U.S. patent application number 15/092195 was filed with the patent office on 2016-10-06 for compositions containing ibrutinib.
The applicant listed for this patent is Janssen Pharmaceutical NV. Invention is credited to Maristella Bernini, Dilip J. Gole, Manish Kumar Gupta, Sabine Inghelbrecht, Binuraj Krishnan Nair, Kaustubh Tambwekar.
Application Number | 20160287594 15/092195 |
Document ID | / |
Family ID | 55806788 |
Filed Date | 2016-10-06 |
United States Patent
Application |
20160287594 |
Kind Code |
A1 |
Gupta; Manish Kumar ; et
al. |
October 6, 2016 |
Compositions Containing Ibrutinib
Abstract
Discussed herein are pharmaceutical compositions containing
Ibrutinib and processes for preparing them. The compositions may be
utilized in the treatment of a variety of conditions including,
without limitation, B-cell proliferative disorders such as
non-Hodgkin lymphoma (diffuse large B cell lymphoma, follicular
lymphoma, mantle cell lymphoma or burkitt lymphoma), Waldenstrom
macroglobulinemia, plasma cell myeloma, chronic lymphocytic
leukemia, lymphoma, or leukemia. These compositions are designed
for oral ingestion. The compositions are contained within a capsule
such as a standard or sprinkle or in a liquid formulation such as a
suspension. In one embodiment, the pharmaceutical composition
contains Ibrutinib, a salt, prodrug, or metabolite thereof,
microcrystalline cellulose, croscarmellose sodium, sodium lauryl
sulfate, and magnesium stearate. In another embodiment, the
pharmaceutical composition contains Ibrutinib, a salt, prodrug, or
metabolite thereof, microcrystalline cellulose,
carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric
acid monohydrate, disodium hydrogen phosphate, sucralose, sodium
methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate,
concentrated hydrochloric acid, sodium hydroxide, and water.
Inventors: |
Gupta; Manish Kumar;
(Mumbai, IN) ; Tambwekar; Kaustubh; (Mumbai,
IN) ; Nair; Binuraj Krishnan; (Mumbai, IN) ;
Gole; Dilip J.; (Plainsboro, NJ) ; Bernini;
Maristella; (Beerse, BE) ; Inghelbrecht; Sabine;
(Stekene, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutical NV |
Beerse |
|
BE |
|
|
Family ID: |
55806788 |
Appl. No.: |
15/092195 |
Filed: |
April 6, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62143659 |
Apr 6, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 47/12 20130101; A61K 31/519 20130101; A61K 9/0053 20130101;
A61P 35/02 20180101; A61J 3/07 20130101; A61K 9/4858 20130101; B01J
2/10 20130101; A61K 9/4866 20130101; A61K 47/38 20130101; A23L
33/10 20160801; A23L 33/16 20160801; A61K 9/4833 20130101; B01J
2/22 20130101; A23V 2002/00 20130101; A61K 47/02 20130101; A61P
35/00 20180101; A61K 9/10 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; B01J 2/10 20060101 B01J002/10; A61J 3/07 20060101
A61J003/07; B01J 2/22 20060101 B01J002/22; A61K 9/48 20060101
A61K009/48; A61K 9/00 20060101 A61K009/00 |
Claims
1. A pharmaceutical composition comprising Ibrutinib, a salt,
prodrug, or metabolite thereof, microcrystalline cellulose,
croscarmellose sodium, sodium lauryl sulfate, and magnesium
stearate.
2. The pharmaceutical composition of claim 1 comprising about 40 to
about 45% by weight of Ibrutinib.
3. The pharmaceutical composition of claim 1, comprising about 50
to about 140 mg of Ibrutinib.
4. The pharmaceutical composition of claim 1, comprising about 44
to about 47% by weight of microcrystalline cellulose.
5. The pharmaceutical composition of claim 1, comprising about 6 to
about 8% by weight of croscarmellose sodium.
6. The pharmaceutical composition of claim 1, comprising about 3 to
about 5% by weight of intragranular croscarmellose sodium.
7. The pharmaceutical composition of claim 1, comprising about 2 to
about 4% by weight of extragranular croscarmellose sodium
8. The pharmaceutical composition of claim 1, comprising about 1 to
about 5% by weight of sodium lauryl sulfate.
9. The pharmaceutical composition of claim 8, comprising about 2.5
to about 3% by weight of intragranular sodium lauryl sulfate.
10. The pharmaceutical composition of claim 8, comprising about 1.2
to about 1.6% by weight of extragranular sodium lauryl sulfate.
11. The pharmaceutical composition of claim 1, comprising about 0.4
to about 0.6% by weight of magnesium stearate.
12. The pharmaceutical composition of claim 1, comprising about
0.45 to about 0.5% by weight of magnesium stearate.
13. The pharmaceutical composition of claim 1, comprising about 0.2
to about 0.3% by weight of intragranular magnesium stearate.
14. The pharmaceutical composition of claim 1, comprising about 0.2
to about 0.3% by weight of extragranular magnesium stearate.
15. The pharmaceutical composition of claim 1 comprising an
intragranulation comprising Ibrutinib, a salt, prodrug, or
metabolite thereof, microcrystalline cellulose, croscarmellose
sodium, sodium lauryl sulfate, and magnesium stearate.
16. The pharmaceutical composition of claim 1, comprising an
extragranulation comprising croscarmellose sodium, sodium lauryl
sulfate, and magnesium stearate.
17. A pharmaceutical composition comprising: (i) about 40 to about
45% by weight of Ibrutinib; (ii) about 44 to about 47% by weight of
microcrystalline cellulose; (iii) about 6 to about 8% by weight of
croscarmellose sodium; (iv) about 1 to about 5% by weight of sodium
lauryl sulfate; and (v) about 0.2 to about 0.3% by weight of
magnesium stearate.
18. A pharmaceutical composition comprising: (i) about 140 mg of
Ibrutinib; (ii) about 151 mg of microcrystalline cellulose; (iii)
about 23 mg of croscarmellose sodium; (iv) about 14 mg of sodium
lauryl sulfate; and (v) about 1.6 mg of magnesium stearate.
19. The pharmaceutical composition of claim 18, wherein said
croscarmellose sodium comprises about 13 mg of intragranular
croscarmellose sodium and about 9.9 mg of extragranular
croscarmellose sodium.
20. The pharmaceutical composition of claim 18, wherein said sodium
lauryl sulfate comprises about 9.4 mg of intragranular sodium
lauryl sulfate and about 4.6 mg of extragranular sodium lauryl
sulfate.
21. The pharmaceutical composition of claim 18, wherein said
magnesium stearate comprises about 0.8 mg of intragranular
magnesium stearate and about 0.8 mg of extragranular magnesium
stearate.
22. A pharmaceutical composition comprising: (i) about 50 mg of
Ibrutinib; (ii) about 54 mg of microcrystalline cellulose; (iii)
about 8 mg of croscarmellose sodium; (iv) about 5 mg of sodium
lauryl sulfate; and (v) about 0.6 mg of magnesium stearate.
23. The pharmaceutical composition of claim 22, wherein said
croscarmellose sodium comprises about 4.6 mg of intragranular
croscarmellose sodium and about 3.5 mg of extragranular
croscarmellose sodium.
24. The pharmaceutical composition of claim 22, wherein said sodium
lauryl sulfate comprises about 3.3 mg of intragranular sodium
lauryl sulfate and about 1.6 mg of extragranular sodium lauryl
sulfate.
25. The pharmaceutical composition of claim 22, wherein said
magnesium stearate comprises about 0.3 mg of intragranular
magnesium stearate and about 0.3 mg of extragranular magnesium
stearate.
26. A capsule comprising the pharmaceutical composition of claim
1.
27. The capsule of claim 26, which is a gelatin capsule.
28. The capsule of claim 26, which is a hard gelatin capsule.
29. The capsule of claim 26, which is a standard or sprinkle
capsule.
30. The capsule of claim 26, which is Swedish orange capsule.
31. The capsule of claim 26, which is a size 0 capsule.
32. A pharmaceutical composition comprising Ibrutinib, a salt,
prodrug, or metabolite thereof, microcrystalline cellulose,
carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric
acid monohydrate, disodium hydrogen phosphate, sucralose, sodium
methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate,
concentrated hydrochloric acid, sodium hydroxide, and water.
33. The pharmaceutical composition of claim 32, comprising about 30
to about 80 mg/mL of Ibrutinib.
34. The pharmaceutical composition of claim 32, comprising about 30
to about 50 mg/mL of Ibrutinib.
35. The pharmaceutical composition of claim 32, comprising about 60
to about 80 mg/mL of Ibrutinib.
36. The pharmaceutical composition of claim 32, comprising about 12
to about 15 mg/mL of microcrystalline cellulose and
carboxymethylcellulose sodium.
37. The pharmaceutical composition of claim 32, comprising about 13
to about 15 mg/mL of microcrystalline cellulose and
carboxymethylcellulose sodium.
38. The pharmaceutical composition of claim 32, comprising about 12
to about 14 mg/mL of microcrystalline cellulose and
carboxymethylcellulose sodium.
39. The pharmaceutical composition of claim 32, comprising about
0.5 to about 3 mg/mL of hydroxypropylmethylcellulose.
40. The pharmaceutical composition of claim 32, comprising about 2
to about 3 mg/mL of hydroxypropylmethylcellulose.
41. The pharmaceutical composition of claim 32, comprising about
0.5 to about 1.5 mg/mL of hydroxypropylmethylcellulose.
42. The pharmaceutical composition of claim 32, comprising about
1.4 to about 1.7 mg/mL of citric acid monohydrate.
