In the composition, a preferentially addictive drug represents opioid, while a non-addictive drug represents acetaminophen. Более предпочтительно, центральная часть дополнительно содержит ацетаминофен.


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2477995
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RU2477995C2
RUSSIAN FEDERATION
FEDERAL SERVICE
FOR INTELLECTUAL PROPERTY
(51)Int. Cl.
A61K9/22
(2006.01)
A61K9/24
(2006.01)
A61K31/16
(2006.01)
A61K31/485
(2006.01)
2477995
ABSTRACT OF INVENTION
(21)(22)Application:
2010106202/15, 20.07.2007
(24)Effective date
20.07.2007
Priority:
(22)Date of filing:
20.07.2007
(43)Application published:
27.08.2011
Bull.24
(45)Date of publication:
27.03.2013Bull.9
(85)Commencement of
national phase:
24.02.2010
(86)PCT application:
US 2007/073957(20.07.2007)
(87)PCT publication:
WO 2009/014534(29.01.2009)
Mail address:
129090, Moskva, ul.B.Spasskaja, 25, str.3, OOO
"Juridicheskaja firma Gorodisskij i Partnery",
pat.pov. A.V.Mitsu, reg.
364
(72)Inventor(s):
LJu Vehj (US)
ROZENBERG Jorg (DE)
VERLE Gerd (DE)
KESSLER Tomas I. (DE)
BRAJTENBAKh Jorg (DE)
DURAK Salikh (DE)
RIKhTER Fridrikh V. (US)
DUTTA Sandip (US)
FORMULATIONS OF NON-OPIOID AND LIMITED OPIOID ANALGESICS
(57)Abstract:
FIELD: medicine, pharmaceutics.
SUBSTANCE: present
invention refers to
medicine and de
cal compositions
having central and non-cen
tral layers for drug
delivery, particularly a
ddictive drugs, substantially
enclosed in a core porti
on, and a non-addictive drug
in a non-core portion. The given compositions having
a reduced addiction potentia
l. In the composition, a
preferentially addictive
drug represents opioid,
while a non-addictive drug
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0,32
:[email protected];@T�A
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:[email protected];@T�A
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=GAK
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90%
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95%
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95%
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99%
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AH8;J;@[email protected];[email protected]=�GAC=8:=LAH;;#V'
(USP Dissolution Apparatus II
@AH=GE�A;
), USP XXV; 37
C, 0,01M HCl, 50
[email protected];GEKA=LE9K&#x;-8.;G12;&#x.1E-;�.9K;&#x-17.;z-2;a.6;&#x=-7.;L-1;.1E; K-1;.70;ABA
�9B8;J9;�E=
KNGKA?AFJ=;:[email protected];EALKG8;JPKAJ�ABA8=GEKA8=
HCl,
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HAG8;JGEKA:5^[email protected]".1;N:99".1;E;[email protected]=:9
[email protected];EL9?;I�=�;G�;[email protected]�;A.70;ABAHAL8NE9D
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120
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240
�:9PE
!=GEKA8;�9;@;L=8GEK;��ABAG8;[email protected];EALKGAAEK;EGEK99GH89:;8A:
AH8;J;@[email protected];[email protected]=�GAC=8:=LAH;;#V'
(USP Dissolution Apparatus II
@AH=GE�A;
), USP XXV; 37
C, 0,01M HCl, 50
[email protected];GEKA=LE9K&#x;-8.;G12;&#x.1E-;�.9K;&#x-17.;z-2;a.6;&#x=-7.;L-1;.1E; K-1;.70;ABA
�9B8;J9;�E=
KNGKA?AFJ=;:[email protected];EALKG8;JPKAJ�ABA8=GEKA8=
HCl,
AH8;J;@[email protected]
HAG8;JGEKA:5^[email protected]".1;N:99".1;E;[email protected]=:9
[email protected];�[email protected];EL=G
:B=O;E=:9�AC�;[email protected]�;A.10;A:HAL8NE99
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9I:;8;��A;;8;I
120
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240
�:9PE
#LA8AGE98=GEKA8;�[email protected];L=8GEK;��ABAG8;[email protected][email protected];@T�A�=
10%
H89L=FJA:E;GE98P;:A:9�E;[email protected];[email protected];JGEK9;9GS�AJA?NGE8ABAKNGKA?AFJ;�9D
=LE9�KABA9�B8;J9;�E=
H89GPEGEKPQ[;[email protected]�;�AA:HAL8NE99
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AH8;J;@[email protected];[email protected]=�GAC=8:=LAH;;#V'
@AH=GE�AMGHAGA?
