U.S. patent application number 14/387533 was filed with the patent office on 2015-04-23 for treatment of brain cancer.
The applicant listed for this patent is Array BioPharma Inc.. Invention is credited to Kevin Koch, Patrice A. Lee, Shannon L. Winski.
Application Number | 20150110780 14/387533 |
Document ID | / |
Family ID | 48048296 |
Filed Date | 2015-04-23 |
United States Patent
Application |
20150110780 |
Kind Code |
A1 |
Lee; Patrice A. ; et
al. |
April 23, 2015 |
TREATMENT OF BRAIN CANCER
Abstract
Compounds for the treatment of brain cancer are provided herein.
Pharmaceutical compositions comprised of those compounds for the
treatment of brain cancer are also provided herein.
Inventors: |
Lee; Patrice A.; (Boulder,
CO) ; Winski; Shannon L.; (Boulder, CO) ;
Koch; Kevin; (Boulder, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Array BioPharma Inc. |
Boulder |
CO |
US |
|
|
Family ID: |
48048296 |
Appl. No.: |
14/387533 |
Filed: |
March 25, 2013 |
PCT Filed: |
March 25, 2013 |
PCT NO: |
PCT/US2013/033751 |
371 Date: |
September 23, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61615082 |
Mar 23, 2012 |
|
|
|
Current U.S.
Class: |
424/133.1 ;
514/266.21 |
Current CPC
Class: |
A61P 35/04 20180101;
A61K 31/7068 20130101; A61K 31/517 20130101; A61K 31/337 20130101;
A61P 35/00 20180101; A61K 45/06 20130101; A61K 31/517 20130101;
A61K 2300/00 20130101; A61K 31/337 20130101; A61K 2300/00 20130101;
A61K 31/7068 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/133.1 ;
514/266.21 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61K 45/06 20060101 A61K045/06 |
Claims
1-17. (canceled)
18. A method of treating local or metastatic brain cancer that is
caused by ErbB2 over-expression or amplification in a mammal
comprising administering a therapeutically effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
the mammal.
19. A method of treating local or metastatic brain cancer that is
caused by ErbB2 over-expression or amplification in a patient
having brain cancer comprising administering a therapeutically
effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
the patient.
20. (canceled)
21. The method of claim 18, wherein the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
administered as an oral dosage form.
22. The method of claim 18, wherein the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
in a tablet.
23. The method of claim 18, wherein the method includes another
therapeutic agent.
24. The method of claim 23, wherein the therapeutic agent is
selected from trastuzumab, capecitabine, bevacizumab, paclitaxel
and docetaxel.
25. The method of claim 18, wherein the method is used after
previous treatment for brain cancer.
26. The method of claim 25, wherein the previous treatment for
brain cancer is selected from surgery, radiation therapy and
chemotherapy or mixtures thereof.
27. The method of claim 25, wherein the previous treatment for
brain cancer is selected from surgery, conventional external
radiation therapy, three-dimensional conformal radiation therapy,
intensity modulated radiation therapy, stereotactic radiosurgery,
fractionated stereotactic radiation therapy, proton radiation
therapy, internal or implant radiation therapy, temozolomide,
bevacizumab, carmustine, lomustine, procarbazine, vincristine,
tumor treating fields therapy, everolimus, procarbazine, lomustine,
cisplatin, carboplatin and methotrexate or mixtures thereof.
28. The method of claim 18, wherein the method is used after
previous treatment for breast cancer.
29. The method of claim 28, wherein the previous treatment for
breast cancer is selected from surgery, sentinel lymph node biopsy
followed by surgery, radiation therapy, chemotherapy, hormone
therapy and targeted therapy.
30. The method of claim 28, wherein the previous treatment for
breast cancer is selected from lumpectomy, partial mastectomy,
segmental mastectomy, total mastectomy, modified radical
mastectomy, external radiation, internal radiation, methotrexate,
paclitaxel albumin-stabilized nanoparticle formulation,
ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus,
anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel,
epirubicin, exemestane, toremifene, fulvestrant, letrozole,
gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen,
pertuzumab and toremifene, or mixtures thereof.
31. The method of claim 18, wherein
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
administered.
32. The method of claim 31, wherein about 550 to about 650 mg twice
per day of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(-
4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
administered.
33. The method of claim 18, wherein
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
administered.
34. The method of claim 33, wherein about 25 to about 1800 mg per
day of
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
administered.
35. (canceled)
36. The method of claim 19, wherein the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
administered as an oral dosage form.
37. The method of claim 19, wherein the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
in the form of a tablet.
38. The method of claim 19, wherein the method includes another
therapeutic agent.
39. The method of claim 38, wherein the therapeutic agent is
selected from trastuzumab, capecitabine, bevacizumab, paclitaxel
and docetaxel.
40. The method of claim 19, wherein the use is after previous
treatment for brain cancer.
41. The method of claim 40, wherein the previous treatment for
brain cancer is selected from surgery, radiation therapy and
chemotherapy or mixtures thereof.
42. The method of claim 40, wherein the previous treatment for
brain cancer is selected from surgery, conventional external
radiation therapy, three-dimensional conformal radiation therapy,
intensity modulated radiation therapy, stereotactic radiosurgery,
fractionated stereotactic radiation therapy, proton radiation
therapy, internal or implant radiation therapy, temozolomide,
bevacizumab, carmustine, lomustine, procarbazine, vincristine,
tumor treating fields therapy, everolimus, procarbazine, lomustine,
cisplatin, carboplatin and methotrexate or mixtures thereof.
43. The method of claim 19, wherein the use is after previous
treatment for breast cancer.
44. The method of claim 43, wherein the previous treatment for
breast cancer is selected from surgery, sentinel lymph node biopsy
followed by surgery, radiation therapy, chemotherapy, hormone
therapy and targeted therapy.
45. The method of claim 43, wherein the previous treatment for
breast cancer is selected from lumpectomy, partial mastectomy,
segmental mastectomy, total mastectomy, modified radical
mastectomy, external radiation, internal radiation, methotrexate,
paclitaxel albumin-stabilized nanoparticle formulation,
ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus,
anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel,
epirubicin, exemestane, toremifene, fulvestrant, letrozole,
gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen,
pertuzumab and toremifene, or mixtures thereof.
46. The method of claims 19, wherein
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
administered.
47. The method of claim 46, wherein about 550 to about 650 mg twice
per day of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(-
4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
administered.
48. The method of claim 19, wherein
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
administered.
49. The method of claim 48, wherein about 25 to about 1800 mg per
day of
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol is
administered.
50-62. (canceled)
63. A method of treating local or metastatic brain cancer that is
caused by ErbB2 over-expression or amplification using
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in a
patient having brain cancer comprising administering an effective
amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4--
dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to the
patient.
64. (canceled)
65. The method of claim 63, wherein the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
administered as an oral dosage form.
66. The method of claim 65, wherein the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is in a
tablet.
67. The method of claim 63, wherein the method includes another
therapeutic agent.
68. The method of claim 67, wherein the therapeutic agent is
selected from trastuzumab, capecitabine, bevacizumab, paclitaxel
and docetaxel.
69. The method of claim 63, wherein the method is used after
previous treatment for brain cancer.
70. The method of claim 69, wherein the previous treatment for
brain cancer is selected from surgery, radiation therapy and
chemotherapy or mixtures thereof.
71. The method of claim 69, wherein the previous treatment for
brain cancer is selected from surgery, conventional external
radiation therapy, three-dimensional conformal radiation therapy,
intensity modulated radiation therapy, stereotactic radiosurgery,
fractionated stereotactic radiation therapy, proton radiation
therapy, internal or implant radiation therapy, temozolomide,
bevacizumab, carmustine, lomustine, procarbazine, vincristine,
tumor treating fields therapy, everolimus, procarbazine, lomustine,
cisplatin, carboplatin and methotrexate or mixtures thereof.
72. The method of claim 63, wherein the method is used after
previous treatment for breast cancer.
73. The method of claim 72, wherein the previous treatment for
breast cancer is selected from surgery, sentinel lymph node biopsy
followed by surgery, radiation therapy, chemotherapy, hormone
therapy and targeted therapy.
74. The method of claim 72, wherein the previous treatment for
breast cancer is selected from lumpectomy, partial mastectomy,
segmental mastectomy, total mastectomy, modified radical
mastectomy, external radiation, internal radiation, methotrexate,
paclitaxel albumin-stabilized nanoparticle formulation,
ado-trastuzumab emtansine, doxorubicin, fluorouracil, everolimus,
anastrozole, exemestane, capecitabine, cyclophosphamide, docetaxel,
epirubicin, exemestane, toremifene, fulvestrant, letrozole,
gemcitabine, trastuzumab, ixabepilone, lapatinib, tamoxifen,
pertuzumab and toremifene, or mixtures thereof.
75. The method of claim 63, wherein about 550 to about 650 mg twice
per day of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(-
4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
administered.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002]
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-
,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the
treatment of brain cancer is provided herein.
[0003] 2. Description of the State of the Art
[0004]
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-
,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (also
called "ARRY-380"), which has the structure:
##STR00001##
is a selective ErbB2 (HER2) inhibitor described in WO 2007/059257,
which is incorporated by reference in its entirety.
