U.S. patent application number 15/467414 was filed with the patent office on 2017-09-14 for pharmaceutical formulations of a bruton's tyrosine kinase inhibitor.
The applicant listed for this patent is Pharmacyclics LLC. Invention is credited to Harisha Atluri, Ching W. Chong, Robert Kuehl, Heow Tan.
Application Number | 20170258729 15/467414 |
Document ID | / |
Family ID | 56848552 |
Filed Date | 2017-09-14 |
United States Patent
Application |
20170258729 |
Kind Code |
A1 |
Chong; Ching W. ; et
al. |
September 14, 2017 |
Pharmaceutical Formulations of a Bruton's Tyrosine Kinase
Inhibitor
Abstract
Described herein are pharmaceutical formulations of Bruton's
tyrosine kinase (Btk) inhibitor
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one. Also disclosed are methods of using
the Btk inhibitor, alone or in combination with other therapeutic
agents, for the treatment of autoimmune diseases or conditions,
heteroimmune diseases or conditions, cancer, including lymphoma,
and inflammatory diseases or conditions.
Inventors: |
Chong; Ching W.; (Fremont,
CA) ; Kuehl; Robert; (San Francisco, CA) ;
Tan; Heow; (Cupertino, CA) ; Atluri; Harisha;
(Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pharmacyclics LLC |
Sunnyvale |
CA |
US |
|
|
Family ID: |
56848552 |
Appl. No.: |
15/467414 |
Filed: |
March 23, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15060010 |
Mar 3, 2016 |
9655857 |
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15467414 |
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62193518 |
Jul 16, 2015 |
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62127717 |
Mar 3, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 9/2013 20130101; A61K 9/2095 20130101; A61P 35/02 20180101;
A61P 29/00 20180101; A61P 35/00 20180101; A61P 43/00 20180101; A61K
9/2018 20130101; A61K 9/2009 20130101; A61K 9/2054 20130101; A61K
9/2027 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/519 20060101 A61K031/519 |
Claims
1. A method of treating cancer or graft versus host disease in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a high-load solid
tablet formulation comprising ibrutinib and one or more
pharmaceutically acceptable excipients, wherein ibrutinib is a
compound with the structure of Compound 1, ##STR00007## and wherein
the high-load solid tablet formulation comprises at least 50% w/w
of ibrutinib, and the excipients comprise, one or more diluents
selected from the group consisting of lactose, sucrose, dextrose,
dextrates, maltodextrin, mannitol, xylitol, sorbitol,
cyclodextrins, calcium phosphate, calcium sulfate, starches,
modified starches, cellulose, microcrystalline cellulose,
microcellulose, and talc; one or more disintegrating agents
selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch, cross-linked polymer, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, and a gum; one or more binders selected
from the group consisting of hydroxypropyl cellulose and
polyvinylpyrrolidone; sodium lauryl sulfate; colloidal silicon
dioxide; and magnesium stearate.
2.-6. (canceled)
7. The method of claim 1, wherein the one or more disintegrating
agents are selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, sodium starch
glycolate, crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum.
8. (canceled)
9. The method of claim 1, wherein the one or more diluents are
lactose or microcrystalline cellulose, or a combination
thereof.
10.-35. (canceled)
36. The method of claim 1, wherein the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
37. The method of claim 1, wherein the excipients comprise
intragranular and extragranular excipients; and the intragranular
excipients comprise lactose, microcrystalline cellulose,
croscarmellose sodium, and hydroxypropyl cellulose; and the
extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium
stearate.
38. The method of claim 1, wherein excipients comprise:
intragranular excipients comprising: lactose in an amount from
about 5% w/w to about 20% w/w, about 8% w/w to about 15% w/w, or
about 8% w/w to about 14% w/w; microcrystalline cellulose in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w; croscarmellose sodium in
an amount from about 0 to about 10% w/w, about 2% w/w to about 5%
w/w, or about 2% w/w to about 4% w/w; and hydroxypropyl cellulose
in an amount from about 0 to about 2% w/w, about 0.1% w/w to about
1.1% w/w, or about 0.1% w/w to about 1% w/w; and extragranular
excipients comprising: croscarmellose sodium in an amount from
about 0 to about 5% w/w, about 2% w/w to about 5% w/w, or about 2%
w/w to about 5% w/w; sodium lauryl sulfate in an amount from about
0 to about 10% w/w, about 4% w/w to about 8% w/w, or about 5% w/w
to about 6% w/w; colloidal silicon dioxide in an amount from about
0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or
about 0.5% w/w to about 0.6% w/w; and magnesium stearate in an
amount from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to
about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.
39. The method of claim 1, wherein the excipients comprise
intragranular and extragranular excipients; and the intragranular
excipients comprise lactose, sodium lauryl sulfate,
polyvinylpyrrolidone and croscarmellose sodium; and the
extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, microcrystalline cellulose, colloidal silicon
dioxide, and magnesium stearate.
40. The method of claim 1, wherein the excipients comprise
intragranular excipients comprising: lactose in an amount from
about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
polyvinylpyrrolidone in an amount from about 0% w/w to about 5%
w/w, or about 1% w/w to about 3% w/w; croscarmellose sodium in an
amount from about 1% w/w to about 10% w/w, or about 3% w/w to about
7% w/w; and sodium lauryl sulfate in an amount from about 0% w/w to
about 2% w/w, or about 0.5% w/w to about 1.5% w/w; and
extragranular excipients comprising: croscarmellose sodium in an
amount from about 0% w/w to about 5% w/w, or about 1% w/w to about
3% w/w; sodium lauryl sulfate in an amount from about 0 w/w to
about 10% w/w or about 0% w/w to about 4% w/w; microcrystalline
cellulose in an amount from about 1% w/w to about 10% w/w, or about
2% w/w to about 5% w/w; colloidal silicon dioxide in an amount from
about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6%
w/w; and magnesium stearate in an amount from about 0.4% w/w to
about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.
41. The method of claim 1, wherein the formulation comprises: a)
about 69% w/w to about 71% w/w of ibrutinib, b) about 13% w/w to
about 15% w/w of lactose monohydrate, c) about 2% w/w to about 5%
w/w of microcrystalline cellulose, d) about 1% w/w to about 3% w/w
of polyvinylpyrrolidone, e) about 6% w/w to about 8% w/w of
croscarmellose sodium, f) about 1% w/w to about 4% w/w of sodium
lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal
silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
42. The method of claim 1, wherein the formulation comprises: a)
about 70% w/w of ibrutinib, b) about 14% w/w of lactose
monohydrate, c) about 5% w/w of microcrystalline cellulose, d)
about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of
croscarmellose sodium, f) about 1% w/w of sodium lauryl sulfate, g)
about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w
of magnesium stearate.
43. The method of claim 1, wherein the formulation comprises: a)
about 70% w/w of ibrutinib, b) about 14% w/w of lactose
monohydrate, c) about 2% w/w of microcrystalline cellulose, d)
about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of
croscarmellose sodium, f) about 4% w/w of sodium lauryl sulfate, g)
about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w
of magnesium stearate.
44. The method of claim 1, wherein the formulation comprises: a)
about 65% w/w to about 75% w/w of ibrutinib, b) about 14% w/w to
about 18% w/w of lactose monohydrate, c) about 1% w/w to about 3%
w/w of polyvinylpyrrolidone, d) about 0.5% w/w to about 1.5% w/w of
sodium lauryl sulfate, e) about 5% w/w to about 15% w/w of
crospovidone, f) about 0.3% w/w to about 0.7% w/w of colloidal
silicon dioxide, and g) about 0.3% w/w to about 0.7% w/w of
magnesium stearate.
45. The method of claim 1, wherein the formulation comprises: a)
about 59% w/w to about 61% w/w of ibrutinib, b) about 13% w/w to
about 15% w/w of lactose, c) about 13% w/w to about 15% w/w of
microcrystalline cellulose, d) about 4% w/w to about 6% w/w of
croscarmellose sodium, e) about 5% w/w to about 7% w/w of sodium
lauryl sulfate, f) about 0.4% w/w to about 0.6% w/w of colloidal
silicon dioxide, and g) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
46. The method of claim 40, wherein the formulation comprises: a)
about 59% w/w to about 61% w/w of ibrutinib, b) about 13% w/w to
about 14% w/w of lactose, c) about 13% w/w to about 14% w/w of
microcrystalline cellulose, d) about 2% w/w to about 3% w/w of
croscarmellose sodium (intragranular), e) about 0.8% w/w to about
1.2% w/w of hydroxypropyl cellulose, f) about 2% w/w to about 3%
w/w of croscarmellose sodium (extragranular), g) about 5.5% w/w to
about 6.5% w/w of sodium lauryl sulfate, h) about 0.4% w/w to about
0.6% w/w of colloidal silicon dioxide, and i) about 0.4% w/w to
about 0.6% w/w of magnesium stearate.
47. The method of claim 40, wherein the formulation comprises: a)
about 69% w/w to about 71% w/w of ibrutinib, b) about 8% w/w to
about 9% w/w of lactose, c) about 8% w/w to about 9% w/w of
microcrystalline cellulose, d) about 2.5% w/w to about 3.5% w/w of
croscarmellose sodium (intragranular), e) about 2.5% w/w to about
3.5% w/w of croscarmellose sodium (extragranular), f) about 5.5%
w/w to about 6.5% w/w of sodium lauryl sulfate, g) about 0.4% w/w
to about 0.6% w/w of colloidal silicon dioxide, and h) about 0.4%
w/w to about 0.6% w/w of magnesium stearate.
48. The method of claim 1, wherein ibrutinib is in an amount of
about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the
tablet.
49. The method of claim 1, wherein the high-load solid tablet
formulation is used for one tablet once a day dosing.
50.-54. (canceled)
55. The method of claim 1, wherein ibrutinib is in an amount of
about 70 mg to about 840 mg in the tablet.
56. The method of claim 1, wherein the formulation comprises about
60% w/w to about 80% w/w of ibrutinib.
57. The method of claim 56, wherein ibrutinib is in an amount of
about 70 mg to about 840 mg in the tablet.
58. The method of claim 56, wherein ibrutinib is in an amount of
about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the
tablet.
59. The method of claim 36, wherein the formulation comprises about
60% w/w to about 80% w/w of ibrutinib.
60. The method of claim 59, wherein ibrutinib is in an amount of
about 70 mg to about 840 mg in the tablet.
61. The method of claim 59, wherein ibrutinib is in an amount of
about 140 mg, about 280 mg, about 420 mg, or about 560 mg in the
tablet.
62. The method of claim 1, wherein the formulation consists
essentially of at least 50% w/w of ibrutinib, one or more diluents
selected from the group consisting of lactose, sucrose, dextrose,
dextrates, maltodextrin, mannitol, xylitol, sorbitol,
cyclodextrins, calcium phosphate, calcium sulfate, starches,
modified starches, cellulose, microcrystalline cellulose,
microcellulose, and talc; one or more disintegrating agents
selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch, cross-linked polymer, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, and a gum; one or more binders selected
from the group consisting of hydroxypropyl cellulose and
polyvinylpyrrolidone; sodium lauryl sulfate; colloidal silicon
dioxide; and magnesium stearate.
63. The method of claim 1, wherein the formulation consists
essentially of: a) about 69% w/w to about 71% w/w of ibrutinib, b)
about 13% w/w to about 15% w/w of lactose monohydrate, c) about 2%
w/w to about 5% w/w of microcrystalline cellulose, d) about 1% w/w
to about 3% w/w of polyvinylpyrrolidone, e) about 6% w/w to about
8% w/w of croscarmellose sodium, f) about 1% w/w to about 4% w/w of
sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of
colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w
of magnesium stearate.
64. The method of claim 1, wherein the formulation consists
essentially of: a) about 70% w/w of ibrutinib, b) about 14% w/w of
lactose monohydrate, c) about 5% w/w of microcrystalline cellulose,
d) about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of
croscarmellose sodium, f) about 1% w/w of sodium lauryl sulfate, g)
about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w
of magnesium stearate.
65. The method of claim 1, wherein the formulation consists
essentially of: a) about 70% w/w of ibrutinib, b) about 14% w/w of
lactose monohydrate, c) about 2% w/w of microcrystalline cellulose,
d) about 2% w/w of polyvinylpyrrolidone, e) about 7% w/w of
croscarmellose sodium, f) about 4% w/w of sodium lauryl sulfate, g)
about 0.5% w/w of colloidal silicon dioxide, and h) about 0.5% w/w
of magnesium stearate.
66. The method of claim 1, wherein the formulation consists
essentially of: a) about 65% w/w to about 75% w/w of ibrutinib, b)
about 14% w/w to about 18% w/w of lactose monohydrate, c) about 1%
w/w to about 3% w/w of polyvinylpyrrolidone, d) about 0.5% w/w to
about 1.5% w/w of sodium lauryl sulfate, e) about 5% w/w to about
15% w/w of crospovidone, f) about 0.3% w/w to about 0.7% w/w of
colloidal silicon dioxide, and g) about 0.3% w/w to about 0.7% w/w
of magnesium stearate.
67. The method of claim 1, wherein the formulation consists
essentially of: a) about 59% w/w to about 61% w/w of ibrutinib, b)
about 13% w/w to about 15% w/w of lactose, c) about 13% w/w to
about 15% w/w of microcrystalline cellulose, d) about 4% w/w to
about 6% w/w of croscarmellose sodium, e) about 5% w/w to about 7%
w/w of sodium lauryl sulfate, f) about 0.4% w/w to about 0.6% w/w
of colloidal silicon dioxide, and g) about 0.4% w/w to about 0.6%
w/w of magnesium stearate.
68. The method of claim 40, wherein the formulation consists
essentially of: a) about 59% w/w to about 61% w/w of ibrutinib, b)
about 13% w/w to about 14% w/w of lactose, c) about 13% w/w to
about 14% w/w of microcrystalline cellulose, d) about 2% w/w to
about 3% w/w of croscarmellose sodium (intragranular), e) about
0.8% w/w to about 1.2% w/w of hydroxypropyl cellulose, f) about 2%
w/w to about 3% w/w of croscarmellose sodium (extragranular), g)
about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate, h) about
0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and i)
about 0.4% w/w to about 0.6% w/w of magnesium stearate.
69. The method of claim 40, wherein the formulation consists
essentially of: a) about 69% w/w to about 71% w/w of ibrutinib, b)
about 8% w/w to about 9% w/w of lactose, c) about 8% w/w to about
9% w/w of microcrystalline cellulose, d) about 2.5% w/w to about
3.5% w/w of croscarmellose sodium (intragranular), e) about 2.5%
w/w to about 3.5% w/w of croscarmellose sodium (extragranular), f)
about 5.5% w/w to about 6.5% w/w of sodium lauryl sulfate, g) about
0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and h)
about 0.4% w/w to about 0.6% w/w of magnesium stearate.
70. A method of treating cancer or graft versus host disease in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a solid tablet
formulation comprising ibrutinib, one or more excipients; wherein:
the excipients comprise: one or more diluents selected from the
group consisting of lactose, sucrose, dextrose, dextrates,
maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium
phosphate, calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc; one or more
disintegrating agents selected from the group consisting of natural
starch, a pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch, cross-linked polymer, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, and a gum; one or more binders selected
from the group consisting of hydroxypropyl cellulose and
polyvinylpyrrolidone; sodium lauryl sulfate; colloidal silicon
dioxide; and magnesium stearate; and wherein ibrutinib is a
compound with the structure of Compound 1, ##STR00008## and is
present at about 60% w/w to about 80% w/w and in an amount of about
70 mg to about 840 mg in the tablet.
71. A method of treating cancer or graft versus host disease in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a solid tablet
formulation comprising: about 50% w/w to about 90% w/w of
ibrutinib; about 10% w/w to about 15% w/w lactose; about 1% w/w to
about 6% w/w microcrystalline cellulose; about 1% w/w to about 5%
w/w polyvinylpyrrolidone; about 1% w/w to about 10% w/w
croscarmellose sodium; about 0.5% w/w to about 5% w/w sodium lauryl
sulfate; about 0.1% w/w to about 1.5% w/w colloidal silicon
dioxide; about 0.01% w/w to about 2% w/w magnesium stearate;
wherein ibrutinib is a compound with the structure of Compound 1,
##STR00009## and is in an amount of about 70 mg to about 840 mg in
the tablet.
72. The method of claim 71, wherein the formulation comprises: a)
about 69% w/w to about 71% w/w of ibrutinib, b) about 13% w/w to
about 15% w/w of lactose monohydrate, c) about 2% w/w to about 5%
w/w of microcrystalline cellulose, d) about 1% w/w to about 3% w/w
of polyvinylpyrrolidone, e) about 6% w/w to about 8% w/w of
croscarmellose sodium, f) about 1% w/w to about 4% w/w of sodium
lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of colloidal
silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
73. The method of claim 71, wherein the formulation consists
essentially of: a) about 69% w/w to about 71% w/w of ibrutinib, b)
about 13% w/w to about 15% w/w of lactose monohydrate, c) about 2%
w/w to about 5% w/w of microcrystalline cellulose, d) about 1% w/w
to about 3% w/w of polyvinylpyrrolidone, e) about 6% w/w to about
8% w/w of croscarmellose sodium, f) about 1% w/w to about 4% w/w of
sodium lauryl sulfate, g) about 0.4% w/w to about 0.6% w/w of
colloidal silicon dioxide, and h) about 0.4% w/w to about 0.6% w/w
of magnesium stearate.
74. A method of treating cancer or graft versus host disease in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a solid tablet
formulation consisting essentially of: about 50% w/w to about 90%
w/w of ibrutinib; about 10% w/w to about 15% w/w lactose; about 1%
w/w to about 6% w/w microcrystalline cellulose; about 1% w/w to
about 5% w/w polyvinylpyrrolidone; about 1% w/w to about 10% w/w
croscarmellose sodium; about 0.5% w/w to about 5% w/w sodium lauryl
sulfate; about 0.1% w/w to about 1.5% w/w colloidal silicon
dioxide; about 0.01% w/w to about 2% w/w magnesium stearate;
wherein ibrutinib is a compound with the structure of Compound 1,
##STR00010## and is in an amount of about 70 mg to about 840 mg in
the tablet.
75. The method of claim 1, wherein the method is a method of
treating cancer.
76. The method of claim 1, wherein the cancer is a hematological
malignancy.
77. The method of claim 1, wherein the cancer is a solid tumor.
78. The method of claim 1, wherein the cancer is a B-cell
malignancy.
79. The method of claim 1, wherein the cancer is a leukemia, a
lymphoma, or a myeloma.
80. The method of claim 1, wherein the cancer is selected from the
group consisting of diffuse large B cell lymphoma, follicular
lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia,
B-cell prolymphocytic leukemia, lymphoplasmacytic
lymphoma/Waldenstrom macroglobulinemia, marginal zone lymphoma,
multiple myeloma, plasmacytoma, mantle cell lymphoma, mediastinal
(thymic) large B cell lymphoma, intravascular large B cell
lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia,
lymphomatoid granulomatosis, primary central nervous system
lymphoma, breast cancer, colorectal cancer, lung cancer, pancreatic
cancer, and renal cell carcinoma.
81. The method of claim 1, wherein the cancer is chronic
lymphocytic leukemia/small lymphocytic lymphoma.
82. The method of claim 1, wherein the cancer is Waldenstrom
macroglobulinemia.
83. The method of claim 1, wherein the cancer is mantle cell
lymphoma.
84. The method of claim 1, wherein the cancer is marginal zone
lymphoma.
85. The method of claim 1, wherein the cancer is follicular
lymphoma.
86. The method of claim 1, wherein the cancer is diffuse large B
cell lymphoma.
87. The method of claim 1, wherein the method is a method of
treating graft versus host disease.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/127,717, filed Mar. 3, 2015, and U.S.
Provisional Application No. 62/193,518, filed Jul. 16, 2015, which
are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] Described herein is the Bruton's tyrosine kinase (Btk)
inhibitor
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, including pharmaceutical
compositions, solvates and pharmaceutically acceptable salts
thereof, as well as pharmaceutical formulations that include the
Btk inhibitor and methods of using the Btk inhibitor compositions
or formulations in the treatment of diseases or conditions that
would benefit from inhibition of Btk activity.
BACKGROUND OF THE INVENTION
[0003] Bruton's tyrosine kinase (Btk), a member of the Tec family
of non-receptor tyrosine kinases, is a key signaling enzyme
expressed in all hematopoietic cells types except T lymphocytes and
natural killer cells. Btk plays an essential role in the B-cell
signaling pathway linking cell surface B-cell receptor (BCR)
stimulation to downstream intracellular responses.
[0004] Btk is a key regulator of B-cell development, activation,
signaling, and survival. In addition, Btk plays a role in a number
of other hematopoietic cell signaling pathways, e.g., Toll like
receptor (TLR) and cytokine receptor-mediated TNF-.alpha.
production in macrophages, IgE receptor (FcepsilonRI) signaling in
Mast cells, inhibition of Fas/APO-1 apoptotic signaling in
B-lineage lymphoid cells, and collagen-stimulated platelet
aggregation.
[0005]
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-
-yl)piperidin-1-yl)prop-2-en-1-one is also known by its IUPAC name
as
1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]p-
iperidin-1-yl}prop-2-en-1-one or 2-Propen-1-one,
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]--
1-piperidinyl-, and has been given the USAN name, ibrutinib. The
various names given for ibrutinib are used interchangeably
herein.
SUMMARY OF THE INVENTION
[0006] Described herein is the Btk inhibitor
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, including pharmaceutically acceptable
compositions, formulations, and methods of uses thereof. Also
described are pharmaceutically acceptable compositions and
formulations of the Btk inhibitor,
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, used in the manufacture of
medicaments for the treatment of diseases or conditions that are
associated with Btk activity.
1-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-1-yl)piperidin-1-yl)prop-2-en-1-one is an irreversible Btk
inhibitor. Further described are pharmaceutical compositions and
formulations of the Btk inhibitor,
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, and methods of using the Btk
inhibitor in the treatment of diseases or conditions (including
diseases or conditions wherein irreversible inhibition of Btk
provides therapeutic benefit to a mammal having the disease or
condition).
[0007] Also described herein is a process for preparing a
pharmaceutical composition of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one by a wet granulation method. Further
described are pharmaceutical formulations that include a
pharmaceutical composition of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one prepared by a wet granulation
method.
[0008] In one aspect is a pharmaceutical composition comprising
ibrutinib, wherein ibrutinib is a compound with the structure of
Compound 1,
##STR00001##
and wherein the pharmaceutical composition comprises at least 50%
w/w of ibrutinib.
[0009] In another embodiment is a pharmaceutical composition
comprising ibrutinib, wherein the pharmaceutical composition
comprises about 50% w/w to about 90% w/w of ibrutinib. In another
embodiment is a pharmaceutical composition comprising ibrutinib,
wherein the pharmaceutical composition comprises about 50% w/w to
about 80% w/w of ibrutinib. In another embodiment is a
pharmaceutical composition comprising ibrutinib, wherein the
pharmaceutical composition comprises about 60% w/w to about 80% w/w
of ibrutinib. In another embodiment is a pharmaceutical composition
comprising ibrutinib, wherein the pharmaceutical composition
comprises about 60% w/w to about 75% w/w of ibrutinib. In another
embodiment is a pharmaceutical composition comprising at least 50%
w/w of ibrutinib, wherein the pharmaceutical composition comprises
intragranular and extragranular ingredients. In another embodiment
is a pharmaceutical composition comprising at least 50% w/w of
ibrutinib, wherein the pharmaceutical composition is prepared using
a wet granulation method. In another embodiment is a pharmaceutical
composition comprising at least 50% w/w of ibrutinib, further
comprising at least one pharmaceutically acceptable excipient.
[0010] In another embodiment is a high-load solid tablet
formulation comprising a pharmaceutical composition comprising at
least 50% w/w of ibrutinib, about 50% w/w to about 90% w/w of
ibrutinib, about 50% w/w to about 80% w/w of ibrutinib, about 60%
w/w to about 80% w/w of ibrutinib, or about 60% w/w to about 75%
w/w of ibrutinib, and one or more pharmaceutically acceptable
excipients. In another embodiment is a high-load solid tablet
formulation comprising a pharmaceutical composition comprising at
least 50% w/w of ibrutinib, about 50% w/w to about 90% w/w of
ibrutinib, about 50% w/w to about 80% w/w of ibrutinib, about 60%
w/w to about 80% w/w of ibrutinib, or about 60% w/w to about 75%
w/w of ibrutinib, and one or more pharmaceutically acceptable
excipients wherein the one or more excipients are present in an
amount from about 10% w/w to about 50% w/w.
[0011] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, about 50% w/w
to about 90% w/w of ibrutinib, about 50% w/w to about 80% w/w of
ibrutinib, about 60% w/w to about 80% w/w of ibrutinib, or about
60% w/w to about 75% w/w of ibrutinib, and one or more
pharmaceutically acceptable excipients wherein the one or more
excipients are selected from the group consisting of diluents,
binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent. In some embodiments, the diluent is selected from the
group consisting of lactose, sucrose, dextrose, dextrates,
maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium
phosphate, calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise, consist
essentially of, or consist, lactose, microcrystalline cellulose,
polyvinylpyrrolidone, croscarmellose sodium, sodium lauryl sulfate,
colloidal silicon dioxide and magnesium stearate. In another
embodiment, the excipients comprise, consist essentially of, or
consist, lactose, polyvinylpyrrolidone, sodium lauryl sulfate,
crospovidone, colloidal silicon dioxide, and magnesium
stearate.
[0012] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, about 50% w/w
to about 90% w/w of ibrutinib, about 50% w/w to about 80% w/w of
ibrutinib, about 60% w/w to about 80% w/w of ibrutinib, or about
60% w/w to about 75% w/w of ibrutinib, and intragranular and
extragranular excipients; wherein the intragranular excipients
comprise, consist essentially of, or consist lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose; and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment is a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, about 50% w/w to about 90% w/w of ibrutinib, about 50%
w/w to about 80% w/w of ibrutinib, about 60% w/w to about 80% w/w
of ibrutinib, or about 60% w/w to about 75% w/w of ibrutinib,
wherein the intragranular excipients comprise [0013] lactose in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
15% w/w, or about 8% w/w to about 14% w/w; [0014] microcrystalline
cellulose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 20% w/w, or about 8% w/w to about 15% w/w; [0015]
croscarmellose sodium in an amount from about 0 to about 10% w/w,
about 2% w/w to about 5% w/w, or about 2% w/w to about 4% w/w; and
[0016] hydroxypropyl cellulose in an amount from about 0% w/w to
about 2% w/w, about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w
to about 1% w/w; and the extragranular excipients comprise [0017]
croscarmellose sodium in an amount from about 0% w/w to about 5%
w/w, about 2% w/w to about 5% w/w, or about 2% w/w to about 5% w/w;
[0018] sodium lauryl sulfate in an amount from about 0% w/w to
about 10% w/w, about 4% w/w to about 8% w/w, or about 5% w/w to
about 6% w/w; [0019] colloidal silicon dioxide in an amount from
about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w,
or about 0.5% w/w to about 0.6% w/w; and [0020] magnesium stearate
in an amount from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w
to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w.
[0021] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, about 50% w/w
to about 90% w/w of ibrutinib, about 50% w/w to about 80% w/w of
ibrutinib, about 60% w/w to about 80% w/w of ibrutinib, or about
60% w/w to about 75% w/w of ibrutinib, and intragranular and
extragranular excipients; wherein the intragranular excipients
comprise lactose, microcrystalline cellulose, sodium lauryl
sulfate, polyvinylpyrrolidone and croscarmellose sodium; and the
extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment is a high-load solid tablet formulation
comprising at least 50% w/w of ibrutinib, about 50% w/w to about
90% w/w of ibrutinib, about 50% w/w to about 80% w/w of ibrutinib,
about 60% w/w to about 80% w/w of ibrutinib, or about 60% w/w to
about 75% w/w of ibrutinib, wherein the intragranular excipients
comprise [0022] lactose in an amount from about 10% w/w to about
20% w/w, or about 12% w/w to about 15% w/w; [0023] microcrystalline
cellulose in an amount from about 1% w/w to about 10% w/w, about 2%
w/w to about 5% w/w; [0024] polyvinylpyrrolidone in an amount from
about 0% w/w to about 5% w/w, about 1% w/w to about 3% w/w; [0025]
croscarmellose sodium in an amount from about 1% w/w to about 10%
w/w, or about 3% w/w to about 7% w/w; and [0026] sodium lauryl
sulfate in an amount from about 0 to about 2% w/w, about 0.5% w/w
to about 1.5% w/w; and the extragranular excipients comprise [0027]
croscarmellose sodium in an amount from about 0 to about 5% w/w,
about 1% w/w to about 3% w/w; [0028] sodium lauryl sulfate in an
amount from about 0 to about 10% w/w or about 0% w/w to about 4%
w/w; [0029] colloidal silicon dioxide in an amount from about 0.4%
w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and
[0030] magnesium stearate in an amount from about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w.
