vodopa vel vodopa vodopa vodopa ge ne ta en mul OMT) lv le ti tre vide s c em le ne me t b c pro me ber Ne v ay, rbo ors, s t: ocopone ra at use a ve l doses. odopa vo) bute f ood at of ric rbidopa Jul-Aug d in ti me the oPha ry, t for s. vide phe nie xyla dev of ion m of onal disa d volunt (CR), bra , /c /c . le i of wit c Theoret (bra fers ore nt nhibit The w l i have nt t onv arbi arbi vodopa v l le nom ev n el o im in s hil dykinesia se ar rm the Cat in bl e for h vodopa oped c dosi t el st nd consta that , he iabi a onjunc it ersi ing led t dopa dopa, e l syst i t w ar a, he eady a evodop nhibito ena) ati he echol- l fluct ors, m br 09 PD. reduc ong hich name y m peripher ically, ng w li on ore ain to brain. ons motor i a em st for motor ost nhibit ty hich - /ca to nt s omach, un uations s c ( H w th b tion to uch 4 tate , , har is p in to ing o- Opportunity een e c owev hic r troub a- e patients and dopaminergic ique including S rbidopa hys to xtended onsis dopa a that m de was ine pla dopamine dev car a f dm a h a fluctua or the luctua b the c 6 e the iolo signe l s l te fr th met) is s er, bidopa ood ling delive dopa times elopment inis enta ha that combination ma pr ts ac e riz RTUNI yltra in deg numbe av e mains gic e ve quir of zing i ter ed ve d tions the tr n pe ailab a leve s copone t ha ra nd ions ide ation nsf a to a a ry nts me daily) riods by lso dation ed w s to f tay ls r CSF Report:Layout 16/25/093:24PMPage55 orm ea . a ith le d of of b of se of y as , p pr worn s t adm m i s I i bee adv O per i f part and B i bas s r of i s abs t ar abs m an 500 t i une n nse n nt nt hi her ncr ntr ood el uspe te pec uch hys eca rphan e any at ogr bet cl eas o est s c ady unf i ed orpti orpti n anc aduode of ri ompa st ape ea s rte c ca i ini ng/m if Norm t ic t use nis a as he x. am appr apsul i al nded of he te outs te e, se ne. ic P nd oldi on ia n d ed l ca uti si r D n eve St tr De on, on d ga ns st bl the ma l dom dir del c s s ea l nie at im sol com l To ov udie at i tom c , pat Pa ontr w oodst ng ) al st de pr es nal poMed as ls and i i ti d ec bl us ive ov l i whi on s i e pai ror id evodopa s rki th m ac ) nt gut addr ai i to d e polym of tly ess t ent a poundi ac er ol ar s t he TY a i es ry esti n ti hro dos l et pum in re C nson’s n pa r ch stab dm imi in poor e h lev ce. ea ent mot 9 of of s. int R- e d t ess w body, of ti a de he and ’s ntiv ne ugh beagl e m oc hours ini l i er H t odopa ent G body o t l p l i er n s Duodopa C vel he a e f al i ng ow U cur EU e t le orm RD wher t l ct t it st concent t ic e his R e ak i ge dis he s hat i t t S s lde s v f nte r opi ive uppe y, he - vi dosa or e igni t e l at odopa m s , es G l w o ev F ver, f ease count duodenum mo i a i or dogs , cal i f i rly drugs a al st ss R em e n ide ng s on i pass n rom i odopa m nd pl ndivi a tom ng fi ina D l absorpt ue, r com ge vem t o a l ai ac s r br t r pat ed ca s cont F w sm off was he eat m and r at can very pr r . l nt age edi show e. ane f ac a i s ntly a Thi i a orm e m ( dual i ead par er ent al on ai m i ent l t ca s. num h n wi l a r ent ot g ha l r s ni ol va ent b of t esul s sset i t r s i . ( ube i l s, on more ed o s, t ant son ng us ly > le s l e hi i s, s i i s t ber n ive t t d- s of he y e n t t ed e a a to Founda for form Ve Br ful admi drug met is the mot compl tab mor gr re FDA tr pr It wor dopa term year (R eff ge thi Rec ext Gl n i aly g c oduc avi al l ner i equi axoS non-g rna s e ly l ended- or ess ept ra t l et sm h l c ent is i s e s e cl dw A A l mi ul yl t ni nt t al and it tr of vodopa s al h t unde y. ra li and ass or f i hrough not pr olub al y suscept p) ea at est t st cat s orm s. ly t bi ne m i sol f , f pidly econd V i L- de ofi ast orm l r as er i on a whi tm om on, V opharm i her i and er, r 1512 i of i fav goni t s i dopa, ut nt r agoni ed ons. el l hK s r 1512 r l i e ent i cont t e ore pr t i ea n i est ula a drugs o ch a ght or The s t on. i i nov qui t in erm pr li n n s t otoc i han us pa st support c se he a b ed V te i ne’s for has ti a i la wat enhanced nd am ne s le s, st inui l s ef w c ernalis , ti n c iquid el on D ntive aceutical ss t Mi kly s S ed ombines re on becaus ents o ha i ols co ul t eff eP i as ipe PD. l t P o er, s f b n o RequipX h ady ng V1512 d o A ormulation uch ce- chael V1512, s een clude n nger sisted symptomatic impair oMed e f ervescent pass car xole ventional ag been V1512 velopments CR form pr this w drugs to N daily o to reed ith as bidopa. ocess e sho on-ergot w de es solub half J. particles company, of s ( ns pr le only ropinir outside ed has availab Mir tart motor velop w and , thr F L, f v oject. tablet with better r dopamine is o the - n odopa . om gut lives. x le ough ape an obtained Phas L-dopa appr to by ther Being pr ole the the the w wor long- le x) of and side- o- ith oach efor e to f are or k I II in e

55 Drug Delivery Technology July/August 2009 Vol 9 No 7 52-57 -DDT Jul-Aug 09 - Opportunity Report:Layout 1 6/25/09 3:24 PM Page 56

OPPORTUNITY REPORT

formulation that uses SkyePharma Women are twice as likely as men to to 4-day interval after application to PLC’s patented Geomatrix technology. suffer from the condition. Urinary intact skin. Transdermal delivery This product is designed to provide incontinence is a leading cause of bypasses the presystemic metabolism of patients with a simpler titration schedule institutionalization among the elderly, oxybutynin, resulting in reduced plasma compared with the recommended with at least 50% of nursing facility levels of N-DEO and reduced side titration schedule for immediate-release admissions listing a diagnosis of effects. The most common side effect of Requip, which is dosed three times a incontinence. Because of the high costs the skin patch is skin irritation. day. This represents a significant of incontinence, estimated between $25 Accordingly, Watson also convenience factor for patients, and $35 billion in the US for overactive developed, GELNIQUE, a second- particularly the elderly. RequipXL was bladder alone, and the increase in generation transdermal delivery system launched in the US market in 2008. prevalence that will occur as the for oxybutynin. GELNIQUE is a quick- Another delivery project that met population ages, there is a growing drying, clear, colorless, fragrance-free, with initial success was the Neupro® market need for convenient delivery and hydroalcoholic gel containing 100 mg/g transdermal patch, developed by formulation modes for drugs to treat this of oxybutynin chloride. The gel is Schwarz Pharma and designed to deliver condition.8 applied once daily to the thigh, a continuous flow of the dopamine Anticholinergic agents such as abdomen, upper arm, or shoulder and agonist, rotigotine, over a 24-hour oxybutnin (Ditropan) and tolterodine delivers a consistent dose of oxybutynin period through the skin. This product (Detrol) are used widely to treat urge transdermally during a 24-hour period. proved very popular with patients in incontinence. Both are available in In addition to reducing the incidence of Europe because it avoided the need for extended-release forms that offer the skin irritation associated with the patch, multiple daily dosing. However, in 2008, advantage of once-a-day dosing over Watson reports that GELNIQUE may UCB, who had acquired Schwarz immediate release. However, these drugs also be associated with a lower Pharma, recalled Neupro from the US are associated with high rates of side incidence rate of dry mouth than market and certain batches in Europe effects, particularly dry mouth and Oxytrol. GELNIQUE was approved by

7 due to problems with solubility of the constipation. Orally administered the FDA in early 2009. In other o N active component in the patch. oxybutynin is metabolized by the liver developments, Antares Pharma is also 9 l o V Apparently, a new formulation will be and intestines to N- developing a topical gel of oxybutynin, 9 0

