.

US005443843A
United States Patent [ 1 9 ] [ 1 1 ] Patent N u m b er : 5 443 843
a 9
C u r ato l o et a1 . [ 45] Date o f Patent: Au g . 2 2 , 1 9 9 5
[ 54] GASTRIC RETEN TION SYSTEM FOR 4, 6 01 , 89 3 7/1 9 86 C ar dinal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4/1 5
C ON TROLLED DRUG RELEASE 4, 6 87, 480 8/1 9 87 Lab y . . . . . . . . . . . . . . . . . .
5, 002 , 772 3/1 9 9 1 C u r ato l o et a1 . . . . . . . . . . . . . . . . . . . _ . 42 4/438
[ 75] Inv ento r s: W il l iam J . C u r ato l o , N iantic ; J eel in
Lo , Ol d Lym e, b o th o f c o m FOREIGN PATEN T DOC UMEN TS
7 - z _ . _ 51 431 2 6 /1 9 77 Au str al ia .
[ 3] Assl g nee Pf iz er Inc N ew Yo r k N Y 079 72 4 5/1 9 83 Eu r o p ean Pat. Of f . .
[ 2 1 ] Ap p l . N O. : 6 32 , 877 2 02 1 59 1 1 /1 9 86 Eu r o p ean Pat. Of f . .
[ 2 2 ] Fil ed: Dec . 2 4, 1 9 9 0 Pr im ar y Ex am iner - Go l l adm u di S. K ish o r e
Assistant Ex am iner - W il l iam E. B ensto n, J r .
Rel ated US, Ap p l ic atio n Data Atto r ney, Ag ent, o r Fir m Peter C . Ric h ar dso n; Pau l H .
[ 6 2 ] Div isio n o f Ser . N o . 2 00, 801 , May 31 , 1 9 88, Pat. N o . Gm sb u r g ; Gm v er F Fu l l er J r
5, 002 , 772 . [ 57] AB STRAC I
[ 51 ] Int. C l . 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A6 1 K 9 /2 0 An o r al dr u g del iv er y system h av ing del ayed g astr o in
[ 52 ] US. C l . . . . . . . . . . . . . . . . . . . . . . . 42 4/46 4; 42 4/438; testinal tr ansit c o m p r ising a no n- c o ntinu o u s c o m p r ess~
42 4/46 9 ib l e el em ent and an attac h ed c o ntr o l l ed r el ease dev ic e
[ 58] Fiel d o f Sear c h . . . . . . . . . . . . . . . . . . . . . 6 04/ 89 2 . 1 ; 42 4/438, and wh ic h in th e ex p anded f o r m r esists g astr o intestinal
42 4/46 4, 46 9 tr ansit; and a m o du l ar system f o r u se th er ein c o m p r ising
[ 56 ] Ref er enc es C ited a no n- c o ntinu o u s c o m p r essib l e el em ent and an attac h ed
r ec ep tac l e m eans f o r r ec eiv ing and h o l ding a dr u g - c o n
U. S. PATEN T DOC UMEN TS taining o r al l y adm inistr ab l e c o ntr o l l ed r el ease dev ic e
3, 844, 2 85 1 0/1 9 74 Lab y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 8/2 6 0 and wh ic h in th e ex p anded f o r m r esists g astr ic tr ansit
4, 2 5l , 506 2 /1 9 81 Lab y . . . . . . . . . . . . . . . .
4, 31 2 , 347 1 / 1 9 82 Mag o o n et a1 . . . . . . . . . . . . . . . . . . . . . . 1 2 8/2 6 0 8 C l aim s, 1 Dr awing Sh eet
5, 443, 843
Au g . 2 2 , 1 9 9 5 US. Patent
P MISC - u
5, 443, 843
1
GASTRIC RETEN TION SYSTEM FOR
C ON TROLLED DRUG RELEASE
Th is is a div isio n o f ap p l ic atio n Ser . N o . 07/2 00, 801 ,
? l ed o n May 31 , 1 9 88, no w US. Pat. N o . 5, 002 , 772 .
B AC K GROUN D OF TH E IN VEN TION
1 . Fiel d o f th e Inv entio n
5
2
Var io u s m eth o ds h av e b een desc r ib ed in th e l iter atu r e
in ef f o r ts to ac h iev e r etentio n and c o ntr o l l ed r el ease o f
dr u g s in th e g astr o intestinal tr ac t.
U. S. Pat. N o . 3, 9 76 , 76 4, issu ed Au g . 2 4, 1 9 76 , de
sc r ib es h o l l o w g l o b u l ar sh el l s h av ing an u nder c o ating
o f a c el l u l o se ac etate- p h th al ate c o p o l ym er and an o u ter
c o ating o f eth yl and h ydr o x yp r o p yl c el l u l o ses in c o m b i
natio n with a p h ar m ac eu tic al l y ac tiv e ing r edient. Said
c o ated g l o b u l ar sh el l s ar e r ep o r ted to ? o at in th e g astr ic
Th is inv entio n r el ates to an o r al dr u g del iv er y system 1 0 j u ic es wh en taken inter nal l y to p r o v ide p r o l o ng ed r e
h av ing del ayed g astr o intestinal tr ansit. Mo r e sp ec i?
c al l y it r el ates to a g astr ic r etentio n system f o r c o n
tr o l l ed r el ease o f dr u g s to th e g astr o intestinal tr ac t. Th e
system c o m p r ises o ne o r m o r e no n- c o ntinu o u s c o m
p r essib l e el em ents, i. e. , r etentio n ar m s, and an attac h ed
c o ntr o l l ed r el ease dev ic e and wh ic h in th e ex p anded
f o r m r esists g astr o intestinal tr ansit. It f u r th er r el ates to
a m o du l ar system f o r u se th er ein c o m p r ising o ne o r
m o r e no n- c o ntinu o u s c o m p r essib l e el em ents and an
attac h ed r ec ep tac l e m eans f o r r ec eiv ing and h o l ding a
dr u g - c o ntaining o r al l y adm inistr ab l e c o ntr o l l ed r el ease
dev ic e and wh ic h in th e ex p anded f o r m r esists g astr o in
testinal tr ansit.
2 . Desc r ip tio n o f th e Pr io r Ar t
Means f o r ac h iev ing r etentio n o f dr u g s in th e g astr o
intestinal tr ac t and f o r c o ntr o l l ed r el ease o f said dr u g s
th er ein ah s b een a l o ng so u g h t o b j ec tiv e. Up o n p er o s
adm inistr atio n o f a dr u g o r dr u g p r ep ar atio n m o st, if no t
al l o f it, u su al l y p asses f r o m th e sto m ac h to th e sm al l
intestine in a r el ativ el y sh o r t tim e, g ener al l y o n th e
o r der o f o ne to two h o u r s. Th is b eh av io r nec essitates
f r eq u ent p er o s adm inistr atio n o f a dr u g , th e b ene? c ial
ef f ec t o f wh ic h is to b e ex h ib ited in th e sto m ac h o r th e
wal l th er eo f . Fo r so m e dr u g s, ef ? c ient ab so r p tio n o c
c u r s o nl y in th e u p p er g astr o intestinal tr ac t, i. e. , th e
sto m ac h and/o r th e sm al l intestine. Sl o w r el ease f o r m u
l atio ns o f su c h dr u g s m ay o nl y b e ef f ec tiv e f o r a sh o r t
tim e p er io d, g ener al l y 4- 5 h o u r s, b ec au se th e f o r m u l a
tio n p asses into th e c o l o n, wh er e dr u g ab so r p tio n m ay
1 5
2 0
2 5
30
35
b e inef ? c ient o r no nex istent. In su c h c ases, r etentio n o f 40
a c o ntr o l l ed r el ease dr u g p r ep ar atio n in th e u p p er g as
tr o intestinal tr ac t wo u l d b e adv antag eo u s.
Retentio n o f dr u g s o r dr u g f o r m u l atio ns in th e p r o x i
m al r eg io n o f th e g astr o intestinal tr ac t in o r der f o r said
dr u g o r f o r m u l atio n to ac h iev e its b ene? c ial ef f ec t p o ses 45
a dif ? c u l t p r o b l em . Dav is et al . , Int. J . Ph ar m . 2 1 ,
331 - 340 ( 1 9 84) teac h th at g astr o intestinal tr ansit o f a
p h ar m ac eu tic al do sag e f o r m dep ends u p o n sev er al f ac
to r s su c h as siz e, sh ap e and natu r e o f th e system ; i. e. ,
wh eth er sing l e u nit o r m u l tip ar tic u l ate; and u p o n p h ysi
o l o g ic al f ac to r s, esp ec ial l y u p o n th e p r esenc e o r ab
senc e o f f o o d in th e sto m ac h . Th e sto m ac h is kno wn to
em p ty dif f er ent m ater ial s at dif f er ent r ates and to b r eak
do wn dig estib l e m ater ial s to ab o u t 2 m m o r l ess b ef o r e
th ey p ass th r o u g h th e p yl o r u s into th e du o denu m .
Meal s o f h ig h c al o r i? c v al u e and c er tain f o o dstu f f s,
esp ec ial l y f ats, ap p ear to h av e an inh ib ito r ef f ec t o n
g astr ic em p tying [ Dav is et al . , Int. J . Ph ar m . 2 1 ,
1 6 7- 1 77, ( 1 9 84) ] .
Retentio n o f indig estib l e m ater ial s in an em p ty sto m
ac h is f u r th er c o m p l ic ated b y th e ab il ity o f th e g astr o in
testinal tr ac t to u nder g o p o wer f u l c o ntr ac tio ns c al l ed
th e inter dig estiv e m yo el ec tr ic c o m p l ex ( IMC ) , al so
kno wn as inter dig estiv e m ig r ating m o to r c o m p l ex , o r
m o r e sim p l y, h o u sekeep er wav e . Th is p h eno m eno n
tends to sweep indig estib l e m ater ial s f r o m an em p ty
sto m ac h p ast th e p yl o r u s into th e du o denu m and
th r o u g h th e r em ainder o f th e sm al l intestine.
55
6 5
l ease o f th e ac tiv e ing r edient. Oth er ? o tatio n dev ic es .
ar e desc r ib ed in US. Pat. N o s. 4, 1 40, 755 and 4, 1 6 7, 558.
EP Ap p l ic atio n 01 6 886 2 , p u b l ish ed J an. 2 2 , 1 9 86 ,
desc r ib es b io deg r adab l e h o l l o w ? b er s c o ntaining an
ac tiv e su b stanc e in th eir c av ities f o r c o ntr o l l ed r el ease
o f said su b stanc e wh en im p l anted su b c u taneo u sl y in
m am m al s. US. p atent ap p l ic atio n Ser . N o . 38, 1 89 , ? l ed
Ap r . 1 4, 1 9 87 desc r ib es dr u g - c o ntaining ? b er s h av ing
an ax ial r atio o f at l east ab o u t 8 wh ic h ar e u sef u l f o r
r etentio n in th e g astr o intestinal tr ac t.