[0031] In another embodiment is a high-load solid tablet
formulation comprising [0032] a) about 69% w/w to about 71% w/w of
ibrutinib, [0033] b) about 13% w/w to about 15% w/w of lactose,
[0034] c) about 2% w/w to about 5% w/w of microcrystalline
cellulose, [0035] d) about 1% w/w to about 3% w/w of
polyvinylpyrrolidone, [0036] e) about 6% w/w to about 8% w/w of
croscarmellose sodium, [0037] f) about 1% w/w to about 4% w/w of
sodium lauryl sulfate, [0038] g) about 0.4% w/w to about 0.6% w/w
of colloidal silicon dioxide, and [0039] h) about 0.4% w/w to about
0.6% w/w of magnesium stearate.
[0040] In another embodiment is a high-load solid tablet
formulation comprising [0041] a) about 70% w/w of ibrutinib, [0042]
b) about 14% w/w of lactose monohydrate, [0043] c) about 5% w/w of
microcrystalline cellulose, [0044] d) about 2% w/w of
polyvinylpyrrolidone, [0045] e) about 7% w/w of croscarmellose
sodium, [0046] f) about 1% w/w of sodium lauryl sulfate, [0047] g)
about 0.5% w/w of colloidal silicon dioxide, and [0048] h) about
0.5% w/w of magnesium stearate.
[0049] In another embodiment is a high-load solid tablet
formulation comprising [0050] a) about 70% w/w of ibrutinib, [0051]
b) about 14% w/w of lactose monohydrate, [0052] c) about 2% w/w of
microcrystalline cellulose, [0053] d) about 2% w/w of
polyvinylpyrrolidone, [0054] e) about 7% w/w of croscarmellose
sodium, [0055] f) about 4% w/w of sodium lauryl sulfate, [0056] g)
about 0.5% w/w of colloidal silicon dioxide, and [0057] h) about
0.5% w/w of magnesium stearate.
[0058] In another embodiment is a high-load solid tablet
formulation comprising [0059] a) about 70% w/w of ibrutinib, [0060]
b) about 16% w/w of lactose, [0061] c) about 2% w/w of
polyvinylpyrrolidone, [0062] d) about 1% w/w of sodium lauryl
sulfate, [0063] e) about 10% w/w of crospovidone, [0064] f) about
0.5% w/w of colloidal silicon dioxide, and [0065] g) about 0.5% w/w
of magnesium stearate.
[0066] In another embodiment is a high-load solid tablet
formulation comprising [0067] a) about 59% w/w to about 61% w/w of
ibrutinib, [0068] b) about 13% w/w to about 15% w/w of lactose,
[0069] c) about 13% w/w to about 15% w/w of microcrystalline
cellulose, [0070] d) about 4% w/w to about 6% w/w of croscarmellose
sodium, [0071] e) about 5% w/w to about 7% w/w of sodium lauryl
sulfate, [0072] f) about 0.4% w/w to about 0.6% w/w of colloidal
silicon dioxide, and [0073] g) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
[0074] In some embodiments, the total weight of a tablet is about
934 mg.
[0075] In another embodiment is a high-load solid tablet
formulation comprising [0076] a) about 59% w/w to about 61% w/w of
ibrutinib, [0077] b) about 13% w/w to about 14% w/w of lactose,
[0078] c) about 13% w/w to about 14% w/w of microcrystalline
cellulose, [0079] d) about 2% w/w to about 3% w/w of croscarmellose
sodium (intragranular), [0080] e) about 0.8% w/w to about 1.2% w/w
of hydroxypropyl cellulose, [0081] f) about 2% w/w to about 3% w/w
of croscarmellose sodium (extragranular), [0082] g) about 5.5 to
about 6.5% w/w of sodium lauryl sulfate, [0083] h) about 0.4% w/w
to about 0.6% w/w of colloidal silicon dioxide, and [0084] i) about
0.4% w/w to about 0.6% w/w of magnesium stearate.
[0085] In some embodiments, the total weight of a tablet is about
934 mg.
[0086] In another embodiment is a high-load solid tablet
formulation comprising [0087] a) about 69% w/w to about 71% w/w of
ibrutinib, [0088] b) about 8% w/w to about 9% w/w of lactose,
[0089] c) about 8 to about 9% w/w of microcrystalline cellulose,
[0090] d) about 2.5 to about 3.5% w/w of croscarmellose sodium
(intragranular), [0091] e) about 2.5 to about 3.5% w/w of
croscarmellose sodium (extragranular), [0092] g) about 5.5 to about
6.5% w/w of sodium lauryl sulfate, [0093] h) about 0.4% w/w to
about 0.6% w/w of colloidal silicon dioxide, and [0094] i) about
0.4% w/w to about 0.6% w/w of magnesium stearate.
[0095] Lactose used herein may be anhydrous lactose and/or hydrous
lactose, such as lactose monohydrate. In some embodiments, the
lactose is anhydrous lactose. In some particular embodiments, the
lacose is hydrous lactose. In more particular embodiments, the
lacose is lactose monohydrate.
[0096] In some embodiments, the total weight of a tablet is about
800 mg.
[0097] In some embodiments of the high-load solid tablet
formulations described herein, the ibrutinib is in an amount of
about 35 mg to about 840 mg per tablet. In some embodiments of the
high-load solid tablet formulations described herein, the ibrutinib
is in an amount of about 140 mg to about 840 mg per tablet. In some
embodiments of the high-load solid tablet formulations described
herein, the ibrutinib is in an amount of about 140 mg, about 280
mg, about 420 mg, about 560 mg, or about 840 mg per tablet, or any
range between any two of the values, end points inclusive. In some
embodiments of the high-load solid tablet formulations described
herein, the ibrutinib is in an amount of about 560 mg. In some
embodiments of the high-load solid tablet formulations described
herein, the ibrutinib is in micronized form. In some embodiments of
the high-load solid tablet formulations described herein, the
formulation is used for once a day dosing. In some embodiments of
the high-load solid tablet formulations described herein, the
formulation is in an oral dosage form containing a therapeutically
effective amount of ibrutinib.
[0098] In another embodiment is a method of treating a disease in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein.
[0099] In another embodiment is a method of treating an autoimmune
disease in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein. In
some embodiments, the autoimmune disease is rheumatoid arthritis or
lupus.
[0100] In another embodiment is a method of treating a heteroimmune
disease in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein.
[0101] In another embodiment is a method of treating cancer in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein. In some embodiments,
the cancer is a B-cell proliferative disorder. In some embodiments,
the cancer is a B-cell proliferative disorder and the B-cell
proliferative disorder is diffuse large B cell lymphoma, follicular
lymphoma or chronic lymphocytic leukemia. In some embodiments, the
cancer is a B cell malignancy. In some embodiments, the cancer is a
B cell malignancy and the B cell malignancy selected from chronic
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle
cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and
multiple myeloma. In some embodiments, the cancer is a lymphoma,
leukemia or a solid tumor. In some embodiments, the cancer is
diffuse large B cell lymphoma, follicular lymphoma, chronic
lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell
prolymphocytic leukemia, lymphoplamacytic lymphoma/Waldenstrom
macroglobulinemia, splenic marginal zone lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma,
nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion lymphoma, burkitt
lymphoma/leukemia, or lymphomatoid granulomatosis.
[0102] In another embodiment is a method of treating mastocytosis
in a patient in need of such treatment, comprising administering to
the patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein.
[0103] In another embodiment is a method of treating osteoporosis
or bone resorption disorders in a patient in need of such
treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein.
[0104] In another embodiment is a method of treating an
inflammatory disease or condition in a patient in need of such
treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein.
[0105] In another embodiment is a method of treating lupus in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein.
[0106] In some embodiments, the formulations and methods described
herein can be used to treat carcinoma of the brain, kidney, liver,
adrenal gland, bladder, breast, stomach, gastric tumors, ovaries,
colon, rectum, prostate, pancreas, lung, vagina, cervix, testis,
genitourinary tract, esophagus, larynx, skin, bone or thyroid,
sarcoma, glioblastomas, neuroblastomas, multiple myeloma,
gastrointestinal cancer, especially colon carcinoma or colorectal
adenoma, a tumor of the neck and head, an epidermal
hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a
neoplasia of epithelial character, adenoma, adenocarcinoma,
keratoacanthoma, epidermoid carcinoma, large cell carcinoma,
non-small-cell lung carcinoma, lymphomas, Hodgkins and
Non-Hodgkins, a mammary carcinoma, follicular carcinoma,
undifferentiated carcinoma, papillary carcinoma, seminoma,
melanoma, or Smoldering of indolent multiple myeloma.
[0107] In some embodiments, the formulations and methods described
herein can be used to treat a central nervous system (CNS)
malignancy. In some embodiments, the CNS malignancy is a primary
CNS lymphoma. In some embodiments the primary CNS lymphoma is a
glioma. In some embodiments the glioma is astrocytomas,
ependymomas, oligodendrogliomas. In some embodiments the CNS
malignancy is astrocytic tumors such as juvenile pilocytic,
subependymal, well differentiated or moderately differentiated
anaplastic astrocytoma; anaplastic astrocytoma; glioblastoma
multiforme; ependymal tumors such as myxopapillary and
well-differentiated ependymoma, anaplastic ependymoma,
ependymoblastoma; oligodendroglial tumors including
well-differentiated oligodendroglioma and anaplastic
oligodendroglioma; mixed tumors such as mixed
astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, mixed
astrocytomaependymoma-oligodendroglioma; or medulloblastoma.
[0108] In some embodiments, the formulations and methods described
herein can be used to treat hematological malignancies such as, but
not limited to, a leukemia, a lymphoma, a myeloma, a non-Hodgkin's
lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell
malignancy. In some embodiments, the hematological malignancy is a
treatment naive hematological malignancy. In some embodiments the
hematological malignancy is a relapsed or refractory hematological
malignancy.
[0109] In some embodiments, the hematologic malignancy is a T-cell
malignancy. In some embodiments, the T-cell malignancy is
peripheral T-cell lymphoma not otherwise specified (PTCL-NOS),
anaplastic large cell lymphoma, angioimmunoblastic lymphoma,
cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL),
blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma,
hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma,
nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.
In some embodiments, the T-cell malignancy is a relapsed or
refractory T-cell malignancy. In some embodiments, the T-cell
malignancy is a treatment naive T-cell malignancy.
[0110] In some embodiments, the hematologic malignancy is a B-cell
proliferative disorder. In some embodiments, the cancer is chronic
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high
risk CLL, a non-CLL/SLL lymphoma, or prolymphocytic leukemia (PLL).
In some embodiments, the cancer is follicular lymphoma (FL),
diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL),
Waldenstrom's macroglobulinemia, multiple myeloma, extranodal
marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,
Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary
mediastinal B-cell lymphoma (PMBL), immunoblastic large cell
lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic
leukemia, lymphoplamacytic lymphoma, splenic marginal zone
lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic)
large B cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, or lymphomatoid granulomatosis. In some
embodiments, DLBCL is further divided into subtypes: activated
B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center
diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH)
DLBCL. In some embodiments, ABC-DLBCL is characterized by a CD79B
mutation. In some embodiments, ABC-DLBCL is characterized by a
CD79A mutation. In some embodiments, the ABC-DLBCL is characterized
by a mutation in MyD88, A20, or a combination thereof. In some
embodiments, the cancer is acute or chronic myelogenous (or
myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic
leukemia. In some embodiments, the B-cell proliferative disorder is
a relapsed and refractory B-cell proliferative disorder. In some
embodiments, the B-cell proliferative disorder is a treatment naive
B-cell proliferative disorder.
[0111] In some embodiments, the formulations and methods described
herein can be used to treat fibrosis. In some embodiments, the
fibrosis is not associated with graft versus host disease (GVHD).
In some embodiments, the fibrosis is not associated with
sclerodermatous GVHD, lung chronic GVHD, or liver chronic GVHD. In
some embodiments, the fibrosis is of the liver, lung, pancreas,
kidney, bone marrow, heart, skin, intestine, or joints. In some
embodiments, the fibrosis is of the liver. In some embodiments, the
fibrosis is of the lung. In some embodiments, the fibrosis is of
the pancreas. In some embodiments, the patient has cirrhosis,
chronic pancreatitis, or cystic fibrosis.
[0112] In another aspect is a process for preparing a
pharmaceutical composition or tablet formulation comprising
ibrutinib as described herein, wherein the process comprises a wet
granulation method.
[0113] In another aspect is a high-load solid tablet formulation
comprising ibrutinib, wherein ibrutinib is a compound with the
structure of Compound 1,
##STR00002##
and the tablet comprises about 560 mg of ibrutinib.
[0114] In another embodiment is a high-load solid tablet
formulation, wherein ibrutinib is in micronized form. In another
embodiment, ibrutinib is in spray-dried form. In another
embodiment, ibrutinib is not in spray-dried form. In another
embodiment, the particle size is about or less than 30 micron. In
one embodiment, ibrutinib is in micronized form and the particle
size is about 1-30 micron. In another embodiment, the particle size
is about or less than 10 micron. In another embodiment, the
particle size is <1 micron. In another embodiment is a high-load
solid tablet formulation, wherein the tablet is used for once a day
oral dosing.
[0115] In another aspect, provided herein are methods for treating
a patient by administering Compound 1. In some embodiments,
provided herein is a method of inhibiting the activity of tyrsoine
kinase(s), such as Btk, or of treating a disease, disorder, or
condition, which would benefit from inhibition of tyrosine
kinase(s), such as Btk, in a mammal, which includes administering
to the mammal a therapeutically effective amount of Compound 1, or
pharmaceutically acceptable salt, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate.
[0116] In another aspect, provided herein is the use of Compound 1
for inhibiting Bruton's tyrosine kinase (Btk) activity or for the
treatment of a disease, disorder, or condition, which would benefit
from inhibition of Bruton's tyrosine kinase (Btk) activity.
[0117] In some embodiments, a pharmaceutical composition comprising
crystalline Compound 1 is administered to a human. In some
embodiments, a pharmaceutical composition comprising amorphous
Compound 1 is administered to a human.
[0118] In some embodiments, a pharmaceutical composition comprising
crystalline Compound 1 is orally administered. In some embodiments,
a pharmaceutical composition comprising amorphous Compound 1 is
orally administered.
[0119] In some embodiments, a pharmaceutical composition comprising
crystalline Compound 1 is used for the formulation of a medicament
for the inhibition of tyrosine kinase activity. In some other
embodiments, a pharmaceutical composition comprising crystalline
Compound 1 is used for the formulation of a medicament for the
inhibition of Bruton's tyrosine kinase (Btk) activity. In some
embodiments, a pharmaceutical composition comprising amorphous
Compound 1 is used for the formulation of a medicament for the
inhibition of tyrosine kinase activity. In some other embodiments,
a pharmaceutical composition comprising amorphous Compound 1 is
used for the formulation of a medicament for the inhibition of
Bruton's tyrosine kinase (Btk) activity.
[0120] In some embodiments, in any of the embodiments disclosed
herein (including compositions, methods, uses, formulations,
combination therapy, etc.), Compound 1, or a pharmaceutically
acceptable salt or solvate thereof, is optically pure (i.e. greater
than 99% chiral purity by HPLC). In some embodiments, in any of the
embodiments disclosed herein (including compositions, methods,
uses, formulations, combination therapy, etc.), Compound 1, or a
pharmaceutically acceptable salt or solvate thereof, is replaced
with: a) Compound 1, or a pharmaceutically acceptable salt or
solvate thereof, of lower chiral purity; b)
1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt
or solvate thereof of any optical purity; or c) racemic
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-
din-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt or
solvate thereof.
[0121] In any of the embodiments disclosed herein (including
compositions, methods, uses, formulations, combination therapy,
etc.), amorphous Compound 1 is used. In any of the embodiments
disclosed herein (including compositions, methods, uses,
formulations, combination therapy, etc.), crystalline Compound 1 is
used.
[0122] In some embodiments, in any of the embodiments disclosed
herein (including compositions, methods, uses, formulations,
combination therapy, etc.), Compound 1, or a pharmaceutically
acceptable salt thereof, is replaced with an active metabolite of
Compound 1. In some embodiments, the active metabolite is in a
crystalline form. In some embodiments, the active metabolite is in
an amorphous phase. In further embodiments the metabolite is
isolated. In some embodiments, in any of the embodiments disclosed
herein (including compositions, methods, uses, formulations,
combination therapy, etc.), Compound 1, or a pharmaceutically
acceptable salt thereof, is replaced with a prodrug of Compound 1,
or a deuterated analog of Compound 1, or a pharmaceutically
acceptable salt thereof.
[0123] Other objects, features and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the present disclosure will become apparent to those
skilled in the art from this detailed description. The section
headings used herein are for organizational purposes only and are
not to be construed as limiting the subject matter described. All
documents, or portions of documents, cited in the application
including, but not limited to, patents, patent applications,
articles, books, manuals, and treatises are hereby expressly
incorporated by reference in their entirety for any purpose.
INCORPORATION BY REFERENCE
[0124] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the extent
applicable and relevant.
BRIEF DESCRIPTION OF THE FIGURES
[0125] FIG. 1 shows mean plasma concentration-time profiles of
ibrutinib following single oral dose administration of a capsule
formulation versus three different wet tablet formulations to
fasted beagle dogs (Dose=140 mg).
[0126] FIG. 2 shows mean plasma concentration-time profiles of
ibrutinib following single oral dose administration of a capsule
formulation versus two different dry tablet formulations to fasted
beagle dogs (Dose=140 mg).
[0127] FIG. 3 is a photo of examples: (A) a capsule comprising 140
mg ibrutinib (Formulation A), and tablets of the invention (B-E)
designed to comprise 560 mg, 420 mg, 280 mg, and 140 mg of
ibrutinib, respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0128] The diverse roles played by Btk signaling in various
hematopoietic cell functions, e.g., B-cell receptor activation,
suggests that small molecule Btk inhibitors, such as Compound 1,
are useful for reducing the risk of or treating a variety of
diseases affected by or affecting many cell types of the
hematopoietic lineage including, e.g., autoimmune diseases,
heteroimmune conditions or diseases, inflammatory diseases, cancer
(e.g., B-cell proliferative disorders), and thromboembolic
disorders. Further, irreversible Btk inhibitor compounds, such as
Compound 1, can be used to inhibit a small subset of other tyrosine
kinases that share homology with Btk by having a cysteine residue
(including a Cys 481 residue) that can form a covalent bond with
the irreversible inhibitor.
[0129] In some embodiments, the compositions or tablet formulations
comprising Compound 1 can be used in the treatment of an autoimmune
disease in a mammal, which includes, but is not limited to,
rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's
disease, juvenile arthritis, lupus, diabetes, myasthenia gravis,
Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease
Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome,
acute disseminated encephalomyelitis, Addison's disease,
opsoclonus-myoclonus syndrome, ankylosing spondylitisis,
antiphospholipid antibody syndrome, aplastic anemia, autoimmune
hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic
thrombocytopenic purpura, optic neuritis, scleroderma, primary
biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,
temporal arteritis, warm autoimmune hemolytic anemia, Wegener's
granulomatosis, psoriasis, alopecia universalis, Behcet's disease,
chronic fatigue, dysautonomia, endometriosis, interstitial
cystitis, neuromyotonia, scleroderma, and vulvodynia.
[0130] In some embodiments, the compositions or tablet formulations
comprising Compound 1 can be used in the treatment of a
heteroimmune disease or condition in a mammal, which include, but
are not limited to graft versus host disease, transplantation,
transfusion, anaphylaxis, allergies (e.g., allergies to plant
pollens, latex, drugs, foods, insect poisons, animal hair, animal
dander, dust mites, or cockroach calyx), type I hypersensitivity,
allergic conjunctivitis, allergic rhinitis, and atopic
dermatitis.
[0131] In some embodiments, the compositions or tablet formulations
comprising Compound 1 can be used in the treatment of an
inflammatory disease in a mammal, which includes, but is not
limited to asthma, inflammatory bowel disease, appendicitis,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fascitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and
vulvitis. In some embodiments, the inflammatory disease is asthma,
appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,
cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,
cystitis, dacryoadenitis, dermatitis, dermatomyositis,
encephalitis, endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fascitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or
vulvitis. In some embodiments, the autoimmune disease is
inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis,
psoriatic arthritis, osteoarthritis, Still's disease, juvenile
arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis,
Ord's thyroiditis, Graves' disease Sjogren's syndrome, multiple
sclerosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus
syndrome, ankylosing spondylitisis, antiphospholipid antibody
syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia
universalis, Behcet's disease, chronic fatigue, dysautonomia,
endometriosis, interstitial cystitis, neuromyotonia, scleroderma,
or vulvodynia.
[0132] In yet other embodiments, the methods described herein can
be used to treat a cancer, e.g., B-cell proliferative disorders,
which include, but are not limited to diffuse large B cell
lymphoma, follicular lymphoma, chronic lymphocytic lymphoma,
chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,
lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia, splenic
marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid
granulomatosis.
[0133] In further embodiments, the methods described herein can be
used to treat thromboembolic disorders, which include, but are not
limited to myocardial infarct, angina pectoris (including unstable
angina), reocclusions or restenoses after angioplasty or
aortocoronary bypass, stroke, transitory ischemia, peripheral
arterial occlusive disorders, pulmonary embolisms, and deep venous
thromboses.
Hematological Malignancies
[0134] Disclosed herein, in certain embodiments, is a method for
treating a hematological malignancy in an individual in need
thereof, comprising: administering to the individual a composition
or tablet formulation described herein comprising an amount of
Compound 1.
[0135] In some embodiments, the hematological malignancy is a
non-Hodgkin's lymphoma (NHL). In some embodiments, the
hematological malignancy is a chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL
lymphoma. In some embodiments, the hematological malignancy is
follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL),
mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia,
multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma,
non-Burkitt high grade B cell lymphoma, or extranodal marginal zone
B cell lymphoma. In some embodiments, the hematological malignancy
is acute or chronic myelogenous (or myeloid) leukemia,
myelodysplastic syndrome, acute lymphoblastic leukemia, or
precursor B-cell acute lymphoblastic leukemia. In some embodiments,
the hematological malignancy is chronic lymphocytic leukemia (CLL).
In some embodiments, the hematological malignancy is mantle cell
lymphoma (MCL). In some embodiments, the hematological malignancy
is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the
hematological malignancy is diffuse large B-cell lymphoma (DLBCL),
ABC subtype. In some embodiments, the hematological malignancy is
diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some
embodiments, the hematological malignancy is Waldenstrom's
macroglobulinemia (WM). In some embodiments, the hematological
malignancy is multiple myeloma (MM). In some embodiments, the
hematological malignancy is Burkitt's lymphoma. In some
embodiments, the hematological malignancy is follicular lymphoma
(FL). In some embodiments, the hematological malignancy is
transformed follicular lymphoma. In some embodiments, the
hematological malignancy is marginal zone lymphoma.
[0136] In some embodiments, the hematological malignancy is
relapsed or refractory non-Hodgkin's lymphoma (NHL). In some
embodiments, the hematological malignancy is relapsed or refractory
diffuse large B-cell lymphoma (DLBCL), relapsed or refractory
mantle cell lymphoma (MCL), relapsed or refractory follicular
lymphoma (FL), relapsed or refractory CLL, relapsed or refractory
SLL, relapsed or refractory multiple myeloma, relapsed or
refractory Waldenstrom's macroglobulinemia, relapsed or refractory
multiple myeloma (MM), relapsed or refractory marginal zone
lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or
refractory non-Burkitt high grade B cell lymphoma, relapsed or
refractory extranodal marginal zone B cell lymphoma. In some
embodiments, the hematological malignancy is a relapsed or
refractory acute or chronic myelogenous (or myeloid) leukemia,
relapsed or refractory myelodysplastic syndrome, relapsed or
refractory acute lymphoblastic leukemia, or relapsed or refractory
precursor B-cell acute lymphoblastic leukemia. In some embodiments,
the hematological malignancy is relapsed or refractory chronic
lymphocytic leukemia (CLL). In some embodiments, the hematological
malignancy is relapsed or refractory mantle cell lymphoma (MCL). In
some embodiments, the hematological malignancy is relapsed or
refractory diffuse large B-cell lymphoma (DLBCL). In some
embodiments, the hematological malignancy is relapsed or refractory
diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some
embodiments, the hematological malignancy is relapsed or refractory
diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some
embodiments, the hematological malignancy is relapsed or refractory
Waldenstrom's macroglobulinemia (WM). In some embodiments, the
hematological malignancy is relapsed or refractory multiple myeloma
(MM). In some embodiments, the hematological malignancy is relapsed
or refractory Burkitt's lymphoma. In some embodiments, the
hematological malignancy is relapsed or refractory follicular
lymphoma (FL).
[0137] In some embodiments, the hematological malignancy is a
hematological malignancy that is classified as high-risk. In some
embodiments, the hematological malignancy is high risk CLL or high
risk SLL.
[0138] B-cell lymphoproliferative disorders (BCLDs) are neoplasms
of the blood and encompass, inter alia, non-Hodgkin lymphoma,
multiple myeloma, and leukemia. BCLDs can originate either in the
lymphatic tissues (as in the case of lymphoma) or in the bone
marrow (as in the case of leukemia and myeloma), and they all are
involved with the uncontrolled growth of lymphocytes or white blood
cells. There are many subtypes of BCLD, e.g., chronic lymphocytic
leukemia (CLL) and non-Hodgkin lymphoma (NHL). The disease course
and treatment of BCLD is dependent on the BCLD subtype; however,
even within each subtype the clinical presentation, morphologic
appearance, and response to therapy is heterogeneous.
[0139] Malignant lymphomas are neoplastic transformations of cells
that reside predominantly within lymphoid tissues. Two groups of
malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's
lymphoma (NHL). Both types of lymphomas infiltrate
reticuloendothelial tissues. However, they differ in the neoplastic
cell of origin, site of disease, presence of systemic symptoms, and
response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas"
Chapter 134, Cancer Medicine, (an approved publication of the
American Cancer Society, B.C. Decker Inc., Hamilton, Ontario,
2003).
Non-Hodgkin's Lymphomas
[0140] Disclosed herein, in certain embodiments, is a method for
treating a non-Hodgkin's lymphoma in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising an amount of Compound
1.
[0141] Further disclosed herein, in certain embodiments, is a
method for treating relapsed or refractory non-Hodgkin's lymphoma
in an individual in need thereof, comprising: administering to the
individual a therapeutically-effective amount of Compound 1. In
some embodiments, the non-Hodgkin's lymphoma is relapsed or
refractory diffuse large B-cell lymphoma (DLBCL), relapsed or
refractory mantle cell lymphoma, relapsed or refractory follicular
lymphoma, or relapsed or refractory CLL.
[0142] Non-Hodgkin lymphomas (NHL) are a diverse group of
malignancies that are predominately of B-cell origin. NHL may
develop in any organs associated with lymphatic system such as
spleen, lymph nodes or tonsils and can occur at any age. NHL is
often marked by enlarged lymph nodes, fever, and weight loss. NHL
is classified as either B-cell or T-cell NHL. Lymphomas related to
lymphoproliferative disorders following bone marrow or stem cell
transplantation are usually B-cell NHL. In the Working Formulation
classification scheme, NHL has been divided into low-,
intermediate-, and high-grade categories by virtue of their natural
histories (see "The Non-Hodgkin's Lymphoma Pathologic
Classification Project," Cancer 49(1982):2112-2135). The low-grade
lymphomas are indolent, with a median survival of 5 to 10 years
(Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475).
Although chemotherapy can induce remissions in the majority of
indolent lymphomas, cures are rare and most patients eventually
relapse, requiring further therapy. The intermediate- and
high-grade lymphomas are more aggressive tumors, but they have a
greater chance for cure with chemotherapy. However, a significant
proportion of these patients will relapse and require further
treatment.
[0143] A non-limiting list of the B-cell NHL includes Burkitt's
lymphoma (e.g., Endemic Burkitt's Lymphoma and Sporadic Burkitt's
Lymphoma), Cutaneous B-Cell Lymphoma, Cutaneous Marginal Zone
Lymphoma (MZL), Diffuse Large Cell Lymphoma (DLBCL), Diffuse Mixed
Small and Large Cell Lymphoma, Diffuse Small Cleaved Cell, Diffuse
Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell
lymphoma, follicular lymphoma, Follicular Small Cleaved Cell (Grade
1), Follicular Mixed Small Cleaved and Large Cell (Grade 2),
Follicular Large Cell (Grade 3), Intravascular Large B-Cell
Lymphoma, Intravascular Lymphomatosis, Large Cell Immunoblastic
Lymphoma, Large Cell Lymphoma (LCL), Lymphoblastic Lymphoma, MALT
Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic large cell
lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma,
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma
(SLL), extranodal marginal zone B-cell lymphoma-mucosa-associated
lymphoid tissue (MALT) lymphoma, Mediastinal Large B-Cell Lymphoma,
nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell
lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmocytic
lymphoma, hairy cell leukemia, Waldenstrom's Macroglobulinemia, and
primary central nervous system (CNS) lymphoma. Additional
non-Hodgkin's lymphomas are contemplated within the scope of the
present invention and apparent to those of ordinary skill in the
art.
