U.S. patent application number 09/886012 was filed with the patent office on 2002-05-16 for systems and methods for treating a mucosal surface.
Invention is credited to Hedenstrom, John C., Jozwiakowski, Michael J., Martinez, Mark, Phares, Kenneth R., Trofatter, Kenneth JR..
Application Number | 20020058674 09/886012 |
Document ID | / |
Family ID | 27494004 |
Filed Date | 2002-05-16 |
United States Patent
Application |
20020058674 |
Kind Code |
A1 |
Hedenstrom, John C. ; et
al. |
May 16, 2002 |
Systems and methods for treating a mucosal surface
Abstract
A system for treating a condition associated with a mucosal
surface, the system comprising an immune response modifier (IRM)
compound chosen from imidazoquinoline amines, imidazopyridine
amines, 6,7-fused cycloalkylimidazopyridine amines,
imidazonaphthyridine amines, oxazoloquinoline amines,
thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and
pharmaceutically acceptable salts thereof and an applicator device
for applying the IRM compound to the mucosal surface. This system
of IRM compounds and applicator may be used to treat conditions
associated with mucosal surfaces such as cervical dysphasia and
cervical intraepithelial neoplasia.
Inventors: |
Hedenstrom, John C.; (St.
Paul, MN) ; Jozwiakowski, Michael J.; (Stillwater,
MN) ; Martinez, Mark; (San Francisco, CA) ;
Phares, Kenneth R.; (Chapel Hill, NC) ; Trofatter,
Kenneth JR.; (Minnetonka, MN) |
Correspondence
Address: |
Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
1300 I Street, N.W.
Washington
DC
20005-3315
US
|
Family ID: |
27494004 |
Appl. No.: |
09/886012 |
Filed: |
June 22, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09886012 |
Jun 22, 2001 |
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09676339 |
Sep 29, 2000 |
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09676339 |
Sep 29, 2000 |
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09479578 |
Jan 7, 2000 |
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6245776 |
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60115253 |
Jan 8, 1999 |
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60213420 |
Jun 22, 2000 |
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Current U.S.
Class: |
514/292 ;
514/293; 514/303 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 9/0034 20130101; A61K 47/10 20130101; A61K 31/437 20130101;
A61M 31/00 20130101; C07D 471/04 20130101; A61K 47/12 20130101;
A61M 2210/1475 20130101; A61K 31/4748 20130101; A61K 31/4745
20130101 |
Class at
Publication: |
514/292 ;
514/293; 514/303 |
International
Class: |
A61K 031/4745 |
Claims
What is claimed is:
1. A system for treating a condition associated with a mucosal
surface, the system comprising: an immune response modifier (IRM)
compound chosen from imidazoquinoline amines, imidazopyridine
amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged
imidazoquinoline amines, and pharmaceutically acceptable salts
thereof; and an applicator device for applying to the mucosal
surface the IRM compound.
2. The system of claim 1, wherein the IRM compound is
1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine.
3. The system of claim 1, wherein the IRM compound is
4-amino-.alpha.,.alpha.-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-
e-1-ethanol.
4. The system of claim 1, wherein the system further comprises a
pharmaceutical formulation comprising: the IRM compound; at least
one fatty acid; and a preservative system comprising propylene
glycol.
5. The system of claim 1, wherein the applicator device is
pre-filled with a therapeutically effective amount of the IRM
compound.
6. The system of claim 1, wherein the IRM compound is contained in
a container separate from the device.
7. The system of claim 1, further comprising measuring marks on the
applicator device for assisting a user in determining the amount of
the IRM compound in the applicator device.
8. The system of claim 1, wherein the condition associated with the
mucosal surface is cervical dysplasia.
9. The system of claim 1, wherein the mucosal surface is on a
cervix.
10. The system of claim 9, wherein the mucosal surface is on the
vaginal part of the cervix.
11. The system of claim 10, wherein the condition associated with
the mucosal surface is cervical intraepithelial neoplasia.
12. The system of claim 1, wherein the applicator device comprises:
a hollow tube comprising a distal delivery end and a proximal end;
and a piston slidably received within the tube.
13. The system of claim 12, further comprising a member configured
to cause movement of the piston toward the distal end.
14. The system of claim 13, wherein the device is configured to
limit retraction movement of the member toward the proximal end
when the piston is located adjacent to the distal end.
15. The system of claim 13, wherein the piston is removably coupled
to the member.
16. The system of claim 13, wherein the member is slidably received
in the hollow tube.
17. The system of claim 12, further comprising a stop limiting
retraction movement of the piston toward the proximal end.
18. The system of claim 12, wherein the piston comprises a portion
extending from the distal end when the piston is positioned at its
farthest location away from the proximal end.
19. The system of claim 12, wherein the distal end is tapered on
its outer surface.
20. The system of claim 13, wherein the member has a length shorter
than the distance between the proximal end and the piston when the
piston is positioned at its furthest location away from the
proximal end.
21. A system for treating a condition associated with a mucosal
surface, the system comprising: an immune response modifier (IRM)
compound chosen from imidazoquinoline amines, imidazopyridine
amines, 6,7-fused cycloalkylimidazopyridine amines,
imidazonaphthyridine amines, oxazoloquinoline amines,
thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and
pharmaceutically acceptable salts thereof; and an applicator device
for applying to the mucosal surface the IRM compound.
22. The system of claim 21, wherein the IRM compound is
1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine.
23. The system of claim 21, wherein the IRM compound is
4-amino-.alpha.,.alpha.-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-
e-1-ethanol.
24. The system of claim 21, wherein the IRM compound is
2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.
25. The system of claim 21, wherein the system further comprises a
pharmaceutical formulation comprising: the IRM compound; at least
one fatty acid; and a preservative system comprising propylene
glycol.
26. The system of claim 21, wherein the applicator device is
pre-filled with a therapeutically effective amount of the IRM
compound.
27. The system of claim 21, wherein the IRM compound is contained
in a container separate from the device.
28. The system of claim 21, further comprising measuring marks on
the applicator device for assisting a user in determining the
amount of the IRM compound in the applicator device.
29. The system of claim 21, wherein the condition associated with
the mucosal surface is cervical dysplasia.
30. The system of claim 21, wherein the mucosal surface is on a
cervix.
31. The system of claim 30, wherein the mucosal surface is on the
vaginal part of the cervix.
32. The system of claim 31, wherein the condition associated with
the mucosal surface is cervical intraepithelial neoplasia.
33. The system of claim 21, wherein the applicator device
comprises: a hollow tube comprising a distal delivery end and a
proximal end; and a piston slidably received within the tube.
34. The system of claim 33, further comprising a member configured
to cause movement of the piston toward the distal end.
35. The system of claim 34, wherein the device is configured to
limit retraction movement of the member toward the proximal end
when the piston is located adjacent to the distal end.
36. The system of claim 34, wherein the piston is removably coupled
to the member.
37. The system of claim 34, wherein the member is slidably received
in the hollow tube.
38. The system of claim 33, further comprising a stop limiting
retraction movement of the piston toward the proximal end.
39. The system of claim 33, wherein the piston comprises a portion
extending from the distal end when the piston is positioned at its
farthest location away from the proximal end.
40. The system of claim 33, wherein the distal end is tapered on
its outer surface.
41. The system of claim 34, wherein the member has a length shorter
than the distance between the proximal end and the piston when the
piston is positioned at its furthest location away from the
proximal end.
42. A method for treating a condition associated with a mucosal
surface, the method comprising: providing an immune response
modifier (IRM) compound chosen from imidazoquinoline amines,
imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines,
imidazonaphthyridine amines, oxazoloquinoline amines,
thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and
pharmaceutically acceptable salts thereof; providing an applicator
device for applying to the mucosal surface the IRM compound; and
applying the IRM compound to the mucosal surface with the
applicator device.
43. The method of claim 42, wherein the IRM compound is
1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine.
44. The method of claim 42, wherein the IRM compound is
4-amino-.alpha.,.alpha.-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-
e-1-ethanol.
45. The method of claim 42, wherein the IRM compound is
2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.
46. The method of claim 42, wherein the applicator device is
pre-filled with a therapeutically effective amount of the IRM
compound.
47. The method of claim 42, further comprising filling the
applicator device with the IRM compound, wherein the IRM compound
is contained in a container separate from the device.
48. The method of claim 47, wherein the applicator device comprises
measuring marks and wherein the method further comprises using the
marks to determine the amount of the IRM compound in the applicator
device.
49. The method of claim 42, further comprising: inserting the
applicator device into the vagina; positioning a distal end of the
applicator device adjacent to the mucosal surface; and applying the
IRM compound to the mucosal surface, wherein the mucosal surface is
on a cervix.
50. The method of claim 42, further comprising positioning a distal
end of the applicator device adjacent to the vaginal part of the
cervix, and applying the IRM compound to the mucosal surface,
wherein the mucosal surface is on the vaginal part of the
cervix.
51. The method of claim 42, wherein the condition associated with
the mucosal surface is cervical intraepithelial neoplasia.
52. The method of claim 42, wherein the applicator device comprises
a hollow tube comprising a distal delivery end and a proximal end,
and a piston slidably received within the tube and wherein the
method comprises moving the piston in the tube to cause dispensing
of the IRM compound via the distal end.
53. The method of claim 52, wherein the applicator device further
comprises a member configured to cause movement of the piston
toward the distal end, and wherein the method comprises moving the
member to cause the movement of the piston.
54. The method of claim 53, further comprising limiting retraction
movement of the member toward the proximal end when the piston is
located adjacent to the distal end.
55. The method of claim 53, wherein the piston is removably coupled
to the member and wherein the method further comprises uncoupling
the member from the piston.
56. The method of claim 53, further comprising sliding the member
in the hollow tube.
57. The method of claim 52, further comprising limiting retraction
movement of the piston toward the proximal end.
58. The method of claim 52, further comprising extending a portion
of the piston from the distal end when the piston is positioned at
its farthest location away from the proximal end.
Description
[0001] This application is a continuation-in-part (CIP) of
co-pending application Ser. No. 09/676,339 filed Sep. 29, 2000,
which is a continuation of application Ser. No. 09/479,578 filed
Jan. 7, 2000 (now U.S. Pat. No. 6,245,776), which claimed priority
to application Ser. No. 60/115,253 filed Jan. 8,1999. This
application also claims the benefit of priority of the provisional
application No. 60/213,420 filed Jun. 22, 2000. In addition, the
disclosure of each of the above mentioned applications is
incorporated herein by reference.
DESCRIPTION OF THE INVENTION
FIELD OF THE INVENTION
[0002] The present invention relates to systems and methods for
treating a condition associated with a mucosal surface, such as the
vaginal part of the cervix. In particular, the systems and methods
may involve an immune response modifier (IRM) compound chosen from
imidazoquinoline amines, imidazopyridine amines, 6,7-fused
cycloalkylimidazopyridine amines, imidazonaphthyridine amines,
oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridged
imidazoquinoline amines, and pharmaceutically acceptable salts
thereof. In one optional embodiment, the invention provides systems
and methods which are particularly advantageous for topical
application to the cervix for treatment of cervical conditions such
as cervical dysplasias including dysplasia associated with human
papillomavirus (HPV).
[0003] The present invention is also directed to medicament
delivery arrangements and methods of use. Some aspects of the
invention are directed to the delivery of a pharmacological agent
to a selected location with minimal delivery to regions surrounding
the selected location. In some optional embodiments the invention
is particularly advantageous for topical delivery of a
pharmacological agent to the uterine cervix.