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine has been
tested in human clinical trials for hyperproliferative diseases,
particularly cancer, and more particularly metastatic breast
cancer, colorectal cancer, and salivary gland cancer (see Koch,
Kevin. "ARRY-380: A Selective, Oral HER2 Inhibitor for the
Treatment of Solid Tumors." American Association of Cancer Research
102.sup.nd Annual Meeting, Apr. 3, 2011; which may also be found
at:
http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf-
).
[0005] Amplification or over-expression of ErbB2 has been shown to
play a role in the pathogenesis and progression of certain cancers,
such as breast, ovarian, gastric, uterine, colorectal and non-small
cell lung cancer.
[0006] In breast cancer patients, brain metastases are a leading
cause of death in ErbB2+ breast cancer patients and a serious unmet
medical need. Patients with ErbB2+ breast cancer have a
significantly increased incidence of brain metastases following
trastuzumab therapy. There is an increasing incidence of brain
metastases as women are living longer due to better treatments for
systemic disease.
[0007] Accordingly, there remains a need for the treatment of brain
cancer.
SUMMARY OF THE INVENTION
[0008] One aspect of the present invention provides
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
use in treating brain cancer.
[0009] Another aspect provides a method of treating brain cancer in
a mammal comprising administering a therapeutically effective
amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
the mammal.
[0010] Another aspect provides a method of treating brain cancer in
a patient having brain cancer comprising administering a
therapeutically effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
the patient.
[0011] Another aspect provides a method of treating or preventing
brain cancer in a mammal in need of such treatment, wherein the
method comprises administering to said mammal a therapeutically
effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4--
dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
[0012] Another aspect provides a use of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in
the manufacture of a medicament for the treatment of brain
cancer.
[0013] Another aspect provides a pharmaceutical composition for the
treatment of brain cancer, comprising
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1 shows the results of the growth of NCI-N87 cells
implanted intracranially in mice.
[0015] FIG. 2 shows the results of xenograft growth study of
NCI-N87 cells implanted intracranially in mice.
[0016] FIG. 3 shows the results of xenograft growth study of
NCI-N87 cells implanted intracranially in mice.
[0017] FIG. 4 shows the plasma results of brain pharmacokinetic
study in mice.
[0018] FIG. 5 shows the brain results of brain pharmacokinetic
study in mice.
[0019] FIG. 6 shows the results of xenograft growth study of BT474
cells implanted intracranially in mice.
[0020] FIG. 7 shows the results of xenograft growth study of
NCI-N87 cells implanted subcutaneously in mice.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Reference will now be made in detail to certain embodiments.
While enumerated embodiments will be described, it will be
understood that they are not intended to limit the invention to
those embodiments. On the contrary, the invention is intended to
cover all alternatives, modifications, and equivalents, which may
be included within the scope of the present invention as defined by
the claims. One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. In the
event that one or more of the incorporated literature and similar
materials differs from or contradicts this application, including
but not limited to defined terms, term usage, described techniques,
or the like, this application controls.
[0022] Definitions
[0023] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
20%.
[0024] The term "amorphous" means a solid in a solid state that is
a non-crystalline state. Amorphous solids generally possess
crystal-like short range molecular arrangement, but no long range
order of molecular packing as found in crystalline solids. The
solid state form of a solid may be determined by polarized light
microscopy, x-ray powder diffraction, differential scanning
calorimetry, or other standard techniques known to those of skill
in the art.
[0025] The phrase "amorphous solid dispersion" means a solid
comprising a drug substance and a dispersion polymer. The amorphous
solid dispersion discussed herein comprises amorphous
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol as
the drug substance component and a dispersion polymer, wherein the
amorphous solid dispersion contains the drug substance component in
a substantially amorphous solid state form. In certain embodiments,
the substantially amorphous solid state form means at least 80%
amorphous drug substance component. In certain embodiments, the
substantially amorphous solid state form means at least 85% drug
substance component. In certain embodiments, the substantially
amorphous solid state form means at least 90% amorphous drug
substance component. In certain embodiments, the substantially
amorphous solid state form means at least 95% amorphous drug
substance component.
[0026] The phrase "dispersion polymer" means a polymer that allows
for
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
be dispersed throughout such that a solid dispersion may form. The
dispersion polymer is preferably neutral or basic. The dispersion
polymer may contain a mixture of two or more polymers. Examples of
dispersion polymers include, but are not limited to, vinyl polymers
and copolymers, vinylpyrrolidine vinylacetate copolymer ("PVP-VA"),
polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers,
polyvinyl pyrrolidine ("PVP"), acrylate and methacrylate
copolymers, methylacrylic acid methyl methacrylate copolymer (such
as Eudragit.RTM.), polyethylene polyvinyl alcohol copolymers,
polyoxyethylene-polyoxypropylene block copolymers (also referred to
as poloxamers), graft copolymer comprised of polyethylene glycol,
polyvinyl caprolactam and polyvinyl acetate (such as
Soluplus.RTM.), cellulosic polymers, such as hydroxypropyl methyl
cellulose acetate ("HPMCA"), hydroxypropyl methyl cellulose
("HPMC"), hydroxypropyl cellulose ("HPC"), methyl cellulose,
hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl
cellulose acetate, and hydroxyethyl ethyl cellulose, hydroxypropyl
methyl cellulose acetate succinate ("HPMCAS"), hydroxypropyl methyl
cellulose phthalate ("HPMCP"), carboxymethylethyl cellulose
("CMEC"), cellulose acetate phthalate ("CAP"), cellulose acetate
succinate ("CAS"), hydroxypropyl methyl cellulose acetate phthalate
("HPMCAP"), cellulose acetate trimellitate ("CAT"), hydroxypropyl
methyl cellulose acetate trimellitate ("HPMCAT"), and
carboxymethylcellulose acetate butyrate ("CMCAB"), and the
like.
[0027] The term "drug substance component" means the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol
component of the solid dispersion.
[0028] The term "mammal" means a warm-blooded animal that has or is
at risk of developing a disease described herein and includes, but
is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,
and primates, including humans.
[0029] The phrase "pharmaceutically acceptable" indicates that the
substance or composition is compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0030] The phrase "solid dispersion" means a system in a solid
state comprising at least two components, wherein one component is
dispersed throughout the other component. The solid dispersion
discussed herein comprises one component of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol, the
drug substance component, dispersed throughout another component,
particularly a dispersion polymer.
[0031] The phrase "spray drying" means processes involved in
breaking up liquid mixtures into small droplets (atomization) and
rapidly removing solvent from the mixture in a spray drying
apparatus where there is a strong driving force for evaporation of
solvent from the droplets. The phrase spray drying is used
conventionally and broadly. Spray drying processes and spray drying
equipment are described generally in Perry, Robert H., and Don W.
Green (eds.). Perry's Chemical Engineers' Handbook. New York:
McGraw-Hill, 2007 (8.sup.th edition).
[0032] The phrases "therapeutically effective amount" or "effective
amount" mean an amount of a compound described herein that, when
administered to a mammal in need of such treatment, sufficient to
(i) treat or prevent the particular disease, condition, or
disorder, (ii) attenuate, ameliorate, or eliminate one or more
symptoms of the particular disease, condition, or disorder, or
(iii) prevent or delay the onset of one or more symptoms of the
particular disease, condition, or disorder described herein. The
amount of a compound that will correspond to such an amount will
vary depending upon factors such as the particular compound,
disease condition and its severity, the identity (e.g., weight) of
the mammal in need of treatment, but can nevertheless be routinely
determined by one skilled in the art.
[0033] The terms "treat" or "treatment" refer to therapeutic,
prophylactic, palliative or preventative measures. Beneficial or
desired clinical results include, but are not limited to,
alleviation of symptoms, diminishment of extent of disease,
stabilized (i.e., not worsening) state of disease, delay or slowing
of disease progression, amelioration or palliation of the disease
state, and remission (whether partial or total), whether detectable
or undetectable. "Treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment. Those in
need of treatment include those already with the condition or
disorder, as well as those prone to have the condition or disorder
or those in which the condition or disorder is to be prevented.
[0034] Treatment of Brain Cancer
[0035] Provided herein is
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in
treating brain cancer.
[0036] It has been found that
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol
(also called "AR00440993"), which has the structure:
##STR00002##
is an active metabolite of ARRY-380.
(2-((4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol has
higher brain penetration than either ARRY-380 or lapatinib (see
Example 1). This active metabolite helps maintain sustained levels
of drug in the brain after oral dosing of ARRY-380, which may
contribute to enhanced activity.
[0037] In certain embodiments,
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the
treatment of brain cancer is provided.
[0038] In certain embodiments,
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
use in the treatment of brain cancer is provided.
[0039] In certain embodiments,
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for use in the treatment of brain cancer are
provided.
[0040] In certain embodiments,
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
use in the treatment of brain cancer comprising administering
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
provided.
[0041] Brain cancer includes anaplastic astrocytoma, anaplastic
mixed glioma, anaplastic oligoastrocytoma, anaplastic
oligodendroglioma, germinoma, glioblastoma multiforme, gliosarcoma,
low grade astrocytoma, low grade mixed oligoastrocytoma, low grade
oligodendroglioma, central nervous system lymphoma,
medulloblastoma, meningioma, pilocytic astrocytoma, acoustic
neuroma, chordoma, craniopharyngioma, brain stem glioma,
ependymoma, optic nerve glioma, subependymoma, metastaic brain
tumors, pituitary tumors, primitive neuroectodermal and
scwannoma.