43. The pharmaceutical composition of claim 32, comprising about
1.4 mg/mL of disodium hydrogen phosphate.
44. The pharmaceutical composition of claim 32, comprising about
0.5 to about 1.5 mg/mL of sucralose.
45. The pharmaceutical composition of claim 32, comprising about 1
to about 1.5 mg/mL of sodium methyl parahydroxybenzoate.
46. The pharmaceutical composition of claim 32, comprising about
0.5 to about 0.7 mg/mL of sodium ethyl parahydroxybenzoate.
47. The pharmaceutical composition of claim 32, comprising a
sufficient amount of concentrated hydrochloric acid to sustain a pH
of about 6.
48. The pharmaceutical composition of claim 32, comprising a
sufficient amount of sodium hydroxide to sustain a pH of about
6.
49. The pharmaceutical composition of claim 32, comprising a
sufficient amount of water to ensure a total volume of 1 mL.
50. The pharmaceutical composition of claim 32, which is a liquid
suspension.
51. The pharmaceutical composition of claim 32, comprising: (i)
about 70 mg/mL of Ibrutinib; (ii) about 13 mg/mL of
microcrystalline cellulose and carboxymethylcellulose sodium; (iii)
about 2.5 mg/mL of hydroxypropylmethylcellulose; (iv) about 1.5
mg/mL of citric acid monohydrate; (v) about 1.4 mg/mL of disodium
hydrogen phosphate; (vi) about 1 mg/mL of sucralose; (vii) about 1
mg/mL of sodium methyl parahydroxybenzoate; and (viii) about 0.6
mg/mL of sodium ethyl parahydroxybenzoate.
52. The pharmaceutical composition of claim 32, comprising: (i)
about 40 mg/mL of Ibrutinib; (ii) about 14 mg/mL of
microcrystalline cellulose and carboxymethylcellulose sodium; (iii)
about 1 mg/mL of hydroxypropylmethylcellulose; (iv) about 1.6 mg/mL
of citric acid monohydrate; (v) about 1.4 mg/mL of disodium
hydrogen phosphate; (vi) about 0.5 mg/mL of sucralose; (vii) about
1.4 mg/mL of sodium methyl parahydroxybenzoate; and (viii) about
0.7 mg/mL of sodium ethyl parahydroxybenzoate.
53. A method for treating a B-cell proliferative disorder
comprising administering a pharmaceutical composition of claim 1 to
a subject in need thereof.
54. The method of claim 53, wherein said B-cell proliferative
disorder is a non-Hodgkin lymphoma, Waldenstrom macroglobulinemia,
plasma cell myeloma, or chronic lymphocytic leukemia.
55. The method of claim 54, wherein the non-Hodgkin lymphoma is
selected from the group consisting of diffuse large B cell
lymphoma, follicular lymphoma, mantle cell lymphoma and burkitt
lymphoma.
56. The method of claim 53, wherein the composition is administered
orally.
57. A method for treating a lymphoma comprising administering a
composition of claim 1 to a subject in need thereof.
58. A method of treating a leukemia, said method comprising
administering a composition of claim 1 to a subject in need
thereof.
59. A method for treating mantle cell lymphoma in a subject who has
already received at least one prior therapy for mantle cell
lymphoma, said method comprising administering to the subject a
composition of claim 1 once per day.
60. The method of claim 53, wherein the subject is a human.
61. The method of claim 53, wherein the composition is scattered
into food.
62. The method of claim 61, wherein the food is soft food.
63. The method of claim 61, wherein the subject is a human
child.
64. A process for preparing a composition of claim 1, said process
comprising: (a) blending the microcrystalline cellulose, a first
portion of sodium lauryl sulfate, and a first portion of
croscarmellose sodium; (b) blending the product of step (a) with a
first portion of Ibrutinib; (c) blending the product of step (b)
with a second portion of Ibrutinib; (d) blending the product of
step (c) with a first portion of magnesium stearate; (e) roller
compacting the product of step (d); (f) milling the ribbons
produced in step (e); (g) blending the granules produced in step (0
with a second portion of sodium lauryl sulfate and croscarmellose
sodium; and (h) blending the product of step (g) with a second
portion of magnesium stearate.
65. The process of claim 64, further comprising: (i) adding the
product of step (h) to a capsule.
66. A process for preparing a composition of claim 32, said process
comprising: (a) mixing water, microcrystalline cellulose
croscarmellose sodium; (b) mixing water and with
hydroxypropylmethylcellulose; (c) mixing the product of step (b)
with Ibrutinib; (d) mixing the product of steps (a) and (c); (e)
mixing the product of step (d) with sucralose; (f) mixing the
product of step (e) with sodium methyl parahydroxybenzoate and
sodium ethyl parahydroxybenzoate; (g) mixing the product of step
(f) with monohydrate citric acid; and (h) mixing the product of
step (g) with anhydrous disodium hydrogen phosphate.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/143,659, filed Apr. 6, 2015, the entirety of
which is incorporated by reference.
TECHNICAL FIELD
[0002] This invention relates to compositions containing Ibrutinib
and methods for using same.
BACKGROUND
[0003] Targeted therapy involves identifying specific differences
between cancer cells and normal cells. These differences are used
to create a targeted therapy to attack the cancer cells without
damaging the normal cells, thus leading to fewer side effects.
Differences exist between the various types of targeted therapy but
all interfere with the ability of the cancer cell to grow, divide,
repair and/or communicate with other cells.
[0004] Ibrutinib is an anticancer drug targeting B-cell
malignancies. Ibrutinib blocks signals that stimulate malignant B
cells to grow and divide uncontrollably. It was approved by the US
FDA in November 2013 for the treatment of mantle cell lymphoma and
in February 2014 for the treatment of chronic lymphocytic leukemia.
It is an orally-administered, selective and covalent inhibitor
(IC.sub.50=0.46 nM) of the enzyme Bruton's tyrosine kinase (BTK)
via a covalent bond to the cysteine residue Cys-481 in the BTK
active site. BTK is a signaling molecule of the B-cell antigen
receptor (BCR) and cytokine receptor pathways. The BCR pathway is
implicated in several B-cell malignancies, including MCL and B-cell
CLL. Ibrutinib is marked in the US in oral capsule form
(Imbruvica.TM.).
[0005] What is needed in the art are alternate formulations
containing Ibrutinib.
SUMMARY OF THE INVENTION
[0006] In one aspect, pharmaceutical compositions are provided
comprising Ibrutinib, a salt, prodrug, or metabolite thereof,
microcrystalline cellulose, croscarmellose sodium, sodium lauryl
sulfate, and magnesium stearate. In one embodiment, the composition
contains about 40 to about 45% by weight of Ibrutinib.
[0007] In another aspect, pharmaceutical compositions are provided
comprising (i) about 40 to about 45% by weight of Ibrutinib; (ii)
about 44 to about 47% by weight of microcrystalline cellulose;
(iii) about 6 to about 8% by weight of croscarmellose sodium; (iv)
about 1 to about 5% by weight of sodium lauryl sulfate; and (v)
about 0.2 to about 0.3% by weight of magnesium stearate.
[0008] In a further aspect, pharmaceutical compositions are
provided comprising (i) about 140 mg of Ibrutinib; (ii) about 151
mg of microcrystalline cellulose; (iii) about 23 mg of
croscarmellose sodium; (iv) about 14 mg of sodium lauryl sulfate;
and (v) about 1.6 mg of magnesium stearate.
[0009] In still another aspect, pharmaceutical compositions are
provided comprising (i) about 50 mg of Ibrutinib; (ii) about 54 mg
of microcrystalline cellulose; (iii) about 8 mg of croscarmellose
sodium; (iv) about 5 mg of sodium lauryl sulfate; and (v) about 0.6
mg of magnesium stearate.
[0010] In yet a further aspect, capsules or sachets are provided
comprising at least one of the pharmaceutical compositions
described herein. In certain embodiments, the capsule is a standard
or sprinkle.
[0011] In another aspect, pharmaceutical compositions are provided
comprising Ibrutinib, a salt, prodrug, or metabolite thereof,
microcrystalline cellulose, carboxymethylcellulose sodium,
hydroxypropylmethylcellulose, citric acid monohydrate, disodium
hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate,
sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid,
sodium hydroxide, and water.
[0012] In still a further aspect, pharmaceutical compositions are
provided comprising (i) about 70 mg/mL of Ibrutinib; (ii) about 13
mg/mL of a combination of microcrystalline cellulose and
carboxymethylcellulose sodium; (iii) about 2.5 mg/mL of
hydroxypropylmethylcellulose; (iv) about 1.5 mg/mL of citric acid
monohydrate; (v) about 1.4 mg/mL of disodium hydrogen phosphate;
(vi) about 1 mg/mL of sucralose; (vii) about 1 mg/mL of sodium
methyl parahydroxybenzoate; and (viii) about 0.6 mg/mL of sodium
ethyl parahydroxybenzoate.
[0013] In other aspects, pharmaceutical compositions are provided
comprising (i) about 40 mg/mL of Ibrutinib; (ii) about 14 mg/mL of
a combination of microcrystalline cellulose and
carboxymethylcellulose sodium; (iii) about 1 mg/mL of
hydroxypropylmethylcellulose; (iv) about 1.5 mg/mL of citric acid
monohydrate; (v) about 1.4 mg/mL of disodium hydrogen phosphate;
(vi) about 0.5 mg/mL of sucralose; (vii) about 1.4 mg/mL of sodium
methyl parahydroxybenzoate; and (viii) about 0.6 mg/mL of sodium
ethyl parahydroxybenzoate.
