United S ta tes Pa tent [ 1 9 ]

Pil l a y et a l .
US 00609 041 1 A
6, 09 0, 41 1
J u l . 1 8 , 2 000
[ 1 1 ] Pa tent Nu mber:
[ 45 ] Da te o f Pa tent:
[ 5 4] MONOLITHIC TABLET FOR CONTROLLED
DRUG RELEAS E
[ 7 5 ] Inv ento rs : V ines s Pil l a y , Ph il a del p h ia ; Rez a
Fa s s ih i, Ambl er, bo th o f Pa .
[ 7 3 ] As s ig nee: Temp l e Univ ers ity , Ph il a del p h ia , Pa .
[ 2 1 ] Ap p l . No . : 09 / 03 7 , 09 6
[ 2 2 ] Fil ed: Ma r. 9 , 1 9 9 8
[ 5 1 ] Int. Cl . 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . A61 K 47 / 02 ; A61 K 9 / 2 2 ;
A61 K 47 / 3 8 ; A61 K 47 / 3 4
[ 5 2 ] US . Cl . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4/ 468 ; 42 4/ 48 6; 42 4/ 48 8 ;
5 1 4/ 9 60
[ 5 8 ] Fiel d o f S ea rch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4/ 48 6, 48 8 ,
42 4/ 466, 465 , 468 ; 5 1 4/ 9 60
[ 5 6] Ref erences Cited
U. S . PATENT DOCUMENTS
3 , 9 1 7 , 8 1 3 1 1 / 1 9 7 5 Peders en .
3 , 9 5 4, 9 5 9 5 / 1 9 7 6 Peders en .
4, 7 5 5 , 1 8 0 7 / 1 9 8 8 Ay er et a 1 . .
4, 7 7 7 , 03 3 1 0/ 1 9 8 8 Iku ra et a 1 . .
4, 8 9 8 , 7 3 7 2 / 1 9 9 0 Pa no Z et a 1 . .
4, 9 1 9 , 9 3 8 4/ 1 9 9 0 Lo v eg ro v e et a 1 . .
4, 9 46, 68 6 8 / 1 9 9 0 McCl el l a nd et a 1 . .
4, 9 66, 7 68 1 0/ 1 9 9 0 Mich el u cci et a 1 . .
5 , 002 , 7 7 6 3 / 1 9 9 1 Geo g h eg a n et a 1 . .
5 , 5 1 8 , 7 3 7 5 / 1 9 9 6 Urtti et a 1 . .
5 , 5 2 0, 9 3 1 5 / 1 9 9 6 Pers s o n et a 1 . .
5 , 5 2 9 , 7 9 0 6/ 1 9 9 6 Eich el et a 1 . .
5 , 5 2 9 , 7 9 1 6/ 1 9 9 6 Debo eck et a 1 . .
5 , 5 60, 9 2 8 1 0/ 1 9 9 6 DeFel ice.
5 , 603 , 9 5 5 2 / 1 9 9 7 Geh rke et a 1 . .
OTHER PUBLICATIONS
PereZMa rco s et a l . ; In? u ence o f p H o n th e Rel ea s e o f
Pro p ra no l o l Hy dro ch l o ride f ro m Ma trices Co nta ining
Hy dro x y p ro p y l meth y l cel l u s l o s e K4M a nd Ca rbo p o l 9 7 4 ,
J . Ph a rm. S ci. , v . 8 5 , Ma r. 1 9 9 6, 3 3 04.
Ch a kra ba rti et a l ; Co ntro l o f Po o rl y S o l u bl e Dru g Dis s o
l u tio n in Co nditio ns S imu l a ting th e Ga s tro intes tina l Tra ct
Fl o W . 1 . Ef f ect o f Ta bl et Geo metry in Bu f f ered Mediu m ; J .
o f Ph a rm. S ci. , v . 8 5 , Ma r. 1 9 9 6, p p . 3 1 3 3 1 9 .
CORE
A 3 HOURS
B
Ch a kra ba rti et a l . ; Co ntro l o f Po o rl y S o l u bl e Dru g Do s s o
l u tio n in Co nditio ns S imu l a ting th e Ga s tro intes tina l Tra ct
Fl o W . 2 . Co co mp res s io n o f Dru g s W ith Bu f f ers ; J . o f
Ph a rm. S ci. , v . 8 6, 1 9 9 7 , p p . 465 469 .