[0042] In certain embodiments, the brain cancer is local or
metastatic brain cancer that is ErbB2 driven. In certain
embodiments, the brain cancer is local or metastatic brain cancer
that is driven by ErbB2. In certain embodiments, the brain cancer
is local or metastatic brain cancer that is caused by ErbB2
over-expression and amplification. In certain embodiments, the
brain cancer is local or metastatic brain cancer that is caused by
ErbB2 over-expression or amplification. In certain embodiments, the
brain cancer is local or metastatic brain cancer that is caused by
ErbB2 over-expression. In certain embodiments, the brain cancer is
local or metastatic brain cancer that is caused by ErbB2
amplification. In certain embodiments, the brain cancer is local or
metastatic brain cancer that is ErbB2 positive.
[0043] Brain cancer includes gliomas, meningiomas, pituitary
adenomas and nerve sheath tumors. Brain cancer also includes
anaplastic astrocytoma, anaplastic mixed glioma, anaplastic
oligoastrocytoma, anaplastic oligodendroglioma, germinoma,
glioblastoma multiforme, gliosarcoma, low grade astrocytoma, low
grade mixed oligoastrocytoma, low grade oligodendroglioma, central
nervous system lymphoma, medulloblastoma, meningioma (particularly
WHO Grade II and III), and pilocytic astrocytoma. Brain cancer also
includes acoustic neuroma, pilocytic astrocytoma (WHO Grade I),
low-grade astrocytoma (WHO Grade II), anaplastic astrocytoma (WHO
Grade III), glioblastoma multiforme (WHO Grade IV), chordoma,
central nervous system lymphoma, craniopharyngioma, brain stem
glioma, ependymoma, mixed glioma, optic nerve glioma,
subependymoma, medulloblastoma, meningioma, metastaic brain tumors,
oligodendroglioma, pituitary tumors, primitive neuroectodermal, and
scwannoma. In certain embodiments, the brain cancer is ErbB2
positive. In certain embodiments, the brain cancer is caused by
ErbB2 over-expression or amplification.
[0044] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for use in the
treatment of brain cancer is administered from about 0.1 to about
2000 mg per day. The total dose need not be administered all at
once. In certain embodiments, the administration is from about 25
to about 1600 mg per day. In certain embodiments, the
administration is from about 100 to about 1600 mg per day. In
certain embodiments, the administration is from about 800 to about
1600 mg per day. In certain embodiments, the administration is at
800 to 1600 mg per day. In certain embodiments, the administration
is from about 800 to about 1300 mg per day. In certain embodiments,
the administration is at 800 to 1300 mg per day. In certain
embodiments, the administration is from about 1100 to about 1300 mg
per day. In certain embodiments, the administration is at 1100 to
1300 mg per day. In certain embodiments, the administration is from
about 1200 to about 1300 mg per day. In certain embodiments, the
administration is at 1200 to 1300 mg per day. In certain
embodiments, the administration is from about 1200 mg per day. In
certain embodiments, the administration is at 1200 mg per day.
[0045] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the
treatment of brain cancer is administered from about 400 to about
800 mg twice per day. In certain embodiments, the administration is
at 400 to 800 mg twice per day. In certain embodiments, the
administration is from about 400 to about 650 mg twice per day. In
certain embodiments, the administration is at 400 to 650 mg twice
per day. In certain embodiments, the administration is from about
550 to about 650 mg twice per day. In certain embodiments, the
administration is at 550 to 650 mg twice per day. In certain
embodiments, the administration is from about 600 to about 650 mg
twice per day. In certain embodiments, the administration is at 600
to 650 mg twice per day. In certain embodiments, the administration
is at about 600 mg twice per day. In certain embodiments, the
administration is at 600 mg twice per day.
[0046] In certain embodiments, the
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
the treatment of brain cancer is administered from about 0.1 to
about 2000 mg per day. The total dose need not be administered all
at once. In certain embodiments, the administration is from about
25 to about 1800 mg per day. In certain embodiments, the
administration is from about 25 to about 1600 mg per day. In
certain embodiments, the administration is from about 100 to about
1800 mg per day. In certain embodiments, the administration is from
about 100 to about 1600 mg per day. In certain embodiments, the
administration is from about 800 to about 1600 mg per day. In
certain embodiments, the administration is at 800 to 1600 mg per
day. In certain embodiments, the administration is from about 800
to about 1300 mg per day. In certain embodiments, the
administration at 800 to 1300 mg per day. In certain embodiments,
the administration is from about 1100 to about 1300 mg per day. In
certain embodiments, the administration is at 1100 to 1300 mg per
day. In certain embodiments, the administration is from about 1200
to about 1300 mg per day. In certain embodiments, the
administration is at 1200 to 1300 mg per day. In certain
embodiments, the administration is at about 1200 mg per day. In
certain embodiments, the administration is at 1200 mg per day.
[0047] In certain embodiments, the
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
the treatment of brain cancer is admininstered from about 100 to
about 1000 mg twice per day. In certain embodiments, the
administration is from about 100 to about 800 mg twice per day. In
certain embodiments, the administration is from about 100 to about
750 mg twice per day. In certain embodiments, the administration is
from about 100 to about 600 mg twice per day. In certain
embodiments, the administration is from about 200 to about 800 mg
twice per day. In certain embodiments, the administration is from
about 400 to about 800 mg twice per day. In certain embodiments,
the administration is at 400 to 800 mg twice per day. In certain
embodiments, the administration is from about 400 to about 650 mg
twice per day. In certain embodiments, the administration is at 400
to 650 mg twice per day. In certain embodiments, the administration
is from about 550 to about 650 mg twice per day. In certain
embodiments, the administration is at 550 to 650 mg twice per day.
In certain embodiments, the administration is from about 600 to
about 650 mg twice per day. In certain embodiments, the
administration is at 600 to 650 mg twice per day. In certain
embodiments, the administration is at about 600 mg twice per day.
In certain embodiments, the administration is at 600 mg twice per
day.
[0048] In certain embodiments, the mixture of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
the treatment of brain cancer is administered from about 0.1 to
about 2000 mg per day. The total dose need not be administered all
at once. In certain embodiments, the administration is from about
25 to about 1800 mg per day. In certain embodiments, the
administration is from about 25 to about 1600 mg per day. In
certain embodiments, the administration is from about 100 to about
1800 mg per day. In certain embodiments, the administration is from
about 100 to about 1600 mg per day. In certain embodiments, the
administration is from about 800 to about 1600 mg per day. In
certain embodiments, the administration is at 800 to 1600 mg per
day. In certain embodiments, the administration is from about 800
to about 1300 mg per day. In certain embodiments, the
administration is at 800 to 1300 mg per day. In certain
embodiments, the administration is from about 1100 to about 1300 mg
per day. In certain embodiments, the administration is at 1100 to
1300 mg per day. In certain embodiments, the administration is from
about 1200 to about 1300 mg per day. In certain embodiments, the
administration is at 1200 to 1300 mg per day. In certain
embodiments, the administration is at about 1200 mg per day. In
certain embodiments, the administration is at 1200 mg per day.
[0049] In certain embodiments, the mixture of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol for
the treatment of brain cancer is administered from about 100 to
about 1000 mg twice per day. In certain embodiments, the
administration is from about 100 to about 800 mg twice per day. In
certain embodiments, the administration is from about 100 to about
750 mg twice per day. In certain embodiments, the administration is
from about 100 to about 600 mg twice per day. In certain
embodiments, the administration is from about 200 to about 800 mg
twice per day. In certain embodiments, the administration is from
about 400 to about 800 mg twice per day. In certain embodiments,
the administration is at 400 to 800 mg twice per day. In certain
embodiments, the administration is from about 400 to about 650 mg
twice per day. In certain embodiments, the administration is at 400
to 650 mg twice per day. In certain embodiments, the administration
is from about 550 to about 650 mg twice per day. In certain
embodiments, the administration is at 550 to 650 mg twice per day.
In certain embodiments, the administration is from about 600 to
about 650 mg twice per day. In certain embodiments, the
administration is at 600 to 650 mg twice per day. In certain
embodiments, the administration is at about 600 mg twice per day.
In certain embodiments, the administration is at 600 mg twice per
day.
[0050] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for the treatment of brain cancer is administered
as an oral dosage form.
[0051] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for the treatment of brain cancer is provided in a
solid dispersion dosage form. In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for the treatment of brain cancer is provided in a
solid dispersion oral dosage form.
[0052] Solid dispersions are generally prepared by dissolving the
drug substance and the dispersion polymer in a suitable solvent to
form a feed solution, and then the feed solution may be spray dried
to form the solid dispersion (and remove the solvent). Spray drying
is a known process. Spray drying is generally performed by
dissolving the drug substance component and the dispersion polymer
in a suitable solvent to prepare a feed solution. The feed solution
may be pumped through an atomizer into a drying chamber. The feed
solution can be atomized by conventional means known in the art,
such as a two-fluid sonicating nozzle, a pressure nozzle, a
rotating nozzle and a two-fluid non-sonicating nozzle. Then, the
solvent is removed in the drying chamber to form the solid
dispersion. A typical drying chamber uses hot gases, such as forced
air, nitrogen, nitrogen-enriched air, or argon to dry particles.
