PV.112dLiH111111WE
`DO4AGE FORMS
`
`Clinical Protocol Design for Gastroretendve Dosage Forms
`
`By Matthew D. Burke" PhD, and Pt essor Clive G. Wilson
`
`PLIRPOSL
`
`To highlight key factors of a clinical protocol design that can impact evaluation of gastroretentive dosage
`forms_ A6), to provide a prefened clinical pmt co( din to allow potential. Ytandandization of clinical evaluation
`and direct omparisons of inventions_
`
`INTRODUCTION
`
`The stomach is a large and ;DP=
`rrri_cular 2darcalion of the gut, fashioned to
`form a reservoir that tore food and
`proccgscs it into chyme. It has the unus=ual
`properties of scenting hydn.ichk)ric acid
`and enzymes. To the Scot_ the sheep's
`stomach forms the bass fora national dish
`(the ha.ggjs), and the skin, .a favorite
`musical inArurnent (the hagpir,.-s). The
`impression. of other nationalities as to the
`merits of these inventions vary, but to the
`phatiriat.entigal scientist„ the mu...ern:pat of
`thingsin and out of the stomach. is a. Saute&
`of many drug delivery portents. The
`development of a dosage foam that can he
`retained in the storna.ch is a challenging
`go:al, although are phenomenon has bet= of
`interest for longer than. most people realize.
`The first recorded public demonstration of
`retarded gastric emptying was perfaitned
`by the Holy Roman Emperor Frederic U
`(circa 1
`(cid:9) AD), who examined the impact
`of exercise on gaAric emptying after a large
`ineal_l He ordered two mien to CM a tares
`meal and sen.t one to rest and the other to
`met-cis-T. violently, then killed and
`disemboweled the .tr..en. It was. found that
`the resting inan's stomach WM (cid:9)
`while
`the exercised MD ArifilaCh wad full.
`Fortunately, in modern times, Les,s 1 bat
`clinical endpoints are used for such
`in
`(cid:9) although, the question still
`remains: c-an vim auourately predict and
`control gastric emptying of ingested
`entities?
`This paper attempts to highlight kr).
`
`lah Tr (cid:9)
`
`I' (cid:9)
`
`2.15
`
` asEPects fnr considmation vaken
`designing. protocols to iterestigaie tie
`performance of gastroretentive dosage
`forms in mark_ It is hoped that these
`obfferiputions w7j &mut in the move toward
`standardized clinical evaluations for direct
`compares m5 of novel 1:141=1:1011•51 •
`The maroon strategies utilized to
`prolong gamic reRidence time for dosage
`forms vane recently reviewzd by Bardo.nact
`and 'include (a) trioadhesirmi (b) large rim,
`(o) tinfoldim, (d) floguation, and (e) high
`density (Fir= l l as well as co-dosing with
`agents that al-ter ga,ctric rriorility2 Each
`gLrater has ad.i.zniages and vrZ:a.k..11165C*.
`For eXai iple. gasuotetennon based on a
`large size is belimd b some to have the
`least drawbacks, although the minimum
`target sit and rnei:h.trii[l strength needed
`to maintain a gascroreterurpie formulas it
`has rArt bcca ectermined It bas 1-cen
`teported in the endosctipic
`literature that a 5-an length
`by 2-cm diameter ngid
`object will. Doi pass through
`the stnmarialt Such
`anecdotal rn.formanice is
`11,1•6111:11.2 no scientifically
`the shay
`of the mouth changes
`dutnng contaction to form. a
`cylimIrical space, tic
`pyloric Winder Studies lay
`the Smith AfniNin. radiologist
`A.D. Kw (cid:9)
`esuiblished
`char ilac shape and
`diftetiMpriS of 'flit Cylliadet
`vary significantly larrarca
`individna, whether this will
`
`cumplic,ale application of gasirordentive
`technologies is not known.5 Whilst cleat
`identification of the key requirements to
`aohieue a guEzmisful psi:tweet-dive
`formulation m the clinic environment is not
`established it is possible to perform clinical
`51111i7C;5that Ocarninc the advantages a
`gastroretentive formulation might conier.