Mitr a, Po l ym er Pr ep r ints, AC S Div . Po l ym er C h em
istr y, 2 4 ( 1 ) , 51 - 52 ( 1 9 83) , and US. Pat. N o . 4, 451 , 2 6 0,
issu ed May 2 9 , 1 9 84, desc r ib es an o r al su stained r el ease
dr u g del iv er y system , a l am inate, c o m p r ising a c ar r ier
? l m c o ntaining dr u g in a m atr ix and a b ar r ier ? l m o n
o ne o r b o th su r f ac es o f th e c ar r ier ? l m . Th e b ar r ier ? l m
ser v es to c o ntr o l th e r ate o f r el ease o f th e dr u g and al so
p r o v ides b u o yanc y to th e del iv er y system b y v ir tu e o f
air b u b b l es b etween it and th e c ar r ier ? l m . Th e c o m p o s
ite is g ener al l y c u t into l o ng nar r o w str ip s 2 . 1 X 1 4 c m 2 ,
o p tio nal l y p l eated b ef o r e b eing p ac ked into g el atin c ap
su l es.
EP 2 02 1 59 , p u b l ish ed N o v . 2 0, 1 9 86 , desc r ib es g astr ic
r etentio n dev ic es c o m p r ising a c o ntinu o u s so l id- stic k
? g u r e, a p l anar ? g u r e o r r ing ? g u r e m ade f r o m p o l y
m er s. A dr u g m ay b e disp er sed with in th e dev ic e as an
integ r al p ar t th er eo f , o r m ay b e attac h ed as a c o ntr o l l ed
r el ease dr u g m o du l e to th e af o r em entio ned r etentio n
dev ic es.
Or al l y adm inistr ab l e dev ic es o f v ar iab l e g eo m etr y;
i. e. , dev ic es wh ic h h av e o ne c o n? g u r atio n desig ned to
p er m it th eir o r al adm inistr atio n and wh ic h , wh en in th e
env ir o nm ent o f u se, assu m e a sec o nd c o n? g u r atio n
desig ned to p r ev ent th eir ex p u l sio n ar e kno wn in th e
l iter atu r e. Pr inc ip l e f o c u s u p o n su c h dev ic es h as o c
c u r r ed in anim al h u sb andr y and p ar tic u l ar l y in th e tr eat
m ent o f r u m inants. Rep r esentativ e o f su c h dev ic es ar e
th o se disc l o sed in US. Pat. N o . 3, 844, 2 85 and 4, 6 01 , 89 3.
In sp ite o f th e dev el o p m ents in g astr ic r etentio n de
v ic es th e need f o r p r ac tic al m eans f o r ac h iev ing r eten
tio n o f dr u g s o r dr u g f o r m u l atio ns in th e sto m ac h f o r
c o ntr o l l ed ( su stained, p r edic tab l e and r ep r o du c ib l e)
r el ease o f dr u g s r eg ar dl ess o f wh eth er th e sto m ac h is
f u l l , em p ty o r anywh er e in b etween is h ig h l y desir ab l e.
Esp ec ial l y desir ab l e is su c h a system wh ic h c an b e ap
p l ied to ex isting o r al l y adm inistr ab l e c o ntr o l l ed r el ease
dev ic es to enh anc e th eir g astr ic r etentio n so as to r ender
th em essential l y indep endent o f th e c o nditio n o f th e
sto m ac h .
SUMMARY OF TH E IN VEN TION
Th is inv entio n r el ates to an o r al dr u g del iv er y system
f o r h u m an o r anim al u se. Th e system , a g astr ic r etentio n
system , ex h ib its del ayed g astr o intestinal tr ansit. It c o m
p r ises o ne o r m o r e r etentio n ar m s, said ar m s b eing a
no n- c o ntinu o u s c o m p r essib l e el em ent, and an attac h ed
c o ntr o l l ed r el ease dev ic e and wh ic h in th e ex p anded
f o r m r esists g astr ic tr ansit; and to a m o du l ar system f o r
5, 443, 843
3
u se th er ein c o m p r ising a no n- c o ntinu o u s c o m p r essib l e
el em ent and an attac h ed r ec ep tac l e m eans f o r r ec eiv ing
and h o l ding a dr u g - c o ntaining o r al l y adm inistr ab l e c o n
tr o l l ed r el ease dev ic e and wh ic h in th e ex p anded f o r m
r esists g astr ic tr ansit. It esp ec ial l y r el ates to su c h sys
tem s to wh ic h ar e attac h ed two o r m o r e ? ex ib l e r eten
tio n ar m s. Mo r e sp ec i? c al l y it r el ates to su c h system s
wh er ein th e no n- c o ntinu o u s el em ents, e. g . r etentio n
ar m s, ar e c o m p r essib l e ab o u t th e dev ic e o r th e r ec ep ta
c l e m eans to an o v er al l siz e su itab l e f o r o r al adm inistr a
tio n th er eo f and wh ic h , in a l iq u id u se env ir o nm ent, ar e
ex p andab l e to an o v er al l siz e su f ? c ient to p r ev ent p as
sag e th er eo f th r o u g h a p yl o r u s, said r ec ep tac l e m eans
and/o r said no n- c o ntinu o u s el em ents b eing er o dib l e in
th e u se env ir o nm ent.
B RIEF DESC RIPTION OF TH E DRAW IN G
FIG. I sh o ws a p ar tial l y u nc o il ed system o f th is in
v entio n ( 1 ) c o m p r ising a r ec ep tac l e ( 2 ) to wh ic h ar e
attac h ed f o u r r etentio n ar m s ( 3) and h av ing a c o ntr o l l ed
r el ease tab l et ( 4) in th e r ec ep tac l e.
DETAILED DESC RIPTION OF TH E
IN VEN TION
Th e ter m o r al l y adm inistr ab l e c o ntr o l l ed r el ease
dev ic e as u sed h er ein is intended to r ef er to tab l ets and
c ap su l es g ener al l y desc r ib ed as p r o l o ng ed, c o ntr o l l ed,
del ayed o r su stained r el ease dev ic es desig ned f o r o r al
adm inistr atio n. Th e m ec h anism b y wh ic h su c h dev ic es
o p er ate is im m ater ial to th e p r esent inv entio n. Su c h
dev ic es p er se f o r m no p ar t o f th is inv entio n. Th e c o n
tr o l l ed r el ease dev ic es c an, o n th e b asis o f th eir c o n
str u c tio n, b e r ef er r ed to as m atr ix , l am inate ( o r sand
wic h ) , c o ated m atr ix , r eser v o ir o r o sm o tic dev ic es.
Al ter nativ el y, f r o m th e standp o int o f th eir m ec h anism
o f ac tio n th ey c an b e c h ar ac ter iz ed as dif f u sio n o r o s
m o tic dev ic es. Th e m atr ix typ e inc l u des tab l ets h av ing
th e dr u g disso l v ed o r su sp ended in th em , and l am inated
dev ic es su c h as th o se wh er ein th e dr u g - c o ntaining c ar
r ier is sandwic h ed o r inter p o sed b etween no n- dr u g
c o ntaining l ayer s o f a c ar r ier . Th e r eser v o ir dev ic es
c o m p r ise a dr u g su p p l y o r dr u g p l u s ex c ip ient c o r e
su r r o u nded b y a wal l f o r m ed b y a p o l ym er ic o r wax
c ar r ier .
Rep r esentativ e o f an o sm o tic dev ic e is o ne wh ic h
c o m p r ises a water - inso l u b l e, water p er m eab l e p o l ym er ,
o p tio nal l y c o m p r ising a p o r o sig en disp er sed th er ein and
c o ntaining with in th e r eser v o ir an o sm o tic enh anc ing
ag ent and dr u g su p p l y.
Rep r esentativ e o f su c h dev ic es ar e th o se desc r ib ed in
U. S. Pat. N o s. 4, 6 87, 6 6 0; 4, 572 , 833; 4, 552 , 6 2 5;
4, 454, 1 08; 4, 434, 1 53; 4, 389 , 39 3; 4, 32 7, 72 5; 3, 845, 770;
3, 835, 2 2 1 ; 2 , 887, 438; EP 1 6 9 , 1 05 and EP 1 6 2 , 49 2 .
As u sed h er ein, th e ter m c o ntr o l l ed r el ease is in
tended to em b r ac e no t o nl y th e c o nc ep t o f su stained
r el ease o f dr u g o v er a p r o l o ng ed p er io d o f tim e; i. e. ,
r el ativ e to th e tim e p er io d th e dr u g r esp o nse is r eal iz ed
b y adm inistr atio n o f a sing l e do se o f th e dr u g ; b u t th o se
o f p r edic tab il ity and r ep r o du c ib il ity. Th u s, th is inv en
1 5
2 5
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45
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tio n p er m its b o th r ate- wise and tim e- wise r el ease o f 6 0
dr u g ; i. e. , dr u g is r el eased at a ? x ed, r ep r o du c ib l e r ate
o v er a p r edeter m ined p er io d o f tim e. In th e p r esent
instanc e, th e h er ein desc r ib ed g astr ic r etentio n system
ex tends th e ter m to inc l u de dr u g r el ease p r im ar il y at a
p r e- deter m ined site; nam el y, th e p r o x im al r eg io n o f th e
g astr o intestinal tr ac t.
Th e ter m s r ec ep tac l e and r ec ep tac l e m eans r ef er
to any m eans f o r r ec eiv ing and h o l ding a c o ntr o l l ed
6 5
4
r el ease tab l et o r c o ntr o l l ed r el ease c ap su l e. It c an, b y
de? nitio n, h av e any o f a v ar iety o f c o n? g u r atio ns and
dim ensio ns dep ending u p o n th e siz e and sh ap e o f th e
dev ic e ( tab l et o r c ap su l e) to b e u sed. Fo r c o nv enient u se
f o r o r al adm inistr atio n o f dr u g s, its m ax im u m siz e is, o f
c o u r se, l im ited b y th e h o st to b e tr eated; e. g . h u m ans o r
anim al s. Ag ain, f o r c o nv enienc e and ease o f adm inistr a
tio n, it sh o u l d h av e no sh ar p o r p r o j ec ting f eatu r es and
is desir ab l y r o u nd, c ir c u l ar o r el l ip tic al .
Th e r ec ep tac l e c an, in o ne m o di? c atio n o f th is inv en
tio n, b e in th e f o r m o f a c o l l ar o r a b el t wh ic h ? ts ab o u t,
i. e. c o ntains, a g iv en c o ntr o l l ed r el ease dev ic e so as to
h o l d it u ntil su c h tim e as it is to b e ex p el l ed f r o m th e
h o st to wh o m it was adm inister ed. .
