U.S. patent application number 13/529615 was filed with the patent office on 2013-04-04 for methods and compositions for the treatment of cancer, tumors, and tumor-related disorders.
This patent application is currently assigned to Tragara Pharmaceuticals, Inc.. The applicant listed for this patent is Thomas M. Estok, Tracy Lawhon, Robert K. Mansfield, Sara L. Zaknoen. Invention is credited to Thomas M. Estok, Tracy Lawhon, Robert K. Mansfield, Sara L. Zaknoen.
Application Number | 20130084281 13/529615 |
Document ID | / |
Family ID | 40229105 |
Filed Date | 2013-04-04 |
United States Patent
Application |
20130084281 |
Kind Code |
A1 |
Estok; Thomas M. ; et
al. |
April 4, 2013 |
METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER, TUMORS, AND
TUMOR-RELATED DISORDERS
Abstract
Described herein are compositions and methods for using these
compositions in the treatment of cancer, tumors, and tumor-related
disorders in a subject.
Inventors: |
Estok; Thomas M.; (Carlsbad,
CA) ; Zaknoen; Sara L.; (Carlsbad, CA) ;
Mansfield; Robert K.; (Carlsbad, CA) ; Lawhon;
Tracy; (Encinitas, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Estok; Thomas M.
Zaknoen; Sara L.
Mansfield; Robert K.
Lawhon; Tracy |
Carlsbad
Carlsbad
Carlsbad
Encinitas |
CA
CA
CA
CA |
US
US
US
US |
|
|
Assignee: |
Tragara Pharmaceuticals,
Inc.
San Diego
CA
|
Family ID: |
40229105 |
Appl. No.: |
13/529615 |
Filed: |
June 21, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12172202 |
Jul 11, 2008 |
8247423 |
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13529615 |
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60949483 |
Jul 12, 2007 |
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60990900 |
Nov 28, 2007 |
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61044425 |
Apr 11, 2008 |
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Current U.S.
Class: |
424/133.1 ;
424/143.1; 424/174.1; 514/266.4 |
Current CPC
Class: |
A61K 31/352 20130101;
A61K 31/4706 20130101; A61K 31/352 20130101; A61K 31/402 20130101;
A61K 31/4706 20130101; A61K 31/5377 20130101; A61K 31/517 20130101;
A61P 35/02 20180101; A61P 35/00 20180101; A61K 31/05 20130101; A61K
31/7068 20130101; A61K 45/06 20130101; A61K 31/402 20130101; A61K
31/506 20130101; A61K 31/05 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/519 20130101; A61K 31/5377 20130101; A61K
31/506 20130101; A61K 31/517 20130101; A61K 31/519 20130101; A61P
43/00 20180101; A61K 31/7068 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/133.1 ;
514/266.4; 424/174.1; 424/143.1 |
International
Class: |
A61K 31/402 20060101
A61K031/402; A61K 31/517 20060101 A61K031/517 |
Claims
1. A method for treating a subject having cancer, comprising
administering to the subject, a therapeutically effective amount of
a combination comprising a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor or their respective pharmaceutically acceptable
salt, solvate, polymorph or prodrug.
2. The method of claim 1 wherein the 1,2-diphenylpyrrole derivative
has the following formula: ##STR00010## wherein: R is a hydrogen
atom, a halogen atom or an alkyl group having from 1 to 6 carbon
atoms; R.sup.1 is an alkyl group having from 1 to 6 carbon atoms or
an amino group; R.sup.2 is a phenyl group which is unsubstituted or
is substituted by at least one substituent selected from the group
consisting of substituents .alpha. and substituents .beta.; R.sup.3
is a hydrogen atom, a halogen atom or an alkyl group which has from
1 to 6 carbon atoms and which is unsubstituted or is substituted by
at least one substituent selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 6
carbon atoms and an alkylthio group having from 1 to 6 carbon
atoms; R.sup.4 is a hydrogen atom; an alkyl group which has from 1
to 6 carbon atoms and which is unsubstituted or is substituted by
at least one substituent selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 6
carbon atoms and an alkylthio group having from 1 to 6 carbon
atoms; a cycloalkyl group having from 3 to 8 carbon atoms, an aryl
group; or an aralkyl group; said aryl group having from 6 to 14
ring carbon atoms in a carbocyclic ring and are unsubstituted or
are substituted by at least one substituent selected from the group
consisting of substituents .alpha. and substituents .beta.; said
aralkyl group are an alkyl group having from 1 to 6 carbon atoms
and which are substituted by at least one aryl group as defined
above; said substituents .alpha. are selected from the group
consisting of a hydroxy group, a halogen atom, an alkoxy group
having from 1 to 6 carbon atoms and an alkylthio group having from
1 to 6 carbon atoms; said substituents .beta. are selected from the
group consisting of an alkyl group which has from 1 to 6 carbon
atoms and which is unsubstituted or are substituted by at least one
substituent selected from the group consisting of a hydroxy group,
a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and
an alkylthio group having from 1 to 6 carbon atoms; an alkanoyloxy
group having from 1 to 6 carbon atoms; a mercapto group; an
alkanoylthio group having from 1 to 6 carbon atoms; an
alkylsulfinyl group having from 1 to 6 carbon atoms; a cycloalkloxy
group having from 3 to 8 carbon atoms; a haloalkoxy group having
from 1 to 6 carbon atoms; and an alkylenedioxy group having from 1
to 6 carbon atoms; or a pharmaceutically acceptable salt, solvate,
or prodrug.
3. The method of claim 2 wherein: R is a hydrogen atom, a halogen
atom or an alkyl group having from 1 to 4 carbon atoms; R.sup.1 is
a methyl group or an amino group; R.sup.2 is an unsubstituted
phenyl group or a phenyl group which is substituted by at least one
substituent selected from the group consisting of a halogen atom;
an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group
having from 1 to 4 carbon atoms; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4
carbon atoms and which is substituted by at least one substituent
selected from the group consisting of a halogen atom, an alkoxy
group having from 1 to 4 carbon atoms and an alkylthio group having
from 1 to 4 carbon atoms; a haloalkoxy group having from 1 to 4
carbon atoms; and an alkylenedioxy group having from 1 to 4 carbon
atoms; R.sup.3 is a hydrogen atom, a halogen atom, an unsubstituted
alkyl group having from 1 to 4 carbon atoms or a substituted alkyl
group having from 1 to 4 carbon atoms and substituted by at least
one substituent selected from the group consisting of a halogen
atom, an alkoxy group having from 1 to 4 carbon atoms and an
alkylthio group having from 1 to 4 carbon atoms; R.sup.4 is a
hydrogen atom; an unsubstituted alkyl group having from 1 to 4
carbon atoms; a substituted alkyl group having from 1 to 4 carbon
atoms and substituted by at least one substituent selected from the
group consisting of a hydroxy group, a halogen atom, an alkoxy
group having from 1 to 4 carbon atoms and an alkylthio group having
from 1 to carbon atoms; a cycloalkyl group having from 3 to 6
carbon atoms; an aryl group which has from 6 to 10 ring carbon
atoms and which is unsubstituted or is substituted by at least one
substituent selected from the group consisting of a halogen atom;
an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group
having from 1 to 4 carbon atoms; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4
carbon atoms and substituted by at least one substituent selected
from the group consisting of a hydroxy group, a halogen atom, an
alkoxy group having from 1 to 4 carbon atoms and an alkylthio group
having from 1 to 4 carbon atoms; and a cycloalkyloxy group having
from 3 to 7 carbon atoms; an aralkyl group having from 1 to 4
carbon atoms in the alkyl part and containing at least one said
aryl group; or a pharmaceutically acceptable salt, solvate, or
prodrug.
4. The method of claim 3 wherein: R is a hydrogen atom; R.sup.1 is
an amino group; R.sup.2 is an unsubstituted phenyl group or a
phenyl group which is substituted by at least one substituent
selected from the group consisting of a halogen atom, an alkoxy
group having from 1 to 4 carbon atoms, an alkylthio group having
from 1 to 4 carbon atoms, an alkyl group having from 1 to 4 carbon
atoms, a haloalkyl group having from 1 to 4 carbon atoms, a
haloalkoxy group having from 1 to 4 carbon atoms and a
alkylenedioxy group having from 1 to 4 carbon atoms; R.sup.3 is a
hydrogen atom, a halogen atom, an alkyl group having from 1 to 4
carbon atoms or a haloalkyl group having from 1 to 4 carbon atoms;
R.sup.4 is a hydrogen atom; an unsubstituted alkyl group having
from 1 to 4 carbon atoms; a substituted alkyl group having from 1
to 4 carbon atoms and substituted by at least one substituent
selected from the group consisting of a hydroxy group and an alkoxy
group having from 1 to 4 carbon atoms; a cycloalkyl group having
from 3 to 6 carbon atoms; an aryl group which has from 6 to 10 ring
carbon atoms and which is unsubstituted or is substituted by at
least one substituent selected from the group consisting of a
hydroxy group; a halogen atom; an alkoxy group having from 1 to 4
carbon atoms; an unsubstituted alkyl group having from 1 to 4
carbon atoms; an alkyl group having from 1 to 4 carbon atoms and
which is unsubstituted or substituted by at least one halogen atom;
and a cycloalkyloxy group having from 3 to 7 carbon atoms; and an
aralkyl group having from 1 to 4 carbon atoms in the alkyl part and
containing at least one said aryl group; or a pharmaceutically
acceptable salt, solvate, or prodrug.
5. The method of claim 4 wherein the 1,2-diphenylpyrrole derivative
is selected from the group consisting of:
4-methyl-2-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxy-3-methylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3-fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3,4-dimethylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylphenyl)pyrrole;
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(4-methoxyphenyl)pyrrole;
and
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(3,4-dimethylphenyl)pyrrole.
6. The method of claim 5 wherein the 1,2-diphenylpyrrole derivative
is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
7. The method of claim 1 wherein the EGFR inhibitor is
erlotinib.
8. The method of claim 1 wherein the 1,2-diphenylpyrrole derivative
is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
the EGFR inhibitor is erlotinib.
9. The method of claim 1 wherein the 1,2-diphenylpyrrole derivative
and the EGFR inhibitor are administered sequentially in either
order or simultaneously.
10. The method of claim 1 wherein the 1,2-diphenylpyrrole
derivative is administered first.
11. The method of claim 1 wherein the EGFR inhibitor is
administered first.
12. The method of claim 1 wherein administering the combination
enhances treatment of the subject.
13. The method of claim 1 wherein administering the combination
reduces the side effects of the treatment of cancer compared to a
treatment of the EGFR inhibitor alone or a treatment of the
1,2-diphenylpyrrole derivative alone.
14. The method of claim 1 wherein administering the combination is
through oral, parenteral, buccal, intranasal, epidural, sublingual,
pulmonary, local, rectal, or transdermal administration.
15. The method of claim 14 wherein administering the combination is
through parenteral administration.
16. The method of claim 15 wherein parenteral administration is
intravenous, subcutaneous, intrathecal, or intramuscular.
17. The method of claim 14 wherein oral administration is in a
single dosage form.
18. The method of claim 17 wherein the single dosage form enhances
patient compliance and/or reduces pill burden.
19. The method of claim 17 wherein the single dosage form is a
single capsule or a single tablet.
20. The method of claim 19 wherein the composition is a single
tablet.
21. The method of claim 20 wherein the single tablet comprises from
about 1 mg to about 1200 mg of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and from
about 25 mg to about 450 mg of erlotinib.
22. The method of claim 21 wherein the single tablet comprises from
about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
25 mg of erlotinib.
23. The method of claim 21 wherein the single tablet comprises from
about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
100 mg of erlotinib.
24. The method of claim 21 wherein the single tablet comprises from
about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
150 mg of erlotinib.
25. The method of claim 21 wherein the single tablet comprises from
about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
200 mg of erlotinib.
26. The method of claim 21 wherein the single tablet comprises from
about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
300 mg of erlotinib.
27. The method of claim 21 wherein the single tablet comprises from
about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
450 mg of erlotinib.
28. The method of claim 1 wherein the cancer is selected from the
group consisting of: oral cancer, prostate cancer, rectal cancer,
non-small cell lung cancer, lip and oral cavity cancer, liver
cancer, lung cancer, anal cancer, kidney cancer, vulvar cancer,
breast cancer, oropharyngeal cancer, nasal cavity and paranasal
sinus cancer, nasopharyngeal cancer, urethra cancer, small
intestine cancer, bile duct cancer, bladder cancer, ovarian cancer,
laryngeal cancer, hypopharyngeal cancer, gallbladder cancer, colon
cancer, colorectal cancer, head and neck cancer, parathyroid
cancer, penile cancer, vaginal cancer, thyroid cancer, pancreatic
cancer, esophageal cancer, Hodgkin's lymphoma, leukemia-related
disorders, mycosis fungoides, and myelodysplastic syndrome.
29. The method of claim 28 wherein the cancer is non-small cell
lung cancer, pancreatic cancer, breast cancer, ovarian cancer,
colorectal cancer, and head and neck cancer.
30. The method of claim 1 wherein the cancer is a carcinoma, a
tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma, and
a blastoma.
31. The method of claim 30 wherein the carcinoma is selected from
the group consisting of: carcinoma, adenocarcinoma, adenoid cystic
carcinoma, adenosquamous carcinoma, adrenocortical carcinoma, well
differentiated carcinoma, squamous cell carcinoma, serous
carcinoma, small cell carcinoma, invasive squamous cell carcinoma,
large cell carcinoma, islet cell carcinoma, oat cell carcinoma,
squamous carcinoma, undifferentiatied carcinoma, verrucous
carcinoma, renal cell carcinoma, papillary serous adenocarcinoma,
merkel cell carcinoma, hepatocellular carcinoma, soft tissue
carcinomas, bronchial gland carcinomas, capillary carcinoma,
bartholin gland carcinoma, basal cell carcinoma, carcinosarcoma,
papilloma/carcinoma, clear cell carcinoma, endometrioid
adenocarcinoma, mesothelial, metastatic carcinoma, mucoepidermoid
carcinoma, cholangiocarcinoma, actinic keratoses, cystadenoma, and
hepatic adenomatosis.
32. The method of claim 30 wherein the tumor is selected from the
group consisting of: astrocytic tumors, malignant mesothelial
tumors, ovarian germ cell tumor, supratentorial primitive
neuroectodermal tumors, Wilm's tumor, pituitary tumors,
extragonadal germ cell tumor, gastrinoma, germ cell tumors,
gestational trophoblastic tumor, brain tumors, pineal and
supratentorial primitive neuroectodermal tumors, pituitary tumor,
somatostatin-secreting tumor, endodermal sinus tumor, carcinoids,
central cerebral astrocytoma, glucagonoma, hepatic adenoma,
insulinoma, medulloepithelioma, plasmacytoma, vipoma, and
pheochromocytoma.
33. The method of claim 30 wherein the neoplasm is selected from
the group consisting of: intaepithelial neoplasia, multiple
myeloma/plasma cell neoplasm, plasma cell neoplasm, interepithelial
squamous cell neoplasia, endometrial hyperplasia, focal nodular
hyperplasia, hemangioendothelioma, and malignant thymoma.
34. The method of claim 30 wherein the lymphoma is selected from
the group consisting of: nervous system lymphoma, AIDS-related
lymphoma, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma,
lymphoma, and Waldenstrom's macroglobulinemia.
35. The method of claim 30 wherein the melanoma is selected from
the group consisting of: acral lentiginous melanoma, superficial
spreading melanoma, uveal melanoma, lentigo maligna melanomas,
melanoma, intraocular melanoma, adenocarcinoma nodular melanoma,
and hemangioma.
36. The method of claim 30 wherein the sarcoma is selected from the
group consisting of: adenomas, adenosarcoma, chondosarcoma,
endometrial stromal sarcoma, Ewing's sarcoma, Kaposi's sarcoma,
leiomyosarcoma, rhabdomyosarcoma, sarcoma, uterine sarcoma,
osteosarcoma, and pseudosarcoma.
37. The method of claim 30 wherein the glioma is selected from the
group consisting of: glioma, brain stem glioma, and hypothalamic
and visual pathway glioma.
38. The method of claim 30 wherein the blastoma is selected from
the group consisting of: pulmonary blastoma, pleuropulmonary
blastoma, retinoblastoma, neuroblastoma, medulloblastoma,
glioblastoma, and hemangiblastomas.
39. The method of claim 1 wherein the EGFR inhibitor is a small
molecule compound or an antibody.
40. The method of claim 39 wherein the small molecule compound is
selected from the group consisting of: ZM-254530, BIBX-1382,
reveromycin A, gefitinib, CGP-57148, CGP-59326,
4-(3-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, tyrphostin,
PKI-166, PD 153035, EKB-569, and 4-(phenylamino)quinazolines, or
their pharmaceutically acceptable salts, solvates, or prodrugs.
41. The method of claim 39 wherein the antibody is selected from
the group consisting of: EGF receptor antibody, MR1scFvPE38KDEL
MDX-447, MDX-210, MD-72000, MDX-260, wayne anti-EGFR Mabs,
anti-EGFr Mab, anti-EGFr MAb, Genen anti-EGFR Mab, MAb DC-101,
trastuzumab, anti-VEGF monoclonal, anti-EGFR-DM1 Ab. MAb 4D5,
BAB-447, EMD-55900, EMD-6200, -82633, anti-EGFR Mab, MAb 4D5,
cetuximab, anti-EGFr MAb, anti-flk-1, CCX, CCZ, anti-flk-1, AG-514,
AG-568, nti-EGFR-DM1 Ab, MDX-447, TgDCC-E1A, C225, matuzurnab,
panitumumab, DWP-408, and RC-3940II.
42. The method of claim 1 wherein the EGFR inhibitor is selected
from the group consisting of: muellerian-inhibiting hormone,
TNP-470, tecogalan sodium, EGF receptor antisense, PI-88,
oligonucleotide, bromelain molecules, amphiregulin, EGF fusion
toxin, EGF fusion protein, Amphiregulin hbEGF-toxin, hbEGF-toxin,
and EGF fusion protein.
43. A method of inducing differentiation of tumor cells, the method
comprising contacting the cells with an effective amount of a
combination comprising a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor whereby the combination induces differentiation of tumor
cells.
44. A method of inhibiting proliferation of cancer cells, the
method comprising contacting a cancer cell with a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
whereby the combination inhibits proliferation of cancer cells.
45. A method for reducing proliferation of cancer cells, the method
comprising delivering to the cells a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, whereby the
reduction of cell proliferation is greater than a reduction caused
by either a 1,2-diphenylpyrrole derivative alone or an EGFR
inhibitor alone.
46. A method of modulating autophosphorylation with a molecule of
ATP, the method comprising delivering to a cancer cell an effective
amount of a combination comprising a 1,2-diphenylpyrrole derivative
and an EGFR inhibitor wherein the combination inhibits
autophosphorylation with a molecule of ATP.
47. A method of inhibiting metastases of tumor cells, the method
comprising administering an effective amount of a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
such that the combination inhibits metastatic activity of tumor
cells.
48. A method for inducing apoptosis in cancer cells, the method
comprising contacting the cancer cells with a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR kinase
sufficient to induce apoptosis.
49. A method for sensitizing EGFR inhibitor resistant cancer cells
to an EGFR inhibitor, the method comprising administering a
combination comprising a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the combination sensitizes the cancer cells to
the EGFR inhibitor.
50. A method of treating EGFR resistance in a cancer cell, the
method comprising, administering a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor.
51. A method of modulating prostaglandin synthesis in a cancer
cell, the method comprising contacting the cell with a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the combination inhibits prostaglandin synthesis in a
cancer cell.
52. A method of modulating cyclooxygenase expression in a cancer
cell, the method comprising delivering to the cell a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the combination inhibits cyclooxygenase expression in a
cancer cell.
53. A method of modulating angiogenesis in a cancer cell, the
method comprising contacting the cell with a combination comprising
a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits angiogenesis in a cancer cell.
54. A method of reducing the dosage in conventional treatment for
neoplasia and/or neoplasia related disorders in a subject, the
method comprising administering to a subject a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination reduces the dosage in conventional treatment for
neoplasia and/or neoplasia-related disorders.
55. A method of treating neoplasia and/or neoplasia related
disorders, the method comprising administering a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor.
56. A composition for treating cancer comprising, a combination of
a 1,2-diphenylpyrrole derivative and an EGFR inhibitor or their
respective pharmaceutically acceptable salt, solvate or
prodrug.
57. The composition of claim 56 wherein the 1,2-diphenylpyrrole
derivative has the following formula: ##STR00011## wherein: R is a
hydrogen atom, a halogen atom or an alkyl group having from 1 to 6
carbon atoms; R.sup.1 is an alkyl group having from 1 to 6 carbon
atoms or an amino group; R.sup.2 is a phenyl group which is
unsubstituted or is substituted by at least one substituent
selected from the group consisting of substituents .alpha. and
substituents .beta.; R.sup.3 is a hydrogen atom, a halogen atom or
an alkyl group which has from 1 to 6 carbon atoms and which is
unsubstituted or is substituted by at least one substituent
selected from the group consisting of a hydroxy group, a halogen
atom, an alkoxy group having from 1 to 6 carbon atoms and an
alkylthio group having from 1 to 6 carbon atoms; R.sup.4 is a
hydrogen atom; an alkyl group which has from 1 to 6 carbon atoms
and which is unsubstituted or is substituted by at least one
substituent selected from the group consisting of a hydroxy group,
a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and
an alkylthio group having from 1 to 6 carbon atoms; a cycloalkyl
group having from 3 to 8 carbon atoms, an aryl group; or an aralkyl
group; said aryl group having from 6 to 14 ring carbon atoms in a
carbocyclic ring and are unsubstituted or are substituted by at
least one substituent selected from the group consisting of
substituents .alpha. and substituents .beta.; said aralkyl group
are an alkyl group having from 1 to 6 carbon atoms and which are
substituted by at least one aryl group as defined above; said
substituents .alpha. are selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 6
carbon atoms and an alkylthio group having from 1 to 6 carbon
atoms; said substituents .beta. are selected from the group
consisting of an alkyl group which has from 1 to 6 carbon atoms and
which is unsubstituted or are substituted by at least one
substituent selected from the group consisting of a hydroxy group,
a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and
an alkylthio group having from 1 to 6 carbon atoms; an alkanoyloxy
group having from 1 to 6 carbon atoms; a mercapto group; an
alkanoylthio group having from 1 to 6 carbon atoms; an
alkylsulfinyl group having from 1 to 6 carbon atoms; a cycloalkloxy
group having from 3 to 8 carbon atoms; a haloalkoxy group having
from 1 to 6 carbon atoms; and an alkylenedioxy group having from 1
to 6 carbon atoms; or a pharmaceutically acceptable salt, solvate,
or prodrug.
58. The composition of claim 57 wherein the 1,2-diphenylpyrrole
derivative has the following formula: ##STR00012## wherein: R is a
hydrogen atom, a halogen atom or an alkyl group having from 1 to 4
carbon atoms; R.sup.1 is a methyl group or an amino group; R.sup.2
is an unsubstituted phenyl group or a phenyl group which is
substituted by at least one substituent selected from the group
consisting of a halogen atom; an alkoxy group having from 1 to 4
carbon atoms; an alkylthio group having from 1 to 4 carbon atoms;
an unsubstituted alkyl group having from 1 to 4 carbon atoms; an
alkyl group having from 1 to 4 carbon atoms and which is
substituted by at least one substituent selected from the group
consisting of a halogen atom, an alkoxy group having from 1 to 4
carbon atoms and an alkylthio group having from 1 to 4 carbon
atoms; a haloalkoxy group having from 1 to 4 carbon atoms; and an
alkylenedioxy group having from 1 to 4 carbon atoms; R.sup.3 is a
hydrogen atom, a halogen atom, an unsubstituted alkyl group having
from 1 to 4 carbon atoms or a substituted alkyl group having from 1
to 4 carbon atoms and substituted by at least one substituent
selected from the group consisting of a halogen atom, an alkoxy
group having from 1 to 4 carbon atoms and an alkylthio group having
from 1 to 4 carbon atoms; R.sup.4 is a hydrogen atom; an
unsubstituted alkyl group having from 1 to 4 carbon atoms; a
substituted alkyl group having from 1 to 4 carbon atoms and
substituted by at least one substituent selected from the group
consisting of a hydroxy group, a halogen atom, an alkoxy group
having from 1 to 4 carbon atoms and an alkylthio group having from
1 to carbon atoms; a cycloalkyl group having from 3 to 6 carbon
atoms; an aryl group which has from 6 to 10 ring carbon atoms and
which is unsubstituted or is substituted by at least one
substituent selected from the group consisting of a halogen atom;
an alkoxy group having from 1 to 4 carbon atoms; an alkylthio group
having from 1 to 4 carbon atoms; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4
carbon atoms and substituted by at least one substituent selected
from the group consisting of a hydroxy group, a halogen atom, an
alkoxy group having from 1 to 4 carbon atoms and an alkylthio group
having from 1 to 4 carbon atoms; and a cycloalkyloxy group having
from 3 to 7 carbon atoms; an aralkyl group having from 1 to 4
carbon atoms in the alkyl part and containing at least one said
aryl group; or a pharmaceutically acceptable salt, solvate, or
prodrug.
59. The composition of claim 57 wherein the 1,2-diphenylpyrrole
derivative has the following formula: ##STR00013## wherein: R is a
hydrogen atom; R.sup.1 is an amino group; R.sup.2 is an
unsubstituted phenyl group or a phenyl group which is substituted
by at least one substituent selected from the group consisting of a
halogen atom, an alkoxy group having from 1 to 4 carbon atoms, an
alkylthio group having from 1 to 4 carbon atoms, an alkyl group
having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to
4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms
and a alkylenedioxy group having from 1 to 4 carbon atoms; R.sup.3
is a hydrogen atom, a halogen atom, an alkyl group having from 1 to
4 carbon atoms or a haloalkyl group having from 1 to 4 carbon
atoms; R.sup.4 is a hydrogen atom; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; a substituted alkyl group having
from 1 to 4 carbon atoms and substituted by at least one
substituent selected from the group consisting of a hydroxy group
and an alkoxy group having from 1 to 4 carbon atoms; a cycloalkyl
group having from 3 to 6 carbon atoms; an aryl group which has from
6 to 10 ring carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a hydroxy group; a halogen atom; an alkoxy group
having from 1 to 4 carbon atoms; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4
carbon atoms and which is unsubstituted or substituted by at least
one halogen atom; and a cycloalkyloxy group having from 3 to 7
carbon atoms; and an aralkyl group having from 1 to 4 carbon atoms
in the alkyl part and containing at least one said aryl group; or a
pharmaceutically acceptable salt, solvate, or prodrug.
60. The composition of claim 59 wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
61. The composition of claim 56 wherein the EGFR inhibitor is
erlotinib.
62. The composition of claim 56 wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
63. The composition of claim 56 wherein the composition is a single
dosage form.
64. The composition of claim 63 wherein the single dosage form
enhances patient compliance and/or reduces pill burden.
65. The composition of claim 62 wherein the combination is in an
oral, parenteral, buccal, intranasal, epidural, sublingual,
pulmonary, local, rectal, or transdermal form.
66. The composition of claim 65 wherein the combination is in the
parenteral form.
67. The composition of claim 66 wherein the parenteral form is
intravenous, subcutaneous, intrathecal, or intramuscular.
68. The composition of claim 63 wherein the single dosage form is a
single capsule or a single tablet.
69. The composition of claim 68 wherein the composition is a single
tablet.
70. The composition of claim 69 wherein the single tablet comprises
from about 1 mg to about 1200 mg of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and from
about 25 mg to about 450 mg of erlotinib.
71. The composition of claim 70 wherein the single tablet comprises
from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
25 mg of erlotinib.
72. The composition of claim 70 wherein the single tablet comprises
from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
100 mg of erlotinib.
73. The composition of claim 70 wherein the single tablet comprises
from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
150 mg of erlotinib.
74. The composition of claim 70 wherein the single tablet comprises
from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
200 mg of erlotinib.
75. The composition of claim 70 wherein the single tablet comprises
from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
300 mg of erlotinib.
76. The composition of claim 70 wherein the single tablet comprises
from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
450 mg of erlotinib.
77. The composition of claim 70 wherein the composition is suitable
for once-daily administration.
78. The composition of claim 56 wherein the EGFR inhibitor is a
small molecule compound or an antibody.
79. The composition of claim 78 wherein the small molecule compound
is selected from the group consisting of: ZM-254530, BIBX-1382,
reveromycin A, gefitinib, CGP-57148, CGP-59326,
4-(3-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, tyrphostin,
PKI-166, PD 153035, EKB-569, and 4-(phenylamino)quinazolines, or
their pharmaceutically acceptable salts, solvates, or prodrugs.
80. The composition of claim 78 wherein the antibody is selected
from the group consisting of: EGF receptor antibody, MR1scFvPE38
KDEL MDX-447, MDX-210, MD-72000, MDX-260, wayne anti-EGFR Mabs,
anti-EGFr Mab, anti-EGFr MAb, Genen anti-EGFR Mab, MAb DC-101,
trastuzumab, anti-VEGF monoclonal, anti-EGFR-DM1 Ab, MAb 4D5,
BAB-447, EMD-55900, EMD-6200, -82633, anti-EGFR Mab, MAb 4D5,
cetuximab, anti-EGFr MAb, anti-flk-1, CCX, CCZ, anti-flk-1, AG-514,
AG-568, nti-EGFR-DM1 Ab, MDX-447, TgDCC-E1A, C225, matuzumab,
panitumumab, DWP-408, and RC-3940II.