`
`THE SIPPING TEST: WILL
`GASTRORETENTION
`BE AN ADVANTAGE?
`
`The rationale to pursue a ,aslint-cicr.iiiet
`10111•1414011 are corturrionly based on the
`properties of the drug or a target
`pharrnace.kinetic (P/Cyphatinacodynarnic
`(PD profile. For example. a drug may
`exhibit "difficult- properties, including a
`short PK and PD balf-life, or a localized
`Iran :Torun- ahgorpnon mcchanigrri, pH-
`
`Gasnoritmatthie Doug§ Form Mechanisms: (al Bloadherlon,
`i[e) High Density
`Ili) urile sire, del &tatting, (d) (cid:9)
`
`(cid:9)
`

`

`DOSAGE FORMS
`
`TABLE 1
`
`meal at Time (cid:9)
`
`DIO5ing
`
`Gastric Emptying Time airs)
`
`Faatec
`
`Light Breakfast (154 kcal)
`
`Heavy Breakfast (795 kcal)
`
`1 +0.4
`
`+0.9
`
`S.8 + 5.9
`
`Impact of Fond on Gamic Emptying of Dosage Forms
`
`ancLunulaling mthe stomach is termed the
`Mivrating Motor Convict NEC) This car,
`be tee riled enernally with clectrode,s o the
`abdomen. The 11/241VIC is characterized. by Ikea
`plhiasCS" Ph-3-5C I BCE MOW cirri conic 05 to
`160 nun). ?hue 11. a period of intermittent.
`apparently randcan„ stationary Derdractions
`are imeaker than the Ph (cid:9)-' (cid:9)
`11 contractions
`(-30 min). and Foam 1.11. a period of rhythmic
`conmacrioas %kith a maximal frequency of two
`to thr contractions per mimic in the antrum
`that cyclically clears the std and IS often
`referred IC as the '-holasielreeper %me' (5 co 15
`min), During the 1100010. thc pyloric sphiroctcr
`or "gatekeeper- of the stomach has been
`suggested to be ahmosz
`peritxiir-ally ulOsed_
`Fur Phase I and II. small particle s and liquids
`pass dimly*. then m coordination
`with the 6trotig Phase III
`ulna-actions. The 5phincier
`opens to allow larger entries to
`be cleared.
`In additii~ to traddrrsurnding
`the mechmical. cligeFtrvc forces of
`the 1$1301C. it is imporiara ro
`conEidier the role uf the duo: m=
`and stomach in regulzi:mg thc
`Dow of nutrients. into the
`intestines for al:psi:176mi
`(t hi* INC111 'report/xi that food is
`passed out of the stomach at a
`his dear
`rare Of (-3 (cid:9)
`that food may not =ivy kom tbc
`stomach in a linear Ladino& atifi
`the pane-03 i=in be Figrooid,
`linear. or exponential deperAlent
`on the physical ALIFC of the meal.
`la trite A these reserValiem, this
`
`Magma Auyulpvir Opmeniratun fjArrvirl
`
`depundient 9rIubiLiry, poor transport across
`t:lie lower small intestine or colon_
`receptorsitareis of interest located only in
`upper Cd trait[, and an inte6tinal
`window due to slow clissotun.on in the colon as
`limited amount of unbound water is available.
`T-loweieer out
`(cid:9) of testing thc inventi.no., it is
`also possible to examine the advantages that a
`8.astboreletlive formulation milt confer. Ati.
`ExA,:ellent literaEure example Of this type of
`clinicol study was pt armed using Acyclorkeir
`by Lewis (Figure 2).'. Lewis and colleagues
`compared. ari. IR fOrMulation to a sipez.i.1
`solution of the sortie close ovci- a 4-hour
`period. The sipped solution doubled the Ar....12
`rarripared. Lo the tablet_ A related clinical study
`design was utilized internally for a GSK
`conipound, where a single 1R tablet dose was
`Compared LLB S sequential doses [If US the MN]
`TR don over a 4-hour
`period. In this case, the AUC increased by
`27%, indicating a benefit in pursuing a
`gagrorelmlive foundation (Figatc 3)7 In
`both case. carefill clinical study design
`allowed the SimulatiOm of advantams that a
`gastroretentivc dosage form might prcwidc
`before a final design is selected. Translation of
`these obSerleatiats into Ibe dehion. of a
`protocol mire is aurae qonsickration allnail of
`the clinical trial to evaluate vithether a dosage
`form is truly gastroretentive.