[0144] DLBCL
[0145] Disclosed herein, in certain embodiments, is a method for
treating a DLCBL in an individual in need thereof, comprising:
administering to the individual a composition or tablet formulation
described herein comprising an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory DLCBL in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising a therapeutically-effective
amount of Compound 1.
[0146] As used herein, the term "Diffuse large B-cell lymphoma
(DLBCL)" refers to a neoplasm of the germinal center B lymphocytes
with a diffuse growth pattern and a high-intermediate proliferation
index. DLBCLs represent approximately 30% of all lymphomas and may
present with several morphological variants including the
centroblastic, immunoblastic, T-cell/histiocyte rich, anaplastic
and plasmoblastic subtypes. Genetic tests have shown that there are
different subtypes of DLBCL. These subtypes seem to have different
outlooks (prognoses) and responses to treatment. DLBCL can affect
any age group but occurs mostly in older people (the average age is
mid-60s).
[0147] Disclosed herein, in certain embodiments, is a method for
treating diffuse large B-cell lymphoma, activated B cell-like
subtype (ABC-DLBCL), in an individual in need thereof, comprising:
administering to the individual an irreversible Btk inhibitor in an
amount from 300 mg/day up to, and including, 1000 mg/day. The ABC
subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to
arise from post germinal center B cells that are arrested during
plasmatic differentiation. The ABC subtype of DLBCL (ABC-DLBCL)
accounts for approximately 30% total DLBCL diagnoses. It is
considered the least curable of the DLBCL molecular subtypes and,
as such, patients diagnosed with the ABC-DLBCL typically display
significantly reduced survival rates compared with individuals with
other types of DLCBL. ABC-DLBCL is most commonly associated with
chromosomal translocations deregulating the germinal center master
regulator BCL6 and with mutations inactivating the PRDM1 gene,
which encodes a transcriptional repressor required for plasma cell
differentiation.
[0148] A particularly relevant signaling pathway in the
pathogenesis of ABC-DLBCL is the one mediated by the nuclear factor
(NF)-.kappa.B transcription complex. The NF-.kappa.B family
comprises 5 members (p50, p52, p65, c-rel and RelB) that form homo-
and heterodimers and function as transcriptional factors to mediate
a variety of proliferation, apoptosis, inflammatory and immune
responses and are critical for normal B-cell development and
survival. NF-.kappa.B is widely used by eukaryotic cells as a
regulator of genes that control cell proliferation and cell
survival. As such, many different types of human tumors have
misregulated NF-.kappa.B: that is, NF-.kappa.B is constitutively
active. Active NF-.kappa.B turns on the expression of genes that
keep the cell proliferating and protect the cell from conditions
that would otherwise cause it to die via apoptosis.
[0149] The dependence of ABC DLBCLs on NF-kB depends on a signaling
pathway upstream of IkB kinase comprised of CARD11, BCL10 and MALT1
(the CBM complex). Interference with the CBM pathway extinguishes
NF-kB signaling in ABC DLBCL cells and induces apoptosis. The
molecular basis for constitutive activity of the NF-kB pathway is a
subject of current investigation but some somatic alterations to
the genome of ABC DLBCLs clearly invoke this pathway. For example,
somatic mutations of the coiled-coil domain of CARD11 in DLBCL
render this signaling scaffold protein able to spontaneously
nucleate protein-protein interaction with MALT1 and BCL10, causing
IKK activity and NF-kB activation. Constitutive activity of the B
cell receptor signaling pathway has been implicated in the
activation of NF-kB in ABC DLBCLs with wild type CARD11, and this
is associated with mutations within the cytoplasmic tails of the B
cell receptor subunits CD79A and CD79B. Oncogenic activating
mutations in the signaling adapter MYD88 activate NF-kB and
synergize with B cell receptor signaling in sustaining the survival
of ABC DLBCL cells. In addition, inactivating mutations in a
negative regulator of the NF-kB pathway, A20, occur almost
exclusively in ABC DLBCL.
[0150] Indeed, genetic alterations affecting multiple components of
the NF-.kappa.B signaling pathway have been recently identified in
more than 50% of ABC-DLBCL patients, where these lesions promote
constitutive NF-.kappa.B activation, thereby contributing to
lymphoma growth. These include mutations of CARD11 (.about.10% of
the cases), a lymphocyte-specific cytoplasmic scaffolding protein
that--together with MALT1 and BCL10--forms the BCR signalosome,
which relays signals from antigen receptors to the downstream
mediators of NF-.kappa.B activation. An even larger fraction of
cases (.about.30%) carry biallelic genetic lesions inactivating the
negative NF-.kappa.B regulator A20. Further, high levels of
expression of NF-.kappa.B target genes have been observed in
ABC-DLBCL tumor samples. See, e.g., U. Klein et al., (2008), Nature
Reviews Immunology 8:22-23; R. E. Davis et al., (2001), Journal of
Experimental Medicine 194:1861-1874; G. Lentz et al., (2008),
Science 319:1676-1679; M. Compagno et al., (2009), Nature
459:712-721; and L. Srinivasan et al., (2009), Cell
139:573-586).
[0151] DLBCL cells of the ABC subtype, such as OCI-Ly10, have
chronic active BCR signaling and are very sensitive to the Btk
inhibitor described herein. The irreversible Btk inhibitor
described herein potently and irreversibly inhibits the growth of
OCI-Ly10 (EC.sub.50 continuous exposure=10 nM, EC.sub.50 1 hour
pulse=50 nM). In addition, induction of apoptosis, as shown by
capsase activation, Annexin-V flow cytometry and increase in sub-GO
fraction is observed in OCILy10. Both sensitive and resistant cells
express Btk at similar levels, and the active site of Btk is fully
occupied by the inhibitor in both as shown using a fluorescently
labeled affinity probe. OCI-Ly10 cells are shown to have
chronically active BCR signaling to NF-kB which is dose dependently
inhibited by the Btk inhibitors described herein. The activity of
Btk inhibitors in the cell lines studied herein are also
characterized by comparing signal transduction profiles (Btk,
PLC.gamma., ERK, NF-kB, AKT), cytokine secretion profiles and mRNA
expression profiles, both with and without BCR stimulation, and
observed significant differences in these profiles that lead to
clinical biomarkers that identify the most sensitive patient
populations to Btk inhibitor treatment. See U.S. Pat. No. 7,711,492
and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the
contents of which are incorporated by reference in their
entirety.
[0152] Follicular Lymphoma
[0153] Disclosed herein, in certain embodiments, is a method for
treating a follicular lymphoma in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising an amount of Compound 1.
Further disclosed herein, in certain embodiments, is a method for
treating relapsed or refractory follicular lymphoma in an
individual in need thereof, comprising: administering to the
individual a composition or tablet formulation described herein
comprising a therapeutically-effective amount of Compound 1.
[0154] As used herein, the term "follicular lymphoma" refers to any
of several types of non-Hodgkin's lymphoma in which the
lymphomatous cells are clustered into nodules or follicles. The
term follicular is used because the cells tend to grow in a
circular, or nodular, pattern in lymph nodes. The average age for
people with this lymphoma is about 60.
[0155] CLL/SLL
[0156] Disclosed herein, in certain embodiments, is a method for
treating a CLL or SLL in an individual in need thereof, comprising:
administering to the individual a composition or tablet formulation
described herein comprising an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory CLL or SLL in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising a therapeutically-effective
amount of Compound 1.
[0157] Chronic lymphocytic leukemia and small lymphocytic lymphoma
(CLL/SLL) are commonly thought as the same disease with slightly
different manifestations. Where the cancerous cells gather
determines whether it is called CLL or SLL. When the cancer cells
are primarily found in the lymph nodes, lima bean shaped structures
of the lymphatic system (a system primarily of tiny vessels found
in the body), it is called SLL. SLL accounts for about 5% to 10% of
all lymphomas. When most of the cancer cells are in the bloodstream
and the bone marrow, it is called CLL.
[0158] Both CLL and SLL are slow-growing diseases, although CLL,
which is much more common, tends to grow slower. CLL and SLL are
treated the same way. They are usually not considered curable with
standard treatments, but depending on the stage and growth rate of
the disease, most patients live longer than 10 years. Occasionally
over time, these slow-growing lymphomas may transform into a more
aggressive type of lymphoma.
[0159] Chronic lymphoid leukemia (CLL) is the most common type of
leukemia. It is estimated that 100,760 people in the United States
are living with or are in remission from CLL. Most (>75%) people
newly diagnosed with CLL are over the age of 50. Currently CLL
treatment focuses on controlling the disease and its symptoms
rather than on an outright cure. CLL is treated by chemotherapy,
radiation therapy, biological therapy, or bone marrow
transplantation. Symptoms are sometimes treated surgically
(splenectomy removal of enlarged spleen) or by radiation therapy
("de-bulking" swollen lymph nodes). Though CLL progresses slowly in
most cases, it is considered generally incurable. Certain CLLs are
classified as high-risk. As used herein, "high risk CLL" means CLL
characterized by at least one of the following 1) 17p13-; 2)
11q22-; 3) unmutated IgVH together with ZAP-70+ and/or CD38+; or 4)
trisomy 12.
[0160] CLL treatment is typically administered when the patient's
clinical symptoms or blood counts indicate that the disease has
progressed to a point where it may affect the patient's quality of
life.
[0161] Small lymphocytic leukemia (SLL) is very similar to CLL
described supra, and is also a cancer of B-cells. In SLL the
abnormal lymphocytes mainly affect the lymph nodes. However, in CLL
the abnormal cells mainly affect the blood and the bone marrow. The
spleen may be affected in both conditions. SLL accounts for about 1
in 25 of all cases of non-Hodgkin lymphoma. It can occur at any
time from young adulthood to old age, but is rare under the age of
50. SLL is considered an indolent lymphoma. This means that the
disease progresses very slowly, and patients tend to live many
years after diagnosis. However, most patients are diagnosed with
advanced disease, and although SLL responds well to a variety of
chemotherapy drugs, it is generally considered to be incurable.
Although some cancers tend to occur more often in one gender or the
other, cases and deaths due to SLL are evenly split between men and
women. The average age at the time of diagnosis is 60 years.
[0162] Although SLL is indolent, it is persistently progressive.
The usual pattern of this disease is one of high response rates to
radiation therapy and/or chemotherapy, with a period of disease
remission. This is followed months or years later by an inevitable
relapse. Re-treatment leads to a response again, but again the
disease will relapse. This means that although the short-term
prognosis of SLL is quite good, over time, many patients develop
fatal complications of recurrent disease. Considering the age of
the individuals typically diagnosed with CLL and SLL, there is a
need in the art for a simple and effective treatment of the disease
with minimum side-effects that do not impede on the patient's
quality of life. The instant invention fulfills this long standing
need in the art.
[0163] Mantle Cell Lymphoma
[0164] Disclosed herein, in certain embodiments, is a method for
treating a Mantle cell lymphoma in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising an amount of Compound 1.
Further disclosed herein, in certain embodiments, is a method for
treating relapsed or refractory Mantle cell lymphoma in an
individual in need thereof, comprising: administering to the
individual a composition or tablet formulation described herein
comprising a therapeutically-effective amount of Compound 1.
[0165] As used herein, the term, "Mantle cell lymphoma" refers to a
subtype of B-cell lymphoma, due to CD5 positive antigen-naive
pregerminal center B-cell within the mantle zone that surrounds
normal germinal center follicles. MCL cells generally over-express
cyclin D1 due to a t(11:14) chromosomal translocation in the DNA.
More specifically, the translocation is at t(11;14)(q13;q32). Only
about 5% of lymphomas are of this type. The cells are small to
medium in size. Men are affected most often. The average age of
patients is in the early 60s. The lymphoma is usually widespread
when it is diagnosed, involving lymph nodes, bone marrow, and, very
often, the spleen. Mantle cell lymphoma is not a very fast growing
lymphoma, but is difficult to treat.
[0166] Marginal Zone B-Cell Lymphoma
[0167] Disclosed herein, in certain embodiments, is a method for
treating a marginal zone B-cell lymphoma in an individual in need
thereof, comprising: administering to the individual a composition
or tablet formulation described herein comprising an amount of
Compound 1. Further disclosed herein, in certain embodiments, is a
method for treating relapsed or refractory marginal zone B-cell
lymphoma in an individual in need thereof, comprising:
administering to the individual a composition or tablet formulation
described herein comprising a therapeutically-effective amount of
Compound 1.
[0168] As used herein, the term "marginal zone B-cell lymphoma"
refers to a group of related B-cell neoplasms that involve the
lymphoid tissues in the marginal zone, the patchy area outside the
follicular mantle zone. Marginal zone lymphomas account for about
5% to 10% of lymphomas. The cells in these lymphomas look small
under the microscope. There are 3 main types of marginal zone
lymphomas including extranodal marginal zone B-cell lymphomas,
nodal marginal zone B-cell lymphoma, and splenic marginal zone
lymphoma.
[0169] MALT
[0170] Disclosed herein, in certain embodiments, is a method for
treating a MALT in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory MALT in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising a therapeutically-effective
amount of Compound 1.
[0171] The term "mucosa-associated lymphoid tissue (MALT)
lymphoma", as used herein, refers to extranodal manifestations of
marginal-zone lymphomas. Most MALT lymphoma are a low grade,
although a minority either manifest initially as intermediate-grade
non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most
of the MALT lymphoma occur in the stomach, and roughly 70% of
gastric MALT lymphoma are associated with Helicobacter pylori
infection. Several cytogenetic abnormalities have been identified,
the most common being trisomy 3 or t(11;18). Many of these other
MALT lymphoma have also been linked to infections with bacteria or
viruses. The average age of patients with MALT lymphoma is about
60.
[0172] Nodal Marginal Zone B-Cell Lymphoma
[0173] Disclosed herein, in certain embodiments, is a method for
treating a nodal marginal zone B-cell lymphoma in an individual in
need thereof, comprising: administering to the individual a
composition or tablet formulation described herein comprising an
amount of Compound 1. Further disclosed herein, in certain
embodiments, is a method for treating relapsed or refractory nodal
marginal zone B-cell lymphoma in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising a therapeutically-effective
amount of Compound 1.
[0174] The term "nodal marginal zone B-cell lymphoma" refers to an
indolent B-cell lymphoma that is found mostly in the lymph nodes.
The disease is rare and only accounts for 1% of all Non-Hodgkin's
Lymphomas (NHL). It is most commonly diagnosed in older patients,
with women more susceptible than men. The disease is classified as
a marginal zone lymphoma because the mutation occurs in the
marginal zone of the B-cells. Due to its confinement in the lymph
nodes, this disease is also classified as nodal.
[0175] Splenic Marginal Zone B-Cell Lymphoma
[0176] Disclosed herein, in certain embodiments, is a method for
treating a splenic marginal zone B-cell lymphoma in an individual
in need thereof, comprising: administering to the individual a
composition or tablet formulation described herein comprising an
amount of Compound 1. Further disclosed herein, in certain
embodiments, is a method for treating relapsed or refractory
splenic marginal zone B-cell lymphoma in an individual in need
thereof, comprising: administering to the individual a composition
or tablet formulation described herein comprising a
therapeutically-effective amount of Compound 1.
[0177] The term "splenic marginal zone B-cell lymphoma" refers to
specific low-grade small B-cell lymphoma that is incorporated in
the World Health Organization classification. Characteristic
features are splenomegaly, moderate lymphocytosis with villous
morphology, intrasinusoidal pattern of involvement of various
organs, especially bone marrow, and relative indolent course. Tumor
progression with increase of blastic forms and aggressive behavior
are observed in a minority of patients. Molecular and cytogenetic
studies have shown heterogeneous results probably because of the
lack of standardized diagnostic criteria.
[0178] Burkitt Lymphoma
[0179] Disclosed herein, in certain embodiments, is a method for
treating a Burkitt lymphoma in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising an amount of Compound 1.
Further disclosed herein, in certain embodiments, is a method for
treating relapsed or refractory Burkitt lymphoma in an individual
in need thereof, comprising: administering to the individual a
composition or tablet formulation described herein comprising a
therapeutically-effective amount of Compound 1.
[0180] The term "Burkitt lymphoma" refers to a type of Non-Hodgkin
Lymphoma (NHL) that commonly affects children. It is a highly
aggressive type of B-cell lymphoma that often starts and involves
body parts other than lymph nodes. In spite of its fast-growing
nature, Burkitt's lymphoma is often curable with modern intensive
therapies. There are two broad types of Burkitt's lymphoma--the
sporadic and the endemic varieties:
[0181] Endemic Burkitt's lymphoma: The disease involves children
much more than adults, and is related to Epstein Barr Virus (EBV)
infection in 95% cases. It occurs primarily is equatorial Africa,
where about half of all childhood cancers are Burkitt's lymphoma.
It characteristically has a high chance of involving the jawbone, a
rather distinctive feature that is rare in sporadic Burkitt's. It
also commonly involves the abdomen.
[0182] Sporadic Burkitt's lymphoma: The type of Burkitt's lymphoma
that affects the rest of the world, including Europe and the
Americas is the sporadic type. Here too, it's mainly a disease in
children. The link between Epstein Barr Virus (EBV) is not as
strong as with the endemic variety, though direct evidence of EBV
infection is present in one out of five patients. More than the
involvement of lymph nodes, it is the abdomen that is notably
affected in more than 90% of the children. Bone marrow involvement
is more common than in the sporadic variety.
[0183] Waldenstrom Macroglobulinemia
[0184] Disclosed herein, in certain embodiments, is a method for
treating a Waldenstrom macroglobulinemia in an individual in need
thereof, comprising: administering to the individual a composition
or tablet formulation described herein comprising an amount of
Compound 1. Further disclosed herein, in certain embodiments, is a
method for treating relapsed or refractory Waldenstrom
macroglobulinemia in an individual in need thereof, comprising:
administering to the individual a composition or tablet formulation
described herein comprising a therapeutically-effective amount of
Compound 1.
[0185] The term "Waldenstrom macroglobulinemia", also known as
lymphoplasmacytic lymphoma, is cancer involving a subtype of white
blood cells called lymphocytes. It is characterized by an
uncontrolled clonal proliferation of terminally differentiated B
lymphocytes. It is also characterized by the lymphoma cells making
an antibody called immunoglobulin M (IgM). The IgM antibodies
circulate in the blood in large amounts, and cause the liquid part
of the blood to thicken, like syrup. This can lead to decreased
blood flow to many organs, which can cause problems with vision
(because of poor circulation in blood vessels in the back of the
eyes) and neurological problems (such as headache, dizziness, and
confusion) caused by poor blood flow within the brain. Other
symptoms can include feeling tired and weak, and a tendency to
bleed easily. The underlying etiology is not fully understood but a
number of risk factors have been identified, including the locus
6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of
developing WM in people with a personal history of autoimmune
diseases with autoantibodies and particularly elevated risks
associated with hepatitis, human immunodeficiency virus, and
rickettsiosis.
[0186] Multiple Myeloma
[0187] Disclosed herein, in certain embodiments, is a method for
treating a myeloma in an individual in need thereof, comprising:
administering to the individual a composition or tablet formulation
described herein comprising an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory myeloma in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising a therapeutically-effective
amount of Compound 1.
[0188] Multiple myeloma, also known as MM, myeloma, plasma cell
myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of
the white blood cells known as plasma cells. A type of B cell,
plasma cells are a crucial part of the immune system responsible
for the production of antibodies in humans and other vertebrates.
They are produced in the bone marrow and are transported through
the lymphatic system.
[0189] Leukemia
[0190] Disclosed herein, in certain embodiments, is a method for
treating a leukemia in an individual in need thereof, comprising:
administering to the individual a composition or tablet formulation
described herein comprising an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory leukemia in an individual in need thereof,
comprising: administering to the individual a composition or tablet
formulation described herein comprising a therapeutically-effective
amount of Compound 1.
[0191] Leukemia is a cancer of the blood or bone marrow
characterized by an abnormal increase of blood cells, usually
leukocytes (white blood cells). Leukemia is a broad term covering a
spectrum of diseases. The first division is between its acute and
chronic forms: (i) acute leukemia is characterized by the rapid
increase of immature blood cells. This crowding makes the bone
marrow unable to produce healthy blood cells. Immediate treatment
is required in acute leukemia due to the rapid progression and
accumulation of the malignant cells, which then spill over into the
bloodstream and spread to other organs of the body. Acute forms of
leukemia are the most common forms of leukemia in children; (ii)
chronic leukemia is distinguished by the excessive build up of
relatively mature, but still abnormal, white blood cells. Typically
taking months or years to progress, the cells are produced at a
much higher rate than normal cells, resulting in many abnormal
white blood cells in the blood. Chronic leukemia mostly occurs in
older people, but can theoretically occur in any age group.
Additionally, the diseases are subdivided according to which kind
of blood cell is affected. This split divides leukemias into
lymphoblastic or lymphocytic leukemias and myeloid or myelogenous
leukemias: (i) lymphoblastic or lymphocytic leukemias, the
cancerous change takes place in a type of marrow cell that normally
goes on to form lymphocytes, which are infection-fighting immune
system cells; (ii) myeloid or myelogenous leukemias, the cancerous
change takes place in a type of marrow cell that normally goes on
to form red blood cells, some other types of white cells, and
platelets.
[0192] Within these main categories, there are several
subcategories including, but not limited to, Acute lymphoblastic
leukemia (ALL), precursor B-cell acute lymphoblastic leukemia
(precursor B-ALL; also called precursor B-lymphoblastic leukemia),
Acute myelogenous leukemia (AML), Chronic myelogenous leukemia
(CML), and Hairy cell leukemia (HCL). Accordingly, disclosed
herein, in certain embodiments, is a method for treating Acute
lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic
leukemia (precursor B-ALL; also called precursor B-lymphoblastic
leukemia), Acute myelogenous leukemia (AML), Chronic myelogenous
leukemia (CML), or Hairy cell leukemia (HCL) in an individual in
need thereof, comprising: administering to the individual an amount
of Compound 1. In some embodiments, the leukemia is a relapsed or
refractory leukemia. In some embodiments, the leukemia is a
relapsed or refractory Acute lymphoblastic leukemia (ALL), relapsed
or refractory precursor B-cell acute lymphoblastic leukemia
(precursor B-ALL; also called precursor B-lymphoblastic leukemia),
relapsed or refractory Acute myelogenous leukemia (AML), relapsed
or refractory Chronic myelogenous leukemia (CML), or relapsed or
refractory Hairy cell leukemia (HCL).
[0193] Symptoms, diagnostic tests, and prognostic tests for each of
the above-mentioned conditions are known. See, e.g., Harrison's
Principles of Internal Medicine.COPYRGT.," 16th ed., 2004, The
McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24),
and the "Revised European American Lymphoma" (REAL) classification
system (see, e.g., the website maintained by the National Cancer
Institute).
[0194] A number of animal models of are useful for establishing a
range of therapeutically effective doses of irreversible Btk
inhibitor compounds, such as Compound 1, for treating any of the
foregoing diseases.
[0195] The therapeutic efficacy of Compound 1 for any one of the
foregoing diseases can be optimized during a course of treatment.
For example, a subject being treated can undergo a diagnostic
evaluation to correlate the relief of disease symptoms or
pathologies to inhibition of in vivo Btk activity achieved by
administering a given dose of Compound 1. Cellular assays known in
the art can be used to determine in vivo activity of Btk in the
presence or absence of an irreversible Btk inhibitor. For example,
since activated Btk is phosphorylated at tyrosine 223 (Y223) and
tyrosine 551 (Y551), phospho-specific immunocytochemical staining
of P-Y223 or P-Y551-positive cells can be used to detect or
quantify activation of Btk in a population of cells (e.g., by FACS
analysis of stained vs unstained cells). See, e.g., Nisitani et al.
(1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount
of the Btk inhibitor compound that is administered to a subject can
be increased or decreased as needed so as to maintain a level of
Btk inhibition optimal for treating the subject's disease
state.
[0196] Compound 1 can irreversibly inhibit Btk and may be used to
treat mammals suffering from Bruton's tyrosine kinase-dependent or
Bruton's tyrosine kinase mediated conditions or diseases,
including, but not limited to, cancer, autoimmune and other
inflammatory diseases. Compound 1 has shown efficacy is a wide
variety of diseases and conditions that are described herein.
[0197] In some embodiments, Compound 1 is used for the manufacture
of a medicament for treating any of the foregoing conditions (e.g.,
autoimmune diseases, inflammatory diseases, allergy disorders,
B-cell proliferative disorders, or thromboembolic disorders).
Compound 1, and Pharmaceutically Acceptable Salts Thereof
[0198] The Btk inhibitor compound described herein (i.e. Compound
1) is selective for Btk and kinases having a cysteine residue in an
amino acid sequence position of the tyrosine kinase that is
homologous to the amino acid sequence position of cysteine 481 in
Btk. The Btk inhibitor compound can form a covalent bond with Cys
481 of Btk (e.g., via a Michael reaction).
[0199] "Compound 1" or
"1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)p-
iperidin-1-yl)prop-2-en-1-one" or
"1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-
piperidin-1-yl}prop-2-en-1-one" or "2-Propen-1-one,
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]--
1-piperidinyl-" or ibrutinib or any other suitable name refers to
the compound with the following structure:
##STR00003##
[0200] A wide variety of pharmaceutically acceptable salts is
formed from Compound 1 and includes: [0201] acid addition salts
formed by reacting Compound 1 with an organic acid, which includes
aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic
acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, amino acids, etc. and
include, for example, acetic acid, trifluoroacetic acid, propionic
acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,
malonic acid, succinic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,
and the like; [0202] acid addition salts formed by reacting
Compound 1 with an inorganic acid, which includes hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric
acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the
like.
[0203] The term "pharmaceutically acceptable salts" in reference to
Compound 1 refers to a salt of Compound 1, which does not cause
significant irritation to a mammal to which it is administered and
does not substantially abrogate the biological activity and
properties of the compound.
[0204] It should be understood that a reference to a
pharmaceutically acceptable salt includes the solvent addition
forms (solvates). Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and are formed during the
process of product formation or isolation with pharmaceutically
acceptable solvents such as water, ethanol, methanol, methyl
tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate,
isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone
(MIBK), methyl ethyl ketone (MEK), acetone, nitromethane,
tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes,
toluene, anisole, acetonitrile, and the like. In one aspect,
solvates are formed using, but not limited to, Class 3 solvent(s).
Categories of solvents are defined in, for example, the
International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH),
"Impurities: Guidelines for Residual Solvents, Q3C(R3), (November
2005). Hydrates are formed when the solvent is water, or
alcoholates are formed when the solvent is alcohol. In some
embodiments, solvates of Compound 1, or pharmaceutically acceptable
salts thereof, are conveniently prepared or formed during the
processes described herein. In some embodiments, solvates of
Compound 1 are anhydrous. In some embodiments, Compound 1, or
pharmaceutically acceptable salts thereof, exist in unsolvated
form. In some embodiments, Compound 1, or pharmaceutically
acceptable salts thereof, exist in unsolvated form and are
anhydrous.
[0205] In yet other embodiments, Compound 1, or a pharmaceutically
acceptable salt thereof, is prepared in various forms, including
but not limited to, amorphous phase, crystalline forms, milled
forms and nano-particulate forms. In some embodiments, Compound 1,
or a pharmaceutically acceptable salt thereof, is amorphous. In
some embodiments, Compound 1, or a pharmaceutically acceptable salt
thereof, is amorphous and anhydrous. In some embodiments, Compound
1, or a pharmaceutically acceptable salt thereof, is crystalline.
In some embodiments, Compound 1, or a pharmaceutically acceptable
salt thereof, is crystalline and anhydrous.
[0206] In some embodiments, Compound 1 is prepared as outlined in
U.S. Pat. No. 7,514,444.
Certain Terminology
[0207] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs. It
is to be understood that the foregoing general description and the
following detailed description are exemplary and explanatory only
and are not restrictive of any subject matter claimed. In this
application, the use of the singular includes the plural unless
specifically stated otherwise. It must be noted that, as used in
the specification and the appended claims, the singular forms "a,"
"an" and "the" include plural referents unless the context clearly
dictates otherwise. In this application, the use of "or" means
"and/or" unless stated otherwise. Furthermore, use of the term
"including" as well as other forms, such as "include", "includes,"
and "included," is not limiting.
[0208] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, but not limited to, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
[0209] The term "about" when used before a numerical value
indicates that the value may vary within a reasonable range, such
as within .+-.10%, .+-.5% or .+-.1% of the stated value.
[0210] As used herein, the term "comprising" or its grammatic
variants is intended to mean that the compositions and methods,
etc., include the recited elements, but do not exclude others.
"Consisting essentially of" or its grammatic variants when used to
define compositions and methods, shall mean excluding other
elements of any essential significance to the combination for the
intended use, but not excluding elements that do not materially
affect the characteristic(s) of the compositions or methods.
"Consisting of" or its grammatic variants shall mean excluding
elements not specifically recited. Embodiments defined by each of
these transition terms are within the scope of this invention. For
example, when a formulation is described as comprising ingredients
A, B and C, a formulation consisting essentially of A, B and C, and
a formulation consisting of A, B and C are independently within the
scope of this invention.