Mo o ney et a l . ; Dis s o l u tio n Kinetics o f Ca rbo x y l ic Acids I:
Ef f ect o f p H u nder Unbu f f ered Co nditio ns ; J . o f Ph a rm.
S ci. , v . 7 0, J a n. 1 9 8 1 , p p . 1 3 2 2 .
Mo o ney et a l . , Dis s o l u tio n Kinetics o f Ca rbo x y l ic Acids II:
Ef f ect o f Bu f f ers ; J . o f Ph a rm. S ci. , v . 7 0, J a n. 1 9 8 1 , p p .
2 2 3 2 .
Au nins et a l . , Dis s o l u tio n o f Ca rbo x y l ic Acids III: Th e
Ef f ect o f Po l y io niZa bl e Bu f f ers ; J . o f Ph a rm. S ci. , v . 7 4;
Dec. 1 9 8 7 , p p . 1 3 05 1 3 1 6.
Neerv a nna n et a l . , A Co nv ectiv eDif f u s io n Mo del f o r
Dis s o l u tio n o f TW o No nintera cting Dru g Mix tu res f ro m
Co co mp res s ed S l a bs Under La mina r Hy dro dy na mic Co n
ditio ns ; Ph a rm. Res ea rch , v . 1 1 , 1 9 9 4, p p . 1 2 8 8 1 2 9 5 .
S o u th a rd et a l . , Dis s o l u tio n o f Io niZa bl e Dru g s into Unbu f
f ered S o l u tio n: A Co mp reh ens iv e Mo del f o r Ma s s Tra ns p o rt
a nd Rea ctio n in th e Ro ta ting Dis k Geo metry ; Ph a rm.
Res ea rch , v . 9 , 1 9 9 2 , p p . 5 8 69 .
McNa ma ra et a l . , Dis s o l u tio n o f Acidic a nd Ba s ic Co m
p o u nds f ro m th e Ro ta ting Dis k: In? u ence o f Co nv ectiv e
Dif f u s io n a nd Rea ctio n ; J . o f Ph rm. S ci. , v . 7 5 , S ep . 1 9 8 6,
p p . 8 5 8 8 68 .
Prima ry Ex a minerEdW a rd J . W ebma n
Atto rney , Ag ent, o r FirmRa tner & Pres tia
[ 5 7 ] ABS TRACT
A s W el l a bl e h y dro p h il l ic ma trix ta bl et th a t del iv ers dru g s in
a co ntro l l ed ma nner o v er a l o ng p erio d o f time a nd is ea s y
to ma nu f a ctu re. Mo re s p eci? ca l l y , th e dru g is dis p o s ed in a
ma trix co mp o s ed o f HPMC o r p o l y eth y l ene o x ide, in th e
p res ence o f a s a l t, W h ich ma y be a co mbina tio n o f s a l ts .
S u ita bl e s a l ts incl u de s o diu m bica rbo na te, s o diu m ch l o ride,
p o ta s s iu m bica rbo na te, ca l ciu m ch l o ride, s o diu m bis u l f a te,
s o diu m s u l ? te, a nd ma g nes iu m s u l f a te. Ou tw a rd dif f u s io n o f
th e dru g is co ntro l l ed by a n inw a rdl y p ro g res s ing h a rdening
rea ctio n betW een th e s a l t a nd th e dis s o l u tio n mediu m, p o s
s ibl y a l s o inv o l v ing th e dru g its el f .
7 Cl a ims , 1 7 Dra w ing S h eets
PRES ENCE OF AIR BUBBLES
1 5 HOURS >2 2 HOURS
0 D
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 2 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
o x l Ll l l l l l l l l l l l l l l l Il l l l
0. 8 -
0. 6 -
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
' B1 (CTHL) +8 2 9 " B3 " B4 X B5
FIG. 2
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 3 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
0. a . i
a s
0. 6- -' +, ii
0. 2 -. *
Ll l l l l l l l l l l l Ll l l l l l
4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
' C1 (CTFIL) +02 * c3 - 04 X 05
FIG. 3
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 4 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
x v i
x i
x x
x x
v im
+. v ex
+. v ex
+. x x
+ X!
+ X
. + v . . .
1 . x
. + in
. + x !