In ano th er m o di? c atio n, th e r ec ep tac l e m eans is an
o p en- ended c o ntainer , i. e. , a c u p - sh ap ed c o ntainer ; th e
o v er al l c o n? g u r atio n and dim ensio ns o f wh ic h ar e de
ter m ined b y th o se o f th e c o ntr o l l ed r el ease dev ic e it is
to c o ntain.
In th o se instanc es wh er ein th e r ec ep tac l e is a c o l l ar o r
an o p en- ended c o ntainer , it c an b e c o nstr u c ted f r o m a
so l id im p er m eab l e p o l ym er sinc e in m any situ atio ns
th er e wil l b e su f ? c ient ex p o su r e o f th e c o ntr o l l ed r e
l ease dev ic e to th e l iq u id o f th e env ir o nm ent.
In a f u r th er m o di? c atio n, th e r ec ep tac l e m eans c an b e
a c l o sed c o ntainer ; i. e. o ne h av ing a to p , a b o tto m and
sides, wh ic h c o m p l etel y enc l o se th e c o ntr o l l ed r el ease
dev ic e, h av ing su b stantial l y th e sam e c o n? g u r atio n b u t
so m ewh at l ar g er dim ensio ns to ac c o m m o date th e de
v ic e. Fo r su c h m o di? c atio n th e r ec ep tac l e is g ener al l y
c o nstr u c ted o f a p o l ym er wh ic h is p er m eab l e, inc l u ding
m ic r o p o r o u s, as disc u ssed b el o w with r esp ec t to th e
r etentio n ar m s. Al ter nativ el y, it c an b e c o nstr u c ted
f r o m an im p er m eab l e o r sem ip er m eab l e p o l ym er in
wh ic h m ac r o p er f o r atio ns h av e b een m ade to p er m it
p assag e o f env ir o nm ental l iq u id into th e r ec ep tac l e and
p assag e o f env ir o nm ental l iq u id p l u s dr u g into th e env i
r o nm ent.
Th e ter m dr u g as u sed h er ein inc l u des p h ysio l o g i
c al l y o r p h ar m ac o l o g ic al l y ac tiv e su b stanc es wh ic h
p r o du c e a system ic o r l o c al iz ed ef f ec t o r ef f ec ts in a
m am m al , inc l u ding h u m ans and anim al s. Inc l u ded in
th is ter m ar e sedativ es su c h as p h eno b ar b ital , th io p ental
and so diu m p ento b ar b ital ; anal g esic s su c h as c o deine,
m o r p h ine and m ep endine; l ev o - do p a; tr anq u il iz er s su c h
as r eser p ine, c h l o r p r o m az ine and tl u p h enaz ine; antib ac
ter ial s su c h as tetr ac yc l ine, o x ytetr ac yc l ine, p enic il l in,
su l f o nam ides and c h l o r am p h enic o l ; antif u ng al s su c h as
tio c o naz o l e, g r iseo f u l v in and nystatin; antiin? am m ato
r ies su c h as asp ir in and sal ic yl am ide; nu tr itio nal ag ents
su c h as essential am ino ac ids, v itam ins C and B 1 2 ; b r o n
c h o dil ato r s su c h as p ir b u ter o l ; diu r etic s su c h as f u r o se
m ide; antih yp er tensiv es su c h as p r az o sin and do x az o sin;
v aso dil ato r s su c h as nif edip ine; p r o stag l andins, anth el
m intic s, antiu l c er ag ents; and o th er s kno wn to th o se
skil l ed in th e ar t.
Th e am o u nt o f a g iv en dr u g wh ic h m u st b e u sed in a
del iv er y system o f th is inv entio n to ac h iev e a g iv en
r el ease r ate, o r th e r el ease r ate o f a g iv en system o f th is
inv entio n, is deter m ined b y an in v itr o test as th o se
skil l ed in th e ar t wil l r ec o g niz e. In g ener al , su c h a test
inv o l v es p l ac ing o ne o r m o r e o f th e system s in q u estio n
in an env ir o nm ent ap p r o x im ating th e am b ient env ir o n
m ent o f u l tim ate u se intended f o r said dr u g del iv er y
system and m easu r ing b y ap p r o p r iate m eth o do l o g y
kno wn to th o se skil l ed in th e ar t th e am o u nt o f dr u g
r el eased to said env ir o nm ent o v er a g iv en p er io d o f tim e
5, 443, 843
5
and/ o r b y deter m ining th e am o u nt o f dr u g r em aining in
th e system af ter a g iv en p er io d o f tim e.
As r eg ar ds so l u b il ity o f a g iv en dr u g , th er e is no
u p p er l im it sinc e th e r el ease r ate c an b e r eg u l ated b y
j u dic io u s c h o ic e o f p o l ym er o r p o l ym er s. As r eg ar ds a
l o wer l im it o f so l u b il ity, th e dr u g sh o u l d b e o f su f f ic ient
so l u b il ity to p er m it ac h iev em ent o f a b ene? c ial do se o f
th e dr u g f r o m th e m ax im u m nu m b er o f system s wh ic h
c an b e p r ac tic al l y adm inister ed to a g iv en su b j ec t.
Th e ter m r etentio n ar m r ef er s to any r ib b o n, r ib
b o n- l ike, ? b er , o r ? b er - l ike str u c tu r e in wh ic h o ne di
m ensio n, e. g . , l eng th , is sig ni? c antl y g r eater th an th e
o th er dim ensio ns, e. g . , width , th ic kness, o r diam eter .
Said af o r em entio ned str u c tu r es c an b e so l id o r h o l l o w
and, if h o l l o w, c an b e c l o sed at th e end o r ends. Th e
r etentio n ar m s c an th em sel v es ser v e as c o ntr o l l ed r e
l ease dev ic es f o r th e sam e o r dif f er ent dr u g f r o m th at o f
th e c o ntr o l l ed r el ease dev ic e ( tab l et o r c ap su l e) . Th u s,
th e o p p o r tu nity f o r c o nc u r r ent c o ntr o l l ed r el ease o f
m o r e th an o ne dr u g in a c o nv enient and sim p l e m anner
is m ade av ail ab l e.
As r eg ar ds th e p r esent inv entio n, it is g ener al l y p r e
f er r ed to u se r etentio n ar m s wh ic h ar e no t th em sel v es
c o ntr o l l ed r el ease dev ic es sinc e su c h system s ar e sim
p l er to c o nstr u c t.
Th e r etentio n ar m s c an c o m p r ise a m ater ial wh ic h is
b io er o dib l e and, esp ec ial l y wh en th e r etentio n ar m s ar e
to ser v e as a c o ntr o l l ed r el ease dev ic e, it c an b e p er m ea
b l e, inc l u ding m ic r o p o r o u s, sem ip er m eab l e o r im p er m e
ab l e. B y p er m eab l e r etentio n ar m is m eant o ne c o m p r is
ing a p o l ym er , wh ic h al l o ws p assag e o f env ir o nm ental
? u id and o f dr u g . A sem i- p er m eab l e r etentio n ar m , o n
th e o th er h and, is o ne wh ic h is p er m eab l e to env ir o n
m ental ? u id and essential l y im p er m eab l e to th e dr u g o r
v ic e- v er sa. An im p er m eab l e r etentio n ar m is o ne c o m
p r ising m ater ial essential l y im p er m eab l e to env ir o nm en
tal ? u id and dr u g . Th e sel ec ted m ater ial c an, in addi
tio n, b e no n- er o dib l e o r b io er o dib l e in th e u se env ir o n
m ent.
Th e r etentio n ar m m ater ial wh ic h is u sed m u st b e
no n- to x ic to th e m am m al , inc l u ding a h u m an, to wh ic h
th e dr u g del iv er y system is to b e adm inister ed, and
su f f ic ientl y ? ex ib l e to p er m it ease o f adm inistr atio n and
to av o id in? ic tio n o f p u nc tu r e wo u nds du r ing and su b
seq u ent to adm inistr atio n. Rep r esentativ e o f th e p o l y
m er ic m ater ial s wh ic h c an b e u sed ar e p o l yeth yl ene,
p o l yp r o p yl ene, p o l ystyr ene, p o l ytetr a? u o r o eth yl ene,
p o l yv inyl c h l o r ide, c el l u l o se ac etate, c el l u l o se nitr ate,
c el l u l o se tr iac etate, eth yl ene v inyl ac etate, p o l yester s,
p o l yanh ydr ides, p o l yo r th o ester s, h ydr o x yl ated- eth y
l ene v inyl ac etate, h ydr o x yeth yl c el l u l o se, ac etyl ated
h ydr o x yeth yl c el l u l o se, ? b r o in, p o l yg l yc o l ic ac id, p o l y
l ac tic ac id, p o l y( l ac tic g l yc o l ic ) ac id, c el l u l o se ac etate
su c c inate, c el l u l o se eth er s, p o l y( v inyl m eth yl eth er )
c o p o l ym er s, c el l u l o se ac etate l au r ate, p o l yac r yl ates,
o r g ano sil ic o n p o l ym er s, m eth yl c el l u l o se, p o l yeth er
and p o l yester u r eth anes, p o l yac r yl o nitr il e, p o l ysu l ? de
el asto m er , p o l yiso p r ene, p o l y ( v inyl p yr r o l ido ne) , p o l y
am ides, p o l yir nides, p o l yam ides and m eth ac r yl ates. Stil l
f u r th er , th e ar m c an b e c o nstr u c ted o f a m etal o r
m etal al l o y. A p o l ym er ic system o f inter est c o m p r ises a
p o l ym er wh ic h is enter ic ; i. e. , a p o l ym er wh ic h is
inso l u b l e at g astr ic p H and so l u b l e at intestinal p H ( e. g .
c el l u l o se ac etate- p h th al ate) .