`
`STOMACH MECHANISMS TRYING
`TO EMPTY THE DOSE FORM:
`FASTING & FEEDING
`
`The main electrophysiological event
`controlling gAstric emptying of dqtrit-u4
`
`(cid:9)Or!iwrry Tecnnril rigg 5rpttrnher 2006 Vnl 6 kh
`
`Or
`
`28
`
`"role of thumb" is useful to approxhriate food
`son the performance (If the gastroretentive
`dosage form bee...luso Phasic El of the filiD4C gill
`not be initiated-until the nutrients have emptied.
`Therefore, if a pea-son continues to snack during
`thc 00‘113C of a clinical study and the
`mechanism by which the gasharetentive dosage
`Farm leavms. die licomach. is. a Phase Ili citara:61.11,
`emaratilen of an Crow large dosage form may riot
`occur. A clear example of the effects of food was
`FeNt-Lted in a. paper by Wilson et al (Table 1.).'
`A largO, raclialatoded In-mtamed-release Labia
`was administered in the .morning in date
`different dosing scenario& In all lave scenarios,
`[Le voiuntects %%we given a morning Fnack (7S
`kcal) at 2.5 6CPUrS post dose, followed by lunch.
`(995 kcal) at 5.13 hours post dose, and rthally an
`afternoon rack (IJ:1 Icca1} at 7.5 haws post dom.
`When dosed after fasting, the blood sugar
`is low,. and initiation of an !AMC is uncerlain,
`thus in mid Pha6e ill, a honekeeper wave
`occur immediately flushing the tablet
`from the stomach. 20.1ernatively, the IkellivIC
`may be al. Phase 1, and gime time will pass
`before the Phase ID sequence,. thus an
`increased likelihood of liable( retention in the
`MI:mach. This pi.rscs an interesting problem for
`expanding system, which must unfold or
`
`FIGURE 2
`
`'2
`
`8
`Time (hr}
`Foitriulatlen. Reproduced
`
`ie
`
`Simulatian of a rastricretsgi (cid:9)
`VIM Data From Lewis el al..'
`
`(cid:9)
`

`

`rillJLr;1. (cid:9) 1ail-PREI7E1W1E
`DOSAGE FORMS
`
`TABLE
`
`Ssquauce
`I
`
`, (cid:9)
`
`El enit
`E., ...: ...: z Meal (-1 Oal kcal) (cid:9) at 14 c• .i. predose
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Chverright fast followed by blood gl,...Poose tewt on arrival at clink
`
`Dose in the morning following a heft breakfast (-280 kcal')
`
`Walter allowed ab libitum but record the quantities ingested
`
`Lunch (— I Cl00. kcal) at 5 hrs post dose
`
`Ahernoon Snack' 150 kcal). at 7.5 heS imagt close
`
`Evening Meal (-1 OXI kar) al 10 hrs. pert dose
`
`titimested Clinical Protocol Desion for GashicretenItue Dosage For=
`
`!WC" hOUSICIZCCInr INMVEZ, sin-riving into the post
`lunch period (5.-F hours). A norraai meal at
`lunch would probably permit more than an 8-
`'Flour retention_ Finally, it is impciriant to note
`that thc; voktrkteers shoe]d be ambulatory
`duri the study period to simulate a normal
`day's activity.
`
`MONITORING THE LOCATION
`OF THE GRDF
`
`Another key aspect of the (1illif-A.1 protocol
`design is tb.e selection of a technique to
`monitor the /ocation of the GRF in the
`gastrointescinal toot kicar.y, a. norpirivasive
`approach 'hat does not all= the physical
`properties of the GRF is preferred and the
`frequency of imaging should be at lent every
`30 minUldS for the first 6 to S hours followed
`by cvery hour until bechime, teaming in the
`morning if required. Gamma scintigraphy is
`often the gold standard for hanSit srudies and has.