, USP XXV;
C, 0,01M HCl, 50
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[email protected];GEKA=LE9K&#x;22.;GE9;&#x.3KA;&#x-251;&#x.4=L;.3E; K12;&#x.900;ABA&#x;22.;GE9;&#x.3KA;&#x-251;&#x.4=L;.3E; K12;&#x.900;9B8;J9;&#x;22.;GE9;&#x.3KA;&#x-251;&#x.4=L;.3E; K12;&#x.900;E=
KNGKA?AFJ=;:ABA9I
[email protected];EALKG8;JPKA�JABA8=GEKA8=
HCl,
AH8;J;@[email protected];JGEKA:5^[email protected]�9N:9
�9E;[email protected]=:9
[email protected];EL=?;I�=��;G;[email protected];��AABAHAL8NE9D
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120
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240
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9I:;8;��A;;8;I
360
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480
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[email protected]�;[email protected];EL=GA
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:B=O;E=:�9AC�;[email protected];�A�.90;A:HAL8NE99
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120
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240
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360
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480
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#LA8AGE98=GEKA8;�[email protected];L=8GEK;��ABAG8;[email protected][email protected];@T�A�=
25%
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H89GPEGEKPQ[;[email protected]�;�AA:HAL8NE99
4;GE98�AK=9;[email protected]
L=L9KH89:;8;
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Kollicoat
[email protected][email protected];8JNMHA8AUAL�=AG�AK;[email protected]:;[email protected];@@[email protected]
LAEA8NM
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L8=G�AK=ENS
LA89.10;;[email protected].10;;[email protected];[email protected][email protected]=JLAM9A.10;JA8AJ.10;AM
4;[email protected]
L=LKH89:;8;
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Kollicoat
[email protected][email protected]
EK;8JNMHA8AUAL�=AG�AK;[email protected][email protected]=
3AL8NEN;[email protected];�[email protected];EL9
[email protected];.9;;(.1;.9;;(.1;N;KGAAEK;EGEK99GH89:;8=:9
3, 7
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[email protected]
[email protected];�A.9;[email protected]@
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[email protected]�=HAK;8S�AGE9U;[email protected];[email protected]?;��AI=:;E;�
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11:
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8=GEKA�8;9DAH8;J;@�;�NSLA:HAI9O9MK
HCl
20%
KA�JA:8=GEKA8;\E=�[email protected]=
[email protected]
[email protected];JA�K=9DGLA8AGE98=GEKA8;�9DK
40%
KAJ�A:8=GEKA8;\E=�[email protected]=:AF�A
[email protected]=ETGSAJ�N;GHAGA?N
[email protected]=GEKA8;�9DK
0,01
[email protected][email protected];9
20/40%
KA�JA:8=GEKA8;
\E=�[email protected][email protected][email protected]@;JPQ[;;PGE8AMGEKA9GHAGA?N
(I)
0,01
. HCl
0GE8AMGEKA
: USP Dissolution Apparatus II (
@AH=GE�A;
40%
0GE8AMGEKA
: USP Dissolution Apparatus II (
@AH=GE�A;
RU2477995C2
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4;:H;8=EP8=
58;:[email protected];GE98AK=�9DKNGKA?AFJ;�9DKE;;.5;&#x;9.3;9;
30/60/120/180/240/360/420/480/600/720/840/1080/1320/1560/1800
:9�PE
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[email protected];�9;A?8=IO=
[email protected];EGDL=L;GET
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J;E;LO9D
[email protected][email protected]�N
280
III.