. + x -x
+ x -x
+ . XX
+ . x x
+ X . . X
_ ___
8 6 4 . U 0. 0 0
o il ! l l l l l l l l Ll l l l l l l l l l l l
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
' D1 (CTFl L) +D2 9 " D3 ' D4 X D5
FIG. 4
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 6 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
Ox l l l l l l l l l Il l l l l l l l l l l l l
IX
XI X
V I X
I X
X X
IX X
IX X
IX X
IXX
IXX
+ . I XX
+ . I
+ . . I X
+. _ IXX
+. IX X
+. _ X X +. X
+. XI X
+. XI X
+_. XI X
+ XIX
XIX
+ XIX
. T
_ ___
a . 5 4. 2 0 0 0 0
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
- F1 (CTRL) +F2 * F3 - F4 >< F5
FIG. 6
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 7 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
0. 2 - +
+
l l l l l l l l l l l l l l l l l l l l
4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
Gl l
02
- G1 (CTHL) + G2
FIG. 7
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 8 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
+__
0. 8 ' +
+
+
+
+
0. 6-- +
- +
+
+
+
0. 4 +
+
+
+
+
0. 2 ++
+
+
++
o l l l l l l l l LLl l l l l l Ll l l l l l
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
- H1 (CTHL) + H2
FIG. 8
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 9 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
0. 8 - _. ' '
0. 6- _' +
0. 4- . +
0. 2 - - +
n i,
+
+ l
l l ILl l l l l l l l l l l l l Il l l
4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
GLL
02
- l 1 (CTHL) + l 2
FIG. 9
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 0 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
+
Il l l l l l l l l l l l l l l l l l l l l l
O 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
0. 8 -
0. 6 h
0. 4
0. 2 -
0
TIME (HOURS )
- J 1 (CTRL) + J 2
FIG. 1 0
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 1 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
1 1
+++T
++-"
+. '
+T'
0-8 - +
+.
T.
T
' k'
0. 6" +
+
+
+
0. 4
" . T'
4' .
0. 2 -.
+
Gl l l l l l il Ll l l l l l l l l l l l l l
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
~ K1 (CTHL) + K2
FIG. 1 1
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 2 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
1
+__
_. 0. 8 + u
+_
+.
+I
+.
0. 6- +'
+
_4
I+
0. 4- _' +
+
+
' +
_; _+
0. 2 - ++
+
+.
+.
Gl l l l l l l l l l ILl l l l l l l l l l l
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
- L1 (CTHL) + L2
FIG. 1 2
J u l . 1 8 , 2 000 S h eet 1 3 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
U. S . Pa tent
0. 6 -
0. 4
0 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
' M1 (CTHL) + M2 " M3 " DILACOR XR (M4)
FIG. 1 3
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 4 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
1
l I I I F F l
02 468 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
X p H 1 . 5 + p H 5 . 4 + p H 6
-5 p H 6. 4 + p H 6. 8
FIG. 1 4
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 5 0f 1 7 6, 09 0, 41 1
FRACTION RELEAS ED
l l l l Ll Il l l Ll l l l l l l l l l l l
0 IIIIIIIIIII
o 2 4 6 8 1 01 2 1 41 61 8 2 02 2 2 4
TIME (HOURS )
+ 01 (CTRL) -| 02 >K 03
FIG. 1 5
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 6 0f 1 7 6, 09 0, 41 1
- Na Bis u l f a te
I: K Bica rbo na te
. Mg S u l f a te
. Ca Ch l o ride
0. 8 -
0. 7 -0
" 0 .
6 5 4
3 0 2 5 2 0
TIME (HOURS )
FIG. 1 6
U. S . Pa tent J u l . 1 8 , 2 000 S h eet 1 7 0f 1 7 6, 09 0, 41 1
-I co ntro l
+A5
H 6 p H 0. 4 p H 6. 8
/ " / /
p H 3
Q I p H 5 . 4
TIME (HOURS )
FIG. 1 7
PRES ENCE OF AIR BUBBLES
CORE
1 5 HOURS >2 2 HOURS
D
C
3 HOURS
B
FIG. 1 8
6, 09 0, 41 1
1
MONOLITHIC TABLET FOR CONTROLLED
DRUG RELEAS E
BACKGROUND OF THE INV ENTION
Th e p res ent inv entio n p erta ins to a co ntro l l ed rel ea s e
do s a g e f o rm, ba s ed o n a mo di? ed h y dro p h il l ic ma trix co m
p o s itio n.