0 required to address this solubility issue, desmethyloxybutynin (N-DEO), which ANTUROL, using their proprietary 2 t s

u and it is not known if and when Neupro is active and contributes to the dry ATD gel technology. g u A /

y will make it back to the US market. mouth. Elderly patients are more l u J sensitive to side effects of these agents, AGE-RELATED MACULAR y

g DEGENERATION o

l URINARY INCONTINENCE

o which often lead to discontinuation of n h c e

T therapy. y

r Perhaps in no disease area are the

e Urinary incontinence is a common v

i To address this problem, Watson l

e needs and the challenges for drug D problem among elderly individuals, with

g developed Oxytrol, a transdermal patch u r delivery and formulation greater than D prevalence of patients as high as 15% to designed to deliver oxybutynin 7 those in ocular diseases, such as age- 56 35% in the 65 and over population. continuously and consistently over a 3- related macular degeneration (AMD). 52-57 Enc the c transpa im plat a hav im im nonbi preva and are conce syst of are Ph deliv in vis repea Am ey 50 defi reti medi drugs. associ sid t ta Ideal AMD -DDT he i OPPO REPORT l l rget vasiv e ow ia pla pla pla arm the ion e or na, e be no bac ma form. eri apsul em niti in m ry One ef eri ly, ca be te le ed nte nt nts. odeg ntra ol ing at a ic ca e is ac fe Jul-Aug an cul loss Ho appro s e insi ne k d rent ti nt nd on, ng y en der ed drug ropar . tha ct t ns, ons dire d e, e ca y of intra at hat such B urotrophi ti ar from we utic Neur studied, s c rade de in ge dr appreci wit ed , ec used ons i many in t onti , ge t t a a a ved c he ver c do ugs t rel net nd nd is ause t the ti f vit a the tly he onsi her the Cel l h fect exam cl l’ able otech's of of nuous t confined eye ease s, not sys ical hat 09 real l by i t e centr treatments to ow to vi s opica apy int bac l el s dr sts AMD, NT ab f i of Te c the t ncluding ormula temic the der the mo the and reous ly us rea - lies pl ra ugs fa le r th injec k chnology the -5 of for etina a e ing ocular ther Opportunity modified devic leading ctor l er ly. re of l ch qua dete 01, re poste i biode oc between huma portion f s apeutic A difficulties dry or to tina tha de tions the Curre humor its the apeutic Ne tions ular MD ntities upta a (CNTF r adults e for liv long n iora n nanopa rior delive A urotec , e gra is ba n RTUNI intr to ye. 10 ery c MD. ( ar , k s the ntly, c a ECT) c tion to of , hould a e de ells use , s limi the per e k a million nd aoc dos egme By a ) of age s quite ry the of a mos nd h 9 rticle ec into b iods t in Report:Layout 16/25/093:24PMPage57 of lens of that t ula he e le the d re be of nt t re te r ce pr pl c i s s announc degr phot gr s geo 1. m t C gr pr s gr 2. r com pr del 3. 4. el f n echnol epr or tudy tudy ta eve a Bonne ma Vi 2004;38( outc Ne Kel Ma pat Ca onti der ast edi oduced oduct ovi ow ow ow ll psul fr rt k re ive ur rk ie usk le gr drug s ome S ese nts ol et y ont pl P ra ore ada A, Re i r ly cat oph ha pivot s. th th ing de BJ, t c, C nuous M. aphi tr s o re Ma i f 2) rm. De ia li l e e of n or n. Pe at : nt J cogni ogi Opport 303-312. pat cept s A drug ci xwe fac i whi diff i ti d nce ed me a i conv 2007;25( 2005; te n ed , si on pat s deve ger P rs nd tha on. on wi dic N ll a in a c b al en t r es ma ie CJ, tor th a n uniti Re hi 11(3) y at mor use T- a ch RC at ie m or ion i r i adv t sour nts the ways st iva Hoga 3) t at i n eni del s REF t In tha es pos . e ion 501 lope rophy m de nts a ana :577- he :231- s Al a st udi ca C, SU c al dhe ma a ri re the i es zhe TY nd m n i port and ances Le Mar ence cont iv nt c i r t D l re 609. 239. pab R gine of it c genet i e ow e wi gem B me e of ha nc es drivi e r ERE r port ery i MMA popul W . o t ive t ke l e ger n s M r nabl i le hat or C ’ a a s na ant t nge ea pr ;2005. m , (G l s t ch the i dise i as h done , a S e he t n sur ong nues se nyde ent s t ia and proof and ot i ng AM s i a Phas he in e NCE of i pr A n G se pe ca me e 2009, t s e mi n b tr at e e r r he i ect z RY a ni me gm ) nt, EH m i usi et A ne es nd drugs l i l or bac pr re ; si C i in c rging ly perm f c on pr . D s. t mi i port t or i erve D num w ormul us gnif o N e na. i - scui A ob hey S ng e nes popula l rug r n d ua of e nn om engi nt k. i la U I TF i c l ha nv N ogni ncr te S I 2010. pe le P c - a ha . s, a t ge C s r concept r ea The t ic eur cl ng ber hem sis ot e ms pl nt a rma s ol t effi o r i nd ia se v N pr st t neer ease at ant e e i tr bl l tt e an nt c vi ni be he impa ic ed ings. r othe TF ti ot dyi ote i pa a a of of e drug ca on l ng cal on th tte t fr ech r. irme t e J e . t o rns c ng in Ma o i gy t om d s y, he nt. f nag or a 5 6 8 7 9 . . . . . i As PhD Di paten also from Uni th com Pharm dev i Pharm com senior dev He deli licens deli th the Fr 2008;167:390- Pa D a fa F O T tota pote Re a n nclud dults: pproa or e ri nukwugha c olic nns r in tor kinson er e scov r l e ose s ntia c i e peer- va D a s t h J ociation, c versi has elopmen elopmen e sting c A very, very B onomic t st f dt com m panies L. h. he l or , , i igimine a i Logr Wi mpa S A t n A dis ts in Boston ur erciali L, e aceuticals aceuticals he m i age ery E, t r Fellow ine level e nvolvi t e e c Link , M a 397. osc J g vi ov nborn bur t review licensi - Zuc se ty pany’ Ma r ew techn of le e pa and icrobiolog an ino l Uni i A a P A R G O I B de services a n k er ne na ka tc C Depart t of r , e e a n e and L, h. rm G w JS d g ge dvanc a d of t t t zi i , he ma Ca Eur C , S roles t a G n 20 r in vers holds Zha ng te n ommunity ov e s has programs and r a fir ng technology c a o er clu e IH a zi ula e ologi tm e ed ng, N . d r st s ng r no f Cardiovas 2009; ac e his , a e W r a ur c tr M y , . nt ge novel ti ia dege X JM, th a i me di olog D several v s de full fir Reilly Dr. BDHORI c ears nsde ll , . j ty . e D His over N , i R&D 14 y H Ne A o to M m bla H a n e n ne Kurt oneyc a r rc MB four y ll (4):S es. m Rev. e c velopment urnals nd urol. rma . n y ra dder h a Ki g an of lt pharma American D tion Opht t. from h et Reilly Thomas range pharma, h nl l , experien 90-97. 2008; utt that of T. hni A BTG (BA ay C 2009; t formulat i agin , re 80 A n experience oyne Delaware. through Inci He ha AA, a c JB t differen tm includin al he t C in cular drug lm is 3(1):20-22. bus ZONS, . 72(5):432-438. ly H) denc e . Y H com P US KS DuPon ol. Le nt publicat reval di Rutgers and S earn g, provides Finan Foun se for v : , urv t directed of 2009; e he erse Va a in sne a enc di Alz nd ey. t ye s panies and sea ces drug es Diseas popula S busines V 127(4): a e re and Am Heart M hei ion B DuPon , r ed of se LLC, ma Mul t 2050: , der g t s me Sa ce -spe . a J ini nd He ti addi l Epi r’s 533-540. ins ion on his ng in c risk t and i he di fi dem ne C of of risk . a c se a es D. is t s a J. i s se ol The of . –

57 Drug Delivery Technology July/August 2009 Vol 9 No 7 58-61 DDT Jul-Aug 2009 - DDE Henkel:Layout 1 6/25/09 3:25 PM Page 58

HENKEL: PROVIDING ADVANCED ADHESIVE SOLUTIONS FOR DRUG DELIVERY SYSTEMS enkel is a leading global supplier of adhesive systems for transdermal drug Michael Trisch delivery systems, offering a wide range of innovative products coupled with Global Business Director, Transdermal H confidential technical support. With the acquisition of the National Starch Business H and Chemical Adhesives business in 2008, Henkel gained a business unit with over 35 Henkel years experience in acrylic copolymers and one that has been an integral part of the

“A number of factors transdermal market since its inception more than 25 years ago. Today, Henkel’s portfolio contribute to our includes pressure sensitive adhesives that are approved in over 40 unique commercial success. A very patches marketed throughout the world. Under the Henkel umbrella, the Transdermal important one is our committed and team continues to offer the same innovative DURO-TAK products, the same level of undying focus on the manufacturing expertise, and the same high level of customer service that transdermal transdermal market patch developers, manufacturers, and marketers demand. Drug Delivery Technology and the development of close relationships recently interviewed Michael Trisch, Global Business Director of Henkel’s Transdermal with our customers, Business, to learn more about Henkel’s products, innovations, and business strategy. some of whom have been with us for more than 2 decades. Our Q: Can you provide us some chemical compositions and performance customers know that insights into Henkel’s transdermal properties. The DURO-TAK brand also we are dedicated to 7 adhesives product portfolio? represents our platform of polyisobutylene o

N the transdermal

9 (PIB) and styrenic rubber adhesives, which l business long-term.” o V A: We have three areas of focus, or platforms offer additional options for transdermal system 9 0