0,01
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#AGE=KG?NGE8N:KNGKA?AF�J;9;:
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0,01
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H89
H8;[email protected];��[email protected];
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#AGE=K
,;�[email protected]�=D=GET3AL8NE9;
65,42%
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150
:B=O;E=:9�AC;�=
9,29% Eudragit RL-PO48
Kollicoat IR
9,29%
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Ph. Eur. USP 2208 Type V 100 (Methocel K100)
9,29%
[email protected];@@[email protected]
Ph. Eur. Type EF
2,99% Polaxamer 188 Ph. Eur./NF
2,8%
B9J8ALAJA�=f
1% Aerosil 200
"?[=D:=GG=O;�[email protected]�AM=GE9
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H8;[email protected];�NJ=��N;HA8=GEKA8;�[email protected]�=
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:9�
#8�;J;;I�=;&#x;-30;&#x.900;9;
3014
6027
12043
18057
24067
30076
36084
42090
48094
60098
72098
84098
108099
132099
156099
1800100
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. HCl
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#8�;J;;I�=&#x-17.; 00;;9;
.: 41
RU2477995C2
3033
6039
12046
18056
24064
30071
36078
42085
48090
60098
720100
840101
1080100
1320100
1560100
1800100
#AGE=KGI=:;J�@;�N:KNGKA?AFJ;�9;:
KA�EAU�;99=O;E=:9�AC;�=
0,01
HCl
H89
H8;[email protected];�[email protected];
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[email protected];
H8;[email protected];�GAGE=KO�;[email protected]�AM
=GE99HAL8NE9DGAGE=K=
#AGE=K
�,;[email protected]�=D=GET
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55,88%
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120
:B=O;E=:9�AC�;=
13,50% Eudragit RL-PO
38,4
Kollicoat IR
11,0%
B9H8A:;@@AIN
Ph, Eur, USP 2208 Type V 100 (Methocel K100)
3,01%
B9H8A:;@@AIN
Ph, Eur, 2208 Type V 20000 (Methocel K100M)
13,40%
[email protected]=
Ph, Eur,/NF
4P8
Xylisorb 90
2,21%
B9J8ALAJA�f
1% Aerosil 200 Ph, Eur,/NF
"?[=D:=GG=O;�[email protected]�AM=GE9
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#8;J�;;I�=&#x;000;;9;
3017
6031
12046
18057
24067
30075
36082
42088
48091
60096
72097
84098
108099
132099
156099
1800100
.: 42
RU2477995C2
XII(b)
5NGKA?AFJ;�9;@;L=8GEK;��ABAG8;JGEK=
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0,01
. HCl
6A:;�EK8;:�;9E;GE98AK=�9D
:9�
#8;J�;;I�=).5;&#x;000;;9;
3034
6041
12047
18051
24056
30060
36065
42068
48071
60076
72080
84084
108089
1320100
1560100
1800100
IV.
40%
#AGE=KG?NGE8N:KNGKA?AF�J;9;:
KA�EAU;�99=O;E�=:9AC�;=
40%
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8=GEKA8;�\[email protected]=H89
H8;[email protected];�[email protected];
XIV.
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#AGE=K
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65,42%
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150
:B=O;E=:9�AC;�=
9,29% Eudragit RL-PO
Kollicoat IR
9,29%
B9H8A:;@@AIN
Ph, Eur, USP 2208 Type V 100 (Methocel K100)
9,29%
[email protected];@@[email protected]
Ph, Eur, Type EF
2,99% Polaxamer 188 Ph, Eur,/NF
2,8%
B9J8ALAJ�A=f
1% Aerosil 200
"?[=D:=GG=O;�[email protected]�AM=GE9
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H8;[email protected];�NJ=��N;8=GEKA�8;[email protected]�A=
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(XIV (b)).