81. The composition of claim 56 wherein the composition contains a
lower dose of EGFR inhibitor than a conventional treatment for
cancer.
82. The composition of claim 56 wherein the composition reduces the
side effects of the treatment of cancer.
83. The composition of claim 56 wherein the composition enhances
treatment of cancer.
84. A pharmaceutical composition for treating cancer comprising, a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor, and a pharmaceutically acceptable excipient or
carrier.
85. The pharmaceutical composition of claim 84 wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
86. The pharmaceutical composition of claim 84 wherein the EGFR
inhibitor is erlotinib.
87. The pharmaceutical composition of claim 84 wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
88. A kit for treating cancer comprising a single dosage form
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor and instructions on how to administer the dosage
form.
89. The kit of claim 88 wherein the 1,2-diphenylpyrrole derivative
is 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
the EGFR inhibitor is erlotinib.
90. The method of claim 6 further comprising administering to the
subject one or more therapies in addition to the combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor.
91. The method of claim 90 wherein the one or more therapies
comprise one or more of surgery, radiation therapy, chemotherapy,
high dose chemotherapy with stem cell transplant; hormone therapy,
and monoclonal antibody therapy.
92. The method of claim 91 wherein radiation therapy comprises
internal and/or external radiation therapy.
93. The method of 91 wherein the chemotherapy comprises
administering to the subject gemcitabine.
94. A method for treating a subject having cancer, comprising
administering to the subject, a therapeutically effective amount of
a combination comprising
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole,
erlotinib and gemcitabine, or their respective pharmaceutically
acceptable salt, solvate, polymorph or prodrug.
95. The method of claim 94 wherein the
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole is
administered at a dose of 100-1200 mg per day, the erlotinib is
administered at a dose of 50-250 mg per day, and the gemcitabine is
administered at a dose of 500-1500 mg per meter squared of body
surface area per weekly intravenous administration.
96. The method of claim 95 wherein the
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole is
administered at a dose of 400 mg per day, the erlotinib is
administered at a dose of 100 mg per day, and the gemcitabine is
administered at a dose of 1000 mg per meter squared of body surface
area per weekly intravenous administration.
97. The method of claim 95 wherein the
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole is
administered at a dose of 400 mg per day, the erlotinib is
administered at a dose of 150 mg per day, and the gemcitabine is
administered at a dose of 1000 mg per meter squared of body surface
area per weekly intravenous administration.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/949,483, filed Jul. 12, 2007; U.S. Provisional
Application No. 60/990,900, filed Nov. 28, 2007; and U.S.
Provisional Application No. 61/044,425, filed Apr. 11, 2008, the
contents of which are incorporated herein by reference in their
entirety.
FIELD
[0002] The present invention relates to combination compositions
and the use of such combinations for the treatment of cancer,
tumors, and tumor-related disorders.
BACKGROUND
[0003] Cancer, tumors, tumor-related disorders, and neoplastic
disease states are serious and often times life-threatening
conditions. These diseases and disorders, which are characterized
by rapidly-proliferating cell growth, continue to be the subject of
research efforts directed toward the identification of therapeutic
agents which are effective in the treatment thereof. Such agents
prolong the survival of the patient, inhibit the
rapidly-proliferating cell growth associated with the neoplasm, or
effect a regression of the neoplasm.
[0004] Generally, surgery and radiation therapy are the first
modalities considered for the treatment of cancer that is
considered locally confined, and offer the best prognosis.
Chemotherapy treatment of certain cancers typically results in
disappointing survival rates but still offer a survival benefit.
For example, in patients with non-small cell lung cancer,
platinum-based chemotherapy regimens, such as the use of either
cisplatin or carboplatin plus one of either paclitaxel, docetaxel,
gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine, or
bevacizumab is employed. If patients cannot tolerate this therapy,
a single agent, such as
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine,
commonly known as erlotinib (Tarceva.RTM.), can be used. Erlotinib
targets the epidermal growth factor receptor tyrosine kinase which
is highly expressed and occasionally mutated in various forms of
cancer. If patients fail to respond to an erlotinib treatment,
additional conventional treatment offers limited benefit.
[0005] Despite erlotinib's approval for the treatment of stage IIIB
and IV non-small cell lung cancer, as with most therapeutic agents,
side-effects result from its use. For example, common side effects,
occurring in greater than 30% of patients taking erlotinib,
include, rash, diarrhea, poor appetite, fatigue, shortness of
breath, cough, nausea and vomiting. Additionally, less common side
effects include infection, mouth sores, itching, dry skin, eye
irritation, pulmonary fibrosis, and abdominal pain. Of greater
concern, is the growing view that, while utilization of erlotinib
for the treatment of tumors may initially shrink the size of the
tumor, the tumor may eventually enlarge in size, indicating, among
other things, the development of resistance. Erlotinib may be
representative of the types of therapeutic agents being used for
cancer treatment; in that its use has an effect on cancer, but
because of other factors, which are not entirely known, the tumor
develops resistance and progresses.
[0006] What is needed, therefore, are compositions and/or methods
of treatment for cancer which take advantage of the synergy found
in a therapeutic combination that could increase the effectiveness
of the agents and reduce and/or eliminate the side effects
typically associated with conventional treatments.
SUMMARY OF THE INVENTION
[0007] The present invention is based at least in part on a
synergistic effect obtained in treating conditions such as cancer
by a combination comprising a COX-2 selective inhibitor and an EGFR
inhibitor. Some of the possible favorable outcomes for synergism
include 1) increasing the efficacy of the therapeutic effect, 2)
decreasing the dosage but increasing or maintaining the same
efficacy to avoid toxicity, 3) minimizing or slowing down the
development of drug resistance, and 4) providing selective
synergism against target (or efficacy synergism) versus host (or
toxicity antagonism).
[0008] While some embodiments of the invention are illustrated
through a fixed dose combination comprising a COX-2 inhibitor and
an EGFR inhibitor, the embodiments of the invention cover
compositions and methods wherein the COX-2 inhibitor and the EGFR
inhibitor are provided in separate dosage forms.
[0009] The present invention is based, at least in part on the
discovery that combinations of a 1,2-diphenylpyrrole derivative and
an EGFR inhibitor provide numerous advantages in the treatment of
cancer, tumors, and tumor-related disorders. These combinations may
allow for lesser amounts of each particular agent to be delivered
and may produce the same or better effect as a greater amount of
each particular agent. For example, a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor (provided in
one fixed dose or in two separate dosage forms) will increase
therapeutic efficacy, reduce side effects, reduce resistance, and
when a fixed dose is used reduce the pill burden, enhance patient
compliance, and thus, support a more favorable treatment setting
and outcome. Such combinations can further increase the benefit of
each particular agent which otherwise would be only marginally
effective. As such, this synergistic or enhancement effect can be
employed in the treatment of cancer, tumors, and tumor-related
disorders, and may overcome resistance of tumors to drugs at
conventional doses.
Methods of Use
[0010] The present invention provides a method for treating cancer,
tumors, and tumor-related disorders. For example, the method
comprises administering to a subject in a combination therapy an
amount of a COX-2 selective inhibitor and an EGFR inhibitor,
wherein the COX-2 selective inhibitor and the EGFR inhibitor
combine to give a therapy suitable for treating a cancer, tumor,
and tumor-related disorders.
[0011] The invention further provides combinations of COX-2
selective inhibitors and EGFR inhibitors for antineoplastic,
anti-tumor, anti-cancer combination therapy. In one embodiment the
invention provides compositions comprising a combination of a COX-2
selective inhibitor and an EGFR inhibitor. The invention also
provides for the use of combinations of 1,2-diphenylpyrrole
derivatives and an EGFR inhibitor and/or their pharmaceutically
acceptable salt, solvate, or prodrug, as antineoplastic,
anti-tumor, or anti-cancer combination therapy.
[0012] In one embodiment, the invention provides a method for
treating a subject having cancer, comprising administering to the
subject, a therapeutically effective amount of a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
or their respective pharmaceutically acceptable salt, solvate or
prodrug.
[0013] In one embodiment, the 1,2-diphenylpyrrole derivative of the
combination composition has the following formula:
##STR00001##
[0014] wherein:
[0015] R is a hydrogen atom, a halogen atom or an alkyl group
having from 1 to 6 carbon atoms;
[0016] R.sup.1 is an alkyl group having from 1 to 6 carbon atoms or
an amino group;
[0017] R.sup.2 is a phenyl group which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of substituents .alpha. and substituents .beta.;
[0018] R.sup.3 is a hydrogen atom, a halogen atom or an alkyl group
which has from 1 to 6 carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a hydroxy group, a halogen atom, an alkoxy group
having from 1 to 6 carbon atoms and an alkylthio group having from
1 to 6 carbon atoms;
[0019] R.sup.4 is a hydrogen atom; an alkyl group which has from 1
to 6 carbon atoms and which is unsubstituted or is substituted by
at least one substituent selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 6
carbon atoms and an alkylthio group having from 1 to 6 carbon
atoms; a cycloalkyl group having from 3 to 8 carbon atoms, an aryl
group; or an aralkyl group; said aryl group having from 6 to 14
ring carbon atoms in a carbocyclic ring and are unsubstituted or
are substituted by at least one substituent selected from the group
consisting of substituents .alpha. and substituents .beta.;
[0020] said aralkyl group are an alkyl group having from 1 to 6
carbon atoms and which are substituted by at least one aryl group
as defined above;
[0021] said substituents .alpha. are selected from the group
consisting of a hydroxy group, a halogen atom, an alkoxy group
having from 1 to 6 carbon atoms and an alkylthio group having from
1 to 6 carbon atoms;
said substituents .beta. are selected from the group consisting of
an alkyl group which has from 1 to 6 carbon atoms and which is
unsubstituted or are substituted by at least one substituent
selected from the group consisting of a hydroxy group, a halogen
atom, an alkoxy group having from 1 to 6 carbon atoms and an
alkylthio group having from 1 to 6 carbon atoms; an alkanoyloxy
group having from 1 to 6 carbon atoms; a mercapto group; an
alkanoylthio group having from 1 to 6 carbon atoms; an
alkylsulfinyl group having from 1 to 6 carbon atoms; a cycloalkloxy
group having from 3 to 8 carbon atoms; a haloalkoxy group having
from 1 to 6 carbon atoms; and an alkylenedioxy group having from 1
to 6 carbon atoms; or a pharmaceutically acceptable salt, solvate,
or prodrug.
[0022] In another embodiment, a 1,2-diphenylpyrrole derivative of
the combination composition has the following formula:
##STR00002##
[0023] R is a hydrogen atom, a halogen atom or an alkyl group
having from 1 to 4 carbon atoms;
[0024] R.sup.1 is a methyl group or an amino group;
[0025] R.sup.2 is an unsubstituted phenyl group or a phenyl group
which is substituted by at least one substituent selected from the
group consisting of a halogen atom; an alkoxy group having from 1
to 4 carbon atoms; an alkylthio group having from 1 to 4 carbon
atoms; an unsubstituted alkyl group having from 1 to 4 carbon
atoms; an alkyl group having from 1 to 4 carbon atoms and which is
substituted by at least one substituent selected from the group
consisting of a halogen atom, an alkoxy group having from 1 to 4
carbon atoms and an alkylthio group having from 1 to 4 carbon
atoms; a haloalkoxy group having from 1 to 4 carbon atoms; and an
alkylenedioxy group having from 1 to 4 carbon atoms;
[0026] R.sup.3 is a hydrogen atom, a halogen atom, an unsubstituted
alkyl group having from 1 to 4 carbon atoms or a substituted alkyl
group having from 1 to 4 carbon atoms and substituted by at least
one substituent selected from the group consisting of a halogen
atom, an alkoxy group having from 1 to 4 carbon atoms and an
alkylthio group having from 1 to 4 carbon atoms;
[0027] R.sup.4 is a hydrogen atom; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; a substituted alkyl group having
from 1 to 4 carbon atoms and substituted by at least one
substituent selected from the group consisting of a hydroxy group,
a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and
an alkylthio group having from 1 to carbon atoms; a cycloalkyl
group having from 3 to 6 carbon atoms; an aryl group which has from
6 to 10 ring carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a halogen atom; an alkoxy group having from 1 to 4
carbon atoms; an alkylthio group having from 1 to 4 carbon atoms;
an unsubstituted alkyl group having from 1 to 4 carbon atoms; an
alkyl group having from 1 to 4 carbon atoms and substituted by at
least one substituent selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 4
carbon atoms and an alkylthio group having from 1 to 4 carbon
atoms; and a cycloalkyloxy group having from 3 to 7 carbon atoms;
an aralkyl group having from 1 to 4 carbon atoms in the alkyl part
and containing at least one said aryl group; or a pharmaceutically
acceptable salt, solvate, or prodrug.
[0028] In a further embodiment, the invention provides a
1,2-diphenylpyrrole derivative of the combination composition
wherein:
[0029] R is a hydrogen atom;
[0030] R.sup.1 is an amino group;
[0031] R.sup.2 is an unsubstituted phenyl group or a phenyl group
which is substituted by at least one substituent selected from the
group consisting of a halogen atom, an alkoxy group having from 1
to 4 carbon atoms, an alkylthio group having from 1 to 4 carbon
atoms, an alkyl group having from 1 to 4 carbon atoms, a haloalkyl
group having from 1 to 4 carbon atoms, a haloalkoxy group having
from 1 to 4 carbon atoms and a alkylenedioxy group having from 1 to
4 carbon atoms;
[0032] R.sup.3 is a hydrogen atom, a halogen atom, an alkyl group
having from 1 to 4 carbon atoms or a haloalkyl group having from 1
to 4 carbon atoms;
[0033] R.sup.4 is a hydrogen atom; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; a substituted alkyl group having
from 1 to 4 carbon atoms and substituted by at least one
substituent selected from the group consisting of a hydroxy group
and an alkoxy group having from 1 to 4 carbon atoms; a cycloalkyl
group having from 3 to 6 carbon atoms; an aryl group which has from
6 to 10 ring carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a hydroxy group; a halogen atom; an alkoxy group
having from 1 to 4 carbon atoms; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4
carbon atoms and which is unsubstituted or substituted by at least
one halogen atom; and a cycloalkyloxy group having from 3 to 7
carbon atoms; and an aralkyl group having from 1 to 4 carbon atoms
in the alkyl part and containing at least one said aryl group; or a
pharmaceutically acceptable salt, solvate, or prodrug.
[0034] In yet a further embodiment, the 1,2-diphenylpyrrole
derivative is selected from the group consisting of:
4-methyl-2-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxy-3-methylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3-fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3,4-dimethylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylphenyl)pyrrole;
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(4-methoxyphenyl)pyrrole;
and
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(3,4-dimethylphenyl)pyrrole.
[0035] In one embodiment the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole2-(4-ethoxypheny-
l)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
[0036] In another embodiment the EGFR inhibitor is erlotinib.
[0037] In a further embodiment, the 1,2-diphenylpyrrole derivative
is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole2-(4-ethoxypheny-
l)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the EGFR inhibitor is
erlotinib.
[0038] In yet a further embodiment the 1,2-diphenylpyrrole
derivative and the EGFR inhibitor are administered sequentially in
either order or simultaneously.
[0039] In one embodiment the 1,2-diphenylpyrrole derivative is
administered first.
[0040] In another embodiment the EGFR inhibitor is administered
first.
[0041] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders, comprising
administering the combination by a mode of administration
comprising oral, parenteral, buccal, intranasal, epidural,
sublingual, pulmonary, local, rectal, or transdermal
administration.
[0042] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
combination is orally administered as a single dosage form.
[0043] In another embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single dosage form enhances patient compliance and/or reduces pill
burden.
[0044] In a further embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single dosage form is a single capsule or a single tablet.
[0045] In yet a further embodiment, the invention provides a method
for treating cancer, tumors, and tumor-related disorders wherein
the composition is provided as a single tablet.
[0046] In a further embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders, comprising
administering the combination by a mode of parenteral
administration selected from intravenous, subcutaneous,
intrathecal, and intramuscular administration.
Dosages
[0047] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders comprising
administering the combination in a single tablet wherein the single
tablet comprises from about 1 mg to about 1200 mg of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and from
about 25 mg to about 450 mg of erlotinib.
[0048] In another embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
25 mg of erlotinib.
[0049] In a further embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
100 mg of erlotinib.
[0050] In yet a further embodiment, the invention provides a method
for treating cancer, tumors, and tumor-related disorders wherein
the single tablet comprises from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
150 mg of erlotinib.
[0051] In another embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
200 mg of erlotinib.
[0052] In yet another embodiment, the invention provides a method
for treating cancer, tumors, and tumor-related disorders wherein
the single tablet comprises from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
300 mg of erlotinib.
[0053] In a further embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises from about 1 mg to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
450 mg of erlotinib.
[0054] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises about 1 mg, about 5 mg, about 10 mg, about
25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
25 mg of erlotinib.
[0055] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises about 1 mg, about 5 mg, about 10 mg, about
25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
100 mg of erlotinib.
[0056] In another embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises about 1 mg, about 5 mg, about 10 mg, about
25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
150 mg of erlotinib.
[0057] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises about 1 mg, about 5 mg, about 10 mg, about
25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
200 mg of erlotinib.
[0058] In another embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises about 1 mg, about 5 mg, about 10 mg, about
25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
300 mg of erlotinib.
[0059] In a further embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders wherein the
single tablet comprises about 1 mg, about 5 mg, about 10 mg, about
25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about
400 mg, about 600 mg, about 800 mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
450 mg of erlotinib.
[0060] In one embodiment, the invention provides a method of
treating cancer, tumors, and tumor-related disorders comprising
administering a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
composition is suitable for once-daily administration.
[0061] In a further embodiment, the invention provides a method
wherein administering the combination enhances treatment of the
subject compared to administering one component of the combination
alone.
Types of Cancer
[0062] In yet a further embodiment, the invention provides a method
wherein administering the combination reduces the side effects of
treatment for a cancer, tumor, and tumor-related disorders.
[0063] In one embodiment the cancer is selected from the group
consisting of: oral cancer, prostate cancer, rectal cancer,
non-small cell lung cancer, lip and oral cavity cancer, liver
cancer, lung cancer, anal cancer, kidney cancer, vulvar cancer,
breast cancer, oropharyngeal cancer, nasal cavity and paranasal
sinus cancer, nasopharyngeal cancer, urethra cancer, small
intestine cancer, bile duct cancer, bladder cancer, ovarian cancer,
laryngeal cancer, hypopharyngeal cancer, gallbladder cancer, colon
cancer, colorectal cancer, head and neck cancer, glioma;
parathyroid cancer, penile cancer, vaginal cancer, thyroid cancer,
pancreatic cancer, esophageal cancer, Hodgkin's lymphoma,
leukemia-related disorders, mycosis fungoides, and myelodysplastic
syndrome.
[0064] In another embodiment the cancer is non-small cell lung
cancer, pancreatic cancer, breast cancer, ovarian cancer,
colorectal cancer, or head and neck cancer.
[0065] In yet another embodiment the cancer is a carcinoma, a
tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma, or
a blastoma.
[0066] In one embodiment the carcinoma is selected from the group
consisting of: carcinoma, adenocarcinoma, adenoid cystic carcinoma,
adenosquamous carcinoma, adrenocortical carcinoma, well
differentiated carcinoma, squamous cell carcinoma, serous
carcinoma, small cell carcinoma, invasive squamous cell carcinoma,
large cell carcinoma, islet cell carcinoma, oat cell carcinoma,
squamous carcinoma, undifferentiatied carcinoma, verrucous
carcinoma, renal cell carcinoma, papillary serous adenocarcinoma,
merkel cell carcinoma, hepatocellular carcinoma, soft tissue
carcinomas, bronchial gland carcinomas, capillary carcinoma,
bartholin gland carcinoma, basal cell carcinoma, carcinosarcoma,
papilloma/carcinoma, clear cell carcinoma, endometrioid
adenocarcinoma, mesothelial, metastatic carcinoma, mucoepidermoid
carcinoma, cholangiocarcinoma, actinic keratoses, cystadenoma, and
hepatic adenomatosis.
[0067] In another embodiment the tumor is selected from the group
consisting of: astrocytic tumors, malignant mesothelial tumors,
ovarian germ cell tumors, supratentorial primitive neuroectodermal
tumors, Wilm's tumors, pituitary tumors, extragonadal germ cell
tumors, gastrinoma, germ cell tumors, gestational trophoblastic
tumors, brain tumors, pineal and supratentorial primitive
neuroectodermal tumors, pituitary tumors, somatostatin-secreting
tumors, endodermal sinus tumors, carcinoids, central cerebral
astrocytoma, glucagonoma, hepatic adenoma, insulinoma,
medulloepithelioma, plasmacytoma, vipoma, and pheochromocytoma.
[0068] In yet another embodiment the neoplasm is selected from the
group consisting of: intraepithelial neoplasia, multiple
myeloma/plasma cell neoplasm, plasma cell neoplasm, interepithelial
squamous cell neoplasia, endometrial hyperplasia, focal nodular
hyperplasia, hemangioendothelioma, and malignant thymoma.
[0069] In a further embodiment the lymphoma is selected from the
group consisting of: nervous system lymphoma, AIDS-related
lymphoma, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma,
lymphoma, and Waldenstrom's macroglobulinemia.
[0070] In another embodiment the melanoma is selected from the
group consisting of: acral lentiginous melanoma, superficial
spreading melanoma, uveal melanoma, lentigo maligna melanomas,
melanoma, intraocular melanoma, adenocarcinoma nodular melanoma,
and hemangioma.
[0071] In yet another embodiment the sarcoma is selected from the
group consisting of: adenomas, adenosarcoma, chondosarcoma,
endometrial stromal sarcoma, Ewing's sarcoma, Kaposi's sarcoma,
leiomyosarcoma, rhabdomyosarcoma, sarcoma, uterine sarcoma,
osteosarcoma, and pseudosarcoma.
[0072] In one embodiment the glioma is selected from the group
consisting of: glioma, brain stem glioma, and hypothalamic and
visual pathway glioma.
[0073] In another embodiment the blastoma is selected from the
group consisting of: pulmonary blastoma, pleuropulmonary blastoma,
retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, and
hemangiblastomas.
EGFR Inhibitors
[0074] In a further embodiment, the invention provides a method
wherein the EGFR inhibitor is a small molecule compound or an
antibody.
[0075] In one embodiment, the invention provides a method wherein
the small molecule compound is selected from the group consisting
of: ZM-254530, BIBX-1382, reveromycin A, gefitinib, CGP-57148,
CGP-59326, 4-(3-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine,
tyrphostin, PKI-166, PD 153035, EKB-569, and
4-(phenylamino)quinazolines, or their pharmaceutically acceptable
salts, solvates, or prodrugs.
[0076] In another embodiment the invention provides a method
wherein the antibody is selected from the group consisting of: EGF
receptor antibody, MR1scFvPE38 KDEL MDX-447, MDX-210, MD-72000,
MDX-260, wayne anti-EGFR Mabs, anti-EGFr Mab, anti-EGFr MAb, Genen
anti-EGFR Mab, MAb DC-101, trastuzumab, anti-VEGF monoclonal,
anti-EGFR-DM1 Ab, MAb 4D5, BAB-447, EMD-55900, EMD-6200, -82633,
anti-EGFR Mab, MAb 4D5, cetuximab, anti-EGFr MAb, anti-flk-1, CCX,
CCZ, anti-flk-1, AG-514, AG-568, nti-EGFR-DM1 Ab, MDX-447,
TgDCC-E1A and C225, matuzumab, panitumumab, DWP-408, and
RC-3940II.
[0077] In another embodiment the EGFR inhibitor is selected from
the group consisting of: muellerian-inhibiting hormone, TNP-470,
tecogalan sodium, EGF receptor antisense, PI-88, oligonucleotide,
bromelain molecules, amphiregulin, EGF fusion toxin, EGF fusion
protein, Amphiregulin hbEGF-toxin, hbEGF-toxin, and EGF fusion
protein.
Further Methods of Use
[0078] In one embodiment, the invention provides a method of
inducing differentiation of tumor cells, the method comprising
contacting the cells with an effective amount of a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
whereby the combination induces differentiation of tumor cells.
[0079] In one embodiment, the invention provides a method of
inhibiting proliferation of cancer cells, the method comprising
contacting a cancer cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor whereby the
combination inhibits proliferation of cancer cells.
[0080] In another embodiment, the invention provides a method for
reducing proliferation of cancer cells, the method comprising
delivering to the cells a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, whereby the
reduction of cell proliferation is greater than a reduction caused
by either a 1,2-diphenylpyrrole derivative alone or an EGFR
inhibitor alone.
[0081] In one embodiment, the invention provides a method of
modulating autophosphorylation with a molecule of ATP, the method
comprising delivering to a cancer cell an effective amount of a
combination comprising a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the combination inhibits autophosphorylation with
a molecule of ATP.
[0082] In a further embodiment, the invention provides a method of
inhibiting metastases of tumor cells, the method comprising
administering an effective amount of a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor such that the
combination inhibits metastatic activity of tumor cells.
[0083] In one embodiment, the invention provides a method for
inducing apoptosis in cancer cells, the method comprising
contacting the cancer cells with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR kinase sufficient to
induce apoptosis.
[0084] In another embodiment, the invention provides a method for
sensitizing EGFR-inhibitor resistant cancer cells to an EGFR
inhibitor, the method comprising administering a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the combination sensitizes the cancer cells to the EGFR
inhibitor.
[0085] In one embodiment, the invention provides a method of
treating EGFR resistance in a cancer cell, the method comprising,
administering a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor
[0086] In a further embodiment, the invention provides a method of
modulating prostaglandin synthesis in a cancer cell, the method
comprising contacting the cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits prostaglandin synthesis in a cancer cell.
[0087] In one embodiment, the invention provides a method of
modulating cyclooxygenase expression in a cancer cell, the method
comprising delivering to the cell a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits cyclooxygenase expression in a cancer
cell.
[0088] In one embodiment, the invention provides a method of
modulating angiogenesis in a cancer cell, the method comprising
contacting the cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits angiogenesis in a cancer cell.
[0089] In another embodiment, the invention provides a method of
reducing the dosage in conventional treatment for neoplasia and/or
neoplasia related disorders in a subject, the method comprising
administering to a subject a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the combination reduces
the dosage in conventional treatment for neoplasia and/or
neoplasia-related disorders.
[0090] In one embodiment, the invention provides a method of
treating neoplasia and/or neoplasia related disorders, the method
comprising administering a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor
[0091] In one embodiment, the invention provides a composition for
treating cancer comprising, a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor or their respective
pharmaceutically acceptable salt, solvate or prodrug.
[0092] In one embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
[0093] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor, wherein the EGFR inhibitor is erlotinib.
[0094] In yet another embodiment, the invention provides a method
of treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0095] In one embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the composition is a single dosage form.
[0096] In a further embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein a single dosage form enhances patient compliance
and/or reduces pill burden.
[0097] In one embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders, comprising
administering a combination according to the invention by a mode of
administration comprising oral, parenteral, buccal, intranasal,
epidural, sublingual, pulmonary, local, rectal, or transdermal
administration.
[0098] In a further embodiment, the invention provides a method for
treating cancer, tumors, and tumor-related disorders, comprising a
combination according to the invention by parenteral administration
selected from intravenous, subcutaneous, intrathecal, and
intramuscular administration.
[0099] In one embodiment, the invention provides a method
comprising administering the combination in a single dosage
form.
[0100] In yet a further embodiment, the invention provides a method
of treatment comprising administering a composition comprising a
single tablet combination of a 1,2-diphenylpyrrole derivative and
an EGFR inhibitor wherein a single dosage form is a single capsule
or a single tablet.
[0101] In one embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the composition is in the form of a single
tablet.
[0102] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the single tablet comprises from about 1 mg to
about 1200 mg of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and from
about 25 mg to about 450 mg of erlotinib.
[0103] In yet another embodiment, the invention provides a method
of treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the single tablet comprises from about 1 mg to
about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
25 mg of erlotinib.
[0104] In one embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg
to about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
100 mg of erlotinib.
[0105] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the single tablet comprises from about 1 mg to
about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
150 mg of erlotinib.
[0106] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the single tablet comprises from about 1 mg to
about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
200 mg of erlotinib.
[0107] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the single tablet comprises from about 1 mg to
about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
300 mg of erlotinib.
[0108] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the single tablet comprises from about 1 mg to
about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
450 mg of erlotinib.
[0109] In a further embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg,
about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg,
about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800
mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
25 mg of erlotinib.
[0110] In a further embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg,
about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg,
about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800
mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
100 mg of erlotinib.
[0111] In a further embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg,
about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg,
about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800
mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
150 mg of erlotinib.
[0112] In a further embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg,
about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg,
about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800
mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
200 mg of erlotinib.
[0113] In a further embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg,
about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg,
about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800
mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
300 mg of erlotinib.
[0114] In a further embodiment, the invention provides a method of
treatment comprising administering a single tablet composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the single tablet comprises from about 1 mg,
about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg,
about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800
mg, about 1000 mg, or about 1200 mg
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and about
450 mg of erlotinib.
[0115] In one embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the composition is suitable for once-daily
administration.
[0116] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the EGFR inhibitor is a small molecule compound
or an antibody.