BACKGROUND OF THE INVENTION
[0004] Many imidazoquinoline amine, imidazopyridine amine,
6,7-fused cycloalkylimidazopyridine amine, 1,2-bridged
imidazoquinoline amine, thiazolo- and oxazolo-quinolinamines and
pyridinamines, imidazonaphthyridine and
tetrahydroimidazonaphthyridine amine compounds have demonstrated
potent immunostimulating, antiviral and antitumor (including
anticancer) activity, and have also been shown to be useful as
vaccine adjuvants to enhance the protective immune system response
to vaccines. These compounds are hereinafter sometimes collectively
referred to as the "IRM" (immune response modifier) compounds of
the invention. An IRM compound may be selected from the group
comprising imidazoquinoline amines, imidazopyridine amines,
6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine
amines, oxazoloquinoline amines, thiazoloquinoline amines
1,2-bridged imidazoquinoline amines, and pharmaceutically
acceptable salts thereof. Methods for preparing such IRMs and
pharmaceutical compositions containing them are disclosed in, for
example, U.S. Pat. Nos. 4,689,338; 5,389,640; 5,268,376; 4,929,624;
5,266,575; 5,352,784; 5,494,916; 5,482,936; 5,346,905; 5,395,937;
5,238,944; 5,525,612; 5,175,296; 5,693,811; 5,741,908; 5,939,090;
6,110,929; 4,988,815; 5,376,076; and PCT Publications WO 99/29693;
WO 00/76505; WO 00/76518; and WO 00/76519. The entire disclosure of
each of these patents and patent applications is incorporated
herein by reference.
[0005] The immunostimulating, antiviral and antitumor activities of
these compounds have been discussed in detail, and certain specific
diseases have been identified as being susceptible to treatment
therewith, including basal cell carcinoma, eczema, essential
thrombocythaemia, hepatitis B, multiple sclerosis, neoplastic
diseases, psoriasis, rheumatoid arthritis, type I herpes simplex,
type II herpes simplex, and warts. One of these IRM compounds,
known as imiquimod, has been commercialized in a topical
formulation, Aldara.TM., for the treatment of anogenital warts
associated with human papillomavirus.
[0006] The mechanism for the antiviral and antitumor activity of
these IRM compounds is thought to be due in substantial part to
enhancement of the immune response due to induction of various
important cytokines (e.g., interferons, interleukins, tumor
necrosis factor, etc.). Such compounds have been shown to stimulate
a rapid release of certain monocyte/macrophage-derived cytokines
and are also capable of stimulating B cells to secrete antibodies
which play an important role in these IRM compounds' antiviral and
antitumor activities. One of the predominant immunostimulating
responses to these compounds is the induction of interferon
(IFN)-.alpha. production, which is believed to be very important in
the acute antiviral and antitumor activities seen. Moreover, up
regulation of cytokines such as, for example, tumor necrosis factor
(TNF), IL-1 and IL-6 also have potentially beneficial activities
and are believed to contribute to the antiviral and antitumor
properties of these compounds.
[0007] Although some of the beneficial effects of IRMs are known,
the ability to provide therapeutic benefit via topical application
of an IRM for treatment of a particular condition at a particular
location may be hindered due to tissue irritation, formulation wash
away, poor permeation or undesired systemic delivery of the
topically applied compound. Accordingly, there is a need for new
methods, formulations, and systems to provide the greatest
therapeutic benefit from this class of compounds.
[0008] Topical administration of a pharmacological agent to a
tissue surface can provide localized therapeutic benefit without
concomitant systemic effects. However, topical application is often
difficult or impossible due to the anatomical location of the
tissue. In some cases, application of the agent to a general
anatomical region that includes or surrounds the target tissue may
be an alternative to direct topical application. But, if the agent
has irritating properties, this alternative disadvantageously
carries with it the possibility of irritating tissues surrounding
the target tissue. In addition, even if the agent is
non-irritating, regional application typically requires use of a
greater volume or concentration of the agent to achieve a
therapeutic result equivalent to that achieved by direct
application to the target tissue.
[0009] The uterine cervix is one example of a target tissue to
which it is difficult to apply a topical agent. Relative to a
standing position, the cervix is typically located at the uppermost
portion of the vaginal cavity. However, while the cervix is located
at the uppermost portion of the vaginal cavity, age, the stage of
the estrous cycle, pregnancy, and other factors cause variability
of the location of the cervix between different women and in the
same woman at different stages of life.
[0010] Certain cervical conditions can be advantageously treated by
topical administration of a pharmacological agent. Cervical
dysplasia is an example of a pathological condition that can be
effectively treated by direct delivery of medication to the surface
of the cervix where the abnormal cells are typically found.
Unfortunately, most currently available applicators for vaginal
drug delivery are inadequate for applying a medication to the
surface of the cervix. And, since cervical dysplasia can lead to
cervical cancer, an applicator that is less than optimal is not an
acceptable option.
[0011] Most presently available vaginal applicators are for
application to the vaginal cavity generally and not for direct
application to the cervix. In general, the length and configuration
of the applicators are insufficient to ensure delivery of an agent
to the uppermost portion of the vaginal cavity. Delivery to the
middle or lower portion of the vagina does not ensure that an agent
will reach the cervical tissue in the upper portion of the vagina.
In addition, with the exception of certain body orientations,
gravity tends to drain agents away from the cervix. Normal
discharge and flow of fluids, both menstrual and non-menstrual,
also drain away from the cervix. Thus, any applicator that is not
capable of repeatedly delivering an appropriate amount of agent to
the uppermost end of the vaginal cavity risks less than optimal
treatment.
[0012] Overcoming the inaccuracy of present vaginal applicators,
when used for cervical delivery of an agent, by delivering an
excess volume or concentration of the medication may be
unacceptable due to the risk of undesired effects to surrounding
tissues. However, delivery of reduced volumes or concentrations to
avoid irritation to surrounding tissue risks the serious
consequences of ineffective treatment.
[0013] Accordingly, there is continuing need for improved delivery
systems and methods for topical application of a pharmacological
agent.
SUMMARY OF THE INVENTION
[0014] One aspect of the invention includes a system for treating a
condition associated with a mucosal surface. The system comprises
an immune response modifier (IRM) compound chosen from
imidazoquinoline amines, imidazopyridine amines, 6,7-fused
cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline
amines, and pharmaceutically acceptable salts thereof. The system
also comprises an applicator device for applying the IRM compound
to the mucosal surface.
[0015] Another aspect of the invention includes a system comprising
an immune response modifier (IRM) compound chosen from
imidazoquinoline amines, imidazopyridine amines, 6,7-fused
cycloalkylimidazopyridine amines, imidazonaphthyridine amines,
oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridged
imidazoquinoline amines, and pharmaceutically acceptable salts
thereof. The system also includes an applicator device for applying
to the mucosal surface the IRM compound.
[0016] For example, the IRM compound may be
1-(2-methylpropyl)-1H-imidazo[- 4,5-c]-quinolin-4-amine, or
4-amino-.alpha.,.alpha.-dimethyl-2-ethoxymethy-
l-1H-imidazo[4,5-c]quinoline-1-ethanol or
2-propyl[1,3]thiazolo[4,5-c]quin- olin-4-amine.
[0017] The system may be used for treating a condition associated
with the mucosal surface on a cervix, optionally, the vaginal part
of the cervix. Exemplary conditions associated with the mucosal
surface include cervical dysphasia and cervical intraepithelial
neoplasia.
[0018] In an exemplary embodiment, the applicator device may
comprise a hollow tube and a piston slidably received within the
tube.
[0019] Yet another aspect of the invention includes a method for
treating a condition associated with a mucosal surface. The method
comprises providing an immune response modifier (IRM) chosen from
imidazoquinoline amines, imidazopyridine amines, 6,7-fused
cycloalkylimidazopyridine amines, imidazonaphthyridine amines,
oxazoloquinoline amines, thiazoloquinolines amines, 1,2-bridged
imidazoquinoline amines, and pharmaceutically acceptable salts
thereof. The method also includes providing an applicator device
for applying to the mucosal surface the IRM compound. In addition,
the method further includes applying the IRM compound to the
mucosal surface with an applicator device.
[0020] The method may involve inserting the applicator device into
the vagina, positioning a distal end of the applicator device
adjacent to the vaginal part of the cervix, and applying the IRM
compound to the vaginal part of the cervix.
[0021] At least some of the embodiments disclosed herein provide
medicament application systems and methods suitable for topical
administration of an agent to a target tissue. The systems and
methods could be advantageous for intravaginal delivery of a
pharmacological formulation. For example, some embodiments provide
effective topical application of a pharmacological agent to the
cervix for treatment or prevention of conditions including, for
example, cervical dysplasia.
[0022] Additional aspects will be set forth in part in the
description which follows, and in part will be obvious from the
description, or may be learned by practice of the invention. It
will be appreciated that at several locations throughout the
specification, guidance is provided through lists of examples. In
each instance, the recited list serves only as a representative
group; it is not meant that the list is exclusive.
[0023] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive.
[0024] The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate several
embodiments of the invention and together with the description,
serve to explain the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1A is a top view of a treatment system including an
applicator device and a container containing an IRM compound
packaged together;
[0026] FIG. 1B is a top view of a treatment system with several
pre-filled cartridges of the IRM compound;
[0027] FIG. 2 is an exploded perspective view of components of a
intravaginal delivery device;
[0028] FIG. 3 is a proximal end-on view of an exemplary
intravaginal delivery device;
[0029] FIG. 4 is a longitudinal cross-section view of an exemplary
intravaginal delivery device taken through line 4-4 with the
pushing member retracted proximally;
[0030] FIG. 5 is a longitudinal cross-section of an exemplary
intravaginal delivery device with the pushing member advanced
distally;
[0031] FIG. 6 is a close-up view of the proximal end of the
intravaginal delivery device illustrated in FIG. 5;
[0032] FIG. 7 is a close-up view of the distal end of the
intravaginal delivery device illustrated in FIG. 5;
[0033] FIG. 8 is an exploded perspective view of components of an
optional alternative embodiment of an intravaginal delivery device
according to the invention;
[0034] FIG. 9 is a longitudinal cross-section view of the
intravaginal delivery device of FIG. 8 with the pushing member
retracted proximally;
[0035] FIG. 10 is a longitudinal cross-section view of the
intravaginal delivery device of FIG. 8 with the pushing member
distally advanced;
[0036] FIG. 11 is a close-up view of the distal end of the
intravaginal delivery device illustrated in FIG. 10;
[0037] FIG. 12 is a close-up view of the proximal end of the drug
delivery device of FIG. 10;
[0038] FIG. 13 is a perspective view of an alternative proximal end
for an intravaginal delivery device;
[0039] FIG. 14 is a perspective view of another alternative
proximal end for an intravaginal delivery device;
[0040] FIG. 15 is a longitudinal cross section view of an exemplary
intravaginal delivery device pre-filled with a formulation;
[0041] FIG. 16 is a graph comparing imiquimod transport across
hairless mouse skin from three pharmaceutical formulations each
containing 5% imiquimod;
[0042] FIG. 17 is a graph comparing imiquimod transport across
hairless mouse skin from four pharmaceutical formulations
containing varied concentrations of imiquimod and isostearic
acid;
[0043] FIG. 18 is a graph comparing mean serum imiquimod
concentration in rats after a single intravaginal dose of
Formulation A or Formulation B; and
[0044] FIGS. 19A and 19B provide bar graphs of the pharmacokinetic
comparison of imiquimod in rats after vaginal dosing of Formulation
A or Formulation B.
DESCRIPTION OF THE EMBODIMENTS
[0045] Reference will now be made in detail to some exemplary
embodiments of the invention, examples of which are illustrated in
the accompanying drawings. Wherever possible, the same reference
numbers will be used throughout the drawings to refer to the same
or like parts.
[0046] The present invention may be, in part, directed to
medicament applicators and methods for delivery of a
pharmacological agent to a selected location. In some optional
embodiments, the dispensers may be particularly suited for
intravaginal delivery of a pharmacological agent. In optional
embodiments, the disclosed dispensers may provide for topical
application of the pharmacological agent to an itravaginal
location, such as the cervix, for treatment of conditions
including, for example, cervical dysplasia. In general, the
dispensers may be used to deliver a pharmacological agent in a
frequency and amount necessary to obtain a desired treatment
result.
[0047] Throughout the specification, guidance may be provided
through lists of examples. In each instance, the recited list
serves only as a representative group. It is not meant, however,
that the list is exclusive.
[0048] As used herein the term "pharmacological agent" includes any
agent or combination of agents that can be used to diagnose, treat,
cure, ameliorate, prevent or otherwise manage a condition of a
patient. The term "condition" refers to any infectious,
non-infectious, pathological, physiological, biochemical or other
state of a patient's body that can be treated according to the
invention.