Co ntro l l ed rel ea s e p h a rma ceu tica l do s a g e f o rms h a v e
receiv ed mu ch a ttentio n in recent y ea rs a nd a re h ig h l y
des ira bl e f o r p ro v iding a co ns ta nt l ev el o f p h a rma ceu tica l
a g ent to a p a tient o v er s o me ex tended p erio d o f time. Th e
u s e o f s ing l e o r mu l tip l e u nit do s a g e f o rms a s co ntro l l ed
dru g del iv ery dev ices enco mp a s s es a W ide ra ng e o f tech
no l o g ies a nd incl u des p o l y meric a s W el l a s no np o l y meric
ex cip ients . Th es e do s a g e f o rms o p timiZe th e dru g inp u t ra te
into th e s y s temic circu l a tio n, imp ro v e p a tient co mp l ia nce,
minimiZe s ide ef f ects , a nd ma x imiZe dru g p ro du ct ef f ica cy .
Th e u s e o f co ntro l l ed rel ea s e p ro du cts is f req u entl y nec
es s a ry f o r ch ro nic dru g a dminis tra tio n, s u ch a s in th e del iv
ery o f th e ca l ciu m-ch a nnel bl o ckers nif edip ine a nd dil tia Zem
a nd th e beta -a drenerg ic bl o cker Pro p ra no l o l in th e ma na g e
ment o f a ng ina a nd h y p ertens io n Fo r del iv ery s y s tem
des ig n, p h y s io ch emica l p ro p erties a nd intrins ic ch a ra cteris
tics o f th e dru g , s u ch a s h ig h o r l o W s o l u bil ity , l imited
a ds o rp tio n, o r p res y s temic meta bo l is m, ma y imp o s e s p eci? c
co ns tra ints du ring p ro du ct dev el o p ment.
Adv a ncements o f ex tended rel ea s e dru g p ro du cts h a v e
co me a bo u t by th e s imu l ta neo u s co nv erg ence o f ma ny
f a cto rs , incl u ding th e dis co v ery o f no v el p o l y mers , f o rmu
l a tio n o p timiZa tio n, better u nders ta nding o f p h y s io l o g ica l
a nd p a th o l o g ica l co ns tra ints , p ro h ibitiv e co s t o f dev el o p ing
neW dru g entities , a nd th e intro du ctio n o f bio p h a rma ceu tics
in dru g p ro du ct des ig n.
One a s p ect o f res ea rch a bo u t co ntro l l ed-rel ea s e del iv ery
s y s tems inv o l v es des ig ning a s y s tem W h ich p ro du ces s tea dy
s ta te p l a s ma dru g l ev el s , W h ich is a l s o ref erred to a s Zero
o rder dru g rel ea s e kinetics . To meet th is o bj ectiv e, nu mero u s
des ig n v a ria tio ns h a v e been a ttemp ted, a nd th eir ma j o r
co ntro l l ing mech a nis ms incl u de dif f u s io n/ dis s o l u tio n,
ch emica l rea ctio ns , th e u s e o f o s mo tic p u mp dev ices , a nd
mu l tip l e l a y er ta bl et des ig ns , a l l o f W h ich inco rp o ra te
nu mero u s ma nu f a ctu ring s tep s a nd ma ny a s s o cia ted dru g
rel ea s e mech a nis ms . Th e co mp l ica ted p ro ces s es inv o l v ed in
th e ma nu f a ctu re o f s u ch u l tima tel y co ntribu tes to increa s ed
co s ts to th e co ns u mer.