Th e entir e o r al dr u g del iv er y system o r o nl y a p o r
tio n th er eo f c an b e m ade f r o m p o l ym er s wh ic h l o se
str eng th v ia er o sio n b y disso l u tio n, h ydr o l ysis o r enz y
m atic deg r adatio n. Th ese p o l ym er s inc l u de: p o l yeth yl
2 5
40
45
6 5
6
ene g l yc o l , p o l yeth yl ene o x ide, p o l yac r yl ic ac id, p o l y
v inyl al c o h o l , dex tr an, g el atin, p o l yv inyl p yr r o l ido ne,
h ydr o x yp r o p yl m eth yl c el l u l o se, c el l u l o se ac etate
p h th al ate, h ydr o x yp r o p yl c el l u l o se, h ydr o x yp r o p yl m e
th yl c el l u l o se p h th al ate, p o l yv inyl ac etate p h th al ate,
p o l yac r yl am ide, p o l ysac c h ar ides, g u m ar ab ic , Eu dr ag it
E1 00 ( c o p o l ym er o f dim eth yl am ino eth yl m eth ac r yl ate
and m eth ac r yl ic ac id ester ) , Eu dr ag it L1 00 ( c o p o l ym er
o f m eth ac r yl ic ac id and m eth ac r yl ic ac id ester ) , p o l yo r
th o ester s, p o l yp h o sp h ates, g l u tam ic ac id and eth yl g l u
tam ate c o p o l ym er , p o l yg l yc o l ic ac id, p o l yl ac tic ac id,
c o p o l ym er o f l ac tide and e- c ap r o l ac to ne, ter p o l ym er o f
l ac tide, g l yc o l ide and e- c ap r o l ac to ne.
N o n- p o l ym er ic additiv es wh ic h disso l v e u p o n h ydr a
tio n to dec r ease th e str eng th o f th e stif f c o m p o nent o f
th e dev ic e inc l u de: o r g anic su b stanc es su c h as c itr ic
ac id, g l u c o se and th e l ike; and ino r g anic sal ts su c h as
so diu m b ic ar b o nate, so diu m c h l o r ide and th e l ike.
Par t o f th e dev ic e c an al so b e m ade f r o m p o l ym er s
wh ic h l o se str eng th u p o n h ydr atio n. Th ese p o l ym er s
inc l u de c r o ssl inked h ydr o g el s su c h as p o l yh ydr o x ye
th yl m eth ac r yl ate and th e l ike.
Meth o ds to c o m b ine m ater ial s to g iv e th e desir ed
p r o p er ties ar e kno wn to th o se skil l ed in th e ar t and
inc l u de b l ending , l am inating , c asting , c o ex tr u sio n, in
j ec tio n m o l ding and c o m p r essio n m o l ding o f p o l ym er s;
adding o r g anic su b stanc es, ino r g anic sal ts o r r u b b er
p ar tic l es to a p o l ym er , with o r with o u t c o u p l ing ag ents
su c h as o r g anic titanates and sil anes; c r o ssl inking o f two
p o l ym er s with h ydr o l yz ab l e b o nds; and c o p o l ym er iz a
tio n.
Th e r etentio n ar m s c an b e attac h ed dir ec tl y to th e
c o ntr o l l ed r el ease dev ic e b y ap p r o p r iate m eans su c h as
b y g l u ing o r b y f u sing th em to said dev ic e. Th is l atter
m eth o d is p ar tic u l ar l y c o nv enient wh en th e dev ic e and
r etentio n ar m s ar e c o nstr u c ted f r o m th e sam e p o l ym er .
Th e f u sio n c an b e ac c o m p l ish ed b y th er m al m eans f o r
c er tain p o l ym er s e. g . p o l yeth yl ene; o r b y m eans o f a
su itab l e so l v ent. In eith er instanc e, th e r etentio n ar m s
and dev ic e b ec o m e an integ r ated u nit. Al ter nativ el y,
th e r ec ep tac l e and r etentio n ar m s m ay b e c o nstr u c ted as
a sing l e p iec e f r o m a m ater ial wh ic h p o ssesses th e r eq u i
site p r o p er ties to su p p o r t g astr ic r etentio n and to insu r e
ev entu al l o ss o f p h ysic al integ r ity in o r der to assu r e saf e
p assag e o u t o f th e sto m ac h . It m ay in c er tain situ atio ns
b e dif f ic u l t to c o nc l u de h o w m any r etentio n ar m s ar e
attac h ed to a g iv en dev ic e. In o r der to av o id sem antic
p r o b l em s o n th is issu e it is intended, f o r p u r p o ses o f th is
inv entio n, th at wh en any r etentio n ar m s ex tends b eyo nd
a g iv en edg e o f th e c o ntr o l l ed r el ease dev ic e it is c o nsid
er ed a sep ar ate r etentio n ar m .
Th e r etentio n ar m s ( o r sim p l y, ar m s) m u st b e ? ex ib l e
eno u g h to p r ev ent p u nc tu r e o f th e sto m ac h o r intestinal
wal l and to p er m it th eir b eing wr ap p ed o r o th er wise
c o m p r essed ab o u t th e dev ic e o r r ec ep tac l e m eans f o r
adm inistr atio n p u r p o ses. Th e desir ed ? ex ib il ity is r e
l ated to th e l eng th o f th e ar m u sed. Lo ng ar m s r eq u ir e
a g r eater deg r ee o f ? ex ib il ity th an do sh o r t ar m s. Th ey
m u st al so p o ssess th e ab il ity, in th e u se env ir o nm ent, o f
ex p anding f r o m th eir c o m p r essed state to , o r ap p r o x i
m atel y to , th eir c o n? g u r atio n p r io r to th eir b eing c o m
p r essed. Th e su itab il ity o f a p ar tic u l ar ar m l eng th is
deter m ined b y em p ir ic al deter m inatio n o f g astr o intesti
nal tr ansit tim e assayed, f o r ex am p l e, b y X- r ay r adio g r a
p h y o r sc intig r ap h y. Th e ? ex ib il ity o f m ater ial s u sed in
c o nstr u c ting r etentio n ar m s f o u nd ac c ep tab l e b y eith er
o f th ese m eth o ds is th en m easu r ed, if desir ed, b y th e
Am er ic an N atio nal Standar d AN SI/ASTM Standar d
5, 443, 843
7
Test Meth o d f o r Stif f ness o f Fab r ic s, Dl 388- 6 4, Q p tio n
B Do u b l e C antil ev er Test.
Th e ab o v e desc r ib ed X- r ay r adio g r ap h y o r sc intig r a
p h y m eth o ds ar e al so u sed to deter m ine th e r etentio n
tim e o f a g iv en system in th e h o st to wh ic h it is adm inis
ter ed.
Th e o v er al l dim ensio ns o f th e o r al l y adm inistr ab l e
system s o f th is inv entio n ar e deter m ined b y th e anato m y
and p h ysio l o g y o f th e m am m al to wh ic h th ey ar e to b e
adm inister ed. In th e u nu sed c o nditio n th ey m u st b e o f a
siz e su itab l e f o r o r al adm inistr atio n to th e m am m al to b e
tr eated. Fo r h u m an u se, f r o m a p r ac tic al standp o int, th e
l ar g est dim ensio n o f th e system s in th e ex p anded c o ndi
tio n c an v ar y f r o m 2 . 5 to 6 . 0 c m , and p r ef er ab l y f r o m
3. 0 to 5. 0 c m . Th e h er ein desc r ib ed system s c an h av e a
v ar iety o f c o n? g u r atio ns deter m ined in p ar t b y th at o f
th e c o ntr o l l ed r el ease dev ic e u sed. W h en th e system is
o th er th an r o u nd o r c ir c u l ar , th e m inim u m and m ax i
m u m dim ensio ns ar e 2 . 5 and 6 . 0 c m , r esp ec tiv el y f o r th e
ex p anded f o r m .
Th e m aj o r f ac to r s r esp o nsib l e f o r r etaining th e h er ein
desc r ib ed del iv er y system s in th e g astr o intestinal tr ac t
ar e th eir o v er al dim ensio ns ( l eng th and width ) , th eir
c o n? g u r atio n and th e stif f ness o f th e ar m s. Th u s, f o r
system s h av ing ar m s o f identic al dim ensio ns b u t dif f er
ent stif f ness, th e l east ? ex ib l e wil l b e r etained f o r a
l o ng er p er io d o f tim e.
Th e p r ef er r ed c o n? g u r atio n f o r th e o r al dr u g del iv
er y system s o f th is inv entio n is th at o f a c o il o r sp ir al . In
th o se system s in wh ic h a sing l e ar m is p r esent, th e c o n
tr o l l ed r el ease dev ic e, o r th e m o du l e, is l o c ated at th e
c enter o f th e c o il ; i. e. , th e r etentio n ar m is c o il ed ar o u nd
th e said dev ic e o r m o du l e. As a m atter o f f ac t, in th e
p r ef er r ed c o n? g u r atio n o f al l o r al dr u g del iv er y sys
tem s o f th is inv entio n, th e c o ntr o l l ed r el ease dev ic e o r
m o du l e is l o c ated at th e c enter o f th e c o il .
Var io u s em b o dim ents o f th e c u r r ent inv entio n ar e
p o ssib l e. A p r ef er r ed em b o dim ent o f th is inv entio n is
o ne in wh ic h a sing l e r etentio n ar m is attac h ed to and
c o il ed ab o u t th e c o ntr o l l ed r el ease tab l et o r c ap su l e,
eith er dir ec tl y o r v ia a r ec ep tac l e, and in wh ic h th e
r etentio n ar m u nc o il s at l east p ar tial l y in th e env ir o n
m ent o f u se, to f o r m a c o il o r c o il - l ike c o n? g u r atio n
ar o u nd th e c o ntr o l l ed r el ease dev ic e. In th is em b o di
m ent, th e r etentio n ar m m ay p o ssess a ? b er - l ike o r a
r ib b o n- l ike sh ap e. Th e p r ef er r ed r etentio n ar m l eng th
f o r th is em b o dim ent dep ends u p o n th e stif f ness o f th e
m ater ial f r o m wh ic h th e r etentio n ar m is c o nstr u c ted;
f o r a stif f er m ater ial , a sh o r ter l eng th m ay b e r eq u ir ed.
In th e u nc o il ed state, th e diam eter o f th e c o il f o r m ed b y
th e r etentio n ar m is p r ef er ab l y g r eater th an ap p r o x i
m atel y 3 c m . Th e l eng th o f th e r etentio n ar m in th is
em b o dim ent is typ ic al l y 1 0- 30 c m .
A m o r e p r ef er r ed em b o dim ent is o ne in wh ic h two o r
m o r e, m o st p r ef er ab l y f o u r , r etentio n ar m s ar e attac h ed
to and c o il ed ab o u t th e c o ntr o l l ed r el ease tab l et o r c ap
su l e, eith er dir ec tl y o r p r ef er ab l y v ia a r ec ep tac l e, and
in wh ic h th e r etentio n ar m s u nc o il at l east p ar tial l y in
th e env ir o nm ent o f u se. In th is m o st p r ef er r ed em b o di
m ent, th e r etentio n ar m s p r ef er ab l y p o ssess a r ib b o n
l ike sh ap e. Th e p r ef er r ed r etentio n ar m l eng th f o r th is
em b o dim ent dep ends u p o n th e stif f ness o f teh m ater ial
f r o m wh ic h th e r etentio n ar m is c o nstr u c ted; f o r a
stif f er m ater ial , a sh o r ter l eng th m ay b e r eq u ir ed. In th e
1 5
2 0
2 5
35
40
45
50
55
6 0
u nc o il ed state in th e env ir o nm ent o f u se, th e diam eter o f 6 5
th e g astr ic r etentio n system is p r ef er ab l y g r eater th an
ap p r o x im atel y 3 c m . Th e l eng th o f th e r etentio n ar m s in
su c h em b o dim ent is typ ic al l y 2 - 6 c m .