`bnemu5ed gctenxively for tracking the :14.warion of
`dotage formsi vivo. Although the preferred
`approadi, other techniques Pach as inapetio
`rmorgince irnagjhg and iluopy, have beun
`useful. An iniportsnl aspen of scarri.graphy is the
`Atiiityto use a long.er-lived, high.er energy
`
`8 sequential doses
`of 21_5 ring
`
`172rng IR Tablet
`
`meil at an appropriate race in gastric
`criarlitions to avoid. prernature evacuation (cid:9)
`without risk of esophagcal obstruction. (cid:9)
`In the case of the lift bye akfab-t_ our rale (cid:9)
`of thumb (--3 kcal:min) predicts that the food. (cid:9)
`will empty within the heu, and then the (cid:9)
`stomach would enter Phase UI contractions
`and impel the dosage form out of the stomach_
`pattarn of MEW is extremely vanable (cid:9)
`within and. between subjecis,. and we have (cid:9)
`noted that inclusion of a. Eight break Fast in a
`protocol rather than fasting reduces. variability
`in emptying of intact tablets_ When the tablet
`is dosed with a heavy breakfast, our rule of
`thumb predicts that the food will empty in
`approx 4A hours: however, the morning snack
`will add to it rrinants of breakfast intending
`this rime. in some eases even through lunch.
`The periodic M.MC. once irkitated will recut
`meal/ 3 to 4 Ilona, but the ingestion of foix.1
`will abolish ark existing MM C and lestorc a
`digestive panerri of motility. This prolongs the
`gastric emptying significantly and clearly
`inglicate9 that an artificially good
`gastrorctentive result can be produced by
`ontuinual itt$EStiOt. of foal. A similar good
`UMOUIC Can he (ihtained fur floating aysterns
`if the volunteer periodically eats and drinks A
`tote of caution. retenti011 of floating devices is
`heavily influenced. by pixture as lying on the
`
`Drug °gluey TechneLaw Sepitenber 20D6 V 6 Pla
`
`30
`
`right side =pities Homing objelat ahead
`of a. meal_ In praciicie., any marked changes
`in p:isturc chirmg tic trial can have large
`effeLIS on ihe emptying of large matrix
`systems that ran find tlocroselv (cid:9)
`the pro mini storm&
`By taking into amok= the effect of meal
`size and frequency Oa gaslric. =Ming and
`amtruirig tkial the Phase 1
`contractions of the stomach are
`Elie rrirma r1-6Allm*Fig phccgancna.
`chat ai g.aFt-toceteritive dosage f'x
`will undergo kb the s:DOnlarek. a
`suggested clinical. protocol [Inc*
`is pre eared (Table 2).
`The rationale for this
`suggested clinical protocol design
`is to initially cri,sEre ancrkewpie
`food intake ha not 4x:clamed prim
`arrival at the clinical site. his
`erected that two housekeeper
`
`i,mos. lirlizely at LO AM and
`waves
`1 PM) should oi=tr during the
`time how= larealcia,c1. and tanicl_
`The afternoon period rarely
`proves cbine.nf.jrip, as the galtric
`3Q miry ulisicles.m the nin-rnal
`circa dran rhythm A successful
`gastroideniime dosage form
`should be able lo ism-rive ail
`
`d in
`
`
`
`
`500
`
`440
`
`1:0
`
`FloSrne CDricenlyetIDn Vighyt.)
`
`1
`
`D (cid:9)
`
`2 (cid:9)
`
`21 (cid:9)
`
`8
`
`10
`
`15
`Time (no
`firriulatiori ILA a GaStricrsheritive Formulation. Data po urtesy el
`Dr. Vi nod "Mimi.
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`DOSAGE FORMS
`
`entffric. recirculation, Which 04:Euld a1so molt
`the humps in the PK profile.