[0014] In yet another aspect, methods for treating a B-cell
proliferative disorder are provided comprising the steps of
administering at least one pharmaceutical composition described
herein to a subject in need thereof. In certain embodiments, the
B-cell proliferative disorder is a non-Hodgkin lymphoma,
Waldenstrom macroglobulinemia, plasma cell myeloma, or chronic
lymphocytic leukemia.
[0015] In a further aspect, methods for treating a lymphoma are
provided comprising administering at least one composition
described herein to a subject in need thereof.
[0016] In another aspect, methods of treating a leukemia are
provided comprising administering at least one composition
described herein to a subject in need thereof.
[0017] In still a further aspect, methods for treating mantle cell
lymphoma in a subject who has already received at least one prior
therapy for mantle cell lymphoma are provided comprising
administering at least one composition described herein to the
subject once per day.
[0018] In a further aspect, the treatment methods herein involve
use of a sprinkle capsule that is open to facilitate sprinkling of
the capsule's contents into food or a beverage. In one embodiment,
the beverage is water. In another embodiment, the food is a soft
food. Capsule contents can also be administered via feeding tube
after spending into suitable vehicle such as water, milk or other
common beverages. Please note the suspension formulation can also
be administered via feeding tube.
[0019] In yet another aspect, processes for preparing compositions
described herein are provided comprising (a) blending
microcrystalline cellulose, a first portion of sodium lauryl
sulfate, and a first portion of croscarmellose sodium; (b) blending
the product of step (a) with a first portion of Ibrutinib; (c)
blending the product of step (b) with a second portion of
Ibrutinib; (d) blending the product of step (c) with a first
portion of magnesium stearate; (e) roller compacting the product of
step (d); (f) milling the ribbons produced in step (e); (g)
blending the granules produced in step (e) with a second portion of
sodium lauryl sulfate and croscarmellose sodium; and (h) blending
the product of step (g) with a second portion of magnesium
stearate. In one embodiment, the process further includes (i)
adding the product of step (h) to a capsule.
[0020] In a further aspect, processes for preparing compositions
described herein are provided comprising (a) mixing water,
microcrystalline cellulose croscarmellose sodium; (b) mixing water
with hydroxypropylmethylcellulose; (c) mixing the product of step
(b) with Ibrutinib; (d) mixing the product of steps (a) and (c);
(e) mixing the product of the step (d) with sucralose; (f) mixing
the product of step (e) with sodium methyl parahydroxybenzoate and
sodium ethyl parahydroxybenzoate; (g) mixing the product of step
(f) with monohydrate citric acid; and (h) mixing the product of
step (g) with anhydrous disodium hydrogen phosphate. In one
embodiment, the process further includes (i) adjusting the pH of
the product of step (h) to a pH of about 6. In another embodiment,
the processes further include adding water to the product of step
(h) or (i). In a further aspect, the processes further include
adding the composition to a vial.
[0021] Other aspects and advantages of the present invention are
described further in the following detailed description of the
preferred embodiments thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The present application is further understood when read in
conjunction with the appended drawings. For the purpose of
illustrating the subject matter, there are shown in the drawings
exemplary embodiments of the subject matter; however, the presently
disclosed subject matter is not limited to the specific
compositions, methods, devices, and systems disclosed. In addition,
the drawings are not necessarily drawn to scale.
[0023] FIG. 1 provides a process flow diagram for preparing
capsules containing Ibrutinib.
[0024] FIG. 2 provides a process flow diagram for preparing liquid
formulations containing Ibrutinib.
[0025] FIG. 3 provides a process flow diagram for a large scale
preparation of a liquid formulation containing Ibrutinib.
DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS
[0026] The present invention may be understood more readily by
reference to the following description taken in connection with the
accompanying Figures and Examples, all of which form a part of this
disclosure. It is to be understood that this invention is not
limited to the specific products, methods, conditions or parameters
described and/or shown herein, and that the terminology used herein
is for the purpose of describing particular embodiments by way of
example only and is not intended to be limiting of any claimed
invention. Similarly, unless otherwise stated, any description as
to a possible mechanism or mode of action or reason for improvement
is meant to be illustrative only, and the invention herein is not
to be constrained by the correctness or incorrectness of any such
suggested mechanism or mode of action or reason for improvement.
Throughout this text, it is recognized that the descriptions refer
both to the features and methods of making and using the
compositions described herein.
[0027] In the present disclosure the singular forms "a", "an" and
"the" include the plural reference, and reference to a particular
numerical value includes at least that particular value, unless the
context clearly indicates otherwise. Thus, for example, a reference
to "a material" is a reference to at least one of such materials
and equivalents thereof known to those skilled in the art, and so
forth.
[0028] When a value is expressed as an approximation by use of the
descriptor "about" or "substantially" it will be understood that
the particular value forms another embodiment. In general, use of
the term "about" or "substantially" indicates approximations that
can vary depending on the desired properties sought to be obtained
by the disclosed subject matter and is to be interpreted in the
specific context in which it is used, based on its function. The
person skilled in the art will be able to interpret this as a
matter of routine. In some cases, the number of significant figures
used for a particular value may be one non-limiting method of
determining the extent of the word "about" or "substantially". In
other cases, the gradations used in a series of values may be used
to determine the intended range available to the term "about" or
"substantially" for each value. Where present, all ranges are
inclusive and combinable. That is, references to values stated in
ranges include every value within that range.
[0029] When a list is presented, unless stated otherwise, it is to
be understood that each individual element of that list and every
combination of that list is to be interpreted as a separate
embodiment. For example, a list of embodiments presented as "A, B,
or C" is to be interpreted as including the embodiments, "A," "B,"
"C," "A or B," "A or C," "B or C," or "A, B, or C."
[0030] It is to be appreciated that certain features of the
invention which are, for clarity, described herein in the context
of separate embodiments, may also be provided in combination in a
single embodiment. That is, unless obviously incompatible or
excluded, each individual embodiment is deemed to be combinable
with any other embodiment(s) and such a combination is considered
to be another embodiment. Conversely, various features of the
invention that are, for brevity, described in the context of a
single embodiment, may also be provided separately or in any
sub-combination. It is further noted that the claims may be drafted
to exclude any optional element. As such, this statement is
intended to serve as antecedent basis for use of such exclusive
terminology as "solely," "only" and the like in connection with the
recitation of claim elements, or use of a "negative" limitation.
Finally, while an embodiment may be described as part of a series
of steps or part of a more general structure, each said step may
also be considered an independent embodiment in itself.
[0031] The term "subject" as used herein refers to an animal being
treated for a condition requiring Ibrutinib. In one embodiment, the
subject is a human. In another embodiment, the subject is an adult,
including a young adult, mature adult, or elderly adult, or child,
including a teenager.
[0032] The term "purified" as used herein preferably refers to
Ibrutinib that contains less than about 1% impurities. In one
embodiment, the Ibrutinib contains less than about 0.5% impurities.
In another embodiment, the Ibrutinib contains less than about 0.1%
impurities. In a further embodiment, the Ibrutinib is about 100%
pure.
[0033] The terms intragranular and extragranular as used herein are
known in the art of formulations. An intragranular form of a
formulation component is added before granule formation. Similarly,
an extragranular form of a formulation component is added to the
granules of the formulation prior to compression. Simply stated,
the extragranular portion breaks the composition into granules and
the intragranular portion disintegrates the granules to release the
Ibrutinib, a salt, prodrug, or metabolite thereof.
[0034] Abbreviations used herein include CCS (croscarmellose
sodium), MCC (microcrystalline cellulose), SLS (sodium lauryl
sulfate), HPMC (hydroxypropylmethylcellulose; hypromellose), DSC
(differential scanning calorimeter), BHT (butylated
hydroxytoluene), BHA (butylated hydroxyanisole), sodium methyl
parahydroxybenzoate, sodium ethyl, CLL (chronic lymphocytic
leukemia), and SLL (small lymphocytic lymphoma).
[0035] A. Ibrutinib Form
[0036] The compositions described herein contain Ibrutinib
(Imbruvica) as the active agent. Ibrutinib is described and may be
prepared as set forth in U.S. Pat. Nos. 7,514,444; 8,003,309;
8,697,711; 8,735,403; 8,957,079; and 8,754,091, which are
incorporated by reference. As known in the art, Ibrutinib is
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4
d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the
following structure. Ibrutinib has a melting point range of about
149.degree. C. to about 158.degree. C., a partition coefficient of
about 4 at a pH of about 7, a dissociation constant of about 3.7,
and a DSC melting point initiating at about 156.degree. C.
##STR00001##
[0037] The Ibrutinib utilized herein may include other forms,
including metabolites thereof, provided that the Ibrutinib form is
stable and non-toxic. The Ibrutinib form may also have some or the
same activity as the base Ibrutinib molecule. In one embodiment, an
active metabolite of Ibrutinib is of the following structure.
##STR00002##
[0038] The Ibrutinib form utilized herein may encompass tautomeric
forms of Ibrutinib, prodrugs and salts. In one embodiment, the
Ibrutinib salts may be derived from pharmaceutically or
physiologically acceptable acids, bases, alkali metals and alkaline
earth metals. Physiologically acceptable acids include those from
inorganic and organic acids. Inorganic acids are known in the art
and include, without limitation, hydrochloric, hydrobromic,
hydroiodic, sulfuric, nitric, and phosphoric acids. Organic acids
are also known in the art and include, without limitation, lactic,
formic, acetic, fumaric, citric, propionic, oxalic, succinic,
glycolic, glucuronic, maleic, furoic, glutamic, benzoic,
anthranilic, salicylic, tartaric, malonic, mallic, phenylacetic,
mandelic, embonic, methanesulfonic, ethanesulfonic, panthenoic,
benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic, and
galacturonic acids. Inorganic bases are known in the art and
include, without limitation, aluminum, calcium, lithium, magnesium,
potassium, sodium, and zinc sulfate or phosphates. Similarly,
organic bases are known in the art and include, without limitation,
N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, and procaine. Alkali
salts and alkaline earth metal salts can include, without
limitation, sodium, potassium, calcium and magnesium salts in the
form of esters, and carbamates.