One a ttra ctiv e des ig n f o r p o tentia l Zero -o rder dru g rel ea s e
is th e u s e o f h y dro p h il ic s W el l a bl e ma trices . Dru g dif f u s io n
f ro m th e ma trix is a cco mp l is h ed by s W el l ing , dis s o l u tio n
a nd/ o r ero s io n. Th e ma j o r co mp o nent o f th es e s y s tems is a
h y dro p h il ic p o l y mer. In g enera l , dif f u s iv ity is h ig h in p o l y
mers co nta ining ? ex ibl e ch a ins a nd l o W in cry s ta l l ine p o l y
mers . W ith ch a ng es in mo rp h o l o g ica l ch a ra cteris tics , th e
mo bil ity o f th e p o l y mer s eg ments W il l ch a ng e a nd dif f u s iv
ity ca n be co ntro l l ed. Additio n o f o th er co mp o nents , s u ch a s
a dru g , a no th er p o l y mer, s o l u bl e o r ins o l u bl e ? l l ers , o r
s o l v ent, ca n a l ter th e intermo l ecu l a r f o rces , f ree v o l u me,
g l a s s tra ns itio n temp era tu re, a nd co ns eq u entl y , ca n a l ter th e
tra ns p o rt mech a nis ms . Co s t is a l s o a f a cto r in th es e mo di? ed
co mp o s itio ns . S til l better co ntro l l ed, time dep endent dru g
rel ea s e f ro m th es e co mp o s itio ns is a co ntinu ing o bj ectiv e o f
res ea rch in th is a rea , a s is co ntro l l ed dif f u s iv ity co mp o s i
tio ns W h ich a re mo re ea s il y ma nu f a ctu red. S u ch
co mp o s itio ns , W h ich a re mo re ea s il y ma nu f a ctu ra bl e, h a v e
th e p o tentia l to l o W er co s t o f th e do s a g e f o rm.
S UMMARY OF THE INV ENTION
Th e p res ent inv entio n is a neW mo no l ith ic do s a g e f o rm
th a t del iv ers p h a rma ceu tica l l y a ctiv e a g ents in a co ntro l l ed
1 5
2 5
3 5
45
5 5
65
2
rel ea s e ma nner, a nd th a t is ea s y to ma nu f a ctu re. Th is do s a g e
f o rm, in a f o rm s u ch a s a mo no l ith ic ta bl et, ma y a p p ro a ch
Zero o rder del iv ery o f dru g s W h ich a re eith er o f h ig h o r l o W
s o l u bil ity . Th is do s a g e f o rm o r ta bl et is co mp ris ed o f a
h y dro p h il ic s W el l a bl e ma trix , in W h ich is dis p o s ed a p h a r
ma ceu tica l l y a ctiv e a g ent a nd a s a l t Th e s a l t, eith er in
co mbina tio n W ith th e dru g o r a no th er s a l t u p o n rea ctio n in
a n a q u eo u s mediu m, ca u s es a h a rdening rea ctio n o f th e
ma trix . Th e ra te o f o u tW a rd dif f u s io n is co ntro l l ed by
ex p o s ing th e p ro du ct to a n a q u eo u s mediu m. Th is in tu rn
ca u s es a h a rdening rea ctio n to o ccu r in a time dep endent
ma nner f ro m th e o u ter bo u nda ries to W a rds th e inner bo u nd
a ries o f th e p ro du ct; th e h a rdened rea ctio n p ro du ct, in tu rn
l imits o u tW a rd dif f u s io n o f th e dru g a s th e inW a rd ing res s o f
a q u eo u s mediu m ca u s es a p ro g res s iv e h a rdening f ro m th e
o u ter bo u nda ries o f th e do s a g e f o rm o r ta bl et in a directio n
to W a rds th e inner co re th ere.
BRIEF DES CRIPTION OF DRAW INGS
FIG. 1 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 1 o f th e p res ent inv entio n a nd f o rmu l a tio ns A1 A5
o f Ta bl e 1 .
FIG. 2 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 2 o f th e p res ent inv entio n a nd f o rmu l a tio ns B1 B5
o f Ta bl e 2 .
FIG. 3 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 3 o f th e p res ent inv entio n a nd f o rmu l a tio ns C1 C5
o f Ta bl e 3 .
FIG. 4 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 4 o f th e p res ent inv entio n a nd f o rmu l a tio ns D1 D5
o f Ta bl e 4.
FIG. 5 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m th e ta bl ets in a cco rda nce W ith
Ex a mp l e 5 o f th e p res ent inv entio n a nd f o rmu l a tio ns E1 E5
o f Ta bl e 5 .
FIG. 6 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 6 o f th e p res ent inv entio n a nd f o rmu l a tio ns F1 F5
o f Ta bl e 6.
FIG. 7 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
Pro p ra no l o l HCl f ro m ta bl ets in a cco rda nce W ith Ex a mp l e 7
o f th e p res ent inv entio n a nd f o rmu l a tio ns G1 G2 o f Ta bl e 7 .