The size of the drying chamber may be adjusted to achieve particle
properties or throughput.
[0053] Although the solid dispersion are preferably prepared by
conventional spray drying techniques, other techniques known in the
art may be used, such as melt extrusion, freeze drying, rotary
evaporation, drum drying or other solvent removal processes.
[0054] In certain embodiments, the dispersion polymer is selected
from PVP-VA, methylacrylic acid methyl methacrylate copolymer,
HPMCP, CAP, HPMCAS and HPMC and mixtures thereof. In certain
embodiments, the dispersion polymer is selected from PVP-VA,
methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP,
HPMCAS and HPMC. In certain embodiments, the dispersion polymer is
selected from PVP-VA, Eudragit.RTM. L100, HPMCP H-55, CAP, HPMCAS
Grade M, HPMC and mixtures thereof. In certain embodiments, the
dispersion polymer is selected from PVP-VA, Eudragit.RTM. L100,
HPMCP H-55, CAP, HPMCAS Grade M and HPMC.
[0055] In certain embodiments, the dispersion polymer is selected
from PVP-VA, methylacrylic acid methyl methacrylate copolymer,
HPMCP, CAP and HPMCAS, and mixtures thereof. In certain
embodiments, the dispersion polymer is selected from PVP-VA,
methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and
HPMCAS. In certain embodiments, the dispersion polymer is selected
from PVP-VA, Eudragit.RTM. L100, HPMCP H-55, CAP and HPMCAS Grade
M, and mixtures thereof. In certain embodiments, the dispersion
polymer is selected from PVP-VA, Eudragit.RTM. L100, HPMCP H-55,
CAP and HPMCAS Grade M.
[0056] In certain embodiments, the dispersion polymer is selected
from PVP-VA, methylacrylic acid methyl methacrylate copolymer,
HPMCP, CAP and HPMC, and mixtures thereof. In certain embodiments,
the dispersion polymer is selected from PVP-VA, methylacrylic acid
methyl methacrylate copolymer, HPMCP, CAP and HPMC. In certain
embodiments, the dispersion polymer is selected from PVP-VA,
Eudragit.RTM. L100, HPMCP H-55, CAP and HPMC, and mixtures thereof.
In certain embodiments, the dispersion polymer is selected from
PVP-VA, Eudragit.RTM. L100, HPMCP H-55, CAP and HPMC.
[0057] In certain embodiments, the dispersion polymer is selected
from PVP-VA, methylacrylic acid methyl methacrylate copolymer,
HPMCP and CAP, and mixtures thereof. In certain embodiments, the
dispersion polymer is selected from PVP-VA, methylacrylic acid
methyl methacrylate copolymer, HPMCP and CAP. In certain
embodiments, the dispersion polymer is selected from PVP-VA,
Eudragit.RTM. L100, HPMCP H-55 and CAP, and mixtures thereof. In
certain embodiments, the dispersion polymer is selected from
PVP-VA, Eudragit.RTM. L100, HPMCP H-55 and CAP.
[0058] In certain embodiments, the dispersion polymer is
PVP-VA.
[0059] In certain embodiments, the dispersion polymer is
methylacrylic acid methyl methacrylate copolymer. In certain
embodiments, the dispersion polymer is Eudragit.RTM.. In certain
embodiments, the dispersion polymer is Eudragit.RTM. L100.
[0060] In certain embodiments, the dispersion polymer is HPMCP. In
certain embodiments, the dispersion polymer is HPMCP H-55.
[0061] In certain embodiments, the dispersion polymer is CAP.
[0062] In certain embodiments, the dispersion polymer is HPMCAS. In
certain embodiments, the dispersion polymer is HPMCAS Grade M.
[0063] In certain embodiments, the dispersion polymer is preferably
neutral or basic.
[0064] In certain embodiments, the dispersion polymer is selected
from PVP-VA and HPMC. In certain embodiments, the dispersion
polymer is HPMC.
[0065] Suitable solvents are a solvent or mixture of solvents in
which both drug substance component and the dispersion polymer have
adequate solubility (solubility greater than 1 mg/mL). A mixture of
solvents may be used if each component of the solid dispersion
(i.e., drug substance component and dispersion polymer) requires
different solvents to obtain the desired solubility. The solvent
may be volatile with a boiling point of 150.degree. C. or less. In
addition, the solvent should have relatively low toxicity and be
removed from the dispersion to a level that is acceptable to The
International Committee on Harmonization ("ICH") guidelines.
Removal of solvent to this level may require a subsequent
processing step, such as tray drying. Examples of suitable solvents
include, but are not limited to, alcohols, such as methanol
("MeOH"), ethanol ("EtOH"), n-propanol, isopropanol ("IPA") and
butanol; ketones, such as acetone, methyl ethyl ketone ("MEK") and
methyl isobutyl ketone; esters, such as ethyl acetate ("EA") and
propyl acetate; and various other solvents, such as tetrahydrofuran
("THF"), acetonitrile ("ACN"), methylene chloride, toluene and
1,1,1-trichloroethane. Lower volatility solvents, such as dimethyl
acetate or dimethylsulfoxide ("DMSO"), may be used. Mixtures of
solvents with water may also be used, so long as the dispersion
polymer and the drug substance are sufficiently soluble to make the
spray drying process practicable. Generally, due to the hydrophobic
nature of low solubility drugs, non-aqueous solvents may be used,
meaning the solvent comprises less than about 10 weight %
water.
[0066] In certain embodiments, the suitable solvent is selected
from MeOH and THF, and mixtures thereof. In certain embodiments,
the suitable solvent is MeOH:THF solvent system of about 1:3. In
certain embodiments, the suitable solvent is a 1:3 MeOH:THF solvent
system.
[0067] In certain embodiments, the suitable solvent is selected
from MeOH, THF and water, and mixtures thereof. In certain
embodiments, the suitable solvent is selected from MeOH, THF and
water. In certain embodiments, the suitable solvent is a
THF:MeOH:water solvent system of about 80:10:10. In certain
embodiments, the suitable solvent is a 80:10:10 THF:MeOH:water
solvent system. In certain embodiments, the suitable solvent is a
THF:MeOH:water solvent system of about 82:8:10. In certain
embodiments, the suitable solvent is a 82:8:10 THF:MeOH:water
solvent system. In certain embodiments, the suitable solvent is a
THF:MeOH:water solvent system of about 82.2:8.2:9.6. In certain
embodiments, the suitable solvent is a 82.2:8.2:9.6 THF:MeOH:water
solvent system.
[0068] In certain embodiments, the amount of drug substance
component in the solid dispersion ranges from about 0.1% to about
70% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid
dispersion ranges from 0.1% to 70% by weight relative to the
dispersion polymer.
[0069] In certain embodiments, the amount of drug substance
component in the solid dispersion ranges from about 1% to about 60%
by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid
dispersion ranges from 1% to 60% by weight relative to the
dispersion polymer.
[0070] In certain embodiments, the amount of drug substance
component in the solid dispersion ranges from about 5% to about 60%
by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid
dispersion ranges from 5% to 60% by weight relative to the
dispersion polymer.
[0071] In certain embodiments, the amount of drug substance
component in the solid dispersion ranges from about 55% to about
65% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid
dispersion ranges from 55% to 65% by weight relative to the
dispersion polymer. In certain embodiments, the amount of drug
substance component in the solid dispersion is about 60% by weight
relative to the dispersion polymer. In certain embodiments, the
amount of drug substance component in the solid dispersion is 60%
by weight relative to the dispersion polymer.
[0072] In certain embodiments, the amount of drug substance
component in the solid dispersion ranges from about 25% to about
35% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid
dispersion ranges from 25% to 35% by weight relative to the
dispersion polymer. In certain embodiments, the amount of drug
substance component in the solid dispersion is about 30% by weight
relative to the dispersion polymer. In certain embodiments, the
amount of drug substance component in the solid dispersion is 30%
by weight relative to the dispersion polymer.
[0073] In certain embodiments, the amount of drug substance
component in the solid dispersion ranges from about 45% to about
55% by weight relative to the dispersion polymer. In certain
embodiments, the amount of drug substance component in the solid
dispersion ranges from 45% to 55% by weight relative to the
dispersion polymer. In certain embodiments, the amount of drug
substance component in the solid dispersion is about 50% by weight
relative to the dispersion polymer. In certain embodiments, the
amount of drug substance component in the solid dispersion is 50%
by weight relative to the dispersion polymer.
[0074] In certain embodiments, the solid dispersion is an amorphous
solid dispersion. In certain embodiments, the solid dispersion is
administered orally. In certain embodiments, the solid dispersion
is in a tablet. In certain embodiments, the amorphous solid
dispersion is in a tablet.
[0075] In certain embodiments, the administration of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof is administered orally. In certain embodiments,
the administration of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof is administered in the form of a tablet.
[0076] In certain embodiments, the treatment of brain cancer with
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof is in combination with another therapeutic agent.