[0039] Prodrugs of Ibrutinib are also contemplated and include,
without limitation, esters, carbamates, sulfates, ethers, oximes,
carbonates, among others. The prodrug forms, which, when
administered in such form, convert to the active moiety in vivo.
See, Testa, "Prodrugs Revisited: The "Ad Hoc" Approach as a
Complement to Ligand Design", Medicinal Research Reviews,
16(3):233-241, ed., John Wiley & Sons (1996), which is
incorporated by reference.
[0040] A "metabolite" of Ibrutinib may also be utilized as
described herein. As known in the art, a metabolite is a compound
of Ibrutinib formed when the compound is metabolized as described
in "The Pharmacological Basis of Therapeutics," 9th Edition,
McGraw-Hill (1996), which is incorporated by reference.
[0041] B. Solid Formulations
[0042] Ibrutinib may be formulated in solid formulations for
administration to a subject. The solid formulation is substantially
dry, i.e., free from liquid. In one embodiment, the solid
formulation is about 90% or greater dry.
[0043] In one embodiment, a pharmaceutical composition discussed
herein contains Ibrutinib, a salt, prodrug, or metabolite thereof,
microcrystalline cellulose, croscarmellose sodium, sodium lauryl
sulfate, and magnesium stearate. As noted above, the Ibrutinib
contained in this composition may be the base molecule, salt,
prodrug, or metabolite thereof.
[0044] The composition contains about 40 to about 45% by weight of
Ibrutinib, a salt, prodrug, or metabolite thereof. In one
embodiment, the composition contains about 41 to about 44% by
weight of Ibrutinib, a salt, prodrug, or metabolite thereof. In a
further embodiment, the composition contains about 42 to about 43%
by weight of Ibrutinib, a salt, prodrug, or metabolite thereof. In
another embodiment, the composition contains about 42 or about 43%
by weight of Ibrutinib, a salt, prodrug, or metabolite thereof. In
yet a further embodiment, the composition contains about 50 to
about 140 mg of Ibrutinib, a salt, prodrug, or metabolite thereof.
In still another embodiment, the composition contains about 50 mg
of Ibrutinib, a salt, prodrug, or metabolite thereof.
[0045] One or more suspending agent may be included in the liquid
composition discussed herein. In one embodiment, microcrystalline
cellulose is also included in the compositions described herein. In
further embodiments, the composition contains about 44 to about 47%
by weight of microcrystalline cellulose. In another embodiment, the
composition contains about 45 to about 46% by weight of
microcrystalline cellulose.
[0046] The compositions may also contain croscarmellose sodium. The
croscarmellose sodium may be in an intragranular or extragranular
form. In one embodiment, the composition contains about 6 to about
8% by weight of croscarmellose sodium. In another embodiment, the
composition contains about 7% by weight of croscarmellose sodium.
In a further embodiment, the composition contains about 3 to about
5% by weight of intragranular croscarmellose sodium. In yet another
embodiment, the composition contains about 4% by weight of
intragranular croscarmellose sodium. In still a further embodiment,
the composition contains about 2 to about 4% by weight of
extragranular croscarmellose sodium. In another embodiment, the
composition contains about 3% by weight of croscarmellose sodium.
In a further embodiment, the composition contains about 13 mg of
intragranular croscarmellose sodium and about 9.9 mg of
extragranular croscarmellose sodium. In a further embodiment, the
composition contains about 4.6 mg of intragranular croscarmellose
sodium and about 3.5 mg of extragranular croscarmellose sodium.
[0047] Sodium lauryl sulfate may also be included in the
compositions discussed herein. The sodium lauryl sulfate may be in
intragranular and/or extragranular forms. In one embodiment, the
composition contains about 1 to about 5% by weight of sodium lauryl
sulfate. In another embodiment, the composition contains about 2 to
about 4.5% by weight of sodium lauryl sulfate. In a further
embodiment, the composition contains about 3 to about 4% by weight
of sodium lauryl sulfate. In still another embodiment, the
composition contains about 2.5 to about 3% by weight of
intragranular sodium lauryl sulfate. In yet a further embodiment,
the composition contains about 3% by weight of intragranular sodium
lauryl sulfate. In another embodiment, the composition contains
about 1 to about 2% by weight of extragranular sodium lauryl
sulfate. In still a further embodiment, the composition contains
about 1.4% by weight of extragranular sodium lauryl sulfate. In yet
another embodiment, the composition contains about 9.4 mg of
intragranular sodium lauryl sulfate and about 4.6 mg of
extragranular sodium lauryl sulfate. In a further embodiment, the
composition contains about 3.3 mg of intragranular sodium lauryl
sulfate and about 1.6 mg of extragranular sodium lauryl
sulfate.
[0048] The compositions described herein may also contain magnesium
stearate. The magnesium stearate may be in intragranular and/or
extragranular forms. In one embodiment, the composition contains
about 0.4 to about 0.6% by weight of magnesium stearate. In another
embodiment, the composition contains about 0.4 to about 0.5% by
weight of magnesium stearate. In another embodiment, the
composition contains about 0.45 to about 0.5% by weight of
magnesium stearate. In a further embodiment, the composition
contains about 0.2 to about 0.3% by weight of intragranular
magnesium stearate. In still another embodiment, the composition
contains about 0.2 to about 0.3% by weight of extragranular
magnesium stearate. In yet a further embodiment, the composition
contains about 0.8 mg of intragranular magnesium stearate and about
0.8 mg of extragranular magnesium stearate. In another embodiment,
the composition contains about 0.3 mg of intragranular magnesium
stearate and about 0.3 mg of extragranular magnesium stearate.
[0049] In one embodiment, a pharmaceutical composition is described
herein and includes an intragranulation containing Ibrutinib, a
salt, prodrug, or metabolite thereof, microcrystalline cellulose,
croscarmellose sodium, sodium lauryl sulfate, and magnesium
stearate.
[0050] In another embodiment, the pharmaceutical composition
includes an extragranulation containing croscarmellose sodium,
sodium lauryl sulfate, and magnesium stearate.
[0051] In a further embodiment, a pharmaceutical composition is
provided and contains (i) about 40 to about 45% by weight of
Ibrutinib; (ii) about 44 to about 47% by weight of microcrystalline
cellulose; (iii) about 6 to about 8% by weight of croscarmellose
sodium; (iv) about 1 to about 5% by weight of sodium lauryl
sulfate; and (v) about 0.2 to about 0.3% by weight of magnesium
stearate.
[0052] In still another embodiment, a pharmaceutical composition is
provided and contains (i) about 140 mg of Ibrutinib; (ii) about 151
mg of microcrystalline cellulose; (iii) about 23 mg of
croscarmellose sodium; (iv) about 14 mg of sodium lauryl sulfate;
and (v) about 1.6 mg of magnesium stearate.
[0053] In yet a further embodiment, a pharmaceutical composition is
provided and contains (i) about 50 mg of Ibrutinib; (ii) about 54
mg of microcrystalline cellulose; (iii) about 8 mg of
croscarmellose sodium; (iv) about 5 mg of sodium lauryl sulfate;
and (v) about 0.6 mg of magnesium stearate.
[0054] In another embodiment, pharmaceutical compositions
containing the components of Table 1 are provided.
TABLE-US-00001 TABLE 1 Amount (mg) Amount (mg) Ingredient 140 mg
capsule 50 mg capsule Intragranular Ibrutinib, micronized (Lonza,
Nansha) 140.00 50.00 Microcrystalline Cellulose 151.40 54.07
(Avicel PH 101) Croscarmellose Sodium (Ac-di-sol) 13.10 4.68 Sodium
lauryl Sulfate 9.40 3.36 (Kolliphor SLS fine) Magnesium Stearate
0.80 0.29 (Non-Bovine #5712) Extragranular Croscarmellose Sodium
(Ac-di-sol) 9.90 3.54 Sodium lauryl Sulfate 4.60 1.64 (Kolliphor
SLS fine) Magnesium Stearate 0.80 0.29 (Non-Bovine #5712) Total
fill weight 330.00 117.87 Hard Gelatin Capsule size 0 1 1
[0055] The solid compositions described herein contain particles of
an optimal size to permit dissolution of the composition, e.g., the
particles are less than or equal to about 10.mu.. The sizes of the
particles of the composition may be measured by passing the solid
composition through screens of varying sizes. If the particles of
the composition are larger than the optimal size and if the same
have not yet been encapsulated in a capsule or dissolved in one or
more excipient, the same can be subject to further milling and
screening steps, among others, to reduce the particle size.
Ibrutinib may optionally be micronized under nitrogen and
conventional micronizing techniques, for example with a Trost or
jet mill, applied to non-micronized Ibrutinib. However, the
compositions described herein are not limited to the method by
which the Ibrutinib is produced. Ibrutinib may have a median
particle size of less than about 10 .mu.m, less than about 7 .mu.m,
or than about 5 .mu.m. Specifically, 90% of the particles are less
than or equal to about 10 .mu.m and 50% are less than or equal to
about 10 .mu.m as determined by the Malvern method, which is
readily understood by one of skill in the art.