0 developers. 2 if you will, within our excipient offerings. t s

u ® g They are Henkel’s DURO-TAK transdermal- u A /

y TM l grade pressure sensitive adhesives, PROLOC Q: Why should patch developers u J y

g bioadhesives for transmucosal delivery, and choose DURO-TAK for o l o

n TM

h VELOX MCS (microcrystalline starch) for transdermal patches? c e T y

r multiparticulate delivery. e v i l

e A: We’re the number one supplier of acrylic

D The cornerstone of our business is the well- g u

r solution pressure sensitive adhesives for

D recognized DURO-TAK brand, representing transdermal patches. We’re confident that 58 dozens of acrylic copolymers with a variety of 58-61 DDT Jul-Aug a re the DUR throug com To al for de tha supor produc two-fl and throug i conf asure syt wi wi de expe son conta a int t Q: when DU RO- T do cu m A: pe so l bee n hat nd dhe gula v v thi th ub i mula r of thi ia el el re DURO - em Can ug Dr apro sp ou Adit rie sive the te n O w de op oper the c quis s t l a f t d u te it his en t t, y or r t d, . el -T t rom ecti d: nc 2009 nicates e s, nti he t t y t m Patch d c reaft a m ransde ion nd, l a hat AK AK cons DU ust n ed e s f val to pr nd d Mast i as by ali t or y t on onal y t supor e emo ns t and TAK ransde opti t t ve? ompt ust r ou Henk he heir omer provi for w th r ty RO- eff ma er. regul acy r a t br - a pr ider t he e de his wi w er ou de a m and oce know- DDE ic tec actur nuf w t B e s us ve he , pat i p pa , TA al li de s th de t i ve el g F e eca or xpand al r be w erf y ator cr rat e expe , cs d mal , ho l s i i ne tc ntly to ’s hnical ope sa les t r e k ch , l it our He K patch r hi r Henkel:Layout opme the or ed . use A h and an ans ut gi ic ed s s under f how, wor O nd . ta t upor e is ma de PI r nke dev ve delive rs al ge ty a as t t expe ur c ing ff inov he in der n the of velopmnt us tec we the ar k excipent a nc d i nt pr tes o of elopr l pos de goa upon nd orde pa tome ye e f c our ma we pr str e hnical c oject tiser f pr lose ar al ting, dr yr ontrls e t i ar the ative ha ovides s to c r l tsxper ict ll oce l e ib s ug h r s. is t s rs do m ly le. to s, is s , . 1 6/25/09 3:25PMPage59 low pro s li pro tra te tra w b dev w re c id spe a sup di ev rhe we ha a id a c of- t NMR , mo a c th Wor k mo sc de v ol oll bou na na ha na ust o y po ork he a spon en rec en rou ie er s nsd nsd m ut l ol v le de p e lyt lysi rac lyt po e e a he ab oc nt i phi Ad sp F re yt ti ti skin en d e lop lo p re ion t t cu og me gh ur in c li fy i f tr with -ar tr ic ic er er ora al hin t ec rg ou c st s te om siv yo he ng dit s, GP ll supp ie ca la g th om ic th ers ed al al s ma ma o riz rs t ic ia our re t s. he r ir u a te wi al g roug e, u er ti io of i ple re eq sp ec li C, ser rg ou nd n p mo merc r rit to Henke He d on at p a l l fro DU kn more n sts fe on re a th w sou or right r c re o D u pa ma ion . all i t n a u and v ustome , m ma s e el r ur i se nke d ow h tion, t a m UR gs pme th ic ia l c e in tc in p p R hi e y c l y rce o l rke ia om n d ma ysi roje l , es a li st ese R& D O-T te d , he pre we ha v ing ghe T ta in de l l’ pa the liz ev syst mol th we O-T by e I s ria s hey expe nt t. s ti ny l s. posi rg oup a s c at dic ar e a ble pa a He c pr o on. mol e nd e dr AK t a rs. r S spe n a a l hav tio o ts, wo in em ec -t c AK n’ He n ye o w nd so re ug rg ou p, a he S ope nke e IR ti r o pr ie goo W t ul n. te ork e suc o no Pa an c rld, sti E d ts lubil a e ona f P nke . say mist th n-sit ia c th e rs d ar mo M. p hile T t IB pro an a ula d ra tc ng l suppo o lis t at oly ma d h ta to his h o you glo l str d h a te l d ve e ity po l T r as w are f r r vi ble he e an we is n y s the wit h y tte me our HP he uc use sta e me te ough b ding in lp to a d ym e for a ca a tr r a ture r to s rs. te l L s m ed nt ou n in a C, - s r r We manufac TAK A produc Q ar Q guide Sa A inov Henk The ce re numbe adhesive and With whi deve wi alc re and tha s they Cal Dr o cust ac the u nline e a s : : r r ppor : : lisb ll ug ohl is t ir tif yli ct c ch enab se have ome Where What pre th We I m suppl u lo ta req ive AP -In-Pol ie lin this tra c la can ur at ee nce pe f he r t, tool d c a solut el ati tor. uire es. ma r nsde y I of rs isio ts l c ugs dr He expe s rs esi lp a , i dev ts? iliti i ma y ’s ng thi nd n t NC, t t the c ons? hat nuf we Th th o o In n us a st . ture yme n ust are ions. a nk r ke nuf el re es pl a se follow col rie ll DUR ance ma doe ir i is a , t to a n oped se del ome l at or ddit e of c ylic- acr c e a API of n a r i c d m l tu na vr re f ent s c the c c some a S ms or An produ iver our ont DUR e turin f ind s n re O-T a se w e ion, o b l r , IS ow, adhes le IP lubil co pr de ith kno a a Henk veral s twe ou inua , O ol nd ud s D adhesive e E A ov the nf li g uber r we f xcelnt ubil r c ou U god and C 9001 v w its r K or t e ity e ide ide O-TAK D p, of e s ll RO -GM xp x ives r yr p e He a y UR hos in higly pe e i xamples a Be dhe n el ty a er t impr t -T go tia he c c r n O- ti tis t lgiu P h h h tha of ke AK s l al se a ybrid i ye e v l o s e m. v a e r . , .