XIV(a)
5NGKA?AFJ;�9;@;L=8GEK;��ABAG8;JGEK=
B9J8ALAJA�=
.: 43
RU2477995C2
36097
42097
48098
60098
72099
840100
108098
132099
156099
1800100
XIV(b)
5NGKA?AFJ;�9;@;L=8GEK;��ABAG8;JGEK=
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#AGE=KGI=:;J�@;�N:KNGKA?AFJ;�9;:
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40%
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XVI.
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#AGE=K
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55,88%
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120
:B=O;E=:�9AC;�=
13,50% Eudragit RL-PO
38,4
Kollicoat IR
11,0%
B9H8A:;@@AIN
Ph, Eur, USP 2208 Type V 100 (Methocel K100)
3,01%
B9H8A:;@@AIN
Ph, Eur, 2208 Type V 20000 (Methocel K100M)
13,40%
[email protected]=
Ph, Eur,/NF
4P8
Xylisorb 90
2,21%
B9J8ALAJ�A=f
1% Aerosil 200 Ph, Eur,/NF
"?[=D:=GG=O;�[email protected]�AM=GE9
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XVI
H8;[email protected];�NJ=��N;8=GEKA�8;[email protected]�A=
(XVI(a))
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(XVI(b)).
XVI(a)
5NGKA?AF�J;9;@;L=8GEK;��ABAG8;JGEK=
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.: 44
RU2477995C2
6A:;�EK8;:�;9E;GE98AK=�9D
:9�
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3012
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12038
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1320102
1560101
1800100
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5NGKA?AF�J;9;@;L=8GEK;��ABAG8;JGEK=
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, 60
40%
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~20000-50000
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(XVII(a))
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(XVII(b))
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40%
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.: 46
RU2477995C2
3033
6045
12062
18073
24080
30084
36087
42088
48089
VI.
0,01
. HCl
#AGE=KG?NGE8N:KNGKA?AF�J;9;:
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0,01
. HCl
H89
H8;[email protected];�[email protected];
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(XIX(a))
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(XIX(b))
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KA�EAU�;99=O;E=:9�AC;�=
0,01
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XX.
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RU2477995C2
12017
18023
24028
30032
36037
42041
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4,69
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(N=69),
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IX.
0,01
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KA�EAU�;99=O;E=:�9AC;�=
0,01
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H89
H8;[email protected];�[email protected][email protected]�NSGAGE=KAK
9-12
[email protected]=S
XXII
XXIII.
&A:HAI9O99GAGE=KAKH8;[email protected]�;[email protected];
XXI.
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XXI
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12,6% Eudragit RL-PO12,6% Eudragit RL-PO12,6% Eudragit RL-PO12,6% Eudragit RL-PO
.: 48
RU2477995C2
6,0%
B9H8A:;@@AIN
Ph.
Eur. USP 2208 Type V 100
(Methocel
100)
6,0%
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6,0%
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6,0%
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6,0%
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6,0%
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6,0%
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Ph.
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6,0%
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Ph.
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(Methocel K100M)
12,6% X
[email protected]=
Ph.
Eur./NF
4P8
Xylisorb 90
12,6%
[email protected]=
Ph. Eur./NF
4P8
Xylisorb 90
12,6%
[email protected]=
Ph. Eur./NF
4P8
Xylisorb 90
12,6%
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Ph. Eur./NF
4P8
Xylisorb 90
1,8%
B9J8ALAJ�A=
1,8%
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1,8%
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1,8%
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1% Aerosil 200 Ph.
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1% Aerosil 200
Ph. Eur./NF
1% Aerosil 200
Ph. Eur./NF
1% Aerosil 200 Ph. Eur./NF
3AL8NE9;f
50,0
:B=O;E=:9�AC;�=
85,0
:B=O;E=:9�AC�;=
120,0
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16,0
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833
899
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99,39
XXII
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00000
3021201916
6030303028
12042434443
18051535453
24058606261
30064676867
36069727473
42074777978
48078818382
XXIII
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00000
307151922
6011192326
12017252932
18022293336
24026333740
30030364043
36033394245
42036424548
48039454851
0,01
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#AGE=KG?NGE8N:KNGKA?AF�J;9;:
KA�EAU;�99=O;E�=:9AC�;=
0,01
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H89
H8;[email protected];�[email protected];
XXV.