[0056] A variety of equipment may be utilized to perform the
manufacturing processes of preparing the solid compositions and
includes bags of small, medium, and large sizes, screens of varying
sizes, and blenders. The process may also include mixing,
extruding, fusing, compacting and/or milling of the composition,
typically using compactors and mills selected by those skilled in
the art. The milling step may be performed on particles of varying
sizes, i.e., large particles, powders, and fine powders to obtain a
more uniform particle size. The milling may include one or more
separating, recycling, and screening steps to obtain the desired
particle sizes. In one embodiment, the compositions may be prepared
by dry mixing Ibrutinib, based upon the total weight of the
composition, with the other components of the composition. In
another embodiment, the compositions described herein are prepared
by wet mixing Ibrutinib, based upon the total weight of the
composition, with the other components of the composition. Drying
may be performed using drying instruments selected by one of skill
in the art. See, e.g., Lachman, "The Theory and Practice of
Industrial Pharmacy", 3.sup.rd ed. (1986), which is incorporated by
reference.
[0057] In one embodiment, the solid compositions discussed herein
are prepared by (a) blending microcrystalline cellulose, a first
portion of sodium lauryl sulfate, and a first portion of
croscarmellose sodium; (b) blending the product of step (a) with a
first portion of Ibrutinib; (c) blending the product of step (b)
with a second portion of Ibrutinib; (d) blending the product of
step (c) with a first portion of magnesium stearate; (e) roller
compacting the product of step (d); (0 milling the ribbons produced
in step (e); (g) blending the granules produced in step (0 with a
second portion of sodium lauryl sulfate and croscarmellose sodium;
and (h) blending the product of step (g) with a second portion of
magnesium stearate. In another embodiment, the solid compositions
are prepared as described in FIG. 1.
[0058] The solid compositions may then be formed into a suitable
dosing unit for delivery to a patient as determined by one skilled
in the art. Suitable dosing units include oral dosing units. In one
embodiment, the composition is added to a capsule. In a further
embodiment, the capsule is for pediatric administration. In yet
another embodiment, the capsule is for administration by an adult
who is incapable of swallowing a solid drug formulation. In another
embodiment, the capsule is a HPMC (hypromellose) capsule. In yet a
further embodiment, the capsule is a gelatin capsule. In still
another embodiment, the capsule is a hard gelatin capsule. In still
another embodiment, the capsule is a standard or sprinkle capsule.
In a further embodiment, the capsule is a Swedish orange capsule.
In another embodiment, the capsule is a size 0 capsule. In yet
another embodiment, the sprinkle capsule may be opened and the
contents added to a substance such as a food or drink which may be
ingested by the subject. The food may be a semi-solid or a solid,
including soft food.
[0059] In another embodiment the capsules containing Ibrutinib are
film-coated. Suitable film-coatings are known to those of skill in
the art. For example, the film-coating may be a polymer such as
HPMC, ethyl cellulose, polyvinyl alcohol, or combinations
thereof.
[0060] The solid compositions may also be added to a sachet. The
term "sachet" as used herein refers to a bag or case which is
capable of holding a composition described herein. The size of the
sachet depends on the amount of the composition to be added. In one
embodiment, the sachet is a single dose sachet. In another
embodiment, the sachet contains a bulk amount of the compositions
described herein. In the latter case, the patient, physician, or
caretaker measures the appropriate dosage of the compositions for
administration. In a further embodiment, the sachet is a
paper/aluminum/polyethylene laminate or
polyester/aluminum/polyethylene laminate, both of which may
optionally be located with a barrier coating such as ethylenevinyl
acetate, polyvinyl acetate, polysiloxane, or melamine, among
others. In another embodiment, the sachet may be opened and the
contents added to a substance such as a food or drink which may be
ingested by the subject. The drink may include, without limitation,
water, milk, or other common beverages.
[0061] The liquid formulation of solid composition (formulated in a
liquid) may be administered to a subject via a feeding tube. The
feeding tube may be temporarily or permanently affixed to a patient
using skill in the art. The patient may be conscious,
semi-conscious, or asleep, depending on the need as determined by
the attending physician. Several types of feeding tubes are known
in the art and may be selected by the attending physician.
[0062] C. Liquid Formulation
[0063] Ibrutinib may be also formulated in liquid formulations for
administration to a subject. Liquids include, without limitation,
suspensions, syrups, and elixirs. These dosing units are readily
prepared using the methods described herein and those known to
those of skill in the art. When formulated as suspension, particle
settling may occur, thereby requiring resuspending particles in the
suspension using skill in the art.
[0064] The liquid compositions described herein contain Ibrutinib,
a salt, prodrug, or metabolite thereof, microcrystalline cellulose,
carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric
acid monohydrate, disodium hydrogen phosphate, sucralose, sodium
methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate,
concentrated hydrochloric acid, sodium hydroxide, and water.
[0065] Accordingly, the liquid composition contains about 30 to
about 80 mg/mL of Ibrutinib, a salt, prodrug, or metabolite
thereof. In some embodiments, the composition contains about 30 to
about 50 mg/mL of Ibrutinib, a salt, prodrug, or metabolite
thereof. In further embodiments, the composition contains about 40
mg/mL of Ibrutinib, a salt, prodrug, or metabolite thereof. In
other embodiments, the composition contains about 60 to about 80
mg/mL to about 70 mg/mL of Ibrutinib, a salt, prodrug, or
metabolite thereof. In yet further embodiments, the composition
contains about 70 mg/mL of Ibrutinib, a salt, prodrug, or
metabolite thereof.
[0066] One or more suspending agent may be included in the liquid
composition discussed herein. In one embodiment, microcrystalline
cellulose and carboxymethylcellulose sodium may also be included in
the liquid composition. In some embodiments, the composition
contains about 12 to about 15 mg/mL of the suspending agent. In
further embodiments, the composition contains about 13 to about 15
mg/mL of suspending agent. In other embodiments, the composition
contains about 12 to about 14 mg/mL of the suspending agent. In a
further embodiment, the composition contains about 13 mg/mL of the
suspending agent. In another embodiment, the composition contains
about 14 mg/mL of the suspending agent.
[0067] The composition may also contain one or more of a wetting
agent. In one embodiment, the composition contains
hydroxypropylmethylcellulose. In some embodiments, the composition
contains about 0.5 to about 3 mg/mL of the wetting agent. In other
embodiments, the composition contains about 2 to about 3 mg/mL of
the wetting agent. In another embodiment, the composition contains
about 2.5 mg/mL of the wetting agent. In further embodiments, the
composition contains about 0.5 to about 1.5 mg/mL of the wetting
agent. In yet other embodiments, the composition contains about 1
mg/mL of the wetting agent.
[0068] One or more buffering agent may be included in the
composition, solid or liquid. In one embodiment, the buffering
agent is citric acid monohydrate or disodium hydrogen phosphate. In
another embodiment, the composition contains about 2.5 to about 3.5
mg/mL of a buffering agent. In some embodiments, the composition
contains about 1 to about 1.5 mg/mL of a first buffering agent. In
other embodiments, the composition contains about 0.5 to about 0.7
mg/mL of the buffering agent. In a further embodiment, the
composition contains about 1.5 mg/mL of a first buffering agent and
about 1.5 mg/mL of a second buffering agent. In other embodiments,
the composition contains about 1.6 mg/mL of a first buffering agent
and about 1.4 mg/mL of a second buffering agent. In yet another
embodiment, the composition contains about 1.5 mg/mL or 1.6 mg/mL
of citric acid monohydrate. In still a further embodiment, the
composition contains about 1.4 mg/mL of disodium hydrogen
phosphate.
[0069] Sweeteners may also be included in the compositions, solid
or liquid, described herein. In one embodiment, the sweeter is
sucralose. In another embodiment, the composition contains about
0.1 to about 1.5 mg/mL of the sweetener. In other embodiments, the
composition contains 0.5 to about 1.5 mg/mL of the sweetener. In a
further embodiment, the composition contains about 1 mg/mL of the
sweetener. In another embodiment, the composition contains about
0.5 mg/mL of the sweetener.
[0070] One or more of a preservative may further be included in the
compositions, solid or liquid. The preservative desirably provides
an optimal microbiological activity in the liquid formulation. In
one embodiment, the composition retains the optimal activity of the
methyl/ethyl parabens. In one embodiment, the preservative is
sodium methyl parahydroxybenzoate. In another embodiment, the
preservative is sodium ethyl parahydroxybenzoate. In a further
embodiment, the composition contains about 1.5 to about 2.5 mg/mL
of the preservative. In other embodiments, the composition contains
about 1.5 to about 2 mg/mL of the preservative. In a further
embodiment, the composition contains about 0.5 to about 1.8 mg/mL
of a first preservative. In yet another embodiment, the composition
contains about 1.0 to about 1.8 mg/mL of a first preservative. In
still a further embodiment, the composition contains about 1.25 to
about 1.5 mg/mL of a second preservative. In another embodiment,
the composition contains about 1.1 mg/mL of a first preservative
and about 0.6 mg/mL of a second preservative. In other embodiments,
the composition contains about 1.4 mg/mL of a first preservative
and about 0.7 mg/mL of a second preservative. In yet a further
embodiment, the composition contains about 1 mg/mL of sodium methyl
parahydroxybenzoate. In still another embodiment, the composition
contains about 0.6 mg/mL of sodium ethyl parahydroxybenzoate. In
further embodiments, the composition contains about 1.4 mg/mL of
sodium methyl parahydroxybenzoate. In still another embodiment, the
composition contains about 0.7 mg/mL of sodium ethyl
parahydroxybenzoate.
