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5,741,908
5,741,909
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5,977,366
6,069,149
US 6,245,776 B1
*Jun. 12, 2001
2/1998 Gerster.
4/1998
4/1998
3/1999
11/1999
5/2000
Gerster et al. .
Gerster et al. .
Nikolaides et al. .
Gerster et al. .
Nanba et al. .
2/1998 (EP) .
9-208584
8/1997 (JP).
97-41884
97-48704
98-24436
00-06577
00-09506
93-09119
99/29693
12/1997
11/1997
5/1993
6/1998
6/1999
2/2000
(*)
Notice:
154(a)(2).
(60)
(51>
(52>
(58>
(56)
References Cited
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3,917,624
4,689,338 *
4,698,348
8/1987
10/1987 Gerster.
5/1990 Gerster et al. .
4,988,815
5,238,944 *
8/1991 Gerster.
12/1992 Gerster.
8/1993
4,929,624
5,037,986
5,175,296
OTHER PUBLICATIONS
(57)
ABSTRACT
5,266,575
5,268,376
5,346,905
12/1993 Gerster.
9/1994 Gerster.
5,352,784
5,367,076
11/1994 Gerster.
5,389,640 *
2/1995
5,395,937
5,444,065
5,446,153
5,482,936
1/1996 Lindstrom.
5,494,916
5,525,612
6/1996 Gerster.
5,585,612
5,605,899
5,627,281
5,644,063
5,648,516
2/1997
5/1997
7/1997
7/1997
Gerster et al. .
Nikolaides et al. .
Lindstrom et al. .
Nikolaides et al. .
US 6,245,776 B1
Page 2
OTHER PUBLICATIONS
15371540 (1981).
* cited by eXarniner
U.S. Patent
Sheet 1 of3
US 6,245,776 B1
+ Placebo
1400
1200
m9) 3o o
(taomtuanlt
800
600
400
200
1400
+
I
+
><
Formulation
Formulation
Formulation
Formulation
C (1% IRM)
D (1% IBM)
E (3% IBM)
F (3% IBM)
1200
-L O O O
(taom uagnlt)
800
600
400
200
30
U.S. Patent
Sheet 2 of3
US 6,245,776 B1
(Concegt/ramiL)
1O
15
2O
Fig. 3
25
U.S. Patent
Sheet 3 of3
Formulation
A
Formulation
B
Fig. 4A
400 -
300
ALIC
200
100~
Formulation
A
Formulation
B
Fig. 4B
US 6,245,776 B1
US 6,245,776 B1
1
2
Although some of the bene?cial effects of IRMs are
10
20
BACKGROUND
4-amino-2-ethoxymethyl-ot,ot-dimethyl-1H-imidaZo[4,5-c]
35
45
DETAILED DESCRIPTION
50
55
compounds.
tearic acid.
FIG. 3 is a graph comparing mean serum imiquimod
concentration in rats after a single intravaginal dose of
Formulation A or Formulation B.
US 6,245,776 B1
3
the formulations can enhance therapeutic ef?ciency of the
o \H
N
10
(R2)n
{D
'
R12
Wherein
NH;
(Ron
25
I \> R21
R11
Wherein
atoms; and
each R2 is independently selected from the group con
sisting of straight chain or branched chain alkoXy
containing one to four carbon atoms, halogen, and
straight chain or branched chain alkyl containing one to
35
III
45
NH;
55
Wherein
65
US 6,245,776 B1
6
10
Wherein
25
R25 is
4%,
Rs
35
wherein
55
Wherein
65
going.
Preferred 6,7 fused cycloalkylimidaZopyridine amine
IRM compounds are de?ned by Formula VI beloW:
US 6,245,776 B1
8
VI
NH;
N
o w
|
10
wherein m is 1, 2, or 3;
15
chlorine atom;
NH2
N/
> R27
R67
R77
R17
45
Wherein
and CHRxRy
Wherein
55
65
US 6,245,776 B1
9
selected from the group consisting of methyl, methoXy,
and halogen; and morpholinoalkyl Wherein the alkyl
moiety contains one to four carbon atoms;
atoms, With the proviso that R67 and R77 taken together
contain no more than siX carbon atoms, and With the
10
hydrogen;
and pharmaceutically acceptable salts thereof.