[0049] Throughout the specification, unless otherwise stated, the
terms "proximal" and "distal" are relative terms. The term
"proximal" refers to a location nearest the user (for example, the
user's hand that is operating the dispenser) and the term "distal"
refers to a location farthest from the user. Thus, in a typical
embodiment, the proximal end of the delivery device will be nearest
to or grasped by the hand of the user and the distal end of the
instrument will be located nearest to the tissue site at which the
agent will be applied.
[0050] As used herein, a "mucosal associated condition" means an
inflammatory, infectious, neoplastic or other condition that
involves a mucosal surface or that is in sufficient proximity to a
mucosal surface to be affected by a therapeutic or prophylactic
agent topically applied to the mucosal surface.
[0051] Unless stated otherwise, the term "treat", and derivatives
such as "treatment", "treating", etc., are used herein generically
to indicate administration of a pharmacological agent for any
reason to a patient and is not intended to distinguish a
preventative, therapeutic, diagnostic, palliative or other
procedure. The term "therapeutically effective amount" means the
amount of an agent administered to provide a desired therapeutic
effect, such as cytokine induction, antiviral or antitumor
activity. A "therapeutically effective amount" includes a single
dose of an agent used in a course of therapy over a period of time
to achieve a desired therapeutic effect.
[0052] Some optional embodiments of devices and methods of the
invention may be advantageous for delivering an agent to the
uterine cervix through the vagina to treat (i.e., prevent,
diagnose, ameliorate, etc.) a cervical condition. In certain
optional embodiments, the dispensers of the invention may be
particularly advantageous for delivering an immune response
modifier (IRM) to the cervix for a cervical condition. Examples of
immune response modifiers suitable for the invention include those
disclosed in, for example, U.S. Pat. Nos. 4,689,338; 5,389,640;
5,268,376; 4,929,624; 5,266,575; 5,352,784; 5,494,916; 5,482,936;
5,346,905; 5,395,937; 5,238,944; 5,525,612; 5,175,296; 5,693,811;
5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; and PCT
Publications WO 99/29693; WO 00/76505; WO 00/76518; and WO
00/76519. The entire disclosure of each of these patents and patent
applications is incorporated herein by reference. Some optional
IRMs suitable for the invention include
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod)
and compounds and formulations such as disclosed in co-pending U.S.
Ser. No. 09/479,578 and PCT Publication WO 00/06577. The entire
disclosure of each of these patents and applications are
incorporated herein by reference.
[0053] In general, the "user" of the disclosed dispensers (also
referred to herein as applicators) include health care providers
who apply the agent to a patient or the patient themselves for
self-administration of the agent.
[0054] In some optional embodiments, the dispensers can provide for
accurate delivery of a predetermined amount of the pharmacological
agent to a selected location with reduced likelihood of inadvertent
delivery to surrounding tissues. Typically, a predetermined amount
is a therapeutically effective amount for a single dose. Accurate
application of the agent to a selected location can advantageously
reduce the amount of the agent necessary to achieve a therapeutic
result while minimizing the possibility of irritation to tissues
adjacent to the selected site of application.
[0055] In the case of intravaginal applications, the dispenser may
reduce undesired side effects caused by an agent. For example, when
delivery of an agent is desired only to the cervix, such as for a
cervical condition, delivery of the agent to locations other than
the upper portion of the vaginal cavity can unnecessarily expose
the lower vaginal cavity and other surrounding tissues to the
agent. This not only exposes non-targeted tissues to the agent, but
also to potential tissue irritation that can be caused by the agent
or other components in a pharmacological formulation.
[0056] The intravaginal dispensers may optionally provide for
accurate delivery of a volume of an agent (or formulation thereof
that is smaller than volumes typically used for administering other
intravaginal medications. In some optional embodiments, the
intravaginal dispensers may provide for delivery of about 0.01-10
ml, in other optional embodiments about 0.5 to 4 ml and typically
about 1.0 ml.
[0057] The dispensers can be pre-filled with a therapeutically
effective amount of a particular agent or filled by the user at the
time of administration. In the latter situation, the dispensers can
be configured to receive the agent from a source of the agent
(e.g., aluminum tube, plastic tube, etc.) that can mount to the
dispenser for filling. Some optional dispensers may typically
provide for a fixed maximum volume of the agent. Alternatively, or
additionally, the dispensers can have incremental markings for
filling with amounts less than the maximum volume of the
dispenser.
[0058] In an optional embodiment, a pre-filled dispenser may be
provided to eliminate the possibility of filling the delivery
device with an incorrect amount of the agent. In one optional
embodiment, the dispensers may be pre-filled with a formulation
including an amount of immune response modifier (IRM) compound for
a single treatment. The dispenser, whether pre-filled or not, may
be packaged in an outer wrap, such as a foil wrap, which maintains
sterility and can act as a moisture barrier.
[0059] The dispenser may be formed through known methods including
injection molding processes that form a plastic applicator from
polymer materials such as high density polyethylene, low density
polyethylene, linear low density polyethylene, or
polypropylene.
[0060] FIG. 1A shows a treatment system 400 including an applicator
device 10 and a container 401 of a formulation packaged together in
packaging 402. The device 10 could be configured to be filled with
formulation contained in the container 401 by placing them in flow
communication with one another.
[0061] FIG. 1B shows a treatment system 400 where the formulation
is a contained in pre-filled cartridges 401a-401d capable of being
loaded in the dispensing device 10 one at a time.
[0062] FIGS. 2 and 4 show an optional embodiment of an intravaginal
delivery device 10 according to the invention. As illustrated,
device 10 may include a distal end 1, a proximal end 2 and a
longitudinal axis X-X passing therethrough. FIG. 2 is an exploded
perspective view of components of device 10 including elongate tube
3 having a delivery end 4, an operating end 5 and a lumen 6 passing
therethrough. Operating end 5 can include handle arrangement 7 such
as opposing flanges 8a and 8b for holding device 10 during use. In
some embodiments, elongate tube 3 may have a length dimension of
about 6 cm to about 24 cm, typically, about 10 cm to about 18
cm.
[0063] Pushing member 11 may be slidably received within lumen 6 of
elongate tube 3 and may include a pushing end 12 and a driving end
13. Pushing end 12 may include a platform 14 for placement of a
user's thumb or finger to distally advance pushing member 11 within
lumen 6. Piston 15 may be mountable to driving end 13 of pushing
member 11 and may have a distal tip 16 opposite end 17. A cap 18
may be removably mounted to the distal end 4 of device 10 using
known arrangements such as threads or friction fit, for
example.
[0064] FIG. 3 is a distal end view of device 10 and FIG. 4 is a
longitudinal cross-section of device 10 taken through line 4-4 of
FIG. 3. In FIG. 4, piston 15 is shown mounted to the driving end 13
of pushing member 11 and located at a first position that provides
a chamber 20 for containing or receiving a predetermined amount of
a pharmacological agent.
[0065] In some optional embodiments, chamber 20 will provide for a
volume of a pharmacological agent of about 5 ml to 0.1 ml,
typically about 2 ml to 0.5 ml and optionally about 1.0 ml. In an
optional embodiment, the driving end 13 of pushing member 11 may be
removably nested into bore 19 of piston 15. Thus, in this optional
embodiment, if pushing member 11 is retracted proximally the
driving end 13 of pushing member 11 may pull free from bore 19 and
piston 15 will not be retracted proximally with pushing member 11.
This optional aspect may prevent aspiration of an agent after
expulsion of the agent from chamber 20 and may also prevent
aspiration of tissue into the delivery end 4 of tube 3 if pushing
member 11 is retracted proximally.
[0066] In addition, in some optional embodiments, lumen 6 may
include a stop 40, such as protuberance 41 which may protrude into
lumen 6 to prevent proximal retraction of piston 15. Whether device
10 is pre-filled with an agent or filled by the user at the time of
use, the position of stop 40 may provide a fixed maximum volume of
chamber 20 to contain a predetermined amount of an agent. This stop
can advantageously prevent a user from exceeding a particular dose
of an agent if the device 10 is filled with the agent by the user
prior to use.
[0067] Cap 18 is shown mounted at delivery end 4. Cap 18 can be
friction fit to the external surface 35 of delivery end 4.
Alternatively, or in addition, cap 18 can include a stem 18a which
is friction fit into the distal end 1 of lumen 6. Distal end 1 of
lumen 6 could alternatively have female threads (not shown) which
can threadedly receive male threads (not shown) which can be
present on the exterior surface of stem 18a. Cap 18 can also
include a tab 18b which provides for easier gripping of cap 18 when
removing from tube 3.
[0068] Cap 18, could optionally include texturing, such as knurls,
ridges, etc., to facilitate removal. Markings, such as a raised
arrow, can optionally be added to the cap 18 to indicate the
direction to unscrew for removal to contribute to the ease of use
of the device.
[0069] In FIG. 5, pushing member 11 has been distally advanced to a
position that would cause expulsion of a pharmacological agent from
chamber 20. In the optional illustrated embodiment, when pushing
member 11 is distally advanced, the distal tip 16 of piston 15
protrudes beyond the distal end 4 of elongate tube 3. In addition,
distal tip 16 can be convex shaped or domed outwardly to further
ensure complete expulsion of an agent from chamber 20.
[0070] FIG. 6 is a close-up view of an optional embodiment of a
proximal end 2 of delivery device 10. In the illustrated
embodiment, platform 14 of pushing member 11 forms a shoulder 25 at
the junction with the pushing end 12 of pushing member 11. When
pushing member 11 is distally advanced within lumen 6, shoulder 25
may affirmatively stop by abutting against the operating end 5 of
elongate tube 3 which may indicate complete delivery of a
pharmacological agent from chamber 20 of device 10.
[0071] FIG. 7 is a close-up of an optional embodiment of a distal
end 1 of delivery device 10. As illustrated, the distal end of
chamber 20 of lumen 6 may include a converging taper 30. The
external surface 31 of piston 15 may also have a converging taper
32 that may extend to distal tip 16. The corresponding converging
tapers 30 and 32 may facilitate complete delivery of a
pharmacological agent contained within chamber 20 when pushing
member 11 is advanced distally. Piston 15 also may include a
sealing ring 33 such as circumferential flange 34 which may fit
snugly against lumen 6 to assure that a significant portion,
preferably all, of the pharmacological agent is removed from lumen
6 as piston 15 is advanced distally. Thus, lumen 6 may have at
least two different diameters, a lumen diameter L.sub.D and a
delivery diameter D.sub.D. A typical lumen diameter L.sub.D may be
about 5 to about 15 mm and a typical delivery diameter may be about
2 to about 10 mm. In an example of a delivery device 10 with a
maximum chamber volume of about 1 ml, the length of elongate tube 3
can be about 12-20 cm, L.sub.D can be about 10 mm and D.sub.D can
be about 6 mm.
[0072] The external surface 35 of distal end 1 of elongate tube 3
may also have a converging taper 36 to facilitate insertion of the
distal end 1 of device 10 into the vagina. After expulsion of an
agent from chamber 20, converging taper 36 may also ensure that all
of the dispensed agent remains at the site of delivery. For
example, when delivering an agent to the cervix, the vaginal wall
surrounding the distal end 1 can drape closely around the distal
tip 1 to wipe off any of the agent remaining on the tip as compared
to applicators having a square-ended (i.e., right cylinder) tip or
square-ended tip with rounded corners.
[0073] In use, the user can place the thumb and middle finger
proximal to flanges 8a and 8b of handle arrangement 7 to hold
device 10 at a selected location while the user's index finger is
placed on platform 14 to distally advance pushing member 11 such
that distal tip 16 of piston 15 expels the pharmacological agent
from chamber 20 to deliver the agent to an intravaginal location,
such as the mucosal surface of the cervix.
[0074] FIG. 8 is an exploded perspective view of the components of
an optional alternative embodiment of an intravaginal delivery
device 100. As illustrated, delivery device 100 may include a
proximal end 101, a distal end 102 and a longitudinal axis X-X
passing therethrough. Elongate tube 103 may have a delivery end
104, an operating end 105 and a lumen 106 passing therethrough. A
cap 108 can be slidably or threadedly mounted to distal end 102 of
device 100 as described above for cap 18 of device 10.