[0071] If the pH of the solution requires adjustment, a pH adjustor
may be included in the composition. One of skill in the art would
be able select suitable pH adjustor to ensure a safe, stable and
subject-compatible composition. In one embodiment, the pH of the
composition is adjusted to about 6. In another embodiment, the pH
adjustor is an acid or base. In a further embodiment, the pH
adjustor is hydrochloric acid. In still another embodiment, the pH
adjustor is concentrated hydrochloric acid. In yet a further
embodiment the pH adjustor is sodium hydroxide.
[0072] Finally, a sufficient amount of a diluent, such as water,
may be included in the composition to ensure a volume of about 1
mL. In one embodiment, the diluent is purified water. Compositions
containing lesser amounts of Ibrutinib can prepared as described
herein by diluting compositions containing greater amounts of
Ibrutinib using the diluent.
[0073] In one embodiment, a pharmaceutical composition is provided
and contains (i) about 70 mg/mL of Ibrutinib; (ii) about 13 mg/mL
of microcrystalline cellulose and carboxymethylcellulose sodium;
(iii) about 2.5 mg/mL of hydroxypropylmethylcellulose; (iv) about
1.5 mg/mL of citric acid monohydrate; (v) about 1.4 mg/mL of
disodium hydrogen phosphate; (vi) about 1 mg/mL of sucralose; (vii)
about 1 mg/mL of sodium methyl parahydroxybenzoate; and (viii)
about 0.6 mg/mL of sodium ethyl parahydroxybenzoate.
[0074] In another embodiment, a pharmaceutical composition is
provided and contains the components of Table 2.
TABLE-US-00002 TABLE 2 Component Concentration (mg/mL) Ibrutinib
micronized 70 MCC and CMC 13 HPMC 2.5 Citric acid monohydrate 1.513
Disodium hydrogen phosphate 1.38 Sucralose 1 Sodium methyl
parahydroxybenzoate 1.145 Sodium ethyl parahydroxybenzoate
0.575
[0075] In other embodiments, a pharmaceutical composition is
provided and contains (i) about 40 mg/mL of Ibrutinib; (ii) about
14 mg/mL of microcrystalline cellulose and carboxymethylcellulose
sodium; (iii) about 1 mg/mL of hydroxypropylmethylcellulose; (iv)
about 1.6 mg/mL of citric acid monohydrate; (v) about 1.4 mg/mL of
disodium hydrogen phosphate; (vi) about 0.5 mg/mL of sucralose;
(vii) about 1.4 mg/mL of sodium methyl parahydroxybenzoate; and
(viii) about 0.7 mg/mL of sodium ethyl parahydroxybenzoate.
[0076] In further embodiments, a pharmaceutical composition is
provided and contains the components of Table 3.
TABLE-US-00003 TABLE 3 Component Concentration (mg/mL) Ibrutinib
micronized 40 MCC and CMC 14 HPMC 1 Citric acid monohydrate 1.602
Disodium hydrogen phosphate 1.38 Sucralose 0.5 Sodium methyl
parahydroxybenzoate 1.3582 Sodium ethyl parahydroxybenzoate
0.6773
[0077] The liquid compositions may be prepared by (a) mixing water,
microcrystalline cellulose croscarmellose sodium; (b) mixing water
with hydroxypropylmethylcellulose; (c) mixing the product of step
(b) with Ibrutinib; (d) mixing the product of steps (a) and (c);
(e) mixing the product of step (d) with sucralose; (f) mixing the
product of step (e) with sodium methyl parahydroxybenzoate and
sodium ethyl parahydroxybenzoate; (g) mixing the product of step
(f) with monohydrate citric acid; and (h) mixing the product of
step (g) with anhydrous disodium hydrogen phosphate. The process my
further include (i) adjusting the pH of the product of step (h) to
a pH of about 6. In one embodiment, step (i) is performed using
hydrochloric acid or sodium hydroxide. The process may also include
adding water to the product of step (h) or (i). It is also
envisioned that the product of step (a) may be homogenized using
skill known in the art.
[0078] Liquid formulations may then be stored as a bulk unit or
distributed into separate, smaller vials for storage or purchasing
by the customer. One of skill in the art would readily be able to
select suitable vials for use herein. In one embodiment, the liquid
composition is added to a vial. In a further embodiment, the vial
is glass. In another embodiment, the vial is clear or amber. In a
further embodiment, the vial may be sealed. In yet another
embodiment, the vial is sealed with a rubber stopper. In a further
embodiment, the vial is sealed with a Teflon coated rubber stopper.
The stopper optionally contains a removable, i.e., tearable,
aluminum cap. In still another embodiment, the vial is a 10 mL/20
mm vial. In yet a further embodiment, the vial is a drinking
vial.
[0079] Additionally, the drug product will be administered as mono
dose to each subject after a suitable sample shaking to resuspend
particles before administration. Furthermore, after drug product
administration, vial will be rinsed with an adequate amount of
water and the entire contents of the vial will be administered to
subject. For reasons mentioned above, even if settling happens, it
is not expected to have an effect on the delivered dose.
[0080] D. Additional Components
[0081] Other components can be added to the compositions described
herein as determined by one of skill in the art. The additional
components may be inert and do not interfere with the function of
the required components of the compositions. The compositions may,
therefore, include other adjuvants, syrups, elixirs, diluents,
binders, lubricants, surfactants, granulating agents,
disintegrating agents, emollients, metal chelators, pH adjustors,
coloring preservatives, antioxidants, agents, surfactants, fillers,
disintegrants, or combinations thereof.
[0082] Preservatives may include ascorbic acid, BHT and BHA, sodium
methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, or
combinations thereof.
[0083] Sweeteners such as natural or artificial sweeteners, or a
combination thereof, may be included in the compositions described
herein. In one embodiment, the natural sweetener is sucrose
including raw sugar, granulated sugar, brown sugar, confectioner's
sugar, and turbinado sugar, fructose, honey, fruit sugar, high
fructose corn syrup, corn syrup, sugar alcohols such as mannitol,
sorbitol, xylitol, erythritol, hydrogenated starch hydrolysate,
lactitol, or maltitol, osmalt, dextrose, invert sugar, agave
nectar, glucose, lactose, maltose, maple sugar, date sugar,
molasses, stevia extract, tagatose, trehalose, or any combinations
thereof. Another embodiment, the artificial sweetener is sucralose,
aspartame, saccharine, neotame, advantame, or acesulfame potassium.
In still a further embodiment, sugar may be included in the
compositions.
[0084] Binders may include, without limitation, cellulose,
methylcellulose, hydroxymethylcellulose, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
polypropylpyrrolidone, polyvinylpyrrolidone (povidone, PVP),
gelatin, gum arabic and acacia, polyethylene glycols, starch,
sugars such as sucrose, kaolin, dextrose, and lactose, cholesterol,
tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides),
cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates,
dextrin, glyceryl monooleate, glyceryl monostearate, glyceryl
palmitostearate, polyoxyethylene alkyl ethers, polyoxyethylene
castor oil derivatives, polyoxyethylene stearates, polyvinyl
alcohol, and gelatin, among others.
[0085] Lubricants may include anhydrous silicic acid, talc, stearic
acid, sodium lauryl sulfate, magnesium stearate and sodium stearyl
fumarate, among others.
[0086] Granulating agents may include, without limitation, silicon
dioxide, starch, calcium carbonate, pectin, crospovidone, and
polyplasdone.
[0087] Disintegrating agents or disintegrants may include, without
limitation, starch, carboxymethylcellulose, substituted
hydroxypropylcellulose, sodium bicarbonate, calcium phosphate,
calcium citrate, sodium starch glycolate, pregelatinized starch or
crospovidone.
[0088] Emollients may include, without limitation, stearyl alcohol,
mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate,
polyethylene glycol, olive oil, petroleum jelly, palmitic acid,
oleic acid, and myristyl myristate.
[0089] Surfactants may include, without limitation, polysorbates,
sorbitan esters, poloxamer, or sodium lauryl sulfate.
[0090] Metal chelators may include, without limitation,
physiologically acceptable chelating agents including edetic acid,
malic acid, or fumaric acid.
[0091] The compositions described herein, in dry or liquid form,
have a pH of about 5.5 to about 6.5. pH adjusters may be utilized
to adjust the pH of a solution containing Ibrutinib to about 6. pH
adjustors may include, without limitation, citric acid, ascorbic
acid, fumaric acid, malic acid, hydrochloric acid, sodium
hydroxide, salts thereof, or combinations thereof.
[0092] E. Stability of the Compositions
[0093] The Ibrutinib compositions as described herein, whether in
solid or liquid form, are stable under neutral conditions, i.e., a
pH of about 6 to about 8. The compositions are also stable under
light irradiation. In one embodiment, the compositions are stable
over a period of about 1 month for samples stored at varying
temperatures and humidities. The term stable as used herein refers
to the compositions described herein which degrade less than about
3%. In one embodiment, the compositions are stable at about
20.degree. C/50% relative humidity to about 45.degree. C./75%
relative humidity. In another embodiment, the compositions
described herein degrade less than about 3% over a period of
greater than 1 month at temperatures at or greater than about
25.degree. C. and a relative humidity at or greater than about
60%.
[0094] The solid compositions are also stable for at least about 6
hours when combined with an agent that is semi-solid or liquid. In
one embodiment, the solid compositions may be suspended in a liquid
or semi-solid and re-dispersed after 6 hours. In another
embodiment, the solid compositions suspended in a liquid or
semi-solid are stable for up to about 6 hours.