[0117] In a further embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and a small
molecule wherein the small molecule compound is selected from the
group consisting of: ZM-254530, BIBX-1382, reveromycin A,
gefitinib, CGP-57148, CGP-59326,
4-(3-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, tyrphostin,
PKI-166, PD 153035, EKB-569, and 4-(phenylamino)quinazolines, or
their pharmaceutically acceptable salts, solvates, or prodrugs.
[0118] In another embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the EGFR inhibitor is an antibody selected from
the group consisting of: EGF receptor antibody, MR1scFvPE38 KDEL
MDX-447, MDX-210, MD-72000, MDX-260, wayne anti-EGFR Mabs,
anti-EGFr Mab, anti-EGFr MAb, Genen anti-EGFR Mab, MAb DC-101,
trastuzumab, anti-VEGF monoclonal, anti-EGFR-DM1 Ab, MAb 4D5,
BAB-447, EMD-55900, EMD-6200, -82633, anti-EGFR Mab, MAb 4D5,
cetuximab, anti-EGFr MAb, anti-flk-1, CCX, CCZ, anti-flk-1, AG-514,
AG-568, nti-EGFR-DM1 Ab, MDX-447, TgDCC-E1A, C225, matuzumab,
panitumumab, DWP-408, and RC-3940II.
[0119] In yet another embodiment, the invention provides a method
of treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the composition contains a lower dose of an EGFR
inhibitor than a conventional treatment for cancer.
[0120] In a further embodiment, the invention provides a method of
treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the composition reduces the side effects of
cancer treatment.
[0121] In yet a further embodiment, the invention provides a method
of treatment comprising administering a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the composition enhances treatment of cancer.
Pharmaceutical Compositions
[0122] In one embodiment the invention provides a pharmaceutical
composition for treating cancer comprising, a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, and a
pharmaceutically acceptable excipient or carrier.
[0123] In one embodiment, the invention provides a pharmaceutical
composition for treating cancer wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
[0124] In another embodiment, the invention provides a
pharmaceutical composition for treating cancer wherein the EGFR
inhibitor is erlotinib.
[0125] In yet another embodiment, the invention provides a
pharmaceutical composition for treating cancer wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
Kits/Articles of Manufacture
[0126] In one embodiment the invention provides a kit for treating
cancer comprising a single dosage form comprising a combination of
a 1,2-diphenylpyrrole derivative and an EGFR inhibitor and
instructions on administration.
[0127] In one embodiment the invention provides a kit for treating
cancer having a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
INCORPORATION BY REFERENCE
[0128] All publications, patents, and patent applications described
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0129] FIG. 1 provides graphs illustrating COX-2 expression levels
in colorectal cancer.
[0130] FIG. 2 provides an illustration of the interactions between
the EGFR and COX pathways.
[0131] FIG. 3 provides a graph illustrating the results of a A431
squamous vulvar carcinoma xenograft study.
DETAILED DESCRIPTION
[0132] To facilitate understanding of the disclosure set forth
herein, a number of terms are defined below.
DEFINITIONS
[0133] As used herein, "abnormal cell growth," refers to cell
growth that is independent of normal regulatory mechanisms (e.g.,
loss of contact inhibition), including the abnormal growth of
normal cells and the growth of abnormal cells. This includes, but
is not limited to, the abnormal growth of: (1) tumor cells
(tumors), both benign and malignant, expressing an activated Ras
oncogene; (2) tumor cells, both benign and malignant, in which the
Ras protein is activated as a result of oncogenic mutation in
another gene; (3) benign and malignant cells of other proliferative
diseases in which aberrant Ras activation occurs. Examples of such
benign proliferative diseases are psoriasis, benign prostatic
hypertrophy, human papilloma virus (HPV), and restenosis. Abnormal
cell growth, also refers to and includes the abnormal growth of
cells, both benign and malignant, resulting from activity of the
enzymes farnesyl protein transferase, protein kinases, protein
phosphatases, lipid kinases, lipid phosphatases, or activity of
transcription factors, or intracellular or cell surface receptor
proteins.
[0134] "Neoplasia" as described herein, is an abnormal, unregulated
and disorganized proliferation of cells that is distinguished from
normal cells by autonomous growth and somatic mutations. An
accumulation of neoplastic cells is also known as a neoplasm, or
tumor. As neoplastic cells grow and divide they pass on their
genetic mutations and proliferative characteristics to progeny
cells. In some embodiments, the neoplasm can be benign or
malignant.
[0135] "Metastasis," as used herein, refers to the dissemination of
tumor cells via lymphatics or blood vessels. Metastasis also refers
to the migration of tumor cells by direct extension through serous
cavities, or subarachnoid or other spaces. Through the process of
metastasis, tumor cell migration to other areas of the body
establishes neoplasms in areas away from the site of initial
appearance.
[0136] As discussed herein, "angiogenesis" is prominent in tumor
formation and metastasis. Angiogenic factors have been found
associated with several solid tumors such as rhabdomyosarcomas,
retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma. A
tumor cannot expand without a blood supply to provide nutrients and
remove cellular wastes. Tumors in which angiogenesis is important
include solid tumors such as renal cell carcinoma, hepatocellular
carcinoma, and benign tumors such as acoustic neuroma, and
neurofibroma, trachoma and pyogenic granulomas. Angiogenesis has
been associated with blood-born tumors such as leukemias. It is
believed that angiogenesis plays a role in the abnormalities in the
bone marrow that give rise to leukemia. Prevention of angiogenesis
could halt the growth of cancerous tumors and the resultant damage
to the subject due to the presence of the tumor.
[0137] The term "subject" refers to an animal, including, but not
limited to, a primate (e.g., human), cow, sheep, goat, horse, dog,
cat, rabbit, rat, or mouse. The terms "subject" and "patient" are
used interchangeably herein in reference, for example, to a
mammalian subject, such as a human subject.
[0138] The terms "treat," "treating," and "treatment" are meant to
include alleviating or abrogating a disorder, disease, or
condition; or one or more of the symptoms associated with the
disorder, disease, or condition; or alleviating or eradicating the
cause(s) of the disorder, disease, or condition itself.
[0139] The term "therapeutically effective amount" refers to the
amount of a compound that, when administered, is sufficient to
prevent development of, or alleviate to some extent, one or more of
the symptoms of the disorder, disease, or condition being treated.
The term "therapeutically effective amount" also refers to the
amount of a compound that is sufficient to elicit the biological or
medical response of a cell, tissue, system, animal, or human that
is being sought by a researcher, veterinarian, medical doctor, or
clinician.
[0140] The term "pharmaceutically acceptable carrier,"
"pharmaceutically acceptable excipient," "physiologically
acceptable carrier," or "physiologically acceptable excipient"
refers to a pharmaceutically-acceptable material, composition, or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent, or encapsulating material. Each component must be
"pharmaceutically acceptable" in the sense of being compatible with
the other ingredients of a pharmaceutical formulation. It must also
be suitable for use in contact with the tissue or organ of humans
and animals without excessive toxicity, irritation, allergic
response, immunogenicity, or other problems or complications,
commensurate with a reasonable benefit/risk ratio. See, Remington:
The Science and Practice of Pharmacy, 21st Edition; Lippincott
Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of
Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The
Pharmaceutical Press and the American Pharmaceutical Association:
2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash
and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical
Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca
Raton, Fla., 2004).
[0141] The term "pharmaceutical composition" refers to a mixture of
a compound disclosed herein with other chemical components, such as
diluents or carriers. The pharmaceutical composition facilitates
administration of the compound to an organism. Multiple techniques
of administering a compound exist in the art including, but not
limited to, oral, injection, aerosol, parenteral, and topical
administration. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like.
Cyclooxygenase
[0142] Cyclooxygenase (COX) is an enzyme that is responsible for
the formation of important biological mediators called prostanoids,
including prostaglandins, prostacyclin and thromboxane. COX
converts arachidonic acid, an .omega.-6 essential fatty acid, to
prostaglandin H.sub.2 (PGH.sub.2), the precursor of the series-2
prostanoids. The enzyme contains two active sites: a heme with
peroxidase activity, responsible for the reduction of PGG.sub.2 to
PGH.sub.2, and a cyclooxygenase site, where arachidonic acid is
converted into the hydroperoxy endoperoxide prostaglandin G.sub.2
(PGG.sub.2). The reaction proceeds through a hydrogen atom
abstraction from arachidonic acid by a tyrosine radical generated
by the peroxidase active site, then two oxygen molecules react with
the arachidonic acid radical, giving PGG.sub.2.
[0143] COX-1 is a constitutive enzyme responsible for biosynthesis
of prostaglandins in the gastric mucosa and in the kidney among
other sites. COX-2 is an enzyme that is produced by an inducible
gene that is responsible for biosynthesis of prostaglandins in
inflammatory cells. Inflammation causes induction of COX-2, leading
to release of prostanoids (prostaglandin E2), which sensitize
peripheral nociceptor terminals and produce localized pain
hypersensitivity, inflammation and edema.
[0144] Historically, physicians have treated inflammation-related
disorders with a regimen of NSAIDs such as, for example, aspirin
and ibuprofen. Undesirably, however, some NSAIDs are known to cause
gastrointestinal (GI) bleeding or ulcers in patients undergoing
consistent long term regimens of NSAID therapy. Henry et al.,
Lancet, 1991, 337, 730. A reduction of unwanted side effects of
common NSAIDs was made possible by the discovery that the two
cyclooxygenases involved in the transformation of arachidonic acid
as the first step in the prostaglandin synthesis pathway were
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
[0145] Many common NSAIDs are now known to be inhibitors of both
COX-1 and COX-2. Accordingly, when administered in sufficiently
high levels, these NSAIDs not only alleviate the inflammatory
consequences of COX-2 activity, but also inhibit the beneficial
gastric maintenance activities of COX-1. Research into the area of
arachidonic acid metabolism has resulted in the discovery of
compounds that selectively inhibit the COX-2 enzyme to a greater
extent than they inhibit COX-1. These COX-2 selective inhibitors
are believed to offer advantages that include the capacity to
prevent or reduce inflammation while avoiding harmful side effects
associated with the inhibition of COX-1. Thus, COX-2 selective
inhibitors have shown great promise for use in therapies,
especially in therapies that require maintenance administration,
such as for pain and inflammation control.
[0146] As described herein, the terms "cyclooxygenase-2 inhibitor"
and "Cox-2 inhibitor", which can be used interchangeably herein,
denote compounds which inhibit the cyclooxygenase-2 enzyme (COX-2)
regardless of the degree of inhibition of the cyclooxygenase-1
enzyme (COX-1), and include pharmaceutically acceptable racemates,
enantiomers, tautomers, salts, esters and prodrugs of those
compounds. Thus, for purposes of the present disclosure, a compound
is considered a COX-2 inhibitor although the compound inhibits
COX-2 to an equal, greater, or lesser degree than it inhibits
COX-1. COX-2 inhibitors herein therefore encompass many traditional
non-selective NSAIDs.
COX-2 Selective Inhibitors
[0147] COX-2 inhibitors useful according to embodiments of the
present disclosure are agents and compounds that selectively or
preferentially inhibit COX-2 to a greater degree than they inhibit
COX-1. Such agents and compounds are termed "COX-2 selective
inhibitors" herein.
[0148] In practice, in a test for selectivity of a COX-2 selective
inhibitor, the observed selectivity varies depending upon the
conditions under which the test is performed and on the compound
being tested. For example, selectivity of a COX-2 inhibitor can be
measured as a ratio of the in vitro or in vivo IC.sub.50 value for
inhibition of COX-1, divided by the corresponding IC.sub.50 value
for inhibition of COX-2 (COX-1 IC.sub.50/COX-2 IC.sub.50). A COX-2
selective inhibitor herein is thus any inhibitor for which COX-1
IC.sub.50/COX-2 IC.sub.50 is greater than 1. In various
embodiments, this ratio is greater than about 2, greater than about
5, greater than about 10, greater than about 50, or greater than
about 100.
[0149] In one embodiment, the invention provides a composition,
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the ratio of selectivity of COX-2 over COX-1
inhibition is greater than about 1. In another embodiment, the
invention provides a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
ratio of selectivity of COX-2 over COX-1 inhibition is greater than
about 2. In a further embodiment, the invention provides a
composition comprising combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the ratio of selectivity
of COX-2 over COX-1 inhibition is greater than about 5. In another
embodiment, the invention provides a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the ratio of selectivity of COX-2 over COX-1
inhibition is greater than about 7.8. In yet a further embodiment,
the invention provides a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
ratio of selectivity of COX-2 over COX-1 inhibition is greater than
about 10. In another embodiment, the invention provides a
composition comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the ratio of selectivity
of COX-2 over COX-1 inhibition is greater than about 20. In a
further embodiment, the invention provides a composition comprising
a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the ratio of selectivity of COX-2 over COX-1
inhibition is greater than about 50. In yet a further embodiment,
the invention provides a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
ratio of selectivity of COX-2 over COX-1 inhibition is greater than
about 100. In one embodiment, the invention provides a composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein 1-2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole. In
another embodiment, the invention provides a composition comprising
a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the EGFR inhibitor is erlotinib. In a further
embodiment, the invention provides a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1-2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib and wherein the ratio of selectivity of
COX-2 over COX-1 inhibition is greater than about 1, about 2, about
5, about 7.8, about 10, about 20, about 50, and about 100.
[0150] In one embodiment, the invention provides a method for
treating a tumor and/or tumor related disease comprising
administering a combination of a 1,2-diphenylpyrrole derivative and
an EGFR inhibitor wherein the ratio of selectivity of COX-2 over
COX-1 inhibition is greater than about 1. In one embodiment, the
invention provides a method for treating a tumor and/or tumor
related disease comprising administering a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
ratio of selectivity of COX-2 over COX-1 inhibition is greater than
about 2. In a further embodiment, the invention provides a method
for treating a tumor and/or tumor related disease comprising
administering a combination of a 1,2-diphenylpyrrole derivative and
an EGFR inhibitor wherein the ratio of selectivity of COX-2 over
COX-1 inhibition is greater than about 5. In yet a further
embodiment, the invention provides a method for treating a tumor
and/or tumor related disease comprising administering a combination
of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein
the ratio of selectivity of COX-2 over COX-1 inhibition is greater
than about 10. In some embodiments, the invention provides methods
for treating a tumor and/or tumor related disease comprising
administering a combination of a 1,2-diphenylpyrrole derivative and
an EGFR inhibitor wherein the ratio of selectivity of COX-2 over
COX-1 inhibition is greater than about 20, than about 50, and about
100. In other embodiments, the invention provides methods for
treating a tumor and/or tumor related disease comprising
administering a combination of a 1,2-diphenylpyrrole derivative and
an EGFR inhibitor wherein the 1-2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib wherein the ratio of selectivity of
COX-2 over COX-1 inhibition is greater than about 1, about 2, about
5, about 7.8, about 10, about 20, about 50, and about 100.
[0151] As used herein, the term "IC.sub.50" with respect to a COX-1
or COX-2 inhibitor refers to the concentration of a compound that
is required to produce 50% inhibition of activity of COX-1 or
COX-2. In one embodiment, 1,2-diphenylpyrrole derivatives useful in
the present disclosure can have a COX-2 IC.sub.50 of less than
about 3 .mu.M. In another embodiment, the 1,2-diphenylpyrrole
derivative has a COX-2 IC.sub.50 of less than about 2.8 .mu.M. In
yet another embodiment, the 1,2-diphenylpyrrole derivative has a
COX-2 IC.sub.50 of less than about 2 .mu.M. In some embodiments,
1,2-diphenylpyrrole derivative useful in the present disclosure can
have a COX-2 IC.sub.50 of less than about 1 .mu.M, less than about
0.5 .mu.M, or less than about 0.2 .mu.M. 1,2-diphenylpyrrole
derivatives useful in the present disclosure can have a COX-1
IC.sub.50 of greater than about 1 .mu.M, for example greater than
about 20 .mu.M. In one embodiment, the invention provides a
composition comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the IC.sub.50 is less than
about 1 .mu.M. In another embodiment, the invention provides a
composition comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the IC.sub.50 is less than
about 0.5 .mu.M. In a further embodiment, the invention provides a
composition comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the IC.sub.50 is less than
about 0.2 .mu.M. In one embodiment the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole. In
another embodiment the EGFR inhibitor is erlotinib. In a further
embodiment the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib wherein the IC.sub.50 is less than
about 3 .mu.M, about 2.8 .mu.M, about 2 .mu.M, about 1 .mu.M, about
0.5 .mu.M, and about 0.2 .mu.M.
[0152] COX-2 inhibitors exhibiting a high degree of selectivity for
COX-2 over COX-1 inhibition can indicate ability to reduce
incidence of common NSAID-induced side effects. In one embodiment,
the invention provides a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
NSAID-induced side effects are substantially diminished. For
example, NSAID-induced side effects include, but are not limited
to, nausea, vomiting, diarrhea, constipation, decreased appetite,
rash, dizziness, headache, drowsiness, fluid retention, edema,
kidney failure, liver failure, ulcers and prolonged bleeding after
surgery. In another embodiment, the invention provides a
composition comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib and wherein the NSAID-induced side
effects are substantially diminished.
[0153] A COX-2 selective inhibitor can be used in a form of a
prodrug thereof. As described herein, a "COX-2 prodrug" is a
compound that can be converted into an active COX-2 selective
inhibitor by metabolic or simple chemical processes within the body
of the subject. One example of a prodrug for a COX-2 selective
inhibitor is parecoxib, for example in a form of a salt such as
parecoxib sodium, which is a therapeutically effective prodrug of
the tricyclic COX-2 selective inhibitor valdecoxib.
Overexpression of COX-2 and Cancer
[0154] The overexpression of COX-2 and also the upstream and
downstream enzymes of the prostaglandin synthesis pathway has been
demonstrated in multiple cancer types and some pre-neoplastic
lesions. Direct interactions of prostaglandins with their receptors
through autocrine or paracrine pathways to enhance cellular
survival or stimulate angiogenesis have been proposed as molecular
mechanisms underlying the pro-carcinogenic functions of COX
enzymes. In this respect, preclinical studies suggest that COX-2
may be involved in the molecular pathogenesis of some types of lung
cancer. Most of the studies point to its involvement in non-small
cell lung cancer. Survival of patients with non-small cell lung
cancer expressing high levels of COX-2 is markedly reduced.
Treatment of humans with the selective COX-2 inhibitor celecoxib
augments the antitumor effects of chemotherapy in patients with
non-small cell lung cancer. Studies indicate that prostaglandins
synthesized by cyclooxygenase play a critical role in the
initiation and promotion of cancer. Aberrant COX-2 expression was
reported in colorectal carcinomas and adenomas, and has been
detected in various human cancers, including those of the breast.
Moreover, COX-2 is overexpressed in neoplastic lesions of the
colon, breast, lung, prostate, esophagus, pancreas, intestine,
cervix, ovaries, urinary bladder and head and neck (see Table 1
below).
TABLE-US-00001 TABLE 1 COX-2 Expression in Tumors Tumor Type %
Tissue expressing COX-2 Colorectal Cancer 70-95 Non-small Cell Lung
Cancer 70-90 Gastric Cancer 45-75 Pancreatic Cancer 40-80
Glioblastoma Multiforme 40-70 Bladder Cancer 50-60 Esophageal
Cancer 50-60 Breast Cancer 40-50 Ovarian Cancer 40-60 Prostate
Cancer 40-60
[0155] COX-2 overexpression in murine mammary glands is sufficient
to cause tumor formation. In several in vitro and animal models,
COX-2 inhibitors have inhibited tumor growth and metastasis.
[0156] In addition to cancers per se, COX-2 is also expressed in
the angiogenic vasculature within and adjacent to hyperplastic and
neoplastic lesions indicating that COX-2 plays a role in
angiogenesis. In both the mouse and rat, COX-2 inhibitors markedly
inhibited bFGF-induces neovascularization. The utility of COX-2
inhibitors as chemopreventive, antiangiogenic and chemotherapeutic
agents is described in the literature. Koki et al., Exp. Opin.,
Invest. Drugs, 1999, 8(10) 1623-38.
[0157] COX-2 has been shown to regulate some embodiments of
tumor-associated angiogenesis. Angiogenesis is an attractive
therapeutic target because it is a multi-step process that occurs
in a specific sequence, thus providing several possible targets for
drug action. Angiogenesis is important in two stages of tumor
metastasis. The first stage where angiogenesis stimulation is
important is in the vascularization of the tumor which allows the
tumor cells to enter the blood stream and to circulate throughout
the body. After the tumor cells have left the primary site and have
settled into the secondary, metastasis site, angiogenesis must
occur before the new tumor can grow and expand. Therefore,
prevention of angiogenesis could lead to the prevention of
metastasis of tumors and possibly contain the neoplastic growth at
the primary site. Examples of agents that interfere with several of
these steps include, angiostatin, endostatin, interferon alpha and
COX-2 selective inhibitors that prevent the growth of cells that
form new blood vessels; and protein-based compounds that
simultaneously interfere with several of these targets.
[0158] Additionally, several studies have suggested that COX-2
expression is associated with parameters of aggressive breast
cancer, including large tumor size, positive axillary lymph node
metastases, and HER2-positive tumor status. Studies of mammary
tumors in mice and rats have indicated that moderate to high COX-2
expression is related to the genesis of mammary tumors that are
sensitive to treatment with nonspecific and specific COX-2
inhibitors. Further studies have shown that increased amounts of
prostaglandins and COX-2 are commonly found in a wide range of
premalignant tissues and malignant tumors including cervical
dysplasia and cancer. Elevated prostaglandin and COX-2 levels
substantially contribute to carcinogenesis by inhibiting apoptosis
and stimulating angiogenesis. Tsujii and DuBois, Cell, 1995, 83,
493-501.
[0159] Further, COX-2 is also highly expressed in prostate cancer,
particularly in the epithelial cell of high-grade prostatic
intraepithelial neoplasia and cancer. It was shown that treatment
of human prostate cancer cell lines with a selective COX-2
inhibitor induces apoptosis both in vitro and in vivo. The in vivo
results also indicate that the COX-2 inhibitor decreases tumor
microvessel density and angiogenesis. COX-2 inhibitors can prevent
the hypnoxic upregulation of a potent angiogenic factor, vascular
endothelial growth factor.
[0160] Overexpression of COX-2 has been documented in several
premalignant and malignant tissues. Subbaramaiah et al., Trends
Pharmacol. Sci., 2003, 24, 96-102. Without wishing to be bound by
any particular theory, this increase in expression is thought to be
a product of stimulation of PKC signaling, which stimulates
activity of MAPK, enhancing transcription of COX-2 by nuclear
factors. Additionally, enhanced stability of COX-2 mRNA transcripts
in cancer cells due to augmented binding of the RNA-binding protein
HuR, as well as activation of extracellular signal related kinase 1
and 2 (ERK 1 and 2) and p38, is thought to contribute to increased
expression of COX-2.
[0161] These results indicate that COX-2 inhibitors may serve as
effective chemopreventive and therapeutic agents in cancer of the
prostate.
COX-2 Selective Inhibitors
[0162] It has recently been found that the use of nonsteroidal
anti-inflammatory drugs (NSAIDs) has been associated with the
prevention and treatment of several types of cancer. Thun et al.,
J. National Cancer Inst., 2002, 94(4), 252-66. COX-2 inhibitors
have been utilized for the treatment of cancer and for the
treatment of tumors. For example, celecoxib, a COX-2 selective
inhibitor, exerted a potent inhibition of fibroblast growth
factor-induced corneal angiogenesis in rats. Masferrer et al.,
Proc. Am. Assoc. Cancer Research, 1999, 40, 396. Other COX-2
inhibitors have been described for the treatment of cancer, tumors
and neoplasia. FR 27 71 005 describes compositions containing a
COX-2 inhibitor and N-methyl-d-aspartate (NMDA) antagonist used to
treat cancer and other diseases. Further, WO 99/18960 describes a
combination comprising a COX-2 inhibitor that can be used to treat
colorectal and breast cancer. Additionally, WO 97/36497 describes a
combination comprising a COX-2 inhibitor and a 5-lipoxygenase
inhibitor useful in treating cancer.
1,2-Diphenylpyrrole Derivatives
[0163] 1,2-Diphenylpyrrole derivatives and pharmaceutically
acceptable salts, solvates, or prodrugs are known to have analgesic
and antiphlogistic properties. Further, they have been shown to act
as COX-2 selective inhibitors and are thus effective for the
prophylaxis and therapy of diseases mediated by COX-2 and/or
inflammatory cytokines. In addition, 1,2-diphenylpyrrole
derivatives have been shown to treat diseases involving or
resulting from the resorption of bone, such as osteoporosis,
rheumatoid arthritis and osteoarthritis.
[0164] These types of analgesics, anti-inflammatory agents and/or
antipyretics exhibit effects not only on inflammatory diseases,
such as pain, pyrexia, and edema, but also on chronic inflammatory
diseases, such as chronic rheumatoid arthritis and osteoarthritis,
allergic inflammatory diseases, asthma, sepsis, psoriasis, various
autoimmune diseases, systemic lupus erythematosus, juvenile onset
diabetes, autoimmune intestinal diseases (such as ulcerative
colitis, Crohn's disease), viral infection, and
glomerulonephritis.
[0165] 1,2-Diphenylpyrrole derivatives described herein have the
general formula:
##STR00003##
[0166] wherein:
[0167] R is a hydrogen atom, a halogen atom or an alkyl group
having from 1 to 6 carbon atoms;
[0168] R.sup.1 is an alkyl group having from 1 to 6 carbon atoms or
an amino group;
[0169] R.sup.2 is a phenyl group which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of substituents .alpha. and substituents .beta.;
[0170] R.sup.3 is a hydrogen atom, a halogen atom or an alkyl group
which has from 1 to 6 carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a hydroxy group, a halogen atom, an alkoxy group
having from 1 to 6 carbon atoms and an alkylthio group having from
1 to 6 carbon atoms;
[0171] R.sup.4 is a hydrogen atom; an alkyl group which has from 1
to 6 carbon atoms and which is unsubstituted or is substituted by
at least one substituent selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 6
carbon atoms and an alkylthio group having from 1 to 6 carbon
atoms; a cycloalkyl group having from 3 to 8 carbon atoms, an aryl
group; or an aralkyl group; said aryl group having from 6 to 14
ring carbon atoms in a carbocyclic ring and are unsubstituted or
are substituted by at least one substituent selected from the group
consisting of substituents .alpha. and substituents .beta.; said
aralkyl group are an alkyl group having from 1 to 6 carbon atoms
and which are substituted by at least one aryl group as defined
above;
[0172] said substituents .alpha. are selected from the group
consisting of a hydroxy group, a halogen atom, an alkoxy group
having from 1 to 6 carbon atoms and an alkylthio group having from
1 to 6 carbon atoms;
[0173] said substituents .beta. are selected from the group
consisting of an alkyl group which has from 1 to 6 carbon atoms and
which is unsubstituted or are substituted by at least one
substituent selected from the group consisting of a hydroxy group,
a halogen atom, an alkoxy group having from 1 to 6 carbon atoms and
an alkylthio group having from 1 to 6 carbon atoms; an alkanoyloxy
group having from 1 to 6 carbon atoms; a mercapto group; an
alkanoylthio group having from 1 to 6 carbon atoms; an
alkylsulfinyl group having from 1 to 6 carbon atoms; a cycloalkloxy
group having from 3 to 8 carbon atoms; a haloalkoxy group having
from 1 to 6 carbon atoms; and an alkylenedioxy group having from 1
to 6 carbon atoms; or a pharmaceutically acceptable salt, solvate,
or prodrug.
[0174] In one embodiment, the invention provides a
1,2-diphenylpyrrole derivative having the formula:
##STR00004##
[0175] wherein:
[0176] R is a hydrogen atom, a halogen atom or an alkyl group
having from 1 to 4 carbon atoms;
[0177] R.sup.1 is a methyl group or an amino group;
[0178] R.sup.2 is an unsubstituted phenyl group or a phenyl group
which is substituted by at least one substituent selected from the
group consisting of a halogen atom; an alkoxy group having from 1
to 4 carbon atoms; an alkylthio group having from 1 to 4 carbon
atoms; an unsubstituted alkyl group having from 1 to 4 carbon
atoms; an alkyl group having from 1 to 4 carbon atoms and which is
substituted by at least one substituent selected from the group
consisting of a halogen atom, an alkoxy group having from 1 to 4
carbon atoms and an alkylthio group having from 1 to 4 carbon
atoms; a haloalkoxy group having from 1 to 4 carbon atoms; and an
alkylenedioxy group having from 1 to 4 carbon atoms;
[0179] R.sup.3 is a hydrogen atom, a halogen atom, an unsubstituted
alkyl group having from 1 to 4 carbon atoms or a substituted alkyl
group having from 1 to 4 carbon atoms and substituted by at least
one substituent selected from the group consisting of a halogen
atom, an alkoxy group having from 1 to 4 carbon atoms and an
alkylthio group having from 1 to 4 carbon atoms;
[0180] R.sup.4 is a hydrogen atom; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; a substituted alkyl group having
from 1 to 4 carbon atoms and substituted by at least one
substituent selected from the group consisting of a hydroxy group,
a halogen atom, an alkoxy group having from 1 to 4 carbon atoms and
an alkylthio group having from 1 to carbon atoms; a cycloalkyl
group having from 3 to 6 carbon atoms; an aryl group which has from
6 to 10 ring carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a halogen atom; an alkoxy group having from 1 to 4
carbon atoms; an alkylthio group having from 1 to 4 carbon atoms;
an unsubstituted alkyl group having from 1 to 4 carbon atoms; an
alkyl group having from 1 to 4 carbon atoms and substituted by at
least one substituent selected from the group consisting of a
hydroxy group, a halogen atom, an alkoxy group having from 1 to 4
carbon atoms and an alkylthio group having from 1 to 4 carbon
atoms; and a cycloalkyloxy group having from 3 to 7 carbon atoms;
an aralkyl group having from 1 to 4 carbon atoms in the alkyl part
and containing at least one said aryl group; or a pharmaceutically
acceptable salt, solvate, or prodrug.