`
`SUMMARY
`
`(cid:9) prOLOCJO I design is a
`I.n conclusion, Clini
`critical farmer whim evaluati ng. gastroreteoliv*
`formulations in rrian. ,A.1-iich can significantly
`impact the clinical outcome. and this short
`review has attempted to tkietei.d.. Ictown pitfalls.
`There remain many other important topics to
`consider, outside of the sixppe of this article,
`which include the selection ofd
`vitro dissohtion tocl-miques (nime has Inal.
`agreed rst), proper use of preclinical >n era
`(day differ from man in the regularity of the
`Mrid1C). and other hiopharmarzulical imirms. The
`benefits of a robust but safe gasiroretcritivc
`formulation are clear to the pharmaceutical
`industry .arid. codicil= lo Fuel interest. in
`acadiortia and it
`
`REFERENCES
`
`t 1W& gagric soptrost trial fligriatmi. malt t:474i-4nk.
`.1: lisdaart.11.„ (cid:9)
`11{ (cid:9)
`11:1•7sristim damps
`Sel:d ..7443R41.4 !Ed opmit Fmk. quialicKbrogi f7-611. eme (cid:9)
`?MR 13 3:1 -
`I
`1 Lath 11 elpiodris 4r.3am any ukreankninal YrKlarow L117;1.1(21,-51-4:1
`or pm fotraial ukiza.1
`t 1114:614101. Alacciffccnol. cL ixsi (cid:9)
`krilAr. 15•11:41311111zol. Ilailakqpg 11615S41.35-SL
`14—L 41:1 lb- P31,41e 50u:work cricAliCsi BoalkodDIftiam
`Remerrigir lc garcon rerd. (cid:9)
`yiN144.)734 2$11,
`t. !cum M.D.:N.1c .L.1.11, (cid:9)
`Ityc A, [Loco (cid:9)
`liSzoaa
`aku.srplisci nryalwe ID= ilia du Areal aikuic.n and awn! wldiat 311
`Plarria.41. 39:PF2045M52.
`C (cid:9)
`• ein ingrrad drool 3krLp r..{dsrliqy sf 1k Vn 7rd ihru
`L LAisrc b, .rhea r7 &aa IbTh(Le acs Coral Druz 1 rcriw-r..hzoare (cid:9)
`ream Cam, ihaliageso arrrpn Jt., nada. &K. IC 3ixii LAX,
`Litivird (cid:9)
`4.1rug id 11 KIM atiLd drb:4141kti atm!.
`iamb mer ig hCrIrtig 4141 plaraiziplall (cid:9)
`*pia migly
`1.4.kmba, ._der (cid:9)
`c•sodzuzu if 1N:el mkai • rk P hismakmd.
`OW1:1.1161.
`IO Mar MD. SW= 15, lirivike4.69{ Aited.HEL Calla MD A hail I thideJ av
`ii4pikiril wing ita5prom Jbrabraaal Mc gam la %EDF! xl'a.11•=0.ff
`' 20.34.).
`Thum Mell Ink (cid:9)
`
`1.
`
`radionuclide, such as indimn-111 u;kradinlahel
`the ORE and utilize a. second sAch as
`technerium-99rn, to radiolahel the food_ This
`allow the outline of and the positicni of the
`Stomach to be established lt is usual m
`sciruigraphy protocols to image bow frontally
`and laterally try provide grumotric rocan
`rucasurtments of radioptiainsa (cid:9)
`mime or
`erosim although the proper location of the GRP
`can be captured in single (cid:9)
`imavies nelathe
`cozrnal (Log arid abdorninat MUM,
`In order to image a GRF using gamma
`scintigraphy, the radionuclide needs to be
`retained within the dc6ice for an =cicada
`period of time. This can pose a serious
`challenge with large charges in the gastric
`environment. A nil approach has nwrotly
`been submitted for publication we the
`radiophannaceutical is end in an
`and
`insoluble pcElyrner mercer that is latier mill
`incorporated as a powder or saspenFion dining
`the normal manufacturing prixecturc of a
`GRF.'D 14.Vhichever technique i WiliTrsi. it is
`important to vczify that pierriarcue lealragc of
`the radiotabel does not cc cur. u this
`would condom:I 11LiC itkietpretation of gastric-
`crriPtYing clakx
`As an alternative to visualizing the GRF
`through direct imaging,. oria may purer a
`pharmanokinelit approach; however. this
`information. is not as definitim Riboflavin is a
`common example of a model drug utilized tor
`this propose; Eunwever, =Ai should be used
`in interpretation of the PK d to east= that
`an improvement irk the PH is solely be to
`gastroretention and not =mbar ftruruhition
`factor, such
`solubility-intamstog ex.cipjer4i
`MIZortioe.ofamorpholo =coat interpretation
`of the shape of the irregular F'K curve may be
`confining as periodic. "humps- wino- in the
`plasma COnetninition-nme prof& As the
`stomach becomes empty, it claw; shape,
`and the mater immature sags in the abdomen.