[0075] The operating end 105 of elongate tube 103 may include a
handle arrangement 107 including tip 118 to facilitate handling of
device 100 during use. In the optional illustrated embodiment, lip
118 may extend continuously around the circumference of the
operating end 105. However, it will be appreciated that lip 118
need not be continuous and, in other embodiments, lip 118 can be
omitted.
[0076] Pushing member 111 can be slidably received into lumen 106
and may include a pushing end 113, driving end 114 and a shaft 115
extending therebetween. The pushing end 113 can include a platform
116 for placement of a user's thumb or finger to distally advance
pushing member 111 during use. Platform 116 can have a concave
surface 117 to better conform to the tip of a user's finger or
thumb. Piston 120 can be fixedly mounted to driving end 114 of
pushing member 111 or driving end 114 can be removably nested into
bore 122a at end 122. Piston 120 may include a distal tip 121. In
some embodiments, distal tip 121 can be convexed distally or domed
outwardly to further ensure complete expulsion of the agent.
[0077] FIG. 9 is a longitudinal cross-section view of device 100
showing chamber 130 for containing or receiving a predetermined
amount of a pharmacological agent when pushing member 111 is
proximally retracted within lumen 106 of elongate tube 103. FIG. 10
illustrates that when pushing member 111 is distally advanced, the
distal tip 121 of piston 120 may extend beyond the distal end 102
of elongate tube 103.
[0078] FIG. 11 is a close-up view of the distal end 102 of the view
of device 100 illustrating that chamber 130 may include a
converging taper 131 at the distal end 102 of lumen 106. The
optional converging taper 131 of chamber 130 may be configured to
match with a corresponding converging taper 132 in a distal portion
of piston 120. The converging surfaces 131 and 132 may facilitate
complete expulsion of a pharmacological agent contained within
chamber 130.
[0079] Piston 120 also can include a sealing ring 133 such as
circumferential flange 134 which may fit snugly against lumen 106
to ensure complete expulsion of the agent as piston 120 is advanced
distally. The external surface 135 of the distal end 102 of
elongate tube 103 may be tapered 136 for reasons discussed
above.
[0080] As with device 10, in some optional embodiments, lumen 106
can include a stop 140 such as protuberance 141 which may protrude
into lumen 106 to prevent proximal retraction of piston 120.
Whether device 100 is pre-filled with an agent or filled by the
user at the time of use, the position of stop 140 may provide a
fixed maximum volume of chamber 130 to contain a predetermined
amount of an agent.
[0081] FIG. 12 is a close-up view of an optional embodiment of a
proximal end 101 of device 100 of FIG. 10 illustrating that when
pushing member 111 is fully advanced distally, platform 116 of
pushing end 113 may be recessed within the operating end 105 of
elongate tube 103. This feature reduces the likelihood that some or
all of the pharmacological agent dispensed from chamber 130 will be
aspirated back into the chamber 130 after delivery by inadvertent
proximal retraction of pushing member 111 after the pharmacological
agent has been expelled.
[0082] Also, in some optional embodiments, the operating end 105 of
elongate tube 103 and the pushing end 113 of pushing member 111 can
be constructed to provide audible and/or tactile feedback to the
user when expulsion of the agent is complete. According to this
optional embodiment, the operating end 105 of lumen 106 can include
a projecting surface 145 such as ridge 146 at a location proximal
to platform 116 when pushing member 111 is fully advanced distally.
Platform 116 may be sized such that as platform 116 is pushed
distally past ridge 146 a click can be heard and the movement past
ridge 146 creates a tactile click to inform the user of complete
expulsion of the agent. Ridge 146 may also act to "lock" pushing
member 111 in the distally advanced portion and may prevent
proximal retraction of pushing member 111.
[0083] It will be appreciated that in addition to lumen diameter
L.sub.D and delivery diameter D.sub.D, lumen 106 also has a
diameter P.sub.O at operating end 105. Lumen 106 thus may have a
taper 150 extending between diameter P.sub.O and L.sub.D. In an
example of a delivery device 100 having a maximum chamber volume of
about 1 ml, the length of elongate tube 103 is about 15 to about 17
cm, L.sub.D is about 11-15 mm and D.sub.D is about 7-12 mm.
[0084] In an optional alternative embodiment, the region of
elongate tube 103, shown as having parallel sides (see e.g., FIG.
9) extending from the proximal end to the distal end, can
alternatively have a converging taper from the proximal end to
distal end. This may advantageously provide for filling the
delivery device with a pharmacological agent from the proximal end
of elongate tube rather than the distal end. That is, without a
taper as just described, attempting to push the piston into place
distally along a non-tapered tube, after loading the formulation
could be hindered by air that can be trapped between the piston
seal and wall of the lumen. By tapering the elongate lumen as
described, a gap may be maintained between the piston and the wall
that may allow for air to escape as the piston is advanced
distally. Such a taper could occur gradually over the length of the
elongate tube, or there can be an abrupt taper near where the
piston is to be placed for setting a predetermined volume at the
distal end of the elongate tube.
[0085] FIG. 13 illustrates another optional embodiment of the
operating end of an elongate tube suitable for an intravaginal
delivery device 10, 100 according to the invention. According to
this embodiment, the operating end 201 of elongate tube 200 may
include a configuration which provides an indicator 203 of the
orientation of device 200 around longitudinal axis X-X. Thus, in
the embodiment of FIG. 13, opposing sides 204 and 205 are linear
giving the operating end an oval cross-sectional configuration. In
this embodiment, lip 206 may extend around the perimeter of the
operating end 201. It will be appreciated, however, that the lip
may be completely absent or discontinuous around the perimeter.
[0086] FIG. 14 illustrates another optional embodiment of the
operating end of an elongate tube 300 suitable for an intravaginal
delivery device according to the invention. In this embodiment, the
operating end 301 of elongate tube 300 may include a configuration
which also provides an indicator 303 for the orientation of device
300 around longitudinal axis X-X. Operating end 301 may include
corners 304a-304d. The walls 305a-305d of operating end 301 between
corners 304a-304d form a converging taper moving from operating end
diameter P.sub.O to lumen diameter L.sub.D. In the illustrated
embodiment, the proximal aspect of each of walls 305a-305d may
include a concave void 306a-306d extending distally into the
surface of the walls 305a-305d, respectively. In addition, the
platform 350 of the pushing member (not visible) may have a
distally concave surface 351 and four corners 352a-352d configured
to mate with the corners 304a-304d of walls 305a-305d. A lip or
flanges (not shown in this embodiment) may or may not be present
around the proximal edge of the operating end 301 as described for
device 10 and 110.
[0087] The intravaginal delivery device may provide for accurate
delivery of a volume of an agent that is less than the volumes
typically used for other vaginal medications. Many vaginal
applicators are designed to deliver about 5 ml of an agent and the
application is not localized but rather it is delivered to the
vaginal cavity in general.
[0088] In optional embodiments, such as that shown in FIG. 15, the
applicator 10 may be pre-filled with a product P to eliminate the
possibility of incorrect filling of the applicator. However, if the
device is to be filled at the time of use, structure such as stops
in the device, may set a maximum volume that can help to eliminate
the chance of exceeding a predetermined dosage.
[0089] Any of the above-mentioned applicators may have a length
sufficient to allow the distal end of the applicator to be located
at, or very close to, the cervix while a portion of the applicator
passes through the vagina and proximal end is positioned outside
the vagina. The length of the applicator may be configured to
assure delivery of an IRM compound to the uppermost end of the
vaginal cavity while the proximal end is outside the vagina. For
example, the length of the applicator may be sufficient to
accommodate anatomical variability among women, so that treatment
of women with longer vaginal cavities will not be compromised.
[0090] In use, the intravaginal delivery device could be held at
the proximal end between the thumb and middle finger and the
platform of the pushing member depressed (i.e., advanced distally)
with the index finger to deliver the agent.
[0091] In optional embodiments, the pushing member may be
pre-positioned within the lumen of the elongate tube, ready for
use. If the delivery device is to be filled prior to use, the
distal end of the elongate tube can include female threads to fit
with male threads of a medicament source, such as an aluminum tube,
to provide a threaded seal while transferring the medicament from
the source to the chamber of the delivery device.
[0092] The dispensers can be packaged in an overwrap pouch that
provides for asepsis as well as a moisture barrier. The overwrap
pouch can be made from any material suitable for protecting the
pharmacological agent such as foils or foil laminates (e.g., a
metal and plastic layer). In some embodiments, the overwrap can
protect against moisture loss from the formulation or oxidation of
the formulation.
[0093] The applicator device could be part of a system or component
used in a method involving additional parts or components. In one
optional embodiment, the systems and methods include an immune
response modifier (IRM) compound to treat or prevent conditions
associated with a mucosal surface. For example, the IRM compound
could be in a formulation which can be applied to the mucosal
surface of the cervix to treat cervical conditions including
cervical dysplasias such as cervical intraepithelial neoplasia.
[0094] In some optional embodiments, the certain formulations may
be used for application of an IRM compound to a mucosal surface. In
some optional embodiments, the formulations can enhance therapeutic
efficiency of the IRM by facilitating mucosal permeation or
increasing the duration of contact of the IRM with the mucosal
surface. The pharmaceutical formulation may contain a preservative
system that renders the formulations suitable for packaging in
multiple-use containers.
[0095] IRM Compounds
[0096] As noted above, many of the imidazoquinoline amine,
imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine,
1,2-bridged imidazoquinoline amine, thiazolo- and
oxazolo-quinolinamines and pyridinamines, imidazonaphthyridine and
tetrahydroimidazonaphthyridine amine IRM compounds of the present
invention have demonstrated significant immunomodulating activity.