FIG. 8 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
Pro p ra no l o l f ro m ta bl ets in a cco rda nce W ith Ex a mp l e 8 o f
th e p res ent inv entio n a nd f o rmu l a tio ns H1 H2 o f Ta bl e 8 .
FIG. 9 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
V era p a mil HCl f ro m ta bl ets in a cco rda nce W ith Ex a mp l e 9
o f th e p res ent inv entio n a nd f o rmu l a tio ns I1 I2 o f Ta bl e 9 .
FIG. 1 0 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
V era p a mil HCl f ro m ta bl ets in a cco rda nce W ith Ex a mp l e 1 0
o f th e p res ent inv entio n a nd f o rmu l a tio ns J 1 J 2 o f Ta bl e 1 0.
FIG. 1 1 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 1 1 o f th e p res ent inv entio n a nd f o rmu l a tio ns
K1 K2 o f Ta bl e 1 1 .
FIG. 1 2 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
ex a mp l e 1 2 o f th e p res ent inv entio n a nd f o rmu l a tio ns L1 L2
o f Ta bl e 1 2 .
FIG. 1 3 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
6, 09 0, 41 1
3
Ex a mp l e 1 3 o f th e p res ent inv entio n a nd f o rmu l a tio ns
M1 M4 o f Ta bl e 1 3 .
FIG. 1 4 is a g ra p h s h o w ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets in a cco rda nce W ith
Ex a mp l e 1 4 o f th e p res ent inv entio n a nd f o rmu l a tio n N1 o f
Ta bl e 1 4.
FIG. 1 5 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
Meto p ro l o l f ro m ta bl ets in a cco rda nce W ith Ex a mp l e 1 5 o f
th e p res ent inv entio n a nd f o rmu l a tio ns O1 O3 o f Ta bl e 1 5 .
FIG. 1 6 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
dil tia Zem h y dro ch l o ride f ro m ta bl ets u s ing s a l t co mbina
tio ns o f s o diu m bis u l f a te, p o ta s s iu m bica rbo na te, ma g ne
s iu m s u l f a te, a nd ca l ciu m ch l o ride.
FIG. 1 7 is a g ra p h s h o W ing th e f ra ctio na l rel ea s e o f
f o rmu l a tio n A5 o f th e p res ent inv entio n du ring ex p o s u re to
co ntinu o u s l y ch a ng ing p H l ev el s .
FIG. 1 8 is a s ch ema tic rep res enta tio n dep icting th e dis
s o l u tio n o f th e ? o a ta bl e mo no l ith ic ma trix ta bl et o v er time.
DETAILED DES CRIPTION OF THE
INV ENTION
Th e inv entio n enco mp a s s es f o rmu l a tio ns f o r th e co n
tro l l ed rel ea s e, p ref era bl y Zero o rder rel ea s e, o f bio a ctiv e
ma teria l f ro m a neW mo no l ith ic s y s tem.
Th es e f o rmu l a tio ns a re ba s ed o n s imp l e s W el l a bl e h y dro
dy na mica l l y ba l a nced mo no l ith ic ma trix ta bl et in W h ich ma y
be inco rp o ra ted a ra ng e o f W a ter-s o l u bl e (l o W to h ig h )
bio a ctiv e dru g s a nd s a l ts . Ex tended o r Zero o rder rel ea s e is
a cco mp l is h ed th ro u g h th e no v el a p p l ica tio n o f p o l y meric
ma trix mo di? ca tio n, a s deta il ed bel o W , by inco rp o ra ting a
s a l t in a s W el l a bl e ma trix :
As a ta bl et p a s s es th ro u g h th e h u ma n dig es tiv e tra ct, it is
s u bj ected to p H v a l u es ra ng ing f ro m 1 . 5 to 7 . 4. Th e s a l iv a
o f th e mo u th h a s a neu tra l p H, th e s to ma ch h a s a p H v a ry ing
f ro m 2 . 04. 0, a nd th e p H o f th e intes tines ca rries a p H
betW een 5 . 07 . 5 . Th eref o re, it is imp o rta nt to co ns ider th e
ef f ects o f th is p H ra ng e o n dis s o l u tio n o f a dru g ta bl et. Fo r
a dru g to a p p ro a ch Zero -o rder rel ea s e, its dis s o l u tio n mu s t
be indep endent o f th e p H in th e s u rro u nding env iro nment.