Such therapeutic agents are suitably present in combination in
amounts that are effective for the purpose intended. The compounds
may be administered together in a unitary pharmaceutical
composition or separately and, when administered separately this
may occur simultaneously or sequentially in any order. Such
sequential administration may be close in time or remote in
time.
[0077] In certain embodiments, the therapeutic agent is selected
from trastuzumab, capecitabine, bevacizumab, and taxanes. In
certain embodiments, the therapeutic agent is selected from
trastuzumab, capecitabine, bevacizumab, paclitaxel and docetaxel.
In certain embodiments, the therapeutic agent is trastuzumab. In
certain embodiments, the therapeutic agent is capecitabine. In
certain embodiments, the therapeutic agent is bevacizumab. In
certain embodiments, the therapeutic agent is paclitaxel. In
certain embodiments, the therapeutic agent is docetaxel.
[0078] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for use in treating brain cancer, is used after
previous treatment for cancer.
[0079] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for use in treating brain cancer, is used after
previous treatment for brain cancer. In certain embodiments, the
previous treatment for brain cancer is selected from surgery,
radiation therapy and chemotherapy or mixtures thereof. In certain
embodiments, the previous treatment for brain cancer is selected
from surgery, conventional external radiation therapy,
three-dimensional conformal radiation therapy, intensity modulated
radiation therapy, stereotactic radiosurgery, fractionated
stereotactic radiation therapy, proton radiation therapy, internal
or implant radiation therapy, temozolomide, bevacizumab,
carmustine, lomustine, procarbazine, vincristine, tumor treating
fields therapy, everolimus, procarbazine, lomustine, cisplatin,
carboplatin and methotrexate or mixtures thereof.
[0080] In certain embodiments, the
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof for use in treating brain cancer, is used after
previous treatment for breast cancer. In certain embodiments, the
previous treatment for breast cancer is selected from surgery,
sentinel lymph node biopsy followed by surgery, radiation therapy,
chemotherapy, hormone therapy and targeted therapy. In certain
embodiments, the previous treatment for breast cancer is selected
from lumpectomy, partial mastectomy, segmental mastectomy, total
mastectomy, modified radical mastectomy, external radiation,
internal radiation, ado-trastuzumab emtansine, anastrozole,
bevacizumab, capecitabine, carboplatin, cyclophosphamide,
darbepoetin alfa, daunorubicin, denosumab, docetaxel, doxorubicin,
epirubicin, epoetin alfa, eribulin, everolimus, exemestane,
filgrastim, fluorouracil, fluoxymesterone, fulvestrant,
gemcitabine, goserelin, ixabepilone, lapatinib, letrozole,
leucovorin, leuprolide, megestrol, methotrexate, mitoxantrone,
mutamycin, paclitaxel, paclitaxel albumin-stabilized nanoparticle
formulation, pamidronate, pegfilgrastim, pertuzumab, raloxifene,
tamoxifen, thiotepa, toremifene, trastuzumab, trastuzumab
emtansine, triptorelin, vincristine, vinorelbine and zoledronic
acid or mixtures thereof. In certain embodiments, the previous
treatment for breast cancer is selected from bevacizumab,
capecitabine, carboplatin, cyclophosphamide, daunorubicin,
docetaxel, doxorubicin, epirubicin, eribulin, everolimus,
fluorouracil, gemcitabine, ixabepilone, methotrexate, mitoxantrone,
mutamycin, paclitaxel, paclitaxel albumin-stabilized nanoparticle
formulation, tamoxifen, trastuzumab, trastuzumab emtansine,
vincristine and vinorelbine or mixtures thereof.
[0081] In another embodiment, a method of treating brain cancer in
a mammal comprising administering a therapeutically effective
amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
the mammal is provided.
[0082] In another embodiment, a method of treating brain cancer in
a patient having brain cancer comprising administering a
therapeutically effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to
the patient is provided.
[0083] In another embodiment, a method of treating or preventing
brain cancer in a mammal in need of such treatment, wherein the
method comprises administering to said mammal a therapeutically
effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4--
dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
[0084] In another embodiment, a method of treating brain cancer in
a mammal using
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol
comprising administering an effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to the mammal
is provided.
[0085] In another embodiment, a method of treating brain cancer
using
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in a
patient having brain cancer comprising administering an effective
amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4--
dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to the
patient is provided.
[0086] In another embodiment, a method of treating or preventing
local or metastatic brain cancer that is caused by ErbB2
over-expression or amplification using
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in a
mammal in need of such treatment, wherein the method comprises
administering to the mammal an effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is
provided.
[0087] In certain embodiments, the effective amount is a
therapeutically effective amount.
[0088] Another embodiment provides the use of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol in
the manufacture of a medicament for the treatment of brain
cancer.
[0089] Suitable carriers and excipients are well known to those
skilled in the art and are described in detail in, e.g., Ansel,
Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug
Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,
2004; Gennaro, Alfonso R., et al. Remington: The Science and
Practice of Pharmacy. Philadelphia: Lippincott, Williams &
Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical
Excipients. Chicago, Pharmaceutical Press, 2005.
[0090] The pharmaceutical compositions may also include one or more
additional components, such as buffers, dispersion agents,
surfactants, wetting agents, lubricating agents, emulsifiers,
suspending agents, preservatives, antioxidants, opaquing agents,
glidants, processing aids, colorants, sweeteners, perfuming agents,
flavoring agents, diluents and other known additives to provide an
elegant presentation of the drug, i.e., a compound described herein
or pharmaceutical composition thereof, or aid in the manufacturing
of the pharmaceutical product, i.e., medicament (see Ansel;
Gennaro; and Rowe above). The components of the pharmaceutical
composition should be pharmaceutically acceptable.
[0091] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0092] (a) about 1 to
about 70 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0093] (b) about 0.1 to about 20 weight % of a
disintegrant; [0094] (c) about 0.1 to about 25 weight % of an
osmogen; [0095] (d) about 0.1 to about 10 weight % of a glidant;
[0096] (e) about 0.1 to about 10 weight % of a lubricant; and
[0097] (f) about 0.1 to about 25 weight % of a binder/diluent. In a
further embodiment, the pharmaceutical composition for the
treatment of brain cancer comprises: [0098] (a) 1 to 70 weight % of
a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0099] (b) 0.1 to 20 weight % of a disintegrant;
[0100] (c) 0.1 to 25 weight % of an osmogen; [0101] (d) 0.1 to 10
weight % of a glidant; [0102] (e) 0.1 to 10 weight % of a
lubricant; and [0103] (f) 0.1 to 25 weight % of a
binder/diluent.
[0104] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0105] (a) about 25 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0106] (b) about 5 to about 15 weight % of a
disintegrant; [0107] (c) about 15 to about 25 weight % of an
osmogen; [0108] (d) about 0.1 to about 3 weight % of a glidant;
[0109] (e) about 0.1 to about 3 weight % of a lubricant; and [0110]
(f) about 10 to about 25 weight % of a binder/diluent. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0111] (a) 25 to 60 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5 -dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0112] (b) 5 to 15 weight % of a disintegrant;
[0113] (c) 15 to 25 weight % of an osmogen; [0114] (d) 0.1 to 3
weight % of a glidant; [0115] (e) 0.1 to 3 weight % of a lubricant;
and [0116] (f) 10 to 25 weight % of a binder/diluent.
[0117] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0118] (a) about 40 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0119] (b) about 5 to about 15 weight % of a
disintegrant; [0120] (c) about 15 to about 25 weight % of an
osmogen; [0121] (d) about 0.1 to about 3 weight % of a glidant;
[0122] (e) about 0.1 to about 3 weight % of a lubricant; and [0123]
(f) about 10 to about 25 weight % of a binder/diluent. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0124] (a) 40 to 60 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0125] (b) 5 to 15 weight % of a disintegrant;
[0126] (c) 15 to 25 weight % of an osmogen; [0127] (d) 0.1 to 3
weight % of a glidant; [0128] (e) 0.1 to 3 weight % of a lubricant;
and [0129] (f) 10 to 25 weight % of a binder/diluent.
[0130] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0131] (a) about 1 to
about 70 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0132] (b) about 0.1 to about 20 weight % of a
disintegrant; [0133] (c) about 0.1 to about 25 weight % of an
osmogen; [0134] (d) about 0.1 to about 10 weight % of a glidant;
[0135] (e) about 0.1 to about 10 weight % of a lubricant; and
[0136] (f) about 0.1 to about 25 weight % of a filler. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0137] (a) 1 to 70 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0138] (b) 0.1 to 20 weight % of a disintegrant;
[0139] (c) 0.1 to 25 weight % of an osmogen; [0140] (d) 0.1 to 10
weight % of a glidant; [0141] (e) 0.1 to 10 weight % of a
lubricant; and [0142] (f) 0.1 to 25 weight % of a filler.
[0143] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0144] (a) about 25 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0145] (b) about 1 to about 10 weight % of a
disintegrant; [0146] (c) about 15 to about 25 weight % of an
osmogen; [0147] (d) about 0.1 to about 3 weight % of a glidant;
[0148] (e) about 0.1 to about 3 weight % of a lubricant; and [0149]
(f) about 10 to about 25 weight % of a filler. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0150] (a) 25 to 60 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0151] (b) 1 to 10 weight % of a disintegrant;
[0152] (c) 15 to 25 weight % of an osmogen; [0153] (d) 0.1 to 3
weight % of a glidant; [0154] (e) 0.1 to 3 weight % of a lubricant;
and [0155] (f) 10 to 25 weight % of a filler.