59 Drug Delivery Technology July/August 2009 Vol 9 No 7 58-61

60 Drug Delivery Technology July/August 2009 Vol 9 No 7 DDT uniqe adhe offe Adit inc e cha adhe and Also, com skin, suc pat St coplym te Bi promt dev phase Q: adhe He ad sy A: Bi polyca polysac Bi the singl is de a va Jul-Aug st nd chnol arc rious provi l oadhe oadhe s a pora or che ive oadhesiv vant ngi e m b W r n te We a a pet e lopm siv siv siv e l h dhes c y and sful y act anuf iona k ishe r we m ug dr ros s rbo phase. et hat a ing en og e c ng therapui es e es c a hav nd tha sive sive ust ha e l ’re ages pt bsor pro project tes 2009 ci off e ent devel r y d regul xylat ion l y to tha P t r our m pl Chem o om es e l st a ide par cons , vides oadin ROL gives dem m pl powder ure a ucosal atf be ems r is proi P w scien ec in er enab e r? et ed atf U y ator ROL op pro e io an - doe our or s a ticul tanly SP polymer of drug onstr wi ne i n c m. or nt polyme tha g. d m ca DDE f s cus ge spe god r OC uper s age le r -g ly e l e the om ac a mebra l ites Another s y ietar f ntle ta ds. r t mater . or t da e USP C c ic cif dis begun ylic r ated omize r ade O y r ar the quire nts ontiue Henkel:Layout wor es P This ior our . ys, Bioadhe we tra deliv ur pe ROL The r pond r proc s e r -g loca ial, king cie into nsde PR our ar means mo and e rs block whe N ments. ftsfor d nes ed- re ade ationl on nce es OL val. whic l y er to to c a malr C n s on ent siv at y we f to or C e 1 di co A: come must adi r ut ca PR t Thes absorptin and i b B on projec detail Q: Q: br pos A: devel sor i ov O m whi ca bi t o ntr por ncor echnol ect uca ioa 6/25/09 3:25PMPage60 ur re il ucosa oadhes and. n pac ve er be es cl iz an l al ct Wi OLC W Y al Can -t w t e ib ri i f dhesiv e in iona , ed es ide it -c he- l/ so e’r ng re del r hat ma abs opment? We sal y st l sub ha ogy s , ca ompr . th it ma as t at e al i be ive c for s y al ive l c rk nde about rcial , l pti or ount I ing l ome li pr ve you ha a and oking l tha e in f wor cur entl al et ca pr ca ngual or y r t pe higer powder oject es i ve hes ed s Bioadhe ovi ng n st t be d. f e on the r si k, is si sui oc lexib i r of m for te a s unde prov i e form nzocai on The rc des gent b nt tes, st PR , s. l ula ye num si t t abs uca t t ia va e he i o t echnol o t ug dr you l ta . d hes t es l OL l anc r super a The gi r po l ta t pti or bl anot pr f e y del ide o be t or t t ? l ty ha ne ke na he he et hin w t ity oduct is e be t in o r sive l abl iyver . ed, ve pes der l C oadi pow w ogy, for her on , of i on t t O v or any he hat st i f i in et r pr t iable and udi proj h l a ca si mout m der ng i j ov of and bas s e t t it n he e l e or a ® en ec s, i d. s be n t e h ts d adhes PRO a ar such pr B f PRO pr A: Q: l t t perform Q: po ph t to for A: Bioadhe er e acr tha ar do to e to to ne arger o hat r m or xam p xam p m ansder ut var e ea odes om oces eds ys wde ma er s del n ha os ev e ma One What In H no od pr ica a LO LO PR t rode , i v as is nag e hat er et ive ion o f e le, le, t m n ovi r) e o adi t ing or a a l f a y m ed he y int f C C b way , w ol f l f f r the OLC le r o w a a l act of at va the enab des da ’s e et om al t ecul B r xib il i t m r anc r her xam t t e t siv t nt he m long ans h a . esul ria awa ion pl ys er about or, i abs a a ucos bl e a oadhesiv i H i o act f ppl ic n s f pt bsor wit t at re , apeut ra bl l mul or he es w a e ity es ( o ple de a f pti or t vin g e f t t es t al te s? ilm hat f s o m or ve ab hin cou l y? t a com pr pen t tha ue r c of wi f ati does , of pr he vacinto, Bi to our y r or le ca odu c i has i f w c on thi n on. od a s ator t on. t, t m or d e din g c n f aid h deliy ver PR p e oadhesive aplictons excited it. benf ill agents r se or ons ma it ilm, f b osi ared uct alo e mater site genratd e , t complet y s er the muco- th it tte D is tak ide o OLC the de on with ode ver n. at w eliyver th r tak to ve , e sys r, or , of t acr ial Fo s e for h about. th satily lop e . bu of s e a an oo te F h er r e os is or t our wa m e ner w d s e y s 58-61 DDT Jul-Aug prot exist re ne and Bioa tha of our syt dr re re re bra apli line syt of man by si unde re A: Q: A: be P Q: low posi one ina f de dire posit c RO w form dir the the u eiv e ar f nd. e s em em What ori ec nci As The Ho via po e n r in gs? e dh ug dr rw ca bil for ge xt ra ffe c ed dosage, t LOC ec PR i g ginal i si ti ion, , Exist a reci t es s b ay 2009 ens oned I abs peuti m it ions l market w on c le ugs.dr t te exi pr ulati se y ver i ting ion ive OLC retu t ent es mol s, f c ions pti or aven oduc e or has extendi and hnol st are , i pos wi rep c . ng i can or is: and - in t, ved Bioadhe b ec By wel ns. e ng t er oth and re g t ue a f on re dev h DDE t it o pr ul PRO he f es nd the B pr s gy the e l i s c w t l for r i on. oducts e ulting c aking . ompunds. a i fe for ent ng ca and so OTC ovide s oadhes elopd bi e e ts W pid extend ha cyc Henkel:Layout m xistng a LO n . a ge e Simply the Henke nd be delive re tr ula s , f imple r ha ar? em le dir a C be adva a in st c si pid the a c nef life tion nd ve mingir onf ive an into en ec uniqe ve pate ben f ndous y r ewer pr Rx t onse ntage be s of it Thes of taed l ojects of ne nt s nt itf a w t of e , 1 6/25/09 3:25PMPage61 exc about exc about Q: dec has Q: (microc VE w hav w dev on i t sm phys sphe area Henke A: excip cont ext A: sphe adi r pr di V ( ar f s o el mi ri e it ELOX e si ovi our abi our eas ot usi r the h ip ip ade cr e el ar nteg a What What V A r t L roni re ic ls ion, our ast ding be opme ys ocr li e . contrib e ELOX ent ent h, O c al o s num suc VELOX t of on tr s. dei om y, of r i s ans Henk X to za uni n a l’ n pr MC cus Our VEL nt? uit for offer a t ces sph rystali r po drug s e wi hi ti nt ta nd be ope api t ca MCS s m der f ra can busine e on, t i l m or suce gh S M d s. ome t t i r e e of t cust di h t n i t rly d OX ed xt r i ti r ed ne he of com ut f ng A CS oni MC ti us el’ or yi t off and cl usi r he es al onal s rs t sol deliv act f and ed ce y ver y om re el ose o pher MC w za ent for er s i ou , pl ne ma t S d G s sul l s t e’r on- o com ubl som ing t he er ne et or ul a I i w m i er undyi r MC on pr S mor s rk nothe t e e el im s t ely ose) i i s in tel starch) e i r ery? t s an ng t strategy ost oduce c pr w act y ver et ra kno t pl at e h cont he ugs. dr pr t por vi C c e oduce m nsder i of et l l and y i onshi oat spher o , oc , a ng deal r t w es e our us w han to whom t ri new ant e es he ing. sent t xci f b t hat oc s he ut I s ps e . 2 n one s t al us e ed i I al n year de usi b tec re a manuf als re cur in re he chal solut solubi easi tol in pos thei enabl the hi sam entr wi be sta vest c qui ghly dic avi hind t cl o bil hnic ent h si best r er, epr s e Wi le nes s, ose, t i a r bl nt opt ly e o at i to ons t ed em ngi ly t l i w y i f t ski e. s en our m ed al ant t t s ct h le r i uch m hem y e of i n egul i and si ent c m e, l uri nv xi H t supor to ong- l hav ak cal i onf gl i R ur gni ci um cust both ed enk bl t est s. ng & obal he as our ugs. dr e . i pat at r cul al e , e i f N esour D, our W dent t ed y y or r pat el t m er can- om aci f i cant espon he aproch. e n at wor cus e get , br vestd t i fu r or t ch our ha n c er eam, ia ans r d lity. . i W ces ustomer do ly equir tomers ture . ngi ug-in r lds. a Througt the s ve l A as e tner par ne to malder to customer ive nd have of W in icently eff long- and in The w de emnts met vestd e Henk we tnerpar A adhes a velop polymer f ha ’s t or y creatd we ship mter the work job ve get el s ha ive and the get a ve to as

61 Drug Delivery Technology July/August 2009 Vol 9 No 7 62-65- DDT Jul-Aug 09-Tech Showcase:Layout 1 6/25/09 3:27 PM Page 62

MDI COMPONENTS LICENSING OPPORTUNITIES

3M Drug Delivery Systems has been a major supplier of metered-dose Aveva has numerous products for license from its development pipeline inhaler valves and canisters for more than 50 years. As the developers of along with a full compliment of R&D capabilities to produce transdermal the first CFC-free MDI, we are experienced at overcoming the challenges drug delivery systems that fortify R&D pipelines and maximize product life that designing components for use with CFC-free propellants presents. 3M cycles. Aveva Drug Delivery Systems is one of the world’s largest is the only MDI component supplier that manufactures both valves and manufacturers of and a pioneer in transdermal drug delivery systems of canisters, allowing optimization of these components simultaneously, providing pharmaceutical partners with fully integrated, controlled-release ensuring compatibility, while delivering the convenience of a single source. transdermal products that fulfill unmet market needs. Products for For more information, contact 3M Drug Delivery Systems at (800) 643- licensing include Sufentanil, Fentanyl, Clonidine, and Nicotine. For more 8086 or visit www.3M.com/dds. information, contact Robert Bloder, VP of Business Development, at (954) 624-1374 or visit www.avevadds.com.

DEVELOPMENT SERVICES PREFILLABLE DELIVERY SYSTEMS

BD Medical - Pharmaceutical Systems is dedicated to developing prefillable drug delivery systems designed to fit the needs of the pharmaceutical industry. Whether a glass or plastic 7

o Azopharma Product Development Group, The Total Product Development

N prefillable syringe, a nasal TM 9 Company , is dedicated to providing clients with comprehensive spray system, a dry drug l o

V product development services from discovery through reconstitution system, an injection or self-injection device, BD

9 commercialization. Azopharma maximizes communication and Medical - Pharmaceutical Systems provides the expertise and 0 0

2 minimizes downtime by bundling services from key sections of the drug experience required by the pharmaceutical industry in a packaging t s

u development process, including the Preclinical, CMC, and Clinical partner. We deliver cost-effective alternatives to conventional drug g

u phases. Our capabilities include Full NCE Development, Full IND A delivery methods, which differentiate pharmaceutical products and / y l Development, Full NDA Development, Full ANDA Development, and Full contribute to the optimization of drug therapy. All of its prefillable u J Medical Device Development. Whether it’s a stand-alone service or a devices are designed to meet healthcare professionals' demands for y

g comprehensive program, Azopharma has the solution to fit your needs! o safety and convenience and to fulfill patients' needs for comfort. BD’s l o

n Our group of companies includes Azopharma Contract Pharmaceutical worldwide presence, market awareness, and pharmaceutical h c

e Services, AniClin Preclinical Services, and AvivoClin Clinical Services. For T packaging know-how allow it to propose suitable solutions for all y r more information, contact Azopharma Product Development Group at e regional markets and parenteral drug delivery needs. For more v i l

e (954) 433-7480, [email protected], or visit information, contact BD Medical - Pharmaceutical Systems at (201) D