[0211] The term "acceptable" or "pharmaceutically acceptable", with
respect to a formulation, composition or ingredient, as used
herein, means having no persistent detrimental effect on the
general health of the subject being treated or does not abrogate
the biological activity or properties of the compound, and is
relatively nontoxic.
[0212] As used herein, the term "agonist" refers to a compound, the
presence of which results in a biological activity of a protein
that is the same as the biological activity resulting from the
presence of a naturally occurring ligand for the protein, such as,
for example, Btk.
[0213] As used herein, the term "partial agonist" refers to a
compound the presence of which results in a biological activity of
a protein that is of the same type as that resulting from the
presence of a naturally occurring ligand for the protein, but of a
lower magnitude.
[0214] As used herein, the term "antagonist" refers to a compound,
the presence of which results in a decrease in the magnitude of a
biological activity of a protein. In certain embodiments, the
presence of an antagonist results in complete inhibition of a
biological activity of a protein, such as, for example, Btk. In
certain embodiments, an antagonist is an inhibitor.
[0215] As used herein, "amelioration" of the symptoms of a
particular disease, disorder or condition by administration of a
particular compound or pharmaceutical composition refers to any
lessening of severity, delay in onset, slowing of progression, or
shortening of duration, whether permanent or temporary, lasting or
transient that can be attributed to or associated with
administration of the compound or composition.
[0216] "Bioavailability" refers to the percentage of Compound 1
dosed that is delivered into the general circulation of the animal
or human being studied. The total exposure (AUC.sub.(0-.infin.)) of
a drug when administered intravenously is usually defined as 100%
bioavailable (F %). "Oral bioavailability" refers to the extent to
which Compound 1 is absorbed into the general circulation when the
pharmaceutical composition is taken orally as compared to
intravenous injection.
[0217] "Blood plasma concentration" refers to the concentration of
Compound 1 in the plasma component of blood of a subject. It is
understood that the plasma concentration of Compound 1 may vary
significantly between subjects, due to variability with respect to
metabolism and/or possible interactions with other therapeutic
agents. In accordance with one embodiment disclosed herein, the
blood plasma concentration of Compound 1 may vary from subject to
subject. Likewise, values such as maximum plasma concentration
(C.sub.max) or time to reach maximum plasma concentration
(T.sub.max), or total area under the plasma concentration time
curve (AUC.sub.(0-.apprxeq.)) may vary from subject to subject. Due
to this variability, the amount necessary to constitute "a
therapeutically effective amount" of Compound 1 may vary from
subject to subject.
[0218] The term "Bruton's tyrosine kinase," as used herein, refers
to Bruton's tyrosine kinase from Homo sapiens, as disclosed in,
e.g., U.S. Pat. No. 6,326,469 (GenBank Accession No.
NP_000052).
[0219] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different time.
In some embodiments, the term "co-administration" or the like, is
meant to encompass the administration of the selected therapeutic
agents in the same cycle(s). In these embodiments, the selected
therapeutic agents may be administered on the same or different
days of the cycle(s).
[0220] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result can be reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
including a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms without undue
adverse side effects. An appropriate "effective amount" in any
individual case may be determined using techniques, such as a dose
escalation study. The term "therapeutically effective amount"
includes, for example, a prophylactically effective amount. An
"effective amount" of a compound disclosed herein is an amount
effective to achieve a desired pharmacologic effect or therapeutic
improvement without undue adverse side effects. It is understood
that "an effect amount" or "a therapeutically effective amount" can
vary from subject to subject, due to variation in metabolism of
Compound 1, age, weight, general condition of the subject, the
condition being treated, the severity of the condition being
treated, and the judgment of the prescribing physician. By way of
example only, therapeutically effective amounts may be determined
by routine experimentation, including but not limited to a dose
escalation clinical trial.
[0221] The terms "enhance" or "enhancing" means to increase or
prolong either in potency or duration a desired effect. By way of
example, "enhancing" the effect of therapeutic agents refers to the
ability to increase or prolong, either in potency or duration, the
effect of therapeutic agents on during treatment of a disease,
disorder or condition. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of a
therapeutic agent in the treatment of a disease, disorder or
condition. When used in a patient, amounts effective for this use
will depend on the severity and course of the disease, disorder or
condition, previous therapy, the patient's health status and
response to the drugs, and the judgment of the treating
physician.
[0222] The terms "inhibits", "inhibiting", or "inhibitor" of a
kinase, as used herein, refer to inhibition of enzymatic
phosphotransferase activity.
[0223] The term "irreversible inhibitor," as used herein, refers to
a compound that, upon contact with a target protein (e.g., a
kinase) causes the formation of a new covalent bond with or within
the protein, whereby one or more of the target protein's biological
activities (e.g., phosphotransferase activity) is diminished or
abolished notwithstanding the subsequent presence or absence of the
irreversible inhibitor.
[0224] The term "irreversible Btk inhibitor," as used herein,
refers to an inhibitor of Btk that can form a covalent bond with an
amino acid residue of Btk. In one embodiment, the irreversible
inhibitor of Btk can form a covalent bond with a Cys residue of
Btk; in particular embodiments, the irreversible inhibitor can form
a covalent bond with a Cys 481 residue (or a homolog thereof) of
Btk or a cysteine residue in the homologous corresponding position
of another tyrosine kinase.
[0225] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0226] As used herein, the term "modulator" refers to a compound
that alters an activity of a molecule. For example, a modulator can
cause an increase or decrease in the magnitude of a certain
activity of a molecule compared to the magnitude of the activity in
the absence of the modulator. In certain embodiments, a modulator
is an inhibitor, which decreases the magnitude of one or more
activities of a molecule. In certain embodiments, an inhibitor
completely prevents one or more activities of a molecule. In
certain embodiments, a modulator is an activator, which increases
the magnitude of at least one activity of a molecule. In certain
embodiments the presence of a modulator results in an activity that
does not occur in the absence of the modulator.
[0227] The term "prophylactically effective amount," as used
herein, refers that amount of a composition applied to a patient
which will relieve to some extent one or more of the symptoms of a
disease, condition or disorder being treated. In such prophylactic
applications, such amounts may depend on the patient's state of
health, weight, and the like. It is considered well within the
skill of the art for one to determine such prophylactically
effective amounts by routine experimentation, including, but not
limited to, a dose escalation clinical trial.
[0228] The term "individual," "subject" or "patient" as used
herein, refers to an animal which is the object of treatment,
observation or experiment. By way of example only, a subject may
be, but is not limited to, a mammal including, but not limited to,
a human.
[0229] The term "wet granulation" as used herein, refers to the
formation of granules using a granulation liquid (water, organic
solvent, or a solution).
[0230] The term "dry granulation" as used herein, refers to the
formation of granules without using a granulation liquid (water,
organic solvent, or a solution).
[0231] The term "high-load solid tablet formulation" as used
herein, refers to a solid tablet formulation comprising at least
50% w/w of ibrutinib per tablet.
[0232] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, such as inhibition of Btk,
in an assay that measures such response.
[0233] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
[0234] Pharmaceutical Compositions/Formulations
[0235] A pharmaceutical composition or pharmaceutical formulation,
as used herein, refers to a mixture of Compound 1 with other
chemical components, such as carriers, stabilizers, diluents,
dispersing agents, suspending agents, thickening agents, and/or
excipients. The pharmaceutical composition facilitates
administration of the compound to a mammal. The compounds can be
used singly or in combination with one or more therapeutic agents
as components of mixtures.
[0236] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. Compound 1 and
a co-agent, are both administered to a patient simultaneously in
the form of a single entity or dosage. The term "non-fixed
combination" means that the active ingredients, e.g. Compound 1 and
a co-agent, are administered to a patient as separate entities
either simultaneously, concurrently or sequentially with no
specific intervening time limits, wherein such administration
provides effective levels of the two compounds in the body of the
patient. The latter also applies to cocktail therapy, e.g. the
administration of three or more active ingredients.
[0237] In some embodiments, crystalline Compound 1 is incorporated
into pharmaceutical compositions to provide solid oral dosage
forms, such as powders, immediate release formulations, controlled
release formulations, fast melt formulations, tablets, capsules,
pills, delayed release formulations, extended release formulations,
pulsatile release formulations, multiparticulate formulations, and
mixed immediate and controlled release formulations.
[0238] Ibrutinib is currently used in the clinic at a unit dose of
420 mg or 560 mg which is administered orally in three or four
capsules comprising 140 mg ibrutinib per capsule. High load tablet
formulations would allow administration of one tablet per dose.
However, high load tablet formulations that meet pharmaceutically
acceptable properties, such as, suitable compressibility,
compactability, granulate flowability, granulate density, integrity
during manufacture, shipping and storage, proper hardness,
stability, swallowbility and disintegration properties when
administered, are considerately more difficult to prepare than
capsule formations due to the limited amount of excipients that can
be used to adjust the tablet properties. Further, tablet
formulations tend to have lower C.sub.max as compared with the
capsule formulations due to the process of its disintegration and
absorption after administration, especially for ibrutinib which has
a very low water solubility. It is challenging to prepare high load
tablet formulations of ibrutinib that possess both pharmaceutically
acceptable properties and desired PK properties, such as a high
C.sub.max.
[0239] In some embodiments is a pharmaceutical composition
comprising ibrutinib, wherein ibrutinib is a compound with the
structure of Compound 1,
##STR00004##
and wherein the pharmaceutical composition comprises at least 50%
w/w of ibrutinib.
[0240] In another embodiment is a pharmaceutical composition
comprising ibrutinib, wherein the pharmaceutical composition
comprises at least about 20% w/w of ibrutinib. In another
embodiment is a pharmaceutical composition comprising ibrutinib,
wherein the pharmaceutical composition comprises about 20% w/w to
about 90% w/w of ibrutinib. In another embodiment is a
pharmaceutical composition comprising ibrutinib, wherein the
pharmaceutical composition comprises about 30% w/w to about 90% w/w
of ibrutinib. In another embodiment is a pharmaceutical composition
comprising ibrutinib, wherein the pharmaceutical composition
comprises about 40% w/w to about 90% w/w of ibrutinib. In another
embodiment is a pharmaceutical composition comprising ibrutinib,
wherein the pharmaceutical composition comprises about 50% w/w to
about 90% w/w of ibrutinib. In another embodiment is a
pharmaceutical composition comprising ibrutinib, wherein the
pharmaceutical composition comprises about 40% w/w to about 80% w/w
of ibrutinib. In another embodiment is a pharmaceutical composition
comprising ibrutinib, wherein the pharmaceutical composition
comprises about 50% w/w to about 80% w/w of ibrutinib. In another
embodiment is a pharmaceutical composition comprising ibrutinib,
wherein the pharmaceutical composition comprises about 60% w/w to
about 80% w/w of ibrutinib. In another embodiment is a
pharmaceutical composition comprising ibrutinib, wherein the
pharmaceutical composition comprises about 50% w/w to about 75% w/w
of ibrutinib. In another embodiment is a pharmaceutical composition
comprising ibrutinib, wherein the pharmaceutical composition
comprises about 60% w/w to about 75% w/w of ibrutinib. In another
embodiment is a pharmaceutical composition comprising at least 50%
w/w of ibrutinib, wherein the pharmaceutical composition comprises
intragranular and extragranular ingredients. In another embodiment
is a pharmaceutical composition comprising at least 50% w/w of
ibrutinib, wherein the pharmaceutical composition is prepared using
a wet granulation method. In another embodiment is a pharmaceutical
composition comprising at least 50% w/w of ibrutinib, further
comprising at least one pharmaceutically acceptable excipient.
[0241] In some embodiments, the pharmaceutical compositions
described herein are prepared by a process comprising a wet
granulation method.
[0242] In another embodiment is a solid tablet formulation
comprising ibrutinib, wherein the solid tablet formulation
comprises at least about 20% w/w of ibrutinib. In another
embodiment is a solid tablet formulation comprising ibrutinib,
wherein the solid tablet formulation comprises about 20% w/w to
about 90% w/w of ibrutinib. In another embodiment is a high-load
solid tablet formulation comprising at least 20% w/w or 30% w/w of
ibrutinib, and one or more pharmaceutically acceptable excipients.
In another embodiment is a high-load solid tablet formulation
comprising at least 40% w/w of ibrutinib, and one or more
pharmaceutically acceptable excipients. In another embodiment is a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, and one or more pharmaceutically acceptable excipients.
In another embodiment is a high-load solid tablet formulation
comprising about 30% w/w to about 90% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients. In another embodiment
is a high-load solid tablet formulation comprising about 40% w/w to
about 90% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients. In another embodiment is a high-load solid
tablet formulation comprising about 50% w/w to about 90% w/w of
ibrutinib, and one or more pharmaceutically acceptable excipients.
In another embodiment is a high-load solid tablet formulation
comprising about 40% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients. In another embodiment
is a high-load solid tablet formulation comprising about 50% w/w to
about 80% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients. In another embodiment is a high-load solid
tablet formulation comprising about 60% w/w to about 80% w/w of
ibrutinib, and one or more pharmaceutically acceptable excipients.
In another embodiment is a high-load solid tablet formulation
comprising about 50% w/w to about 75% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients. In another embodiment
is a high-load solid tablet formulation comprising about 60% w/w to
about 75% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients.
[0243] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients wherein the one or more
excipients are present in an amount from about 10% w/w to about 50%
w/w. In another embodiment is a high-load solid tablet formulation
comprising about 50% w/w to about 90% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients wherein the one or more
excipients are present in an amount from about 10% w/w to about 50%
w/w. In another embodiment is a high-load solid tablet formulation
comprising about 60% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients wherein the one or more
excipients are present in an amount from about 20% w/w to about 40%
w/w. In another embodiment is a high-load solid tablet formulation
comprising about 60% w/w to about 75% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients wherein the one or more
excipients are present in an amount from about 25% w/w to about 40%
w/w.
[0244] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients wherein the one or more
excipients are selected from the group consisting of diluents,
binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent. In some embodiments, the diluent is selected from the
group consisting of lactose, sucrose (e.g., Dipac.RTM.), dextrose,
dextrates, maltodextrin, mannitol, xylitol (e.g., Xylitab.RTM.),
sorbitol, cyclodextrins, calcium phosphate, calcium sulfate,
starches, modified starches, cellulose, microcrystalline cellulose
(e.g., Avicel.RTM.), microcellulose, and talc. In some embodiments,
the diluent is cellulose. In some embodiments, the diluent is the
diluent is lactose; and lactose is present in an amount from about
5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or about 8%
w/w to about 15% w/w. In some embodiments, the diluent is lactose;
and lactose is present in an amount of about 8.5% w/w or about 14%
w/w. In some embodiments, the diluent is microcrystalline
cellulose. In some embodiments, the diluent is microcrystalline
cellulose and the microcrystalline cellulose is present in an
amount from about 1% w/w to about 20% w/w, about 1% w/w to about
10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about 2% w/w,
about 5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or
about 8% w/w to about 15% w/w. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 6% w/w or about
8.5% w/w or about 14% w/w. In some embodiments, the diluent
comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose (e.g., Methocel.RTM.), croscarmellose,
croscarmellose sodium, cross-linked sodium carboxymethylcellulose,
cross-linked carboxymethylcellulose, cross-linked croscarmellose,
cross-linked starch such as sodium starch glycolate, cross-linked
polymer such as crospovidone, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone
(e.g., PVP K15, PVP K19, PVP K25, PVP K30, Povidone.RTM. CL,
Kollidon.RTM. CL, Polyplasdone.RTM. XL-10, and Povidone.RTM. K-12).
In some embodiments, the polyvinylpyrrolidone is present in an
amount from about 0 to about 10% w/w, about 1 to about 5% w/w, or
about 2% w/w. In some embodiments, the binder is hydroxypropyl
cellulose; and hydroxypropyl cellulose is present in an amount from
about 0 to about 10% w/w, about 0 to about 5% w/w, about 0 to about
2% w/w, about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to
about 1% w/w. In some embodiments, the formulation comprises
lactose, microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate (SLS). In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0245] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, and
intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment, the intragranular excipients comprise:
[0246] lactose in an amount from about 5% w/w to about 20% w/w,
about 8% w/w to about 15% w/w, or about 8% w/w to about 14% w/w;
[0247] microcrystalline cellulose in an amount from about 5% w/w to
about 20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to
about 15% w/w; [0248] croscarmellose sodium in an amount from about
0% w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2%
w/w to about 4% w/w; and [0249] hydroxypropyl cellulose in an
amount from about 0% w/w to about 2% w/w, about 0.1% w/w to about
1.1% w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise: [0250] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0251] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0252] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0253] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0254] In another embodiment is a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, and
intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium; and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment, the
intragranular excipients comprise: [0255] lactose in an amount from
about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
[0256] microcrystalline cellulose in an amount from about 1% w/w to
about 10% w/w, about 2% w/w to about 5% w/w; [0257]
polyvinylpyrrolidone in an amount from about 0% w/w to about 5%
w/w, about 1% w/w to about 3% w/w; [0258] croscarmellose sodium in
an amount from about 1% w/w to about 10% w/w, or about 3% w/w to
about 7% w/w; and [0259] sodium lauryl sulfate in an amount from
about 0% w/w to about 2% w/w, about 0.5% w/w to about 1.5% w/w; and
the extragranular excipients comprise: [0260] croscarmellose sodium
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0261] sodium lauryl sulfate in an amount from about
0% w/w to about 10% w/w or about 0% w/w to about 4% w/w; [0262]
colloidal silicon dioxide in an amount from about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and [0263] magnesium
stearate in an amount from about 0.4% w/w to about 0.8% w/w, or
about 0.5% w/w to about 0.6% w/w.
[0264] In another embodiment is a high-load solid tablet
formulation comprising about 50% w/w to about 90% w/w of ibrutinib,
and one or more pharmaceutically acceptable excipients wherein the
one or more excipients are selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent. In some embodiments, the diluent is selected from the
group consisting of lactose, sucrose, dextrose, dextrates,
maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium
phosphate, calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0265] In another embodiment is a high-load solid tablet
formulation comprising about 50% w/w to about 90% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment, the intragranular excipients comprise:
[0266] lactose in an amount from about 5% w/w to about 20% w/w,
about 8% w/w to about 15% w/w, or about 8% w/w to about 14% w/w;
[0267] microcrystalline cellulose in an amount from about 5% w/w to
about 20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to
about 15% w/w; [0268] croscarmellose sodium in an amount from about
0% w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2%
w/w to about 4% w/w; and [0269] hydroxypropyl cellulose in an
amount from about 0% w/w to about 2% w/w, about 0.1% w/w to about
1.1% w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise: [0270] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0271] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0272] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0273] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0274] In another embodiment is a high-load solid tablet
formulation comprising about 50% w/w to about 90% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium; and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment, the
intragranular excipients comprise: [0275] lactose in an amount from
about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
[0276] microcrystalline cellulose in an amount from about 1% w/w to
about 10% w/w, about 2% w/w to about 5% w/w; [0277]
polyvinylpyrrolidone in an amount from about 0% w/w to about 5%
w/w, about 1% w/w to about 3% w/w; [0278] croscarmellose sodium in
an amount from about 1% w/w to about 10% w/w, or about 3% w/w to
about 7% w/w; and [0279] sodium lauryl sulfate in an amount from
about 0% w/w to about 2% w/w, about 0.5% w/w to about 1.5% w/w; and
the extragranular excipients comprise [0280] croscarmellose sodium
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0281] sodium lauryl sulfate in an amount from about
0% w/w to about 10% w/w or about 0% w/w to about 4% w/w; [0282]
colloidal silicon dioxide in an amount from about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and [0283] magnesium
stearate in an amount from about 0.4% w/w to about 0.8% w/w, or
about 0.5% w/w to about 0.6% w/w.
[0284] In another embodiment is a high-load solid tablet
formulation comprising about 50% w/w to about 80% w/w of ibrutinib,
and one or more pharmaceutically acceptable excipients wherein the
one or more excipients are selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent. In some embodiments, the diluent is selected from the
group consisting of lactose, sucrose, dextrose, dextrates,
maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium
phosphate, calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0285] In another embodiment is a high-load solid tablet
formulation comprising about 50% w/w to about 80% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment the intragranular excipients comprise: [0286]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0287]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0288] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0289] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise: [0290] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0291] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0292] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0293] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0294] In another embodiment is a high-load solid tablet
formulation comprising about 50% w/w to about 80% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, sodium lauryl sulfate,
polyvinylpyrrolidone and croscarmellose sodium; and the
extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, microcrystalline cellulose, colloidal silicon
dioxide, and magnesium stearate. In another embodiment the
intragranular excipients comprise: [0295] lactose in an amount from
about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
[0296] polyvinylpyrrolidone in an amount from about 0% w/w to about
5% w/w, about 1% w/w to about 3% w/w; [0297] croscarmellose sodium
in an amount from about 1% w/w to about 10% w/w, or about 3% w/w to
about 7% w/w; and [0298] sodium lauryl sulfate in an amount from
about 0% w/w to about 2% w/w, about 0.5% w/w to about 1.5% w/w; and
the extragranular excipients comprise: [0299] croscarmellose sodium
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0300] sodium lauryl sulfate in an amount from about
0% w/w to about 10% w/w or about 0% w/w to about 4% w/w; [0301]
microcrystalline cellulose in an amount from about 1% w/w to about
10% w/w, about 2% w/w to about 5% w/w; [0302] colloidal silicon
dioxide in an amount from about 0.4% w/w to about 0.8% w/w, or
about 0.5% w/w to about 0.6% w/w; and [0303] magnesium stearate in
an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0304] In another embodiment is a high-load solid tablet
formulation comprising about 60% w/w to about 80% w/w of ibrutinib,
and one or more pharmaceutically acceptable excipients wherein the
one or more excipients are selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent. In some embodiments, the diluent is selected from the
group consisting of lactose, sucrose, dextrose, dextrates,
maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium
phosphate, calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0305] In another embodiment is a high-load solid tablet
formulation comprising about 60% w/w to about 80% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment the intragranular excipients comprise [0306]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0307]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0308] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0309] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and [0310] the
extragranular excipients comprise [0311] croscarmellose sodium in
an amount from about 0% w/w to about 5% w/w, about 2% w/w to about
5% w/w, or about 2% w/w to about 5% w/w; [0312] sodium lauryl
sulfate in an amount from about 0% w/w to about 10% w/w, about 4%
w/w to about 8% w/w, or about 5% w/w to about 6% w/w; [0313]
colloidal silicon dioxide in an amount from about 0.1% w/w to about
1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to
about 0.6% w/w; and [0314] magnesium stearate in an amount from
about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8% w/w,
or about 0.5% w/w to about 0.6% w/w.
[0315] In another embodiment is a high-load solid tablet
formulation comprising about 60% w/w to about 80% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium; and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment the
intragranular excipients comprise: [0316] lactose in an amount from
about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
[0317] microcrystalline cellulose in an amount from about 1% w/w to
about 10% w/w, about 2% w/w to about 5% w/w; [0318]
polyvinylpyrrolidone in an amount from about 0% w/w to about 5%
w/w, about 1% w/w to about 3% w/w; [0319] croscarmellose sodium in
an amount from about 1% w/w to about 10% w/w, or about 3% w/w to
about 7% w/w; and [0320] sodium lauryl sulfate in an amount from
about 0% w/w to about 2% w/w, about 0.5% w/w to about 1.5% w/w; and
the extragranular excipients comprise [0321] croscarmellose sodium
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0322] sodium lauryl sulfate in an amount from about
0% w/w to about 10% w/w or about 0% w/w to about 4% w/w; [0323]
colloidal silicon dioxide in an amount from about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and [0324] magnesium
stearate in an amount from about 0.4% w/w to about 0.8% w/w, or
about 0.5% w/w to about 0.6% w/w.
[0325] In another embodiment is a high-load solid tablet
formulation comprising about 60% w/w to about 75% w/w of ibrutinib,
and one or more pharmaceutically acceptable excipients wherein the
one or more excipients are selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent. In some embodiments, the diluent is selected from the
group consisting of lactose, sucrose, dextrose, dextrates,
maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium
phosphate, calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0326] In another embodiment is a high-load solid tablet
formulation comprising about 60% w/w to about 75% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment the intragranular excipients comprise: [0327]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0328]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0329] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0330] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise: [0331] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0332] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0333] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0334] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0335] In another embodiment is a high-load solid tablet
formulation comprising about 60% w/w to about 75% w/w of ibrutinib,
and intragranular and extragranular excipients; wherein the
intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium; and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment the
intragranular excipients comprise: [0336] lactose in an amount from
about 10% w/w to about 20% w/w, or about 12% w/w to about 15% w/w;
[0337] microcrystalline cellulose in an amount from about 1% w/w to
about 10% w/w, about 2% w/w to about 5% w/w; [0338]
polyvinylpyrrolidone in an amount from about 0% w/w to about 5%
w/w, about 1% w/w to about 3% w/w; [0339] croscarmellose sodium in
an amount from about 1% w/w to about 10% w/w, or about 3% w/w to
about 7% w/w; and [0340] sodium lauryl sulfate in an amount from
about 0% w/w to about 2% w/w, about 0.5% w/w to about 1.5% w/w; and
[0341] the extragranular excipients comprise: [0342] croscarmellose
sodium in an amount from about 0% w/w to about 5% w/w, about 1% w/w
to about 3% w/w; [0343] sodium lauryl sulfate in an amount from
about 0% w/w to about 10% w/w or about 0% w/w to about 4% w/w;
[0344] colloidal silicon dioxide in an amount from about 0.4% w/w
to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and [0345]
magnesium stearate in an amount from about 0.4% w/w to about 0.8%
w/w, or about 0.5% w/w to about 0.6% w/w.
[0346] In another embodiment is a high-load solid tablet
formulation comprising: [0347] a) about 69% w/w to about 71% w/w of
ibrutinib, [0348] b) about 13% w/w to about 15% w/w of lactose
monohydrate, [0349] c) about 2% w/w to about 5% w/w of
microcrystalline cellulose, [0350] d) about 1% w/w to about 3% w/w
of polyvinylpyrrolidone, [0351] e) about 6% w/w to about 8% w/w of
croscarmellose sodium, [0352] f) about 1% w/w to about 4% w/w of
sodium lauryl sulfate, [0353] g) about 0.4% w/w to about 0.6% w/w
of colloidal silicon dioxide, and [0354] h) about 0.4% w/w to about
0.6% w/w of magnesium stearate.
[0355] In another embodiment is a high-load solid tablet
formulation comprising: [0356] a) about 70% w/w of ibrutinib,
[0357] b) about 14% w/w of lactose monohydrate, [0358] c) about 5%
w/w of microcrystalline cellulose, [0359] d) about 2% w/w of
polyvinylpyrrolidone, [0360] e) about 7% w/w of croscarmellose
sodium, [0361] f) about 1% w/w of sodium lauryl sulfate, [0362] g)
about 0.5% w/w of colloidal silicon dioxide, and [0363] h) about
0.5% w/w of magnesium stearate.
[0364] In one embodiment, the tablet formulation is as described
above and croscarmellose sodium is about 5% intra and about 2%
extra. In another embodiment, sodium lauryl sulfate is about 1%
intra and about 0% extra.
[0365] In another embodiment is a high-load solid tablet
formulation comprising: [0366] a) about 70% w/w of ibrutinib,
[0367] b) about 14% w/w of lactose monohydrate, [0368] c) about 2%
w/w of microcrystalline cellulose, [0369] d) about 2% w/w of
polyvinylpyrrolidone, [0370] e) about 7% w/w of croscarmellose
sodium, [0371] f) about 4% w/w of sodium lauryl sulfate, [0372] g)
about 0.5% w/w of colloidal silicon dioxide, and [0373] h) about
0.5% w/w of magnesium stearate.
[0374] In one embodiment, the tablet formulation is as described
above and croscarmellose sodium is about 5% intra and about 2%
extra. In another embodiment, sodium lauryl sulfate is about 1%
intra and about 3% extra.
[0375] In another embodiment, the high-load solid tablet comprises
lactose, polyvinylpyrrolidone, sodium lauryl sulfate, crospovidone,
colloidal silicon dioxide, and magnesium stearate. In another
embodiment is a high-load solid tablet formulation comprising:
[0376] a) about 65% w/w to about 75% w/w, or about 70% w/w of
ibrutinib, [0377] b) about 14% w/w to about 18% w/w, or about 16%
w/w of lactose monohydrate, [0378] c) about 1% w/w to about 3% w/w,
or about 2% w/w of polyvinylpyrrolidone, [0379] d) about 0.5% w/w
to about 1.5% w/w, or about 1% w/w of sodium lauryl sulfate, [0380]
e) about 5% w/w to about 15% w/w, or about 10% w/w of crospovidone,
[0381] f) about 0.3% w/w to about 0.7% w/w, or about 0.5% w/w of
colloidal silicon dioxide, and [0382] g) about 0.3% w/w to about
0.7% w/w, or about 0.5% w/w of magnesium stearate.