Th ro u g h p ro ces s es o f io nic intera ctio n/ co mp l ex a tio n/
mo l ecu l a r a nd/ o r s el f a s s o cia tio n betW een a dru g a nd a s a l t
o r s a l t/ dru g co mbina tio ns , h o mo g eneo u s l y dis p ers ed in a
s W el l a bl e p o l y mer s u ch a s h y dro x y p ro p y l meth y l cel l u l o s e
(HPMC), mo dif y th e dy na mics o f th e ma trix s W el l ing ra te
a nd ero s io n o f th e s W el l a bl e p o l y mer, in a cco rda nce W ith
v a ria tio ns in a n ex terna l p H env iro nment ra ng ing f ro m
1 . 5 7 . 0.
Th es e intera ctio ns res u l t in co ntro l l ed ma trix h a rdening .
S u ch h a rdening is res p o ns ibl e f o r th e co ntro l o f p o l y mer
ero s io n/ dis s o l u tio n a nd dru g rel ea s e ra tes . By des ig n, s o l
v ent p enetra tes th e p erip h ery o f th e ta bl et a nd a ra p id initia l
intera ctio n betW een dru g a nd s a l t embedded in th e p o l y
meric ma trix ca u s es immedia te h a rdening o f th e o u ter ta bl et
bo u nda ry , th e ra te o f h a rdening co ns is tentl y decrea s es
to W a rd th e center o f th e ma trix co re in a time-dep endent
ma nner o v er a l o ng p erio d o f time (eg 2 4 h o u rs ).
Th e ef f erv es cent na tu re o f s o diu m bica rbo na te ca u s es a
g enera tio n o f g a s W ith in th e ta bl et a nd p ro du ctio n o f a ir
bu bbl es . Th es e a ir bu bbl es ma y res u l t in ? o a ta tio n o f th e
ta bl et, W h ich ma y increa s e th e g a s tric res idence time o f th e
ta bl et a nd res u l t in a p ro l o ng ed rel ea s e o f th e dru g in th e
a cidic env iro nment. In a dditio n, th is enh a nces th e to ta l mea n
g a s tro intes tina l res idence time a nd a l l o W s f o r increa s ed
bia v a il a bil ity . Th is is s h o W n s ch ema tica l l y in FIG. 1 8 , W h ere
th e ta bl et p ro g res s es o v er time f ro m a n inta ct a nd u ns W o l l en
s ta te to a ? o a ta bl e ma trix W h ich is l o o s e a nd cl ea r.
5
1 0
1 5
2 0
2 5
3 0
3 5
40
45
5 0
5 5
60
65
4
Th e dif f erentia l ra te o f ma trix h a rdening is th e driv ing
p rincip l e in th e no v el s y s tem o f th e p res ent inv entio n, W h ich
is dep endent o n a nd co ntro l l ed by th e ra te o f l iq u id ing res s
to th e ta bl et co re. W ith th e s imu l ta neo u s time-dep endent
decrea s e in g el l a y er integ rity , th e ra te o f dru g dif f u s io n
decrea s es . Th is p h eno meno n co mp ens a tes f o r th e increa s e in
dif f u s io n p a th l eng th a nd decrea s e in th e s u rf a ce a rea o f th e
receding co re W h ich a ris es f ro m th e s W el l ing p ro p erty o f th e
p o l y mer. Hence, better co ntro l l ed, p ref era bl y Zero o rder,
dru g rel ea s e is a ch iev ed. Th e dru g rel ea s e p ro ces s ca n be
ta il o red f o r u p to 2 4 h o u rs . Co ntro l o f th e ch a ng es in co re
h a rdnes s a nd s y nch ro niZa tio n o f th e ru bbery / s W el l ing f ro nt
a nd des cribed receding p h a s e bo u nda ries a s W el l a s ero s io n
o f th e dis s o l u tio n f ro nt bo u nda ry (i. e. ero s io n o f th e ta bl et
p erip h ery ) res u l ts in co ntro l l ed dru g rel ea s e, p ref era bl y
incl u ding Zero o rder kinetics . Op tio na l l y , p o l y mer ma trix
h a rdening s is a l s o ea s il y a ch iev a bl e th ro u g h do u bl e s a l t
intera ctio n. Th is bina ry s a l t co mbina tio n is a l s o u nif o rml y
dis p ers ed in th e p o l y meric ma trix , W h ich th ro u g h io nic
intera ctio n/ co mp l ex a tio n/ mo l ecu l a r a nd/ o r s el f a s s o cia tio n,
increa s es th e rel a tiv e s treng th a nd rig idity o f th e ma trix ,
res u l ting in co ntro l l ed dru g rel ea s e W ith a s imil a r mech a
nis m to th a t des cribed a bo v e.