[0156] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0157] (a) about 40 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0158] (b) about 1 to about 10 weight % of a
disintegrant; [0159] (c) about 15 to about 25 weight % of an
osmogen; [0160] (d) about 0.1 to about 3 weight % of a glidant;
[0161] (e) about 0.1 to about 3 weight % of a lubricant; and [0162]
(f) about 10 to about 25 weight % of a filler. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0163] (a) 40 to 60 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5 -dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0164] (b) 1 to 10 weight % of a disintegrant;
[0165] (c) 15 to 25 weight % of an osmogen; [0166] (d) 0.1 to 3
weight % of a glidant; [0167] (e) 0.1 to 3 weight % of a lubricant;
and [0168] (f) 10 to 25 weight % of a filler.
[0169] In certain embodiments, the pharmaceutical composition for
the treatment of brain cancer comprises a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
[0170] In certain embodiments, the pharmaceutical composition for
the treatment of brain cancer comprises a solid dispersion of
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.
[0171] In certain embodiments, the osmogen is selected from NaCl
and KCl, and mixtures thereof.
[0172] In certain embodiments, the lubricant is magnesium
stearate.
[0173] In certain embodiments, the glidant is colloidal silicon
dioxide.
[0174] In certain embodiments, the binder/diluent is
microcrystalline cellulose. In certain embodiments, the
binder/diluent acts as both a binder and a diluent.
[0175] In certain embodiments, the binder is microcrystalline
cellulose.
[0176] In certain embodiments, the diluent is microcrystalline
cellulose.
[0177] In certain embodiments, the filler is lactose.
[0178] In certain embodiments, the disintegrant is selected from
crospovidone and sodium bicarbonate (NaHCO.sub.3), and mixtures
thereof. In certain embodiments, the disintegrant is selected from
crospovidone and sodium bicarbonate. In certain embodiments, the
disintegrant is sodium bicarbonate. In certain embodiments, the
disintegrant is crospovidone.
[0179] In certain embodiments, the composition contains sodium
bicarbonate.
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may slowly
degrade, through hydrolysis or other means, to a carbamate
impurity:
##STR00003##
Sodium bicarbonate helps to slow the degradation to the carbamate
impurity. Sodium bicarbonate also helps to provide consistent
tablet disintegration when the tablets are exposed to different
humidities.
[0180] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0181] (a)
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0182] (b) sodium bicarbonate.
[0183] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0184] (a) about 1 to
about 70 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0185] (b) about 0.1 to about 30 weight %
sodium bicarbonate. In a further embodiment, the pharmaceutical
composition for the treatment of brain cancer comprises: [0186] (a)
1 to 70 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0187] (b) 0.1 to 30 weight % sodium
bicarbonate.
[0188] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0189] (a) about 1 to
about 70 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0190] (b) about 0.1 to about 30 weight % sodium
bicarbonate; and [0191] (c) the remaining weight is other
pharmaceutically acceptable excipients and carriers. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0192] (a) 1 to 70 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5 -dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0193] (b) 0.1 to 30 weight % sodium bicarbonate;
and [0194] (c) the remaining weight is other pharmaceutically
acceptable excipients and carriers.
[0195] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0196] (a) about 25 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0197] (b) about 1 to about 15 weight % of
sodium bicarbonate. In a further embodiment, the pharmaceutical
composition for the treatment of brain cancer comprises: [0198] (a)
25 to 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5 -dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0199] (b) 1 to 15 weight % of sodium
bicarbonate.
[0200] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0201] (a) about 25 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0202] (b) about 1 to about 15 weight % of sodium
bicarbonate; and [0203] (c) the remaining weight is other
pharmaceutically acceptable excipients and carriers. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0204] (a) 25 to 60 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5 -dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0205] (b) 1 to 15 weight % of sodium
bicarbonate; and [0206] (c) the remaining weight is other
pharmaceutically acceptable excipients and carriers.
[0207] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0208] (a) about 40 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0209] (b) about 1 to about 15 weight % of
sodium bicarbonate. In a further embodiment, the pharmaceutical
composition for the treatment of brain cancer comprises: [0210] (a)
40 to 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5 -dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; and [0211] (b) 1 to 15 weight % of sodium
bicarbonate.
[0212] Certain embodiments provide a pharmaceutical composition for
the treatment of brain cancer comprising: [0213] (a) about 40 to
about 60 weight % of a solid dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0214] (b) about 1 to about 15 weight % of sodium
bicarbonate; [0215] (c) the remaining weight is other
pharmaceutically acceptable excipients and carriers. In a further
embodiment, the pharmaceutical composition for the treatment of
brain cancer comprises: [0216] (a) 40 to 60 weight % of a solid
dispersion of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof; [0217] (b) 1 to 15 weight % of sodium
bicarbonate; [0218] (c) the remaining weight is other
pharmaceutically acceptable excipients and carriers.
[0219] The pharmaceutical composition preferably contains a
therapeutically effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof. However, in some embodiments, each individual
dose contains a portion of a therapeutically effective amount of
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol or
mixtures thereof, such that multiple doses of the composition may
be required (for example, two or more tablets are required for a
therapeutically effective amount). Thus, in this application when
it states that the pharmaceutical composition contains a
therapeutically effective amount it means that the composition may
be one dose (for example, one tablet) or multiple doses (for
example, two tablets).
EXAMPLES
[0220] In the Examples described below, unless otherwise indicated
all temperatures are set forth in degrees Celsius.
Example 1
Growth of NCI-N87 Gastric Carcinoma in Nude Mice Implanted
Intracranially
[0221] Tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda,
Md.) were implanted in nude BALB/c female mice (Charles River
Laboratories International, Inc.) via intracranial injection
directly into the brain. The mice were separated into four groups
(N=5) and were injected with vehicle (saline), 1.times.10.sup.5
tumor cells, 2.5.times.10.sup.5 tumor cells, or 5.times.10.sup.5
tumor cells. The results are shown in FIG. 1. Brain tumor cell
burden was associated with decreased survival in the NCI-N87
model.
[0222] In a pilot study using .sup.14C albumin as the tracer and
mannitol as the positive control for blood brain barrier (BBB)
disruption, it was confirmed that the intracranial inoculation
procedure did not mechanically disrupt the blood brain barrier.
Example 2
Inhibition of NCI-N87 Gastric Carcinoma Xenograft Growth in Mice
Implanted Intracranially
[0223] Anesthetized nude BALB/c female mice (Taconic Laboritories
Inc., Germantown, N.Y.) were inoculated with human tumor cells
(NCI-N87 gastric carcinoma cells, NCI, Bethesda, Md.)
intracranially at lamba suture. 5.times.10.sup.5 cells in saline
were implanted via intracranial injection. The mice were separated
into three groups (N=12); vehicle (acidified 30% Captisol.RTM., pH
about 4.5), 50 mg/kg lapatanib PO BID (30% Captisol.RTM.), and 75
mg/kg
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine PO BID
(acidified 30% Captisol.RTM., pH about 4.5). Dosing began two days
after implantation. The dose may have been reduced as necessary if
drug-related weight loss (approximately 5%) was observed. The mice
were monitored twice daily for general health and
behavioral/neurological effects, and body weights (BW) were
determined twice weekly. At first sign of neurological problem or
body weight loss of greater than 20%, the mice were euthanized by
CO.sub.2 inhalation. Brain and plasma were collected for analyses.
FIG. 2 shows the percentage of surviving mice. FIG. 3 shows that
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine significantly
decreases phospho-ErbB2/total ErbB2 in the brain.
Example 3
Brain Pharmacokinetic (PK) Study in Mice
[0224] Nude female BALB/c mice were administered a single PO dose
(dose volume 10 mL/kg) of lapatanib (50 mg/kg, 30% Captisol.RTM.)
and
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (75 mg/kg, 30%
Captisol, weigh out compound and add 30% Captisol.RTM. to give 7.5
mg/mL solution, then add 5 N HCl in 200 .mu.L increments until it
forms a clear, yellow solution). The mice were separated into
groups and their PK was studied at 4 time points (0.5, 1, 2 and 4
hours, 4 mice per group per timepoint). The animals were euthanized
by CO.sub.2 inhalation at the time points. Whole blood was drawn
(300 .mu.L) by cardiac puncture and placed in an eppendorf tube
containing ethylenediaminetetraacetic acid ("EDTA") (37.5 .mu.L,
1.5%). The samples were centrifuged, and the plasma was decanted
and frozen at -20 .degree. C. until delivered to analytical
chemistry. The brains were collected. The animals were perfused
with 5-10 mL of saline, and the brains were removed, weighed and
placed into a fast prep tube for DMPK analysis.
[0225] The brain penetration of
(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)q-
uinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol was
significantly higher than lapatanib or
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. The plasma
concentration (.mu.g/mL) of the compounds is shown in FIG. 4 and
Table 1. The brain concentration (ng/g) of the compounds is shown
in FIG. 5 and Table 2. The brain:plasma ratio results are shown in
Table 3.