[0383] In another embodiment is a high-load solid tablet
formulation comprising: [0384] a) about 59% w/w to about 61% w/w of
ibrutinib, [0385] b) about 13% w/w to about 15% w/w of lactose,
[0386] c) about 13% w/w to about 15% w/w of microcrystalline
cellulose, [0387] d) about 4% w/w to about 6% w/w of croscarmellose
sodium, [0388] e) about 5% w/w to about 7% w/w of sodium lauryl
sulfate, [0389] f) about 0.4% w/w to about 0.6% w/w of colloidal
silicon dioxide, and [0390] g) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
[0391] In some embodiments, the total weight of a tablet is about
934 mg.
[0392] In another embodiment is a high-load solid tablet
formulation comprising: [0393] a) about 59% w/w to about 61% w/w of
ibrutinib, [0394] b) about 13% w/w to about 14% w/w of lactose,
[0395] c) about 13% w/w to about 14% w/w of microcrystalline
cellulose, [0396] d) about 2% w/w to about 3% w/w of croscarmellose
sodium(intragranular), [0397] e) about 0.8% w/w to about 1.2% w/w
of hydroxypropyl cellulose, [0398] f) about 2% w/w to about 3% w/w
of croscarmellose sodium(extragranular), [0399] g) about 5.5 to
about 6.5% w/w of sodium lauryl sulfate, [0400] h) about 0.4% w/w
to about 0.6% w/w of colloidal silicon dioxide, and [0401] i) about
0.4% w/w to about 0.6% w/w of magnesium stearate.
[0402] In some embodiments, the total weight of a tablet is about
934 mg.
[0403] In another embodiment is a high-load solid tablet
formulation comprising: [0404] a) about 69% w/w to about 71% w/w of
ibrutinib, [0405] b) about 8% w/w to about 9% w/w of lactose,
[0406] c) about 8 to about 9% w/w of microcrystalline cellulose,
[0407] d) about 2.5 to about 3.5% w/w of croscarmellose sodium
(intragranular), [0408] e) about 2.5 to about 3.5% w/w of
croscarmellose sodium (extragranular), [0409] g) about 5.5 to about
6.5% w/w of sodium lauryl sulfate, [0410] h) about 0.4% w/w to
about 0.6% w/w of colloidal silicon dioxide, and [0411] i) about
0.4% w/w to about 0.6% w/w of magnesium stearate.
[0412] In some embodiments of a tablet described herein the total
weight of the tablet is about 50 mg to about 1.2 g, such as about
50 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg,
about 800 mg, or about 1.2 g, or any range between any two of the
values, end points inclusive. In some embodiments, the total weight
of a tablet is about 800 mg.
[0413] In some embodiments of the high-load solid tablet
formulations described herein, the ibrutinib is in an amount of
about 35 mg to about 840 mg per tablet, such as about 35 mg, about
70 mg, about 140 mg, about 280 mg, about 420 mg, about 560 mg, or
about 840 mg, or any range between any two of the values, end
points inclusive. In some embodiments of the high-load solid tablet
formulations described herein, the ibrutinib is in an amount of
about 560 mg. In some embodiments of the high-load solid tablet
formulations described herein, the ibrutinib is in micronized form.
In some embodiments of the high-load solid tablet formulations
described herein, the formulation is used for once a day dosing. In
some embodiments of the high-load solid tablet formulations
described herein, the formulation is in an oral dosage form
containing a therapeutically effective amount of ibrutinib.
[0414] In some embodiments, the high-load solid tablet formulations
described herein are prepared by a process comprising a wet
granulation method.
[0415] In another embodiment is a method of treating a disease in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein.
[0416] In another embodiment is a method of treating an autoimmune
disease in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein. In
some embodiments, the autoimmune disease is rheumatoid arthritis or
lupus. In another embodiment is a method of treating rheumatoid
arthritis in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein. In
another embodiment is a method of treating lupus in a patient in
need of such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein.
[0417] In another embodiment is a method of treating a heteroimmune
disease in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein.
[0418] In another embodiment is a method of treating cancer in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein. In some embodiments,
the cancer is a B-cell proliferative disorder. In some embodiments,
the cancer is a B-cell proliferative disorder and the B-cell
proliferative disorder is diffuse large B cell lymphoma, follicular
lymphoma or chronic lymphocytic leukemia. In some embodiments, the
cancer is a B-cell proliferative disorder and the B-cell
proliferative disorder is diffuse large B cell lymphoma. In some
embodiments, the cancer is a B-cell proliferative disorder and the
B-cell proliferative disorder is follicular lymphoma.
[0419] In another embodiment is a method of treating cancer in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein, wherein the cancer is
a B cell malignancy. In some embodiments, the cancer is a B cell
malignancy and the B cell malignancy selected from chronic
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle
cell lymphoma (MCL), diffuse large B Cell lymphoma (DLBCL), and
multiple myeloma. In some embodiments, the cancer is a B cell
malignancy and the B cell malignancy is chronic lymphocytic
leukemia (CLL)/small lymphocytic lymphoma (SLL). In some
embodiments, the cancer is a B cell malignancy and the B cell
malignancy is mantle cell lymphoma (MCL). In some embodiments, the
cancer is a B cell malignancy and the B cell malignancy is diffuse
large B Cell lymphoma (DLBCL). In some embodiments, the cancer is a
B cell malignancy and the B cell malignancy is multiple
myeloma.
[0420] In another embodiment is a method of treating cancer in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein, wherein the cancer is
a lymphoma, leukemia or a solid tumor. In another embodiment is a
method of treating cancer in a patient in need of such treatment,
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition or formulation described
herein, wherein the cancer is a lymphoma. In another embodiment is
a method of treating cancer in a patient in need of such treatment,
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition or formulation described
herein, wherein the cancer is a leukemia. In another embodiment is
a method of treating cancer in a patient in need of such treatment,
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition or formulation described
herein, wherein the cancer is a solid tumor.
[0421] In another embodiment is a method of treating cancer in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein, wherein the cancer is
diffuse large B cell lymphoma, follicular lymphoma, chronic
lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell
prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom
macroglobulinemia, splenic marginal zone lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma,
nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion lymphoma, burkitt
lymphoma/leukemia, or lymphomatoid granulomatosis. In another
embodiment is a method of treating cancer in a patient in need of
such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is diffuse large B
cell lymphoma. In another embodiment is a method of treating cancer
in a patient in need of such treatment, comprising administering to
the patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein, wherein the cancer is
follicular lymphoma. In another embodiment is a method of treating
cancer in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein,
wherein the cancer is chronic lymphocytic lymphoma. In another
embodiment is a method of treating cancer in a patient in need of
such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is chronic
lymphocytic leukemia. In another embodiment is a method of treating
cancer in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein,
wherein the cancer is B-cell prolymphocytic leukemia. In another
embodiment is a method of treating cancer in a patient in need of
such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is
lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. In
another embodiment is a method of treating cancer in a patient in
need of such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is splenic
marginal zone lymphoma. In another embodiment is a method of
treating cancer in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein,
wherein the cancer is plasma cell myeloma. In another embodiment is
a method of treating cancer in a patient in need of such treatment,
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition or formulation described
herein, wherein the cancer is plasmacytoma. In another embodiment
is a method of treating cancer in a patient in need of such
treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is extranodal
marginal zone B cell lymphoma. In another embodiment is a method of
treating cancer in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein,
wherein the cancer is nodal marginal zone B cell lymphoma. In
another embodiment is a method of treating cancer in a patient in
need of such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is mantle cell
lymphoma. In another embodiment is a method of treating cancer in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein, wherein the cancer is
mediastinal (thymic) large B cell lymphoma. In another embodiment
is a method of treating cancer in a patient in need of such
treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is intravascular
large B cell lymphoma. In another embodiment is a method of
treating cancer in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein,
wherein the cancer is primary effusion lymphoma. In another
embodiment is a method of treating cancer in a patient in need of
such treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein, wherein the cancer is burkitt
lymphoma/leukemia. In another embodiment is a method of treating
cancer in a patient in need of such treatment, comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition or formulation described herein,
wherein the cancer is lymphomatoid granulomatosis.
[0422] In some embodiments, the composition is for use in treatment
of a sarcoma or carcinoma. In some embodiments, the composition is
for use in treatment of a sarcoma. In some embodiments, the
composition is for use in treatment of a carcinoma. In some
embodiments, the sarcoma is selected from alveolar
rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;
angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft
tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small
round cell tumor; embryonal rhabdomyosarcoma; epithelioid
fibrosarcoma; epithelioid hemangioendothelioma; epithelioid
sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid
tumor; extraskeletal myxoid chondrosarcoma; extrasketetal
osteosarcoma; fibrosarcoma; giant cell tumor; hemangiopericytoma;
infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi
sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone;
malignant fibrous histiocytoma (MFH); malignant fibrous
histiocytoma (MFH) of bone; malignant mesenchymoma; malignant
peripheral nerve sheath tumor; mesenchymal chondrosarcoma;
myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic
sarcoma; neoplasms with perivascular epitheioid cell
differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm
with perivascular epitheioid cell differentiation; periosteal
osteosarcoma; pleomorphic liposarcoma; pleomorphic
rhabdomyosarcoma; PNET/extraskeletal Ewing tumor; rhabdomyosarcoma;
round cell liposarcoma; small cell osteosarcoma; solitary fibrous
tumor; synovial sarcoma; telangiectatic osteosarcoma. In some
embodiments, the carcinoma is selected from an adenocarcinoma,
squamous cell carcinoma, adenosquamous carcinoma, anaplastic
carcinoma, large cell carcinoma, or small cell carcinoma. In some
embodiments, the solid tumor is selected from anal cancer; appendix
cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder
cancer; brain tumor; breast cancer; HER2-amplified breast cancer;
cervical cancer; colon cancer; cancer of Unknown Primary (CUP);
esophageal cancer; eye cancer; fallopian tube cancer; kidney
cancer; renal cell carcinoma; liver cancer; lung cancer;
medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic
cancer; pancreatic ductal cancer; parathyroid disease; penile
cancer; pituitary tumor; prostate cancer; rectal cancer; skin
cancer; stomach cancer; testicular cancer; throat cancer; thyroid
cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some
embodiments, the carcinoma is breast cancer. In some embodiments,
the breast cancer is invasive ductal carcinoma, ductal carcinoma in
situ, invasive lobular carcinoma, or lobular carcinoma in situ. In
some embodiments, the carcinoma is pancreatic cancer. In some
embodiments, the pancreatic cancer is adenocarcinoma, or islet cell
carcinoma. In some embodiments, the carcinoma is colorectal cancer.
In some embodiments, the colorectal cancer is adenocarcinoma. In
some embodiments, the solid tumor is a colon polyp. In some
embodiments, the colon polyp is associated with familial
adenomatous polyposis. In some embodiments, the carcinoma is
bladder cancer. In some embodiments, the bladder cancer is
transitional cell bladder cancer, squamous cell bladder cancer, or
adenocarcinoma. In some embodiments, the carcinoma is lung cancer.
In some embodiments, the lung cancer is a non-small cell lung
cancer. In some embodiments, the non-small cell lung cancer is
adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung
carcinoma. In some embodiments, the non-small cell lung cancer is
large cell lung cancer. In some embodiments, the lung cancer is a
small cell lung cancer. In some embodiments, the carcinoma is
prostate cancer. In some embodiments, the prostate cancer is
adenocarcinoma or small cell carcinoma. In some embodiments, the
carcinoma is ovarian cancer. In some embodiments, the ovarian
cancer is epithelial ovarian cancer. In some embodiments, the
carcinoma is bile duct cancer. In some embodiments, the bile duct
cancer is proximal bile duct carcinoma or distal bile duct
carcinoma.
[0423] In another embodiment is a method of treating mastocytosis
in a patient in need of such treatment, comprising administering to
the patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein.
[0424] In another embodiment is a method of treating osteoporosis
or bone resorption disorders in a patient in need of such
treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein. In another embodiment is a method of
treating osteoporosis in a patient in need of such treatment,
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition or formulation described
herein. In another embodiment is a method of treating bone
resorption disorders in a patient in need of such treatment,
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition or formulation described
herein.
[0425] In another embodiment is a method of treating an
inflammatory disease or condition in a patient in need of such
treatment, comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition or
formulation described herein.
[0426] In another embodiment is a method of treating lupus in a
patient in need of such treatment, comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition or formulation described herein.
[0427] In another aspect is a process for preparing a
pharmaceutical composition described herein wherein the process
comprises a wet granulation method.
[0428] In another aspect is a process for preparing a
pharmaceutical composition comprising ibrutinib, wherein ibrutinib
is a compound with the structure of Compound 1,
##STR00005##
the process comprises a wet granulation method; and the
pharmaceutical composition comprises at least 50% w/w of
ibrutinib.
[0429] In another embodiment is a process for preparing a
pharmaceutical composition comprising ibrutinib, wherein the
process comprises a wet granulation method and the pharmaceutical
composition comprises about 30% w/w to about 90% w/w of ibrutinib.
In another embodiment is a process for preparing a pharmaceutical
composition comprising ibrutinib, wherein the process comprises a
wet granulation method and the pharmaceutical composition comprises
about 40% w/w to about 90% w/w of ibrutinib. In another embodiment
is a process for preparing a pharmaceutical composition comprising
ibrutinib, wherein the process comprises a wet granulation method
and the pharmaceutical composition comprises about 50% w/w to about
90% w/w of ibrutinib. In another embodiment is a process for
preparing a pharmaceutical composition comprising ibrutinib,
wherein the process comprises a wet granulation method and the
pharmaceutical composition comprises about 40% w/w to about 80% w/w
of ibrutinib. In another embodiment is a process for preparing a
pharmaceutical composition comprising ibrutinib, wherein the
process comprises a wet granulation method and the pharmaceutical
composition comprises about 50% w/w to about 80% w/w of ibrutinib.
In another embodiment is a process for preparing a pharmaceutical
composition comprising ibrutinib, wherein the process comprises a
wet granulation method and the pharmaceutical composition comprises
about 60% w/w to about 80% w/w of ibrutinib. In another embodiment
is a process for preparing a pharmaceutical composition comprising
ibrutinib, wherein the process comprises a wet granulation method
and the pharmaceutical composition comprises about 50% w/w to about
75% w/w of ibrutinib. In another embodiment is a process for
preparing a pharmaceutical composition comprising ibrutinib,
wherein the process comprises a wet granulation method and the
pharmaceutical composition comprises about 60% w/w to about 75% w/w
of ibrutinib.
[0430] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, about 50% w/w to about 90% w/w of ibrutinib, about 50%
w/w to about 80% w/w of ibrutinib, about 60% w/w to about 80% w/w
of ibrutinib, or about 60% w/w to about 75% w/w of ibrutinib, and
one or more pharmaceutically acceptable excipients, wherein the
process comprises a wet granulation method. In another embodiment
provided is a process for preparing a high-load solid tablet
formulation comprising at least 30% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising at least 40% w/w of ibrutinib, and one or more
pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising at least 50% w/w of ibrutinib, and one or more
pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 30% w/w to about 90% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 40% w/w to about 90% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 50% w/w to about 90% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 40% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 50% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 60% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 50% w/w to about 75% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 60% w/w to about 75% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients, wherein the process
comprises a wet granulation method.
[0431] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, about 50% w/w to about 90% w/w of ibrutinib, about 50%
w/w to about 80% w/w of ibrutinib, about 60% w/w to about 80% w/w
of ibrutinib, or about 60% w/w to about 75% w/w of ibrutinib, and
one or more pharmaceutically acceptable excipients present in a
total amount from about 10% w/w to about 50% w/w, wherein the
process comprises a wet granulation method. In another embodiment
provided is a process for preparing a high-load solid tablet
formulation comprising at least 50% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients present in a total
amount no more than about 50% w/w, wherein the process comprises a
wet granulation method. In another embodiment provided is a process
for preparing a high-load solid tablet formulation comprising about
50% w/w to about 90% w/w of ibrutinib, and one or more
pharmaceutically acceptable excipients present in a total amount
from about 10% w/w to about 50% w/w, wherein the process comprises
a wet granulation method. In another embodiment provided is a
process for preparing a high-load solid tablet formulation
comprising about 50% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients present in a total
amount from about 20% w/w to about 50% w/w, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 60% w/w to about 80% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients present in a total
amount from about 20% w/w to about 40% w/w, wherein the process
comprises a wet granulation method. In another embodiment provided
is a process for preparing a high-load solid tablet formulation
comprising about 60% w/w to about 75% w/w of ibrutinib, and one or
more pharmaceutically acceptable excipients present in a total
amount from about 25% w/w to about 40% w/w, wherein the process
comprises a wet granulation method.
[0432] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, and one or more pharmaceutically acceptable excipients
selected from the group consisting of diluents, binders,
disintegrating agents, lubricants, glidants, and surfactants,
wherein the process comprises a wet granulation method. In some
embodiments, at least one excipient is a diluent. In some
embodiments, the diluent is selected from the group consisting of
lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol,
xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium
sulfate, starches, modified starches, cellulose, microcrystalline
cellulose, microcellulose, and talc. In some embodiments, the
diluent is cellulose. In some embodiments, the diluent is the
diluent is lactose; and lactose is present in an amount from about
5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or about 8%
w/w to about 15% w/w. In some embodiments, the diluent is lactose;
and lactose is present in an amount of about 8.5% w/w or about 14%
w/w. In some embodiments, the diluent is microcrystalline
cellulose. In some embodiments, the diluent is microcrystalline
cellulose and the microcrystalline cellulose is present in an
amount from about 1% w/w to about 20% w/w, about 1% w/w to about
10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about 2% w/w,
about 5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or
about 8% w/w to about 15% w/w. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 6% w/w or about
8.5% w/w or about 14% w/w. In some embodiments, the diluent
comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0433] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, and intragranular and extragranular excipients; wherein
the process comprises a wet granulation method, the intragranular
excipients comprise lactose, microcrystalline cellulose,
croscarmellose sodium, and hydroxypropyl cellulose, and the
extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, wherein the process comprises a wet granulation method,
the intragranular excipients comprise [0434] lactose in an amount
from about 5% w/w to about 20% w/w, about 8% w/w to about 15% w/w,
or about 8% w/w to about 14% w/w; [0435] microcrystalline cellulose
in an amount from about 5% w/w to about 20% w/w, about 8% w/w to
about 20% w/w, or about 8% w/w to about 15% w/w; [0436]
croscarmellose sodium in an amount from about 0% w/w to about 10%
w/w, about 2% w/w to about 5% w/w, or about 2% w/w to about 4% w/w;
and [0437] hydroxypropyl cellulose in an amount from about 0% w/w
to about 2% w/w, about 0.1% w/w to about 1.1% w/w, or about 0.1%
w/w to about 1% w/w; and the extragranular excipients comprise
[0438] croscarmellose sodium in an amount from about 0% w/w to
about 5% w/w, about 2% w/w to about 5% w/w, or about 2% w/w to
about 5% w/w; [0439] sodium lauryl sulfate in an amount from about
0% w/w to about 10% w/w, about 4% w/w to about 8% w/w, or about 5%
w/w to about 6% w/w; [0440] colloidal silicon dioxide in an amount
from about 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about 0.8%
w/w, or about 0.5% w/w to about 0.6% w/w; and [0441] magnesium
stearate in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6%
w/w.
[0442] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, and intragranular and extragranular excipients; wherein
the process comprises a wet granulation method, the intragranular
excipients comprise lactose, microcrystalline cellulose, sodium
lauryl sulfate, polyvinylpyrrolidone and croscarmellose sodium, and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising at least 50% w/w of
ibrutinib, wherein the process comprises a wet granulation method,
the intragranular excipients comprise [0443] lactose in an amount
from about 10% w/w to about 20% w/w, or about 12% w/w to about 15%
w/w; [0444] microcrystalline cellulose in an amount from about 1%
w/w to about 10% w/w, about 2% w/w to about 5% w/w; [0445]
polyvinylpyrrolidone in an amount from about 0% w/w to about 5%
w/w, about 1% w/w to about 3% w/w; [0446] croscarmellose sodium in
an amount from about 1% w/w to about 10% w/w, or about 3% w/w to
about 7% w/w; and [0447] sodium lauryl sulfate in an amount from
about 0% w/w to about 2% w/w, about 0.5% w/w to about 1.5% w/w; and
the extragranular excipients comprise [0448] croscarmellose sodium
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0449] sodium lauryl sulfate in an amount from about
0% w/w to about 10% w/w or about 0% w/w to about 4% w/w; [0450]
colloidal silicon dioxide in an amount from about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w; and [0451] magnesium
stearate in an amount from about 0.4% w/w to about 0.8% w/w, or
about 0.5% w/w to about 0.6% w/w.
[0452] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 90% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants. In some embodiments, at least one excipient is a
diluent, wherein the process comprises a wet granulation method. In
some embodiments, the diluent is selected from the group consisting
of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol,
xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium
sulfate, starches, modified starches, cellulose, microcrystalline
cellulose, microcellulose, and talc. In some embodiments, the
diluent is cellulose. In some embodiments, the diluent is the
diluent is lactose; and lactose is present in an amount from about
5% w/w to about 20% w/w, about 8% w/w to about 20% w/w, or about 8%
w/w to about 15% w/w. In some embodiments, the diluent is lactose;
and lactose is present in an amount of about 8.5% w/w or about 14%
w/w. In some embodiments, the diluent is microcrystalline
cellulose. In some embodiments, the diluent is microcrystalline
cellulose and the microcrystalline cellulose is present in an
amount from about 1% w/w to about 20% w/w, about 1% w/w to about
10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about 2% w/w, 5%
w/w to about 20% w/w, about 8% w/w to about 20% w/w, or about 8%
w/w to about 15% w/w. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 6% w/w or about
8.5% w/w or about 14% w/w. In some embodiments, the diluent
comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0453] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 90% w/w of ibrutinib, and intragranular and extragranular
excipients; wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 90% w/w of ibrutinib, wherein the process comprises a wet
granulation method, the intragranular excipients comprise [0454]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0455]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0456] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0457] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise [0458] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0459] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0460] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0461] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0462] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 90% w/w of ibrutinib, and intragranular and extragranular
excipients; wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium, and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment provided is
a process for preparing a high-load solid tablet formulation
comprising about 50% w/w to about 90% w/w of ibrutinib, wherein the
process comprises a wet granulation method, the intragranular
excipients comprise [0463] lactose in an amount from about 10% w/w
to about 20% w/w, or about 12% w/w to about 15% w/w; [0464]
microcrystalline cellulose in an amount from about 1% w/w to about
10% w/w, about 2% w/w to about 5% w/w; [0465] polyvinylpyrrolidone
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0466] croscarmellose sodium in an amount from about
1% w/w to about 10% w/w, or about 3% w/w to about 7% w/w; and
[0467] sodium lauryl sulfate in an amount from about 0% w/w to
about 2% w/w, about 0.5% w/w to about 1.5% w/w; and the
extragranular excipients comprise [0468] croscarmellose sodium in
an amount from about 0% w/w to about 5% w/w, about 1% w/w to about
3% w/w; [0469] sodium lauryl sulfate in an amount from about 0% w/w
to about 10% w/w or about 0% w/w to about 4% w/w; [0470] colloidal
silicon dioxide in an amount from about 0.4% w/w to about 0.8% w/w,
or about 0.5% w/w to about 0.6% w/w; and [0471] magnesium stearate
in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5%
w/w to about 0.6% w/w.
[0472] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 80% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants, wherein the process comprises a wet granulation
method. In some embodiments, at least one excipient is a diluent.
In some embodiments, the diluent is selected from the group
consisting of lactose, sucrose, dextrose, dextrates, maltodextrin,
mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate,
calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0473] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 80% w/w of ibrutinib and intragranular and extragranular
excipients, wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 80% w/w of ibrutinib, wherein the process comprises a wet
granulation method, the intragranular excipients comprise [0474]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0475]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0476] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0477] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise [0478] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0479] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0480] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0481] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0482] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 50% w/w to
about 80% w/w of ibrutinib, and intragranular and extragranular
excipients, wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium, and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment provided is
a process for preparing a high-load solid tablet formulation
comprising about 50% w/w to about 80% w/w of ibrutinib, wherein the
process comprises a wet granulation method, the intragranular
excipients comprise [0483] lactose in an amount from about 10% w/w
to about 20% w/w, or about 12% w/w to about 15% w/w; [0484]
microcrystalline cellulose in an amount from about 1% w/w to about
10% w/w, about 2% w/w to about 5% w/w; [0485] polyvinylpyrrolidone
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0486] croscarmellose sodium in an amount from about
1% w/w to about 10% w/w, or about 3% w/w to about 7% w/w; and
[0487] sodium lauryl sulfate in an amount from about 0% w/w to
about 2% w/w, about 0.5% w/w to about 1.5% w/w; and the
extragranular excipients comprise [0488] croscarmellose sodium in
an amount from about 0% w/w to about 5% w/w, about 1% w/w to about
3% w/w; [0489] sodium lauryl sulfate in an amount from about 0% w/w
to about 10% w/w or about 0% w/w to about 4% w/w; [0490] colloidal
silicon dioxide in an amount from about 0.4% w/w to about 0.8% w/w,
or about 0.5% w/w to about 0.6% w/w; and [0491] magnesium stearate
in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5%
w/w to about 0.6% w/w.
[0492] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 80% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants, wherein the process comprises a wet granulation
method. In some embodiments, at least one excipient is a diluent.
In some embodiments, the diluent is selected from the group
consisting of lactose, sucrose, dextrose, dextrates, maltodextrin,
mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate,
calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0493] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 80% w/w of ibrutinib, and intragranular and extragranular
excipients, wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 80% w/w of ibrutinib, wherein the process comprises a wet
granulation method, the intragranular excipients comprise [0494]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0495]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0496] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0497] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise [0498] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0499] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0500] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0501] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0502] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 80% w/w of ibrutinib, and intragranular and extragranular
excipients, wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium, and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment provided is
a process for preparing a high-load solid tablet formulation
comprising about 60% w/w to about 80% w/w of ibrutinib, wherein the
process comprises a wet granulation method, the intragranular
excipients comprise [0503] lactose in an amount from about 10% w/w
to about 20% w/w, or about 12% w/w to about 15% w/w; [0504]
microcrystalline cellulose in an amount from about 1% w/w to about
10% w/w, about 2% w/w to about 5% w/w; polyvinylpyrrolidone in an
amount from about 0% w/w to about 5% w/w, about 1% w/w to about 3%
w/w; [0505] croscarmellose sodium in an amount from about 1% w/w to
about 10% w/w, or about 3% w/w to about 7% w/w; and [0506] sodium
lauryl sulfate in an amount from about 0% w/w to about 2% w/w,
about 0.5% w/w to about 1.5% w/w; and the extragranular excipients
comprise [0507] croscarmellose sodium in an amount from about 0%
w/w to about 5% w/w, about 1% w/w to about 3% w/w; [0508] sodium
lauryl sulfate in an amount from about 0% w/w to about 10% w/w or
about 0% w/w to about 4% w/w; [0509] colloidal silicon dioxide in
an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w; and [0510] magnesium stearate in an amount from
about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6%
w/w.
[0511] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 75% w/w of ibrutinib, and one or more pharmaceutically
acceptable excipients selected from the group consisting of
diluents, binders, disintegrating agents, lubricants, glidants, and
surfactants, wherein the process comprises a wet granulation
method. In some embodiments, at least one excipient is a diluent.