[0095] Stability may be monitored by a number of methods known in
the art. In one embodiment, the capsules and liquids may be
observed to detect any physical aspect or color change. In one
embodiment, a capsule color change or deformation of the capsule
may indicate degradation or deterioration of capsule and thus
affect safety or efficacy.
[0096] The compositions described herein may be stored at reduced,
room, or elected temperatures. In one embodiment, the compositions
are stored at temperatures of about 0 to about 10.degree. C. In
another embodiment, the compositions are stored at temperatures of
about 2 to about 8.degree. C. The compositions may be stored in the
absence of water, air, and moisture. However, storage at room
temperature, among other atmospheric conditions, does not affect
the overall stability of the compositions.
[0097] F. Methods of Using the Compositions
[0098] Also provided are method of delivering Ibrutinib to a
patient, where the method includes administering a composition
described herein to a patient. The compositions are thereby useful
in treating or preventing conditions. In some embodiments, the
conditions are those recited in U.S. Pat. Nos. 8,497,277;
8,476,284; 8,703,780; and 8,754,090, which are incorporated by
reference herein.
[0099] The compositions are useful in therapeutically treating a
subject having one or more of any of the conditions noted herein.
The compositions may also be prophylactically useful, i.e., the
compositions may be administered to a patient susceptible to or
otherwise at risk of developing a malignancy. The compositions may
further be used in maintenance therapy, i.e., administered to a
patient who is in remission.
[0100] In certain embodiments, the methods include treating one or
more autoimmune disease. In one embodiment, the autoimmune disorder
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.
[0101] In other embodiment, the methods include treating one or
more heteroimmune disorder. In one embodiment, the heteroimmune
disorder is graft versus host disease, transplantation,
transfusion, anaphylaxis, allergy, type I hypersensitivity,
allergic conjunctivitis, allergic rhinitis, or atopic
dermatitis.
[0102] In certain embodiments, the methods include treating one or
more inflammatory disease. In one embodiment, the inflammatory
disease is arthritis, asthma, appendicitis, blepharitis,
bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,
cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,
dermatitis, dermatomyositis, encephalitis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, 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.
[0103] In still other embodiments, the methods include treating one
or more cancer. In one embodiment, the cancer is a B-cell
proliferative disorder. In still another embodiment, the cancer is
a hematological malignancy. In a further embodiment, the cancer is
B-cell prolymphocytic leukemia, leukemia, lymphoma,
lymphoproliferative disorder, lymphoplasmacytic lymphoma,
Waldenstrom macroglobulinemia, myeloid disorder, plasma cell
myeloma, plasmacytoma, mediastinal large B cell lymphoma,
intravascular large B cell lymphoma, primary effusion lymphoma,
lymphomatoid granulomatosis, non-Hodgkin's CLL, SLL, high risk CLL,
non-CLL/SLL lymphoma, follicular lymphoma, diffuse large B-cell
lymphoma, mantle cell lymphoma, multiple myeloma, marginal zone
lymphoma, non-Burkitt high grade B cell lymphoma, extranodal
marginal zone B cell lymphoma, acute or chronic myelogenous
leukemia, myelodysplastic syndrome, lymphoblastic leukemia,
relapsed or refractory diffuse large B-cell lymphoma, relapsed or
refractory mantle cell lymphoma, relapsed or refractory follicular
lymphoma, relapsed or refractory CLL, relapsed or refractory SLL,
relapsed or refractory multiple myeloma, Burkitt's lymphoma,
cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma,
diffuse mixed small and large cell lymphoma, diffuse small cleaved
cell, extranodal follicular small cleaved cell, follicular mixed
small cleaved and large cell, follicular large cell, intravascular
lymphomatosis, large cell immunoblastic lymphoma, large cell
lymphoma, mucosa associated lymphoid tissue Lymphoma, immunoblastic
large cell lymphoma, precursor B-lymphoblastic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma, nodal marginal
zone B-cell lymphoma, splenic marginal zone B-cell lymphoma,
primary mediastinal B-cell lymphoma, hairy cell leukemia, and
primary central nervous system lymphoma. In another embodiment, the
B-cell proliferative disorder is non-Hodgkin lymphoma, Waldenstrom
macroglobulinemia, plasma cell myeloma, or chronic lymphocytic
leukemia. In a further embodiment, the B-cell proliferative
disorder is diffuse large B cell lymphoma, follicular lymphoma,
mantle cell lymphoma and Burkitt lymphoma. In still another
embodiment, the cancer is leukemia. In yet another embodiment, the
cancer is a lymphoma.
[0104] In yet other embodiments, the methods include treating a
thromboembolic disorder. In one embodiment, the thromboembolic
disorder is myocardial infarct, angina pectoris, reocclusion after
angioplasty, restenosis after angioplasty, reocclusion after
aortocoronary bypass, restenosis after aortocoronary bypass,
stroke, transitory ischemia, a peripheral arterial occlusive
disorder, pulmonary embolism, or deep venous thrombosis.
[0105] The dosage requirements of Ibrutinib may vary based on the
severity of the symptoms presented and the particular subject being
treated. Treatment may be initiated with small dosages less than
the optimum dose of Ibrutinib. Thereafter the dosage may be
increased until the optimum effect under the circumstances is
reached. Precise dosages will be determined by the administering
physician based on experience with the individual subject treated.
In one embodiment, the composition is administered at a
concentration that will afford effective results without causing
any unacceptable harmful or deleterious side effects.
[0106] The term "effective amount," as used herein, refers to a
sufficient amount of an agent or a compound being administered
which will relieve one or more symptom of a B-cell proliferative
disorder. The result may be reduction and/or alleviation of the
signs, symptoms, or causes of the disorder. In certain embodiments,
the effective amount achieves the desired pharmacologic effect or
therapeutic improvement without undue adverse side effects.
[0107] An effective amount of Ibrutinib can vary depending on the
components of the composition, mode of delivery, severity of the
condition being treated, the patient's age and weight, and any
other active ingredients used in the composition. The dosing
regimen can also be adjusted to provide the optimal therapeutic
response. Several divided doses may be delivered daily, e.g., in
divided doses 2 to 4 times a day, or a single dose can be
delivered. The dose can however be proportionally reduced or
increased as indicated by the exigencies of the therapeutic
situation. In one embodiment, the delivery is on a daily, weekly,
or monthly basis. In another embodiment, the delivery is on a daily
delivery. The composition may be administered daily. In some
embodiments, the composition may be administered every other day.
In some embodiments, the composition may be administered once or
more times per day. In some embodiments, the composition may be
administered two or more times per day. In some embodiments, the
composition may be administered three or more times per day.
[0108] The dosages may also be lowered or raised based on the
periodic delivery. The attending physician also has the flexibility
to continue the same administration for a period of time or may
decide to alter the administration schedule. This may be as a
result of improved conditions, adverse, but not fatal, reactions to
the composition, or the like. If administration is halted,
re-administration may be continued if the patient stabilizes or
improvement of the condition has materialized. Accordingly, the
dosage, frequency of administration, or combination thereof may be
reduced or increased as needed.
[0109] The amount of Ibrutinib administered may vary depending upon
severity of the disease, weight of the subject, age of the subject,
among others. In one embodiment, an effective amount is about 0.1
to about 5000 mg/day. In one embodiment, an effective amount of
Ibrutinib is about 1 to about 1500 mg/day. In another embodiment,
the effective amount of Ibrutinib is about 20 to about 450 mg/day.
In a further embodiment, the effective amount of Ibrutinib is about
20 to about 420 mg/day. In yet another embodiment, the effective
amount of Ibrutinib is about 30 to about 300 mg/day. In still a
further embodiment, the effective amount of Ibrutinib is about 50
to about 200 mg/day. In another embodiment, the effective amount of
Ibrutinib is about 70 to about 140 mg/day.
[0110] 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.
[0111] The compositions may be delivered to the subject by any
suitable route as directed by the attending physician. In one
embodiment, the compositions are delivered orally.