[0181] In one embodiment, the invention provides a
1,2-diphenylpyrrole derivative wherein:
[0182] R is a hydrogen atom;
[0183] R.sup.1 is an amino group;
[0184] R.sup.2 is an unsubstituted phenyl group or a phenyl group
which is substituted by at least one substituent selected from the
group consisting of a halogen atom, an alkoxy group having from 1
to 4 carbon atoms, an alkylthio group having from 1 to 4 carbon
atoms, an alkyl group having from 1 to 4 carbon atoms, a haloalkyl
group having from 1 to 4 carbon atoms, a haloalkoxy group having
from 1 to 4 carbon atoms and a alkylenedioxy group having from 1 to
4 carbon atoms;
[0185] R.sup.3 is a hydrogen atom, a halogen atom, an alkyl group
having from 1 to 4 carbon atoms or a haloalkyl group having from 1
to 4 carbon atoms;
[0186] R.sup.4 is a hydrogen atom; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; a substituted alkyl group having
from 1 to 4 carbon atoms and substituted by at least one
substituent selected from the group consisting of a hydroxy group
and an alkoxy group having from 1 to 4 carbon atoms; a cycloalkyl
group having from 3 to 6 carbon atoms; an aryl group which has from
6 to 10 ring carbon atoms and which is unsubstituted or is
substituted by at least one substituent selected from the group
consisting of a hydroxy group; a halogen atom; an alkoxy group
having from 1 to 4 carbon atoms; an unsubstituted alkyl group
having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4
carbon atoms and which is unsubstituted or substituted by at least
one halogen atom; and a cycloalkyloxy group having from 3 to 7
carbon atoms; and an aralkyl group having from 1 to 4 carbon atoms
in the alkyl part and containing at least one said aryl group; or a
pharmaceutically acceptable salt, solvate, or prodrug.
[0187] In one embodiment, R is a hydrogen atom. In another
embodiment, R is a fluorine atom.
[0188] In a further embodiment, R is a chlorine atom. In yet a
further embodiment, R is a methyl group.
[0189] In one embodiment, R.sup.1 is a methyl group. In another
embodiment, R.sup.1 is an amino group.
[0190] In one embodiment, R.sup.2 is a phenyl group.
[0191] In one embodiment, R.sup.3 is a hydrogen atom. In another
embodiment, R.sup.3 is a halogen atom.
[0192] In one embodiment, R.sup.4 is a hydrogen atom.
[0193] The term "aryl" refers to a carbocyclic aromatic hydrocarbon
group having from 6 to 14 carbon atoms in one or more aromatic
rings or such a group which is fused to a cycloalkyl group having
from 3 to 10 carbon atoms, and the group is unsubstituted or it is
substituted by at least one substituent selected from the group
consisting of hydroxy groups, halogen atoms, lower alkoxy groups,
lower alkylthio groups, lower alkyl groups, alkanoyloxy groups,
mercapto groups, alknoylthio groups, lower alkylsulfinyl groups,
lower alkyl groups having at least one substituent selected from
the group consisting of cycloalkloxy groups, lower haloalkoxy
groups, and lower alkylenedioxy groups.
[0194] In some embodiments, the 1,2-diphenylpyrrole derivative is
selected from the group consisting of compounds 2-1-2-213 of Table
2 as disclosed in U.S. Pat. No. 6,887,893, which is herein
incorporated in its entirety by reference.
[0195] In one embodiment, the 1,2-diphenylpyrrole derivative is
selected from the group consisting of:
4-methyl-2-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxy-3-methylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3-fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3,4-dimethylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylphenyl)pyrrole;
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(4-methoxyphenyl)pyrrole;
and
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(3,4-dimethylphenyl)pyrrole.
In another embodiment, the invention provides a method wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
[0196] In another embodiment, the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
[0197] The methods for synthesizing 1,2-diphenylpyrrole
derivatives, illustrated herein, are described in the Examples
section and in U.S. RE39,420, which is incorporated herein by
reference in its entirety.
##STR00005##
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
[0198] 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
has alternative chemical names, including
4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl benzenesulfonamide,
4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide,
TG01, CS-706 and apricoxib. It has a molecular formula of
C.sub.19H.sub.20N.sub.2O.sub.3S, a molecular weight of 356.4 and
the CAS registry number is 197904-84-0.
Receptor Tyrosine Kinases
[0199] Protein tyrosine kinases are a class of enzymes that
catalyze the transfer of a phosphate group from ATP or GTP to the
tyrosine residue located on protein substrates. Protein tyrosine
kinases clearly play a role in normal cell growth. Many of the
growth factor receptor proteins function as tyrosine kinases and it
is by this process that they effect signaling. The interaction of
growth factors with these receptors is a necessary event in normal
regulation of cell growth. Under certain conditions, however, as a
result of either mutation or overexpression, these receptors can
become deregulated; the result of which is uncontrolled cell
proliferation which can lead to tumor growth and ultimately to the
disease known as cancer. Wilks, Adv. Cancer Res., 1993, 60, 43.
Among the growth factor receptor kinases and their proto-oncogenes
that have been identified and which are targets of the combinations
presented herein are the epidermal growth factor receptor kinase
(EGFR kinase, the protein product of the erbB oncogene), and the
product produced by the erbB-2 (also referred to as the neu or
HER2) oncogene. Since the phosphorylation event is a necessary
signal for cell division to occur and since overexpressed or
mutated kinases have been associated with cancer, an inhibitor of
this event, a protein tyrosine inhibitor, will have therapeutic
value for the treatment of cancer and other diseases characterized
by uncontrolled or abnormal cell growth. For example,
overexpression of the receptor kinase product of the erbB-2
oncogene has been associated with human breast and ovarian cancers.
Slamon et. al., Science, 1989, 244, 707. Deregulation of EGFR
kinase has been associated with epidermoid tumors and tumors
involving other major organs. Because of the importance of the role
played by deregulated receptor kinases in the pathogenesis of
cancer, many recent studies have dealt with the development of
specific PTK inhibitors as potential anti-cancer therapeutic
agents.
[0200] Receptor tyrosine kinases span the cell membrane and possess
an extracellular binding domain for growth factors such as
epidermal growth factor (EGF), a transmembrane domain, and an
intracellular portion which functions as a kinase to phosphorylate
specific tyrosine kinase residues in proteins and hence to
influence cell proliferation. The EGF receptor tyrosine kinase
family has four members: EGFR (HER1, erbB1); HER2 (c-erbB2, erbB2,
neu); HER3 (erbB3); and HER4 (erbB4). The ErbB receptors generally
transduce signals through two pathways. It is known that such
kinases are frequently and aberrantly expressed in common human
cancers such as breast cancer, gastrointestinal cancer of colon,
rectum or stomach, leukemia, and ovarian, bronchial or pancreatic
cancer. As discussed previously, epidermal growth factor receptor
(EGFR), is mutated and/or overexpressed in many human cancers such
as brain, lung, squamous cell, bladder, gastric, breast, head and
neck, oesophageal, gynecological and thyroid tumors.
Epidermal Growth Factor Receptors
[0201] Control of cell growth is regulated by the interaction of
soluble growth factors and cell membrane receptors. The first step
in the mitogenic stimulation of epidermal cells is the specific
binding of epidermal growth factor (EGF) to a membrane glycoprotein
known as the epidermal growth factor receptor (EGFR). The EGFR is
composed of 1,186 amino acids which are divided into an
extracellular portion of 621 residues and a cytoplasmic portion of
542 residues connected by a single hydrophobic transmembrane
segment of 23 residues. Ullrich et al., Nature, 1986, vol. 309,
418-25. The external portion of the EGFR can be subdivided into
four domains. Recently, it has been demonstrated that domain III,
residues 333 to 460 which is flanked by two cysteine domains is
likely to contain the EGFR binding site of the receptor. Lax et
al., Mol. And Cell Biol., 1988, vol. 8, 1831-34. The binding of EGF
to domain III leads to the initiation of pleiotropic responses
leading to DNA synthesis and cell proliferation.
[0202] EGFR has also been found in various types of human tumor
cells and that those cells overexpress EGFR. For example, the
cancerous cells of bladder tumors have been shown to have a
relatively large population of EGF receptors. Neal et al., Lancet,
1985, vol. 1, 366-67. Breast cancer cells exhibit a positive
correlation between EGFR density and tumor size and a negative
correlation with the extent of differentiation. Sainsbury et al.,
Lancet, 1985, vol. 1, 364-66. The tumorigenicity of a series of
human vulval epidermoid carcinoma (A431) clonal variants implanted
into athymic mice having different levels of EGFR was found to
correlate directly with the level of expression of the EGF
receptor. Santon et al., Cancer Res., 1986, vol. 46, 4700-01. Thus,
it has been proposed that overexpression of EGFRs play a role in
the origin or tumorigenesis of cancer cells.
EGFR and COX Pathways
[0203] The relationship between the EGFR and COX pathways, to date,
has not yet been fully elucidated. It has been submitted, however,
that induction of COX-2 results in the production of increased
levels of prostaglandins which then stimulate angiogenesis, cell
proliferation and cell differentiation in an autocrine and/or
paracrine manner. As described above, NSAIDs inhibit this process.
Prostaglandins promote angiogenesis, along with cellular
differention and proliferation. They also activate signaling
through the EGFR. EGFR activation leads to phosphorylation on
tyrosine residues by the receptor's tyrosine kinase domain,
initiating a signaling pathway that includes the molecules Grb-2,
SOS, the small G protein Raf. Raf activates Mitogen-Activated
Protein Kinase Kinase (MAPKK) and group of nuclear transcription
factors (c-myc, c-fos, c-jun); (see FIG. 2). These factors initiate
transcription of genes involved in the regulation of cell
proliferation and differentiation. Additionally, these factors
induce transcription of the COX-2. These effects may significantly
amplify the original EGFR mediated signal and lead to
pro-neoplastic effects Inhibiting both signaling pathways could
lead to a significant anti-neoplastic effect.
[0204] Studies have provided support that EGFR induces COX-2 in
intestinal epithelial cells and anti-HER2 antibodies can inhibit
COX-2 expression in colorectal cancer cells. In addition,
overexpression of COX-1 or COX-2 in colon carcinoma cells has been
shown to increase EGFR expression. Thus, COX and EGFR levels appear
to be linked in a positive feedback cycle during colon cancer
development. While the exact mechanism by which dysregulated EGF
signaling promotes colon carcinogenesis is not clearly understood,
it has been submitted that EGFR activation in a variety of cell
types results in stimulation of cell proliferation and alterations
in cell motility and/or adhesion to extra-cellular matrix. Studies
have suggested that COX can positively influence tumor growth by
promoting tumor associated angiogenesis.
[0205] It has also recently been proposed that the activation and
overexpression of COX-2 in adenomatous polyps is due to activation
of the EGFR. EGFR stimulation by one of its ligands, amphiregulin
(AR), induces the nuclear targeting of COX-2, release of
prostaglandins and subsequent mitogenesis, in polarized colonic
epithelial cells. COX-2 inhibitors have been shown to prevent this
series of events.
EGFR Inhibitors
[0206] Accordingly, it has been recognized that inhibitors of
receptor tyrosine kinases are useful as selective inhibitors of the
growth of mammalian cancer cells. For example, erbstatin, a
tyrosine kinase inhibitor, selectively attenuates the growth in
athymic nude mice of a transplanted human mammary carcinoma which
expresses EGFR but is without effect on the growth of another
carcinoma which does not express the EGFR.
[0207] Various other compounds, such as styrene derivatives, have
also been shown to possess tyrosine kinase inhibitory properties.
Others have disclosed that certain quinazoline derivatives possess
anti-cancer properties which result from their tyrosine inhibitory
properties.
[0208] As described herein, an "EGFR inhibitor" is a molecule which
inhibits the kinase domain of the epidermal growth factor receptor.
Compounds which are EGFR inhibitors can readily be identified by
one skilled in the art using methods such as, for example, standard
pharmacological test procedures which measure the inhibition of the
phosphorylation of the tyrosine residue of a peptide substrate
catalyzed by EGFR. Briefly, the peptide substrate (RR-SRC) has the
sequence arg-arg-leu-Ile-glu-asp-ala-glu-tyr-ala-ala-arg-gly. The
enzyme is obtained as a membrane extract of A431 cells (American
Type Culture Collection, Rockville, Md.). A431 cells are grown in
T175 flasks to 80% confluency. The cells are washed twice with
phosphate buffered saline (PBS) without Ca.sup.2+. Flasks are
rotated for 1.5 hours in 20 ml PBS with 1.0 mM
ethylenediaminetetraacetic acid (EDTA) at room temperature and
centrifuged at 600 g for 10 minutes. The cells are solubilized in 1
ml per 5.times.10.sup.6 cells of cold lysis buffer {10 mM
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.6,
10 mM NaCl, 2 mM EDTA, 1 mM phenylmethylsulfonyl-fluoride (PMSF),
10 mg/ml aprotinin, 10 mg/ml leupeptin, 0.1 mM sodium
orthovanadate} in a Dounce homogenizer with 10 strokes on ice. The
lysate is centrifuged at 600 g for 10 minutes first to clear cell
debris and the supernatant further centrifuged at 100,000 g for 30
min at 4.degree. C. The membrane pellet is suspended in 1.5 ml HNG
buffer (50 mM HEPES, pH 7.6, 125 mM NaCl, 10% glycerol). The
membrane extract is divided into aliquots, immediately frozen in
liquid nitrogen and stored at -70.degree. C.
[0209] Compositions to be evaluated are made into 10 mg/ml stock
solutions in 100% dimethylsulfoxide (DMSO). Stock solutions are
diluted to 500 mM with buffer (30 mM Hepes pH 7.4) and then
serially diluted to the desired concentration. An aliquot of the
A431 membrane extract (10 mg/ml) is diluted in 30 mM HEPES (pH 7.4)
to give a protein concentration of 50 .mu.g/ml. To 4 .mu.l of
enzyme preparation, EGF (1 .mu.l at 12 .mu.g/ml) is added and
incubated for 10 min on ice followed by 4ml of the test compound or
buffer; this mix is incubated on ice for 30 min. To this is added
the .sup.33P-ATP (10 mCi/ml) diluted 1:10 in assay buffer along
with the substrate peptide at a concentration of 0.5 mM (control
reactions get no test compound) and the reaction is allowed to
proceed for 30 min at 30.degree. C. The reaction is stopped with
10% TCA and left on ice for at least 10 min after which tubes are
microcentrifuged at full speed for 15 min A portion of the
supernatants are then spotted on P81 phosphocellulose discs and
washed twice in 1% acetic acid then water for 5 min each followed
by scintillation counting. The results obtained can be expressed as
an IC.sub.50. The IC.sub.50 is the concentration of test compound
needed to reduce the total amount of phosphorylated substrate by
50%. The % inhibition of the test compound is determined for at
least three different concentrations and the IC.sub.50 value is
evaluated from the dose response curve. The % inhibition is
evaluated with the following formula:
% inhibition=100-[CPM(drug)/CPM(control)].times.100
where CPM(drug) is in units of counts per minute and is a number
expressing the amount of radiolabeled ATP (g-.sup.33 P)
incorporated onto the RR-SRC peptide substrate by the enzyme after
30 minutes at 30.degree. C. in the presence of test compound as
measured by liquid scintillation counting. CPM(control) is in units
of counts per minute and is a number expressing the amount of
radiolabeled ATP (g-.sup.33 P) incorporated into the RR-SRC peptide
substrate by the enzyme after 30 minutes at 30.degree. C. in the
absence of test compound as measured by liquid scintillation
counting. The CPM values are corrected for the background counts
produced by ATP in the absence of the enzymatic reaction. Compounds
having an IC.sub.50 of about 200 nM or less are considered to be
significantly active EGFR inhibitors.
[0210] The identification of EGFR as an oncogene has led to the
development of anticancer therapeutics directed against EGFR,
including gefitinib and cetuximab for colon cancer. Cetuximab is an
example of a monoclonal antibody inhibitor, while gefitinib is a
small molecule inhibitor.
Monoclonal Antibodies
[0211] The monoclonal antibodies block the extracellular ligand
binding domain. With the binding site blocked, signal molecules can
no longer attach there and activate the tyrosine kinase.
[0212] Cetuximab is a chimeric monoclonal antibody generated from
fusion of the variable region of the murine anti-EGFR monoclonal
antibody M225 and the human IgG1 constant region. The resulting
antibody retains high affinity and specificity to EGFR and reduces
immunogenicity. Preclinical studies have demonstrated that
cetuximab effectively inhibits the proliferation of a variety of
EGFR-expressing cancer cells in vitro and that it inhibits tumor
growth in xenograft models. In an orthotopic pancreatic cancer
model, cetuximab significantly suppressed the growth of
orthotopically implanted pancreatic tumors, and this effect was
enhanced by the addition of gemcitabine. Histologic analysis of
tumor specimens revealed that cetuximab induced apoptosis and
suppressed proliferation of tumor cells. Interestingly, cetuximab
also induced apoptosis of endothelial cells, which are not believed
to be direct targets of EGFR inhibition. Moreover, an
antiangiogenic effect, characterized by decreased microvascular
densities associated with reduced expression of tumor-related VEGF
and interleukin-8, was observed. These data suggest that, in
addition to direct antiproliferative activity, antiangiogenic
activity contributes significantly to the antitumor effect of EGFR
inhibitors.
[0213] Panitumumab (ABX-EGF) is a fully human monoclonal antibody
specific to EGFR and is produced by immunization of transgenic
mice, that are able to produce human immunoglobulin light and heavy
chains. Following immunization, a specific clone of B cells that
produced the antibody against EGFR are selected and immortalized
for the generation of the antibody.
[0214] Effective anti-EGFR monoclonal antibodies compete with
endogenous ligands, primarily EGF and transforming growth factor a
for receptor ligand-binding sites. Binding to EGFR blocks critical
signaling pathways and interferes with the growth of tumors
expressing EGFR. Anti-EGFR monoclonal antibodies that are currently
under study include EMD 55900 and ICR 62.
Small Molecules
[0215] Another method is using small molecules to inhibit the EGFR
tyrosine kinase, which is on the cytoplasmic side of the receptor.
Without kinase activity, EGFR is unable to activate itself, which
is a prerequisite for binding of downstream adaptor proteins.
Ostensibly by halting the signaling cascade in cells that rely on
this pathway for growth, tumor proliferation and migration is
diminished.
[0216] Gefitinib is currently only indicated for the treatment of
locally advanced or metastatic non-small cell lung cancer (NSCLC)
in patients who have previously received chemotherapy. While
gefitinib has yet to be proven to be effective in other cancers,
there is potential for its use in the treatment of other cancers
where EGFR overexpression is involved.
Erlotinib
[0217]
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine,
also known as erlotinib (Tarceva.RTM.), is currently being used to
help treat advanced non-small cell lung cancer, and in combination
with gemcitabine in the treatment for advanced metastatic
pancreatic cancer. U.S. Pat. No. 5,747,498 describes the
preparation of erlotinib and other chemically-related compounds.
Additionally, U.S. Pat. No. 6,900,221 describes the use of a stable
polymorph of erlotinib as an inhibitor of the erbB family of
oncogenic and protoncogenic protein kinases such as EGFR. Also, the
patent illustrates methods for the treatment of non-small cell lung
cancer, pediatric malignancies, cervical and other tumors caused or
promoted by human papilloma virus (HPV), melanoma, Barrett's
esophagus (pre-malignant syndrome), adrenal and skin cancers and
auto immune, neoplastic cutaneous diseases and atherosclerosis.
##STR00006##
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
##STR00007##
[0219] Gemcitabine is a nucleoside analog that exhibits antitumor
activity. The chemical name for gemcitabine is
.beta.-2'-deoxy-2',2'-difluorocytidine and is administered as the
hydrochloride salt. The cytotoxic effect of gemcitabine is
attributed to two actions. First, gemcitabine diphosphate inhibits
ribonucleotide reductase causing a reduction in deoxynucleotides
available for DNA synthesis. Second, gemcitabine triphosphate
competes with dCTP for incorporation into DNA. The two actions
working in combination lead to high levels of gemcitabine
nucleotide incorporation into growing DNA chains. This leads to
inhibition of further DNA synthesis and chain termination.
[0220] Gemcitabine is indicated for use in the treatment of
ovarian, breast, NSCL and pancreatic cancer. Gemcitabine
hydrochloride is administered as an intravenous infusion of a 1000
mg/m.sup.2 dose over 30 minutes once a week for up to 7 weeks. This
is followed by one week of rest and then subsequent cycles of
weekly infusions for 3 weeks of a 4 week cycle. Complete details
are provided in the prescribing instructions for gemcitabine, which
is included by reference in its entirety.
[0221] In one embodiment the invention provides a composition
comprising a combination of a COX-2 selective inhibitor and an EGFR
inhibitor disclosed herein for the treatment and prevention of
cancer, tumors, and tumor-related disorders, and neoplastic disease
states. In one embodiment, the EGFR inhibitor is a small molecule
compound or an antibody.
[0222] In one embodiment, the EGFR inhibitor is selected from
gefitinib, cetuximab, and erlotinib. In another embodiment, the
EGFR inhibitor is erlotinib.
[0223] In another embodiment the small molecule compound is
selected from the group consisting of: ZM-254530, BIBX-1382,
reveromycin A, gefitinib, CGP-57148, CGP-59326,
4-(m-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, tyrphostin,
PKI-166, PD 153035, EKB-569, and 4-(phenylamino)quinazolines, or
their pharmaceutically acceptable salts, solvates, or prodrugs. In
another embodiment, the small molecule is selected from the
compounds disclosed in PCT/US04/027574 which is herein incorporated
by reference in its entirety.
[0224] In another embodiment, the antibody is selected from the
group consisting of: EGF receptor antibody, MR1scFvPE38 KDEL
MDX-447, MDX-210, MD-72000, MDX-260, wayne anti-EGFR Mabs,
anti-EGFr Mab, anti-EGFr MAb, Genen anti-EGFR Mab, MAb DC-101,
trastuzumab, anti-VEGF monoclonal, anti-EGFR-DM1 Ab, MAb 4D5,
BAB-447, EMD-55900, EMD-6200, -82633, anti-EGFR Mab, MAb 4D5,
cetuximab, anti-EGFr MAb, anti-flk-1, CCX, CCZ, anti-flk-1, AG-514,
AG-568, nti-EGFR-DM1 Ab, MDX-447, TgDCC-E1A, of:
muellerian-inhibiting hormone, TNP-470, tecogalan sodium, C C225,
matuzumab, panitumumab, DWP-408, and RC-3940II. In another
embodiment are provided compositions wherein the EGFR inhibitor is
selected from the inhibitors disclosed in PCT/US04/027574 which is
herein incorporated by reference in its entirety.
[0225] In a further embodiment the EGFR inhibitor is selected from
the group consisting EGF receptor antisense, PI-88,
oligonucleotide, bromelain molecules, amphiregulin, EGF fusion
toxin, EGF fusion protein, Amphiregulin hbEGF-toxin, hbEGF-toxin,
and EGF fusion protein.
[0226] As described herein "a selective EGFR inhibitory effect" is
meant that the composition comprising a combination of a
1,2-diphenylpyrrole derivative with erlotinib displays selective
inhibition against EGFR than other kinases. In some embodiments,
combinations presently disclosed display selective inhibition
against EGFR kinase than against other tyrosine kinases such as
other erbBRs such as erbB2. For example in one embodiment, the
invention provides a composition comprising a combination of a
1,2-diphenylpyrrole derivative with erlotinib is at least 5 times
or at least 10 times selective against EGFR than it is against
erbB2, as determined from the relative IC.sub.50 values in suitable
assays (for example by comparing the IC.sub.50 value from the KB
cell assay with the IC.sub.50 value from the Clone 24 phospho-erbB2
cell assay for a given composition as described above). In another
embodiment, the invention provides a composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib wherein the combination is at least 5
times or at least 10 times selective against EGFR than it is
against erbB2.
[0227] The compositions provided herein may be enantiomerically
pure, such as a single enantiomer or a single diastereomer, or be
stereoisomeric mixtures, such as a mixture of enantiomers, a
racemic mixture, or a diastereomeric mixture, or a polymorph of the
active agent, for example for erlotinib, polymorphs, including but
not limited to polymorphs A, B, and E, and amorphous forms or solid
amorphous dispersions as disclosed in US20060154941. As such, one
of skill in the art will recognize that administration of a
compound in its (R) form is equivalent, for compounds that undergo
epimerization in vivo, to administration of the compound in its (S)
form. Conventional techniques for the preparation/isolation of
individual enantiomers include chiral synthesis from a suitable
optically pure precursor or resolution of the racemate using, for
example, chiral chromatography, recrystallization, resolution,
diastereomeric salt formation, or derivatization into
diastereomeric adducts followed by separation.
[0228] When the composition described herein contains an acidic or
basic moiety, it may also be provided as a pharmaceutically
acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19;
and "Handbook of Pharmaceutical Salts, Properties, and Use," Stah
and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).
[0229] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0230] Suitable bases for use in the preparation of
pharmaceutically acceptable salts, including, but not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, secondary amines, triethanolamine, trimethylamine,
triethylamine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
[0231] The composition described herein may also be provided as a
prodrug, which is a functional derivative of the
1,2-diphenylpyrrole derivative and/or the EGFR inhibitor and is
readily convertible into the parent compound in vivo. Prodrugs are
often useful because, in some situations, they may be easier to
administer than the parent compound. They may, for instance, be
bioavailable by oral administration whereas the parent compound is
not. The prodrug may also have enhanced solubility in
pharmaceutical compositions over the parent compound. A prodrug may
be converted into the parent drug by various mechanisms, including
enzymatic processes and metabolic hydrolysis. See Harper, Progress
in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of
Biopharmaceutical Properties through Prodrugs and Analogs," Roche
Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug
in Drug Design, Theory and Application," Roche Ed., APHA Acad.
Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985;
Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al.,
Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm.
Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem.
1996, 671-696; Asgharnejad in "Transport Processes in
Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker,
185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet.
1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999,
39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12;
Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled
Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev.
1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19,
115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381;
Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al.,
J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard,
Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm.
Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs
1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.
1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et
al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug
Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug
Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug
Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac.
1989, 28, 497-507.
Methods of Use
[0232] The invention provides a method for treating a subject
having tumors, tumor-related disorders, and/or cancer, comprising
administering to the subject, a therapeutically effective amount of
a combination comprising
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib.
[0233] In one embodiment, the invention provides a method for
treating a subject having tumors, tumor-related disorders, and/or
cancer, comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole.
[0234] In another embodiment, the invention provides a method for
treating a subject having tumors, tumor-related disorders, and/or
cancer, comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the EGFR inhibitor is
erlotinib.
[0235] In yet another embodiment, the invention provides a method
for treating a subject having a tumors, tumor-related disorders,
and/or cancer, comprising administering to the subject, a
therapeutically effective amount of a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor or their
respective pharmaceutically acceptable salt, solvate or
prodrug.
[0236] In one embodiment, the invention provides a method for
treating a subject having tumors, tumor-related disorders, and/or
cancer, comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is selected from the group consisting of:
4-methyl-2-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxy-3-methylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3-fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3,4-dimethylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylphenyl)pyrrole;
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(4-methoxyphenyl)pyrrole;
and
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(3,4-dimethylphenyl)pyrrole.
[0237] In yet another embodiment, the invention provides a method
for treating a subject having tumors, tumor-related disorders,
and/or cancer, comprising administering to the subject, a
therapeutically effective amount of a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative and the EGFR inhibitor are
administered sequentially in either order or simultaneously. In a
further embodiment, the invention provides a method for treating a
subject having tumors, tumor-related disorders, and/or cancer,
comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is administered first. In one embodiment, the invention
provides a method for treating a subject having tumors,
tumor-related disorders, and/or cancer, comprising administering to
the subject, a therapeutically effective amount of a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the EGFR inhibitor is administered first. In another
embodiment, the invention provides a method for treating a subject
having tumors, tumor-related disorders, and/or cancer, comprising
administering to the subject, a therapeutically effective amount of
a combination comprising a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein administering the combination enhances
treatment of the subject in comparison to a treatment of either a
1,2-diphenylpyrrole derivative or an EGFR inhibitor alone. In yet
another embodiment, the invention provides a method for treating a
subject having tumors, tumor-related disorders, and/or cancer,
comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein administering the
combination reduces the side effects of the treatment of tumors,
tumor-related disorders, and/or cancer.
[0238] In one embodiment, the invention provides a method for
treating a subject having tumors, tumor-related disorders, and/or
cancer, comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the cancer is selected
from the group consisting of: oral cancer, prostate cancer, rectal
cancer, non-small cell lung cancer, lip and oral cavity cancer,
liver cancer, lung cancer, anal cancer, kidney cancer, vulvar
cancer, breast cancer, oropharyngeal cancer, nasal cavity and
paranasal sinus cancer, nasopharyngeal cancer, urethra cancer,
small intestine cancer, bile duct cancer, bladder cancer, ovarian
cancer, laryngeal cancer, hypopharyngeal cancer, gallbladder
cancer, colon cancer, colorectal cancer, head and neck cancer,
parathyroid cancer, penile cancer, vaginal cancer, thyroid cancer,
pancreatic cancer, esophageal cancer, Hodgkin's lymphoma,
leukemia-related disorders, mycosis fungoides, and myelodysplastic
syndrome.