g www.azopodogroup.com. 847-4017 or visit www.bdpharma.com. u r D

62 62-65- DDT b B a s r Di s d a e E likel eff in in ww out the fam cycl candi estab our bi a Jul-Aug ol tr ct l n e r u i so o f oa te u f h r e or t fu or u i ri a g and licen he o anc n odext devel ily w b in y vail pplie s s a mat c ts, be n. gth, le dat e lish B nd aps .c ter wil a a ® of Eura e nd cute we abil at y drugs, us se ion na i es l IOA dex ed e n d drug op r c require en is ins) xte ed www. cre yclo drug ou l to ity, par , ut m nd’ m r tail a care con 09-Tech pha esource nt r in a ilizin en , e ar mu de s saf t V the ses s C wh na ner olu o com mor ke com t aptisol tact d pro eura AILABI rma x f S bl and ety, hospital ltip reby ich tr g ts. ab PK bi t wi e ins he PE pri our e bi bi li C artic s, sorp .co form We th are ty nd. and/o co ext p yD nati na etary “i en desi exp rofil technol C drug in estab mmer ntrin m Showcase:Layout ex ti ensiv co ul ha tion a han ul on on setting IAL . th erience ate e, gned r paten m ve at ati Biori s. e dosin L si wi f ci an lished ormu o e on ci (913 or GI c de ogy Th IT syste ng f th T alization dev d d dru t . se t e velop trac e of o iss Y o Fo , g o the mai pr Y )685 to lation pti Di and th impr elopment gs an i of m p otected r ol nso t. P er ffu ir har thir mal those E l utio d ed a th from Fo us ‐ b t ove ca Eura lu H Di echnol 8850 numbe m io at N of d technol r a bl n rele ps at ffu ava a par m A pro p po HA , e ra pr sol ora co nd rovi ore spe pa c R dru an drugs a r te” ila od tie aps o duct tfo mpan ubility og se r rtne l r MA te d de bility o 1 s. uct cifi g- do info N of visit li y, of gy c thera limit designed drug phar i Pharm Cy com the com ® com pr o s s F hno re sa AP cally r we CEMENT candidates te or a a of of poo cand s@ Dex ies. rma f , (Ca 6/25/09 3:27PMPage63 lea lex nd ch ge dev a stabil specialty ations Is. ile merci pany mercialization m s more logies product nd/ pies ar e rly s ptisol no specifically ible aceuti aceuti s We t modified t To ur fo e idates elopment o e ion, o fo lo rms. and. sy wa ity focusing impro r to focused in max aliza r gi al dos of ons to st ® , vis s so e t ad selected cal cals, ingle er em f c s curren tha or imize a tion it o et dress - ve ca g m. e use c t o and n Inc. t a on on f of he n t C ( co au ha in so T re o ph m bi co 2 e v 01) mp ma o to-i v u f c e l OMBI n a o u e p l hn r t rm t rm t ha r i si i ani ny njec p t 457 ol on he o gnifi l a u r e l l e ma es og ce dis s l at d- a -112 n tor t N c u e i can o e in ea e c re ti ti xt e N s, eng t e v c l s th h u EW ea e 0 x t a 5 e e I t ATIO i e n l ex i st ch or c i sta s ye c in nee a f a e i ield . per n ng e , d vis l a te d pr m a u pr rs r A ienc t s s s it . b p o ic o . t F ( io a f an and ry w 8 d Fo a i or U N te l p 1 u es l ’s w e d h r c 3 co n mo T i ts a . w ) t t te mo h C n hera echni Th r m O 8 i . . m g d re part e 3 I p hl r t A e lc ac b 7 - e ou inf i peut y l - s d a I o cal n PS i e 0 n e m p n c o eri a ut NJ 79 fo l u kb rmat d bet fle E inj gau inc Flu lea Fle and and is ly for m aut med i -m v ve ic st i bl lc s ng r ophi U ca e an 6 e f x ma w p p p p c U p t b o T m I e c p u aff d xi- am orpo or i n i w o-i i he r d r cla EC ib c d c ap ap ge, n f n h ro a h ro i h a s e ti y o ing y l V i o ne d agem icat LE wi u rugs ti i iz ll ee te ha ti te ar ar e on, p ilit l di r Ma Q ital i dru p evic ti d nject on iz liz l v b sy has e nd sse s s e t i h e b Medi t h r r v id o nt n i sy i m m l n c rate vi f y u u i h n n ff l -c em Ca d a w e i n TO e f i ine a st n d d on n al s u le la co ec gs e t ce ti sco d rm e -p S in a a 0 g s p rm s. es. , in s orl us T a i r n o s l me rs ent. e work r t i c c p t ors .3- s r i ugs .com harma , c gns form, geme s ntac e m en c tr e t -b tw e m cus - e e , c of O www.in o in a i v a ontact t . d tr ac e sity ed m v o n ies h al ECH a u u As th ur R ia p ce the . T u n wid 1.0 a n e t y f o- d e ffe pr t t d a pre Fl E a fe r h d e se ls se i i e tomiz w phy rec M in ed c t ut esi ca ca , so u w to lca rt uniq e d u an v e . p ovides w rs a L nt, h Elcam inje a c e ti it te o ceut g in onito d a edic ml, me d xi- ti o- ie ay fill n d l l ea nd l ti c nly i h gned entl r w l m u c OEM t sical c ue m a OEM epackage e d Inner a c c n I t a h liq inje ed Dr b al Q ti ue o hn it ct ex n l n NO o e l ati n el n to g l NE ne iv th e o the u Me ical h ated beneficial mp f uid d er ta y an ring io DV ug e a i p ns u h a lt pi e o s on: v ct u c plat many n deliv edle M n lly r n t laun d a i l fo y ry l er cap.com s a -p phas se d h i C o d r o pa h ors d Fle ze rd ri va a D uppli co ing edica i or re to ica f e du r g a ap s LO y orce nge n te s di dos h s el d form b rtne y n l d n ys i mpan i des xi- ys s che as sy er spos es le am fe- en c iver l c for c to he o pate e l ts i e tem e ngth s ead er and a te s ff e st Q , , s l e r, G cy . d ge i . d l d er a g self- at a y, fi with of m l e B w PFS w of able , n n cle t ies its m s . ing Y oth s nt s d ed ith e & . s

63 Drug Delivery Technology July/August 2009 Vol 9 No 7 62-65- DDT Jul-Aug 09-Tech Showcase:Layout 1 6/25/09 3:27 PM Page 64

AIRLESS BOTTLE TRANSDERMAL & ORAL FILMS

LABLABO’s new EasyFoil bottle is fitted with a pouch consisting of an aluminum multilayer film rolled up and welded around a superior ring and an inferior cup, both produced in a thick plastic material. The film is composed of an exterior PET layer and an interior PP or PE layer wrapping a central aluminum layer LTS Lohmann Therapie-Systeme AG is a world-class developer and of 12 microns in thickness. manufacturer of transdermal systems, oral film drug delivery systems, and Depending on the nature of the adhesive laminates. We use leading-edge technology to manufacture product used, the internal layer developed products on a large and cost-effective commercial scale. LTS choice will be PP or PE, the ring and develops products from inception through commercialization in our cup being produced in the same facilities in Germany and the US under GMP conditions, both approved by material with a sufficient thickness the FDA and European Authorities. Our partners include many of the to provide a perfect barrier, world’s successful pharmaceutical, consumer healthcare, medical device, especially against oxygen or UV. and diagnostic companies. Our resources include research & EasyFoil accepts the most viscous development, clinical pharmacology, technology transfer, analytical, products (> 100.000 cps) and the most fluid (alcohol) and offers excellent regulatory affairs, quality assurance, operations, and product support. For restitution, the bottle could be used upside-down, precise dosage delivery, more information, contact LTS Business Development at or containment of the pouch at a stand still position, an ideal packaging [email protected] or visit www.ltslohmann.com. for transdermal applications. For more information, visit Lablabo at www.lablabo.com, or e-mail [email protected].

DEVELOPMENT & MANUFACTURING KNOWLEDGE MANAGEMENT 7

o PharmaCircle is an innovative knowledge management company N specializing in the drug delivery, pharmaceutical, and biotechnology 9 l

o fields, with a current client base ranging from start-up life science V companies to world leaders in Big Pharma. Clients choose 9 0

0 Pharma Solutions is the Contract Development and Manufacturing PharmaCircle’s services and content for its comprehensive technical 2 t

s division of Piramal Healthcare, a leading pharmaceutical company in (pipeline, products, molecule, and technology) and business (deals, u g

u India. Pharma Solutions is one of the very few Contract Manufacturing acquisitions, royalty, licensing, drug revenues, market information, A /

y etc) related information and analysis, which are ideal for all segments l Organizations (CMOs) that can provide end-to-end support for bringing a u J drug to market or managing the life cycle of a launched drug. of small and large companies. PharmaCircle helps facilitate product y

g We offer Clinical Phase API synthesis and Formulations Development life cycle management (LCM), partnering, licensing, and competitive o l

o intelligence efforts as well as supplements internal efforts and costs

n services and scale-up to Commercial API and Finished Dosage form h c

e supply. We seamlessly integrate all contract manufacturing services at a fraction of the cost if performed internally. For more information, T y

r across our global network of assets in North America, UK, and India to contact PharmaCircle at (847) 729-2960 or visit e v i l provide our customers with geographical flexibility, reduction in drug www.pharmacircle.com. e D