In some embodiments, the diluent is selected from the group
consisting of lactose, sucrose, dextrose, dextrates, maltodextrin,
mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate,
calcium sulfate, starches, modified starches, cellulose,
microcrystalline cellulose, microcellulose, and talc. In some
embodiments, the diluent is cellulose. In some embodiments, the
diluent is the diluent is lactose; and lactose is present in an
amount from about 5% w/w to about 20% w/w, about 8% w/w to about
20% w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is lactose; and lactose is present in an amount of about
8.5% w/w or about 14% w/w. In some embodiments, the diluent is
microcrystalline cellulose. In some embodiments, the diluent is
microcrystalline cellulose and the microcrystalline cellulose is
present in an amount from about 1% w/w to about 20% w/w, about 1%
w/w to about 10% w/w, about 1% w/w to about 5% w/w, 1% w/w to about
2% w/w, about 5% w/w to about 20% w/w, about 8% w/w to about 20%
w/w, or about 8% w/w to about 15% w/w. In some embodiments, the
diluent is microcrystalline cellulose and the microcrystalline
cellulose is present in an amount from about 1% w/w to about 6% w/w
or about 8.5% w/w or about 14% w/w. In some embodiments, the
diluent comprises lactose and microcrystalline cellulose. In some
embodiments, the lactose is present in an amount of about 10% w/w
to about 15% w/w and microcrystalline cellulose is present in an
amount from about 1% w/w to about 6% w/w. In some embodiments, the
lactose is present in an amount of about 14% w/w and
microcrystalline cellulose is present in an amount from about 2%
w/w to about 5% w/w. In some embodiments, at least one excipient is
a disintegrating agent. In some embodiments, the disintegrating
agent is selected from the group consisting of natural starch, a
pregelatinized starch, a sodium starch, methylcrystalline
cellulose, methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, and a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium; and croscarmellose
sodium is present in an amount from about 0 to about 20% w/w, about
1% w/w to about 10% w/w, about 5% w/w to about 10% w/w, about 6%
w/w to about 8% w/w, about 4% w/w to about 6% w/w, or about 2% w/w
to about 4% w/w. In some embodiments, at least one excipient is a
binder. In some embodiments, the binder is polyvinylpyrrolidone. In
some embodiments, the polyvinylpyrrolidone is present in an amount
from about 0 to about 10% w/w, about 1 to about 5% w/w, or about 2%
w/w. In some embodiments, the binder is hydroxypropyl cellulose;
and hydroxypropyl cellulose is present in an amount from about 0 to
about 10% w/w, about 0 to about 5% w/w, about 0 to about 2% w/w,
about 0.1% w/w to about 1.1% w/w, or about 0.1% w/w to about 1%
w/w. In some embodiments, the formulation comprises lactose,
microcrystalline cellulose, croscarmellose sodium, and
hydroxypropyl cellulose. In some embodiments, at least one
excipient is a surfactant. In some embodiments, the surfactant is
sodium lauryl sulfate. In some embodiments, the surfactant is
sodium lauryl sulfate in an amount from about 0 to about 10% w/w,
about 0.5 to about 5% w/w, about 1 to about 4% w/w, about 4% w/w to
about 8% w/w, or about 5% w/w to about 6% w/w. In some embodiments,
at least one excipient is a glidant. In some embodiments, the
glidant is silica (colloidal silicon dioxide). In some embodiments,
the glidant is silica (colloidal silicon dioxide) and the silica
(colloidal silicon dioxide) is present in an amount from about 0 to
about 5% w/w, 0.1% w/w to about 1.5% w/w, about 0.4% w/w to about
0.8% w/w, or about 0.5% w/w to about 0.6% w/w. In some embodiments,
at least one excipient is a lubricant. In some embodiments, the
lubricant is magnesium stearate. In some embodiments, the lubricant
is magnesium stearate and the magnesium stearate is present in an
amount from about 0.01% w/w to about 5% w/w, 0.01% w/w to about 2%
w/w, 0.1% w/w to about 0.7% w/w, or about 0.5% w/w to about 0.6%
w/w. In some embodiments, the excipients comprise lactose,
microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose
sodium, sodium lauryl sulfate, colloidal silicon dioxide and
magnesium stearate.
[0512] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 75% w/w of ibrutinib, and intragranular and extragranular
excipients; wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, croscarmellose sodium, and hydroxypropyl cellulose; and
the extragranular excipients comprise croscarmellose sodium, sodium
lauryl sulfate, colloidal silicon dioxide, and magnesium stearate.
In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 75% w/w of ibrutinib, wherein the process comprises a wet
granulation method, the intragranular excipients comprise [0513]
lactose in an amount from about 5% w/w to about 20% w/w, about 8%
w/w to about 15% w/w, or about 8% w/w to about 14% w/w; [0514]
microcrystalline cellulose in an amount from about 5% w/w to about
20% w/w, about 8% w/w to about 20% w/w, or about 8% w/w to about
15% w/w; [0515] croscarmellose sodium in an amount from about 0%
w/w to about 10% w/w, about 2% w/w to about 5% w/w, or about 2% w/w
to about 4% w/w; and [0516] hydroxypropyl cellulose in an amount
from about 0% w/w to about 2% w/w, about 0.1% w/w to about 1.1%
w/w, or about 0.1% w/w to about 1% w/w; and the extragranular
excipients comprise [0517] croscarmellose sodium in an amount from
about 0% w/w to about 5% w/w, about 2% w/w to about 5% w/w, or
about 2% w/w to about 5% w/w; [0518] sodium lauryl sulfate in an
amount from about 0% w/w to about 10% w/w, about 4% w/w to about 8%
w/w, or about 5% w/w to about 6% w/w; [0519] colloidal silicon
dioxide in an amount from about 0.1% w/w to about 1.5% w/w, about
0.4% w/w to about 0.8% w/w, or about 0.5% w/w to about 0.6% w/w;
and [0520] magnesium stearate in an amount from about 0.1% w/w to
about 1.5% w/w, about 0.4% w/w to about 0.8% w/w, or about 0.5% w/w
to about 0.6% w/w.
[0521] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising about 60% w/w to
about 75% w/w of ibrutinib, and intragranular and extragranular
excipients; wherein the process comprises a wet granulation method,
the intragranular excipients comprise lactose, microcrystalline
cellulose, sodium lauryl sulfate, polyvinylpyrrolidone and
croscarmellose sodium, and the extragranular excipients comprise
croscarmellose sodium, sodium lauryl sulfate, colloidal silicon
dioxide, and magnesium stearate. In another embodiment provided is
a process for preparing a high-load solid tablet formulation
comprising about 60% w/w to about 75% w/w of ibrutinib, wherein the
process comprises a wet granulation method, the intragranular
excipients comprise [0522] lactose in an amount from about 10% w/w
to about 20% w/w, or about 12% w/w to about 15% w/w; [0523]
microcrystalline cellulose in an amount from about 1% w/w to about
10% w/w, about 2% w/w to about 5% w/w; [0524] polyvinylpyrrolidone
in an amount from about 0% w/w to about 5% w/w, about 1% w/w to
about 3% w/w; [0525] croscarmellose sodium in an amount from about
1% w/w to about 10% w/w, or about 3% w/w to about 7% w/w; and
[0526] sodium lauryl sulfate in an amount from about 0% w/w to
about 2% w/w, about 0.5% w/w to about 1.5% w/w; and the
extragranular excipients comprise [0527] croscarmellose sodium in
an amount from about 0% w/w to about 5% w/w, about 1% w/w to about
3% w/w; [0528] sodium lauryl sulfate in an amount from about 0% w/w
to about 10% w/w or about 0% w/w to about 4% w/w; [0529] colloidal
silicon dioxide in an amount from about 0.4% w/w to about 0.8% w/w,
or about 0.5% w/w to about 0.6% w/w; and [0530] magnesium stearate
in an amount from about 0.4% w/w to about 0.8% w/w, or about 0.5%
w/w to about 0.6% w/w.
[0531] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and the formulation
comprises: [0532] a) about 69% w/w to about 71% w/w of ibrutinib,
[0533] b) about 13% w/w to about 15% w/w of lactose, [0534] c)
about 2% w/w to about 5% w/w of microcrystalline cellulose, [0535]
d) about 1% w/w to about 3% w/w of polyvinylpyrrolidone, [0536] e)
about 6% w/w to about 8% w/w of croscarmellose sodium, [0537] f)
about 1% w/w to about 4% w/w of sodium lauryl sulfate, [0538] g)
about 0.4% w/w to about 0.6% w/w of colloidal silicon dioxide, and
[0539] h) about 0.4% w/w to about 0.6% w/w of magnesium
stearate.
[0540] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and the formulation
comprises: [0541] a) about 70% w/w of ibrutinib, [0542] b) about
14% w/w of lactose, [0543] c) about 5% w/w of microcrystalline
cellulose, [0544] d) about 2% w/w of polyvinylpyrrolidone, [0545]
e) about 7% w/w of croscarmellose sodium, [0546] f) about 1% w/w of
sodium lauryl sulfate, [0547] g) about 0.5% w/w of colloidal
silicon dioxide, and [0548] h) about 0.5% w/w of magnesium
stearate.
[0549] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and the formulation
comprises: [0550] a) about 70% w/w of ibrutinib, [0551] b) about
14% w/w of lactose, [0552] c) about 2% w/w of microcrystalline
cellulose, [0553] d) about 2% w/w of polyvinylpyrrolidone, [0554]
e) about 7% w/w of croscarmellose sodium, [0555] f) about 4% w/w of
sodium lauryl sulfate, [0556] g) about 0.5% w/w of colloidal
silicon dioxide, and [0557] h) about 0.5% w/w of magnesium
stearate.
[0558] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and wherein the
formulation comprises: [0559] a) about 65% w/w to about 75% w/w, or
about 70% w/w of ibrutinib, [0560] b) about 14% w/w to about 18%
w/w, or about 16% w/w of lactose monohydrate, [0561] c) about 1%
w/w to about 3% w/w, or about 2% w/w of polyvinylpyrrolidone,
[0562] d) about 0.5% w/w to about 1.5% w/w, or about 1% w/w of
sodium lauryl sulfate, e) about 5% w/w to about 15% w/w, or about
10% w/w of crospovidone, [0563] f) about 0.3% w/w to about 0.7%
w/w, or about 0.5% w/w of colloidal silicon dioxide, and [0564] g)
about 0.3% w/w to about 0.7% w/w, or about 0.5% w/w of magnesium
stearate.
[0565] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and wherein the
formulation comprises: [0566] a) about 59% w/w to about 61% w/w of
ibrutinib, [0567] b) about 13% w/w to about 15% w/w of lactose,
[0568] c) about 13% w/w to about 15% w/w of microcrystalline
cellulose, [0569] d) about 4% w/w to about 6% w/w of croscarmellose
sodium, [0570] e) about 5% w/w to about 7% w/w of sodium lauryl
sulfate, [0571] f) about 0.4% w/w to about 0.6% w/w of colloidal
silicon dioxide, and [0572] g) about 0.4% w/w to about 0.6% w/w of
magnesium stearate.
[0573] In some embodiments, the total weight of a tablet is about
934 mg.
[0574] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and wherein the
formulation comprises: [0575] a) about 59% w/w to about 61% w/w of
ibrutinib, [0576] b) about 13% w/w to about 14% w/w of lactose,
[0577] c) about 13% w/w to about 14% w/w of microcrystalline
cellulose, [0578] d) about 2% w/w to about 3% w/w of croscarmellose
sodium(intragranular), [0579] e) about 0.8% w/w to about 1.2% w/w
of hydroxypropyl cellulose, [0580] f) about 2% w/w to about 3% w/w
of croscarmellose sodium(extragranular), [0581] g) about 5.5 to
about 6.5% w/w of sodium lauryl sulfate, [0582] h) about 0.4% w/w
to about 0.6% w/w of colloidal silicon dioxide, and [0583] i) about
0.4% w/w to about 0.6% w/w of magnesium stearate.
[0584] In some embodiments, the total weight of a tablet is about
934 mg.
[0585] In another embodiment provided is a process for preparing a
high-load solid tablet formulation comprising ibrutinib, wherein
the process comprises a wet granulation method, and wherein the
formulation comprises: [0586] a) about 69% w/w to about 71% w/w of
ibrutinib, [0587] b) about 8% w/w to about 9% w/w of lactose,
[0588] c) about 8 to about 9% w/w of microcrystalline cellulose,
[0589] d) about 2.5 to about 3.5% w/w of croscarmellose sodium
(intragranular), [0590] e) about 2.5 to about 3.5% w/w of
croscarmellose sodium (extragranular), [0591] g) about 5.5 to about
6.5% w/w of sodium lauryl sulfate, [0592] h) about 0.4% w/w to
about 0.6% w/w of colloidal silicon dioxide, and [0593] i) about
0.4% w/w to about 0.6% w/w of magnesium stearate.
[0594] In some embodiments, the total weight of a tablet is about
800 mg.
[0595] In some embodiments of the high-load solid tablet
formulations described herein comprising ibrutinib and prepared
using a wet granulation method, the ibrutinib is in an amount of
about 560 mg. In some embodiments of the high-load solid tablet
formulations described herein comprising ibrutinib and prepared
using a wet granulation method, the ibrutinib is in micronized
form. In some embodiments of the high-load solid tablet
formulations described herein comprising ibrutinib and prepared
using a wet granulation method, the formulation is used for once a
day dosing. In some embodiments of the high-load solid tablet
formulations described herein comprising ibrutinib and prepared
using a wet granulation method, the formulation is in an oral
dosage form containing a therapeutically effective amount of
ibrutinib.
[0596] Moreover, the pharmaceutical compositions described herein,
which include Compound 1 can be formulated into any suitable dosage
form, including but not limited to, solid oral dosage forms,
controlled release formulations, fast melt formulations,
effervescent formulations, tablets, powders, pills, capsules,
delayed release formulations, extended release formulations,
pulsatile release formulations, multiparticulate formulations, and
mixed immediate release and controlled release formulations. In
some embodiments, the tablets described herein are for immediate
release and do not comprise a viscosity increasing agent, such as
poloxamer or glyceryl behenate.
[0597] In some embodiments, the solid dosage forms disclosed herein
may be in the form of a tablet, including a suspension tablet, a
fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration tablet, an effervescent tablet, or a caplet.
In other embodiments, the pharmaceutical formulation is in the form
of a powder. In still other embodiments, the pharmaceutical
formulation is in the form of a tablet, including but not limited
to, a fast-melt tablet. Additionally, pharmaceutical formulations
described herein may be administered as a single capsule or in
multiple capsule dosage form. In some embodiments, the
pharmaceutical formulation is administered in two, or three, or
four, tablets.
[0598] In some embodiments, the compositions described herein are
prepared by mixing particles of Compound 1 with one or more
pharmaceutical excipients to form a bulk blend composition. When
referring to these bulk blend compositions as homogeneous, it is
meant that the particles of Compound 1 are dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective unit dosage forms, such as
tablets, pills, and capsules. The individual unit dosages may also
include film coatings, which disintegrate upon oral ingestion or
upon contact with diluent.
[0599] In some embodiments, the wet granulation method comprises
granulating the mixture of ibrutinib and the intragranular
excipients with a granulation liquid, such as purified water, under
granulation conditions, such as high shear granulation conditions,
to form granules.
[0600] In some embodiments, the compositions or formulations
described herein are prepared by a method comprising (1) mixing
ibrutinib with the intragranular excipients such as filler, binder,
disintegrant and surfactant; (2) granulating the mixture of
ibrutinib and the intragranular excipients with purified water or
an aqueous binder solution under high shear granulation conditions
to form granules; (3) drying the granules to form dried granules;
(4) milling the dried granules; (5) blending the milled granules
with the extragranular excipients such as filler, disintegrant,
surfactant and lubricant; and (6) compressing the mixture of milled
granules and the extragranular excipients to form tablets.
[0601] The pharmaceutical compositions or formulations described
herein can further include a flavoring agent, sweetening agent,
colorant, antioxidant, preservative, or one or more combination
thereof. In still other aspects, using standard coating procedures,
such as those described in Remington's Pharmaceutical Sciences,
20th Edition (2000), a film coating is provided around the
formulation of Compound 1. In one embodiment, some or all of the
particles of the Compound 1 are coated. In another embodiment, some
or all of the particles of the Compound 1 are microencapsulated. In
still another embodiment, the particles of the Compound 1 are not
microencapsulated and are uncoated.
[0602] Suitable antioxidants for use in the compositions or
formulations described herein include, for example, e.g., butylated
hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
[0603] It should be appreciated that there is considerable overlap
between additives used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of additives that can be
included in the compositions or formulations described herein. The
amounts of such additives can be readily determined by one skilled
in the art, according to the particular properties desired.
[0604] Compressed tablets are solid dosage forms prepared by
compacting the bulk blend of the formulations described above. In
various embodiments, compressed tablets which are designed to
dissolve in the mouth will include one or more flavoring agents. In
other embodiments, the compressed tablets will include a film
surrounding the final compressed tablet. In some embodiments, the
film coating can provide a delayed release of Compound 1 from the
formulation. In other embodiments, the film coating aids in patient
compliance (e.g., Opadry.RTM. coatings or sugar coating). Film
coatings including Opadry.RTM. typically range from about 1% to
about 3% of the tablet weight. In other embodiments, the compressed
tablets include one or more excipients.
[0605] In some embodiments, the compositions or formulations
described herein can be formulated as enteric coated delayed
release oral dosage forms, i.e., as an oral dosage form of a
pharmaceutical composition as described herein which utilizes an
enteric coating to affect release in the small intestine of the
gastrointestinal tract. The enteric coated dosage form may be a
compressed or molded or extruded tablet/mold (coated or uncoated)
containing granules, powder, pellets, beads or particles of the
active ingredient and/or other composition components, which are
themselves coated or uncoated. The enteric coated oral dosage form
may also be a capsule (coated or uncoated) containing pellets,
beads or granules of the solid carrier or the composition, which
are themselves coated or uncoated.
[0606] The term "delayed release" as used herein refers to the
delivery so that the release can be accomplished at some generally
predictable location in the intestinal tract more distal to that
which would have been accomplished if there had been no delayed
release alterations. In some embodiments the method for delay of
release is coating. Any coatings should be applied to a sufficient
thickness such that the entire coating does not dissolve in the
gastrointestinal fluids at pH below about 5, but does dissolve at
pH about 5 and above. It is expected that any anionic polymer
exhibiting a pH-dependent solubility profile can be used as an
enteric coating in the methods and compositions described herein to
achieve delivery to the lower gastrointestinal tract. In some
embodiments the polymers described herein are anionic carboxylic
polymers. In other embodiments, the polymers and compatible
mixtures thereof, and some of their properties, include, but are
not limited to:
[0607] Shellac, also called purified lac, a refined product
obtained from the resinous secretion of an insect. This coating
dissolves in media of pH>7;
[0608] Acrylic polymers. The performance of acrylic polymers
(primarily their solubility in biological fluids) can vary based on
the degree and type of substitution. Examples of suitable acrylic
polymers include methacrylic acid copolymers and ammonium
methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE
(Rohm Pharma) are available as solubilized in organic solvent,
aqueous dispersion, or dry powders. The Eudragit series RL, NE, and
RS are insoluble in the gastrointestinal tract but are permeable
and are used primarily for colonic targeting. The Eudragit series E
dissolve in the stomach. The Eudragit series L, L-30D and S are
insoluble in stomach and dissolve in the intestine;
[0609] Cellulose Derivatives. Examples of suitable cellulose
derivatives are: ethyl cellulose; reaction mixtures of partial
acetate esters of cellulose with phthalic anhydride. The
performance can vary based on the degree and type of substitution.
Cellulose acetate phthalate (CAP) dissolves in pH>6. Aquateric
(FMC) is an aqueous based system and is a spray dried CAP
psuedolatex with particles <1 .mu.m. Other components in
Aquateric can include pluronics, Tweens, and acetylated
monoglycerides. Other suitable cellulose derivatives include:
cellulose acetate trimellitate (Eastman); methylcellulose
(Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate
(HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin
Etsu)). The performance can vary based on the degree and type of
substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S,
HP-55F grades are suitable. The performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate include, but are not
limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which
dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
These polymers are offered as granules, or as fine powders for
aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP
dissolves in pH>5, and it is much less permeable to water vapor
and gastric fluids.
[0610] In some embodiments, the coating can, and usually does,
contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in
the art. Suitable plasticizers include triethyl citrate (Citroflex
2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl
phthalate, tributyl citrate, acetylated monoglycerides, glycerol,
fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers usually will
contain 10-25% by weight of a plasticizer, especially dibutyl
phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are
employed to apply coatings. The coating thickness must be
sufficient to ensure that the oral dosage form remains intact until
the desired site of topical delivery in the intestinal tract is
reached.
[0611] Colorants, detackifiers, surfactants, antifoaming agents,
lubricants (e.g., carnuba wax or PEG) may be added to the coatings
besides plasticizers to solubilize or disperse the coating
material, and to improve coating performance and the coated
product.
[0612] In other embodiments, the formulations described herein,
which include Compound 1, are delivered using a pulsatile dosage
form. A pulsatile dosage form is capable of providing one or more
immediate release pulses at predetermined time points after a
controlled lag time or at specific sites. Many other types of
controlled release systems known to those of ordinary skill in the
art and are suitable for use with the formulations described
herein. Examples of such delivery systems include, e.g.,
polymer-based systems, such as polylactic and polyglycolic acid,
plyanhydrides and polycaprolactone; porous matrices,
nonpolymer-based systems that are lipids, including sterols, such
as cholesterol, cholesterol esters and fatty acids, or neutral
fats, such as mono-, di- and triglycerides; hydrogel release
systems; silastic systems; peptide-based systems; wax coatings,
bioerodible dosage forms, compressed tablets using conventional
binders and the like. See, e.g., Liberman et al., Pharmaceutical
Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al.,
Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed., pp.
751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,
5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,
5,977,175, 6,465,014 and 6,932,983, each of which is specifically
incorporated by reference.
[0613] In some embodiments, pharmaceutical formulations are
provided that include particles of Compound 1 and at least one
dispersing agent or suspending agent for oral administration to a
subject. The formulations may be a powder and/or granules for
suspension, and upon admixture with water, a substantially uniform
suspension is obtained.
[0614] It is to be appreciated that there is overlap between the
above-listed additives used in the aqueous dispersions or
suspensions described herein, since a given additive is often
classified differently by different practitioners in the field, or
is commonly used for any of several different functions. Thus, the
above-listed additives should be taken as merely exemplary, and not
limiting, of the types of additives that can be included in
formulations described herein. The amounts of such additives can be
readily determined by one skilled in the art, according to the
particular properties desired.
Dosing and Treatment Regimens
[0615] In some embodiments, the amount of Compound 1 that is
administered to a mammal is from 300 mg/day up to, and including,
1000 mg/day. In some embodiments, the amount of Compound 1 that is
administered to a mammal is from 420 mg/day up to, and including,
840 mg/day. In some embodiments, the amount of Compound 1 that is
administered to a mammal is about 420 mg/day, about 560 mg/day, or
about 840 mg/day. In some embodiments, the amount of Compound 1
that is administered to a mammal is about 420 mg/day. In some
embodiments, the amount of Compound 1 that is administered to a
mammal is about 560 mg/day. In some embodiments, the AUC.sub.0-24
of Compound 1 is between about 150 and about 3500 ng*h/mL. In some
embodiments, the AUC.sub.0-24 of Compound 1 is between about 500
and about 1100 ng*h/mL. In some embodiments, Compound 1 is
administered orally. In some embodiments, Compound 1 is
administered once per day, twice per day, or three times per day.
In some embodiments, Compound 1 is administered daily. In some
embodiments, Compound 1 is administered once daily. In some
embodiments, Compound 1 is administered every other day. In some
embodiments, the Compound 1 is a maintenance therapy.
[0616] Compound 1 can be used in the preparation of medicaments for
the inhibition of Btk or a homolog thereof, or for the treatment of
diseases or conditions that would benefit, at least in part, from
inhibition of Btk or a homolog thereof, including a subject
diagnosed with a hematological malignancy. In addition, a method
for treating any of the diseases or conditions described herein in
a subject in need of such treatment, involves administration of
pharmaceutical compositions containing Compound 1, or a
pharmaceutically acceptable salt, pharmaceutically acceptable
N-oxide, pharmaceutically active metabolite, pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate thereof,
in therapeutically effective amounts to said subject.
[0617] The compositions containing Compound 1 can be administered
for prophylactic, therapeutic, or maintenance treatment. In some
embodiments, compositions containing Compound 1 are administered
for therapeutic applications (e.g., administered to a subject
diagnosed with a hematological malignancy). In some embodiments,
compositions containing Compound 1 are administered for therapeutic
applications (e.g., administered to a subject susceptible to or
otherwise at risk of developing a hematological malignancy). In
some embodiments, compositions containing Compound 1 are
administered to a patient who is in remission as a maintenance
therapy.
[0618] Amounts of Compound 1 will depend on the use (e.g.,
therapeutic, prophylactic, or maintenance). Amounts of Compound 1
will depend on severity and course of the disease or condition,
previous therapy, the patient's health status, weight, and response
to the drugs, and the judgment of the treating physician. It is
considered well within the skill of the art for one to determine
such therapeutically effective amounts by routine experimentation
(including, but not limited to, a dose escalation clinical trial).
In some embodiments, the amount of Compound 1 is from 300 mg/day up
to, and including, 1000 mg/day. In some embodiments, the amount of
Compound 1 is from 420 mg/day up to, and including, 840 mg/day. In
some embodiments, the amount of Compound 1 is from 400 mg/day up
to, and including, 860 mg/day. In some embodiments, the amount of
Compound 1 is about 360 mg/day. In some embodiments, the amount of
Compound 1 is about 420 mg/day. In some embodiments, the amount of
Compound 1 is about 560 mg/day. In some embodiments, the amount of
Compound 1 is about 840 mg/day. In some embodiments, the amount of
Compound 1 is from 2 mg/kg/day up to, and including, 13 mg/kg/day.
In some embodiments, the amount of Compound 1 is from 2.5 mg/kg/day
up to, and including, 8 mg/kg/day. In some embodiments, the amount
of Compound 1 is from 2.5 mg/kg/day up to, and including, 6
mg/kg/day. In some embodiments, the amount of Compound 1 is from
2.5 mg/kg/day up to, and including, 4 mg/kg/day. In some
embodiments, the amount of Compound 1 is about 2.5 mg/kg/day. In
some embodiments, the amount of Compound 1 is about 8
mg/kg/day.
[0619] In one embodiment, the tablet formulation of the invention
with 140 mg of dose in dogs produces C.sub.max of about 260 to 400
ng/mL (Fed), and about 300 to 400 ng/mL (Fasted). In another
embodiment, the formulation produces C.sub.max of about 280 to 380
ng/mL (Fed), and about 360 to 380 ng/mL (Fasted). In a particular
embodiment, the formulation produces C.sub.max of about 290 ng/mL
(Fed), and about 370 ng/mL (Fasted). In another particular
embodiment, the formulation produces C.sub.max of about 370 ng/mL
(Fed), and about 370 ng/mL (Fasted). In one embodiment, the
formulation is a wet granulation formulation. In one embodiment,
the tablet formulation is Formulation BK02, BK21A, or BK21B. In a
particular embodiment, the tablet formulation is Formulation BK21A.
In another particular embodiment, the tablet formulation is
Formulation BK21B. (Table 1E and 1F).
[0620] In one embodiment, the tablet formulation of the invention
with 140 mg of dose in dogs produces AUC of about 850 to 1050
ng*h/mL (Fed), and about 850 to 1050 ng*h/mL (Fasted). In another
embodiment, the formulation produces AUC of about 870 to 1050
ng*h/mL (Fed), and about 840 to 1000 ng*h/mL (Fasted). In a
particular embodiment, the formulation produces AUC of about 875
ng*h/mL (Fed), and about 1000 ng*h/mL (Fasted). In another
particular embodiment, the formulation produces AUC of about 1000
ng*h/mL (Fed), and about 850 ng*h/mL (Fasted). In one embodiment,
the formulation is a wet granulation formulation. In one
embodiment, the tablet formulation is Formulation BK02, BK21A, or
BK21B. In a particular embodiment, the tablet formulation is
Formulation BK21A. In another particular embodiment, the tablet
formulation is Formulation BK21B. (Table 1E and 1F).
[0621] In one embodiment, the tablet formulation of the invention
with 140 mg of dose in dogs produces % F.sub.rel (tablet/capsule)
(C.sub.max) value of about 150-250 (Fed) and 100-160 (Fasted). In a
particular embodiment, the formulation produces % F.sub.rel
(tablet/capsule) (C.sub.max) value of about 170 (Fed) and about 110
(Fasted). In another particular embodiment, the formulation
produces % F.sub.rel (tablet/capsule) (C.sub.max) value of about
230 (Fed) and about 150 (Fasted). In one embodiment, the
formulation is a wet granulation formulation. In one embodiment,
the tablet formulation is Formulation BK02, BK21A, or BK21B. In a
particular embodiment, the tablet formulation is Formulation BK21A.
In another particular embodiment, the tablet formulation is
Formulation BK21B. (Table 1E and 1F).
[0622] In one embodiment, the tablet formulation of the invention
with 140 mg of dose in dogs produces % F.sub.rel (tablet/capsule)
(AUC) value of about 110-150 (Fed) and 100-140 (Fasted). In a
particular embodiment, the formulation produces % F.sub.rel
(tablet/capsule) (AUC) value of about 120 (Fed) and about 110
(Fasted). In another particular embodiment, the formulation
produces % F.sub.rel (tablet/capsule) (AUC) value of about 150
(Fed) and about 130 (Fasted). In one embodiment, the formulation is
a wet granulation formulation. In one embodiment, the tablet
formulation is Formulation BK02, BK21A, or BK21B. In a particular
embodiment, the tablet formulation is Formulation BK21A. In another
particular embodiment, the tablet formulation is Formulation BK21B.
(Table 1E and 1F).
[0623] In one embodiment, the tablet formulation of the invention
with 140 mg of dose in dogs produces % F.sub.rel (Fed/Fasted)
(C.sub.max) value of about 90-105. In a particular embodiment, the
formulation produces % F.sub.rel (Fed/Fasted) (C.sub.max) value of
about 95. In another particular embodiment, the formulation
produces % F.sub.rel (Fed/Fasted) (C.sub.max) value of about 100.
In one embodiment, the formulation is a wet granulation
formulation. In one embodiment, the tablet formulation is
Formulation BK02, BK21A, or BK21B. In a particular embodiment, the
tablet formulation is Formulation BK21A. In another particular
embodiment, the tablet formulation is Formulation BK21B. (Table 1E
and 1F).