[0239] In another embodiment, the invention provides a method for
treating a subject having tumors, tumor-related disorders, and/or
cancer, comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the cancer is non-small
cell lung cancer, pancreatic cancer, breast cancer, ovarian cancer,
colorectal cancer, and head and neck cancer.
[0240] In one embodiment, the invention provides a method for
treating a subject having tumors, tumor-related disorders, and/or
cancer, comprising administering to the subject, a therapeutically
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the cancer is a carcinoma,
a tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma,
and a blastoma. In another embodiment, the invention provides a
method for treating a subject having a carcinoma, comprising
administering to the subject, a therapeutically effective amount of
a combination comprising a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the carcinoma is selected from the group
consisting of: carcinoma, adenocarcinoma, adenoid cystic carcinoma,
adenosquamous carcinoma, adrenocortical carcinoma, well
differentiated carcinoma, squamous cell carcinoma, serous
carcinoma, small cell carcinoma, invasive squamous cell carcinoma,
large cell carcinoma, islet cell carcinoma, oat cell carcinoma,
squamous carcinoma, undifferentiatied carcinoma, verrucous
carcinoma, renal cell carcinoma, papillary serous adenocarcinoma,
merkel cell carcinoma, hepatocellular carcinoma, soft tissue
carcinomas, bronchial gland carcinomas, capillary carcinoma,
bartholin gland carcinoma, basal cell carcinoma, carcinosarcoma,
papilloma/carcinoma, clear cell carcinoma, endometrioid
adenocarcinoma, mesothelial, metastatic carcinoma, mucoepidermoid
carcinoma, cholangiocarcinoma, actinic keratoses, cystadenoma, and
hepatic adenomatosis. In a further embodiment the tumor is selected
from the group consisting of: astrocytic tumors, malignant
mesothelial tumors, ovarian germ cell tumor, supratentorial
primitive neuroectodermal tumors, Wilm's tumor, pituitary tumors,
extragonadal germ cell tumor, gastrinoma, germ cell tumors,
gestational trophoblastic tumor, brain tumors, pineal and
supratentorial primitive neuroectodermal tumors, pituitary tumor,
somatostatin-secreting tumor, endodermal sinus tumor, carcinoids,
central cerebral astrocytoma, glucagonoma, hepatic adenoma,
insulinoma, medulloepithelioma, plasmacytoma, vipoma, and
pheochromocytoma. In yet another embodiment, the invention provides
a method for treating a subject having a neoplasm, comprising
administering to the subject, a therapeutically effective amount of
a combination comprising a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the neoplasm is selected from the group
consisting of: intaepithelial neoplasia, multiple myeloma/plasma
cell neoplasm, plasma cell neoplasm, interepithelial squamous cell
neoplasia, endometrial hyperplasia, focal nodular hyperplasia,
hemangioendothelioma, and malignant thymoma. In one embodiment the
lymphoma is selected from the group consisting of: nervous system
lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma,
non-Hodgkin's lymphoma, lymphoma, and Waldenstrom's
macroglobulinemia. In another embodiment the melanoma is selected
from the group consisting of: acral lentiginous melanoma,
superficial spreading melanoma, uveal melanoma, lentigo maligna
melanomas, melanoma, intraocular melanoma, adenocarcinoma nodular
melanoma, and hemangioma.
[0241] In a further embodiment, the invention provides a method for
treating a subject having a sarcoma, comprising administering to
the subject, a therapeutically effective amount of a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the sarcoma is selected from the group consisting of:
adenomas, adenosarcoma, chondosarcoma, endometrial stromal sarcoma,
Ewing's sarcoma, Kaposi's sarcoma, leiomyosarcoma, sarcoma, uterine
sarcoma, osteosarcoma, and pseudosarcoma. In one embodiment, the
glioma is selected from the group consisting of: glioma, brain stem
glioma, and hypothalamic and visual pathway glioma. In another
embodiment, the invention provides a method for treating a subject
having a blastoma, comprising administering to the subject, a
therapeutically effective amount of a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
blastoma is selected from the group consisting of: pulmonary
blastoma, pleuropulmonary blastoma, retinoblastoma, neuroblastoma,
medulloblastoma, glioblastoma, and hemangiblastomas.
[0242] In one embodiment the EGFR inhibitor is a small molecule
compound or an antibody. In another embodiment the EGFR inhibitor
is a small molecule compound is selected from the group consisting
of: ZM-254530, BIBX-1382, reveromycin A, gefitinib, CGP-57148,
CGP-59326, 4-(m-chloro)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine,
tyrphostin, PKI-166, PD 153035, EKB-569, and
4-(phenylamino)quinazolines, or their pharmaceutically acceptable
salts, solvates, or prodrugs. In a further embodiment, the EGFR
inhibitor is an antibody is selected from the group consisting of:
EGF receptor antibody, MR1scFvPE38 KDEL MDX-447, MDX-210, MD-72000,
MDX-260, wayne anti-EGFR Mabs, anti-EGFr Mab, anti-EGFr MAb, Genen
anti-EGFR Mab, MAb DC-101, trastuzumab, anti-VEGF monoclonal,
anti-EGFR-DM1 Ab, MAb 4D5, BAB-447, EMD-55900, EMD-6200, -82633,
anti-EGFR Mab, MAb 4D5, cetuximab, anti-EGFr MAb, anti-flk-1, CCX,
CCZ, anti-flk-1, AG-514, AG-568, nti-EGFR-DM1 Ab, MDX-447,
TgDCC-E1A, C225, matuzumab, panitumumab, DWP-408, and RC-3940II. In
yet a further embodiment the EGFR inhibitor is selected from the
group consisting of: muellerian-inhibiting hormone, TNP-470,
tecogalan sodium, EGF receptor antisense, PI-88, oligonucleotide,
bromelain molecules, amphiregulin, EGF fusion toxin, EGF fusion
protein, Amphiregulin hbEGF-toxin, hbEGF-toxin, and EGF fusion
protein.
[0243] In one embodiment the invention provides a method of
inducing differentiation of tumor cells, the method comprising
contacting the cells with an effective amount of a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
whereby the combination induces differentiation of tumor cells. In
one embodiment, the invention provides a method of inducing
differentiation of tumor cells, the method comprising contacting
the cells with an effective amount of a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0244] In one embodiment the invention provides a method of
inhibiting proliferation of cancer cells, the method comprising
contacting a cancer cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor whereby the
combination inhibits proliferation of cancer cells. In one
embodiment, the invention provides a method of inhibiting
proliferation of cancer cells, the method comprising contacting a
cancer cell with a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0245] In another embodiment the invention provides a method for
reducing proliferation of cancer cells, the method comprising
delivering to the cells a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, whereby the
reduction of cell proliferation is greater than a reduction caused
by either a 1,2-diphenylpyrrole derivative alone or an EGFR
inhibitor alone. In one embodiment, the invention provides a method
for reducing proliferation of cancer cells, the method comprising
delivering to the cells a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0246] In one embodiment the invention provides a method of
modulating autophosphorylation with a molecule of ATP, the method
comprising delivering to a cancer cell an effective amount of a
combination comprising a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the combination inhibits autophosphorylation with
a molecule of ATP. In one embodiment, the invention provides a
method of modulating autophosphorylation with a molecule of ATP,
the method comprising delivering to a cancer cell an effective
amount of a combination comprising a 1,2-diphenylpyrrole derivative
and an EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0247] In a further embodiment the invention provides a method of
inhibiting metastases of tumor cells, the method comprising
administering an effective amount of a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor such that the
combination inhibits metastatic activity of tumor cells. In one
embodiment, the invention provides a method of inhibiting
metastases of tumor cells, the method comprising administering an
effective amount of a combination comprising a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0248] In one embodiment the invention provides a method for
inducing apoptosis in cancer cells, the method comprising
contacting the cancer cells with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor sufficient to
induce apoptosis. In one embodiment, the invention provides a
method for inducing apoptosis in cancer cells, the method
comprising contacting the cancer cells with a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0249] In another embodiment the invention provides a method for
sensitizing EGFR inhibitor resistant cancer cells to an EGFR
inhibitor, the method comprising administering a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the combination sensitizes the cancer cells to the EGFR
inhibitor. In one embodiment, the invention provides a method for
sensitizing EGFR inhibitor resistant cancer cells to an EGFR
inhibitor, the method comprising administering a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0250] In a further embodiment the invention provides a method of
modulating prostaglandin synthesis in a cancer cell, the method
comprising contacting the cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits prostaglandin synthesis in a cancer cell. In
one embodiment, the invention provides a method of modulating
prostaglandin synthesis in a cancer cell, the method comprising
contacting the cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0251] In one embodiment the invention provides a method of
modulating cyclooxygenase expression in a cancer cell, the method
comprising delivering to the cell a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits cyclooxygenase expression in a cancer cell. In
one embodiment, the invention provides a method of modulating
cyclooxygenase expression in a cancer cell, the method comprising
delivering to the cell a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0252] In one embodiment the invention provides a method of
modulating angiogenesis in a cancer cell, the method comprising
contacting the cell with a combination comprising a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
combination inhibits angiogenesis in a cancer cell. In one
embodiment the invention provides a method of modulating
angiogenesis in a cancer cell, the method comprising contacting the
cell with a combination comprising a 1,2-diphenylpyrrole derivative
and an EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0253] In another embodiment the invention provides a method of
reducing the dosage in conventional treatment for neoplasia and/or
neoplasia related disorders in a subject, the method comprising
administering to a subject a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the combination reduces
the dosage in conventional treatment for neoplasia and/or
neoplasia-related disorders. In one embodiment, the invention
provides a method of reducing the dosage in conventional treatment
for neoplasia and/or neoplasia related disorders in a subject, the
method comprising administering to a subject a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0254] In one embodiment the invention provides a method of
treating neoplasia and/or neoplasia related disorders, the method
comprising administering a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor. In one embodiment, embodiment the
invention provides a method of treating neoplasia and/or neoplasia
related disorders, the method comprising administering a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0255] The combinations presently described herein may also be
useful in the treatment of additional disorders in which aberrant
expression ligand/receptor interactions or activation or signalling
events related to various protein tyrosine kinases are involved.
Such disorders may include those of neuronal, glial, astrocytal,
hypothalamic, glandular, macrophagal, epithelial, stromal, or
blastocoelic nature in which aberrant function, expression,
activation or signalling of the erbB tyrosine kinases are involved.
In addition, the combinations presented herein may have therapeutic
utility in inflammatory, angiogenic and immunologic disorders
involving both identified and as yet unidentified tyrosine kinases
that are inhibited by the combinations presented herein.
Combination Therapy
[0256] In some embodiments, the composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor described herein, has an effect that is additive of the
effects of the 1,2-diphenylpyrrole derivative alone and the effects
of the EGFR inhibitor alone. In another embodiment, the invention
provides a composition comprising, a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is additive of the effects of the
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole alone and
the effects of erlotinib alone.
[0257] In some other embodiments, the composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor described herein, has an effect that is greater than the
additive effects of the 1,2-diphenylpyrrole derivative alone and
the effects of the EGFR inhibitor alone. In another embodiment, the
invention provides a composition comprising, a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is greater than the additive effects of the
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole alone and
the effects of erlotinib alone.
[0258] In some embodiments, the composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor described herein, has an effect that is greater than the
effects of the 1,2-diphenylpyrrole derivative alone (e.g.,
cyclooxygenase-2 inhibition alone). In another embodiment, the
invention provides a composition comprising, a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is greater than the effects of the
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
alone.
[0259] In other embodiments, the composition comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor described herein, has an effect that is greater than the
effects of the EGFR inhibitor alone (epidermal growth factor
receptor kinase inhibition alone). In another embodiment, the
invention provides a composition comprising, a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is greater than the effects of erlotinib alone.
[0260] In other embodiments, the invention provides a method for
treating cancer, tumors, and tumor-related disorders comprising
administering a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor described
herein, wherein the combination has an effect that is additive of
the effects of the 1,2-diphenylpyrrole derivative alone and the
effects of the EGFR inhibitor alone. In further embodiments, the
invention provides a method for treating cancer, tumors, and
tumor-related disorders comprising administering a composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is additive of the effects of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole alone and
the effects of erlotinib alone.
[0261] In some other embodiments, the invention provides a method
for treating cancer, tumors, and tumor-related disorders,
comprising administering a composition comprising a combination of
a 1,2-diphenylpyrrole derivative and an EGFR inhibitor described
herein, wherein the combination has an effect that is greater than
the additive effects of the effects of the 1,2-diphenylpyrrole
derivative alone and the effects of the EGFR inhibitor alone. In
other embodiments, the invention provides method for treating
cancer, tumors, and tumor-related disorders, comprising
administering a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is greater than the additive effects of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole alone and
the effects of erlotinib alone.
[0262] In some embodiments, the invention provides a method for
treating cancer, tumors, and tumor-related disorders comprising
administering a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor described
herein, wherein the combination has an effect that is greater than
the effects of the 1,2-diphenylpyrrole derivative alone (e.g.,
cyclooxygenase-2 inhibition alone). In other embodiments, the
invention provides a method for treating cancer, tumors, and
tumor-related disorders comprising administering a composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is greater than the effects of is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
alone.
[0263] In further embodiments, the invention provides a method for
treating cancer, tumors, and tumor-related disorders comprising
administering a composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor described
herein, wherein the combination has an effect that is greater than
the effects of the EGFR inhibitor alone (epidermal growth factor
receptor kinase inhibition alone). In other embodiments, the
invention provides a method for treating cancer, tumors, and
tumor-related disorders comprising administering a composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, wherein the combination has an effect
that is greater than the effects of erlotinib alone.
[0264] Synergism of the composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, may be used
to obtain the desired effect at doses to which side effects are
minimal. For example, a patient may be treated for a disease,
disorder, or condition which benefits from EGFR inhibition, such as
tumors, tumor-related diseases, cancer, neoplasia, while
concomitantly being treated for a side effect of the EGFR
inhibition, such as inflammation, through the benefit of the
1,2-diphenylpyrrole derivative inhibitor. In one embodiment, the
invention provides a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib which may be used to obtain the desired effect at doses
to which side effects are minimal
[0265] The composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, may be
applied as a sole therapy or may involve one or more other
materials and treatment agents such as but not limited to a
combination of inhibitors of MMP (matrix-metallo-proteinase), other
tyrosine kinases including VEGFR (vascular endothelial growth
factor receptor), farnesyl transferase, CTLA.sub.4 (cytotoxic
T-lymphocyte antigen 4) and erbB2, as well as MAb to VEGFr, and
other cancer-related antibodies including rhuMAb-VEGF, the erbB2
MAb, or avb3.
[0266] Thus, the composition comprising a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor, may be
applied with one or more other anti-tumor substances, for example,
those selected from, mitotic inhibitors, for example vinblastine;
alkylating agents, for example, cis-platin, carboplatin, and
cyclophosphamide; anti-metabolites, for example 5-fluorouracil,
cytosine arabinoside and hydroxyurea, or, for example,
anti-metabolites such as
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]--
2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle
inhibitors; intercalating antibiotics, for example adriamycin and
bleomycin; enzymes, for example interferon; and anti-hormones, for
example anti-estrogens such as Nolvadex.RTM. (tamoxifen) or, for
example anti-androgens such as Casodex.RTM.
(4'-cyano-3-(4-fluorophenyl
sulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide).
In one embodiment, the invention provides a combination a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, may be applied with one or more other
anti-tumor substances, for example, those selected from, mitotic
inhibitors, for example vinblastine; alkylating agents, for
example, cis-platin, carboplatin, and cyclophosphamide;
anti-metabolites, for example 5-fluorouracil, cytosine arabinoside
and hydroxyurea, or, for example, anti-metabolites such as
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]--
2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle
inhibitors; intercalating antibiotics, for example adriamycin and
bleomycin; enzymes, for example interferon; and anti-hormones, for
example anti-estrogens such as Nolvadex.RTM. (tamoxifen) or, for
example anti-androgens such as Casodex.RTM.
(4'-cyano-3-(4-fluorophenyl
sulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide).
[0267] For the combination therapies including combination
therapies having pharmaceutical compositions described herein, the
effective amounts of the compound presently described herein useful
for inhibiting abnormal cell growth (e.g., other antiproliferative
agent, anti-angiogenic, signal transduction inhibitor or
immune-system enhancer) can be determined by those of ordinary
skill in the art, based on the effective amounts for the compound
described herein and those known or described for the
chemotherapeutic or other agent. The formulations and routes of
administration for such therapies and compositions can be based on
the information described herein for compositions and therapies
comprising the combinations presented herein as the sole active
agent and on information provided for the chemotherapeutic or other
agent in combination therewith.
[0268] In one embodiment, the invention provides a method for
inhibiting abnormal cell growth in a subject comprising
administering to the subject an effective amount of a composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor, or their pharmaceutically acceptable salt, solvate
or prodrug thereof, in combination with radiation therapy effective
in inhibiting abnormal cell growth in the subject. Techniques for
administering radiation therapy are known to a person of skill in
the art and these techniques can be used in the combination therapy
described herein.
Additional Therapy
[0269] Available additional treatments for cancer that may be
advantageously employed in combination with the therapies and
compositions disclosed herein include, without limitation, surgery,
radiation therapy, chemotherapy, high dose chemotherapy with stem
cell transplant; hormone therapy, and monoclonal antibody
therapy.
[0270] Surgical procedure are often used in the treatment of
cancer.
[0271] Radiation therapy is a cancer treatment that uses
high-energy x-rays or other types of radiation to kill cancer cells
or keep them from growing.
[0272] Chemotherapy is a cancer treatment that uses drugs to stop
the growth of cancer cells, either by killing the cells or by
stopping them from dividing. When chemotherapy is taken by mouth or
injected into a vein or muscle, the drugs enter the bloodstream and
can reach cancer cells throughout the body (systemic chemotherapy).
When chemotherapy is placed directly into the spinal column, an
organ, or a body cavity such as the abdomen, the drugs mainly
affect cancer cells in those areas (regional chemotherapy). The way
the chemotherapy is given depends on the type and stage of the
cancer being treated.
[0273] Different chemotherapeutic agents are known in the art for
treating cancer. Cytoxic agents used for treating cancer include
doxorubicin, cyclophosphamide, methotrexate, 5-fluorouracil,
mitomycin C, mitoxantrone, paclitaxel, taxane formulations such as
by way of example only, Abraxane.RTM. (ABI-007),
Paclitaxel-Cremophor EL, Paclitaxel poliglumex, and Paclitaxel
injectable emulsion (PIE), gemcitabine, docetaxel, capecitabine and
epirubicin.
[0274] Other chemotherapy against cancer includes treatment with
one or more of bendamustine, carboplatin (for example,
Paraplatin.RTM.), carmustine (for example, BCNU.RTM.), chlorambucil
(for example, Leukeran.RTM.), cisplatin (for example,
Platinol.RTM.), cyclophosphamide injection (for example,
Cytoxan.RTM.), oral cyclophosphamide (for example, Cytoxan.RTM.),
dacarbazine (for example, DTIC.RTM.), ifosfamide (for example,
Ifex.RTM.), lomustine (for example, CCNUO), mechlorethamine (for
example, nitrogen mustard, Mustargen.RTM.), melphalan (for example,
Alkerant), procarbazine (for example, Matulane.RTM.), bleomycin
(for example, Blenoxane.RTM.), doxorubicin (for example,
Adriamycin.RTM., Rubex.RTM.), epirubicin, Idarubicin (for example,
Idamycin.RTM.), mitoxantrone (for example, Novantrone.RTM.),
gemcitabine (for example, Gemzar.RTM.), oral mercaptopurine (for
example, Purinethol.RTM.), methotrexate, pentostatin IV (for
example, Nipent.RTM.), oral thioguanine (for example, Lanvis.RTM.),
oral etoposide (for example, VP-16, VePesid.RTM.,
Etopophos)--etoposide IV (for example, VP-16, VePesid.RTM.,
Etopophos), vinblastine (for example, Velban.RTM.), vincristine
(for example, Oncovin.RTM.), vinorelbine (for example,
Navelbine.RTM.), dexamethasone (for example, Decadron.RTM.),
methylprednisolone (for example, Medrol.RTM.), and prednisone (for
example, Deltasone.RTM.). Erlotinib in combination with gemcitabine
is indicated for the treatment of advanced pancreatic cancer.
[0275] Monoclonal antibody therapy is a cancer treatment that uses
antibodies made in the laboratory, from a single type of immune
system cell. These antibodies can identify substances on cancer
cells or normal substances that may help cancer cells grow. The
antibodies attach to the substances and kill the cancer cells,
block their growth, or keep them from spreading. Monoclonal
antibodies are given by infusion. They may be used alone or to
carry drugs, toxins, or radioactive material directly to cancer
cells. Monoclonal antibodies are also used in combination with
chemotherapy as adjuvant therapy.
[0276] Trastuzumab (Herceptin.RTM.) is a monoclonal antibody that
blocks the effects of the growth factor protein HER2, which
transmits growth signals to breast cancer cells.
[0277] Trastuzumab leads to clinical responses as a single agent
and improves survival when added to chemotherapy for advanced
HER2-positive breast cancer. However, some patients do not respond
to trastuzumab, and most eventually develop clinical resistance.
Mechanisms of intrinsic and acquired trastuzumab resistance are
poorly understood. One study which utilized a cell line-based
approach to delineate genetic and protein alterations associated
with resistance has been reported. (D. Tripathy et al Journal of
Clinical Oncology, 2005 Vol 23, No 16S, 3121. These researchers
studied two HER2-positive breast cancer cell lines (BT474 and
SKBR3) that were serially passaged in the presence of trastuzumab
until in vitro resistance was documented. Resistant cell lines
emerged after 12 months and exhibited a 3-fold more rapid growth
rate in the absence of trastuzumab. Following trastuzumab exposure,
G.sub.0/G.sub.1 arrest was observed insensitive compared to
resistant cells (84 vs. 68%), with fewer cells in S-phase (3 vs.
14%). Resistant cell lines exhibited fewer changes in gene
expression with trastuzumab as well as upregulation of the
chemokine receptor CXCR4 and mitotic checkpoint regulators, and
downregulation of PTEN compared to sensitive cells.
[0278] Additional, illustrative, treatments that may be
advantageously combined with the compositions and therapies
disclosed herein may include, without limitation, administration of
agents including, but not limited to capecitabine, docetaxel,
epirubicin, epothilone A, B or D, goserelin acetate, paclitaxel,
pamidronate, bevacizumab, and trastuzumab.
EGFR Resistance
[0279] Studies have shown that after a period of about 8-12 months
of EGFR-directed treatments, the cancer cells become resistant to
the treatment, most commonly by 1) recruiting a mutated IGF-1
receptor to act as one of the EGFR partners in the homodimer, thus,
forming a heterodimer (this allows the signal to be transmitted
even in the presence of an EGFR inhibitor); 2) the presence of
redundant tyrosine kinase receptors; 3) increased angiogenesis; 4)
the constitutive activation of downstream mediators; and 5) the
existence of specific EGFR mutations. Understanding the molecular
mechanisms of resistance and sensitivity may lead to improvements
in therapies that target EGFR.
[0280] IGF-1R activates many of the same downstream pathways as
EGFR and can lead to tumorigenesis, increased proliferation,
angiogenesis, and metastasis. PI-3K/Akt signaling is a critical
component of the downstream mediation of EGFR and also plays a
functional role in IGF-1R signaling. Without wishing to be bound by
any particular theory, this redundancy may explain how the
receptors can mimic the function of one another. Chakravarti et
al., identified two glioblastoma cell lines that each overexpressed
EGFR but exhibited very different responses to EGFR inhibitors. The
resistant cell line significantly overexpressed IGF-1R and showed
further increases in IGF-1R expression in response to EGFR
inhibition by AG1478, an EGFR TKI. PI-3K/Akt signaling persisted in
these resistant cell lines in response to AG1478 treatment, and
these cells also maintained their invasive and antiapoptotic
characteristics. These studies support the concept of redundant
signaling through IGF-1R that maintains activation of critical
pathways for survival in the presence of EGFR inhibition Inhibiting
both IGF-1R and EGFR may significantly reduce the growth and
invasiveness of cells that are resistant to EGFR inhibitors alone.
Further evidence that IGF-1R activation may bypass inhibition of
other tyrosine kinase receptors comes from a study by Lu et al.,
who showed that the degree of overexpression of IGF-1R was
inversely related to the response of breast cancer cells to
trastuzumab, an antibody directed against ErbB2. SKBR3 human breast
cancer cells, which normally overexpress HER2/neu and minimally
express IGF-1R, showed a 42% decrease in proliferation in response
to trastuzumab. Unlike the parental cell line
[0281] , SKBR3 cells that were engineered to overexpress IGF-1R
showed no response to trastuzumab. When the IGF-1R was inhibited by
IGF-binding protein-3 in the engineered cell lines, the response to
trastuzumab returned to normal. These studies clearly indicate that
activation of alternative tyrosine kinase receptors in tumor cells
may override the effect of EGFR family inhibitors. These examples
suggest that a combination may be able to overcome resistance to a
single receptor inhibitor and thus more effectively inhibit
pathways leading to cancer growth and survival. Recently, an
enhanced response was shown in breast cancer cell lines treated
with either recombinant bispecific antibodies to both EGFR and
IGF-1R or a combination of single receptor antibodies compared with
either antibody alone. Signaling pathways downstream of the
receptors were also more effectively inhibited by the combination
therapy. By combining therapies that attack multiple cell surface
and intracellular signaling pathways, redundant receptor signaling
might be blocked and greater clinical benefit achieved. Thus,
identifying key downstream signaling molecules in which growth
factor receptor signals converge may be important in the
development of therapeutic agents that block signals from multiple
activated growth factor receptors. Similarly, Jung et al. discloses
the use of a combination of mAbs to EGFR and mAbs to VEGFR-2 to
treat gastric cancer grown in nude mice. Both mAbs were modestly
effective at inhibiting tumor growth, but the combination achieved
significantly greater tumor growth inhibition that was also
associated with decreased tumor vascularity and increased tumor
cell apoptosis.
[0282] In one embodiment the invention provides a method for
treating a subject having an EGFR inhibitor resistant cancer cell
comprising administering to the subject a therapeutically effective
amount of a composition comprising a 1,2-diphenylpyrrole derivative
in combination with an EGFR inhibitor. In one embodiment, the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole. In
another embodiment the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib.
[0283] In one embodiment the invention provides a method for
sensitizing EGFR inhibitor resistant cancer cells to an EGFR
inhibitor, the method comprising administering a combination
comprising a 1,2-diphenylpyrrole derivative and an EGFR inhibitor
wherein the combination sensitizes the cancer cells to the EGFR
inhibitor. In one embodiment, the invention provides a method for
sensitizing EGFR inhibitor resistant cancer cells to erlotinib, the
method comprising administering a combination comprising a
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib wherein the combination sensitizes the cancer cells
erlotinib.
Lung Cancer
[0284] In many countries including Japan, Europe and America, the
number of patients with lung cancer is fairly large and continues
to increase year after year and is the most frequent cause of
cancer death in both men and women. Although there are many
potential causes for lung cancer, tobacco use, and particularly
cigarette smoking, is the most important. Additionally, etiologic
factors such as exposure to asbestos, especially in smokers, or
radon are contributory factors. Also occupational hazards such as
exposure to uranium have been identified as an important factor.
Finally, genetic factors have also been identified as another
factor that increases the risk of cancer.
[0285] Lung cancers can be histologically classified into non-small
cell lung cancers (e.g. squamous cell carcinoma (epidermoid),
adenocarcinoma, large cell carcinoma (large cell anaplastic), etc.)
and small cell lung cancer (oat cell). Non-small cell lung cancer
(NSCLC) has different biological properties and responses to
chemotherapeutics from those of small cell lung cancer (SCLC).
Thus, chemotherapeutic formulas and radiation therapy are different
between these two types of lung cancer.
Non-Small Cell Lung Cancer
[0286] Where the location of the non-small cell lung cancer tumor
can be easily excised (stage I and II disease) surgery is the first
option of therapy and offers a relatively good chance for a cure.
In more advanced disease (stage IIIa and greater), however, where
the tumor has extended to tissue beyond the bronchopulmonary lymph
nodes, surgery may not lead to complete excision of the tumor. In
such cases, the patient's chance for a cure by surgery alone is
greatly diminished. Where surgery will not provide complete removal
of the NSCLC tumor, other types of therapies must be utilized.
Today, chemoradiation therapy, is the standard treatment to control
unresectable or inoperable NSCLC. Improved results have been seen
when radiation therapy has been combined with chemotherapy, but
gains have been modest and the search continues for improved
methods of combining modalities.