g development times, and cost competitiveness across the product life u r

D cycle while maintaining high reliability and quality. For more information, contact Pharma Solutions at (732) 549-9451 or visit 64 www.piramalpharmasolutions.com. 62-65- DDT Sa a pr pr in tr bo 54 w in w sol na A Jul-Aug a queo j s it for o o w e dy, f 1 no-size n ta ubl h e‘n’S t t c -9 e e spa w m tio nda t ct ct he .ph a e 7 us ati io io n nd C 0 re com o rd n n 0 F on, withou armaform S nt, und d DA a ONT fro a o olut s pa s r pou s 09-Tech yrin con the pri m v P and the pro rtic ions isit t nd. ng ne ASS ge tact Sa an vid les syri the RAC w ). ed , fe‘n ( P y EPAS th .c ww. es F Ph t harmaF les ng hat a or om D e I ctio ’Sou armaF he EA e VE Sa ti Showcase:Layout m rex ), ck T . can re alth ore n fe‘n an a nd s tracts am b or S pr d to care S orm y help ’Sou in m’s h ocess ERVI is .co th avo as A fo e cG rma au at F in m/pha e nd stat o u id nhance MP/G nl du ETY to ser i ex f i sol l ser P av ser E an d r A cr ser (5 m t i tha orm ange censing s v evelo harma sy s tion y an ma e-of eates 12) per strie ailab apo CE alyt prov uble . cl vice vice vice a th stem t y Co ient u LP ticall rma pha , causes ree tise c -the l ical rativ 834-0449 cont o ation pment, s mpa ing onta le s, s, bi f F com D prov P su Com s a rmaceu or for oavai co gu . and paten techn op nd y and -ar testi wit e ccessful so act RO m ct, mina 1 EV mpo i mulat ar portu sci pounds. n ider, Pr plian t lubil t pat h doesn’ he ant p m the I S a n o r P co d f h S sy exp facil ng labili ecipi light R n u entist eg ique cr t roduct n v eed evi as r af af V ex 6/25/09 3:27PMPage65 ne anufactur ll ie ICE even r tical t e l n d r for or i it eativ ity ee io i niti y ion, e ul e esp t. t an r n eri t nts sy igat am ce I ity de i nt t ty ‘n , n. ty offer g p nu t le u at he p For mat s vi DER ation d t and of es. t es s en assi s np s ’S art o On vel on t an i contr sit pas tem f of is Compa ed e dr just on w e io ion stab or have pl a (a ma : o c poorly c xp ro more nerships. ion t s e n it se ug d sol lients Its regist un op t e a atform s, v h co h p ( sle siv t os a into such e 8 ing, suppor n e in e poorly provi a re ility act e d utions; R t full 47 product c d of n wide ft o sa u d core . e ev ex f te at ce re e T re i th ered l ) a f is r l d he e ed a e e d de s rn e t , m ty d he t to a it agr Fo w ex vi se and ( and col con se tu Pr vi ca fa in de (N co to 9 rtua 8 w s pand r r f c rn o CE lect rv ve p vi v o .5% eem c it sis i more w d el l su c E r om ces - i i ma u r ti ww ll erti ce s) urop ke . o ed tent ion; y pp c e l ed pm e , e m ts d s. s , y C ev t s ficat g , nt at io P di w i . , e fo en i e, dr nfor W its ery an PD n e s St a f r n . wit . O a ci r c n c st c u e , and e ions accep s d l as ia t gl bo om en g u c ri ma as G pro t c count h NTR a o l s d obal c u o de d ce n t tat n s i Pek s, o h n r n wi . i . tio d vid c ta s re LO Thr np v g a e-of i no o a tanc and th n el m c n, nt l ry ce in f n es i e. t t mm fe ha o eg o n an d l g the A cont S ntra y p of ugh BA -H - rs A e cl th u ta th Unio rm me r u p l CT at inica p l e th r i erap f e a r so us gh ate) a g s l d od act i a e st n ng c o L lab a ra ia r n e n . a t tu l rt rate wor c u C i t l d ; n d eutic s of P L Ro e- om c M C ri on labor t lab e es g e s awk a h e a n ffic e rv e sop gica ld. b ar b n a t g rvi f . orat a ENT l t i of i nd d e D o ni m c A ient i e se e PPD ator n ts ces his e anz se xper s ex ll ac s m s NU B ori , d r y h er vi , iome m ticat cr e ed e i fo e y lo iger st a in e vi l c n r ut ti a i e ccur r ecen R cated s se - e i to t s c y ng a p s i or s FA ed e; wit an ca es e m o rvi AL d r a Chin d oduct i a li ica n t ate, f s high l d - d tly ces h l log s or f ( , re or CT its 859) pr f H l a and dos acili at mu a lea an Dev isti ll L ig oducts an -qu N to s FDA t (949) rele h hrou nounc e lations, age cs UR ties s A d a 44 lotions in w elop e C ality t cu s fl ex re ex pr de PP y la rapid ves BS vant i c d c p o f d c m c I P S e ont -inspected and all n n table 2-1 our tron ex o C gh o o h a bs r x e r o h ta ach; i ogra f per ten t c . s r vel a n ga ov D’s hemica p 380- ment m n orms p a v s ING e a m ed i to . We tiga n perfo so ainment ble s e e e tr ll a g rm N 300 ful an ha p g d i ag n c cal opmen u . a e mi siv l r ti b d ra s and ac ort o t ru i n a ourie g i ms ccred it n la For s ampl en i s lo e a za ly p a l tor s n of se loba e te e ze g exc i 43 e nd s es t g has ti t c m gis h Li and y rman are ; or i i th ti c su fer t d eu o es n rvi globa c d w highl l prov h mited A e e o mo 27 si i n g o r lus e thr s tical Entit e c e l pport merica vi n n i a itat t ti tes c s mp th a t G c s t a nd sit es; . c o m n t r entr or iv c ough o MP T h al e i y ion d f e l d l e o l u in h a . id ies e s es s l t e t , l al s t y e

65 Drug Delivery Technology July/August 2009 Vol 9 No 7 66-69-DDT Jul-Aug 09 - SP Feature:Layout 1 6/25/09 3:29 PM Page 66

Outsourcing Outlook Pharmaceutical & Biotechnology Outsourcing – Growth Opportunities, Trends & Strategies

By: Barath Shankar Subramanian, Senior Industry Analyst, Pharmaceuticals & Biotechnology, Frost & Sullivan 7 3 o o N N 9 7 l l o o V V 9 0 0 2 7 T 0 S 0 U 2 G U H A C / R Y A L M U J A A M M R R A A H H P P Y Y T T L L A A I I C C E E P P S S

66 66-69-DDT Jul-Aug 09 - SP Feature:Layout 1 6/25/09 3:29 PM Page 67

utsourcing as a concept within the pharmaceutical and biotechnology industry is becoming more Ointegrated into the value chain, along with several other aspects, such as manufacturing, sales force, customized chemistry, and development services that are gaining traction. Despite the recent slowdown in the outsourcing markets due to the economic downturn, the potential for long-term growth remains fairly strong, backed by solid fundamentals. Contract Research Organizations (CROs) and Contract Manufacturing Organizations (CMOs) continue to make moves in acquisitions and strategic partnerships to strengthen their position in the outsourcing services market. The total pharmaceutical CMO market, which includes solid dosage and sterile and non-sterile semi-solids and liquids, is forecast to grow from $9.29 billion in 2009 to $15.02 billion by 2014 at a compound annual Figure 1. growth rate (CAGR) of 10.1% (Figure 1). In the short-term (2009-2010), we expect the slowdown to affect the expansion which represents the biggest volume market for CROs. This is activities of small-to-medium CMOs. The tight credit situation, likely to have an impact on the overall market growth rate, combined with recessionary effects, is expected to result in which is expected to be lower - between 8% to 10% in 2009 decreased expansion activities. However, given the growth and 2010 versus the low- to mid-teens originally forecast in prospects for this segment, combined with the flurry of generic 2008 by Frost & Sullivan. versions of major blockbuster drugs, the prospects for CMO Any major consolidation in the biopharmaceutical growth continue to remain bullish. industry, as we are currently witnessing, could result in The CRO market has emerged as one of the fastest cutbacks in the number of service providers that with whom growing markets within the pharmaceutical and biotechnology the newly formed entity works. This occurred in the late 1990s industry and continues to drive innovation, productivity, and and early 2000s when the pharmaceutical industry went revenue growth. The US CRO market, which is the largest through a phase of major consolidation, resulting in a global CRO market with a share of over 56.6% of all global slowdown in the outsourcing services markets. trials in 2006, grew from $4.8 billion in 2003 to $9.7 billion in Figure 3 shows the skewed nature of the clinical 2008, with revenues doubling during this period (Figure 2). development pipeline toward early stage development, with This rapid growth in the market was driven by a variety of more than half of the pipeline between NDA and preclinical stages. In the current economic downturn, this segment is 7 o

factors that include the emergence of specialty pharmaceutical N

likely to be adversely impacted from decreased funding to 9 and biotechnology companies as the engine for R&D growth l o and clinical pipeline expansion. The change in business model early and development-stage companies. This is already V and supply-chain landscape of R&D has benefited the CROs resulting in the elimination of several of these companies and 9 0 0

significantly, due to the lack of infrastructure and financial 2 T S

resources within the tier 2 and tier 3 sponsor companies that U G U A

carry out and manage their trials. / Y L U

The primary source of business for CROs is the R&D J budget allocation by sponsor companies. Due to the shift of business volume from Big Pharma and tier 1 companies that A M

have R&D allocations of more than $500 million a year to tier R A H

2 and tier 3 specialty pharmaceutical and biotechnology P Y T companies that have lower R&D allocations, business volume L A I C E

has significantly increased for CROs. The absolute revenue P S associated with this share of the business, however, is expected to be lower than Big Pharma sponsors. With the slowing economy, companies are focusing more Figure 2. on the late-stage trials and cutting back on early stage work, 67 66-69-DDT Jul-Aug 09 - SP Feature:Layout 1 6/25/09 3:29 PM Page 68

investments in these areas cheaper for PE firms. It is likely that there could be more deals, especially amongst top-tier CROs that have a strong history of producing steady operating cash flows (a key metric for acquisition by PE firms). These acquisitions are expected to bode well for the industry, as the PE firms are likely to focus on leveraging CRO and CMO cross-functional efficiencies and improve the working profile of these companies. We are likely to see the emergence of a new layer in the supply chain that not only focuses on bringing lower fixed cost alternatives to their sponsors, but also provides an expanded breadth of services that could enable them to take Figure 3. products from NDA all the way to commercialization and post-commercialization support. could have a severe impact on market growth in the mid- to long-term. The implications of this could be further felt strongly amongst CROs and CMOs that provide services to The Strength of Long-Standing these firms in terms of delayed payments, defaults, and cut- Relationships backs on pipeline candidates. The long-term success of top CMOs has been built on the back of strong long-standing relationships with major industry The Importance of Partnerships & participants. CMOs that offer additional value-added, upstream, and downstream services have remained Equity consistently successful. Proprietary drug delivery platforms In these difficult times, the companies that tend to have also played an important role in ensuring the continued perform well and exceed market expectations are those that success of these mutually beneficial partnerships. The core have been able to strategically partner with their sponsors. strength in manufacturing, which is backed by a strong Strategic partnerships had been the recent buzz phrase in the network of global manufacturing locations across several key industry, especially during the boom times. However, these regions and harmonized for quality and technology, plays an established relationships help service providers survive cycles important part in leveraging the strengths of different regions. in the economy as sponsors look to cut costs and outsource a CROs, such as Covance and PPD, have shown the way 7

o greater amount of “non-core” operations to their strategic forward by entering into partnerships with Big Pharma N