Dru g s s u ch a s th e ca l ciu m-ch a nnel bl o ckers Dil tia Zem
a nd V era p a mil a nd th e beta -a drenerg ic bl o cker Pro p ra no l o l
(a s th e h y dro ch l o ride s a l ts ), W ith W a ter s o l u bil ities o f 5 0, 8
a nd 5 % res p ectiv el y , h a v e been u s ed in th e p res ent inv en
tio n.
One h y dro p h il ic ma trix ma teria l u s ef u l in th e p res ent
inv entio n is HPMC K4M. Th is is a no nio nic s W el l a bl e
h y dro p h il l ic p o l y mer ma nu f a ctu red by Th e Do W Ch emica l
Co mp a ny u nder th e tra dena me Meth o cel . HPMC K4M is
a l s o a bbrev ia ted a s HPMC K4MP, in W h ich th e P ref ers to
p remiu m cel l u l o s e eth er des ig ned f o r co ntro l l ed rel ea s e
f o rmu l a tio ns . Th e 4 in th e a bbrev ia tio n s u g g es ts th a t th e
p o l y mer h a s a no mina l v is co s ity (2 % in W a ter) o f 4000. Th e
p ercent o f meth o x y l a nd h y dro x y p ro p ry l g ro u p s a re 1 9 2 4
a nd 7 1 2 , res p ectiv el y . In its p h y s ica l f o rm, HPMC K4M is
a f ree-? o w ing , o f f -W h ite p o W der W ith a p a rticl e s iZe l imi
ta tio n o f 9 0%< 1 00 mes h s creen. Th ere a re o th er ty p es o f
HPMC s u ch a s K1 00LV P, K1 5 MP, K1 00MP, E4MP a nd
E1 0MP CR W ith no mina l v is co s ities o f 1 00, 1 5 00, 1 00000,
4000, a nd 1 0000 res p ectiv el y .
Fo rmu l a tio ns o f th e p res ent inv entio n ma y a l s o incl u de
s a l ts s u ch a s s o diu m bis u l f a te, p o ta s s iu m bica rbo na te, ma g
nes iu m s u l f a te, ca l ciu m ch l o ride, s o diu m ch l o ride, s o diu m
s u l ? te a nd s o diu m ca rbo na te in th eir f o rmu l a tio ns . FIG. 1 6
il l u s tra tes th e u s e o f s o me o f th es e s a l ts W ith dil tia Zem
h y dro ch l o ride.
It is bel iev ed th a t a n intera ctio n betW een dru g a nd s a l t
f o rms a co mp l ex in th e s u rro u nding s W el l a bl e ma trix in a
l a y ered f a s h io n beca u s e it o ccu rs in a time-dep endent ma n
ner a s th e s o l v ent media f o r dru g rel ea s e p enetra tes th e ta bl et
inW a rdl y . Likew is e, beca u s e th e ca ta l y s t f o r th e initia tio n o f
dru g rel ea s e is l iq u id ing res s , s o to o is th e ra te o f dru g
rel ea s e co ntro l l ed by th e inW a rdl y p ro g res s iv e h a rdening o f
th e s a l t co mp l ex .
A bina ry s a l t s y s tem (eg ca l ciu m ch l o ride a nd s o diu m
ca rbo na te) ma y a l s o be u s ed, ma y a l s o be u s ed, in W h ich
ca s e th e h a rdening rea ctio n ma y be a f u nctio n o f intera ctio n
betW een th e s a l ts . Ca l ciu m ch l o ride ma y be inco rp o ra ted to
f o rm a co mp l ex W ith s o diu m ca rbo na te. W ith th is
co mbina tio n, th e rea ctio n p ro du cts a re ins o l u bl e ca l ciu m
ca rbo na te a nd s o l u bl e ch a nnel f o rmer, s o diu m ch l o ride.
Hence th e ca l ciu m ca rbo na te embeds its el f in th e p o l y mer
ma trix , initia tes h a rdening a nd s l o W l y dis s o l v es W ith l iq u id