TABLE-US-00001 TABLE 1 Average Plasma Time Point Concentration
(.mu.g/mL) (hour) Lapatanib ARRY-380 AR00440993 0.5 1913.75 3350.00
20.20 1 4310.00 6417.50 67.33 2 1743.75 6012.50 134.40 4 1942.50
2640.00 70.43
TABLE-US-00002 TABLE 2 Time Point Average Brain Concentration
(ng/g) (hour) Lapatanib ARRY-380 AR00440993 0.5 44.92 122.38 BLQ 1
90.77 116.44 28.95 2 57.36 134.15 35.84 4 65.43 42.14 39.96
TABLE-US-00003 TABLE 3 Time Point (hour) Lapatanib ARRY-380
AR00440993 0.5 0.026 0.048 -- 1 0.022 0.048 2.083 2 0.039 0.021
0.480 4 0.038 0.019 1.311
Example 4
Inhibition of BT474 Breast Carcinoma Xenograft Growth in Mice
Implanted Intracranially
[0226] Nude NCr female mice (Taconic Laboritories Inc., Germantown,
N.Y.) were split into four groups (N=13). 17.beta.-estradiol (0.5
mg)/progesterone (10 mg) pellets (35-day release) were implanted 1
day prior to BT-474 tumor cell inoculation. Tumor cells
(1.times.10.sup.6 BT474 breast carcinoma cells, ATCC, Manassas,
Va.) were implanted into the mice via intracranial injection
directly into the brain. Treatment with vehicle or drugs began 2
days post-tumor cell implantation. The mice were administered
vehicle (acidified 30% Captisol.RTM., pH about 4.5, 10 mL/kg, PO,
BID), lapatanib (50 mg/kg, PO, BID, 30% Captisol.RTM.), neratinib
(40 mg/kg, QD, PO, acidified 30% Captisol.RTM.) and
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (75 mg/kg, PO,
BID, 30% Captisol, weigh out compound and add 30% Captisol.RTM. to
give 7.5 mg/mL solution, then add 5 N HCl in 200 .mu.L increments
until it forms a clear, yellow solution). The mice were monitored
daily for general health and behavioral/neurological effects, and
body weights were determined twice weekly. At first sign of
neurological problem or body weight loss of greater than 20%, the
mice were euthanized by CO.sub.2 inhalation. Brain and plasma were
collected for analyses. FIG. 6 shows the percentage of surviving
mice.
Example 5
Anti-Tumor Efficacy on N87 Human Gastric Cancer in Murine Xenograft
Model
[0227] Nude nu/nu female mice (NCI, Bethesda, Md.) were split into
five groups (N=8). Tumor cells (NCI-N87 gastric carcinoma cells,
NCI, Bethesda, Md. 1.times.10.sup.7) were implanted into the mice
via subcutaneous injection (100 .mu.L) directly on the right flank.
To ensure good tumor take, the cells should be greater than 90%
viable (thus, the intitial cell suspension of 1.times.10.sup.7
cells/mL were injected for 1.times.10.sup.6 cells injected/100
.mu.L). The tumors were allowed to grow to 150.+-.50 mm.sup.3. The
tumor size was measured, and the mice were weighed. The mice were
administered vehicle (30% Captisol.RTM., 150 g in 500 mL DI water,
PO, BID), lapatanib (50 mg/kg, PO, BID, 30% Captisol.RTM.),
lapatanib (100 mg/kg, PO, BID, 30% Captisol.RTM.),
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (50 mg/kg, PO,
QD, 30% Captisol) and
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (100 mg/kg,
PO, QD, 30% Captisol). The tumor volume was measured. The number of
partial responses in the mice was as follows: lapatanib (50 mg/kg)
0, lapatanib (100 mg/kg) 1, ARRY-380 (50 mg/kg) 1, ARRY-380 (100
mg/kg) 4. The results are shown in FIG. 7.
Example 6
30% Solid Dispersion Using PVP-VA
[0228] A solid dispersion was prepared containing 30 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA
using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 100.degree. C. at a
flow rate of 22 mL/minute, drying gas flow rate of 35 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 19.6 g (87.7% yield) of the solid dispersion.
Physicochemical analysis results are in Table 4. Residual solvent
analysis showed that the dispersion had less than 0.5% THF and no
detectable MeOH.
[0229] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 63.46 .mu.g/mL and 245.05 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 52.50
.mu.g/mL and 204.12 .mu.g/mL*hr, respectively.
Example 7
30% Solid Dispersion Using Eudragit
[0230] A solid dispersion was prepared containing 30 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit
L100 using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 100.degree. C. at a
flow rate of 22 mL/minute, drying gas flow rate of 35 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 18.6 g (82.7% yield) of the solid dispersion.
Physicochemical analysis results are in Table 4. Residual solvent
analysis showed that the dispersion had about 4.5% THF and no
detectable MeOH.
[0231] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 22.70 .mu.g/mL and 71.06 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 9.26
.mu.g/mL and 35.49 .mu.g/mL*hr, respectively.
Example 8
30% Solid Dispersion Using HPMCP
[0232] A solid dispersion was prepared containing 30 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55
using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 100.degree. C. at a
flow rate of 22 mL/minute, drying gas flow rate of 35 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 20.3 g (90.3% yield) of the solid dispersion.
Physicochemical analysis results are in Table 4. Residual solvent
analysis showed that the dispersion had less than 0.5% THF and no
detectable MeOH.
[0233] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 25.00 .mu.g/mL and 96.66 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 16.15
.mu.g/mL and 56.81 .mu.g/mL*hr, respectively.
Example 9
30% Solid Dispersion Using CAP
[0234] A solid dispersion was prepared containing 30 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using
a Buchi B-290 mini spray drier. The solid dispersion was spray
dried from a MeOH:THF (1:3) solvent system, a 5% spray solution
concentration, an inlet temperature of 100.degree. C. at a flow
rate of 22 mL/minute, drying gas flow rate of 35 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 20.0 g (90.4% yield) of the solid dispersion.
Physicochemical analysis results are in Table 4. Residual solvent
analysis showed that the dispersion had less than 0.5% THF and no
detectable MeOH.
[0235] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 11.62 .mu.g/mL and 36.69 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 5.64
.mu.g/mL and 20.58 .mu.g/mL*hr, respectively.
Example 10
30% Solid Dispersion Using HPMCAS
[0236] A solid dispersion was prepared containing 30 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS
Grade M using a Buchi B-290 mini spray drier. The solid dispersion
was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 80.degree. C. at a
flow rate of 35 mL/minute, drying gas flow rate of 40 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 163.19 mg (48.3% yield) of the solid dispersion.
Physicochemical analysis results are in Table 4. Residual solvent
analysis showed that the dispersion had less than 0.5% THF and no
detectable MeOH.
[0237] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 19.04 .mu.g/mL and 68.09 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 13.50
.mu.g/mL and 51.74 .mu.g/mL*hr, respectively.
TABLE-US-00004 TABLE 4 TGA % Hygroscopicity API:Poly- HPLC T.sub.g
wt loss THF (% wt change Example Polymer mer (area %) (.degree. C.)
(%) (w/w) at 80% RH) REF 99.39 4.9 <1% 6 PVP-VA 3:7 99.45 117
2.3 0.5 14.4 7 Eudragit 3:7 98.63 116 5.9 4.5 7.5 L100 8 HPMCP 3:7
97.30 149 1.7 0.3 7.5 H-55 9 CAP 3:7 95.45 179 1.9 0.5 7.8 10
HPMCAS 3:7 113 NA NA NA
Example 11
60% Solid Dispersion Using PVP-VA
[0238] A solid dispersion was prepared containing 60 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA
using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 80.degree. C. at a
flow rate of 35 mL/minute, drying gas flow rate of 40 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 135.0 mg (88.2% yield) of the solid dispersion.
[0239] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 34.80 .mu.g/mL and 133.76 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 21.88
.mu.g/mL and 84.43 .mu.g/mL*hr, respectively.
Example 12
60% Solid Dispersion Using Eudragit
[0240] A solid dispersion was prepared containing 60 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit
L100 using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 80.degree. C. at a
flow rate of 35 mL/minute, drying gas flow rate of 40 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 88.1 mg (52.4% yield) of the solid dispersion.
[0241] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 26.82 .mu.g/mL and 84.49 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 9.85
.mu.g/mL and 34.89 .mu.g/mL*hr, respectively.
Example 13
60% Solid Dispersion Using HPMCP
[0242] A solid dispersion was prepared containing 60 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55
using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 80.degree. C. at a
flow rate of 35 mL/minute, drying gas flow rate of 40 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 98.0 mg (58.0% yield) of the solid dispersion.
[0243] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 32.21 .mu.g/mL and 38.28 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 9.96
.mu.g/mL and 38.28 .mu.g/mL*hr, respectively.
Example 14
60% Solid Dispersion Using CAP
[0244] A solid dispersion was prepared containing 60 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using
a Buchi B-290 mini spray drier. The solid dispersion was spray
dried from a MeOH:THF (1:3) solvent system, a 5% spray solution
concentration, an inlet temperature of 80.degree. C. at a flow rate
of 35 mL/minute, drying gas flow rate of 40 m.sup.3/hour, nozzle
pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour, and a
1.5 mm nozzle type. Secondary drying of the dispersion was done at
40.degree. C. under vacuum for about 16 hours. The spray drying
yielded 74.9 mg (44.6% yield) of the solid dispersion.