Some optional immune response modifier compounds of the invention
include 1H-imidazo[4,5-c]quinolin-4-a- mines defined by one of
Formulas I-V below: 1
[0097] wherein
[0098] R.sub.11 is selected from the group consisting of alkyl of
one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms,
acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to
four carbon atoms or benzoyloxy, and the alkyl moiety contains one
to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, said benzyl,
(phenyl)ethyl or phenyl substituent being optionally substituted on
the benzene ring by one or two moieties independently selected from
the group consisting of alkyl of one to four carbon atoms, alkoxy
of one to four carbon atoms and halogen, with the proviso that if
said benzene ring is substituted by two of said moieties, then said
moieties together contain no more than six carbon atoms;
[0099] R.sub.21 is selected from the group consisting of hydrogen,
alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and
phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being
optionally substituted on the benzene ring by one or two moieties
independently selected from the group consisting of alkyl of one to
four carbon atoms, alkoxy of one to four carbon atoms and halogen,
with the proviso that when the benzene ring is substituted by two
of said moieties, then the moieties together contain no more than
six carbon atoms; and
[0100] each R.sub.1 is independently selected from the group
consisting of alkoxy of one to four carbon atoms, halogen, and
alkyl of one to four carbon atoms, and n is an integer from 0 to 2,
with the proviso that if n is 2, then said R.sub.1 groups together
contain no more than six carbon atoms; 2
[0101] wherein
[0102] R.sub.12 is selected from the group consisting of straight
chain or branched chain alkenyl containing two to ten carbon atoms
and substituted straight chain or branched chain alkenyl containing
two to ten carbon atoms, wherein the substituent is selected from
the group consisting of straight chain or branched chain alkyl
containing one to four carbon atoms and cycloalkyl containing three
to six carbon atoms; and cycloalkyl containing three to six carbon
atoms substituted by straight chain or branched chain alkyl
containing one to four carbon atoms; and
[0103] R.sub.22 is selected from the group consisting of hydrogen,
straight chain or branched alkyl containing one to eight carbon
atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl
or phenyl substituent being optionally substituted on the benzene
ring by one or two moieties independently selected from the group
consisting of straight chain or branched chain alkyl containing one
to four carbon atoms, straight chain or branched chain alkoxy
containing one to four carbon atoms, and halogen, with the proviso
that when the benzene ring is substituted by two such moieties,
then the moieties together contain no more than six carbon atoms;
and
[0104] each R.sub.2 is independently selected from the group
consisting of straight chain or branched chain alkoxy containing
one to four carbon atoms, halogen, and straight chain or branched
chain alkyl containing one to four carbon atoms, and n is an
integer from zero to 2, with the proviso that if n is 2, then said
R.sub.2 groups together contain no more than six carbon atoms;
3
[0105] wherein
[0106] R.sub.23 is selected from the group consisting of hydrogen,
straight chain or branched chain alkyl of one to eight carbon
atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl
or phenyl substituent being optionally substituted on the benzene
ring by one or two moieties independently selected from the group
consisting of straight chain or branched chain alkyl of one to four
carbon atoms, straight chain or branched chain alkoxy of one to
four carbon atoms, and halogen, with the proviso that when the
benzene ring is substituted by two such moieties, then the moieties
together contain no more than six carbon atoms; and
[0107] each R.sub.3 is independently selected from the group
consisting of straight chain or branched chain alkoxy of one to
four carbon atoms, halogen, and straight chain or branched chain
alkyl of one to four carbon atoms, and n is an integer from zero to
2, with the proviso that if n is 2, then said R.sub.3 groups
together contain no more than six carbon atoms; 4
[0108] wherein
[0109] R.sub.14 is --CHR.sub.xR.sub.y wherein R.sub.y is hydrogen
or a carbon-carbon bond, with the proviso that when R.sub.y is
hydrogen R.sub.x is alkoxy of one to four carbon atoms,
hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten
carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy
moiety contains one to four carbon atoms and the alkyl moiety
contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with
the further proviso that when R.sub.y is a carbon-carbon bond
R.sub.y and R.sub.x together form a tetrahydrofuranyl group
optionally substituted with one or more substituents independently
selected from the group consisting of hydroxy and hydroxyalkyl of
one to four carbon atoms;
[0110] R.sub.24 is selected from the group consisting of hydrogen,
alkyl of one to four carbon atoms, phenyl, and substituted phenyl
wherein the substituent is selected from the group consisting of
alkyl of one to four carbon atoms, alkoxy of one to four carbon
atoms, and halogen; and
[0111] R.sub.4 is selected from the group consisting of hydrogen,
straight chain or branched chain alkoxy containing one to four
carbon atoms, halogen, and straight chain or branched chain alkyl
containing one to four carbon atoms; 5
[0112] wherein
[0113] R.sub.15 is selected from the group consisting of: hydrogen;
straight chain or branched chain alkyl containing one to ten carbon
atoms and substituted straight chain or branched chain alkyl
containing one to ten carbon atoms, wherein the substituent is
selected from the group consisting of cycloalkyl containing three
to six carbon atoms and cycloalkyl containing three to six carbon
atoms substituted by straight chain or branched chain alkyl
containing one to four carbon atoms; straight chain or branched
chain alkenyl containing two to ten carbon atoms and substituted
straight chain or branched chain alkenyl containing two to ten
carbon atoms, wherein the substituent is selected from the group
consisting of cycloalkyl containing three to six carbon atoms and
cycloalkyl containing three to six carbon atoms substituted by
straight chain or branched chain alkyl containing one to four
carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl
wherein the alkoxy moiety contains one to four carbon atoms and the
alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein
the acyloxy moiety is alkanoyloxy of two to four carbon atoms or
benzoyloxy, and the alkyl moiety contains one to six carbon atoms;
benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or
phenyl substituent being optionally substituted on the benzene ring
by one or two moieties independently selected from the group
consisting of alkyl of one to four carbon atoms, alkoxy of one to
four carbon atoms, and halogen, with the proviso that when said
benzene ring is substituted by two of said moieties, then the
moieties together contain no more than six carbon atoms; 6
[0114] wherein
[0115] R.sub.S and R.sub.T are independently selected from the
group consisting of hydrogen, alkyl of one to four carbon atoms,
phenyl, and substituted phenyl wherein the substituent is selected
from the group consisting of alkyl of one to four carbon atoms,
alkoxy of one to four carbon atoms, and halogen;
[0116] X is selected from the group consisting of alkoxy containing
one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety
contains one to four carbon atoms and the alkyl moiety contains one
to four carbon atoms, hydroxyalkyl of one to four carbon atoms,
haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl
group contains one to four carbon atoms, amino, substituted amino
wherein the substituent is alkyl or hydroxyalkyl of one to four
carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino,
alkylthio of one to four carbon atoms; and
[0117] R.sub.5 is selected from the group consisting of hydrogen,
straight chain or branched chain alkoxy containing one to four
carbon atoms, halogen, and straight chain or branched chain alkyl
containing one to four carbon atoms;
[0118] or a pharmaceutically acceptable salt of any of the
foregoing.
[0119] Preferred 6,7 fused cycloalkylimidazopyridine amine IRM
compounds are defined by Formula VI below: 7
[0120] wherein
[0121] m is 1, 2, or 3;
[0122] R.sub.16 is selected from the group consisting of hydrogen;
cyclic alkyl of three, four, or five carbon atoms; straight chain
or branched chain alkyl containing one to ten carbon atoms and
substituted straight chain or branched chain alkyl containing one
to ten carbon atoms, wherein the substituent is selected from the
group consisting of cycloalkyl containing three to six carbon atoms
and cycloalkyl containing three to six carbon atoms substituted by
straight chain or branched chain alkyl containing one to four
carbon atoms; fluoro- or chloroalkyl containing from one to ten
carbon atoms and one or more fluorine or chlorine atoms; straight
chain or branched chain alkenyl containing two to ten carbon atoms
and substituted straight chain or branched chain alkenyl containing
two to ten carbon atoms, wherein the substituent is selected from
the group consisting of cycloalkyl containing three to six carbon
atoms and cycloalkyl containing three to six carbon atoms
substituted by straight chain or branched chain alkyl containing
one to four carbon atoms; hydroxyalkyl of one to six carbon atoms;
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to six carbon atoms;
acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to
four carbon atoms or benzoyloxy, and the alkyl moiety contains one
to six carbon atoms, with the proviso that any such alkyl,
substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl,
alkoxyalkyl, or acyloxyalkyl group does not have a fully carbon
substituted carbon atom bonded directly to the nitrogen atom;
benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or
phenyl substituent being optionally substituted on the benzene ring
by one or two moieties independently selected from the group
consisting of alkyl of one to four carbon atoms, alkoxy of one to
four carbon atoms, and halogen, with the proviso that when said
benzene ring is substituted by two of said moieties, then the
moieties together contain no more than six carbon atoms;
[0123] and
--CHR.sub.xR.sub.y
[0124] wherein
[0125] R.sub.y is hydrogen or a carbon-carbon bond, with the
proviso that when R.sub.y is hydrogen R.sub.x is alkoxy of one to
four carbon atoms, hydroxyalkoxy of one to four carbon atoms,
1-alkynyl of two to ten carbon atoms, tetrahydropyranyl,
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to four carbon atoms, 2-,
3-, or 4-pyridyl, and with the further proviso that when R.sub.y is
a carbon-carbon bond R.sub.y and R.sub.x together form a
tetrahydrofuranyl group optionally substituted with one or more
substituents independently selected from the group consisting of
hydroxy and hydroxyalkyl of one to four carbon atoms,
[0126] R.sub.26 is selected from the group consisting of hydrogen,
straight chain or branched chain alkyl containing one to eight
carbon atoms, straight chain or branched chain hydroxyalkyl
containing one to six carbon atoms, morpholinoalkyl, benzyl,
(phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl
substituent being optionally substituted on the benzene ring by a
moiety selected from the group consisting of methyl, methoxy, and
halogen; and
[0127] --C(R.sub.S)(R.sub.T)(X) wherein R.sub.S and R.sub.T are
independently selected from the group consisting of hydrogen, alkyl
of one to four carbon atoms, phenyl, and substituted phenyl wherein
the substituent is selected from the group consisting of alkyl of
one to four carbon atoms, alkoxy of one to four carbon atoms, and
halogen;
[0128] X is selected from the group consisting of alkoxy containing
one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety
contains one to four carbon atoms and the alkyl moiety contains one
to four carbon atoms, haloalkyl of one to four carbon atoms,
alkylamido wherein the alkyl group contains one to four carbon
atoms, amino, substituted amino wherein the substituent is alkyl or
hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one
to four carbon atoms, and morpholinoalkyl wherein the alkyl moiety
contains one to four carbon atoms, and
[0129] R.sub.6 is selected from the group consisting of hydrogen,
fluoro, chloro, straight chain or branched chain alkyl containing
one to four carbon atoms, and straight chain or branched chain
fluoro- or chloroalkyl containing one to four carbon atoms and at
least one fluorine or chlorine atom;
[0130] and pharmaceutically acceptable salts thereof.
[0131] Preferred imidazopyridine amine IRM compounds are defined by
Formula VII below: 8
[0132] wherein
[0133] R.sub.17 is selected from the group consisting of hydrogen;
--CH.sub.2R.sub.W wherein R.sub.W is selected from the group
consisting of straight chain, branched chain, or cyclic alkyl
containing one to ten carbon atoms, straight chain or branched
chain alkenyl containing two to ten carbon atoms, straight chain or
branched chain hydroxyalkyl containing one to six carbon atoms,
alkoxyalkyl wherein the alkoxy moiety contains one to four carbon
atoms and the alkyl moiety contains one to six carbon atoms, and
phenylethyl; and --CH.dbd.CR.sub.ZR.sub.Z wherein each R.sub.Z is
independently straight chain, branched chain, or cyclic alkyl of
one to six carbon atoms;
[0134] R.sub.27 is selected from the group consisting of hydrogen,
straight chain or branched chain alkyl containing one to eight
carbon atoms, straight chain or branched chain hydroxyalkyl
containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy
moiety contains one to four carbon atoms and the alkyl moiety
contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl,
the benzyl, (phenyl)ethyl or phenyl substituent being optionally
substituted on the benzene ring by a moiety selected from the group
consisting of methyl, methoxy, and halogen; and morpholinoalkyl
wherein the alkyl moiety contains one to four carbon atoms;
[0135] R.sub.67 and R.sub.77 are independently selected from the
group consisting of hydrogen and alkyl of one to five carbon atoms,
with the proviso that R.sub.67 and R.sub.77 taken together contain
no more than six carbon atoms, and with the further proviso that
when R.sub.77 is hydrogen then R.sub.67 is other than hydrogen and
R.sub.27 is other than hydrogen or morpholinoalkyl, and with the
further proviso that when R.sub.67 is hydrogen then R.sub.77 and
R.sub.27 are other than hydrogen;
[0136] and pharmaceutically acceptable salts thereof.
[0137] Preferred 1,2-bridged imidazoquinoline amine IRM compounds
are defined by Formula VIII below: 9
[0138] wherein
[0139] Z is selected from the group consisting of:
[0140] --(CH.sub.2).sub.p-- wherein p is 1 to 4;
[0141] --(CH.sub.2).sub.a--C(R.sub.DR.sub.E)(CH.sub.2).sub.b--,
wherein a and b are integers and a+b is 0 to 3, R.sub.D is hydrogen
or alkyl of one to four carbon atoms, and R.sub.E is selected from
the group consisting of alkyl of one to four carbon atoms, hydroxy,
--OR.sub.F wherein R.sub.F is alkyl of one to four carbon atoms,
and --NR.sub.GR'.sub.G wherein R.sub.G and R'.sub.G are
independently hydrogen or alkyl of one to four carbon atoms;
and
[0142] --(CH.sub.2).sub.a--(Y)--(CH.sub.2).sub.b-- wherein a and b
are integers and a+b is 0 to 3, and Y is O, S, or --NR.sub.J--
wherein R.sub.J is hydrogen or alkyl of one to four carbon
atoms;
[0143] and wherein q is 0 or 1 and R.sub.8 is selected from the
group consisting of alkyl of one to four carbon atoms, alkoxy of
one to four carbon atoms, and halogen,
[0144] and pharmaceutically acceptable salts thereof.