[0624] In one embodiment, the tablet formulation of the invention
with 140 mg of dose in dogs produces % F.sub.rel (Fed/Fasted) (AUC)
value of about 90-140. In a particular embodiment, the formulation
produces % F.sub.rel (Fed/Fasted) (AUC) value of about 100. In one
embodiment, the formulation is a wet granulation formulation. In
one embodiment, the tablet formulation is Formulation BK02, BK21A,
or BK21B. In a particular embodiment, the tablet formulation is
Formulation BK21A. In another particular embodiment, the tablet
formulation is Formulation BK21B. (Table 1E and 1F).
[0625] In some embodiments, pharmaceutical compositions described
herein include about 140 mg of Compound 1. In some embodiments, a
tablet formulation is prepared that includes about 140 mg of
Compound 1. In some embodiments, 2, 3, 4, or 5 of the tablet
formulations are administered daily. In some embodiments, 3 or 4 of
the capsules are administered daily. In some embodiments tablet are
administered once daily. In some embodiments, the capsules are
administered once daily. In other embodiments, the tablet are
administered multiple times a day.
[0626] In another aspect is a high-load solid tablet formulation
comprising ibrutinib, wherein ibrutinib is a compound with the
structure of Compound 1,
##STR00006## [0627] and the tablet comprises about 560 mg of
ibrutinib.
[0628] In another embodiment is a high-load solid tablet
formulation, wherein the tablet is used for once a day oral dosing.
The high-load solid tablet formulations described herein make it
possible for one tablet a day administration and contain a large
amount of ibrutinib per tablet of about 420 mg to about 840 mg,
such as about 420 mg, about 560 mg, or about 840 mg, or any range
between any two of the values, end points inclusive. In another
embodiment is a high-load solid tablet formulation, wherein the
tablet comprises 560 mg of ibrutinib. In another embodiment is a
high-load solid tablet formulation, wherein ibrutinib is in
micronized form.
[0629] In some embodiments, Compound 1 is administered daily. In
some embodiments, Compound 1 is administered every other day.
[0630] In some embodiments, Compound 1 is administered once per
day. In some embodiments, Compound 1 is administered twice per day.
In some embodiments, Compound 1 is administered three times per
day. In some embodiments, Compound 1 is administered four times per
day.
[0631] In some embodiments, Compound 1 is administered until
disease progression, unacceptable toxicity, or individual choice.
In some embodiments, Compound 1 is administered daily until disease
progression, unacceptable toxicity, or individual choice. In some
embodiments, Compound 1 is administered every other day until
disease progression, unacceptable toxicity, or individual
choice.
[0632] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously; alternatively, the dose of drug being
administered may be temporarily reduced or temporarily suspended
for a certain length of time (i.e., a "drug holiday"). The length
of the drug holiday can vary between 2 days and 1 year, including
by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7
days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50
days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days,
250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The
dose reduction during a drug holiday may be from 10%-100%,
including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or
100%.
[0633] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disease, disorder or condition is retained. Patients can, however,
require intermittent treatment on a long-term basis upon any
recurrence of symptoms.
[0634] The amount of a given agent that will correspond to such an
amount will vary depending upon factors such as the particular
compound, the severity of the disease, the identity (e.g., weight)
of the subject or host in need of treatment, but can nevertheless
be routinely determined in a manner known in the art according to
the particular circumstances surrounding the case, including, e.g.,
the specific agent being administered, the route of administration,
and the subject or host being treated. In general, however, doses
employed for adult human treatment will typically be in the range
of 0.02-5000 mg per day, or from about 1-1500 mg per day. The
desired dose may conveniently be presented in a single dose or as
divided doses administered simultaneously (or over a short period
of time) or at appropriate intervals, for example as two, three,
four or more sub-doses per day.
[0635] The pharmaceutical compositions or formulations described
herein may be in unit dosage forms suitable for single
administration of precise dosages. In unit dosage form, the
formulation is divided into unit doses containing appropriate
quantities of one or more compound. The unit dosage may be in the
form of a package containing discrete quantities of the
formulation. Non-limiting examples are packaged tablets or
capsules, and powders in vials or ampoules. Aqueous suspension
compositions can be packaged in single-dose non-reclosable
containers. Alternatively, multiple-dose reclosable containers can
be used, in which case it is typical to include a preservative in
the composition. In some embodiments, each unit dosage form
comprises 140 mg of Compound 1. In some embodiments, an individual
is administered 1 unit dosage form per day. In some embodiments, an
individual is administered 2 unit dosage forms per day. In some
embodiments, an individual is administered 3 unit dosage forms per
day. In some embodiments, an individual is administered 4 unit
dosage forms per day.
[0636] The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual treatment regime is large, and
considerable excursions from these recommended values are not
uncommon. Such dosages may be altered depending on a number of
variables, not limited to the activity of the compound used, the
disease or condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the disease
or condition being treated, and the judgment of the
practitioner.
[0637] Toxicity and therapeutic efficacy of such therapeutic
regimens can be determined by standard pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 (the dose lethal to 50% of
the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio between the
toxic and therapeutic effects is the therapeutic index and it can
be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds exhibiting high therapeutic indices are preferred. The
data obtained from cell culture assays and animal studies can be
used in formulating a range of dosage for use in human. The dosage
of such compounds lies preferably within a range of circulating
concentrations that include the ED.sub.50 with minimal toxicity.
The dosage may vary within this range depending upon the dosage
form employed and the route of administration utilized.
Combination Therapy
[0638] In certain instances, it is appropriate to administer
Compound 1 in combination with another therapeutic agent.
[0639] In one embodiment, the compositions and methods described
herein are also used in conjunction with other therapeutic reagents
that are selected for their particular usefulness against the
condition that is being treated. In general, the compositions
described herein and, in embodiments where combinational therapy is
employed, other agents do not have to be administered in the same
pharmaceutical composition, and are, because of different physical
and chemical characteristics, administered by different routes. In
one embodiment, the initial administration is made according to
established protocols, and then, based upon the observed effects,
the dosage, modes of administration and times of administration,
further modified.
[0640] In various embodiments, the compounds are administered
concurrently (e.g., simultaneously, essentially simultaneously or
within the same treatment protocol) or sequentially, depending upon
the nature of the disease, the condition of the patient, and the
actual choice of compounds used. In certain embodiments, the
determination of the order of administration, and the number of
repetitions of administration of each therapeutic agent during a
treatment protocol, is based upon evaluation of the disease being
treated and the condition of the patient.
[0641] For combination therapies described herein, dosages of the
co-administered compounds vary depending on the type of co-drug
employed, on the specific drug employed, on the disease or
condition being treated and so forth.
[0642] The individual compounds of such combinations are
administered either sequentially or simultaneously in separate or
combined pharmaceutical formulations. In one embodiment, the
individual compounds will be administered simultaneously in a
combined pharmaceutical formulation. Appropriate doses of known
therapeutic agents will be appreciated by those skilled in the
art.
[0643] The combinations referred to herein are conveniently
presented for use in the form of a pharmaceutical compositions
together with a pharmaceutically acceptable diluent(s) or
carrier(s).
[0644] Disclosed herein, in certain embodiments, is a method for
treating a cancer in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. In some
embodiments, the method further comprises administering a second
cancer treatment regimen.
[0645] In some embodiments, administering a Btk inhibitor before a
second cancer treatment regimen reduces immune-mediated reactions
to the second cancer treatment regimen. In some embodiments,
administering Compound 1 before ofatumumab reduces immune-mediated
reactions to ofatumumab.
[0646] In some embodiments, the second cancer treatment regimen
comprises a chemotherapeutic agent, a steroid, an immunotherapeutic
agent, a targeted therapy, or a combination thereof. In some
embodiments, the second cancer treatment regimen comprises a B cell
receptor pathway inhibitor. In some embodiments, the B cell
receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor,
a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K
inhibitor, a Blnk inhibitor, a PLC.gamma. inhibitor, a PKC.beta.
inhibitor, or a combination thereof. In some embodiments, the
second cancer treatment regimen comprises an antibody, B cell
receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor,
an mTOR inhibitor, an immunochemotherapy, a radioimmunotherapeutic,
a DNA damaging agent, a proteosome inhibitor, a Cyp3A4 inhibitor, a
histone deacetylase inhibitor, a protein kinase inhibitor, a
hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a
Jak1/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP
inhibitor, or a combination thereof.
[0647] In some embodiments, the second cancer treatment regimen
comprises chlorambucil, ifosphamide, doxorubicin, mesalazine,
thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine,
fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab,
dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab,
bortezomib, pentostatin, endostatin, EPOCH-R, DA-EPOCH-R, rifampin,
selinexor, gemcitabine, obinutuzumab, carmustine, cytarabine,
melphalan, ublituximab, palbociclib, ACP-196 (Acerta Pharma BV),
TGR-1202 (TG Therapeutics, Inc.), TEDDI, TEDD, MEDI4736
(AstraZeneca), ABT-0199 (AbbVie), CC-122 (Celgene Corporation),
LD-AraC, ketoconazole, etoposide, carboplatin, moxifloxacin,
citrovorum, methotrexate, filgrastim, mesna, vincristine,
cyclophosphamide, erythromycin, voriconazole, nivolumab, or a
combination thereof.
[0648] In some embodiments, the second cancer treatment regimen
comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and
prednisone, and optionally, rituximab.
[0649] In some embodiments, the second cancer treatment regimen
comprises bendamustine, and rituximab.
[0650] In some embodiments, the second cancer treatment regimen
comprises fludarabine, cyclophosphamide, and rituximab.
[0651] In some embodiments, the second cancer treatment regimen
comprises cyclophosphamide, vincristine, and prednisone, and
optionally, rituximab.
[0652] In some embodiments, the second cancer treatment regimen
comprises etoposide, doxorubicin, vinristine, cyclophosphamide,
prednisolone, and optionally, rituximab.
[0653] In some embodiments, the second cancer treatment regimen
comprises dexamethasone and lenalidomide.
[0654] In some embodiments, the second cancer treatment comprises a
proteasome inhibitor. In some embodiments, the second treatment
comprises bortezomib. In some embodiments, the second cancer
treatment comprises an epoxyketone. In some embodiments, the second
cancer treatment comprises epoxomicin. In some embodiments, the
second cancer treatment comprises a tetrapeptide epoxyketone. In
some embodiments, the second cancer treatment comprises
carfilzomib. In some embodiments, the second cancer treatment
comprises disulfram, epigallocatechin-3-gallate, salinosporamide A,
ONX 0912m CEP-18770, MLN9708, or MG132.
[0655] In some embodiments, the second cancer treatment comprises a
Cyp3A4 inhibitor. In some embodiments, the second cancer treatment
comprises indinavir, nelfinavir, ritonavir, clarithromycin,
itraconazole, ketoconazole, nefazodone. In some embodiments, the
second cancer treatment comprises ketoconazole.
[0656] In some embodiments, the second cancer treatment comprises a
Janus Kinase (JAK) inhibitor. In some embodiments, the second
treatment comprises Lestaurtinib, Tofacitinib, Ruxolitinib, CYT387,
Baricitinib or Pacritinib.
[0657] In some embodiments, the second cancer treatment comprises a
histone deacetylase inhibitor (HDAC inhibitor, HDI). In some
embodiments, the second cancer treatment comprises a hydroxamic
acid (or hydroxamate), such as trichostatin A, vorinostat (SAHA),
belinostat (PXD101), LAQ824, and panobinostat (LBH589), a cyclic
tetrapeptide, such as trapoxin B, a depsipeptide, a benzamide, such
as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), an
electrophilic ketone, or an aliphatic acid compound, such as
phenylbutyrate and valproic acid.
[0658] Additional cancer treatment regimens include Nitrogen
Mustards such as for example, bendamustine, chlorambucil,
chlormethine, cyclophosphamide, ifosfamide, melphalan,
prednimustine, trofosfamide; Alkyl Sulfonates like busulfan,
mannosulfan, treosulfan; Ethylene Imines like carboquone, thiotepa,
triaziquone; Nitrosoureas like carmustine, fotemustine, lomustine,
nimustine, ranimustine, semustine, streptozocin; Epoxides such as
for example, etoglucid; Other Alkylating Agents such as for example
dacarbazine, mitobronitol, pipobroman, temozolomide; Folic Acid
Analogues such as for example methotrexate, permetrexed,
pralatrexate, raltitrexed; Purine Analogs such as for example
cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine,
tioguanine; Pyrimidine Analogs such as for example azacitidine,
capecitabine, carmofur, cytarabine, decitabine, fluorouracil,
gemcitabine, tegafur; Vinca Alkaloids such as for example
vinblastine, vincristine, vindesine, vinflunine, vinorelbine;
Podophyllotoxin Derivatives such as for example etoposide,
teniposide; Colchicine derivatives such as for example demecolcine;
Taxanes such as for example docetaxel, paclitaxel, paclitaxel
poliglumex; Other Plant Alkaloids and Natural Products such as for
example trabectedin; Actinomycines such as for example
dactinomycin; Antracyclines such as for example aclarubicin,
daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone,
pirarubicin, valrubicin, zorubincin; Other Cytotoxic Antibiotics
such as for example bleomycin, ixabepilone, mitomycin, plicamycin;
Platinum Compounds such as for example carboplatin, cisplatin,
oxaliplatin, satraplatin; Methylhydrazines such as for example
procarbazine; Sensitizers such as for example aminolevulinic acid,
efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin;
Protein Kinase Inhibitors such as for example dasatinib, erlotinib,
everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib,
sorafenib, sunitinib, temsirolimus; Other Antineoplastic Agents
such as for example alitretinoin, altretamine, amzacrine,
anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib,
celecoxib, denileukin diftitox, estramustine, hydroxycarbamide,
irinotecan, lonidamine, masoprocol, miltefosein, mitoguazone,
mitotane, oblimersen, pegaspargase, pentostatin, romidepsin,
sitimagene ceradenovec, tiazofurine, topotecan, tretinoin,
vorinostat; Estrogens such as for example diethylstilbenol,
ethinylestradiol, fosfestrol, polyestradiol phosphate; Progestogens
such as for example gestonorone, medroxyprogesterone, megestrol;
Gonadotropin Releasing Hormone Analogs such as for example
buserelin, goserelin, leuprorelin, triptorelin; Anti-Estrogens such
as for example fulvestrant, tamoxifen, toremifene; Anti-Androgens
such as for example bicalutamide, flutamide, nilutamide; Enzyme
Inhibitors, aminoglutethimide, anastrozole, exemestane, formestane,
letrozole, vorozole; Other Hormone Antagonists such as for example
abarelix, degarelix; Immunostimulants such as for example histamine
dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex,
thymopentin; Immunosuppressants such as for example everolimus,
gusperimus, leflunomide, mycophenolic acid, sirolimus; Calcineurin
Inhibitors such as for example ciclosporin, tacrolimus; Other
Immunosuppressants such as for example azathioprine, lenalidomide,
methotrexate, thalidomide; and Radiopharmaceuticals such as for
example, iobenguane.
[0659] Additional cancer treatment regimens include interferons,
interleukins, Tumor Necrosis Factors, Growth Factors, or the
like.
[0660] Additional cancer treatment regimens include
Immunostimulants such as for example ancestim, filgrastim,
lenograstim, molgramostim, pegfilgrastim, sargramostim; Interferons
such as for example interferon alfa natural, interferon alfa-2a,
interferon alfa-2b, interferon alfacon-1, interferon alfa-n1,
interferon beta natural, interferon beta-1a, interferon beta-1b,
interferon gamma, peginterferon alfa-2a, peginterferon alfa-2b;
Interleukins such as for example aldesleukin, oprelvekin; Other
Immunostimulants such as for example BCG vaccine, glatiramer
acetate, histamine dihydrochloride, immunocyanin, lentinan,
melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor,
poly I:C, poly ICLC, roquinimex, tasonermin, thymopentin;
Immunosuppressants such as for example abatacept, abetimus,
alefacept, antilymphocyte immunoglobulin (horse), antithymocyte
immunoglobulin (rabbit), eculizumab, efalizumab, everolimus,
gusperimus, leflunomide, muromab-CD3, mycophenolic acid,
natalizumab, sirolimus; TNF alpha Inhibitors such as for example
adalimumab, afelimomab, certolizumab pegol, etanercept, golimumab,
infliximab; Interleukin Inhibitors such as for example anakinra,
basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept,
tocilizumab, ustekinumab; Calcineurin Inhibitors such as for
example ciclosporin, tacrolimus; Other Immunosuppressants such as
for example azathioprine, lenalidomide, methotrexate,
thalidomide.
[0661] Additional cancer treatment regimens include Adalimumab,
Alemtuzumab, Basiliximab, Bevacizumab, Cetuximab, Certolizumab
pegol, Daclizumab, Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab
tiuxetan, Infliximab, Muromonab-CD3, Natalizumab, Panitumumab,
Ranibizumab, Rituximab, Tositumomab, Trastuzumab, or the like, or a
combination thereof.
[0662] Additional cancer treatment regimens include Monoclonal
Antibodies such as for example alemtuzumab, bevacizumab,
catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab,
panitumumab, rituximab, trastuzumab, Immunosuppressants,
eculizumab, efalizumab, muromab-CD3, natalizumab; TNF alpha
Inhibitors such as for example adalimumab, afelimomab, certolizumab
pegol, golimumab, infliximab, Interleukin Inhibitors, basiliximab,
canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab,
Radiopharmaceuticals, ibritumomab tiuxetan, tositumomab; Others
Monoclonal Antibodies such as for example abagovomab, adecatumumab,
alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET
monoclonal antibody MetMab, apolizumab, apomab, arcitumomab,
basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab
vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab,
dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab,
ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab,
ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab,
inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab,
lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab,
monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab,
oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab,
sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab,
tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab,
zalutumumab.
[0663] Additional cancer treatment regimens include agents that
affect the tumor micro-environment such as cellular signaling
network (e.g. phosphatidylinositol 3-kinase (PI3K) signaling
pathway, signaling from the B-cell receptor and the IgE receptor).
In some embodiments, the second agent is a PI3K signaling inhibitor
or a syc kinase inhibitor. In one embodiment, the syk inhibitor is
R788. In another embodiment is a PKCy inhibitor such as by way of
example only, enzastaurin.
[0664] In some embodiments, the additional therapeutic agent
comprises an analgesic such as acetaminophen.
[0665] In some embodiments, the additional therapeutic agent
comprises an agent selected from: an inhibitor of LYN, SYK, JAK,
PI3K, PLC.gamma., MAPK, MEK or NF.kappa.B.
[0666] Examples of agents that affect the tumor micro-environment
include PI3K signaling inhibitor, syc kinase inhibitor, Protein
Kinase Inhibitors such as for example dasatinib, erlotinib,
everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib,
sorafenib, sunitinib, temsirolimus; Other Angiogenesis Inhibitors
such as for example GT-111, JI-101, R1530; Other Kinase Inhibitors
such as for example AC220, AC480, ACE-041, AMG 900, AP24534,
Any-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762,
AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI
811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607,
BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036,
dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076,
fostamatinib disodium, GSK2256098, GSK690693, INCB18424, INNO-406,
JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265,
MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937,
ON 01919.Na, OSI-027, OSI-930, Btk inhibitor, PF-00562271,
PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502,
PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763,
ramucirumab, regorafenib, R05185426, SAR103168, SCH 727965,
SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232,
TTP607, XL147, XL228, XL281R05126766, XL418, XL765.
[0667] Further examples of anti-cancer agents for use in
combination with a Btk inhibitor compound include inhibitors of
mitogen-activated protein kinase signaling, e.g., U0126, PD98059,
PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,
wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and
antibodies (e.g., rituxan).
[0668] Other anti-cancer agents that can be employed in combination
with a Btk inhibitor compound include Adriamycin, Dactinomycin,
Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole
hydrochloride; acronine; adozelesin; aldesleukin; altretamine;
ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;
anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
azetepa; azotomycin; batimastat; benzodepa; bicalutamide;
bisantrene hydrochloride; bisnafide dimesylate; bizelesin;
bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin;
carmustine; carubicin hydrochloride; carzelesin; cedefingol;
chlorambucil; cirolemycin; cladribine; crisnatol mesylate;
cyclophosphamide; cytarabine; dacarbazine; daunorubicin
hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine
mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;
iimofosine; interleukin Il (including recombinant interleukin II,
or rlL2), interferon alfa-2a; interferon alfa-2b; interferon
alfa-n1; interferon alfa-n3; interferon beta-1 a; interferon
gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; my cophenolic acid; nocodazoie; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride.
[0669] Other anti-cancer agents that can be employed in combination
with a Btk inhibitor compound include: 20-epi-1, 25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-such as for example growth factor-1 receptor inhibitor;
interferon agonists; interferons; interleukins; iobenguane;
iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate;
sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0670] Yet other anticancer agents that can be employed in
combination with a Btk inhibitor compound include alkylating
agents, antimetabolites, natural products, or hormones, e.g.,
nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, etc.), alkyl sulfonates (e.g., busulfan),
nitrosoureas (e.g., carmustine, lomusitne, ete.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include but are
not limited to folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin).
[0671] Examples of alkylating agents that can be employed in
combination a Btk inhibitor compound include, but are not limited
to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines
(e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g.,
busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine,
streptozocin, etc.), or triazenes (decarbazine, ete.). Examples of
antimetabolites include, but are not limited to folic acid analog
(e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,
floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,
thioguanine, pentostatin.
[0672] Examples of hormones and antagonists include, but are not
limited to, adrenocorticosteroids (e.g., prednisone), progestins
(e.g., hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,
leuprolide).
[0673] Other agents that can be used in the methods and
compositions described herein for the treatment or prevention of
cancer include platinum coordination complexes (e.g., cisplatin,
carboblatin), anthracenedione (e.g., mitoxantrone), substituted
urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g.,
procarbazine), adrenocortical suppressant (e.g., mitotane,
aminoglutethimide).
[0674] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which can be
used in combination with a Btk inhibitor compound include without
limitation the following marketed drugs and drugs in development:
Erbulozole (also known as R-55104), Dolastatin 10 (also known as
DLS-10 and NSC-376128), Mivobulin isethionate (also known as
CI-980), Vincristine, NSC-639829, Discodermolide (also known as
NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins
(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as
Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,
Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and
Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793
and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,
Epothilone C (also known as desoxyepothilone A or dEpoA),
Epothilone D (also referred to as KOS-862, dEpoB, and
desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B
N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,
21-aminoepothilone B (also known as BMS-310705),
21-hydroxyepothilone D (also known as Desoxyepothilone F and
dEpoF), 26-fluoroepothilone), Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H16 (Kansas State
University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (also
known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tularik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi).
[0675] The formulations may be used in any combination with one or
more other anti-thromboembolic agents to treat or prevent
thromboembolic disorder (e.g., stroke). Examples of
anti-thromboembolic agents include, but are not limited any of the
following: thrombolytic agents (e.g., alteplase anistreplase,
streptokinase, urokinase, or tissue plasminogen activator),
heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran
etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux,
rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),
ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315),
ximelagatran, or BIBR 1048.
[0676] In some embodiments, the additional anti-cancer agent that
is a Bcl-2 inhibitor.
[0677] In some embodiments, the additional anti-cancer agent is
immune checkpoint inhibitor. In some embodiments, the immune
checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1
(PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1),
CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3,
B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,
CD160, CD226, CD276, DR3, GALS, GITR, HAVCR2, HVEM, IDO1, IDO2,
ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO
(macrophage receptor with collageneous structure), PS
(phosphatidylserine), OX-40, SLAM, TIGHT, VISTA, VTCN1, or any
combinations thereof. In some embodiments, the immune checkpoint
inhibitor is an inhibitor of PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In
some embodiments, the immune checkpoint inhibitor is an inhibitor
of PD-L1. In some embodiments, the immune checkpoint inhibitor is
an inhibitor of PD-1. In some embodiments, the immune checkpoint
inhibitor is an inhibitor of CTLA-4. In some embodiments, the
immune checkpoint inhibitor is an inhibitor of LAG3. In some
embodiments, the immune checkpoint inhibitor is an inhibitor of
TIM3. In some embodiments, the immune checkpoint inhibitor is an
inhibitor of PD-L2.
[0678] In some embodiments, the formulations are administered in
combination with a CD20 inhibitor. Exemplary CD20 inhibitors
include, but are not limited to, ibritumomab tiuxetan, ofatumumab,
rituximab, tositumomab, and obinutuzumab.
[0679] In some embodiments, the additional anticancer agent used in
combination with the formulations described herein include CDK4
inhibitors (e.g., palbociclib).
[0680] In some embodiments, the additional cancer agent is a
proteosome inhibitor. In some embodimentx, the proteasome inhibitor
is selected from bortezomib or carfilzomib
[0681] In some embodiments, the additional cancer agent that can be
administered in combination with the formulations is an HDAC
inhibitor. In some embodiments, the HDAC inhibitor is abexinostat
or a salt thereof. In some embodiments, the abexinostat or a salt
thereof is abexinostat HCl. In some embodiments, the abexinostat or
a salt thereof is abexinostat tosylate.
[0682] In some embodiments, the additional cancer agent that can be
administered in combination with the formulations is a MALT1
inhibitor, MCL-1 inhibitor, IDHlinhibitor, TLR inhibitor, or PIM
inhibitor.
[0683] In some embodiments, the additional anti-cancer agent that
can be administered in combination with the formulations is an
immunomodulatory agent. Exemplary immunomodulatory agents include,
but are not limited to, lenalidomide, thalidomide, and
pomalidomide.
[0684] Where the individual is suffering from or at risk of
suffering from an autoimmune disease, an inflammatory disease, or
an allergy disease, Compound 1 can be used in with one or more of
the following therapeutic agents in any combination:
immunosuppressants (e.g., tacrolimus, cyclosporin, rapamycin,
methotrexate, cyclophosphamide, azathioprine, mercaptopurine,
mycophenolate, or FTY720), glucocorticoids (e.g., prednisone,
cortisone acetate, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, beclometasone, fludrocortisone
acetate, deoxycorticosterone acetate, aldosterone), non-steroidal
anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,
2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or
sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,
celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold
thiomalate, aurofin, sulfasalazine, hydroxychloroquinine,
minocycline, TNF-.alpha. binding proteins (e.g., infliximab,
etanercept, or adalimumab), abatacept, anakinra, interferon-.beta.,
interferon-.gamma., interleukin-2, allergy vaccines,
antihistamines, antileukotrienes, beta-agonists, theophylline, or
anticholinergics.
Kits/Articles of Manufacture
[0685] For use in the therapeutic methods of use described herein,
kits and articles of manufacture are also described herein. Such
kits include a carrier, package, or container that is
compartmentalized to receive one or more containers such as vials,
tubes, and the like, each of the container(s) comprising one of the
separate elements to be used in a method described herein. Suitable
containers include, for example, bottles, vials, syringes, and test
tubes. In one embodiment, the containers are formed from a variety
of materials such as glass or plastic.
[0686] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products include, e.g., U.S. Pat. No. 5,323,907.
Examples of pharmaceutical packaging materials include, but are not
limited to, blister packs, bottles, tubes, bags, containers,
bottles, and any packaging material suitable for a selected
formulation and intended mode of administration and treatment.
[0687] In some embodiments, the compounds or compositions described
herein, are presented in a package or dispenser device which may
contain one or more unit dosage forms containing the active
ingredient. The compound or composition described herein is
packaged alone, or packaged with another compound or another
ingredient or additive. In some embodiments, the package contains
one or more containers filled with one or more of the ingredients
of the pharmaceutical compositions. In some embodiments, the
package comprises metal or plastic foil, such as a blister pack. In
some embodiments, the package or dispenser device is accompanied by
instructions for administration, such as instructions for
administering the compounds or compositions for treating a
neoplastic disease. In some embodiments, the package or dispenser
is accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. In some embodiments, such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In some embodiments, compositions include a compound
described herein formulated in a compatible pharmaceutical carrier
are prepared, placed in an appropriate container, and labeled for
treatment of an indicated condition.
[0688] For example, the container(s) include Compound 1, optionally
in a composition or in combination with another agent as disclosed
herein. Such kits optionally include an identifying description or
label or instructions relating to its use in the methods described
herein.
[0689] A kit typically includes labels listing contents and/or
instructions for use, and package inserts with instructions for
use. A set of instructions will also typically be included.
[0690] In one embodiment, a label is on or associated with the
container. In one embodiment, a label is on a container when
letters, numbers or other characters forming the label are
attached, molded or etched into the container itself; a label is
associated with a container when it is present within a receptacle
or carrier that also holds the container, e.g., as a package
insert. In one embodiment, a label is used to indicate that the
contents are to be used for a specific therapeutic application. The
label also indicates directions for use of the contents, such as in
the methods described herein.