[0287] Radiation therapy is based on the principle that high-dose
radiation delivered to a target area will result in the death of
reproductive cells in both tumor and normal tissues. The radiation
dosage regimen is generally defined in terms of radiation absorbed
dose (rad), time and fractionation, and must be carefully defined
by the oncologist. The amount of radiation a patient receives will
depend on various consideration but the two most important
considerations are the location of the tumor in relation to other
critical structures or organs of the body, and the extent to which
the tumor has spread. One course of treatment for a patient
undergoing radiation therapy for NSCLC will be a treatment schedule
over a 5 to 6 week period, with a total dose of 50 to 60 Gy
administered to the patient in a single daily fraction of 1.8 to
2.0 Gy, 5 days a week. A Gy is an abbreviation for Gray and refers
to 100 rad of dose.
[0288] As NSCLC is a systemic disease, however, and radiation
therapy is a local modality, radiation therapy as a single mode of
therapy is unlikely to provide a cure for NSCLC, at least for those
tumors that have metastasized distantly outside the zone of
treatment. Thus, the use of radiation therapy with other modality
regimens has important beneficial effects for the treatment of
NSCLC.
[0289] Generally, radiation therapy has been combined temporally
with chemotherapy to improve the outcome of treatment. There are
various terms to describe the temporal relationship of
administering radiation therapy in combination with COX-2
inhibitors and chemotherapy, and the following examples are the
treatment regimens and are provided for illustration only and are
not intended to limit the use of other combinations. "Sequential"
therapy refers to the administration of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and/or radiation therapy separately in time in order to
allow the separate administration of the composition, and/or
radiation therapy. "Concomitant" therapy refers to the
administration of the composition, and/or radiation therapy on the
same day.
[0290] Finally, "alternating" therapy refers to the administration
of radiation therapy on the days in which the composition would not
have been administered if it was given alone. It is reported that
advanced non-small cell lung cancers do not respond favorably to
single-agent chemotherapy and useful therapies for advanced
inoperable cancers have been limited. (Journal of Clinical
Oncology, vol. 10, pp. 829-838 (1992)).
[0291] Japanese Patent Kokai 5-163293 refers to some specified
antibiotics of 16-membered-ring macrolides as a drug delivery
carrier capable of transporting anthracycline-type anticancer drugs
into the lungs for the treatment of lung cancers. Thus, the use of
a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and a macrolide as a drug delivery carrier is
contemplated herein for the treatment of non-small cell lung
cancer.
[0292] Several chemotherapeutic agents have been shown to be
efficacious against NSCLC. Chemotherapeutic agents that can be used
in the present disclosure against NSCLC include cisplatin,
carboplatin, paclitaxel, docetaxel, taxane formulations such as by
way of example only, Abraxane.RTM. (ABI-007), Paclitaxel-Cremophor
EL, Paclitaxel poliglumex, and Paclitaxel injectable emulsion
(PIE), gemcitabine, navelbine, pemetrexate, etoposide,
methotrexate, 5-Fluorouracil, epirubicin, doxorubicin, vinblastine,
cyclophosphamide, ifosfamide, mitomycin C, epirubicin, vindesine,
camptothecins, fotemustine, and edatrexate.
[0293] In one embodiment, the invention provides a method of the
treatment of NSCLC which utilizes a therapeutically effective
amounts of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib. Further, therapy for the treatment of NSCLC utilizes a
therapeutically effective amounts of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib, and one of the following antineoplastic agents:
bevacizumab, docetaxel, gefitinib, gemcitabine, cisplatin,
carboplatin, etoposide, paclitaxel, pemetrexate, vinorelbine, or
radiation therapy.
Small Cell Lung Cancer
[0294] Approximately 15 to 20 percent of all cases of lung cancer
reported worldwide are small cell lung cancer (SCLC). Ihde
DC:Cancer 54:2722, 1984. Currently, treatment of SCLC incorporates
multi-modal therapy, including chemotherapy and radiation therapy.
Response rates of localized or disseminated SCLC remain high to
systemic chemotherapy, however, persistence of the primary tumor
and persistence of the tumor in the associated lymph nodes has led
to the integration of several therapeutic modalities in the
treatment of SCLC.
[0295] Therapy for the treatment of lung cancer according to one
embodiment of the invention utilizes a combination of
therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib. In another embodiment, therapy for the treatment of lung
cancer according to the invention utilizes a combination of
therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and one of the following antineoplastic agents:
vincristine, docetaxel, camptothecin, topotecan cisplatin,
carboplatin, cyclophosphamide, epirubicin (high dose), etoposide
(VP-16) I.V., etoposide (VP-16) oral, isofamide, teniposide
(VM-26), doxorubicin, and amrubicin. Other preferred single-agents
chemotherapeutic agents that may be used in the present disclosure
include BCNU (carmustine), vindesine, hexamethylmelamine
(altretamine), methotrexate, nitrogen mustard, and CCNU
(lomustine). Other chemotherapeutic agents under investigation that
have shown activity against SCLC include iroplatin, gemcitabine,
Ionidamine, and taxol.
Glioma
[0296] A glioma is a type of primary central nervous system (CNS)
tumor that arises from glial cells. The most common site of
involvement of gliomas is the brain, but they can also affect the
spinal cord or any other part of the CNS, such as the optic nerves.
Treatment for brain gliomas depends on the location and the grade.
Often, treatment is a combined approach, using surgery, radiation
therapy, and chemotherapy. The radiation therapy is in the form of
external beam radiation or the stereotactic approach using
radiosurgery. Spinal cord tumors can be treated by surgery and
radiation. Temozolomide is a chemotherapeutic drug that is able to
cross the blood-brain barrier effectively and is being used in
therapy.
[0297] EGFR is frequently amplified, overexpressed, or mutated in
glioblastomas, but generally only 10 to 20% of patients have a
response to EGFR inhibitors. It has been shown that glioblastoma
that overexpresses the EGFRvIII oncogene and are PTEN tumor
suppressor wildtype are sensitive to erlotinib treatment.
[0298] Therapy for the treatment of glioma according to one
embodiment of the invention utilizes a combination of
therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib. In another embodiment, therapy for the treatment of
glioma according to the invention utilizes a combination of
therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and temozolomide.
Head and Neck Cancer
[0299] Head and neck cancer includes cancers of the mouth, nose,
sinuses, salivary glands, throat and lymph nodes in the neck. Most
begin in the moist tissues that line the mouth, nose and throat.
Symptoms include a lump or sore that does not heal, a sore throat
that does not go away, trouble swallowing and a change or
hoarseness in the voice. Using tobacco or alcohol increases cancer
risk. Treatments of head and neck cancer may include surgery,
radiation therapy, chemotherapy or a combination. Treatments can
affect eating, speaking or even breathing, so patients may need
rehabilitation.
[0300] Head and neck cancer is often complex, with many different
sites and staging systems. However, current therapy offers several
alternatives, including surgery, radiation, and chemotherapy,
either alone or in combination.
[0301] Combined modality therapy is becoming the principal method
of treating patients with locally advanced head and neck cancers.
Meanwhile, researchers are actively investigating new treatments
such as gene therapy. Newer chemotherapy agents (e.g., paclitaxel
[Taxol.RTM.], docetaxel [Taxotere.RTM.], gemcitabine [Gemzar.RTM.],
doxorubicin [Doxil.RTM.]) may be combined with established
chemotherapeutic agents (e.g., methotrexate [Trexall.RTM.,
Methotrex.RTM.]) to improve results.
[0302] In March 2006, the Food and Drug Administration (FDA)
approved cetuximab (Erbitux.RTM.), in combination with radiation,
for patients with squamous cell carcinoma of the head and neck that
cannot be treated surgically. Cetuximab also may be used alone
(called monotherapy) in patients with head and neck cancer that has
spread (metastasized) following standard chemotherapy.
[0303] Therapy for the treatment of head and neck cancer according
to one embodiment of the invention utilizes a combination of
therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib. In another embodiment, therapy for the treatment of head
and neck cancer according to the invention utilizes a combination
of therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and one or more chemotherapy agents (e.g., paclitaxel
[Taxol.RTM.], docetaxel [Taxotere.RTM.], gemcitabine [Gemzar.RTM.],
doxorubicin [Doxil.RTM.]) which may be further combined with
established chemotherapeutic agents (e.g., methotrexate
[Trexall.RTM., Methotrex.RTM.]). In another embodiment, therapy for
the treatment of head and neck cancer according to the invention
utilizes a combination of therapeutically effective amount of a
composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and Erbitux.RTM..
Colorectal Cancer
[0304] COX-2 expression levels correlate with survival rates in
colorectal cancer (see FIG. 1.) Survival from colorectal cancer
depends on the stage and grade of the tumor, for example precursor
adenomas to metastatic adenocarcinoma. Generally, colorectal cancer
can be treated by surgically removing the tumor, but overall
survival rates remain between 45 and 60 percent. Colonic excision
morbidity rates are fairly low and are generally associated with
the anastomosis and not the extent of the removal of the tumor and
local tissue. In patients with a high risk of reoccurrence,
however, chemotherapy has been incorporated into the treatment
regimen in order to improve survival rates.
[0305] Tumor metastasis prior to surgery is generally believed to
be the cause of surgical intervention failure and up to one year of
chemotherapy is required to kill the non-excised tumor cells. As
severe toxicity is associated with the chemotherapeutic agents,
only patients at high risk of recurrence are placed on chemotherapy
following surgery. Thus, the incorporation of an antiangiogenesis
inhibitor into the management of colorectal cancer plays an
important role in the treatment of colorectal cancer and lead to
overall improved survival rates for patients diagnosed with
colorectal cancer.
[0306] One embodiment of the invention provides a combination
therapy for the treatment of colorectal cancer including surgery,
followed by a regimen of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib. Further, another embodiment of the invention provides a
combination therapy for the treatment of colorectal cancer
including surgery, followed by a regimen of a composition
comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib, and one or more antiangiogenic agents including an MMP
inhibitor, or an integrin antagonist, cycled over a one year time
period. A further embodiment of the invention provides a
combination therapy for the treatment of colorectal cancer
including a regimen of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib, followed by surgical removal of the tumor from the colon
or rectum and then followed be a regimen of a composition
comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib cycled over a one year time period. Another therapy for
the treatment of colon cancer comprises administering a combination
of therapeutically effective amounts of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib.
[0307] A further therapy for the treatment of colon cancer is a
combination of a treatment with a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib in combination with the following antineoplastic agents:
fluorouracil, Levamisole, camptothecin, oxaliplatin, bevacizumab,
cetuximab, panitumumab, irinotecan, leucovorin, and
capecitabine.
Breast Cancer
[0308] Today, among women in the United States, breast cancer
remains the most frequent diagnosed cancer. One in 8 women in the
United States is at risk of developing breast cancer in their
lifetime. Age, family history, diet, and genetic factors have been
identified as risk factors for breast cancer. Breast cancer is the
second leading cause of death among women.
[0309] Different chemotherapeutic agents are known in art for
treating breast cancer. Cytoxic agents used for treating breast
cancer include doxorubicin, cyclophosphamide, methotrexate,
5-fluorouracil, mitomycin C, mitoxantrone, paclitaxel, taxane
formulations such as by way of example only, Abraxane.RTM.
(ABI-007), Paclitaxel-Cremophor EL, Paclitaxel poliglumex, and
Paclitaxel injectable emulsion (PIE), gemcitabine, docetaxel,
capecitabine, lapatanib, trastuzumab, anastrozole, letrozole,
exemestane, and epirubicin. In the treatment of locally advanced
noninflammatory breast cancer, a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib can be used to treat the disease. Additionally, in
combination with surgery, radiation therapy or with
chemotherapeutic or other antiangiogenic agents. Other combinations
of chemotherapeutic agents, that can be used in combination with
the present disclosure include, but are not limited to anastrozole,
capecitabine, docetaxel, epirubicin, exemestane, fulvestrant,
epothilone A, B or D, goserelin acetate, letrozole, bevacizumab,
paclitaxel, pamidronate, tamoxifen, toremifene, and
trastuzumab.
[0310] Hormone Positive
[0311] Many breast cancers require the hormone oestrogen to grow.
In women who have had their menopause, the main source of oestrogen
is through the conversion of androgens into oestrogens. This
process is carried out by the aromatase enzyme. In the treatment of
hormone positive breast cancer a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib can be used to treat the disease in combination with
other agents, such as, aromatase inhibitors, for e.g., exemestane,
letrozole, and anastrozole.
[0312] HER2/neu Positive Breast Cancer
[0313] In the treatment of HER2/neu positive breast cancer,
compositions comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib can be used to treat the disease in combination with
other antiangiogenic agents, or in combination with surgery,
radiation therapy or with chemotherapeutic agents. Other
chemotherapeutic agents include, for example, trastuzumab,
lapatinib, and CL-387785.
[0314] Triple Negative Breast Cancer
[0315] In the treatment of triple negative breast cancer wherein
the cancer is estrogen receptor-negative, progesterone
receptor-negative and HER2-negative, compositions comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib can be used to treat the disease in combination with
other therapeutic agents. Such agents include, by way of example
only, cetuximab, paclitaxel, docetaxel, taxane formulations, for
example, Abraxane.RTM. (ABI-007), Paclitaxel-Cremophor EL,
Paclitaxel poliglumex, and Paclitaxel injectable emulsion
(PIE).
Ovarian Cancer
[0316] Celomic epithelial carcinoma accounts for approximately 90%
of ovarian cancer cases. One therapy for the treatment of ovary
cancer is a combination of therapeutically effective amounts of a
composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib.
[0317] Other agents that can be used in combination with a
composition comprising a combination
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib include, but are not limited to: alkylating agents,
ifosfamide, cisplatin, carboplatin, paclitaxel, docetaxel,
PEGylated liposomal doxorubicin, gemcitabine, doxorubicin,
epothilone A, B, or D, topotecan, liposomal doxorubicin
5-fluorouracil, methotrexate, mitomycin, hexamethylmelamine,
progestins, antiestrogens, prednimustine, dihydroxybusulfan,
galactitol, interferon alpha, and interferon gama.
[0318] Other combinations for the treatment of celomic epithelial
carcinoma is a combination of therapeutically effective amounts of
a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and one of the following combinations of antineoplastic
agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2)
hexamthylmelamine, cyclosphamide, doxorubicin, cisplatin; 3)
cyclophosphamide, hexamethylmelamine, 5-fluorouracil, cisplatin; 4)
melphalan, hexamethylmelamine, cyclophosphamide; 5) melphalan,
doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin,
carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine,
cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine,
carboplatin; 9) cyclophosphamide, cisplatin; 10)
hexamethylmelamine, doxorubicin, carboplatin; 11) cyclophosphamide,
hexamethimelamine, doxorubicin, cisplatin; 12) carboplatin,
cyclophosphamide; 13) cisplatin, cyclophosphamide.
[0319] Cancer of the fallopian tube accounts for approximately 400
new cancer cases per year in the United States. One therapy
according to the invention is for the treatment of fallopian tube
cancer which includes administering a combination of
therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib. Other agents that can be used in combination with a
composition comprising a combination
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib include, but are not limited to: alkylating agents,
ifosfamide, cisplatin, carboplatin, paclitaxel, docetaxel,
PEGylated liposomal doxorubicin, gemcitabine, doxorubicin,
epothilone A, B, or D, topotecan, liposomal doxorubicin,
5-fluorouracil, methotrexate, mitomycin, hexamethylmelamine,
progestins, antiestrogens, prednimustine, dihydroxybusulfan,
galactitol, interferon .alpha., and interferon .gamma..
[0320] Germ cell ovarian cancer accounts for approximately 5% of
ovarian cancer cases. Germ cell ovarian carcinomas are classified
into two main groups: dysgerminoma, and nondysgerminoma.
Nondysgerminoma is further classified into teratoma, endodermal
sinus tumor, embryonal carcinoma, chloricarcinoma, polyembryoma,
and mixed cell tumors. One therapy for the treatment of germ cell
carcinoma is a combination of therapeutically effective amount of a
composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib.
[0321] One therapy according to the invention is for the treatment
of germ cell carcinoma which comprises administering a combination
of a therapeutically effective amount of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib and the following combinations of antineoplastic agents:
1) vincristine, actinomycin D, cyclophosphamide; 2) bleomycin,
etoposide, cisplatin; 3) vinblastine, bleomycin, cisplatin.
Pancreatic Cancer
[0322] Approximately 2% of new cancer cases diagnosed in the United
States are pancreatic cancer. Pancreatic cancer is generally
classified into two clinical types: 1) adenocarcinoma (metastatic
and non-metastatic), and 2) cystic neoplasms (serous cystadenomas,
mucinous cystic neoplasms, papillary cystic neoplasms, acinar cell
systadenocarcinoma, cystic choriocarcinoma, cystic teratomas,
angiomatous neoplasms). Erlotinib in combination with gemcitabine
is indicated for treatment of patients with locally advanced,
unresectable or metastatic pancreatic cancer.
[0323] Combinations of therapy for the treatment of non-metastatic
adenocarcinoma that may be used in the present disclosure include
the use of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib along with preoperative bilary tract decompression
(patients presenting with obstructive jaundice); surgical
resection, including standard resection, extended or radial
resection and distal pancreatectomy (tumors of body and tail);
adjuvant radiation; antiangiogenic therapy; and chemotherapy.
[0324] For the treatment of metastatic adenocarcinoma, a
combination therapy consists of a composition comprising a
combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib of the present disclosure in combination with continuous
treatment of 5-fluorouracil, followed by weekly cisplatin
therapy.
[0325] Another combination therapy for the treatment of cystic
neoplasms is the use of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib in combination with gemcitabine.
Pharmaceutical Compositions
[0326] Provided herein is a pharmaceutical composition for treating
cancer comprising a combination of a 1,2-diphenylpyrrole derivative
and an EGFR inhibitor; and a pharmaceutically acceptable excipient
or carrier.
[0327] In one embodiment, the invention provides a pharmaceutical
composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib as an active ingredient, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, in a pharmaceutically acceptable
vehicle, carrier, diluent, or excipient, or a mixture thereof; and
one or more pharmaceutically acceptable excipients or carriers.
[0328] In another embodiment, the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and a
pharmaceutically acceptable excipient or carrier. In another
embodiment, the EGFR inhibitor is erlotinib and a pharmaceutically
acceptable excipient or carrier. In a further embodiment the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib and a pharmaceutically acceptable
excipient or carrier.
[0329] In one embodiment, the invention provides a pharmaceutical
composition for treating cancer comprising a combination of a
1,2-diphenylpyrrole derivative selected from the group consisting
of: 4-methyl-2-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-chlorophenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-2-(4-methylthiophenyl)-1-(4-sulfamoylphenyl)pyrrole;
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(4-methoxy-3-methylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3-fluoro-4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
2-(3,4-dimethylphenyl)-4-methyl-1-(4-sulfamoylphenyl)pyrrole;
4-methyl-1-(4-methylthiophenyl)-2-(4-sulfamoylphenyl)pyrrole;
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(4-methoxyphenyl)pyrrole;
and
1-(4-acetylaminosulfonylphenyl)-4-methyl-2-(3,4-dimethylphenyl)pyrrole.
In another embodiment, the invention provides a method wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and an
EGFR inhibitor; and a pharmaceutically acceptable excipient or
carrier.
[0330] Provided herein are pharmaceutical compositions comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor as an active ingredient, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, in a pharmaceutically acceptable
vehicle, carrier, diluent, or excipient, or a mixture thereof; and
one or more pharmaceutically acceptable excipients or carriers.
[0331] Also provided herein are pharmaceutical compositions
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor as an active ingredient, or a pharmaceutically
acceptable salt, solvate, or prodrug thereof, in a pharmaceutically
acceptable vehicle, carrier, diluent, or excipient, or a mixture
thereof; and one or more release controlling excipients as
described herein. Provided herein are pharmaceutical compositions
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, in a
pharmaceutically acceptable vehicle, carrier, diluent, or
excipient, or a mixture thereof; and one or more release
controlling excipients as described herein. Suitable modified
release dosage vehicles include, but are not limited to,
hydrophilic or hydrophobic matrix devices, water-soluble separating
layer coatings, enteric coatings, osmotic devices,
multi-particulate devices, and combinations thereof. The
pharmaceutical compositions may also comprise non-release
controlling excipients.
[0332] Provided herein are pharmaceutical compositions in
film-coated dosage forms, which comprise a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor as an active
ingredient, or a pharmaceutically acceptable salt, solvate, or
prodrug thereof; and one or more tabletting excipients to form a
tablet core using conventional tabletting processes and
subsequently coating the core. The tablet cores can be produced
using conventional granulation methods, for example wet or dry
granulation, with optional comminution of the granules and with
subsequent compression and coating. Granulation methods are
described, for example, in Voigt, pages 156-69 (Voigt, R. (1984):
Lehrbuch der pharmazeutischen Technologie (Textbook of
Pharmaceutical Technology); Verlag Chemie Weinheim--Beerfield
Beach/Florida--Basle).
[0333] Suitable excipients for the production of granules are, for
example pulverulent fillers optionally having flow-conditioning
properties, for example talcum, silicon dioxide, for example
synthetic amorphous anhydrous silicic acid of the Syloid.RTM. type
(Grace), for example SYLOID 244 FP, microcrystalline cellulose, for
example of the Avicel.RTM. type (FMC Corp.), for example of the
types AVICEL PH101, 102, 105, RC581 or RC 591, Emcocel.RTM. type
(Mendell Corp.) or Elcema.RTM. type (Degussa); carbohydrates, such
as sugars, sugar alcohols, starches or starch derivatives, for
example lactose, dextrose, saccharose, glucose, sorbitol, mannitol,
xylitol, potato starch, maize starch, rice starch, wheat starch or
amylopectin, tricalcium phosphate, calcium hydrogen phosphate or
magnesium trisilicate; binders, such as gelatin, tragacanth, agar,
alginic acid, cellulose ethers, for example methylcellulose,
carboxymethylcellulose or hydroxypropylmethylcellulose,
polyethylene glycols or ethylene oxide homopolymers, especially
having a degree of polymerization of approximately from
2.0.times.10.sup.3 to 1.0.times.10.sup.5 and an approximate
molecular weight of about from 1.0.times.10.sup.5 to
5.0.times.10.sup.6, for example excipients known by the name
Polyox.RTM. (Union Carbide), polyvinylpyrrolidone or povidones,
especially having a mean molecular weight of approximately 1000 and
a degree of polymerization of approximately from about 500 to about
2500, and also agar or gelatin; surface-active substances, for
example anionic surfactants of the alkyl sulfate type, for example
sodium, potassium or magnesium n-dodecyl sulfate, n-tetradecyl
sulfate, n-hexadecyl sulfate or n-octadecyl sulfate, of the alkyl
ether sulfate type, for example sodium, potassium or magnesium
n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate,
n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl sulfate, or of
the alkanesulfonate type, for example sodium, potassium or
magnesium n-dodecanesulfonate, n-tetradecanesulfonate,
n-hexadecanesulfonate or n-octadecanesulfonate, or non-ionic
surfactants of the fatty acid polyhydroxy alcohol ester type, such
as sorbitan monolaurate, monooleate, monostearate or monopalmitate,
sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty
acid polyhydroxy alcohol esters, such as polyoxyethylene sorbitan
monolaurate, monooleate, monostearate, monopalmitate, tristearate
or trioleate, polyethylene glycol fatty acid esters, such as
polyoxyethyl stearate, polyethylene glycol 400 stearate,
polyethylene glycol 2000 stearate, especially ethylene
oxide/propylene oxide block polymers of the Pluronics.RTM. (BWC) or
Synperonic.RTM. (ICI) type
[0334] Further provided herein are pharmaceutical compositions in
enteric coated dosage forms, which comprise a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor as an active
ingredient, or a pharmaceutically acceptable salt, solvate, or
prodrug thereof; and one or more release controlling excipients for
use in an enteric coated dosage form. Provided herein are
pharmaceutical compositions in enteric coated dosage forms
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, in a
pharmaceutically acceptable vehicle, carrier, diluent, or
excipient, or a mixture thereof; and one or more release
controlling excipients for use in an enteric coated dosage form.
The pharmaceutical compositions may also comprise non-release
controlling excipients.
[0335] Further provided herein are pharmaceutical compositions in
effervescent dosage forms, which comprise a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor as an active
ingredient, or a pharmaceutically acceptable salt, solvate, or
prodrug thereof; and one or more release controlling excipients for
use in effervescent dosage forms. Also provided herein are
pharmaceutical compositions in effervescent dosage forms comprising
a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, in a
pharmaceutically acceptable vehicle, carrier, diluent, or
excipient, or a mixture thereof; and one or more release
controlling excipients for use in an effervescent dosage forms. The
pharmaceutical compositions may also comprise non-release
controlling excipients.
[0336] Additionally provided are pharmaceutical compositions in a
dosage form that has an instant releasing component and at least
one delayed releasing component, and is capable of giving a
discontinuous release of the compound in the form of at least two
consecutive pulses separated in time from 0.1 up to 24 hours. The
pharmaceutical compositions comprise a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor as an active
ingredient, or a pharmaceutically acceptable salt, solvate, or
prodrug thereof; and one or more release controlling and
non-release controlling excipients, such as those excipients
suitable for a disruptable semi-permeable membrane and as swellable
substances. Additionally, the invention provides pharmaceutical
compositions comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof; and
one or more release controlling and non-release controlling
excipients, such as those excipients suitable for a disruptable
semi-permeable membrane and as swellable substances.
[0337] Provided herein also are pharmaceutical compositions in a
dosage form for oral administration to a subject, which comprises a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor as an active ingredient, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof; and one or more pharmaceutically
acceptable excipients or carriers, enclosed in an intermediate
reactive layer comprising a gastric juice-resistant polymeric
layered material partially neutralized with alkali and having
cation exchange capacity and a gastric juice-resistant outer layer.
Additionally, the invention provides pharmaceutical compositions in
a dosage form for oral administration to a subject comprising a
combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib enclosed in an intermediate reactive
layer comprising a gastric juice-resistant polymeric layered
material partially neutralized with alkali and having cation
exchange capacity and a gastric juice-resistant outer layer.
[0338] Provided herein are pharmaceutical compositions that
comprise about 0.1 to about 1200 mg, about 1 to about 500 mg, about
2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500
mg, about 600 mg, about 800 mg, about 1200 mg of a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor as an active
ingredient, or a pharmaceutically acceptable salt, solvate, or
prodrug thereof, in the form of enteric-coated granules, as
delayed-release capsules for oral administration. Also, the
invention provides for pharmaceutical compositions that comprise
about 0.1 to about 1000 mg, about 1 to about 500 mg, about 2 to
about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about
10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about
100 mg, about 500 mg of a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor wherein the 1,2-diphenylpyrrole
derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, in
the form of enteric-coated granules, as delayed-release capsules
for oral administration.
[0339] Provided herein are pharmaceutical compositions that
comprise about 0.1 to about 1200 mg, about 1 to about 500 mg, about
2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 100 mg, about 500 mg, about 600 mg, about 800 mg, about 1200
mg of a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor as an active ingredient, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof in the form of enteric-coated
pellets, as delayed-release capsules for oral administration. Also,
the invention provides for pharmaceutical compositions that
comprise about 0.1 to about 1200 mg, about 1 to about 500 mg, about
2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 100 mg, about 500 mg, about 600 mg, about 800 mg, about 1200
mg of a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof in
the form of enteric-coated pellets, as delayed-release capsules for
oral administration. The pharmaceutical compositions further
comprise glyceryl monostearate 40-50, hydroxypropyl cellulose,
hypromellose, magnesium stearate, methacrylic acid copolymer type
C, polysorbate 80, sugar spheres, talc, and triethyl citrate.
[0340] Provided herein are pharmaceutical compositions that
comprise about 0.1 to about 1200 mg, about 1 to about 500 mg, about
2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 100 mg, about 500 mg, about 600 mg, about 800 mg, about 1200
mg of a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor as an active ingredient, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, as enteric-coated
delayed-release tablets for oral administration. Also, the
pharmaceutical compositions that comprise about 0.1 to about 1200
mg, about 1 to about 500 mg, about 2 to about 100 mg, about 1 mg,
about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about
30 mg, about 40 mg, about 50 mg, about 100 mg, about 500 mg, about
600 mg, about 800 mg, about 1200 mg of a combination of a
1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein the
1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, as
enteric-coated delayed-release tablets for oral administration. The
pharmaceutical compositions further comprise carnauba wax,
crospovidone, diacetylated monoglycerides, ethylcellulose,
hydroxypropyl cellulose, hypromellose phthalate, magnesium
stearate, mannitol, sodium hydroxide, sodium stearyl fumarate,
talc, titanium dioxide, and yellow ferric oxide.
[0341] Provided herein are pharmaceutical compositions that
comprise about 0.1 to about 1200 mg, about 1 to about 500 mg, about
2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 100 mg, about 500 mg, about 600 mg, about 800 mg, about 1200
mg of a combination of a 1,2-diphenylpyrrole derivative and an EGFR
inhibitor as an active ingredient, or a pharmaceutically acceptable
salt, solvate, or prodrug thereof, as enteric-coated
delayed-release tablets for oral administration. Also provided
herein are pharmaceutical compositions that comprise about 0.1 to
about 1200 mg, about 1 to about 500 mg, about 2 to about 100 mg,
about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about
20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about
500 mg, about 600 mg, about 800 mg, about 1200 mg of a combination
of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor wherein
the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib as an active ingredient, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, as
enteric-coated delayed-release tablets for oral administration. The
pharmaceutical compositions further comprise calcium stearate,
crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol,
methacrylic acid copolymer, polysorbate 80, povidone, propylene
glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide,
and triethyl citrate.