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XXIV
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13.
XXIV
#AGE=K
,;�[email protected]�=D=GET2;IHAL8NE9D
65,42%
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9,29% Eudragit RL-PO
9,29%
B9H8A:;@@AIN
Ph. Eur. USP 2208 Type V 100 (Methocel K10)
.: 49
RU2477995C2
9,29%
[email protected];@@[email protected]
Ph. Eur. Type EF
2,99% Polaxamer 188 Ph. Eur./NF
2,8%
B9J8ALAJA�=
1% Aerosil 200
"?[=D:=GG=
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(XXV(a))
9=O;E=:9�AC;�=
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3028
6038
12050
18062
24072
30080
36088
42095
48098
600100
72098
84097
108097
132097
156097
180098
XXV(b)
5NGKA?AFJ;�9;@;L=8GEK;��ABAG8;JGEK==O;E=:9�AC;�=5
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3013
6019
12027
18041
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36079
42088
48095
600105
720106
840104
1080104
1320104
1560104
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0,01
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H89
H8;[email protected];�[email protected];
XXVII.
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XXVI
H8;[email protected];�GAGE=K
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13.
.: 50
RU2477995C2
XXVI
#AGE=K
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55,88%
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13,50% Eudragit RL-PO
11,0%
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Ph, Eur, USP 2208 Type V 100 (Methocel K100)
3,01%
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Ph, Eur, 2208 Type V 20000 (Methocel K100M)
13,40%
[email protected]=
Ph, Eur./NF
4P8
Xylisorb 90
2,21%
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1% Aerosil 200 Ph, Eur./NF
"?[=D:=GG=
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(XXVII(a))
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3030
6042
12054
18065
24072
30079
36088
42094
48096
60099
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840100
1080100
1320100
1560100
1800100
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3011
6017
12025
18031
24036
30042
36048
42053
48056
60063
72069
84074
108091
132099
1560104
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RU2477995C2
1800103
12:
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GAGE=KAK
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"[email protected];8;I
0, 0,25, 0,5, 0,75,
1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36
[email protected];JAIN&#x=9.6;&#xG8.8; .4;&#xK-26;.9H;.2A;&#xG8.8;&#[email protected];-;ɖ.;JA1;�.6I;.4;&#xN-26;.20;=
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AUC
AUC
CL/F (
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4,4
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14,0
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205
(19%)
209
(l8%)
6,22
(18%)
447
(19%)
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4,4
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13,0
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204
(20%)
209
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5,93
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45,0
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4,8
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12,6
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211
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214
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5,68
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43,5
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.: 52
RU2477995C2
'O;E=:9�AC;�
(N=20)
AUC
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AUC
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CL/F (
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150,74 (66%)206 (25%)21,2 (29%)22,9 (30%)9,85 (46%)24,0 (33%)
#AGE=K
160,82 (82%)2,41 (32%)22,1 (24%)
22,3 (25%)5,59 (21%)23,7 (24%)
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10,83 (22%)2,23 (24%)22,1 (26%)
22,4 (26%)6,47 (24%)23,7 (24%)
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13,950
13,240
12,626
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1,105
1,049
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AUC
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199,636
203,905
206,338
206,338
0,968
0,988
0,919-1,019
0,937-1,042
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AUC
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204,492
208,867
210,187
210,187
0,973
0,994
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2,014
2,395
2,193
0,918
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AUC
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20,580
22,363
21,732
21,732
0,947
1,029
0,899-0,998
0,975-1,086
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AUC
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22,171
22,402
21,987
21,987
1,008
1,023
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0,956-1,095
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15,9
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15,9
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USP
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380,0
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350,0
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91,8
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49,7
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74,8
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28,7
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0,18
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1,51
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0,30
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5,57
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2,75
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RU2477995C2
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=GAK
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=O;E=:9�AC�;=KNGKA?AFJ=;EGD
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RU2477995C2
vitro
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