9 partners. companies in which they lease and run the facility for a l o V Overall, there has been a surge in private equity (PE) specific period of time. CMOs could essentially replicate the interest in the contract services market. In the recent past, JLL model, especially because Big Pharma companies have 9 0

0 Partners acquired PharmaNet and Patheon in 2009. Catalent announced the closure of several plants, and CMOs look to 2 T S was acquired by the Blackstone Group in April 2007, and expand. U G U

A Genstar Capital picked up a minority interest in the deal. / Y L

U Genstar Capital reacquired PRA International in 2007, a J company which they held before it went public in 2004. Conversion of Brand Awareness to Sequoia Capital made a significant investment in an Indian

A Brand Preference

M CRO GVK Biosciences in 2007. R Top CMOs are renowned for their breadth of services, A H

P The investment horizon for PE firms in companies is global reach, and strength of their brand. In a survey of 155 Y T

L typically around 5 to 6 years. The recent investments in these

A pharmaceutical and biotechnology executives, as a part of a I C

E CROs and CMOs by PE firms justify the growth potential that P

S Frost & Sullivan Voice of the Customer Analysis of the US has been touted for the CMO and CRO markets over the long- Pharmaceutical and Biotechnology Contract Manufacturing term and could further drive more transactions. Also, several Markets, there was a clear distinction between CMOs that had publicly traded CROs have been hit by the downturn, and the a high brand awareness and preference. The market leaders 68 stock prices and valuations have fallen significantly, making 66-69-DDT Jul-Aug 09 - SP Feature:Layout 1 6/25/09 3:29 PM Page 69

with strong conversion rates are CMOs that have stayed ahead of the industry curve with strategic initiatives and leverage the strength of their parent brand. Barath Shankar Pfizer CenterSource (PCS) is well positioned to garner a greater share of the Subramanian rapidly growing contract manufacturing business by having the highest brand Senior Industry Analyst, Pharmaceuticals & awareness, as well as brand preference in both pharmaceutical and biotechnology Biotechnology, Frost & markets. The backing of the strong brand name of Pfizer Inc., one of the largest Sullivan global pharmaceutical companies, has helped its contract manufacturing business significantly in building a strong business. Pharmaceutical and biotechnology companies are increasingly demanding sterile manufacturing capabilities, and PCS has been able to align its service offerings with the expectations of the market. Barath Shankar Subramanian is a Senior Industry Analyst with the Frost & Sullivan Customer-Focused Alignment of Services North American Healthcare Practice. He Baxter is considered a top choice for manufacturing outsourcing and is one of focuses on monitoring and analyzing the leading CMOs in the sterile manufacturing market, especially prefilled syringes and lyophilized vials. The key to Baxter’s success in this market has been its ability emerging trends, technologies and market to provide flexible capacity that enables its customers to expand from small-scale to dynamics in the Pharmaceuticals & large-volume manufacturing quite seamlessly, depending on variations in demand. Biotechnology industries in North America CMOs not only need to adopt a highly customer-focused approach to its clients, Since joining Frost & Sullivan in October but also constantly evaluate their needs and measure their satisfaction on an ongoing 2004, Shankar has completed several basis to ensure quality services. By maintaining multiple channels of research studies and consulting projects communication with clients, CMOs can ensure continuous engagement of its clients on Specialty Pharma, Contract Research and flow of information. and Contract Manufacturing. CMOs that are part of a larger pharmaceutical or biotechnology company can also draw expertise from the R&D division to help clients in addressing complex Shankar has received acclaim for his formulation challenges and improve productivity and efficiency of processes. research through articles and quotes published in Drug Delivery Technologies Summary and Specialty Pharma. Long-term growth fundamentals remain strong for the CRO and CMO markets. The markets are experiencing two-tiered growth from Big Pharma, which is Prior to this, Shankar was a Research & outsourcing work to lower fixed costs, while biotechnology and specialty Development intern at IPCA Laboratories pharmaceutical companies outsource work due to the lack of infrastructure. Ltd., Mumbai, India. He brings with him As market leaders aggressively pursue strategic partnerships and acquisitions considerable analytical and quantitative (Covance-Lily, PPD-AbCRO), the gap between tier 1 and tier 2 and tier 3 service experience, giving him a keen perception providers is likely to widen. The demand for functional services, such as data into the functioning of technology in the management, logistics, translation, regulatory, and consulting services, is providing healthcare industry. Shankar holds a BS in the additional level of growth beyond the base-level growth for CROs. Meanwhile, pharmacy from the Birla Institute of the demand for sterile manufacturing, secure tagging in packaging, regulatory, and Technology & Sciences (BITS), in Pilani- consulting services is driving the additional level of growth for CMOs. Rajasthan, India and is currently pursuing Overall, the CRO and CMO markets are expected to remain as two of the top growth areas within the pharmaceutical and biotechnology industries despite short- his MBA from the Tepper School of Business at Carnegie Mellon University. term effects of the economic downturn. N 70-73-DDT June 09 -SP-Exec Sum:Layout 1 6/25/09 3:30 PM Page 70

Executive

John E. Mordock President & CEO Summary Neurologix, Inc.

Neurologix: Targeted Gene Therapies for Brain & CNS Diseases

eurologix is developing a novel gene transfer therapy for the treatment of brain and central Nnervous system (CNS) disorders. The company’s goal is to re-establish biological function at the molecular level by using a gene therapy approach to reintroduce natural proteins that are often deficient due to the particular disease state. Neurologix has already demonstrated feasibility for its approach in Parkinson’s disease and is working to extend its therapeutic platform to the treatment of other serious conditions, including Huntington’s disease, epilepsy, and chronic depression. Within each of these diseases, there are subsets of patients who are either refractory to standard pharmacological treatment or who have no therapy available to them. CEO John Mordock tells 7 o N

9 Specialty Pharma magazine of the opportunities and challenges presented by gene transfer l o V technologies and why gene therapy offers unique benefits as a strategy for improving the treatment 9 0

0 of chronic brain disorders. 2 T S U G U A / Y L U J Q: What is the scientific background Cornell Medical College. During his PhD program at The Rockefeller University, Dr. Kaplitt became very interested in A

M behind the formation of Neurologix? R

A the use of viruses to transfer therapeutic genes for the H P

Y treatment of focal CNS disorders. As a neurosurgery resident T L A: Dr. Michael Kaplitt, one of Neuologix’s founders, is an A I C

E at Cornell, he worked with deep-brain stimulation as an

P internationally recognized expert in the use of gene therapy in S approach to the treatment of late-stage Parkinson’s disease. the brain and molecular neurobiology. He has published more Dr. Kaplitt had observed that if the inhibitory neurotransmitter than 40 papers and has edited two books on the subject, and gamma aminobutyric acid (GABA) - well known to be he currently runs the laboratory for neurological surgery at 70 deficient in Parkinsonian patients - was administered into the 70-73-DDT June 09 -SP-Exec Sum:Layout 1 6/25/09 3:30 PM Page 71

surgical site, there was a positive effect on the patient’s brain Q: Describe the delivery system for this activity. The challenge to exploring GABA’s therapeutic procedure that was developed with potential, however, would be developing a method to re- Medtronic. establish its production within the targeted area of the brain on an ongoing basis. A: It is a fluid infusion system that is the first to be used to In the mid 1990s, Dr. Kaplitt collaborated with Dr. deliver genetic material directly to targeted neuron clusters Matthew During, a world-renown virologist, identifying a within the brain. Our approach is highly dependent upon the transgene capable of stimulating GABA production in the infusion system to simplify the gene delivery procedure and brain as well as an appropriate vector for delivering that reduce the amount of time the patient is in the operating transgene into cells. The scientists selected adeno-associated room. virus (AAV), which is non-pathogenic and non-replicative. The virus has shown to be safe and is currently being used in approximately 30 human clinical trials. Q: Is Parkinson’s disease your only current focus? Q: So Parkinson’s disease is Neurologix’s lead program? What is the current status A: No, we are looking at a number of other CNS disorders. of your work? The brain is a particularly fertile area for the use of gene therapy that can be delivered directly to targeted brain cells via a surgical approach. It has been very difficult to treat A: Neurologix completed its Phase I study in 2006, which brain disorders systemically, due to the presence of the was the first gene therapy study approved by the FDA for blood-brain barrier, as the dosage rates must be so high that Parkinson’s disease. In December 2008, we began treating side-effect levels often become unacceptable. So our patients in our Phase II trial, a bi-lateral randomized, sham- approach represents a new platform for the potential surgery controlled study designed to further establish the treatment of a number of CNS illnesses. effectiveness and the safety of the treatment. The trial is Most recently, we have focused on Huntington’s being conducted at up to 10 US medical centers that will disease, an inherited chromosomal deficiency that leads to 7 o