[0245] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 51.98 .mu.g/mL and 144.91 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 15.07
.mu.g/mL and 59.69 .mu.g/mL*hr, respectively.
Example 15
60% Solid Dispersion Using HPMCAS
[0246] A solid dispersion was prepared containing 60 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS
Grade M using a Buchi B-290 mini spray drier. The solid dispersion
was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray
solution concentration, an inlet temperature of 80.degree. C. at a
flow rate of 35 mL/minute, drying gas flow rate of 40 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 40.degree. C. under vacuum for about 16 hours. The spray
drying yielded 113.3 mg (67.2% yield) of the solid dispersion.
[0247] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The solid dispersion was suspended in H.sub.2O
and added directly to the buffer solution at 37.degree. C. The
dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the total drug species
(colloidal+free) was 26.45 .mu.g/mL and 96.21 .mu.g/mL*hr,
respectively. The Cmax and AUC for the free drug species was 10.96
.mu.g/mL and 42.83 .mu.g/mL*hr, respectively.
Example 16
50% Solid Dispersion Using PVP-PA
[0248] A solid dispersion was prepared containing 50 weight percent
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA
using a Buchi B-290 mini spray drier. The solid dispersion was
spray dried from a MeOH:THF (1:3) solvent system, a 3.9% spray
solution concentration, an inlet temperature of 100.degree. C. at a
flow rate of 30 mL/minute, drying gas flow rate of 40 m.sup.3/hour,
nozzle pressure of 80 psig, nozzle gas flow of 0.66 m.sup.3/hour,
and a 1.5 mm nozzle type. Secondary drying of the dispersion was
done at 50.degree. C. under vacuum for about 72 hours. The spray
drying yielded 28.7 g (72.7% yield) of the solid dispersion.
Example 17
Pharmaceutical Composition 1
[0249] Tablets containing the solid dispersions of any of Examples
6 to 16 may be prepared in a conventional manner comprising:
TABLE-US-00005 Function Ingredient % of Blend API Solid dispersion
as 50 prepared in Example 16 Disintegrant Crospovidone - 6
Polyplasdone .RTM. Osmogen NaCl 5 Osmogen KCl 5 Glidant Colloidal
Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular
Binder/Diluent Microcrystalline 19.25 cellulose - Avicel .RTM.
Osmogen NaCl 4.625 Osmogen KCl 4.625 Disintegrant Polyplasdone 4
Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate
0.25
[0250] In one preparation, tablets were made using OPADRY II
85F92727 at 3% by weight as a tablet coating. The tablets contained
150 mg of API.
Example 18
Pharmaceutical Composition 2
[0251] Tablets containing the solid dispersions of any of Examples
2 to 12 may be prepared in a conventional manner comprising:
TABLE-US-00006 Function Ingredient % of Blend API Solid dispersion
as 50 prepared in Example 16 Disintegrant Crospovidone - 6
Polyplasdone .RTM. Disintegrant NaHCO.sub.3 3 Osmogen NaCl 5
Osmogen KCl 5 Glidant Colloidal Silicon 0.5 Dioxide Lubricant
Magnesium Stearate 0.25 Extragranular Binder/Diluent
Microcrystalline 16.25 cellulose - Avicel .RTM. Osmogen NaCl 4.625
Osmogen KCl 4.625 Disintegrant Polyplasdone 4 Glidant Colloidal
Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25
[0252] In one preparation, tablets were made using OPADRY II
85F92727 at 3% by weight as a tablet coating. The tablets contained
150 mg of API.
Example 19
Pharmaceutical Composition 3
[0253] Tablets containing the solid dispersions of any of Examples
2 to 12 may be prepared in a conventional manner comprising:
TABLE-US-00007 Function Ingredient % of Blend API Solid dispersion
as 50 prepared in Example 16 Disintegrant Crospovidone - 6
Polyplasdone .RTM. Osmogen NaCl 10.625 Osmogen KCl 10.625 Filler
Lactose 21.25 Glidant Colloidal Silicon 0.5 Dioxide Lubricant
Magnesium Stearate 0.25 Extragranular Glidant Colloidal Silicon 0.5
Dioxide Lubricant Magnesium Stearate 0.25
[0254] In one preparation, tablets were made using OPADRY II
85F92727 at 3% by weight as a tablet coating. The tablets contained
150 mg of API.
Example 20
Stability Screen
[0255] A stability screen of the spray dried dispersions was
completed at 40.degree. C., 75% relative humidity under open
conditions, in glass vials, over a period of 8 days. Results are
shown in Table 5.
TABLE-US-00008 TABLE 5 HPLC Area % Time Example 6 Example 7 Example
8 Example 9 Standard 99.39 99.39 99.39 99.39 As received 99.45
98.63 97.30 95.45 4 days 99.21 96.10 93.03 90.89 8 days 99.35 93.16
86.63 87.15
[0256] The main degradant observed was a carbamate impurity, likely
due to the acidic nature of some of these polymers. XRPD analysis
over the course of the study showed no evidence of crystallization
for any solid dispersion of Examples 6-9.
Example 21
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dime-
thyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine freebase
hemi-ethanolate
[0257] Step 1:
(E)-N'-(2-Cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,-
N-dimethylformimidamide was coupled with
4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in
isopropyl acetate:acetic acid (65:35 v/v) at 45.degree. C. to yield
1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)qui-
nazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (91%).
[0258] Step 2:
1-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)qui-
nazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea was
agitated in tetrahydrofuran under basic conditions (2.5N NaOH),
followed by the addition of p-toluenesulfonyl chloride. Water was
charged to yield
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (96%) as a
mixture of polymorphs (generally a mixture containing one or more
of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P).
[0259] Step 3:
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine from Step 2
was triturated in ethanol at greater than 65.degree. C. to provide
N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dim-
ethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine Form B Ethanol
(89%).
[0260] Dissolution testing was performed at a pH of 6.5 in
phosphate buffer. The crystals (particles) were suspended in
H.sub.2O and added directly to the buffer solution at 37.degree. C.
The dissolution profile was collected over a period of about 240
minutes. The Cmax and AUC for the free drug species was 0.44
.mu.g/mL and 5.49 .mu.g/mL*hr, respectively.
Example 22
In Vivo Pharmacokinetics in Beagles
[0261] The solid dispersion of Example 6 was tested against a
crystalline, micronized suspension formulation (d(v, 0.9)=3.0
.mu.m) of Example 21 under normal fasted conditions, as well as
with pretreatment using pentagastrin or famotidine. The solid
dispersion of Example 6 was prepared as a suspension in water and
administered orally. The micronized suspension of Example 21 was
prepared as a suspension with SyrSpend.RTM. SF Dry reconstituted
with water and administered orally. To reduce variability, beagles
were crossed over from pentagastrin to famotidine after a 5 day
washout period. Pentagastrin is a pH modifier to modify gastric pH
to about 2 to 3, and famotidine is a pH modifier to modify gastric
pH to about 5 to 7.5 (Zhou, Rong, et al. "pH-Dependent Dissolution
in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development
of a Canine Model." Pharm. Res. Vol. 22, No. 2 (February 2005): pp.
188-192). There were four beagles per group. Group A received
pentagastrin pretreatment, the micronized suspension of Example 21,
followed by a 5 day washout period, then famotidine pretreatment,
and finally the micronized suspension of Example 21. Group B
received pentagastrin pretreatment, the solid dispersion of Example
6, followed by a 5 day washout period, then famotidine
pretreatment, and finally the solid dispersion of Example 6. Group
C received the micronized suspension of Example 21, followed by a 5
day washout period, and finally the solid dispersion of Example 6.
Results are shown in Table 6.
TABLE-US-00009 TABLE 6 AUC.sub.inf C.sub.max Pretreatment Dosing
Formulation (.mu.g * hr/mL) (.mu.g/mL) None Micronized Suspension
of 7.43 .+-. 1.77 1.88 .+-. 0.35 Example 12 Solid Dispersion of
10.0 .+-. 2.7 2.29 .+-. 0.54 Example 1 6 .mu.g/kg Micronized
Suspension of 17.2 .+-. 2.7 3.29 .+-. 0.13 Pentagastrin Example 12
Solid Dispersion of 13.0 .+-. 3.6 3.12 .+-. 0.62 Example 1 40 mg/kg
Micronized Suspension of 1.74 .+-. 0.39 0.514 .+-. 0.092 Famotidine
Example 12 Solid Dispersion of 6.32 .+-. 2.88 1.45 .+-. 0.54
Example 1
[0262] It will be understood that the enumerated embodiments are
not intended to limit the invention to those embodiments. On the
contrary, the invention is intended to cover all alternatives,
modifications and equivalents, which may be included within the
scope of the present invention as defined by the claims. Thus, the
foregoing description is considered as illustrative only of the
principles of the invention.
[0263] The words "comprise," "comprising," "include," "including,"
and "includes" when used in this specification and in the following
claims are intended to specify the presence of stated features,
integers, components, or steps, but they do not preclude the
presence or addition of one or more other features, integers,
components, steps, or groups thereof.
* * * * *
References