8
In al l p r ef er r ed em b o dim ents, th e r ec ep tac l e and/o r
th e r etentio n ar m s, and/ o r th e adh esiv e wh ic h attac h es
th e r etentio n ar m s to th e r ec ep tac l e o r dir ec tl y to th e
dr u g del iv er y dev ic e, ar e c o nstr u c ted f r o m m ater ial s
wh ic h so f ten, disinteg r ate, disso l v e o r deg r ade in th e
b io l o g ic al env ir o nm ent o f u se, in o r der to p er m it saf e
tim el y ex it f r o m th e sto m ac h and saf e p assag e th r o u g h
th e distal GI tr ac t, with no dang er o f intestinal o b str u c
tio n. _
A p r o c edu r e o f v al u e in deter m ining th e r el ease r ates
o f th e h er ein desc r ib ed dr u g c o ntaining dev ic e is as
f o l l o ws. Th e p r o c edu r e, an in v itr o p r o c edu r e, c o m
p r ises p l ac ing th e dev ic e o r dev ic es in an env ir o nm ent
ap p r o x im ating th at o f th e g astr o intestinal tr ac t and
m easu r ing th e am o u nt o f dr u g r el eased to said env ir o n
m ent as a f u nc tio n o f tim e.
In v iv o r el ease o f dr u g f r o m o r al dr u g del iv er y sys
tem s o f th is inv entio n is deter m ined b y adm inister ing
th em to do g s and m easu r ing th e am o u nt o f dr u g r e
l eased o v er a p er io d o f tim e b y deter m ining th e am o u nt
o f dr u g p r esent in, f o r ex am p l e, th e anim al s b l o o d o r
u r ine. 1
In th e Ex am p l es wh ic h f o l l o w, th e r etentio n ar m s, ar e
p r ef er ab l y sym m etr ic al l y p l ac ed ab o u t th e c o ntr o l l ed
r el ease dev ic e o r th e r ec ep tac l e m eans c o ntaining su c h
a dev ic e sinc e, f o r a g iv en system wh er ein al l r etentio n
ar m s ar e su b stantial l y o f eq u al ? ex ib il ity and o v er al l
dim ensio ns, th ey ar e r etained f o r l o ng er p er io ds th an
th o se system s h av ing no n- sym m etr ic al ar r ang em ent o f
r etentio n ar m s.
Th e f o l l o wing Ex am p l es ar e il l u str ativ e, b u t no t l im
iting o f th e p r esent inv entio n.
In eac h Ex am p l e, th e do g s wer e c o nc u r r entl y do sed
with th e o r al del iv er y system and with a r adio p aq u e
no n- disinteg r ating B aSO4 tab l et to ser v e as inter nal
c o ntr o l . Do g s wer e f ed at 7 h o u r s p o st- do se.
Ab b r ev iatio ns u sed in th e tab l es ar e:
I/I= c o ntr o l tab l et in sto m ac h /del iv er y system in
sto m ac h ; O/I= tab l et o u t/del iv er y system in; 0/0:
tab l et o u t/del iv er y system o u t; N M= no t m easu r ed.
diam = diam eter .
EXAMPLE 1
Gastr ic r etentio n o f ? b er s in u nf ed b eag l e do g s was
assessed u sing x - r ay r adio g r ap h y. H o l l o w p o l yeth yl ene
? b er s ( 1 0 c m l eng th > < l m m o u ter diam eter ) wer e ? l l ed
with a satu r ated so l u tio n o f p o tassiu m io dide, wh ic h
ser v ed as a r adio p aq u e ag ent. Th e ends wer e tied and
th e ? b er was c o il ed and p l ac ed in a #00 g el atin c ap su l e.
Th e g el atin c ap su l e al so c o ntained a 4. 0 m m > < 1 . 5 m m
r adio p aq u e no n- disinteg r ating standar d r o u nd c o nv ex
tab l et o f b ar iu m su l f ate, wh ic h ser v ed as an inter nal
c o ntr o l f o r GI tr ansit stu dies. Fasted b eag l e do g s wer e
do sed with th e c ap su l e, wh ic h c o ntained b o th th e ? b er
and th e tab l et, and wer e x - r ayed at v ar io u s tim es af ter
do sing in o r der to assess th e p o sitio ns o f th e ? b er and
tab l et in th e GI tr ac t. Th e do g s wer e f ed th eir no r m al
dail y f o o d r atio n at ~7 h o u r s p o st- do se. Tab l e I dem o n
str ates th at th e ? b er was c o nsistentl y r etained l o ng er
th an th e tab l et in th e sto m ac h . W h il e th e tab l et was
g ener al l y em p tied f r o m th e sto m ac h in l - 2 h o u r s, th e
? b er was c o nsistentl y g astr ic al l y r etained f o r 2 2 4
h o u r s. Th is g astr ic r etentio n was p ar tic u l ar l y sig ni? c ant
b ec au se it was o b ser v ed in th e u nf ed state, wh ic h is
c h ar ac ter iz ed b y h o u sekeep er wav es wh ic h r em o v e
indig estib l e m ater ial f r o m th e sto m ac h .
Th e g astr ic r etentio n o f tab l ets with attac h ed r eten
tio n ar m s o f p o l yeth yl ene ? b er s was sim il ar l y assessed
5, 443, 843
9
in u nf ed do g s. A 0. 4 c m X 0. 1 5 c m r adio p aq u e no n- disin
teg r ating standar d r o u nd c o nv ex tab l et ( B aSO4) was
dr il l ed th r o u g h with a 0. 1 1 m m h o l e th r o u g h th e c enter
o f th e tab l et f ac e. A 1 0 c m XO. l c m h o l l o w p o l yeth yl
ene ( PE) ? b er was th r eaded into th e h o l e in th e tab l et
f ac e in o ne o f two c o n? g u r atio ns, and was g l u ed to th e
tab l et. In o ne c o n? g u r atio n, th e tab l et was l o c ated at
th e end o f th e ? b er r etentio n ar m ; in th e o th er c o n? g u ~
r atio n th e tab l et was l o c ated at th e c enter o f th e ? b er
r etentio n ar m . Th ese dev ic es c an b e v isu al iz ed as a,
tab l et with a sing l e 1 0 c m ? b er r etentio n ar m attac h ed,
and as a tab l et with two 5 c m ? b er r etentio n ar m s at
tac h ed, r esp ec tiv el y. Th e ? b er r etentio n ar m s wer e
l o aded with a sm al l q u antity o f steel p o wder , as a r adi
o p aq u e ag ent. Eac h dev ic e was l o aded into a #00 c ap
su l e, al o ng with a c o ntr o l r adio p aq u e tab l et. Tab l e I
p r esents th e o b ser v ed ex tent o f g astr ic r etentio n in
u nf ed do g s o f a 0. 4 c m X0. l 5 c m tab l et with a 1 0 c m PE
? b er r etentio n ar m attac h ed, and o f a 0. 4 c m XO. 1 5 c m
tab l et with two 5 c m PE ? b er r etentio n ar m s attac h ed.
Th e tab l et with a sing l e 1 0 c m PE ? b er r etentio n ar m
was r etained f o r o nl y o ne h o u r l o ng er th an th e c o ntr o l
tab l et in o ne do g , and was no t r etained at al l in two
o th er do g s. Th is r esu l t was su r p r ising , sinc e a 1 0 c m PE
? b er al o ne was c o nsistentl y g astr ic al l y r etained f o r 2 2 4
h o u r s ( Tab l e I) . Th ese o b ser v atio ns dem o nstr ate th at
attac h m ent o f a tab l et to a ? b er c an r esu l t in a l ar g e
dec r ease in th e ab il ity o f th e ? b er to with stand h o u se
keep er wav es and b e r etained in th e sto m ac h . Th u s,
desig n o f an ef f ec tiv e g astr ic r etentio n dev ic e f o r a
tab l et is no t a tr iv ial m atter .
Th e b eh av io r o f tab l ets with two 5 c m ? b er r etentio n
ar m s was sig ni? c antl y dif f er ent. Tab l e I dem o nstr ates
th at, in two o u t o f th r ee u nf ed do g s, th is dev ic e was
g astr ic al l y r etained sig ni? c antl y l o ng er th an a c o ntr o l
tab l et. In o ne c ase, th e tab l et/? b er dev ic e was r etained
f o r at l east 2 4 h o u r s. In o ne do g , b o th th e dev ic e and th e
c o ntr o l tab l et wer e r etained f o r l ess th an o ne h o u r .
Th ese data dem o nstr ate th at a tab l et with two ? b er
r etentio n ar m s c an b e g astr ic al l y r etained f o r a sig ni?
c antl y l o ng er tim e th an a c o ntr o l tab l et. H o wev er , th e
du r atio n o f r etentio n is v ar iab l e.
TAB LE I
Tab l et W ith Attac h ed Fib er Retentio n Ar m s
Ef f ec t o f N u m b er o f Fib er s and Fib er Leng th
Gastr ic r etentio n in u nf ed b eag l e do g s o f ( A)
h o l l o w p o l yeth yl ene ( PE) ? b er ( 1 0 c m l eng th X 1 m m
o u ter diam eter ) , ( B ) no n- disinteg r ating tab l et B ASO4
( 4. 0 m m diam eter X 1 . 5 m m th ic kness) with a sing l e
attac h ed h o l l o w PE ? b er r etentio n ar m ( 1 0 c m X 1 m m ) ,
( C ) no n- disinteg r ating tab l et ( 4. 0 m m X 1 . 5 m m ) with
two attac h ed h o l l o w PE ? b er r etentio n ar m s ( 5 c m X 1
m m ) . In eac h c ase a r adio p aq u e no n- disinteg r ating
c o ntr o l tab l et ( 4. 0 m m X 1 . 5 m m ) was do sed al o ng with
th e ex p er im ental dev ic e.