[0342] The pharmaceutical compositions provided herein may be
provided in unit-dosage forms or multiple-dosage forms. Unit-dosage
forms, as used herein, refer to physically discrete units suitable
for administration to human and animal subjects and packaged
individually as is known in the art. Each unit-dose contains a
predetermined quantity of the active ingredient(s) sufficient to
produce the desired therapeutic effect, in association with the
required pharmaceutical carriers or excipients. Examples of
unit-dosage forms include ampules, syringes, and individually
packaged tablets and capsules. Unit-dosage forms may be
administered in fractions or multiples thereof A multiple-dosage
form is a plurality of identical unit-dosage forms packaged in a
single container to be administered in segregated unit-dosage form.
Examples of multiple-dosage forms include vials, bottles of tablets
or capsules, or bottles of pints or gallons.
[0343] The compositions provided herein may be administered alone,
or in combination with one or more other compounds provided herein,
one or more other active ingredients. The pharmaceutical
compositions that comprise a compound provided herein may be
formulated in various dosage forms for oral, parenteral, buccal,
intranasal, epidural, sublingual, pulmonary, local, rectal,
transdermal, or topical administration. The pharmaceutical
compositions may also be formulated as a modified release dosage
form, including delayed-, extended-, prolonged-, sustained-,
pulsatile-, controlled-, accelerated- and fast-, targeted-,
programmed-release, and gastric retention dosage forms. These
dosage forms can be prepared according to conventional methods and
techniques known to those skilled in the art (see, Remington: The
Science and Practice of Pharmacy, supra; Modified-Release Drug
Deliver Technology, Rathbone et al., Eds., Drugs and the
Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002;
Vol. 126).
[0344] The pharmaceutical compositions provided herein may be
administered at once, or multiple times at intervals of time. It is
understood that the precise dosage and duration of treatment may
vary with the age, weight, and condition of the patient being
treated, and may be determined empirically using known testing
protocols or by extrapolation from in vivo or in vitro test or
diagnostic data. It is further understood that for any particular
individual, specific dosage regimens should be adjusted over time
according to the individual need and the professional judgment of
the person administering or supervising the administration of the
formulations.
[0345] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
combinations may be administered chronically, that is, for an
extended period of time, including throughout the duration of the
patient's life in order to ameliorate or otherwise control or limit
the symptoms of the patient's disease or condition.
[0346] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the combinations may
be given continuously or temporarily suspended for a certain length
of time (i.e., a "drug holiday").
[0347] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disease, disorder or condition is retained. Patients can, however,
require intermittent treatment on a long-term basis upon any
recurrence of symptoms.
[0348] As described herein, the compositions and methods for using
the composition comprising a combination of a 1,2-diphenylpyrrole
derivative and an EGFR inhibitor, may be formulated without
carriers or excipients or may be combined with one or more
pharmaceutically acceptable carriers for administration. For
example, solvents, diluents and the like, and may be administered
orally in such forms as tablets, capsules, dispersible powders,
granules, or suspensions containing, for example, from about 0.05
to about 5% of suspending agent, syrups containing, for example,
from about 10 to about 50% of sugar, and elixirs containing, for
example, from about 20 to about 50% ethanol, and the like. Such
pharmaceutical preparations may contain, for example, from about
0.05 up to about 90% of the active ingredient in combination with
the carrier, more usually between about 5% and about 60% by weight.
Also, the compositions and methods for using the composition
comprising a combination of a 1,2-diphenylpyrrole derivative and an
EGFR inhibitor wherein the 1,2-diphenylpyrrole derivative is
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and the
EGFR inhibitor is erlotinib, may be formulated without carriers or
excipients or may be combined with one or more pharmaceutically
acceptable carriers for administration.
[0349] The effective dosage of each active ingredient employed may
vary depending on the particular compound employed, the mode of
administration and the severity of the condition being treated. The
projected daily dosage of the EGFR inhibitor will depend on many
factors. Numerous methods for evaluating and comparing
1,2-diphenylpyrrole derivative inhibitor potency are known to one
of skill in the art. In one embodiment, an oral daily dosage of the
1,2-diphenylpyrrole derivative inhibitor is in the range of about
0.01 to about 30 mg/kg, and the projected daily dosage of the EGFR
inhibitor is in the range of about 0.3 to about 8 mg/kg. This
dosage regimen may be adjusted to provide the optimal therapeutic
response. For example, several divided doses may be administered
daily or the dose may be proportionally reduced as indicated by the
exigencies of the therapeutic situation. The 1,2-diphenylpyrrole
derivative inhibitor and the EGFR inhibitor may also be
administered as a combined dosage unit, or as separate components.
When administered as separate components, each component may be
administered at the same time, or at different times during the
treatment period.
[0350] It is understood, however, that a specific dose level for
any particular patient will depend upon a variety of factors such
as, for example, decreases in the liver and kidney function.
[0351] Treatment dosages generally may be titrated to optimize
safety and efficacy. Typically, dosage-effect relationships from in
vitro studies initially can provide useful guidance on the proper
doses for patient administration. Studies in animal models also
generally may be used for guidance regarding effective dosages for
treatment of cancers in accordance with the present disclosure. In
terms of treatment protocols, it should be appreciated that the
dosage to be administered will depend on several factors, including
the particular agent that is administered, the route administered,
the condition of the particular patient, etc. Determination of
these parameters are well within the skill of the art. These
considerations, as well as effective formulations and
administration procedures are well known in the art and are
described in standard textbooks.
Oral Formulations
[0352] Oral formulations containing the active combinations
described herein may comprise any conventionally used oral forms,
including: tablets, capsules, pills, troches, lozenges, pastilles,
cachets, pellets, medicated chewing gum, granules, bulk powders,
effervescent or non-effervescent powders or granules, solutions,
emulsions, suspensions, solutions, wafers, sprinkles, elixirs,
syrups, buccal forms, and oral liquids. Capsules may contain
mixtures of the active compound(s) with inert fillers and/or
diluents such as the pharmaceutically acceptable starches (e.g.
corn, potato or tapioca starch), sugars, artificial sweetening
agents, powdered celluloses, such as crystalline and
microcrystalline celluloses, flours, gelatins, gums, etc. Useful
tablet formulations may be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically
acceptable diluents, binding agents, lubricants, disintegrants,
surface modifying agents (including surfactants), suspending or
stabilizing agents, including, but not limited to, magnesium
stearate, stearic acid, talc, sodium lauryl sulfate,
microcrystalline cellulose, carboxymethylcellulose calcium,
polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan
gum, sodium citrate, complex silicates, calcium carbonate, glycine,
dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate,
lactose, kaolin, mannitol, sodium chloride, talc, dry starches and
powdered sugar. In some embodiments are surface modifying agents
which include nonionic and anionic surface modifying agents. For
example, surface modifying agents include, but are not limited to,
poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal
silicon dioxide, phosphates, sodium dodecylsulfate, magnesium
aluminum silicate, and triethanolamine Oral formulations herein may
utilize standard delay or time release formulations to alter the
absorption of the active compound(s). The oral formulation may also
consist of administering the active ingredient in water or a fruit
juice, containing appropriate solubilizers or emulsifiers as
needed.
Oral Administration
[0353] As described herein, the combination regimen can be given
simultaneously or can be given in a staggered regimen, with a
1,2-diphenylpyrrole derivative being given at a different time
during the course of chemotherapy than an EGFR inhibitor. This time
differential may range from several minutes, hours, days, weeks, or
longer between administration of the two compounds. Therefore, the
term combination does not necessarily mean administered at the same
time or as a unitary dose, but that each of the components are
administered during a desired treatment period. The agents may also
be administered by different routes. As is typical for
chemotherapeutic regimens, a course of chemotherapy may be repeated
several weeks later, and may follow the same timeframe for
administration of the two compounds, or may be modified based on
patient response.
[0354] In other embodiments, the pharmaceutical compositions
provided herein may be provided in solid, semisolid, or liquid
dosage forms for oral administration. As used herein, oral
administration also include buccal, lingual, and sublingual
administration. Suitable oral dosage forms include, but are not
limited to, tablets, capsules, pills, troches, lozenges, pastilles,
cachets, pellets, medicated chewing gum, granules, bulk powders,
effervescent or non-effervescent powders or granules, solutions,
emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and
syrups. In addition to the active ingredient(s), the pharmaceutical
compositions may contain one or more pharmaceutically acceptable
carriers or excipients, including, but not limited to, binders,
fillers, diluents, disintegrants, wetting agents, lubricants,
glidants, coloring agents, dye-migration inhibitors, sweetening
agents, and flavoring agents.
[0355] Binders or granulators impart cohesiveness to a tablet to
ensure the tablet remaining intact after compression. Suitable
binders or granulators include, but are not limited to, starches,
such as corn starch, potato starch, and pre-gelatinized starch
(e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose,
dextrose, molasses, and lactose; natural and synthetic gums, such
as acacia, alginic acid, alginates, extract of Irish moss, Panwar
gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose,
methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch
arabogalactan, powdered tragacanth, and guar gum; celluloses, such
as ethyl cellulose, cellulose acetate, carboxymethyl cellulose
calcium, sodium carboxymethyl cellulose, methyl cellulose,
hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),
hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses,
such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105
(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable
fillers include, but are not limited to, talc, calcium carbonate,
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler may be present from
about 50 to about 99% by weight in the pharmaceutical compositions
provided herein.
[0356] Suitable diluents include, but are not limited to, dicalcium
phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol,
cellulose, kaolin, mannitol, sodium chloride, dry starch, and
powdered sugar. Certain diluents, such as mannitol, lactose,
sorbitol, sucrose, and inositol, when present in sufficient
quantity, can impart properties to some compressed tablets that
permit disintegration in the mouth by chewing. Such compressed
tablets can be used as chewable tablets.
[0357] Suitable disintegrants include, but are not limited to,
agar; bentonite; celluloses, such as methylcellulose and
carboxymethylcellulose; wood products; natural sponge;
cation-exchange resins; alginic acid; gums, such as guar gum and
Veegum HV; citrus pulp; cross-linked celluloses, such as
croscarmellose; cross-linked polymers, such as crospovidone;
cross-linked starches; calcium carbonate; microcrystalline
cellulose, such as sodium starch glycolate; polacrilin potassium;
starches, such as corn starch, potato starch, tapioca starch, and
pre-gelatinized starch; clays; aligns; and mixtures thereof. The
amount of disintegrant in the pharmaceutical compositions provided
herein varies upon the type of formulation, and is readily
discernible to those of ordinary skill in the art. The
pharmaceutical compositions provided herein may contain from about
0.5 to about 15% or from about Ito about 5% by weight of a
disintegrant.
[0358] Suitable lubricants include, but are not limited to, calcium
stearate; magnesium stearate; mineral oil; light mineral oil;
glycerin; sorbitol; mannitol; glycols, such as glycerol behenate
and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate;
talc; hydrogenated vegetable oil, including peanut oil, cottonseed
oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean
oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch;
lycopodium; silica or silica gels, such as AEROSIL.RTM. 200 (W.R.
Grace Co., Baltimore, Md.) and CAB-O-SIL.RTM. (Cabot Co. of Boston,
Mass.); and mixtures thereof. The pharmaceutical compositions
provided herein may contain about 0.1 to about 5% by weight of a
lubricant.
[0359] Suitable glidants include colloidal silicon dioxide,
CAB-O-SIL.RTM. (Cabot Co. of Boston, Mass.), and asbestos-free
talc. Coloring agents include any of the approved, certified, water
soluble FD&C dyes, and water insoluble FD&C dyes suspended
on alumina hydrate, and color lakes and mixtures thereof. A color
lake is the combination by adsorption of a water-soluble dye to a
hydrous oxide of a heavy metal, resulting in an insoluble form of
the dye. Flavoring agents include natural flavors extracted from
plants, such as fruits, and synthetic blends of compounds which
produce a pleasant taste sensation, such as peppermint and methyl
salicylate. Sweetening agents include sucrose, lactose, mannitol,
syrups, glycerin, and artificial sweeteners, such as saccharin and
aspartame. Suitable emulsifying agents include gelatin, acacia,
tragacanth, bentonite, and surfactants, such as polyoxyethylene
sorbitan monooleate (TWEEN.RTM. 20), polyoxyethylene sorbitan
monooleate 80 (TWEEN.RTM. 80), and triethanolamine oleate.
Suspending and dispersing agents include sodium
carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium
carbomethylcellulose, hydroxypropyl methylcellulose, and
polyvinylpyrolidone. Preservatives include glycerin, methyl and
propylparaben, benzoic add, sodium benzoate and alcohol. Wetting
agents include propylene glycol monostearate, sorbitan monooleate,
diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.
Examples of non-aqueous liquids utilized in emulsions include
mineral oil and cottonseed oil. Organic acids include citric and
tartaric acid. Sources of carbon dioxide include sodium bicarbonate
and sodium carbonate.
[0360] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation.
[0361] In further embodiments, the pharmaceutical compositions
provided herein may be provided as compressed tablets, tablet
triturates, chewable lozenges, rapidly dissolving tablets, multiple
compressed tablets, or enteric-coating tablets, sugar-coated, or
film-coated tablets. Enteric-coated tablets are compressed tablets
coated with substances that resist the action of stomach acid but
dissolve or disintegrate in the intestine, thus protecting the
active ingredients from the acidic environment of the stomach.
Enteric-coatings include, but are not limited to, fatty acids,
fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and
cellulose acetate phthalates. Sugar-coated tablets are compressed
tablets surrounded by a sugar coating, which may be beneficial in
covering up objectionable tastes or odors and in protecting the
tablets from oxidation. Film-coated tablets are compressed tablets
that are covered with a thin layer or film of a water-soluble
material. Film coatings include, but are not limited to,
hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene
glycol 4000, and cellulose acetate phthalate. Film coating imparts
the same general characteristics as sugar coating. Multiple
compressed tablets are compressed tablets made by more than one
compression cycle, including layered tablets, and press-coated or
dry-coated tablets.
[0362] The tablet dosage forms may be prepared from the active
ingredient in powdered, crystalline, or granular forms, alone or in
combination with one or more carriers or excipients described
herein, including binders, disintegrants, controlled-release
polymers, lubricants, diluents, and/or colorants. Flavoring and
sweetening agents are especially useful in the formation of
chewable tablets and lozenges.
[0363] The pharmaceutical compositions provided herein may be
provided as soft or hard capsules, which can be made from gelatin,
methylcellulose, starch, or calcium alginate. The hard gelatin
capsule, also known as the dry-filled capsule (DFC), consists of
two sections, one slipping over the other, thus completely
enclosing the active ingredient. The soft elastic capsule (SEC) is
a soft, globular shell, such as a gelatin shell, which is
plasticized by the addition of glycerin, sorbitol, or a similar
polyol. The soft gelatin shells may contain a preservative to
prevent the growth of microorganisms. Suitable preservatives are
those as described herein, including methyl- and propyl-parabens,
and sorbic acid. The liquid, semisolid, and solid dosage forms
provided herein may be encapsulated in a capsule. Suitable liquid
and semisolid dosage forms include solutions and suspensions in
propylene carbonate, vegetable oils, or triglycerides. Capsules
containing such solutions can be prepared as described in U.S. Pat.
Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be
coated as known by those of skill in the art in order to modify or
sustain dissolution of the active ingredient.
[0364] In other embodiments, the pharmaceutical compositions
provided herein may be provided in liquid and semisolid dosage
forms, including emulsions, solutions, suspensions, elixirs, and
syrups. An emulsion is a two-phase system, in which one liquid is
dispersed in the form of small globules throughout another liquid,
which can be oil-in-water or water-in-oil. Emulsions may include a
pharmaceutically acceptable non-aqueous liquids or solvent,
emulsifying agent, and preservative. Suspensions may include a
pharmaceutically acceptable suspending agent and preservative.
Aqueous alcoholic solutions may include a pharmaceutically
acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl
aldehyde (the term "lower" means an alkyl having between 1 and 6
carbon atoms), e.g., acetaldehyde diethyl acetal; and a
water-miscible solvent having one or more hydroxyl groups, such as
propylene glycol and ethanol. Elixirs are clear, sweetened, and
hydroalcoholic solutions. Syrups are concentrated aqueous solutions
of a sugar, for example, sucrose, and may also contain a
preservative. For a liquid dosage form, for example, a solution in
a polyethylene glycol may be diluted with a sufficient quantity of
a pharmaceutically acceptable liquid carrier, e.g., water, to be
measured conveniently for administration.
[0365] Other useful liquid and semisolid dosage forms include, but
are not limited to, those containing the active ingredient(s)
provided herein, and a dialkylated mono- or poly-alkylene glycol,
including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme,
polyethylene glycol-350-dimethyl ether, polyethylene
glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether,
wherein 350, 550, and 750 refer to the approximate average
molecular weight of the polyethylene glycol. These formulations may
further comprise one or more antioxidants, such as butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl
gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,
lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric
acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its
esters, and dithiocarbamates.
[0366] The pharmaceutical compositions provided herein for oral
administration may be also provided in the forms of liposomes,
micelles, microspheres, or nanosystems. Miccellar dosage forms can
be prepared as described in U.S. Pat. No. 6,350,458.
[0367] In other embodiments, the pharmaceutical compositions
provided herein may be provided as non-effervescent or
effervescent, granules and powders, to be reconstituted into a
liquid dosage form. Pharmaceutically acceptable carriers and
excipients used in the non-effervescent granules or powders may
include diluents, sweeteners, and wetting agents. Pharmaceutically
acceptable carriers and excipients used in the effervescent
granules or powders may include organic acids and a source of
carbon dioxide.
[0368] Coloring and flavoring agents can be used in all of the
above dosage forms.
[0369] The pharmaceutical compositions provided herein may be
formulated as immediate or modified release dosage forms, including
delayed-, sustained, pulsed-, controlled, targeted-, and
programmed-release forms.
[0370] In further embodiments, the pharmaceutical compositions
provided herein may be co-formulated with other active ingredients
which do not impair the desired therapeutic action, or with
substances that supplement the desired action, such as other
cholinergic agents, other serotoninergic agents, alpha adrenergic
agents, CCK.sub.A antagonists, 5-HT.sub.3 antagonists, NMDA
receptor antagonists, opioids, prokinetics, tachykinins,
antalarmin, and Z-338.
Parenteral Administration
[0371] In some embodiments, the pharmaceutical compositions
provided herein may be administered parenterally by injection,
infusion, or implantation, for local or systemic administration.
Parenteral administration, as used herein, include intravenous,
intraarterial, intraperitoneal, intrathecal, intraventricular,
intraurethral, intrasternal, intracranial, intramuscular,
intrasynovial, and subcutaneous administration.
[0372] In other embodiments, the pharmaceutical compositions
provided herein may be formulated in any dosage forms that are
suitable for parenteral administration, including solutions,
suspensions, emulsions, micelles, liposomes, microspheres,
nanosystems, and solid forms suitable for solutions or suspensions
in liquid prior to injection. Such dosage forms can be prepared
according to conventional methods known to those skilled in the art
of pharmaceutical science (see, Remington: The Science and Practice
of Pharmacy, supra).
[0373] The pharmaceutical compositions intended for parenteral
administration may include one or more pharmaceutically acceptable
carriers and excipients, including, but not limited to, aqueous
vehicles, water-miscible vehicles, non-aqueous vehicles,
antimicrobial agents or preservatives against the growth of
microorganisms, stabilizers, solubility enhancers, isotonic agents,
buffering agents, antioxidants, local anesthetics, suspending and
dispersing agents, wetting or emulsifying agents, complexing
agents, sequestering or chelating agents, cryoprotectants,
lyoprotectants, thickening agents, pH adjusting agents, and inert
gases.
[0374] Suitable aqueous vehicles include, but are not limited to,
water, saline, physiological saline or phosphate buffered saline
(PBS), sodium chloride injection, Ringers injection, isotonic
dextrose injection, sterile water injection, dextrose and lactated
Ringers injection. Non-aqueous vehicles include, but are not
limited to, fixed oils of vegetable origin, castor oil, corn oil,
cottonseed oil, olive oil, peanut oil, peppermint oil, safflower
oil, sesame oil, soybean oil, hydrogenated vegetable oils,
hydrogenated soybean oil, and medium-chain triglycerides of coconut
oil, and palm seed oil. Water-miscible vehicles include, but are
not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol
(e.g., polyethylene glycol 300 and polyethylene glycol 400),
propylene glycol, glycerin, N-methyl-2-pyrrolidone,
dimethylacetamide, and dimethylsulfoxide.
[0375] Suitable antimicrobial agents or preservatives include, but
are not limited to, phenols, cresols, mercurials, benzyl alcohol,
chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosal,
benzalkonium chloride, benzethonium chloride, methyl- and
propyl-parabens, and sorbic acid. Suitable isotonic agents include,
but are not limited to, sodium chloride, glycerin, and dextrose.
Suitable buffering agents include, but are not limited to,
phosphate and citrate. Suitable antioxidants are those as described
herein, including bisulfite and sodium metabisulfite. Suitable
local anesthetics include, but are not limited to, procaine
hydrochloride. Suitable suspending and dispersing agents are those
as described herein, including sodium carboxymethylcelluose,
hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable
emulsifying agents include those described herein, including
polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan
monooleate 80, and triethanolamine oleate. Suitable sequestering or
chelating agents include, but are not limited to EDTA. Suitable pH
adjusting agents include, but are not limited to, sodium hydroxide,
hydrochloric acid, citric acid, and lactic acid. Suitable
complexing agents include, but are not limited to, cyclodextrins,
including .alpha.-cyclodextrin, .beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
sulfobutylether-.beta.-cyclodextrin, and sulfobutylether
7-.beta.-cyclodextrin (CAPTISOL.RTM., CyDex, Lenexa, Kans.).
[0376] In some embodiments, the pharmaceutical compositions
provided herein may be formulated for single or multiple dosage
administration. The single dosage formulations are packaged in an
ampule, a vial, or a syringe. The multiple dosage parenteral
formulations must contain an antimicrobial agent at bacteriostatic
or fungistatic concentrations. All parenteral formulations must be
sterile, as known and practiced in the art.
[0377] In one embodiment, the pharmaceutical compositions are
provided as ready-to-use sterile solutions. In another embodiment,
the pharmaceutical compositions are provided as sterile dry soluble
products, including lyophilized powders and hypodermic tablets, to
be reconstituted with a vehicle prior to use. In yet another
embodiment, the pharmaceutical compositions are provided as
ready-to-use sterile suspensions. In yet another embodiment, the
pharmaceutical compositions are provided as sterile dry insoluble
products to be reconstituted with a vehicle prior to use. In still
another embodiment, the pharmaceutical compositions are provided as
ready-to-use sterile emulsions.
[0378] The pharmaceutical compositions provided herein may be
formulated as immediate or modified release dosage forms, including
delayed-, sustained, pulsed-, controlled, targeted-, and
programmed-release forms.
[0379] The pharmaceutical compositions may be formulated as a
suspension, solid, semi-solid, or thixotropic liquid, for
administration as an implanted depot. In one embodiment, the
pharmaceutical compositions provided herein are dispersed in a
solid inner matrix, which is surrounded by an outer polymeric
membrane that is insoluble in body fluids but allows the active
ingredient in the pharmaceutical compositions diffuse through.
[0380] Suitable inner matrixes include polymethylmethacrylate,
polybutylmethacrylate, plasticized or unplasticized
polyvinylchloride, plasticized nylon, plasticized
polyethyleneterephthalate, natural rubber, polyisoprene,
polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate
copolymers, silicone rubbers, polydimethylsiloxanes, silicone
carbonate copolymers, hydrophilic polymers, such as hydrogels of
esters of acrylic and methacrylic acid, collagen, cross-linked
polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl
acetate.
[0381] Suitable outer polymeric membranes include polyethylene,
polypropylene, ethylene/propylene copolymers, ethylene/ethyl
acrylate copolymers, ethylene/vinylacetate copolymers, silicone
rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated
polyethylene, polyvinylchloride, vinylchloride copolymers with
vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer
polyethylene terephthalate, butyl rubber epichlorohydrin rubbers,
ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl
alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
Modified Release
[0382] In other embodiments, the pharmaceutical compositions
provided herein may be formulated as a modified release dosage
form. As used herein, the term "modified release" refers to a
dosage form in which the rate or place of release of the active
ingredient(s) is different from that of an immediate dosage form
when administered by the same route. Modified release dosage forms
include delayed-, extended-, prolonged-, sustained-, pulsatile-,
controlled-, accelerated- and fast-, targeted-, programmed-release,
and gastric retention dosage forms. The pharmaceutical compositions
in modified release dosage forms can be prepared using a variety of
modified release devices and methods known to those skilled in the
art, including, but not limited to, matrix controlled release
devices, osmotic controlled release devices, multiparticulate
controlled release devices, ion-exchange resins, enteric coatings,
multilayered coatings, microspheres, liposomes, and combinations
thereof. The release rate of the active ingredient(s) can also be
modified by varying the particle sizes and polymorphorism of the
active ingredient(s).
[0383] Examples of modified release include, but are not limited
to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;
3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;
5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;
5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;
6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970;
6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and
6,699,500.
Matrix Controlled Release Devices
[0384] In some embodiments, the pharmaceutical compositions
provided herein in a modified release dosage form may be fabricated
using a matrix controlled release device known to those skilled in
the art (see, Takada et al in "Encyclopedia of Controlled Drug
Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999).
[0385] In one embodiment, the pharmaceutical compositions provided
herein in a modified release dosage form is formulated using an
erodible matrix device, which is water-swellable, erodible, or
soluble polymers, including synthetic polymers, and naturally
occurring polymers and derivatives, such as polysaccharides and
proteins.
[0386] Materials useful in forming an erodible matrix include, but
are not limited to, chitin, chitosan, dextran, and pullulan; gum
agar, gum arabic, gum karaya, locust bean gum, gum tragacanth,
carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan;
starches, such as dextrin and maltodextrin; hydrophilic colloids,
such as pectin; phosphatides, such as lecithin; alginates;
propylene glycol alginate; gelatin; collagen; and cellulosics, such
as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl
cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl
cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP),
cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP,
CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,
hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and
ethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone;
polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters;
polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or
methacrylic acid (EUDRAGIT.RTM., Rohm America, Inc., Piscataway,
N.J.); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers
of L-glutamic acid and ethyl-L-glutamate; degradable lactic
acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid;
and other acrylic acid derivatives, such as homopolymers and
copolymers of butylmethacrylate, methylmethacrylate,
ethylmethacrylate, ethylacrylate,
(2-dimethylaminoethyl)methacrylate, and
(trimethylaminoethyl)methacrylate chloride.
[0387] In further embodiments, the pharmaceutical compositions are
formulated with a non-erodible matrix device. The active
ingredient(s) is dissolved or dispersed in an inert matrix and is
released primarily by diffusion through the inert matrix once
administered. Materials suitable for use as a non-erodible matrix
device included, but are not limited to, insoluble plastics, such
as polyethylene, polypropylene, polyisoprene, polyisobutylene,
polybutadiene, polymethylmethacrylate, polybutylmethacrylate,
chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl
methacrylate copolymers, ethylene-vinylacetate copolymers,
ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,
vinylchloride copolymers with vinyl acetate, vinylidene chloride,
ethylene and propylene, ionomer polyethylene terephthalate, butyl
rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized
nylon, plasticized polyethyleneterephthalate, natural rubber,
silicone rubbers, polydimethylsiloxanes, silicone carbonate
copolymers, and; hydrophilic polymers, such as ethyl cellulose,
cellulose acetate, crospovidone, and cross-linked partially
hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba
wax, microcrystalline wax, and triglycerides.
[0388] In a matrix controlled release system, the desired release
kinetics can be controlled, for example, via the polymer type
employed, the polymer viscosity, the particle sizes of the polymer
and/or the active ingredient(s), the ratio of the active
ingredient(s) versus the polymer, and other excipients or carriers
in the compositions.
[0389] In other embodiments, the pharmaceutical compositions
provided herein in a modified release dosage form may be prepared
by methods known to those skilled in the art, including direct
compression, dry or wet granulation followed by compression,
melt-granulation followed by compression.
2. Osmotic Controlled Release Devices
[0390] In some embodiments, the pharmaceutical compositions
provided herein in a modified release dosage form may be fabricated
using an osmotic controlled release device, including one-chamber
system, two-chamber system, asymmetric membrane technology (AMT),
and extruding core system (ECS). In general, such devices have at
least two components: (a) the core which contains the active
ingredient(s); and (b) a semipermeable membrane with at least one
delivery port, which encapsulates the core. The semipermeable
membrane controls the influx of water to the core from an aqueous
environment of use so as to cause drug release by extrusion through
the delivery port(s).
[0391] In addition to the active ingredient(s), the core of the
osmotic device optionally includes an osmotic agent, which creates
a driving force for transport of water from the environment of use
into the core of the device. One class of osmotic agents
water-swellable hydrophilic polymers, which are also referred to as
"osmopolymers" and "hydrogels," including, but not limited to,
hydrophilic vinyl and acrylic polymers, polysaccharides such as
calcium alginate, polyethylene oxide (PEO), polyethylene glycol
(PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl
methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol
(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic
monomers such as methyl methacrylate and vinyl acetate, hydrophilic
polyurethanes containing large PEO blocks, sodium croscarmellose,
carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose
(HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl
cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate,
polycarbophil, gelatin, xanthan gum, and sodium starch
glycolate.