`creating a -srurnp." Periodically with change
`of posture, gastric acid secretion, and Awake of
`the gastric triing volume itmlaining the
`li (cid:9)
`released drug 6 rricrwed to the
`JS important to
`Homer, in this interpretation_
`exclude enterohepatic recirailarkek iacklit0-
`
`DT: 114ettileeN 0- Burka =rut*
`scrims as an Trr,..,wVigateir at
`GlamiSmithlaine in the Product
`Dovelnyment division of
`IPturrnacemical. Development in
`the Rinearch Triangle Pa& site.
`"'Me working at GSK, his
`have irectuded ensuring the
`Tesacin4'h- (cid:9)
`delivery a' :•_; (cid:9)
`-ur13 fur dirricaL evaluatioa
`aitd ruarice. (cid:9)
`aS4urarlte of
`• #ions with enemai
`conctructioe cc. (cid:9)
`partmeffs, rlemelopmenz and implementation a
`chig dethpery systems,. drug deliveTy platforms,
`and (cid:9)
`techrologie5. Within
`ESK. (cid:9)
`as co-chair of an
`debvery netwprk that
`transder-rb, a-€1
`a5lessed (cid:9)
`buccaL When" sysnmrns_ Di_ Burke has
`approximately 213 5 71CIES, paterrb, arid
`symposia present.r. ns. He is ark adjunct
`aniTtarrt prOregi4D" - the iliomolectiliar and
`Chemical Engineera -g department at North
`Carolina Star Milkers-0 and on the ExerLitive
`AthrFsong good Cl tFe Drug Delivery Technology
`magazine_ He is an acb'.' member of the
`Ankeritak Association'. tri Pharmaceutical
`Scicroticts ard American Chemical. Society, Dr.
`Burke earned his R5 in eiochernigtry and
`Chemical Ere:limbering from Virginia Tech arid
`his MS arid PhO in ChruirAl. Engineering from
`North Carolina State thrivergny.
`
`Prefeloor
`holds the gP Todd Eha'r rif
`Pharmaceutics at Strati-1*dt
`lirliversity 1n Stotliand, although
`cLineortly he i on a 541)..haficaL
`rah period_ His work has
`focused Oil the u of imaging
`techniques in fnemlation fieserthr and he has
`received the Ainersharn and. Pfizer awards in
`recognition of his contribution to this field_
`Wi maid vets of research are the telationship
`between gactroirrinal phyetaLosi and drug
`absorpbon and the problems of ocular drug
`delioery. lie has supervised moire than 40 PhD
`gtuderria and has authored over 400
`publications that mane origi- 3 . articles,
`l'eview5.. arid sir ktn.k , The :....:btications reset
`his inurest (cid:9)
`'^1a4 rig, physics. drug
`absorption E (cid:9)
`and
`ph4ffriat8ir (cid:9)
`i. al member of the
`tke Eirrepten jetrniLar
`editoriwit (cid:9)
`Pharnrcannou arpd Blophcraniceutics and Editor
`of the Taylor h Francis series in
`pharmaceutical technology.
`
`4,
`
`1
`
`I
`
`31
`
`