enroll approximately 40 patients, with completion of N

progressive nerve degeneration. The XIAP gene (x-linked 9 l

enrollment expected in the second half of the year. o inhibitor of apoptosis protein) has a neuroprotective property V Phase I results, published in The Lancet and PNAS , that may modify the progress of the disease. In two rodent

indicated that the treatment was safe and well-tolerated in 9 0

models, not only did we prevent further cell death, we have 0 2

patients with advanced Parkinson’s disease, with no evidence T S

shown signs of reversing motor dysfunction in the animals U G

of adverse effects or immunologic reaction related to the U A

treated. / Y treatment. The trial, in which treatment was confined to only L U We have also developed a strong preclinical basis for J one side of the brain, also yielded statistically significant the treatment of epilepsy and depression using AAV to clinical efficacy and neuro-imaging results in the cerebral A

deliver therapeutic genes to focal areas of the brain. M R

cortex of the brain. Additionally, we found the functional A H P Y

data to be highly correlated to a decrease in metabolism in T L A I C

subjects in both the “off” state, when they are not responding E P to pharmacological therapy, and in the “on” state, when they S do benefit from standard Parkinson’s disease drugs.

71 70-73-DDT June 09 -SP-Exec Sum:Layout 1 6/25/09 3:30 PM Page 72

Q: What is likely to be your second indication with an “at-risk” patient population in excess of 100,000 indication to go into clinical trials? and a potential undiagnosed market that is at least as large. No approved therapy for Huntington’s disease currently exists. A: It will most likely be Huntington’s disease. We have very Q: strong preclinical data supporting our approach using the XIAP Does Neurologix plan to take its transgene. We will again be using the non-pathogenic AAV to products through to commercialization deliver the gene. Moreover, the biology of Huntington’s disease on its own or to partner? And if the is pretty well understood, and we believe our therapeutic latter, at what stage? approach is consistent with the biology of the disease. We have A: With respect to Parkinson’s disease, at the end of our Phase seen strong interest from some of the Societies that are looking II trial, which we believe is a major inflection point, we want to

7 for therapies for Huntington’s patients, so there is the o

N enlist at minimum an international partner to help us expand

9 possibility of some financial support for our efforts as well. l o

V our development work to Europe. Whether we also look for a US partnership at that point will depend on who our European

9 partner is and what our need for cash is at that time. Our 0 Q: 0 What kind of market opportunities do 2

T position has always been to take development forward as far as S

U you see for your products? G

U possible ourselves before we are forced to give up value. A / Y L However, if someone came in and made an extremely strong U

J A: We know that there are about 500,000 patients with late- offer for worldwide rights at the end of Phase II, we would stage Parkinson’s disease who are refractory to obviously consider it because we want to do what is in the best A

M pharmacological treatments. About half of those individuals R

A interests of our shareholders. H

P may be contraindicated for surgery, leaving about 250,000 Y

T Huntington’s disease is different because it is an orphan L patients within the United States who might benefit from our A I C

E indication. We may develop and commercialize this indication P

S approach. Moreover, that market is growing substantially as a ourselves or do it on a co-marketing basis. We are still at an function of demographics - some published marketing reports early stage in this program, but given the nature of the disease, expect those numbers to double within the next 10 years. the small market, and high value for an effective therapy, it is With respect to Huntington’s disease, that is an orphan 72 something the company might actually take forward itself. I 70-73-DDT June 09 -SP-Exec Sum:Layout 1 6/25/09 3:30 PM Page 73

Company Pg Phone Web Site

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

AAPS 23 www.aapspharmaceutica.com/annualmeeting

Aveva DDS 7 954-624-1374 www.avevaDDS.com

Azopharma Cover, 4 954-433-7480 www.azopharma.com

BD 19 800-225-3310 www.bdpharma.com

CyDex Pharmaceuticals 9 www.cydexpharma.com

Delivery of Biologics & Beyond 29 www.iirusa.com/biologicsdelivery/home.xml

Drug Delivery Summit 37 www.drugdeliverysummit.com

Elcam Medical Inc. 2 201- 457-1120 www.elcam-medical.com

Eurand 21,76 937-898-9669 www.eurand.com

Innercap Technologies 3 813-837-0796 www.innercap.com 7 o N

Lablabo 15 www.lablabo.com 9 l o V 9 0 0 LTS Lohmann 13 973-276-8921 www.lts-corp.com 2 t s u g u A / y l u

PharmaCircle 75 847-729-2960 www.pharmacircle.com J y g o l o n h PharmaForm 11 512-834-0449 Ext. 264 www.pharmaform.com c e T y r e v i l e D

Rexam 17 847-541-9700 www.rexam.com/pharma g u r D

73 74-75- DDT Jul-Aug 2009 - External Delivery:Layout 1 6/25/09 3:30 PM Page 74

Part-Time Productivity: Your Boss Does Notice! By: John A. Bermingham

eople believe I am crazy because I typically arrive at the and Merchandising Manager and still wet behind the ears. office at 6:30 AM. Sometimes I arrive even earlier. I do We were talking about the hours that he and I were spending PPthis because I want to be focused on what needs to get in the office, and he said the following to me. “John, it is not the done that day, that week, and that month. I want to get ready for hours that you spend here. It is what you accomplish that is the day before anyone arrives so when the bell rings, I am focused important to me.” Basically, it is not just working hard that and ready for the day’s work. I want to have plenty of time to meet matters, it is working smart as well. I have never forgotten that with our people and to walk around to see how everyone is doing. wonderful piece of advice. Certain people show up for work anywhere from 15 to 30 Too many people believe time spent in the office equates to minutes late every day. They spend the first few minutes getting productivity. As most of you probably know already, it doesn’t. It coffee and socializing. Then they will make a few personal calls only means they are spending a lot of time in the office. inside the company and outside. They will check their company In order to be productive and have a significant impact in and personal e-mails, and then look at their schedule for the day. your company and for your career, you have to work hard and you By the time lunch rolls around, they might get in 1 or 2 hours of have to work with efficient intelligence. You have to be focused real work. the entire day, well organized, and very budget-conscious with After lunch, they may get in another 2 or 3 hours of returning your time, not letting others impose on your schedule or interrupt e-mails, so by the end of the work day, they may have put in 3 to 5 you achieving the goals and objectives set for the day. hours of real work. Then, because they arrived late to work that Following the advice of Sharp’s President, I always think day, they stay late another half hour and then leave. Of course, the about the fact that it is not what you tried to do, it is what you last 30 minutes is spent chatting with others. accomplished that counts. N I once had an executive who reported to me who had a six- figure salary plus bonus. Shortly after joining the company as the IOG RA P H Y new CEO, I noticed he arrived every morning at 7:30 AM and was B out the door every afternoon at 5:00 PM sharp. While most of the John A. Bermingham is the President & CEO new management team stayed until 6:00 PM or later, this of Cord Crafts, LLC, a leading manufacturer and executive left every day at exactly 5:00 PM. marketer of permanent botanicals. Prior to Cord Crafts, he was President & CEO of Alco Consumer Being that we were in the early stages of the company’s Products, Inc., an importer of house ware, home turnaround, I brought this to his attention. After explaining why I goods, pet, and safety products under the Alco believed this was an issue and that a lot of important objectives brand name and through licenses from the were accomplished after 5:00 PM, he agreed to stay later every ASPCA and Red Cross. He successfully turned around the company 7

o in 60 days and sold Alco to a strategic buyer. Mr. Bermingham

N day from then on. So he adjusted his time in the office to be from

9 was previously the President & CEO of Lang Holdings, Inc. (an

l 8:00 AM to 5:30 PM. If you are wondering, yes, I did give him an o

V innovative leader in the social sentiment and home décor opportunity to work for another company shortly thereafter.

9 industries) and President, Chairman, and CEO of Ampad (a leading 0

0 When I first started out in the business world, I discovered

2 manufacturer and distributor of office products). With more than t s 20 years of turnaround experience, he also held the positions of u that the senior executives and fast risers in a company were those g

u Chairman, President, and CEO of Centis, Inc., Smith Corona A

/ people who arrived early and focused all day on the important y

l Corporation, and Rolodex Corporation. He turned around several u

J tasks that needed to be accomplished. They worked hard and put business units of AT&T Consumer Products Group and served as the y

g in the hours that would ensure successful accomplishments for the EVP of the Electronics Group and President of the Magnetic o l o

n company as well as themselves. Products Group, Sony Corporation of America. Mr. Bermingham h c e

T One of the important lessons I have carried with me for my served 3 years in the U.S. Army Signal Corps with responsibility y r

e for Top Secret Cryptographic Codes and Top Secret Nuclear Release

v entire career was something the Japanese President of Sharp i l

e Codes, earned his BA in Business Administration from Saint Leo D Electronics, USA said to me. I was new and relatively young at the g University, and completed the Harvard University Graduate School u r D time, having recently become Sharp’s 31-year old National Sales of Business Advanced Management Program.

74 74-75- DDT Jul-Aug 2009 - External Delivery:Layout 1 6/25/09 3:30 PM Page 75 * DDT July-Aug 2009 Covers:DDT Cover/Back April 2006.qx 6/25/09 3:04 PM Page 1