[0392] The other class of osmotic agents are osmogens, which are
capable of imbibing water to affect an osmotic pressure gradient
across the barrier of the surrounding coating. Suitable osmogens
include, but are not limited to, inorganic salts, such as magnesium
sulfate, magnesium chloride, calcium chloride, sodium chloride,
lithium chloride, potassium sulfate, potassium phosphates, sodium
carbonate, sodium sulfite, lithium sulfate, potassium chloride, and
sodium sulfate; sugars, such as dextrose, fructose, glucose,
inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose,
trehalose, and xylitol; organic acids, such as ascorbic acid,
benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid,
sorbic acid, adipic acid, edetic acid, glutamic acid,
p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and
mixtures thereof.
[0393] Osmotic agents of different dissolution rates may be
employed to influence how rapidly the active ingredient(s) is
initially delivered from the dosage form. For example, amorphous
sugars, such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be used
to provide faster delivery during the first couple of hours to
promptly produce the desired therapeutic effect, and gradually and
continually release of the remaining amount to maintain the desired
level of therapeutic or prophylactic effect over an extended period
of time. In this case, the active ingredient(s) is released at such
a rate to replace the amount of the active ingredient metabolized
and excreted.
[0394] The core may also include a wide variety of other excipients
and carriers as described herein to enhance the performance of the
dosage form or to promote stability or processing.
[0395] Materials useful in forming the semi-permeable membrane
include various grades of acrylics, vinyls, ethers, polyamides,
polyesters, and cellulosic derivatives that are water-permeable and
water-insoluble at physiologically relevant pHs, or are susceptible
to being rendered water-insoluble by chemical alteration, such as
crosslinking. Examples of suitable polymers useful in forming the
coating, include plasticized, unplasticized, and reinforced
cellulose acetate (CA), cellulose diacetate, cellulose triacetate,
CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB),
CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate,
cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA
ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl
sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar
acetate, amylose triacetate, beta glucan acetate, beta glucan
triacetate, acetaldehyde dimethyl acetate, triacetate of locust
bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG
copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,
poly(acrylic) acids and esters and poly-(methacrylic) acids and
esters and copolymers thereof, starch, dextran, dextrin, chitosan,
collagen, gelatin, polyalkenes, polyethers, polysulfones,
polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl
esters and ethers, natural waxes, and synthetic waxes.
[0396] Semi-permeable membrane may also be a hydrophobic
microporous membrane, wherein the pores are substantially filled
with a gas and are not wetted by the aqueous medium but are
permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
Such hydrophobic but water-vapor permeable membrane are typically
composed of hydrophobic polymers such as polyalkenes, polyethylene,
polypropylene, polytetrafluoroethylene, polyacrylic acid
derivatives, polyethers, polysulfones, polyethersulfones,
polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl
esters and ethers, natural waxes, and synthetic waxes.
[0397] The delivery port(s) on the semi-permeable membrane may be
formed post-coating by mechanical or laser drilling. Delivery
port(s) may also be formed in situ by erosion of a plug of
water-soluble material or by rupture of a thinner portion of the
membrane over an indentation in the core. In addition, delivery
ports may be formed during coating process, as in the case of
asymmetric membrane coatings of the type disclosed in U.S. Pat.
Nos. 5,612,059 and 5,698,220.
[0398] The total amount of the active ingredient(s) released and
the release rate can substantially by modulated via the thickness
and porosity of the semi-permeable membrane, the composition of the
core, and the number, size, and position of the delivery ports.
[0399] The pharmaceutical compositions in an osmotic
controlled-release dosage form may further comprise additional
conventional excipients or carriers as described herein to promote
performance or processing of the formulation.
[0400] The osmotic controlled-release dosage forms can be prepared
according to conventional methods and techniques known to those
skilled in the art (see, Remington: The Science and Practice of
Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35,
1-21; Verma et al., Drug Development and Industrial Pharmacy 2000,
26, 695-708; Verma et al., J. Controlled Release 2002, 79,
7-27).
[0401] In other embodiments, the pharmaceutical compositions
provided herein are formulated as AMT controlled-release dosage
form, which comprises an asymmetric osmotic membrane that coats a
core comprising the active ingredient(s) and other pharmaceutically
acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and
WO 2002/17918. The AMT controlled-release dosage forms can be
prepared according to conventional methods and techniques known to
those skilled in the art, including direct compression, dry
granulation, wet granulation, and a dip-coating method.
[0402] In certain embodiments, the pharmaceutical compositions
provided herein are formulated as ESC controlled-release dosage
form, which comprises an osmotic membrane that coats a core
comprising the active ingredient(s), a hydroxylethyl cellulose, and
other pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[0403] In some embodiments, the pharmaceutical compositions
provided herein in a modified release dosage form may be fabricated
a multiparticulate controlled release device, which comprises a
multiplicity of particles, granules, or pellets, ranging from about
10 .mu.m to about 3 mm, about 50 .mu.m to about 2.5 mm, or from
about 100 .mu.m to about 1 mm in diameter. Such multiparticulates
may be made by the processes know to those skilled in the art,
including wet- and dry-granulation, extrusion/spheronization,
roller-compaction, melt-congealing, and by spray-coating seed
cores. See, for example, Multiparticulate Oral Drug Delivery;
Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology;
Marcel Dekker: 1989.
[0404] Other excipients or carriers as described herein may be
blended with the pharmaceutical compositions to aid in processing
and forming the multiparticulates. The resulting particles may
themselves constitute the multiparticulate device or may be coated
by various film-forming materials, such as enteric polymers,
water-swellable, and water-soluble polymers. The multiparticulates
can be further processed as a capsule or a tablet.
4. Targeted Delivery
[0405] In some embodiments, the pharmaceutical compositions
provided herein may also be formulated to be targeted to a
particular tissue, receptor, or other area of the body of the
subject to be treated, including liposome-, resealed erythrocyte-,
and antibody-based delivery systems. Examples include, but are not
limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;
6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;
6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;
5,840,674; 5,759,542; and 5,709,874, all of which are incorporated
herein by their entirety.
Immediate Release
[0406] In some embodiments, the pharmaceutical compositions
provided herein in an immediate release dosage form are capable of
releasing not less than 75% of the therapeutically active
ingredient or combination and/or meet the disintegration or
dissolution requirements for immediate release tablets of the
particular therapeutic agents or combination included in the tablet
core, as set forth in USP XXII, 1990 (The United States
Pharmacopeia.)
Topical Administration
[0407] In other embodiments, the pharmaceutical compositions
provided herein may be administered topically to the skin,
orifices, or mucosa. The topical administration, as used herein,
include (intra)dermal, conjuctival, intracorneal, intraocular,
ophthalmic, auricular, transdermal, nasal, vaginal, uretheral,
respiratory, and rectal administration.
[0408] In further embodiments, the pharmaceutical compositions
provided herein may be formulated in any dosage forms that are
suitable for topical administration for local or systemic effect,
including emulsions, solutions, suspensions, creams, gels,
hydrogels, ointments, dusting powders, dressings, elixirs, lotions,
suspensions, tinctures, pastes, foams, films, aerosols,
irrigations, sprays, suppositories, bandages, dermal patches. The
topical formulation of the pharmaceutical compositions provided
herein may also comprise liposomes, micelles, microspheres,
nanosystems, and mixtures thereof.
[0409] Pharmaceutically acceptable carriers and excipients suitable
for use in the topical formulations provided herein include, but
are not limited to, aqueous vehicles, water-miscible vehicles,
non-aqueous vehicles, antimicrobial agents or preservatives against
the growth of microorganisms, stabilizers, solubility enhancers,
isotonic agents, buffering agents, antioxidants, local anesthetics,
suspending and dispersing agents, wetting or emulsifying agents,
complexing agents, sequestering or chelating agents, penetration
enhancers, cryopretectants, lyoprotectants, thickening agents, and
inert gases.
[0410] In some embodiments, the pharmaceutical compositions may
also be administered topically by electroporation, iontophoresis,
phonophoresis, sonophoresis and microneedle or needle-free
injection, such as POWDERJECT.TM. (Chiron Corp., Emeryville,
Calif.), and BIOJECT.TM. (Bioject Medical Technologies Inc.,
Tualatin, Oreg.).
[0411] The pharmaceutical compositions provided herein may be
provided in the forms of ointments, creams, and gels. Suitable
ointment vehicles include oleaginous or hydrocarbon vehicles,
including such as lard, benzoinated lard, olive oil, cottonseed
oil, and other oils, white petrolatum; emulsifiable or absorption
vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate,
and anhydrous lanolin; water-removable vehicles, such as
hydrophilic ointment; water-soluble ointment vehicles, including
polyethylene glycols of varying molecular weight; emulsion
vehicles, either water-in-oil (W/0) emulsions or oil-in-water (0/W)
emulsions, including cetyl alcohol, glyceryl monostearate, lanolin,
and stearic acid (see, Remington: The Science and Practice of
Pharmacy, supra). These vehicles are emollient but generally
require addition of antioxidants and preservatives.
[0412] Suitable cream base can be oil-in-water or water-in-oil.
Cream vehicles may be water-washable, and contain an oil phase, an
emulsifier, and an aqueous phase. The oil phase is also called the
"internal" phase, which is generally comprised of petrolatum and a
fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase
usually, although not necessarily, exceeds the oil phase in volume,
and generally contains a humectant. The emulsifier in a cream
formulation may be a nonionic, anionic, cationic, or amphoteric
surfactant.
[0413] Gels are semisolid, suspension-type systems. Single-phase
gels contain organic macromolecules distributed substantially
uniformly throughout the liquid carrier. Suitable gelling agents
include crosslinked acrylic acid polymers, such as carbomers,
carboxypolyalkylenes, Carbopol.RTM.; hydrophilic polymers, such as
polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers,
and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, and methylcellulose; gums,
such as tragacanth and xanthan gum; sodium alginate; and gelatin.
In order to prepare a uniform gel, dispersing agents such as
alcohol or glycerin can be added, or the gelling agent can be
dispersed by trituration, mechanical mixing, and/or stirring.
[0414] The pharmaceutical compositions provided herein may be
administered rectally, urethrally, vaginally, or perivaginally in
the forms of suppositories, pessaries, bougies, poultices or
cataplasm, pastes, powders, dressings, creams, plasters,
contraceptives, ointments, solutions, emulsions, suspensions,
tampons, gels, foams, sprays, or enemas. These dosage forms can be
manufactured using conventional processes as described in
Remington: The Science and Practice of Pharmacy, supra.
[0415] Rectal, urethral, and vaginal suppositories are solid bodies
for insertion into body orifices, which are solid at ordinary
temperatures but melt or soften at body temperature to release the
active ingredient(s) inside the orifices. Pharmaceutically
acceptable carriers utilized in rectal and vaginal suppositories
include bases or vehicles, such as stiffening agents, which produce
a melting point in the proximity of body temperature, when
formulated with the pharmaceutical compositions provided herein;
and antioxidants as described herein, including bisulfate and
sodium metabisulfite. Suitable vehicles include, but are not
limited to, cocoa butter (theobroma oil), glycerin-gelatin,
carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and
yellow wax, and appropriate mixtures of mono-, di- and
triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol,
hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin.
Combinations of the various vehicles may be used. Rectal and
vaginal suppositories may be prepared by the compressed method or
molding. The typical weight of a rectal and vaginal suppository is
about 2 to about 3 g.
[0416] The pharmaceutical compositions provided herein may be
administered ophthalmically in the forms of solutions, suspensions,
ointments, emulsions, gel-forming solutions, powders for solutions,
gels, ocular inserts, and implants.
[0417] The pharmaceutical compositions provided herein may be
administered intranasally or by inhalation to the respiratory
tract. The pharmaceutical compositions may be provided in the form
of an aerosol or solution for delivery using a pressurized
container, pump, spray, atomizer, such as an atomizer using
electrohydrodynamics to produce a fine mist, or nebulizer, alone or
in combination with a suitable propellant, such as
1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The
pharmaceutical compositions may also be provided as a dry powder
for insufflation, alone or in combination with an inert carrier
such as lactose or phospholipids; and nasal drops. For intranasal
use, the powder may comprise a bioadhesive agent, including
chitosan or cyclodextrin.
[0418] Solutions or suspensions for use in a pressurized container,
pump, spray, atomizer, or nebulizer may be formulated to contain
ethanol, aqueous ethanol, or a suitable alternative agent for
dispersing, solubilizing, or extending release of the active
ingredient provided herein, a propellant as solvent; and/or an
surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0419] In another embodiment, the pharmaceutical compositions
provided herein may be micronized to a size suitable for delivery
by inhalation, such as about 50 micrometers or less, or about 10
micrometers or less. Particles of such sizes may be prepared using
a comminuting method known to those skilled in the art, such as
spiral jet milling, fluid bed jet milling, supercritical fluid
processing to form nanoparticles, high pressure homogenization, or
spray drying.
[0420] Capsules, blisters and cartridges for use in an inhaler or
insufflator may be formulated to contain a powder mix of the
pharmaceutical compositions provided herein; a suitable powder
base, such as lactose or starch; and a performance modifier, such
as l-leucine, mannitol, or magnesium stearate. The lactose may be
anhydrous or in the form of the monohydrate. Other suitable
excipients include dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose, and trehalose. The pharmaceutical compositions
provided herein for inhaled/intranasal administration may further
comprise a suitable flavor, such as menthol and levomenthol, or
sweeteners, such as saccharin or saccharin sodium.
[0421] In one embodiment, the pharmaceutical compositions provided
herein for topical administration may be formulated to be immediate
release or modified release, including delayed-, sustained-,
pulsed-, controlled-, targeted, and programmed release.
EXAMPLES
Example 1
Synthesis of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
##STR00008##
[0423] Substituted benzaldehyde undergoes dehydration condensation
by reaction with aniline compound A in an inert solvent at a
temperature of between 5.degree. C. to 200.degree. C. to give
aldimine compound B. Trimethylsilyl cyanide is then reacted with
aldimine compound B in the presence of a Lewis acid to afford
anilinonitrile C. An .alpha.-.beta.-unsaturated aldehyde is then
reacted with anilinonitrile C to afford compound D which then
undergoes dehydration and dehydrogencyanation under basic
conditions in a modification of the method described in Ann Chem.
589, 176 (1954).
Example 2
Synthesis of Erlotinib
##STR00009##
[0425] Starting material compound H is heated in a suspension of
metal alkali and solvent, then heated to give compound I. Starting
material alcohol F, is placed in a solvent mixture of thionyl
chloride, methylene chloride and dimethylformamide to give the
chloride G. Chloride G is then coupled with compound I to give
erlotinib J.
Example 3
Pharmacokinetics and Metabolism of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
[0426] Orally administered
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole was
rapidly absorbed in all species examined (mice, rats, dogs, and
monkeys). Peak plasma concentrations were achieved between 1 and 3
hours after a dose of 5 mg/kg. The elimination half life
(t.sub.1/2) was 4-5 hours in rodents and dogs, and approximately 2
hours in monkeys. Oral availability was greatest in rodent, and was
reduced in dogs and monkeys (59 and 34% respectively).
Pharmacokinetics in human subjects demonstrated a linear dose
exposure relationship from doses of 2 mg to 800 mg given orally.
The half-life in human subjects is 15-18 hours.
Example 4
Toxicology of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
[0427] Toxicological evaluation of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole in mice,
rats, dogs and monkeys revealed expected findings related to
inhibition of cyclooxygenase and consistent with animal safety
observations with other COX-2 selective inhibitors. In single dose
studies, the minimum lethal dose of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole was 600
mg/kg in rats and >2000 mg/kg in dogs. An endoscopy study
conducted in human subjects demonstrated no increase in gastric or
duodenal toxicity compared to placebo.
Example 5
Biological Evaluation
COX-2 Selective Inhibitors
HT-29 Model:
[0428] Mice are injected subcutaneously in the left paw
(1.times.10.sup.6 tumor cells suspended in 30% Matrigel) and tumor
volume is evaluated using a phlethysmometer twice a week for 30-60
days. Implantation of human colon cancer cells (HT-29) into nude
mice produces tumors that will reach 0.6-2 ml between 30-50 days.
Blood is drawn twice during the experiment in a 24 h protocol to
assess plasma concentration and total exposure by AUC analysis. The
data is expressed as the mean+/-SEM. Student's and Mann-Whitney
tests are used to assess differences between means using the InStat
software package.
[0429] A. Mice injected with HT-29 cancer cells are treated with
cytoxin i.p at doses of 50 mg/kg on days 5, 7 and 9 in the presence
or absence of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib in the diet. The efficacy of both agents are determined
by measuring tumor volume. The results from these studies may
demonstrate that a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib administered in the diet to tumor bearing mice can delay
the growth of tumors and metastasis when administered as sole
therapy.
[0430] B. In a second assay, mice are injected with HT-29 cancer
cells are then treated with 5-FU on days 12 through 15. Mice
injected with HT-29 cancer cells are treated with 5-FU i.p at doses
of 50 mg/kg on days 12, 13, 14, and 15 in the presence or absence
of a composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib in the diet. The efficacy of both agents are determined
by measuring tumor volume. Treatment using the composition may
reduce tumor volume by up to 70%. In the same assay, 5-FU decreases
tumor volume by 61%. Further, the composition and 5-FU may decrease
tumor volume by 83%.
[0431] C. In a third assay, mice injected with HT-29 colon cancer
cells are treated with 5-FU i.p 50 mg/kg on days 14 through 17 in
the presence or absence of a composition comprising a combination
of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib (1600 ppm) and valdecoxib (160 ppm) in the diet. The
efficacy of both agents are determined by measuring tumor volume.
Treatment with 5-FU may result in a 35% reduction in tumor volume.
Treatment with the composition and valdecoxib may reduce tumor
volume by 52% and 69%, respectively. In the same assay, the
combination of 5-FU and the composition may decrease tumor volume
by 72% while the combination of 5-FU and valdecoxib may decrease
tumor volume by 74%.
Example 6
In Vitro Inhibition of EGFR Kinase Activity
[0432] The in vitro activity of the combinations described herein
in inhibiting the receptor tyrosine kinase may be determined by the
following procedure. The activity of the combinations of the
present disclosure, in vitro, can be determined by the amount of
inhibition of the phosphorylation of an exogenous substrate (e.g.,
Lys.sub.3--Gastrin or polyGluTyr (4:1) random copolymer (Posner et
al., J. Biol. Chem., 1992, 267 (29), 20638-472)) on tyrosine by
epidermal growth factor receptor kinase by a test compound relative
to a control. Affinity purified, soluble human EGF receptor (96 ng)
is obtained according to the procedure in G. N. Gill, W. Weber,
Methods in Enzymology, 1987, 146, 82-8 from A431 cells (American
Type Culture Collection, Rockville, Md.) and preincubated in a
microfuge tube with EGF (2 mg/ml) in phosphorylation
buffer+vanadate (PBV: 50 mM HEPES, pH 7.4; 125 mM NaCl; 24 mM
MgCl.sub.2; 100 sodium orthovanadate), in a total volume of 10
.mu.l, for 20-30 minutes at room temperature. The composition
comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib, dissolved in dimethylsulfoxide (DMSO), is diluted in
PBV, and 10 .mu.l is mixed with the EGF receptor/EGF mix, and
incubated for 10-30 minutes at 30.degree. C. The phosphorylation
reaction is initiated by addition of 20 .mu.l .sup.33
P-ATP/substrate mix (120 .mu.M Lys.sub.3-Gastrin (sequence in
single letter code for amino acids, KKKGPWLEEEEEAYGWLDF), 50 mM
Hepes pH 7.4, 40 .mu.M ATP, 2 pCi .gamma.-[.sup.33 P]-ATP) to the
EGFr/EGF mix and incubated for 20 minutes at room temperature. The
reaction is stopped by addition of 10 .mu.l stop solution (0.5 M
EDTA, pH 8; 2 mM ATP) and 6 .mu.l 2N HCl. The tubes are centrifuged
at 14,000 RPM, 4.degree. C., for 10 minutes. 35 .mu.l of
supernatant from each tube is pipetted onto a 2.5 cm circle of
Whatman P81 paper, bulk washed four times in 5% acetic acid, 1
liter per wash, and then air dried. This results in the binding of
substrate to the paper with loss of free ATP on washing. The
[.sup.33 P] incorporated is measured by liquid scintillation
counting. Incorporation in the absence of substrate (e.g.,
lys.sub.3-gastrin) is subtracted from all values as a background
and percent inhibition is calculated relative to controls without
the composition present. Such assays, carried out with a range of
doses of test combinations, allow the determination of an
approximate IC.sub.50 value for the in vitro inhibition of EGFR
kinase activity. Other methods for determining the activity of the
combinations presented herein are described in U.S. Pat. No.
5,747,498, the disclosure of which is incorporated herein.
Example 7
Pharmaceutical Compositions and Dosage Forms
[0433] Dosage formulations comprising pharmaceutical excipients and
carriers and a pharmaceutical composition comprising a combination
of erlotinib (A) and
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole (B)
include:
TABLE-US-00002 Amount of A Combination per tablet (mg) Amount of B
per tablet (mg) A/B 25 1, 5, 10, 25, 50, 100, 200, 300, 400, 600,
800, 1000, 1200 A/B 100 1, 5, 10, 25, 50, 100, 200, 300, 400, 600,
800, 1000, 1200 A/B 150 1, 5, 10, 25, 50, 100, 200, 300, 400, 600,
800, 1000, 1200 A/B 200 1, 5, 10, 25, 50, 100, 200, 300, 400, 600,
800, 1000, 1200 A/B 300 1, 5, 10, 25, 50, 100, 200, 300, 400, 600,
800, 1000, 1200 A/B 450 1, 5, 10, 25, 50, 100, 200, 300, 400, 600,
800, 1000, 1200
[0434] Dosage formulations described herein, including the
formulations set forth in the above table, may be administered in a
single fixed dose comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib or as a separate administration of a single dose of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and a
single dose of erlotinib.
Example 8
Biological Evaluation
COX-2 Selective Inhibitors
A431 Squamous Vulvar Carcinoma Model
[0435] Mice are injected subcutaneously in the left paw
(1.times.10.sup.6 tumor cells suspended in 30% Matrigel) and tumor
volume is evaluated using a phlethysmometer twice a week for 30-60
days. Implantation of squamous vulvar carcinoma (A431) into nude
mice produces tumors that reach 0.6-2 ml between 30-50 days. Blood
is drawn twice during the experiment in a 24 h protocol to assess
plasma concentration and total exposure by AUC analysis. The data
is expressed as the mean+/-SEM. Student's and Mann-Whitney tests
are used to assess differences between means using the InStat
software package.
[0436] Mice injected with A431 cancer cells are treated with a
composition comprising one of the following: 1. erlotinib (75 or
100 mg/kg); 2.
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole (3, 10,
30, or 100 mg/kg); 3. celecoxib (10, 30, 100, or 300 mg/kg); 4.
erlotinib (75 mg/kg) and
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole (3, 10,
or mg/kg); 4. erlotinib (75 mg/kg) and celecoxib (10, 30, or 100
mg/kg). The efficacy is determined by measuring tumor volume. The
results from these studies, shown in FIG. 3, demonstrate that a
composition comprising a combination of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole with
erlotinib administered to tumor bearing mice delayed the growth of
tumors by 55% compared to erlotinib alone. The combination of
erlotinib and celecoxib demonstrated a tumor growth delay of only
36%.
Example 9
[0437] Study of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole in
combination with erlotinib in metastatic or recurrent non-small
cell lung cancer (NSCLC) patients
[0438] Methods: Subjects with recurrent or metastatic NSCLC were
treated with erlotinib (150 mg/day PO) and escalating doses of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole (100-1200
mg/day PO). Pharmacokinetics for
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib were evaluated.
[0439] Results: Nineteen subjects were treated: 3 at
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole 100 mg; 4
at 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole 200
mg; 12 at 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
400 mg. The optimal biologic dose selected was 400 mg.
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
pharmacokinetics reveal a median T.sub.max of 2 hours (range
1.5-4), mean (SD) T1/2 of 11.8 (5.3) hours, C.sub.maxof 313.0
(99.6) ng/ml and AUC (0-t) of 2816 (1204) ng h/ml.
[0440] The results show that
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib have been safely administered in this study.
Example 10
Study of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
in combination with erlotinib in metastatic or recurrent non-small
cell lung cancer (NSCLC) patients
[0441] This study compares the anti-tumor efficacy of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib with placebo and erlotinib as measured by time to disease
progression. The experimental arm consists of 400 mg/day
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, in
combination with 150 mg/day erlotinib. The placebo arm consists of
400 mg/day placebo tablets, in combination with 150 mg/day
erlotinib.
Example 11
Study of 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole
in combination with erlotinib and gemcitabine in advanced
pancreatic cancer patients
[0442] This study compares the anti-tumor efficacy of
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole and
erlotinib/gemcitabine with placebo and erlotinib/gemcitabine as
measured by time to disease progression. The experimental arm will
consist of 400 mg/day
2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, in
combination with 100 mg/day erlotinib, and gemcitabine administered
as an intravenous infusion of a 1000 mg/m.sup.2 dose over 30
minutes once a week for up to 7 weeks followed by one week of rest
and then subsequent cycles of weekly infusions for 3 weeks of a 4
week cycle. The placebo arm consists of 400 mg/day placebo tablets,
in combination with 100 mg/day erlotinib, and gemcitabine
administered as an intravenous infusion of a 1000 mg/m.sup.2 dose
over 30 minutes once a week for up to 7 weeks followed by one week
of rest and then subsequent cycles of weekly infusions for 3 weeks
of a 4 week cycle.
Example 12
Treatment of Non-Small Cell Lung Cancer
[0443] A method for treating a subject having non-small cell lung
cancer comprising administering to the subject a therapeutically
effective amount of a combination comprising
2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-pyrrole and
erlotinib or their respective pharmaceutically acceptable salt,
solvate or prodrug is contemplated. The subject is treated using a
single dosage form of a combination of 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole in about 100, about 200, about 300,
about 400, about 600, about 800, and about 1000 and about 1200 mg
aliquots and erlotinib in about a 150 mg aliquot. The treatment of
the subject using a separate administration of
2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-pyrrole in about
200, about 400, and about 800 mg aliquots and erlotinib in about a
150 mg aliquot is also contemplated. The maximum tolerated dose of
this combination will be an endpoint for this study.
Example 13
Treatment of Breast Cancer
[0444] A method for treating a subject having breast cancer
comprising administering to the subject a therapeutically effective
amount of a combination comprising 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole and erlotinib or their respective
pharmaceutically acceptable salt, solvate or prodrug is
contemplated. Combined treatment with erlotinib and
2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-pyrrole is
expected to achieve increased tumor inhibition compared with
erlotinib administered as a single agent.
Example 14
Treatment of Colorectal Cancer
[0445] A method for treating a subject having colorectal cancer
comprising administering to the subject a therapeutically effective
amount of a combination comprising 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole and erlotinib or their respective
pharmaceutically acceptable salt, solvate or prodrug is
contemplated. Combined treatment with erlotinib and
2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-pyrrole are
expected to achieve significantly increased tumor inhibition
compared with either 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole or erlotinib administered as single
agents.
Example 15
Treatment of Glioma
[0446] A method for treating a subject having glioma comprising
administering to the subject a therapeutically effective amount of
a combination comprising 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole and erlotinib or their respective
pharmaceutically acceptable salt, solvate or prodrug is
contemplated. The subject is treated using a single dosage form of
a combination of 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole in about 1, about 5, about 10, about
25, about 50, about 100, about 200, about 300, about 400, about
600, about 800, about 1000, and about 1200 mg aliquots and
erlotinib in about a 25 mg aliquot. The treatment of the subject
using a separate administration of 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole in about 1, about 5, about 10, about
25, about 50, about 100, about 200, about 300, about 400, about
600, about 800, about 1000, and about 1200 mg aliquots and
erlotinib in about 100, 150, 200, 300, or 450 mg aliquot is also
contemplated. The treatment will also be administered in subjects
with 2.sup.nd temozolomide failures.
Example 16
Treatment of Head and Neck Cancer
[0447] A method for treating a subject having head and neck cancer
comprising administering to the subject a therapeutically effective
amount of a combination comprising 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole and erlotinib or their respective
pharmaceutically acceptable salt, solvate or prodrug is
contemplated. The subject is treated using a single dosage form of
a combination of 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole in about 1, about 5, about 10, about
25, about 50, about 100, about 200, about 300, about 400, about
600, about 800, about 1000, and about 1200 mg aliquots and
erlotinib in about a 25 mg aliquot. The treatment of the subject
using a separate administration of 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole in about 1, about 5, about 10, about
25, about 50, about 100, about 200, about 300, about 400, about
600, about 800, about 1000, and about 1200 mg aliquots and
erlotinib in about 100, 150, 200, 300, or 450 mg aliquot is also
contemplated. The treatment will also be administered in
conjunction with one or one or more chemotherapy agents (e.g.,
paclitaxel [Taxol.RTM.], docetaxel [Taxotere.RTM.], gemcitabine
[Gemzar.RTM.], doxorubicin [Doxil.RTM.]) which may be further
combined with established chemotherapeutic agents (e.g.,
methotrexate [Trexall.RTM., Methotrex.RTM.]). In another
embodiment, therapy for the treatment of head and neck cancer
according to the invention utilizes a combination of
therapeutically effective amount of a composition comprising a
combination of 2-(4-ethoxyphenyl)-4-methyl
1-(4-sulfamoylphenyl)-pyrrole and erlotinib and Erbitux.RTM..
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