GASTRIC RETEN TION AT VARIOUS
TIMES ( H OURS) POST- DOSE
DEVIC E l 2 3 4 5 6 2 4
( A) 1 0 c m PE
Fib er
Do g C I/I O/l O/l O/I O/I O/I O/I
( B ) 0. 4 c m Tab l et
with attac h ed
1 0 c m PE
Do g A U1 U1 O/I O/O N M N M N M
Do g B O/O N M N M N M N M N M N M
Do g C O/O N M N M N M N M N M N M
( C ) 0. 4 c m Tab l et
45
50
55
6 5
1 0
TAB LE I- c o ntinu ed
Tab l et W ith Attac h ed Fib er Retentio n Ar m s
Ef f ec t o f N u m b er o f Fib er s and Fib er Leng th
with two
attac h ed 5 c m
PE FRA
Do g A O/I O/l O/I O/O N M N M N M
Do g A O/I O/I O/I O/I O/I O/I O/I
Do g B O/I O/ I O/ I O/I O/O N M N M
Do g B I/ I I/ I O/ I O/ I O/O N M N M
Do g C O/O N M N M N M N M N M N M
Do g C O/O N M N M N M N M N M N M
PM = ? b er r etentio n ar m ( s) .
EXAMPLE 2
Th e ef f ec ts o f tab l et siz e o n g astr ic r etentio n o f ta
b l et/? b er dev ic es was assessed in u nf ed b eag l e do g s.
Radio p aq u e no n- disinteg r ating tab l ets ( 0. 6 4 c m diam e
ter X0. 32 c m th ic kness) wer e p r ep ar ed with two at
tac h ed h o l l o w r adio p aq u e PE ? b er r etentio n ar m s ( 5
c m l eng th XO. l c m diam eter ) , as desc r ib ed ab o v e in
Ex am p l e 1 ( FIG. 1 B ) . Th ese tab l ets wer e sig ni? c antl y
l ar g er th an th o se r ep o r ted in Ex am p l e 1 ( 0. 4 c m X0. l 5
c m ) . Tab l e II p r esents th e du r atio n o f g astr ic r etentio n
o f th ese dev ic es in u nf ed b eag l e do g s. In o ne do g , th e
dev ic e was g astr ic al l y r etained f o r o nl y o ne h o u r l o ng er
th an a c o ntr o l tab l et. In th e o th er two do g s tested, th e
dev ic e was r etained no l o ng er th an th e c o ntr o l tab l et.
Gastr ic r etentio n data f o r th e 0. 4 c m tab l et with two
attac h ed 5 c m ? b er r etentio n ar m s ar e al so inc l u ded in
Tab l e II. It is c l ear th at th e dev ic e with th e sm al l er
tab l et is b etter r etained.
TAB LE II
Tab l et W ith Attac h ed Fib er Retentio n Ar m s
Ef f ec t o f Tab l et Siz e
Gastr ic r etentio n in u nf ed b eag l e do g s o f ( A) no n
disinteg r ating B ASO4 tab l et ( 0. 6 4 c m diam eter X 32 c m
th ic kness) with two attac h ed h o l l o w PE ? b er r etentio n
ar m s ( 5 c m l eng th X 0. 1 c m o u ter diam eter ) ; ( B )
no n- disinteg r ating tab l et ( 0. 4 c m diam eter X 0. 1 5 c m
th ic kness) with two attac h ed h o l l o w PE ? b er r etentio n
ar m s ( 5 c m l eng th X 0. 1 c m o u ter diam eter ) .
GASTRIC RETEN TION AT VARIOUS
TIMES ( H OURS) POST- DOSE
DEVIC E 1 2 3 4 5 6 2 4
( A) 0. 6 4 c m Tab
l et with two
attac h edSc m
PEFRA
Do g A I/I 0/1 O/I N M N M N M N M
Do g B 0/0 0/0 N M N M N M N M N M
Do g C U1 U1 U1 U1 O/O 0/0 N M
( B ) 0. 4 c m Tab l et
with attac h ed
5c m PE
FRA
Do g A O/I O/I 0/1 0/0 N M N M N M
Do g B O/I O/I O/I 0/1 0/0 N M N M
Do g C 0/0 N M N M N M N M N M N M
Do g C O/O N M N M N M N M N M N M
EXAMPLE 3
Gastr ic r etentio n o f a 0. 4 c m X0. l 5 c m r adio p aq u e
no n- disinteg r ating tab l et ( B aSO4) with two attac h ed 5
c m XO. l c m PE ? b er r etentio n ar m s ( FIG. 1 B ) was
assessed in f ed do g s. Im m ediatel y af ter do sing , eac h do g
was f ed its no r m al dail y r atio n o f dr y f o o d and was
5, 443, 843
1 1
al l o wed ac c ess to water . Tab l e III p r esents g astr ic r e
tentio n data f o r th ese dev ic es in f ed do g s, and al so p r es
ents r etentio n data in u nf ed do g s f o r c o m p ar iso n. Th e
tab l et/ ? b er dev ic e was c o nsistentl y r etained in f ed do g s
1 2
TAB LE IV
Fib er C o il with Attac h ed Tab l et
Gastr ic r etentio n in u nf ed b eag l e do g s o f a
f o r > 1 1 h o u r s ( th e du r atio n o f th e ex p er im ent) . In two 5 tab l et/? b er c o il dev ic e c o nsisting Of a no n
o u t o f th e th r ee do g s, th e no n- disinteg r ating c o ntr o l disinteg r ating B asf 4 ab 1 e ( 1 6 4c m diam e e' _ > < 0' 32 c m
tab l et was al so r etained. Th ese r esu l ts ar e c o nsistent ( 2 0 56 2 g : 1 : 2 2 2 : 2 5; z iial eg z g tl z no ig ac e
with c u r r ent u nder standing o f th e p h ysio l o g y o f sto m - th e tab l et Th e PIE/nyl o n ? b er r etentio n ar m was
ac h em p tying ~ So l id Ob J eC ts e- g - Ph ar m ac eu tic al do sag e set in th e sh ap e o f a c o il , and was f o l ded into a
f o r m s, wh ic h ar e l ar g er th an ~0. 2 ~0. 5 c m ar e r etained 1 0 #000 g el atin c ap su l e. Th is dev ic e o p ened in th e
in th e sto m ac h in th e f ed state, wh il e o b j ec ts in th is siz e sto m ac h to f o r m 1 * c o n? g u r atio n c o nsisting o f a C o il
r ang e ar e q u ic kl y em p tied ( 0_ 2 h o u r s) b y m ig r ating with attac h ed tab l et, with an o v er al l diam eter o f
m o to r c o m p l ex es o r h o u sekeep er wav es in th e u nf ed GASTRIC EEFIEN TION AT VARIOUS
state- TIMES ( H OURS) POST- DOSE
TAB LE III 1 5 DOG 1 2 3 4 2 4
Retentio n in Fed Do g s A 1 /1 0/1 O/I O/I O/l
Gastr ic r etentio n in f ed b eag l e do g s o f a no n- C O/I O/I 0 o n o n
disinteg r ating B ASO4 tab l et ( 0. 4 c m diam eter X 0. 1 5 c m D 0 0 o n O/I 0
th ic kness) with two attac h ed h o l l o w PE ? b er r etentio n
ar m s ( 5 c m l eng th X 0. 1 c m o u ter diam eter ) . 2 0
GASTRIC RETEN TION AT VARIOUS
TIMES ( H OURS) POST- DOSE EXAMPLE 5
DOG 1 2 3 4 5 1 1 A tab l et with an attac h ed c o nc entr ic c o il was p r e
A 1 /1 1 /1 1 /1 1 /1 1 /1 1 1 1 p ar ed. In th is c ase, th e c o il did no t c o nsist o f a ? b er , b u t
3 1 /1 1 / 1 1 /1 1 /1 1 /1 1 /1 2 5 c o nsisted o f a nyl o n r ib b o n o f dim ensio ns 2 0 c m
C O/O 0 o n o n 0 0 l eng th XO. 5 c m diam eter > < 005 c m th ic kness. Th is r ib
b o n was attac h ed to th e side o f a no n- disinteg r ating
EXAMPLE 4 B aSO4 tab l et ( 0. 6 4 c m diam eter XO. 32 c m th ic k) b y
_ c yano ac r yl ate g l u e, c o il ed ar o u nd th e tab l et edg e, p ar
Th e g ast? c Tam m i? " Of a tab l et with an attec h ed c 01 1 30 tial l y u nc o il ed to an o v er al l diam eter ( tab l et p l u s c o n
was assessed. A r adl o p aq u e no n- disinteg r ating tab l et c entr ic c o il ) o f ~4 C m , set b y h eating at 70 c _ f o r 6
( 0- 6 4 c m dl am eter x o ' il z Fm th l c kness) was Pr ep ar ed h o u r s, r ec o il ed, and p l ac ed in a #000 g el atin c ap su l e, as
and a 0. 2 4 c m h o l e was dr il l ed th r o u g h th e entir e tab l et in Ex am p l e 4 Th e nyl o n n- b b o n r etentio n ar m o n th is
at th e c enter o f th e tab l et f ac e. A 2 0c m p iec e o f h o l l o w dev ic e was sig ni? c antl y m o r e ? ex ib l e th am th e PE/ny_
_ PE ? b er _ ( 2 0_ c m l eng th > < 0. 2 4 c m diam eter ) was wo u nd 35 Io n ? b er r etentio n ar m o f Ex am p l e 4.
m to a c o il with an ~ 3 c m d1 am eter , and was h el d 1 n tl ' l l S Tab l et/ . b b . 1 d . d d . b d
c o n? g u r atio n with a p iec e o f au to c l av e tap e. Th e PE n o n C O1 ev l c es p r ep ar e as esc n e
c o il was p l ac ed in a 75 C . o v en f o r 1 h o u r , to p er m it th e ab ? wer e do sf ed to f asted, b eag l e do g s wh o wer e f ed
PE to set in its c o il ed c o n? g u r atio n. A 2 0 c m p iec e o f th e no r m al dal l y f o o d H 1 9 1 1 at ' 7 h c f u r s p o stf do se
nyl o n m o no ? l am ent ? b er ( 2 0 c m l eng th > < 0. 1 3 c m diam - 40 Tab l e V Pr ese_ ntS th e du r atl o n o f g iasm c r el ienno n o f
etel . ) was Sim il ar l y c o il ed and tap ed and was Set in a th ese dev l c es 1 n b eag l e do g s. Gastr ic r etentio n o f . th e
1 2 5 C _ o v en f o r 1 h o u r _ Th e c o il ed nyl o n m o no ? l am ent dev ic es was v ar iab l e, with o b ser v ed r etentio n du r atio ns
was th r ead into th e c o il ed h o l l o w PE ? b er , stainl ess o f O, 4 and 2 4 h o u r s in th r ee do g s- Radio g r ap h s o f de
steel p o wder was p o u r ed into th e v o id sp ac e b etween VIC C S in th e sm al l intestine indic ated th at th e c o nc entr ic
th e nyl o n and PE to p r o v ide r adio p ac ity, and th e ends 45 nyl o n r ib b o n r etentio n ar m was def o r m ed and f o l l o wed
o f th e ? b er wer e seal ed with c yano ac r yl ate g l u e. Th e th e tab l et in its tr ansit do wn th e sm al l intestine. Th u s
end o f th e ? b er was th r ead into th e tab l et h o l e and attac h m ent o f a sing l e ? ex ib l e c o nc entr ic nyl o n r ib b o n
g l u ed. Th e ? nal dev ic e c o nsisted o f an ~3. 5 c m diam e- r etentio n ar m o f th e ? ex ib il ity u sed h er ein is no t su f ?