Preferred 1,2-bridged imidaZoquinoline amine IRM com
pounds are de?ned by Formula VIII beloW:
15
VIII
alkyl-X-aryl;
alkenyl-X-aryl;
heteroaryl;
alkyl-X-heteroaryl; and
alkenyl-X-heteroaryl;
NH;
hydrogen;
CH2
halo;
haloalkyl;
25
(R8)q
Wherein
Z is selected from the group consisting of;
(CH2)p Wherein p is 1 to 4;
each R59 is independently H or C1_8alkyl;
atoms;
and Wherein q is 0 or 1 and R8 is selected from the group
45
hydrogen;
IX
NH;
N/
R39
> R29
heteroaryl;
heterocyclyl;
R19
R49
Wherein:
hydrogen;
alkyl;
65
US 6,245,776 B1
14
13
Noz;
OH; and
SH; or R411 is
% M0
(0)04
wherein Y is N or CR;
hydrogen;
C1-10 alkyl;
aryl
halogen;
N(R311)2;
CON(R311)2;
OH;
COC1_1O alkyl;
N3;
aryl;
heteroaryl;
25
heterocyclyl;
CO-aryl; and
CO-heteroaryl;
35
40
60
Carbopol 974P.
US 6,245,776 B1
15
16
cancer in the US. alone and this is usually secondary to not
detecting the primary cancerous lesion in a timely manner.
Weight.
15
20
25
proteins (E6 and E7) from the high risk genotypes binding
35
40
(e.g., HPV 16, 18, and less frequently 31, 33, 35, 45) are
very likely the exclusive initiating factor (i.e., oncogenic
50
55
60
65
susceptibility.
US 6,245,776 B1
17
18
plasia (CIN).
Results
15
20
25
30
TABLE 1
Components
40
EXAMPLES
Example 1
Evaluation of the Safety, Pharmacokinetics (PK) and Phar
45
50
Formulation A (% W/W)
Imiquimod
5.0
Isostearic Acid
25.0
Benzyl Alcohol
Cetyl Alcohol
Stearyl Alcohol
2.0
2.2
3.1
White Petrolatum
3.0
Polysorbate 60
3.4
Sorbitan Monostearate
0.6
Glycerin
Methyl Paraben
Propyl Paraben
2.0
0.2
0.02
Water
Xanthan Gum
PH
52.98
0.5
5.1
Viscosity (cps)
0.33 x 105
Example 2
55
60
beloW.
Imiquimod Was dissolved in isostearic acid With Span 85.
65
US 6,245,776 B1
19
20
TABLE 2
prior to the time the receptor ?uid Was added to the cell
beloW the skin.
The cell Was then placed in a constant temperature (31
Compounds
Formulation B (% W/W)
Imiquimod
Isostearic acid
Pluronic F68
28
2.98
Puri?ed Water
43.78
Carbopol 974P
1.7
Disodium EDTA
0.05
Propylene glycol
15
10
Sorbic acid
0.15
Methylparaben
0.15
Span 85
2.02
5N NaOH
PH
1.17
5.1
Viscosity (cps)
6.4 x 105
15
Example 3
Example 5
Composition
Imiquimod
25
Formulation
Formulation
Formulation
Formulation
C (% W/W)
D (% W/W)
E (% W/W)
F (% W/W)
1.0
1.0
3.0
3.0
Isostearic acid
Pluronic F68
Puri?ed Water
5.6
1.79
69.05
28.0
1.79
48.30
16.8
1.79
56.25
28.0
1.79
46.75
Carbopol 974P
Disodium
2.8
0.05
2.10
0.05
2.5
0.05
1.80
0.05
15.0
0.15
15.0
0.15
15.0
0.15
15.0
0.15
Span 85
0.15
1.21
0.15
1.21
0.15
1.21
0.15
1.21
5N NaOH
3.2
2.26
3.1
2.1
EDTA
PG"
Sorbic acid
Methylparaben
pH
Viscosity (cps)
Example 4.