[0145] Suitable thiazolo- and oxazolo-quinolinamine and
pyridinamine compounds include compounds of Formula IX: 10
[0146] wherein:
[0147] R.sub.19 is selected from the group consisting of oxygen,
sulfur and selenium;
[0148] R.sub.29 is selected from the group consisting of
[0149] -hydrogen;
[0150] -alkyl;
[0151] -alkyl-OH;
[0152] -haloalkyl;
[0153] -alkenyl;
[0154] -alkyl-X-alkyl;
[0155] -alkyl-X-alkenyl;
[0156] -alkenyl-X-alkyl;
[0157] -alkenyl-X-alkenyl;
[0158] -alkyl-N(R.sub.59).sub.2;
[0159] -alkyl-N.sub.3;
[0160] -alkyl-O--C(O)--N(R.sub.59).sub.2;
[0161] -heterocyclyl;
[0162] -alkyl-X-heterocyclyl;
[0163] -alkenyl-X-heterocyclyl;
[0164] -aryl
[0165] -alkyl-X-aryl;
[0166] -alkenyl-X-aryl;
[0167] -heteroaryl;
[0168] -alkyl-X-heteroaryl; and
[0169] -alkenyl-X-heteroaryl;
[0170] R.sub.39 and R.sub.49 are each independently:
[0171] -hydrogen;
[0172] --X-alkyl;
[0173] -halo;
[0174] -haloalkyl;
[0175] --N(R.sub.59).sub.2;
[0176] or when taken together, R.sub.39 and R49 form a fused
aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
[0177] X is selected from the group consisting of --O--, --S--,
--NR.sub.59--, --C(O)--, --C(O)O--, --OC(O)--, and a bond; and
[0178] each R.sub.59 is independently H or C.sub.1-8alkyl;
[0179] Suitable imidazonaphthyridine and
tetrahydroimidazomaphthyridine IRM compounds are those of Formulae
X and XI below: 11
[0180] wherein
[0181] A is .dbd.N--CR.dbd.CR--CR.dbd.; .dbd.CR--N.dbd.CR--CR.dbd.;
.dbd.CR--CR.dbd.N--CR.dbd.; or .dbd.CR--CR.dbd.CR--N.dbd.;
[0182] R.sub.110 is selected from the group consisting of:
[0183] -hydrogen;
[0184] --C.sub.1-20alkyl or C.sub.2-20alkenyl that is unsubstituted
or substituted by one or more substituents selected from the group
consisting of:
[0185] -aryl;
[0186] -heteroaryl;
[0187] -heterocyclyl;
[0188] --O--C.sub.1-20alkyl,
[0189] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0190] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0191] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0192] --C.sub.1-20alkoxycarbonyl;
[0193] --S(O).sub.0-2--C.sub.1-20alkyl;
[0194] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0195] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0196] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0197] --N(R.sub.310).sub.2;
[0198] --N.sub.3;
[0199] oxo;
[0200] -halogen;
[0201] --NO.sub.2;
[0202] --OH; and
[0203] --SH; and
[0204] --C.sub.1-20alkyl-NR.sub.310--Q--X--R.sub.410 or
--C.sub.2-20alkenyl-NR.sub.310-Q--X--R.sub.410 wherein Q is --CO--
or --SO.sub.2--; X is a bond, --O-- or --NR.sub.310- and R.sub.410
is aryl; heteroaryl; heterocyclyl; or --C.sub.120alkyl or
C.sub.2-20alkenyl that is unsubstituted or substituted by one or
more substituents selected from the group consisting of:
[0205] -aryl;
[0206] -heteroaryl;
[0207] -heterocyclyl;
[0208] --O--C.sub.1-20alkyl,
[0209] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0210] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0211] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0212] --C.sub.1-20alkoxycarbonyl;
[0213] --S(O).sub.0-2--C.sub.1-20alkyl;
[0214] --S(O).sub.0-2--(C.sub.1-20.sub.alkyl).sub.0-1-aryl;
[0215] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0216] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0217] --N(R.sub.310).sub.2;
[0218] --NR.sub.310--CO--O--C.sub.1-20alkyl;
[0219] --N.sub.3;
[0220] oxo;
[0221] -halogen;
[0222] --NO.sub.2;
[0223] --OH; and
[0224] --SH; or R.sub.410 is 12
[0225] wherein Y is --N-- or --CR--;
[0226] R.sub.210 is selected from the group consisting of:
[0227] -hydrogen;
[0228] --C.sub.110alkyl;
[0229] --C.sub.2-10alkenyl;
[0230] -aryl;
[0231] --C.sub.1-10alkyl-O--C.sub.1-10-alkyl;
[0232] --C.sub.1-10alkyl-O--C.sub.2-10alkenyl; and
[0233] --C.sub.1-10alkyl or C.sub.2-10alkenyl substituted by one or
more substituents selected from the group consisting of:
[0234] --OH;
[0235] -halogen;
[0236] --N(R.sub.310).sub.2;
[0237] --CO--N(R.sub.310).sub.2;
[0238] --CO--C.sub.1-10alkyl;
[0239] --N.sub.3;
[0240] -aryl;
[0241] -heteroaryl;
[0242] -heterocyclyl;
[0243] --CO-aryl; and
[0244] --CO-heteroaryl;
[0245] each R.sub.310 is independently selected from the group
consisting of hydrogen and C.sub.1-10alkyl; and
[0246] each R is independently selected from the group consisting
of hydrogen, C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and
trifluoromethyl,
[0247] or a pharmaceutically acceptable salt thereof. 13
[0248] wherein
[0249] B is --NR--C(R).sub.2--C(R).sub.2--C(R).sub.2--;
--C(R).sub.2--NR--C(R).sub.2--C(R).sub.2--;
[0250] --C(R).sub.2--C(R).sub.2--NR--C(R).sub.2-- or
--C(R).sub.2--C(R).sub.2--C(R).sub.2--NR--;
[0251] R.sub.111 is selected from the group consisting of:
[0252] -hydrogen;
[0253] --C.sub.1-20alkyl or C.sub.2-20alkenyl that is unsubstituted
or substituted by one or more substituents selected from the group
consisting of:
[0254] -aryl;
[0255] -heteroaryl;
[0256] -heterocyclyl;
[0257] --O--C.sub.1-20alkyl;
[0258] --O--(C.sub.1-20alkyl).sub.0-1-aryl;
[0259] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0260] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0261] --C.sub.1-20alkoxycarbonyl;
[0262] --S(O).sub.0-2--C.sub.1-20alkyl;
[0263] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0264] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0265] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0266] --N(R.sub.311).sub.2;
[0267] --N.sub.3;
[0268] oxo;
[0269] -halogen;
[0270] --NO.sub.2;
[0271] --OH; and
[0272] --SH; and
[0273] --C.sub.1-20alkyl-NR.sub.311--Q--X--R.sub.411 or
--C.sub.2-20alkenyl-NR.sub.311--Q--X--R.sub.411 wherein Q is --CO--
or --SO.sub.2--; X is a bond, --O-- or --NR.sub.311- and R.sub.411
is aryl; heteroaryl; heterocyclyl; or --C.sub.1-20alkyl or
C.sub.2-20alkenyl that is unsubstituted or substituted by one or
more substituents selected from the group consisting of:
[0274] -aryl;
[0275] -heteroaryl;
[0276] -heterocyclyl;
[0277] --O--C.sub.1-20alkyl,
[0278] --O--(C.sub.1-20alkyl).sub.0-1aryl;
[0279] --O--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0280] --O--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0281] --C.sub.1-20alkoxycarbonyl;
[0282] --S(O).sub.0-2--C.sub.1-20alkyl;
[0283] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-aryl;
[0284] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heteroaryl;
[0285] --S(O).sub.0-2--(C.sub.1-20alkyl).sub.0-1-heterocyclyl;
[0286] --N(R.sub.311).sub.2;
[0287] --N R.sub.311--CO--O--C.sub.1-20alkyl;
[0288] --N.sub.3;
[0289] oxo;
[0290] -halogen;
[0291] --NO.sub.2;
[0292] --OH; and
[0293] --SH; or R.sub.411 is 14
[0294] wherein Y is --N-- or --CR--;
[0295] R.sub.211 is selected from the group consisting of:
[0296] -hydrogen;
[0297] --C.sub.1-10alkyl;
[0298] --C.sub.2-10alkenyl;
[0299] aryl
[0300] 13 C.sub.1-10alkyl-O--C.sub.1-10-alkyl;
[0301] --C.sub.1-10alkyl-O--C.sub.2-10alkenyl; and
[0302] --C.sub.1-10alkyl or C.sub.2-10alkenyl substituted by one or
more substituents selected from the group consisting of:
[0303] --OH;
[0304] -halogen;
[0305] --N(R.sub.311).sub.2;
[0306] --CO--N(R.sub.311).sub.2;
[0307] --CO--C.sub.1-10alkyl;
[0308] --N.sub.3;
[0309] -aryl;
[0310] -heteroaryl;
[0311] -heterocyclyl;
[0312] --CO-aryl; and
[0313] --CO-heteroaryl;
[0314] each R.sub.311 is independently selected from the group
consisting of hydrogen and C.sub.1-10alkyl; and
[0315] each R is independently selected from the group consisting
of hydrogen, C.sub.1-10alkyl, C.sub.1-10alkoxy, halogen and
trifluoromethyl, and pharmaceutically acceptable salts thereof.
[0316] The compounds recited above are disclosed in the patents and
applications noted above in the background, all of which are
incorporated herein by reference.
[0317] The substituents R.sub.11-R.sub.111 above are generally
designated "1-substituents" herein. The preferred 1-substituents
are alkyl containing one to six carbon atoms and hydroxyalkyl
containing one to six carbon atoms. Optionally, the 1-substituent
is 2-methylpropyl or 2-hydroxy-2-methylpropyl.
[0318] The substituents R.sub.21-R.sub.211 above are generally
designated "2-substituents" herein. Optional 2-substituents are
hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl wherein the
alkoxy moiety contains one to four carbon atoms and the alkyl
moiety contains one to four carbon atoms, and hydroxyalkyl of one
to four carbon atoms. Optionally, the 2-substituent is hydrogen,
methyl, butyl, propyl hydroxymethyl, ethoxymethyl or
methoxyethyl.
[0319] In instances where n can be zero, one, or two, n is
preferably zero or one.
[0320] IRM Pharmaceutical Formulations
[0321] The amount of an IRM compound that will be therapeutically
effective in a specific situation will depend on such things as the
activity of the particular compound, the mode of administration,
the particular formulation and the condition being treated. As
such, it is not practical to identify specific administration
amounts herein; however, those skilled in the art will be able to
determine appropriate therapeutically effective amounts based on
the guidance provided herein, information available in the art
pertaining to these compounds, and routine testing.
[0322] The pharmaceutical formulations described below can be used
for topical administration of an IRM. Many of the formulations
provided are particularly advantageous for topical administration
to a mucosal surface. In some embodiments, the formulations can
affect the pharmacokinetics of the IRM such that reduced
concentrations of the IRM provide similar pharmacodynamic affects
as that of other formulations having a greater IRM
concentration.
[0323] Generally, a pharmaceutical formulation of the invention
includes an IRM, a fatty acid, a preservative system and an
optional viscosity enhancing agent such as a carbomer. The IRMs can
be prepared using methods previously described in the patents
listed in the background section above as well as U.S. Pat. Nos.
4,988,815; 5,367,076; 5,175,296; 5,395,937; and 5,741,908, the
disclosures which are incorporated herein by reference. Unless
otherwise specified, all percentages are weight percentages based
on the total composition weight.
[0324] The amount of an IRM present in a pharmaceutical formulation
of the invention will be an amount effective to treat a targeted
condition, to prevent recurrence of the condition, or to promote
immunity against the condition. The amount of IRM is preferably
about 0.1% to about 9% by weight based on the total formulation
weight. Optionally, the IRM amount does not exceed about 5% by
weight and most preferably is about 0.1 to about 3% by weight for
mucosal surface applications.