ter C Ol l , W ith a tab l et attac h ed to o ne end ( v ia th e tab l et g iant to r ep r o du c ib l y h o l d a tab l et in th e sto m ac h f o r
f ac e) . Th e ? b er r etentio n ar m o n th e tab l et/? b er c o il 50 ~2 4 h o m e
dev ic e was c o m p r essed, and th e dev ic e was p l ac ed in a
#000 g el atin c ap su l e. W h en a dev ic e o f th is typ e was TAB LE V
p l ac ed in water o r aq u eo u s b u f f er at 37 C . , th e g el atin Tab l et with C o nc entr ic Rib b o n C o il Retentio n Ar m
c ap su l e disso l v ed with in 5- 1 5 m inu tes and th e ? b er Gastr ic r etentio n in u nf ed b eag l e do g s o f
r etentio n ar m u nc o il ed p ar tial l y so th at th e o v er al l di- 55 tab l et/r ib b o n c o il dev ic es, c o nsisting o f a no n
am eter o f th e u nc o il ed tab l et/? b er dev ic e was ~4 c m . disinteg r ating B A504 Iab 1 eI ( 0- 6 4 c m dif l m eter X 032 c m
Tab l e IV p r esents th e du r atio n o f g astr ic r etentio n o f th c kness) wl th T- Yl m "b b m r etc nt ? an ( 2 0 c m
tab l et/ ? b er c o il dev ic es in f asted b eag l e do g s wh o wer e l eng tr o > t< h g tsag l l z ttg neetif h ieo g iiil : g z c h ed
f ed th eir no r m al dail y f o o d r atio n at "' 7 h o u r s Po st sto m ac h to f o r m a c o n? g u r atio n c o nsisting o f atab l et
do se. In al l c ases, th e tab l et/ ? b er c o il dev ic e was g astr i- 6 0 with a c o nc entr ic c o il , with an o v er al l diam eter o f
c al l y r etained f o r > 2 4 h o u r s, wh il e th e c o ntr o l tab l et ~4 c m ~ .
was r etained f o r < 2 h o u r s. Th is em b o dim ent o f th e GASTRIC RETEN TION AT VARIOUS
inv entio n is a p r ef er r ed o ne b ec au se ( a) a > 2 4 h o u r s TIMES ( H OURS) POST' DOSE
g astr ic r etentio n is o b ser v ed, and ( b ) a l ar g e c o ntr o l l ed DOG 1 2 3 4 5 6 2 4
r el ease tab l et c an b e inc o r p o r ated to del iv er a h ig h 6 5 A W 1 O/O N M N M N M N M N M
su stained do se ex c l u siv el y in th e sto m ac h , th u s im p r o v - C 1 /1 1 /1 O/I 0/1 0/1 O/l O/l
D 1 /1 1 /1 1 /1 1 /1 O/O 0/0 0/0
ing b io av ail ab il ity and el im inating th e windo w o f ab
so r p tio n p r o b l em .
5, 443, 843
1 3
EXAMPLE 6
A dev ic e was p r ep ar ed c o nsisting o f a tab l et with
f o u r c u r v ed nyl o n r ib b o n r etentio n ar m s attac h ed to th e
tab l et edg e. A tig h tl y f itting c yl indr ic al p o l yv inyl c h l o
r ide sl eev e was p l ac ed ar o u nd th e edg e o f a no ndisinte
g r ating r adio p aq u e B aSO4 tab l et ( 0. 6 4 c m diam e
ter XO. 32 c m th ic kness) . Th e dim ensio ns o f th e tab l et
p l u s c o nc entr ic al l y attac h ed sl eev e wer e 1 . 03 c m diam e
ter > < 0. 32 c m th ic kness. One end o f eac h o f f o u r nyl o n
r ib b o ns was g l u ed to th e o u ter edg e o f th e sl eev e with
a c yano ac r yl ate g l u e, in a tang ential f ash io n. Th e di
m ensio ns o f eac h r ib b o n wer e 4 c m l eng th > < 0. 4 c m
width > < 0. 05 c m th ic kness. N o te th at, ex c ep t f o r th e
l eng th , th ese r ib b o ns wer e ap p r o x im atel y th e sam e
width and th ic kness as th e nyl o n r ib b o n u sed in Ex am
p l e 5, and h ad th e sam e deg r ee o f f l ex ib il ity. Th e f o u r
r ib b o n r etentio n ar m s ( attac h ed to th e tab l et) wer e
c o ated with a sm al l am o u nt o f c yano ac r yl ate g l u e, and
wer e sp r inkl ed with stainl ess steel p o wder , to m ake th e
r ib b o ns r adio p aq u e. Th e r ib b o n r etentio n ar m s wer e
c o il ed tig h tl y ar o u nd th e sl eev e edg e, th en wer e p l ac ed
in an al u m inu m f o il c o ntainer wh ic h p er m itted th e de
v ic e to p ar tial l y u nc o il to an o v er al l diam eter o f
~3. 54. 0 c m ( tab l et p l u s sl eev e p l u s inwar dl y c u r v ed
r ib b o n r etentio n ar m s) . Th e p ar tial l y u nc o il ed dev ic e
was h eated at 70 C . f o r 6 h o u r s to p er m it th e nyl o n
r ib b o n r etentio n ar m s to set in said c o n? g u r atio n. Ap
p r o x im atel y o ne day p r io r to do sing , th e tab l et/sl eev e/
r ib b o n c o il dev ic e was tig h tl y r ec o il ed and was p l ac ed
in a #1 3 v eter inar y g el atin c ap su l e.
Th is dev ic e was do sed ( al o ng with a r adio p aq u e c o n
tr o l tab l et) to a f asted b eag l e do g , wh ic h was f ed its
no r m al dail y f o o d r atio n at ~7 h o u r s p o st- do se. Gastr ic
r etentio n was assessed b y r adio g r ap h y at 6 and 2 4
h o u r s. Th e tab l et/ sl eev e/ r ib b o n c o il dev ic e was o b
ser v ed to b e p r esent in th e sto m ac h at 2 4 h o u r s, wh il e
th e c o ntr o l tab l et h ad ex ited th e sto m ac h b y 6 h o u r s
p o st- do se.
EXAMPLE 7
A p r ef er r ed em b o dim ent o f th e c u r r ent inv entio n is
o ne in wh ic h th e g astr ic r etentio n dev ic e is r etained in
th e sto m ac h ef f ec tiv el y inde? nitel y, and m o v es o u t o f
th e sto m ac h wh en th e dev ic e c h ang es sh ap e, f al l s ap ar t,
deg r ades o r disso l v es. Th u s th e du r atio n o f r etentio n
c an b e dic tated b y th e desig n o f th e deg r adatio n m ec h a
nism , m inim iz ing th e ef f ec ts o f p atient- to - p atient v ar i
ab il ity in g astr ic p h ysio l o g y. Th is ex am p l e dem o n
str ates an ap p r o ac h f o r ac h iev ing a dev ic e wh ic h p er
f o r m s th is way. Th is dev ic e is sim il ar to th at desc r ib ed
in Ex am p l e 6 , b u t inc o r p o r ates a m ec h anism f o r disinte
g r atio n.
A disinteg r ating dev ic e was p r ep ar ed as f o l l o ws. A
r adio p aq u e no n- disinteg r ating B aSO4 tab l et ( 1 . 03 c m
diam eter > < 0. 32 c m th ic kness) was p r ep ar ed. A c yl indr i
c al sl eev e ( 1 . 03 c m inner diam eter ; 1 . 1 1 c m o u ter diam e
ter ) c o m p o sed o f 9 5% p o l yv inyl ac etate p h th al ate
( PVAP) and 5% H yc ar r u b b er p ar tic l es to dec r ease
b r ittl eness was p r ep ar ed. PVAP is an enter ic m ate
r ial , i. e. o ne wh ic h r etains its p h ysic al p r o p er ties at l o w
p H b u t so f tens and disso l v es at neu tr al to h ig h p H . Th e
c yl indr ic al PVAP sl eev e was p l ac ed o v er th e tab l et and
was ? r m l y attac h ed to th e tab l et with a c yano ac r yl ate
g l u e. Fo u r nyl o n r ib b o ns ( 4 c m l eng th > < 0. 4 c m
width x 0. 05 c m th ic kness) wer e attac h ed with c yano ac
r yl ate g l u e to th e o u ter edg e o f th e c yl indr ic al PVAP
sl eev e in a tang ential f ash io n. Th ese nyl o n r ib b o n r eten
2 5
35
45
6 5
1 4
tio n ar m s p o ssessed ap p r o x im atel y th e sam e deg r ee o f
? ex ib il ity as th o se in Ex am p l es 5 and 6 . Th e f o u r r ib
b o ns wer e c o ated with a sm al l am o u nt o f g l u e, and wer e
sp r inkl ed with stainl ess steel p o wder to m ake th e r ib
b o ns r adio p aq u e. Th e r ib b o n r etentio n ar m s wer e c o il ed
tig h tl y ar o u nd th e sl eev e edg e, th en wer e p l ac ed in an
al u m inu m f o il c o ntainer wh ic h p er m itted th e dev ic e to
p ar tial l y u nc o il to an o v er al l diam eter o f ~3. 54. 0 c m
( tab l et p l u s sl eev e p l u s inwar dl y c u r v ed r ib b o n r eten
tio n ar m s) . Th e p ar tial l y u nc o il ed dev ic e ( in th e f o il
c o ntainer ) was h eated at 70 C . f o r 6 h o u r s to p er m it th e
nyl o n r ib b o n r etentio n ar m s to set in said c o n? g u r atio n.
Ap p r o x im atel y o ne day p r io r to c l o sing , th e tab l et/
sl eev e/r ib b o n c o il dev ic e was tig h tl y r ec o il ed, and was
p l ac ed in a #1 3 v eter inar y g el atin c ap su l e. Dev ic es o f
th is typ e o p ened to an o v er al l diam eter o f ~3. 6 c m
wh en r em o v ed f r o m th e c ap su l e.
Oth er dev ic es wer e p r ep ar ed wh ic h wer e identic al to
th o se desc r ib ed ab o v e, ex c ep t f o r th e m eth o d o f m aking
th e r ib b o n r etentio n ar m s r adio p aq u e. Rath er th an c o at
ing th e entir e r ib b o n with g l u e and stainl ess steel p o w
der , o nl y ~l c m o f th e o u ter tip o f eac h r ib b o n was
m ade r adio p aq u e with g l u e and stainl ess steel p o wder .