[0691] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device which contains one or more
unit dosage forms containing a compound provided herein. The pack,
for example, contains metal or plastic foil, such as a blister
pack. In one embodiment, the pack or dispenser device is
accompanied by instructions for administration. In one embodiment,
the pack or dispenser is also accompanied with a notice associated
with the container in form prescribed by a governmental agency
regulating the manufacture, use, or sale of pharmaceuticals, which
notice is reflective of approval by the agency of the form of the
drug for human or veterinary administration. Such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In one embodiment, compositions containing a compound
provided herein formulated in a compatible pharmaceutical carrier
are also prepared, placed in an appropriate container, and labeled
for treatment of an indicated condition.
EXAMPLES
[0692] The following ingredients, formulations, processes and
procedures for practicing the methods disclosed herein correspond
to that described above.
Example 1: Wet Granulation Method for the Preparation of High-Load
Tablet Formulations of Ibrutinib
[0693] A high shear mixer is charged with ibrutinib, intragranular
components, such as lactose monohydrate, optionally
microcrystalline cellulose, and optionally croscarmellose sodium
and hydroxypropylcellulose, in W/W proportions as described in
Tables 1A-1F. The ingredients were then mixed and water (or an
aqueous binder solution) was added gradually. Once granulated, the
wet granules were dried in a fluid bed dryer with an inlet
temperature at 60.degree. C. until the loss on drying (LOD) was
<1.5%. The dried granulated material was then passed through a
comil equipped with a 0.04 inch screen. The extragranular
components, such as croscarmellose sodium, sodium lauryl sulfate
and colloidal silicon dioxide were then mixed with the granules in
a blender for 20 minutes. Magnesium stearate was charged to the
blender. The final mixture was blended for another two minutes. The
final blend was then discharged and compressed into tablets. The
tablets are stored at room temperature until they are used.
[0694] Wet granulation tablet formulations W1-W19, W22, W23-W24,
and BK01-BK02, BK04, BK06-BK09, BK21A and BK21B shown below in
Tables 1A-1F were prepared as or similarly to that described
above.
TABLE-US-00001 TABLE 1A Wet Granulation Tablet Formulations w1 w2
w3 w4 w5 w6 w7 Wt mg/ Wt mg/ Wt mg/ Wt mg/ Wt mg/ Wt mg/ Wt mg/ %
Tab % Tab % Tab % Tab % Tab % Tab % Tab Ibrutinib 60.0 560.0 60.0
560.0 60.0 560.0 60.0 560.0 60.0 560.0 60.0 560.0 70.0 560.0 MCC
(Avicel PH101) 12.5 116.7 12.5 116.7 10.75 100.3 25.0 233.3 -- 12.5
116.7 15.0 120.0 Lactose Mono (Fast 12.5 116.6 12.5 116.6 10.75
100.3 -- -- 25.0 233.3 -- -- -- -- Flo 316) Mannitol (Pearlitol 100
-- -- -- -- -- -- -- -- -- 12.5 116.6 -- -- SD)
Hydroxypropylcellulose 3.0 28.0 3.0 28.0 -- -- 3.0 28.0 3.0 28.0
3.0 28.0 3.0 24.0 (Klucel EXF) PVP K30 -- -- -- -- 6.5 60.7 -- --
-- -- -- -- -- -- SLS (Kolliphor Fine) -- -- 3.0 28.0 -- -- -- --
-- -- -- -- -- -- Subtotal (Intra) 88.0 821.3 91.0 849.3 88.0 821.3
88.0 821.3 88.0 821.3 88.0 821.3 88.0 704.0 SLS (Kolliphor Fine)
6.0 56.0 3.0 28.0 6.0 56.0 6.0 56.0 6.0 56.0 6.0 56.0 6.0 48.0
Croscarmellose Na (Ac- 5.0 46.7 5.0 46.7 5.0 46.7 5.0 46.7 5.0 46.7
5.0 46.7 5.0 40.0 Di-Sol) Silicon Dioxide 0.5 4.7 0.5 4.7 0.5 4.7
0.5 4.7 0.5 4.7 0.5 4.7 0.5 4.0 (Cabosil M5P) Magnesium Stearate
0.5 4.6 0.5 4.6 0.5 4.6 0.5 4.6 0.5 4.6 0.5 4.6 0.5 4.0 Total 100
933.3 100 933.3 100 933.3 100 933.3 100 933.3 100 933.3 100%
800.0
TABLE-US-00002 TABLE 1B Wet Granulation Tablet Formulations W8 W10
W9 W11 Ibrutinib 60.0% 60.0% 70.0% 70.0% MCC (Avicel PH101) 14.0%
13.5% 9.0% 8.5% Lactose Mono (Fast Flo 316) 14.0% 13.5% 9.0% 8.5%
Croscarmellose Na (Ac-Di-Sol) -- 2.5% -- 3.0%
Hydroxypropylcellulose (Klucel EXF) -- 1.0% -- -- Subtotal (Intra)
88.0% 90.5% 88.0% 90.0% SLS (Kolliphor Fine) 6.0% 6.0% 6.0% 6.0%
Croscarmellose Na (Ac-Di-Sol) 5.0% 2.5% 5.0% 3.0% Silicon Dioxide
(Cabosil M5P) 0.5% 0.5% 0.5% 0.5% Magnesium Stearate 0.5% 0.5% 0.5%
0.5% Total 100.0%
TABLE-US-00003 TABLE 1C Wet Granulation Tablet Formulations W12 W13
W14 W15 W16 Ibrutinib 60.0% 60.0% 70.0% 70.0% 70.0% MCC (Avicel
PH101) 12.0% 12.0% 7.0% 7.0% -- Lactose Mono 12.0% 12.0% 7.0% 7.0%
14.0% (Fast Flo 316) Croscarmellose 5.0% 5.0% 5.0% 5.0% 5.0% Na
(Ac-Di-Sol) Hydroxypropylcellulose 2.0% -- 2.0% -- -- (SSL)
Povidone (K25) -- 2.0% -- 2.0% 2.0% Subtotal (Intra) 91.0% SLS
(Kolliphor Fine) 6.0% 6.0% 6.0% 6.0% 6.0% Croscarmellose Na 2.0%
2.0% 2.0% 2.0% 2.0% (Ac-Di-Sol) Silicon Dioxide 0.5% 0.5% 0.5% 0.5%
0.5% (Cabosil M5P) Magnesium Stearate 0.5% 0.5% 0.5% 0.5% 0.5%
Total 100.0%
TABLE-US-00004 TABLE 1F Wet Granulation Tablet Formulations
Ingredients BK21A BK21B Ibrutinib (Intra) 70% 70% Lactose
Monohydrate (Intra) 14% 14% Microcrystalline Cellulose (Extra) 5%
2% Binder (PVP K25) (Intra) 2% 2% SLS (% Intra/% Extra) 1% (1/0) 4%
(1/3) Croscarmellose Sodium (% intra/Extra) 7% (5/2) 7% (5/2)
Colloidal Silicon Dioxide (Extra) 0.5% 0.5% Mg Stearate (Extra)
0.5% 0.5%
Example 2: Dry Granulation Method for the Preparation of Ibrutinib
Tablet Formulations
[0695] Ibrutinib, microcrystalline cellulose, croscarmellose
sodium, sodium lauryl sulfate and optionally magnesium stearate
were passed through a 1000 microns sieve. The mixture was then
blended for 10 minutes. The pre-blending was charged to a roller
compactor and compacted at 0.6 kN/cm. The resulting ribbon was
passed through an oscillating mill equipped with a 0.8 mm screen.
The milled granules were then combined with the extragranular
components: microcrystalline cellulose, croscarmellose sodium,
sodium lauryl sulfate and optionally magnesium stearate and blended
for 10 minutes. The blend was then compressed into tablets using a
single station manual press.
[0696] Dry granulation tablet formulations D1 and D5 shown below in
Table 2 were prepared as described above.
TABLE-US-00005 TABLE 2 Dry Granulation Tablet Formulations D1 D5
Component Wt % mg/Tab Wt % mg/Tab Ibrutinib 50.00 560.0 42.42 560.0
MCC (Avicel PH101) 30.00 336.0 45.88 605.7 Croscarmellose Na
(Ac-Di-Sol) 4.00 44.8 3.97 52.4 SLS (Kolliphor Fine) 3.40 38.1 2.85
37.6 Magnesium Stearate -- -- 0.24 3.2 Subtotal (Intra) 87.40 978.9
95.36 1258.9 MCC (Avicel PH200) 7.50 84.0 -- -- SLS (Kolliphor
Fine) 1.60 17.9 1.39 18.3 Croscarmellose Na (Ac-Di-Sol) 3.00 33.6
3.00 39.6 Magnesium Stearate 0.50 5.6 0.24 3.2 Total 100.00 1120.0
100.00 1320.1
Example 3: Preparation of Immediate Release High-Load Tablet
Formulations of Ibrutinib
[0697] Immediate release tablet formulations are prepared using the
components shown in Table 3 following the procedure from Example
1.
TABLE-US-00006 TABLE 3 Components of Immediate Release Tablet
Formulation Ingredient Range Ibrutinib 80 to 90% Lactose 0 to 10%
Croscarmellose sodium 1 to 10% Microcrystalline cellulose 0 to 10%
Colloidal Silicon Dioxide 0 to 1% Magnesium stearate 0.25% to 2.5%
Total Tablet weight range: 622 mg to 700 mg
Example 4: Preparation of Capsule Formulations of Ibrutinib
[0698] The capsule Formulation A manufacturing process includes the
following steps: weigh the indicated amount of the components, mix
together and add into an appropriate size capsule, and close
capsule. The capsules are stored at room temperature until they are
used.
Example 5: In Vivo Evaluation of High-Load, Wet and Dry Granulation
Tablet Formulations of Ibrutinib and Ibrutinib Capsule
Formulation
[0699] The pharmacokinetics of ibrutinib in capsule (Formulation A)
versus different wet granulation (Formulations B, C and D which
correspond to Formulations W8, W10, and W11 in Example 1,
respectively) and dry granulation (Formulations E and F which
correspond to Formulations D1 and D5 in Example 2, respectively)
tablet formulations was studied in fasted male beagle dogs
following single oral administration of 140 mg ibrutinib
formulations administered in a Latin square crossover design. The
wet granulation (Formulations B, C and D) and dry granulation
(Formulations E and F) tablets were studied in two parallel groups
with capsule as internal control in each of the group. The tablet
formulations composition and drug load are presented in Table
4.
TABLE-US-00007 TABLE 4 Ibrutinib Tablet Formulations - Drug Load
and Composition Formulation A B C D E F Process -- Wet Wet Wet Dry
Dry Component w/w % w/w % w/w % w/w % w/w % w/w % Ibrutinib 42.0
60.0 60.0 70.0 50.0 42.0 Lactose Monohydrate NF 0 14 13.5 8.5 0 0
Microcrystalline cellulose NF 46.5 14 13.5 8.5 37.5 46.5
Hydroxypropyl Cellulose NF 0 0 1.0 0 0 0 Croscarmellose sodium NF
7.0 5.0 5.0 6.0 7.0 7.0 Sodium lauryl sulfate NF 4.0 6.0 6.0 6.0
5.0 4.0 Colloidal Silicon Dioxide NF 0 0.5 0.5 0.5 0 0 Magnesium
stearate NF 0.5 0.5 0.5 0.5 0.5 0.5 Tablet Weight 333.3 233.3 233.3
200.0 280.0 333.3
[0700] FIG. 1 and FIG. 2 shows mean plasma concentration-time
profiles of ibrutinib following single oral dose administration of
three different wet and two dry ibrutinib tablet formulations,
respectively to fasted beagle dogs (Dose=140 mg). In general, all
the wet granulation formulation tablets (B, C and D) tested showed
comparable concentrations to the capsule formulation. Specifically,
wet granulation tablet formulations B, C and D showed average %
F.sub.rel values ranging from 72 to 110% (Table 5). However, dry
granulation tablet formulations, E and F showed lower
concentrations compared to capsule with average % F.sub.rel values
ranging from 43 to 52% (Table 6). Furthermore, reduced variability
in ibrutinib exposure was observed with wet granulation
formulations when compared to capsule formulation (Tables 5 and 7).
In some embodiments, the tablet formulation provides unexpected low
variability in ibrutinib exposure in terms of % CV for both
C.sub.max and AUC when administered under fasted and fed
conditions, see, e.g., Formulation BK21B as compared to the capsule
formulation A and tablet formulations BK02 and BK21A (Table 7). In
some embodiments, the tablet formulation provides unexpected
absence of food effect in C.sub.max and T.sub.max when administered
under fed conditions compared to fasted conditions, which is
contemplated to lead to more predictable therapeutic efficacy and
side effects when taking with or without food, see, e.g., Table
7.
TABLE-US-00008 TABLE 5 Mean (% CV) Ibrutinib Plasma PK Parameters
Following Single Dose Administration of Three Different Wet Tablet
Ibrutinib Formulations to Fasted Beagle Dogs (n = 7) Dose C.sub.max
T.sub.max T.sub.1/2 AUC F.sub.rel Formulation (mg) (ng/mL) (h) (h)
(ng*h/mL) (%) A (Capsule) 140 32.1 (93.7) 2.36 ND 146 (106) N/A B
(Wet W8) 140 20.7 (54.1) 1.64 ND 63.2 (37.7) 96 (63.1) C (Wet W10)
140 22.6 (86.1) 1.46 1.10.sup.a 72.6 (66.1) 72 (53.2) D (Wet W11)
140 23.0 (86.9) 2.00 6.50.sup.b (36.5) 93.3 (92.8) 110 (83.3)
F.sub.rel: for each dog, which has received both capsule and tablet
formulations in a cross-over fashion (AUC.sub.Formulation B, C, D,
E or F/AUC.sub.Formulation A)*100; .sup.an = 1; .sup.bn = 3; N/A:
not applicable; ND: not determined
TABLE-US-00009 TABLE 6 Mean (% CV) Ibrutinib Plasma PK Parameters
Following Single Dose Administration of Two Different Dry Tablet
Ibrutinib Formulations to Fasted Beagle Dogs (n = 8) Dose C.sub.max
T.sub.max T.sub.1/2 AUC F.sub.rel Formulation (mg) (ng/mL) (h) (h)
(ng*h/mL) (%) A (Capsule) 140 29.9 (90.2) 5.81 ND 161 (105) N/A E
(Dry D1) 140 10.2 (78.9) 2.72 ND 45.1 (43.7) 42.6 (64.7) F (Dry D5)
140 10.1 (49.5) 2.50 ND 59.9 (77.3) 51.6 (66.5) F.sub.rel: for each
dog, which has received both capsule and tablet formulations in a
cross-over fashion (AUC.sub.Formulation B, C, D, E or
F/AUC.sub.Formulation A)*100; N/A: not applicable; ND: not
determined
Example 6: A Single-Dose, Open-Label, Randomized, Crossover Study
to Assess the Pharmacokinetics of Ibrutinib Tablet Formulations in
Healthy Adult Subjects Compared to the Ibrutinib Capsule
Formulation A
[0701] This is a single-center, open-label, randomized, crossover,
single-dose study in healthy adults. After providing written
informed consent, subjects were screened within 21 days (Day -21 to
-2).
[0702] Main Criteria for Inclusion:
[0703] Healthy men and women between 18 and 55 years of age,
inclusive; body mass index (BMI) between 18 and 30 kg/m.sup.2,
inclusive, and a body weight of not less than 50 kg. Women must be
post-menopausal or surgically sterile.
[0704] Eligible subjects received a single oral dose of ibrutinib
560 mg (in either capsule formulation A comprising 140 mg ibrutinib
per capsule or a tablet formulation comprising 560 mg ibrutinib per
tablet) with 240 mL of noncarbonated water on Day 1 of each
treatment period after fasting at least 10 hours before each dose.
Water was allowed ad libitum beginning 2 hours after each dose, and
lunch was provided beginning 4 hours after each dose.
[0705] Blood samples for pharmacokinetic (PK) analysis of ibrutinib
were collected before dosing and over 48 hours after dosing in each
treatment period.
[0706] Total duration of the study was approximately 70 days
(21-day screening period, 4.times.3-day treatment periods with
7-day washouts between periods, and a 7-day follow-up phase).
[0707] PK parameters including the following were calculated and
the results are in Table 8: [0708] C.sub.max: Maximum observed
concentration [0709] T.sub.max: Time to reach the maximum observed
concentration [0710] AUC.sub.last: Area under the
concentration-time curve from time 0 to last time point [0711]
AUC.sub..infin.: Area under the concentration-time curve from time
0 to infinite time [0712] t.sub.1/2: Apparent elimination half-life
associated with the terminal slope of the semilogarithmic drug
concentration-time curve
[0713] In some embodiments, the high load tablet formulations
possess both pharmaceutically acceptable properties and desired PK
properties, such as a high C.sub.max, similar to that of a capsule
formulation (e.g., BK21A).
Example 7: Safety and Tolerability Study of Compound 1 in Chronic
Lymphocytic Leukemia
[0714] Purpose: The purpose of this study is to establish the
safety and optimal dose of orally administered Compound 1 (420
mg/day) high-load tablets in patients with B-cell chronic
lymphocytic leukemia/small lymphocytic lymphoma/diffuse
well-differentiated lymphocytic lymphoma.
[0715] Primary Outcome Measures: Safety and tolerability of
Compound 1 (frequency, severity, and relatedness of adverse
events).
[0716] Secondary Outcome Measures: Pharmacokinetic/Pharmacodynamic
assessments. Tumor response--overall response rate as defined by
recent guidelines on CLL and SLL (B cell lymphoma) and duration of
response.
[0717] Eligibility: 18 Years and older; both genders are
eligible.
[0718] Inclusion Criteria: 1. For treatment-naive group only: Men
and women .gtoreq.65 years of age with confirmed diagnosis of
CLL/SLL, who require treatment per NCI or International Working
Group guidelines 11-14. 2. For relapsed/refractory group only: Men
and women .gtoreq.18 years of age with a confirmed diagnosis of
relapsed/refractory CLL/SLL unresponsive to therapy (ie, failed
.gtoreq.2 previous treatments for CLL/SLL and at least 1 regimen
had to have had a purine analog [eg, fludarabine] for subjects with
CLL). 3. Body weight .gtoreq.40 kg. 4. ECOG performance status of
.ltoreq.2. 5. Agreement to use contraception during the study and
for 30 days after the last dose of study drug if sexually active
and able to bear children. 6. Willing and able to participate in
all required evaluations and procedures in this study protocol
including swallowing tablets without difficulty. 7. Ability to
understand the purpose and risks of the study and provide signed
and dated informed consent and authorization to use protected
health information (in accordance with national and local subject
privacy regulations).
[0719] Exclusion Criteria: 1. A life-threatening illness, medical
condition or organ system dysfunction which, in the investigator's
opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of Compound 1 PO, or put the study
outcomes at undue risk. 2. Any immunotherapy, chemotherapy,
radiotherapy, or experimental therapy within 4 weeks before first
dose of study drug (corticosteroids for disease-related symptoms
allowed but require 1-week washout before study drug
administration). 3. Central nervous system (CNS) involvement by
lymphoma. 4. Major surgery within 4 weeks before first dose of
study drug. 5. Creatinine>1.5.times.institutional upper limit of
normal (ULN); total bilirubin>1.5.times.ULN (unless due to
Gilbert's disease); and aspartate aminotransferase (AST) or alanine
aminotransferase (ALT)>2.5.times.ULN unless disease related. 6.
Concomitant use of medicines known to cause QT prolongation or
torsades de pointes. 7. Significant screening electrocardiogram
(ECG) abnormalities including left bundle branch block, 2nd degree
AV block type II, 3rd degree block, bradycardia, and QTc>470
msec. 8. Lactating or pregnant.
Example 8: Safety and Efficacy of Compound 1 in Subjects With
Relapsed/Refractory Mantle Cell Lymphoma (MCL)
[0720] The primary objective of this trial is to evaluate the
efficacy of Compound 1 in relapsed/refractory subjects with Mantle
Cell Lymphoma (MCL). The secondary objective is to evaluate the
safety of a fixed daily dosing regimen of Compound 1 (560 mg/day in
the form of tablets) in this population.
[0721] Primary Outcome Measures: To measure the number of
participants with a response to Compound 1.
[0722] Secondary Outcome Measures: To measure the number of
participants with adverse events as a measure of safety and
tolerability. To measure pharmacokinetics to assist in determining
how the body responds to the study drug. Patient reported outcomes
(to measure the number of participants reported outcomes in
determining the health related quality of life).
[0723] Eligibility: 18 Years and older; both genders are
eligible.
[0724] Inclusion Criteria: Men and women .gtoreq.18 years of age.
ECOG performance status of .ltoreq.2. Pathologically confirmed MCL,
with documentation of either overexpression of cyclin D1 or
t(11;14), and measurable disease on cross sectional imaging that is
.gtoreq.2 cm in the longest diameter and measurable in 2
perpendicular dimensions. Documented failure to achieve at least
partial response (PR) with, or documented disease progression
disease after, the most recent treatment regimen. At least 1, but
no more than 5, prior treatment regimens for MCL (Note: Subjects
having received .gtoreq.2 cycles of prior treatment with
bortezomib, either as a single agent or as part of a combination
therapy regimen, will be considered to be bortezomib-exposed.).
Willing and able to participate in all required evaluations and
procedures in this study protocol including swallowing tablets
without difficulty. Ability to understand the purpose and risks of
the study and provide signed and dated informed consent and
authorization to use protected health information (in accordance
with national and local subject privacy regulations).
[0725] Major exclusion criteria: Prior chemotherapy within 3 weeks,
nitrosoureas within 6 weeks, therapeutic anticancer antibodies
within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks,
radiation therapy within 3 weeks, or major surgery within 2 weeks
of first dose of study drug. Any life-threatening illness, medical
condition or organ system dysfunction which, in the investigator's
opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of Compound 1 high-load tablets, or put
the study outcomes at undue risk. Clinically significant
cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction
within 6 months of screening, or any Class 3 or 4 cardiac disease
as defined by the New York Heart Association Functional
Classification. Malabsorption syndrome, disease significantly
affecting gastrointestinal function, or resection of the stomach or
small bowel or ulcerative colitis, symptomatic inflammatory bowel
disease, or partial or complete bowel obstruction. Any of the
following laboratory abnormalities: 1. Absolute neutrophil count
(ANC)<750 cells/mm3 (0.75.times.109/L) unless there is
documented bone marrow involvement. 2. Platelet count <50,000
cells/mm3 (50.times.109/L) independent of transfusion support
unless there is documented bone marrow involvement. 3. Serum
aspartate transaminase (AST/SGOT) or alanine transaminase
(ALT/SGPT).gtoreq.3.0.times.upper limit of normal (ULN). 4.
Creatinine>2.0.times.ULN.
Example 9: Phase 2 Study of the Combination of Compound 1 and
Rituximab in High-Risk Chronic Lymphocytic Leukemia and Small
Lymphocytic Lymphoma Patients
[0726] Purpose: The goal of this clinical research study is to
learn if Compound 1 combined with rituximab can help to control
chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma
(SLL). The safety of this combination will also be studied.
[0727] Rituximab (375 mg/m.sup.2) will be given intravenously (IV)
on Day 1, Day 8, Day 15, and Day 22, then continued once every 4
weeks only on Days 1 during cycles 2-6. Compound 1 will be started
on Day 2 of cycle 1 at a dose of 420 mg (one 420 mg tablet) orally
daily and will be continued daily.
[0728] Primary Outcome Measures: Progression free survival (PFS)
[Time Frame: 3 months]--progression free survival defined as the
time interval from treatment to progressive disease or death,
whichever happens earlier. Patients in complete remission (CR),
partial remission (PR) or stable disease (SD) are all counted as
progression-free. Survival or times to progression functions
estimated using the Kaplan-Meier method.
[0729] Secondary Outcome Measures: Toxicity [Time Frame: 3
months]--toxicity reported by type, frequency and severity. Worst
toxicity grades per patient tabulated for selected adverse events
and laboratory measurements. Toxicity (grade 3 or 4) monitored
based on the Bayesian model (beta-binomial) by assuming a priori
probability of toxicity following beta(1,1).
[0730] Eligibility: 18 Years and older; both genders are
eligible.
[0731] Inclusion Criteria: 1. Patients must have a diagnosis of
high-risk CLL/SLL and be previously treated with up to 3 lines of
prior therapy. High-risk CLL and high-risk SLL is defined by the
presence of a 17p deletion or 11q deletion or TP53 mutation. Any
CLL and SLL patient who has a short remission duration of less than
3 years after prior first-line chemo-immunotherapy, such as the FCR
regimen, also fulfills criteria of high-risk CLL/SLL, regardless of
the presence or absence of cytogenetic abnormalities. 2. CLL and
SLL patients with 17p deletion or TP53 mutation will not be
required to have received any prior therapy, given the poor outcome
of CLL/SLL patients to standard frontline chemo-immunotherapy, such
patients will be eligible if they are untreated or if they have
received up to 3 lines of prior therapy. 3. Patients must have an
indication for treatment by 2008 IWCLL Criteria. 4. Patients age
>18 years at the time of signing informed consent. Understand
and voluntarily sign an informed consent. Be able to comply with
study procedures and follow-up examinations. 5. ECOG/WHO
performance status of 0-1. 6. Patients of childbearing potential
must be willing to practice highly effective birth control (e.g.,
condoms, implants, injectables, combined oral contraceptives, some
intrauterine devices [IUDs], sexual abstinence, or sterilized
partner) during the study and for 30 days after the last dose of
study drug. Women of childbearing potential include any female who
has experienced menarche and who has not undergone successful
surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal. Post menopause is
defined as follows: Amenorrhea >/=12 consecutive months without
another cause and a documented serum follicle stimulating hormone
(FSH) level >35 mIU/mL; a male of childbearing potential is any
male that has not been surgically sterilized. 7. Adequate renal and
hepatic function as indicated by all of the following: Total
bilirubin </=1.5.times.institutional Upper Limit of Normal (ULN)
except for patients with bilirubin elevation due to Gilbert's
disease who will be allowed to participate; an ALT
</=2.5.times.ULN; and an estimated creatinine clearance (CrCl)
of >30 mL/min, as calculated by the Cockroft-Gault equation
unless disease related. 8. Free of prior malignancies for 3 years
with exception of currently treated basal cell, squamous cell
carcinoma of the skin, or carcinoma in situ of the cervix or
breast. 9. A urine pregnancy test (within 7 days of Day 1) is
required for women with childbearing potential.
[0732] Exclusion Criteria: 1. Pregnant or breast-feeding females.
2. Treatment including chemotherapy, chemo-immunotherapy,
monoclonal antibody therapy, radiotherapy, high-dose corticosteroid
therapy (more than 60 mg Prednisone or equivalent daily), or
immunotherapy within 21 days prior to enrollment or concurrent with
this trial. 3. Investigational agent received within 30 days prior
to the first dose of study drug or have previously taken Compound
1. If received any investigational agent prior to this time point,
drug-related toxicities must have recovered to Grade 1 or less
prior to first dose of study drug. 4. Systemic fungal, bacterial,
viral, or other infection not controlled (defined as exhibiting
ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).
5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or
autoimmune thrombocytopenia (ITP). 6. Patients with severe
hematopoietic insufficiency, as defined by an absolute neutrophil
count of less than 500/micro-L and/or a platelet count of less than
30,000/micro-L at time of screening for this protocol. 7. Any other
severe concurrent disease, or have a history of serious organ
dysfunction or disease involving the heart, kidney, liver or other
organ system that may place the patient at undue risk to undergo
therapy with Compound 1 and rituximab. 8. Significant
cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction
within 6 months of screening, or any Class 3 or 4 cardiac disease
as defined by the New York Heart Association Functional
Classification. 9. Significant screening ECG abnormalities
including left bundle branch block, 2nd degree AV block type II,
3rd degree block, bradycardia, and QTc>470 msec. 10. Any serious
medical condition, laboratory abnormality, or psychiatric illness
that places the subject at unacceptable risk if he/she were to
participate in the study. 11. History of stroke or cerebral
hemorrhage within 6 months. 12. Evidence of bleeding diathesis or
coagulopathy. 13. Major surgical procedure, open biopsy, or
significant traumatic injury within 28 days prior to Day 1,
anticipation of need for major surgical procedure during the course
of the study. 14. Minor surgical procedures, fine needle
aspirations or core biopsies within 7 days prior to Day 1. Bone
marrow aspiration and/or biopsy are allowed. 15. Serious,
non-healing wound, ulcer, or bone fracture. 16. Treatment with
Coumadin. Patients who recently received Coumadin must be off
Coumadin for at least 7 days prior to start of the study. 17. Any
chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or
fludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab),
bone marrow transplant, experimental therapy, or radiotherapy is
prohibited during therapy on this study. 18. Use of medications
known to prolong QTc interval or that may be associated with
Torsades de Pointes (refer to Appendix F) are prohibited within 7
days of starting study drug and during study-drug treatment.
[0733] The examples and embodiments described herein are
illustrative and various modifications or changes suggested to
persons skilled in the art are to be included within this
disclosure. As will be appreciated by those skilled in the art, the
specific components listed in the above examples may be replaced
with other functionally equivalent components, e.g., diluents,
binders, lubricants, fillers, and the like.
* * * * *