[0325] Typically, a pharmaceutical formulation of the invention is
an oil in water emulsion. The oil component of the formulation
includes an IRM and a fatty acid. The fatty acid is present in the
formulation in an amount sufficient to solubilize the IRM. This is
generally about 2% to about 45%, typically about 10% to about 30%,
and preferably about 15% to about 18% based on the total weight of
the formulation. Fatty acids such as isostearic acid are suitable
for the formulations. Alternatively, the IRM can be solubilized in
linear chain carboxylic acids of six to eight carbon atoms.
[0326] A pharmaceutical formulation of the invention can also
include an emulsifier such as a non-ionic surfactant. Suitable
surfactants include, for example, polysorbate 60, sorbitan
monostearate, polyglyceryl-4 oleate, polyoxyethylene(4)lauryl
ether, etc. For some formulations, surfactants such as Poloxamers
(e.g., Pluronic F68 available from BASF, Ludwigschafen, Germany)
and sorbitan trioleate (e.g., Span 85 available from Sigma Chemical
Co., St. Louis, Mo.), alone or in combination, are preferred. The
non-ionic surfactant is typically present in an amount of about
0.5% to about 10% of total formulation weight. In preferred
embodiments, the total emulsifier content does not exceed about 5%
of total formulation weight, and is more preferably about 3.5% of
total formulation weight.
[0327] A formulation of the invention can also include a viscosity
enhancing agent such as a carbomer, preferably having mucoadhesive
properties. The carbomer can be present in an amount of about 0.1%
to about 8%, preferably about 0.5% to about 4%, more preferably
about 0.5 to about 3%, and most preferably about 1.0% of total
formulation weight. Suitable carbomers include polyacrylic acids
such as Carbopol 934P, Carbopol 971 P, Carbopol 940 and Carbopol
974P available from B. F. Goodrich. A preferred carbomer is
Carbopol 974P.
[0328] In some optional embodiments, the formulation can also
include a chelating agent. The chelating agent functions to chelate
metal ions. If present, unchelated metal ions can suppress gel
formation by suppressing ionization which facilitates gel formation
in a carbomer containing formulation. An optional chelating agent
is disodium ethylenediaminetetraacetate (EDTA) in a concentration
of about 0.0001 to about 0.5%, typically about 0.0005 to about 0.1%
per total formulation weight.
[0329] A preservative such as methylparaben, sorbic acid, propylene
glycol, etc. can also be added. In one optional embodiment,
methylparaben and sorbic acid are each provided at concentrations
of about 0.05% to about 0.3%, preferably about 0.15% of total
formulation weight and propylene glycol is present in amounts up to
about 30%, preferably about 5%. It was discovered that this
combination of preservatives advantageously meets the Preservation
Effectiveness Test (PET), 1997 European Pharmacopeia, Test 5.1.3
Efficacy Antimicrobial Preservation--Topical Preparations--A
Criteria. This renders the formulation suitable for use in a
multi-dose dispenser without adversely affecting the stability of
the formulation. The methylparaben and sorbic acid can be
solubilized in propylene glycol prior to adding to the
formulation.
[0330] The remainder of the pharmaceutical formulation can be
comprised of water to provide a formulation that can be washed away
from the mucosal surface by normal physiological clearing
mechanisms.
[0331] In addition to providing mucoadhesive properties to the
formulation, the carbomer also increases viscosity by forming a
stabilizing gel. Many factors, such as the amount of oil phase, the
drug load, and the amount of carbomer used will affect the pH at
which gelation occurs. In some formulations, the presence of metal
ions and surfactants increases the pH at which the carbomer will
form a gel. Thus, in the absence of a chelating agent, or in the
presence of increased surfactant levels, the pH at which the
carbomer will gel can be increased. Thus it may be necessary to add
an organic or inorganic base or other substance to facilitate gel
formation. Suitable inorganic bases include, for example, KOH,
NaOH, etc. The pH for a pharmaceutical formulation of the invention
is typically about pH 3.0 to about pH 7.0, preferably about pH 4.0
to about pH 6.0.
[0332] Mucosal Surface Applications
[0333] According to the invention, the compositions can be applied
topically, particularly to non-cornified epithelial surfaces such
as mucosal surfaces. Mucosal surfaces include mucosal membranes
such as buccal, gingival, nasal, tracheal, bronchial,
gastrointestinal, rectal, urethral, ureteral, vaginal, cervical,
uterine, etc. Depending on the IRM concentration, formulation
composition, and mucosal surface, the therapeutic affect of the IRM
may extend only to the superficial layers of the mucosal surface or
to tissues deep to the surface.
[0334] In one embodiment, the disclosed IRMs can be topically
applied to the vaginal or supravaginal region of the cervix for
treatment of dysplastic conditions such as cervical intraepithelial
neoplasia. In some embodiments, the above described formulations
are particularly advantageous for cervical application of an IRM
for a period of time sufficient to obtain a desired therapeutic
effect without undesired systemic absorption of the IRM.
[0335] Cervical Intraepithelial Neoplasia (CIN)
[0336] Approximately 16,000 new cases of invasive cancer of the
cervix are diagnosed each year in the U.S. despite extensive
screening of women to detect predictive cellular changes. There are
also about 3,000 deaths due to cervical cancer in the U.S. alone
and this is usually secondary to not detecting the primary
cancerous lesion in a timely manner.
[0337] The Papanicoulaou Test (Pap smear) is the screening test
which has been accepted since the 1950s as the method to detect
abnormal cells of the cervix, including inflammation and dysplasia,
which includes cervical cancer. This screening test has been widely
adopted in industrialized countries and has had a profound impact
on mortality associated with cervical cancers. An abnormal Pap
smear prompts close observation for disease progression with the
potential for the therapeutic interventions of destruction or
excision of cancerous or pre-cancerous tissues. These excisional
treatments are expensive, uncomfortable and associated with failure
rates which range from 2 to 23% and with higher failure rates
reported for the more advanced lesions. Failure rates have recently
been documented to approximate 10% following laser treatment.
[0338] The etiologic agent for cervical cancer was originally
thought to be the herpes virus. However, there was a gradual shift
from this focus on herpes virus to the human papillomavirus (HPV)
when it was shown that the cytopathic effects of HPV in
experimental systems very closely mimicked what was seen in human
disease. Improved experimental methods over the recent past have
allowed the characterization of a full spectrum of HPV subtypes,
which has resulted in the conclusion that the high risk HPV types
(e.g., HPV 16, 18, and less frequently 31, 33, 35, 45) are very
likely the exclusive initiating factor (i.e., oncogenic agent) for
cervical dysplasia and subsequent cancers. The mechanism of HPV
transformation of the normal cell to a dysplastic cell is
associated with the HPV encoded oncoproteins (E6 and E7) from the
high risk genotypes binding the cell's tumor suppressor gene
products p53 and Rb resulting in disruption of the cell cycle
control mechanism in which p53 and Rb play an important role. In
addition, the application of these molecular methods has resulted
in the epidemilogic observation that HPV is isolated from
approximately 93% of cervical tumors, which has further
strengthened the generally accepted conclusion that HPV infection
is the most important initiating agent for cervical cancer.
[0339] Exposure to HPV is common in sexually active women, but it
does not invariably lead to dysplasia or cancer in most of the
exposed women. Infected women who harbor persistent viral DNA have
about five times the chance of persistent dysplasia compared to
women who are able to eradicate the virus. The importance of
cell-mediated immune (CMI) response to HPV infection is illustrated
by the observation that the antibody mediated immune response is
not effective in eliminating established infections as is
demonstrated by the fact that patients with invasive cervical
dancer often exhibit high antibody levels against the viral E6 and
E7 proteins. This particular antibody response probably reflects
extensive antigen exposure in the face of increasing tumor burden.
In contrast to the apparently inconsequential effect of the humoral
immune response, the cell-mediated immune response (Th-1-Type
Response) appears to be effective in controlling tumor progression.
Regression of intraepithelial lesions is accompanied by a cellular
infiltrate consisting of CD4.sup.+ T-CELLS, CD8.sup.+ T-CELLS,
natural killer cells (NK) and macrophages. This inflammatory
infiltrate was usually associated with tumor regression which is in
contrast to women who lack the ability to mount this inflammatory
response and who experience disease progression. In addition,
patients with a defect in cell-mediated immunity have increased
cervical cancer rates, whereas those with defects in the production
of antibody do not exhibit the same susceptibility.
[0340] In one optional embodiment, the inventors foresee the
topical application of IRMs for the non-invasive treatment of
cervical conditions including cervical intraepithelial neoplasia
(CIN).
[0341] Intravaginal Applicators for an IRM
[0342] To obtain a beneficial therapeutic or prophylactic effect
for a cervical condition, intravaginal application of a herein
disclosed IRM is preferred. The IRM can be applied via a dosing
formulation or dispenser which ensures contact of the IRM with the
mucosal surface of the cervix for a period of time sufficient to
provide the desired therapeutic effect. Any of the dispensers
(i.e., applicators) described herein and/or shown in the drawings
could be used to apply the IRM.
[0343] In addition to the applicators already described, an IRM can
be formulated as a suppository and administered intravaginally
using a suppository applicator. A suitable suppository applicator
includes known cardboard tube applicators for dispensing
medications to the vaginal cavity. Formulations according to the
invention can also be administered using a barrel type applicator,
such as those described herein and/or shown in the drawings. An
example of a suitable barrel type applicator can be found in U.S.
Pat. No. 5,282,789, the disclosure of which is incorporated herein
by reference.
[0344] In optional embodiment, an IRM can be administered directly
to the cervical mucosa. In one such embodiment, the IRM can be
topically applied to the cervical mucosa by using a direct cervical
applicator, as previously described or using a cervical cap. One
example of a suitable cervical cap is found in U.S. Pat. No.
4,858,624, the disclosure of which is incorporated herein by
reference. Suitable IRM formulations for direct cervical
applications are disclosed above and in the Examples below. In
general, an IRM formulated pursuant to any of formulations A-J in
the Examples below can be placed into the concave region of the
cervical cap which is then applied directly over the cervix. These
formulations might also be applied with other types of applicator
devices including those shown in the drawings and described herein.
Optionally, the IRM is formulated to include a viscosity agent,
such as a carbomer, to enhance the residence time of the IRM on the
cervix.
[0345] The following Examples are provided to further describe IRM
formulations and methods according to the invention. The examples,
however, are not intended to limit the formulations and
methods.
EXAMPLES
Example 1
[0346] Evaluation of the Safety, Pharmacokinetics (PK) and
Pharmacodynamics (PD) OF
1-(2-methylpropyl)-1H-imadazo[4,5-c]quinolin-4-a- mine (imiquimod)
Applied to the Cervix.
[0347] Methods
[0348] This was a single dose, randomized, double-blind, placebo
controlled dose escalation study which evaluated five doses of
imiquimod. 50, 100, 150, 200 and 250 mg of imiquimod in a cream
formulation were applied to the cervix for eight hours. The
ingredients of the formulation of the imiquimod cream used for this
study (Formulation A) is presented in Table I below. Each dose
group was composed of 8 subjects (6 active and 2 placebo), with two
subjects treated as dose leaders, and the remaining six subjects
were treated after an acceptable response by the dose leaders.
Safety was assessed by adverse events (AE's), laboratory tests, and
colposcopy with photodocumentation of the cervix at pre-dose and 24
hours post-dose, and 48 hours post-dose if required. Systemic
exposure (PK) was determined by measuring imiquimod and metabolites
through 48 hours post-dose and the PD response was determined by
serum analysis for the cytokines: tumor necrosis factor-.alpha.
(TNF-.alpha.), interferon-.alpha. (IFN-.alpha.), interleukin-1
receptor agonist (IL-1RA), interleukin-6 (IL-6), neopterin (NPT)
and 2'5' oligoadenlyate synthetase (2'5' AS) during dosing and
selected times during the 48 hours post-dose. Statistical tests to
evaluate AE's and demographics, laboratory tests, vital signs and
ECG's were Fisher's Exact, Wilcoxon Rank-Sum and Kruskall Wallis
Tests respectively. Cytokine changes between dose groups were
compared using Wilcoxon Rank-Sum and changes from baseline were
evaluated using Spearman Rank Correlation.