TABLE 4
5.1
5.2
5.2
5.3
5.8 X 105
8.8 X 105
11.0 X 105
10.0 X 105
35
40
IRM
ISA
Formu-
Concentration
Concentration
lation
(% W/W)
(% W/W)
C
D
E
F
1%
1%
3%
3%
5.6%
28%
16.8%
28%
Viscosity
Steady State
18.1
26.1
39.9
71.5
Example 4
Imiquimod Transport Across Hairless Mouse Skin from TWo
Formulations A and B, both at 5% W/W Imiquimod.
FIG. 1 is a graph of the results of imiquimod penetration
studies of Formulations A and B, of Examples 1 and 2, using
hairless mouse skin according to the procedure described in
US. Pat. No. 5,238,944, the entire disclosure of Which is
45
Formulation B
Serum imiquimod concentration versus time pro?les Were
60
Example 6
Pharmacokinetics Comparison of Imiquimod in Rats after
Single Dose Vaginal Application of Formulation A and
65
US 6,245,776 B1
21
22
From the foregoing detailed description and examples, it
Example 7
Preparation of Pharmaceutical Formulation G
The W/W % of the ingredients for Formulation G are
shoWn in Table 5.
tion Was complete the heat Was turned off. Sorbitan trioleate
20
30
imidaZo [4,5-c]-quinoline-4-amine;
35
Example 8
Preparation of Pharmaceutical Formulations HJ Pharma
ceutical formulations HJ Were prepared using the method
of Example 7. The W/W % of the ingredients in the formu
lations is shoWn in Table 5 beloW.
40
Formulation
% W/W
% W/W
% W/W
% W/W
15.00
0.10
15.00
0.50
15.00
1.50
18.00
3.00
1.00
1.00
1.00
1.00
Propylene Glycol
5.00
5.00
5.00
5.00
Sorbic Acid
Methylparaben
Puri?ed Water
Edetate Disodium
Polaxamer 188
Carbomer 974
0.15
0.20
0.15
0.20
0.15
0.20
0.15
0.20
75.00
0.05
2.50
1.00
74.60
0.05
2.50
1.00
73.60
0.05
2.50
1.00
69.10
0.05
2.50
1.00
Sodium Hydroxide
qs
qs
qs
Qs
100
100
100
100
Total % W/W
imidaZo[4,5-c]-quinolin-4-amine;
TABLE 5
Component
solution.
a carbomer.
45
(b)
(c)
(d)
(e)
about
about
about
about
1-(2-methylpropyl)-1H-imidaZo[4,5-c]-quinolin-4-amine.
9. The method according to claim 7 Wherein the mucosal
surface is on a cervix.
60
intraepithelial neoplasia.
65
US 6,245,776 B1
24
23
is 1-(2-methylpropyl)-1H-imidaZo[4,5-c]-quinolin-4-amine.
amines.
21. Amethod for delivering an immune response modi?er
dimethyl-1H-imidaZo[4,5-c]quinoline-1-ethanol.
of:
the IRM;
a fatty acid;
a preservative system; and
a carbomer.
25
CERTIFICATE OF CORRECTION
PATENT NO.
: 6,245,776 B1
DATED
Page 1 of 1
INVENTOR(S) : Raymond Skwierczynski, Kenneth R. Phares, Richard L. Miller, Zheng Jane Li,
Michael J. Jozwiakowski, Terri F. Busch
It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:
Column 1
Line 7, 60/115,256 should read -- 60/115,253
WM RM;
Arresting Officer
NICHOLAS P. GODICI