Th is was do ne to test th e p o ssib il ity th at r etentio n o f
dev ic es in wh ic h th e entir e r ib b o n was c o v er ed with
g l u e and steel p o wder m ig h t b e du e to r ib b o n stif f ness
im p ar ted b y th e g l u e/p o wder , r ath er th an b y th e intr in
sic stif f ness o f th e nyl o n r ib b o n r etentio n ar m s th em
sel v es.
Dev ic es o f th ese typ es wer e do sed to f asted b eag l e
do g s wh o wer e f ed th eir no r m al dail y f o o d r atio n at ~ 7
h o u r s p o st- do se. Tab l e VI p r esents th e du r atio n o f g as
tr ic r etentio n o f th ese dev ic es. In al l c ases, th e tab l et/
r ib b o n c o il dev ic es wer e g astr ic al l y r etained f o r at l east
2 0 h o u r s. W h en dev ic es wer e o b ser v ed in th e sm al l
intestine o r c o l o n b y r adio g r ap h y, it was c l ear th at th e
nyl o n r ib b o n r etentio n ar m s h ad eith er f al l en o f f o r
wer e b ent at th e PVAP b ase and wer e in th e p r o c ess o f
f al l ing o f f . B y desig ning a dev ic e wh ic h is c o nsistentl y
r etained u ntil it f al l s ap ar t af ter a p r edeter m ined p er io d,
two p r o b l em s ar e av o ided: ( l ) p atient- to - p atient v ar i
ab il ity in th e ab il ity o f h o u sekeep er wav es to em p ty
dev ic es f r o m th e sto m ac h , and ( 2 ) th e p o tential f o r a
p atient to h av e nu m er o u s dev ic es c o l l ec t in th e sto m ac h
o r intestine.
Th e dev ic es o f th is Ex am p l e ( and Ex am p l e 6 ) , wh ic h
h ad 4 sh o r t r ib b o n r etentio n ar m s ar r ang ed c o nc entr i
c al l y ar o u nd th e tab l et edg e, wer e ef f ec tiv e g astr ic
r etentio n dev ic es. On th e o th er h and, th e dev ic es o f
Ex am p l e 5, wh ic h h ad a sing l e r ib b o n r etentio n ar m
ar r ang ed c o nc entr ic al l y ar o u nd th e tab l et, ex h ib ited
v ar iab l e g astr ic r etentio n. In b o th c ases, th e dev ic es
o p ened to a diam eter o f ~4 c m . Th u s su c c essf u l r eten
tio n o f th ese dev ic es dep ended no t o nl y u p o n th e siz e o f
th e dev ic e, b u t al so u p o n th e c o n? g u r atio n o f th e at
tac h ed r ib b o n r etentio n ar m s wh ic h f o r m ed th e ex
p anded c o il .
TAB LE VI
Tab l et with Fo u r Rib b o n Retentio n Ar m s
Fo r m ing B io deg r adab l e C o il
Gastr ic r etentio n in u nf ed b eag l e do g s o f tab l et/
r ib b o n c o il dev ic e c o nsisting o f a no n- disinteg r ating
B aSO4 tab l et ( 1 . 03 c m diam eter X 0. 32 c m th ic kness) ,
and a deg r adab l e PVAP sl eev e to wh ic h f o u r nyl o n r ib b o n
r etentio n ar m s wer e attac h ed, as desc r ib ed in Ex am p l e
7. Th e r ib b o n dim ensio ns wer e 4 c m l eng th X 0. 4 c m
W idth X 0. 05 c m th ic kness. Th is dev ic e u nc o il ed in th e
sto m ac h to f o r m a c o n? g u r atio n wh ic h h ad an o v er al l
5, 443, 843
1 5
TAB LE VI- c o ntinu ed
Tab l et with Fo u r Rib b o n Retentio n Ar m s
Fo r m ing B io deg r adab l e C o il
diam eter o f ~3. 6 c m . ( A) W ith r ib b o ns to tal l y c o v er ed
with g l u e and stainl ess steel p o wder to p r o v ide
r adio p ac ity; ( B ) with o nl y r ib b o n tip s c o v er ed with
g l u e and stainl ess steel p o wder to p r o v ide r adio p ac ity;
GASTRIC RETEN TION AT VARIOUS
TIMES ( H OURS) POST- DOSE
DEVIC E 1 3 4 s 6 2 o 2 4
1 5) .
Do g A 0/1 0/1 0/1 0/1 O/l 0/1 0/1
Do g c 0/1 O/I O/l 0/1 0/1 O/I o n
Do g D 1 /1 V1 V1 1 /1 1 /1 0/1 0/0
@L
Do g c 0/1 0/1 0/1 0/1 0/1 0/1 o n
Do g D 1 /1 1 /1 1 /1 1 /1 1 /1 0/1 0/1
EXAMPLE 8
C o ntr o l l ed r el ease tab l ets c o ntaining th e antidiab etic
dr u g g l ip iz ide wer e inser ted into r ec ep tac l es o f r adi
o p aq u e GI r etentio n dev ic es as desc r ib ed in Ex am p l e 7.
Th ese dev ic es wer e do sed to th r ee f asted b eag l e do g s,
wh ic h wer e su b seq u entl y f ed at 1 2 h o u r s p o st- do se. In a
c o ntr o l ex p er im ent, th e sam e do g s wer e do sed with
identic al c o ntr o l l ed r el ease g l ip iz ide tab l ets with o u t GI
r etentio n dev ic es. B l o o d was dr awn at v ar io u s tim es
p o st- do se, and g l ip iz ide p l asm a l ev el s wer e deter m ined,
u sing an H PLC assay. In th e c ase o f do sing with o u t a
GI r etentio n dev ic e, th e av er ag e Tm ax ( tim e at wh ic h
p eak p l asm a c o nc entr atio n was o b ser v ed) was 2 . 7 h o u r s
and th e av er ag e AUC ( ar ea u nder th e p l asm a c o nc en
tr atio n v s. tim e c u r v e) was 35 m ic r o g m - h r /m l . In th e
c ase o f do sing with a GI r etentio n dev ic e, an ap p r o x i
m atel y c o nstant g l ip iz ide p l asm a l ev el was o b ser v ed
wh ic h ex tended f r o m 3 h o u r s to 1 2 h o u r s p o st- do se, and
an av er ag e AUC o f 6 4 m ic r o g m - h r /m l was o b ser v ed.
C o nc u r r ent x - r ay m easu r em ents indic ated th at th e g l ip i
z ide- r el easing GI r etentio n dev ic es wer e l o c ated in th e
sto m ac h f o r at l east 8 h o u r s. Th is ex am p l e c l ear l y dem
o nstr ates th at a GI r etentio n system o f th e c u r r ent in
v entio n c an b e u sed to im p r o v e th e p er f o r m anc e o f a
c o ntr o l l ed r el ease dr u g del iv er y system , b y assu r ing
th at th e dr u g is del iv er ed in an ab so r b ab l e f o r m to th e
u p p er p o r tio n o f th e sm al l intestine, wh er e ab so r p tio n is
g ener al l y m o st ef ? c ient.
1 5
2 0
2 5
30
35
40
45
55
6 0
6 5
1 6
W h at is c l aim ed:
1 . A m o du l ar system f o r u se in an o r al dr u g del iv er y
system in a m am m al , h av ing del ayed g astr o intestinal
tr ansit, wh ic h r el eases a dr u g o r dr u g s in a c o ntr o l l ed
m anner in said g astr o intestinal tr ac t and ex its said g as
tr o intestinal tr ac t af ter said dr u g o r dr u g s h av e b een
su b stantial l y r el eased, said m o du l ar system c o m p r ising
a r ec ep tac l e m eans f o r r ec eiv ing and c o ntaining an
o r al l y adm inistr ab l e c o ntr o l l ed r el ease dev ic e and o ne
o r m o r e ? b er s o r r ib b o ns attac h ed to said r ec ep tac l e
m eans, said ? b er s o r r ib b o ns, c o l l ec tiv el y:
( a) b eing r estr ained in a c o ntr ac ted c o n? g u r atio n at
th e tim e o f do sing , and
( b ) u nc o il ing , u nr o l l ing , o r u nf o l ding af ter entr y into
th e sto m ac h , into a c o nf ig u r atio n h av ing a c ir c u l ar
o r r o u g h l y c ir c u l ar c r o ss- sec tio n h av ing a diam eter
o f at l east ab o u t th r ee c entim eter s,
said m o du l ar system c ap ab l e o f so f tening , disinteg r at
ing , disso l v ing o r deg r ading in th e b io l o g ic al env i
r o nm ent o f th e sto m ac h in o r der to p er m it th e ex it
o f th e m o du l ar system th er ef r o m .
2 . A m o du l ar system ac c o r ding to c l aim 1 wh er ein
said r ec ep tac l e m eans is a c o l l ar wh ic h ? ts ab o u t and
h o l ds a c o ntr o l l ed r el ease dev ic e.
3. A m o du l ar system ac c o r ding to c l aim 1 wh er ein
said r ec ep tac l e m eans c o m p r ises an o p ened wal l m em
b er with an inter nal sp ac e f o r r ec eiv ing and h o l ding said
dev ic e.
4. A m o du l ar system ac c o r ding to c l aim 3 wh er ein
said r ec ep tac l e m eans is c ap p ed f o r c l o sing th e r ec ep ta
c l e m eans h o l ding th e dev ic e, said wal l and/o r said
c ap p ed m em b er h av ing a p assag eway to p er m it p assag e
o f env ir o nm ental ? u id ' into th e r ec ep tac l e m eans and
p assag e o f dr u g th er ef r o m to th e env ir o nm ent.
5. A m o du l ar system ac c o r ding to c l aim 1 wh er ein
o ne end o f said r ib b o ns o r ? b er s ar e attac h ed to said
r ec ep tac l e.
6 . A m o du l ar system ac c o r ding to c l aim 1 wh er ein
two o r m o r e r ib b o ns o r ? b er s o f su b stantial l y eq u al siz e
ar e attac h ed to th e r ec ep tac l e. '
7. A m o du l ar system ac c o r ding to c l aim 6 wh er ein
th e r ib b o ns o r ? b er s ar e sym m etr ic al l y sp ac ed ab o u t th e
r ec ep tac l e.
8. A m o du l ar system ac c o r ding to c l aim 7 h av ing , in
th e ex p anded state, a siz e o f f r o m ab o u t 2 . 5 to 6 . 0 c m in
its l ar g est dim ensio n.
* * * * *