[0349] Results
[0350] Thirty-nine generally healthy, surgically sterilized, 18-50
year-old females within 25% of ideal body weight were included in
the study. All women had normal baseline colposcopy results with
normal and borderline dyskariosis on cervical histology. AE's were
reported in each of the 39 subjects with mild temperature elevation
the most common event (92%). There were no differences among groups
with respect to subjects who experienced one or more events, or in
AE's attributed as possibly or probably related to drug. (Two
serious AE's occurred which were intercurrent events associated
with a fractured ankle and its surgical repair.) There were
statistically significant changes in some laboratory parameters and
pulse rates that were not considered clinically significant. There
were no differences in ECG's or physical exams. Pelvic and
colposcopic examinations revealed few reactions with 2 of 6
receiving 250 mg experiencing cervical changes of minor small
vesicles or smaller ulcer. These reactions resolved within 48
hours. No quantifiable (>5 ng/ml) serum levels of imiquimod were
detected. Significant changes from baseline were seen in IFN and
IL-6 in the 250 mg group and in NPT. 2'5' AS and IL-1RA in the 150
mg, 200 mg, and 250 mg groups.
[0351] The study showed that single doses of imiquimod up to 250 mg
applied to the cervix for 8 hours in healthy volunteers is safe
with minimal systemic exposure. Cervical application of a dose
.gtoreq.150 mg increases the systemic concentration of certain
cytokines.
1 TABLE 1 Components Formulation A (% w/w) Imiquimod 5.0 Isostearic
Acid 25.0 Benzyl Alcohol 2.0 Cetyl Alcohol 2.2 Stearyl Alcohol 3.1
White Petrolatum 3.0 Polysorbate 60 3.4 Sorbitan Monostearate 0.6
Glycerin 2.0 Methyl Paraben 0.2 Propyl Paraben 0.02 Water 52.98
Xanthan Gum 0.5 PH 5.1 Viscosity (cps) 0.33 .times. 10.sup.5
Example 2
[0352] Preparation of Pharmaceutical Formulation B
[0353] This example describes a novel formulation for a vaginal
application, that is a stable formulation, with a high viscosity,
and well preserved to pass the EP preservative effectiveness test
(PET) criteria. The w/w % of ingredients of this formulation
(Formulation B) are shown in Table 2 below.
[0354] Imiquimod was dissolved in isostearic acid with Span 85.
Pluronic F68, EDTA, Carbopol 974P, propylene glycol, sorbic acid,
and methylparaben were dissolved in water. After emulsification to
form an oil-in-water emulsion, sodium hydroxide was added to
achieve a pH of about 5.2. The pH range for this formulation can be
about 4.8 to 6.0.
2 TABLE 2 Components Formulation B (% w/w) Imiquimod 5 Isostearic
acid 28 Pluronic F68 2.98 Purified water 43.78 Carbopol 974P 1.7
Disodium EDTA 0.05 Propylene glycol 15 Sorbic acid 0.15
Methylparaben 0.15 Span 85 2.02 5N NaOH 1.17 PH 5.1 Viscosity (cps)
6.4 .times. 10.sup.5
Example 3
[0355] Preparation of Pharmaceutical Formulations C-F
[0356] Pharmaceutical Formulations C-F were prepared with the
components recited below in Table 3. The method for preparing
Formulations C-F was the same as that disclosed for preparing
Formulation B in Example 2.
3TABLE 3 Formulation Formulation Formulation Formulation C D E F
Components (% w/w) (% w/w) (% w/w) (% w/w) Imiquimod 1.0 1.0 3.0
3.0 Isostearic acid 5.6 28.0 16.8 28.0 Pluronic F68 1.79 1.79 1.79
1.79 Purified water 69.05 48.30 56.25 46.75 Carbopol 974P 2.8 2.10
2.5 1.80 Disodium 0.05 0.05 0.05 0.05 EDTA PG* 15.0 15.0 15.0 15.0
Sorbic acid 0.15 0.15 0.15 0.15 Methylparaben 0.15 0.15 0.15 0.15
Span 85 1.21 1.21 1.21 1.21 5N NaOH 3.2 2.26 3.1 2.1 pH 5.1 5.2 5.2
5.3 Viscosity (cps) 5.8 .times. 10.sup.5 8.8 .times. 10.sup.5 11.0
.times. 10.sup.5 10.0 .times. 10.sup.5 *PG is Propylene glycol
Example 4
[0357] Imiquimod Transport Across Hairless Mouse Skin from Two
Formulations A and B. Both at 5% w/w, Imiquimod
[0358] FIG. 16 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 U.S.
Pat. No. 5,238,944, the entire disclosure of which is incorporated
herein by reference.
[0359] In brief, hairless mouse skin was removed from female
hairless mice that were 5 to 7 weeks old (available from Charles
River). The skin was maintained on ice until used. The mouse skin
was mounted on a diffusion cell of the type shown in U.S. Pat. No.
5,238,944. The mouse skin was mounted with the epidermal side up
between upper and lower portions of the cell which are held
together by means of ball joint clamp.
[0360] The portion of the cell below the mounted skin was
completely filled with 0.1 N HCl receptor fluid such that the
receptor fluid contacted the skin. The receptor fluid was stirred
using a magnetic stir bar and a magnetic stirrer.
[0361] Approximately 100.sup..+-. 5 mg formulation to be tested was
applied to the epidermal (upper) side of the skin to cover in an
even layer only the area of skin that would be in contact with the
receptor fluid when the skin was mounted in the diffusion cell. The
formulations were applied to the skin prior to the time the
receptor fluid was added to the cell below the skin.
[0362] The cell was then placed in a constant temperature
(31.degree. C.) chamber. To maintain constant temperature, the
chamber utilized a heat exchanger coupled to a constant temperature
bath, with a fan to circulate air. The receptor fluid was stirred
by means of a magnetic stirring bar throughout the experiment to
ensure a uniform sample and a reduced diffusion barrier layer on
the dermal side of the skin. At specified time intervals (1, 2, 4,
6, 8, 12 and 24 hours), the entire volume of receptor fluid was
removed and immediately replaced with fresh receptor fluid. The
withdrawn receptor fluid was analyzed for imiquimod content by
conventional high pressure chromatography as follows:
[0363] Detector: UV at 258 nm; Mobile Phase: 25/75
acetonitrile/water containing 1% triethylamine, 0.2% 1-octane
sulfonate with the pH adjusted to 2.0 with H.sub.3PO.sub.4;
Stationary Phase: C8 Zorbax RX-C8 5.mu.; Flow Rate: 2 ml/min; Run
Time: approximately 10 minutes.
[0364] Cumulative amount of penetration was plotted versus time to
obtain the steady state rate.
Example 5
[0365] Imiquimod Transport Across Nude Mouse Skin from Formulations
C-F at 1% w/w and 3% w/w Imiquimod with Varied Concentrations of
Isostearic Acid (USA).
[0366] Table 4 below provides the imiquimod concentration,
isostearic acid concentration, viscosity, pH and steady state rate
(.mu.g/hour) of Formulations C-F across nude mouse skin.
[0367] The results are graphed in FIG. 17. The procedure used to
study skin penetration was the same as that disclosed in Example
4.
4TABLE 4 IRM ISA Formu- Concentration Concentration Viscosity
Steady State lation (% w/w) (% w/w) (.times. 10.sup.-5 cps) Rate
(.mu.g/hr) C 1% 5.6% 5.8 18.1 D 1% 28% 8.8 26.1 E 3% 16.8% 11 39.9
F 3% 28% 10 71.5
Example 6
[0368] Pharmacokinetics Comparison of Imiquimod in Rats After
Single Dose Vaginal Application of Formulation a and Formulation
B
[0369] Serum imiquimod concentration versus time profiles were
compared in ovariectomized rats after single intravaginal doses of
Formulation A or Formulation B. The two 5% w/w formulations were
dosed to provide a dose level of 35 mg/kg. After dosing, each rat
was collared to prevent removal of the formulation by licking.
After about six hours, the vagina was lavaged and the collars
removed. Blood samples were collected at pre-dose and at 0.5, 1, 2,
3, 4 and 24 hours post-dose. Due to the higher viscosity of
Formulation B, intravaginal administration to the rats was
considerably easier and retention of Formulation B was superior to
Formulation A.
[0370] Serum was analyzed by HPLC for imiquimod. Mean serum
imiquimod concentrations versus time are depicted in FIG. 18. The
time to achieve maximum serum concentrations of imiquimod
(T.sub.max) was similar (1 hr) for both formulations. However, the
maximum imiquimod concentration (C.sub.max) for Formulation B was
approximately 1.6 times greater than for Formulation A and the
respective area under the curve versus time (AUC) was 3.3 times
greater (FIGS. 19A and 19B). Based upon these data, the rate and
extent of absorption of imiquimod was greater from Formulation B
than from Formulation A.
Example 7
[0371] Preparation of Pharmaceutical Formulation G
[0372] The w/w % of the ingredients for Formulation G are shown in
Table 5.
[0373] An oil phase was prepared as follows. Imjquimod (20.0 g) was
slowly added with stirring to isostearic acid (3000 g). The mixture
was stirred and heated, as necessary, up to 55.degree. C. to
facilitate dissolution of the imiquimod. After dissolution was
complete the heat was turned off. Sorbitan trioleate (200 g) was
added and thoroughly mixed. Carbomer 974 was slowly added with
mixing. The mixing was continued until the carbomer was uniformly
dispersed in the oil phase. The oil phase was then allowed to cool
to a temperature of less than 30.degree. C.
[0374] An aqueous phase was prepared as follows. Sorbic acid (30.0
g) and methylparaben (40.0 g) were added with stirring to propylene
glycol (1000 g). The resulting mixture was stirred and heated
gently (<45.degree. C.) until a solution was obtained. The heat
source was removed. Polaxamer 188 (500 g) was added to the
solution. The resulting mixture was stirred until the polaxamer was
thoroughly wet. The resulting slurry was then added to a solution
of edetate disodium (10.0 g) in purified water (13950 g). The
resulting mixture was stirred until a clear solution was
obtained.
[0375] A sodium hydroxide solution was prepared by dissolving
sodium hydroxide pellets (50 g) in purified water (1000 g).
[0376] The oil phase was added to the aqueous phase and then the
sodium hydroxide solution was added. The resulting mixture was
mixed for a minimum of 30 minutes until a smooth and shiny cream
was obtained. The pH was determined and adjusted, if necessary, to
5.6-5.8 with sodium hydroxide solution.
Example 8
[0377] Preparation of Pharmaceutical Formulations H-J
[0378] Pharmaceutical formulations H-J were prepared using the
method of Example 7. The w/w % of the ingredients in the
formulations is shown in Table 5 below.
5TABLE 5 Formulation G H I J Component (% w/w) (% w/w) (% w/w) (%
w/w) Isostearic Acid (874) 15.00 15.00 15.00 18.00 Imiquimod 0.10
0.50 1.50 3.00 Sorbitan Trioleate 1.00 1.00 1.00 1.00 Propylene
Glycol 5.00 5.00 5.00 5.00 Sorbic Acid 0.15 0.15 0.15 0.15
Methylparaben 0.20 0.20 0.20 0.20 Purified Water 75.00 74.60 73.60
69.10 Edetate Disodium 0.05 0.05 0.05 0.05 Polaxamer 188 2.50 2.50
2.50 2.50 Carbomer 974 1.00 1.00 1.00 1.00 Sodium Hydroxide qs qs
qs Os Total % w/w 100 100 100 100
[0379] Accordingly, from the foregoing discussion, it will
appreciated that the imidazoquinoline amines, imidazopyridine
amines, 6,7-fused cycloalkylimidazopyridine amines, and 1,2-bridged
imidazoquinoline amines of the present invention can be beneficial
for treating mucosal associated conditions including cervical
dysplasias. In addition, the disclosed pharmaceutical formulations
can be particularly advantageous for topical application of an IRM
to a mucosal surface.
[0380] From the foregoing detailed description and examples, it
will be evident that modifications and variations can be made in
the compounds, formulations, devices, systems, and methods
disclosed herein. Other embodiments will be apparent to those
skilled in the art. It is intended that the specification and
examples be considered as exemplary only.
* * * * *