[0112] The compositions may be co-administered with one or more of
a second agent. The second agent may be administered prior to,
concurrently with, or subsequent to the compositions discussed
herein. In some embodiments, the second agent comprises a
chemotherapeutic agent, steroid, immunotherapeutic agent, among
others. In another embodiment, the second agent is one or more of
actinomycines, alkylating agents, ahtretinoin, altretamine,
amzacrine, anagrelide, angiogenesis inhibitors, antibody,
anti-androgens, anti-estrogens, antimetabolites, anthracyclines,
arsenic trioxide, asparaginase, B cell receptor pathway inhibitor
(CD79A inhibitor, CD79B inhibitor, CD 19 inhibitor, Lyn inhibitor,
Syk inhibitor, PI3K inhibitor, Blnk inhibitor, PLCy inhibitor, PKCP
inhibitor), basiliximab, bexarotene, bortezomib, calcineurin
inhibitors, canakinumab, celecoxib, ceradenovec, colchicine
derivatives, cytotoxic antibiotics, daclizumab, denileukin
diftitox, DNA damaging agent, epoxides, estramustine, estrogens,
ethylene imines, folic acid analogues, gonadotropin releasing
interferons, growth factors, HDAC inhibitor, hedgehog inhibitor,
lisp% inhibitor, histone deacetylase inhibitor, hormones, hormone
analogs, hormone antagonists, hydroxycarbamide, IAP inhibitor,
ibritumomab immunostimulants, immunosuppressants, interleukin
inhibitors, interleukins, irinotecan, Jak1/2 inhibitor, lonidamine,
masoprocol, mepolizumab, miltefosein, mitoguazone, mitotane,
monoclonal antibodies, mTOR inhibitor, methylhydrazines, nitrogen
mustards, nitrosoureas, PI3K inhibitor, oblimersen, PARP inhibitor,
pegaspargase, pentostatin, PKC inhibitor, plant alkaloids, platinum
compounds (carboplatin, cisplatin, oxaliplatin, or satraplatin),
podophyllotoxin derivatives, progestogens, proteasome inhibitor,
protein kinase inhibitor, protease inhibitor, purine analogs,
pyrimidine analogs, radioimmunotherapeutic, sensitizers,
romidepsin, sitimagene tiazofurine, topotecan, tretinoin, tumor
necrosis factors, TNF-.alpha. Inhibitors, tocilizumab, telomerase
inhibitor, tiuxetan, tositumomabtriazenes, ustekinumab, vinca
alkaloids, or vorinstat. In a further embodiment, the second agent
includes, Adriamycin, dactinomycin, bleomycin, Vinblastine,
Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;
acronine; adozelesin; aldesleukin; alemtuzumab, altretamine;
ambomycin; ametantrone acetate; aminoglutethimide, amsacrine,
anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
azetepa; azotomycin; batimastat; bendamustine, bevacizumab;
benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide
dimesylate; bizelesin; bleomycin sulfate; brequinar sodium;
bropirimine; busulfan; cactinomycin; calusterone; caracemide;
carbetimer; carboplatin, carmustine, carubicin hydrochloride;
carzelesin; cedetingol; cetuximab; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; Crizotinib; cyclophosphamide;
cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine;
dexormap latin; 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; fluorocitabine; 5-fluorouracil;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; gemtuzamab; hydroxyurea; idarubicin hydrochloride;
ifosfamide; iimofosine; interleukin II, interferon .alpha.-2a;
interferon .alpha.-2b; interferon .alpha.-n1; interferon
.alpha.-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;
mycophenolic acid; Nexavar.RTM.; nocodazoie; nogalamycin;
ofatumumab; ormaplatin; oxisuran; paclitaxel; pegaspargase;
peliomycin; pentamustine; peplomycin sulfate; perfosfamide;
pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin;
plomestane; porfimer sodium; porfiromycin; prednimustine;
procarbazine hydrochloride; puromycin; puromycin hydrochloride;
pyrazofurin; riboprine; rituaximab; rogletimide; safingol; safingol
hydrochloride; semustine; simtrazene; sparfosate sodium;
sparsomycin; spirogermanium hydrochloride; spiromustine;
spiroplatin; Sprycel.RTM.; streptonigrin; streptozocin; sulofenur;
Sutent.RTM.; talisomycin; Tarceva.RTM.; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; temozolomide; teniposide;
teroxirone; testolactone; thiamiprine; thioguanine; thiotepa;
tiazofurin; tirapazamine; toremifene citrate; trestolone acetate;
triciribine phosphate; trimetrexate; trimetrexate glucuronate;
triptorelin; tubulozole hydrochloride; Tykerb.RTM.; 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; wortmannin;
zeniplatin; zinostatin; zorubicin hydrochloride.
[0113] G. Kits Containing the Compositions
[0114] Also provided are kits or packages containing Ibrutinib and
an optional carrier suitable for administration to a mammalian
subject as discussed above. In one embodiment, the capsules may be
packaged in bottles, blister packs, pill boxes, or the like. In
another embodiment, the liquid formulation may be packaged in a
bottle optionally coated with a piercable cap, ampule, drop
counter, or in a saline bag.
[0115] The kits or packages containing the compositions described
herein are designed for use in the methods described herein. The
kit can optionally further contain instructions for administering
composition, a carrier suitable for administration of the
composition, one or more instruments including, without limitation,
syringe, pipette, forceps, measuring spoon, or the like. Other
components for inclusion in the kits would be clear to those
skilled in the art, taking into consideration the desired
indication and mode of delivery.
[0116] The following Examples are provided to illustrate some of
the concepts described within this disclosure. While each Example
is considered to provide specific individual embodiments of
composition, methods of preparation and use, none of the Examples
should be considered to limit the more general embodiments
described herein.
[0117] In the following examples, efforts have been made to ensure
accuracy with respect to numbers used (e.g. amounts, temperature,
etc.) but some experimental error and deviation should be accounted
for. Unless indicated otherwise, temperature is in degrees C.,
pressure is at or near atmospheric.
EXAMPLES
Example 1
Solid Compositions Containing Ibrutinib
[0118] Solid compositions containing Ibrutinib were prepared for
inclusion in a capsule as described in the following.
[0119] A. 140 mg Capsule
[0120] In this process, an intragranular blend was prepared by
mixing MCC (151.49 mg; Avicel PH 101), SLS (9.40 mg; Kolliphor;
fine), and CCS (13.10 mg; Ac-di-sol) in a vessel. This was then
mixed with Ibrutinib (70 mg; micronized, Lonza, Nansha). The
remaining Ibrutinib (70 mg) was then added and the composition
mixed. Magnesium stearate (0.8 mg; Non-Bovine #5712) was then added
to this mixture and the same blended to provide a pre-roller
compaction blend. The pre-roller compaction blend was then roller
compacted to form ribbons. The ribbons were then milled to provide
a composition containing granules.
[0121] The granules were then blended with a second portion of SLS
(4.6 mg; Kolliphor; fine) and CCS (9.9 mg; Ac-di-sol). To this
blend was then added a second portion of magnesium stearate (0.8
mg; Non-Bovine #5712) to provide a lubricated blend. This
lubricated blend was then added to a size 0 Swedish orange hard
gelatin capsule.
[0122] B. 50 mg Ibrutinib Capsule
[0123] In this process, an intragranular blend was prepared by
mixing MCC (54.07 mg; Avicel PH 101), SLS (3.36 mg; Kolliphor;
fine), and CCS (4.68 mg; Ac-di-sol). This was then mixed with
Ibrutinib (25 mg; micronized, Lonza, Nansha). The remaining
Ibrutinib (25 mg) was then added and the composition mixed.
Magnesium stearate (0.29 mg; Non-Bovine #5712) was then added to
this mixture and the same blended to provide a pre-roller
compaction blend. The pre-roller compaction blend was then roller
compacted to form ribbons. The ribbons were then milled to provide
a composition containing granules.
[0124] The granules were then blended with a second portion of SLS
(1.64 mg; Kolliphor; fine) and CCS (3.54 mg; Ac-di-sol). To this
blend was then added magnesium stearate (0.29 mg; Non-Bovine #5712)
to provide a lubricated blend. This lubricated blend (117.87 mg)
was then added, independently, to a size 0 Swedish orange hard
gelatin capsule and a Swedish orange sprinkle capsule.
Example 2
Liquid Suspension Composition Containing Ibrutinib
[0125] (i) 70 mg/mL Ibrutinib Liquid Suspension
[0126] A liquid composition containing 70 mg/mL of Ibrutinib was
prepared. Specifically, water (300 mL) was mixed with a composition
MCC of CCS (Avicel RC591; 6.5 g) for 30 minutes. This dispersion
was then homogenized for 30 seconds using a SILVERSON.RTM.
homogenizer L2R at the maximal speed (7500 rpm). HPMC (2910 5 mPas;
1.25 g) was mixed with water (120 mL) until homogeneous using a
magnetic stirrer. Micronized Ibrutinib (35 g, Lonza Clinical) was
then added to the HPMC solution and mixed for 120 minutes. The
MCC/CCS dispersion was then mixed with the Ibrutinib mixture.
Sucralose (0.5 g), sodium methyl parahydroxybenzoate (0.5725 g),
and sodium ethyl parahydroxybenzoate (0.2875 g) were added to the
mixture. After about 10 minutes stirring, citric acid monohydrate
(0.7565 g), and disodium hydrogen phosphate anhydrous parenteral
(0.69 g) were then added to this mixture. The mixture was stirred
for about 10 minutes until the content solubilized. The pH of the
mixture was measured and found to be 5.99, thereby eliminating the
need to adjust the pH. The mixture was then diluted with purified
water until a final weight of 510.5 g. The mixture was again
measured and found to be about 6.
[0127] The concentration for each component in the final liquid
composition is provided in Table 2.
[0128] (ii) 40 mg/mL Ibrutinib Liquid Suspension
[0129] A liquid composition containing 40 mg/mL of Ibrutinib was
prepared. Specifically, water (300 mL) was mixed with a composition
MCC of CCS (Avicel RC591; 7 g) for 30 minutes. This dispersion was
then homogenized for 30 seconds using a SILVERSON.RTM. homogenizer
L2R at the maximal speed (7500 rpm). HPMC (2910 5 mPas; 0.5 g) was
mixed with water (120 mL) until homogeneous using a magnetic
stirrer. Micronized Ibrutinib (20 g, Lonza Clinical) was then added
to the HPMC solution and mixed for 120 minutes. The MCC/CCS
dispersion was then mixed with the Ibrutinib mixture. Sucralose
(0.25 g), sodium methyl parahydroxybenzoate (0.6791 g) and sodium
ethyl parahydroxybenzoate (0.3387 g) were added to the mixture.
After about 10 minutes stirring, citric acid monohydrate (0.801 g),
and disodium hydrogen phosphate anhydrous parenteral (0.69 g) were
then added to this mixture. The mixture was stirred for about 10
minutes until the contents solubilized. The pH of the mixture was
measured and found to be about 5.99, thereby eliminating the need
to adjust the pH. The mixture was then diluted with purified water
until final weight of 507 g. This mixture was then homogenized. The
pH was again measured and found to be about 6.
[0130] The concentration for each component in the final liquid
composition is provided in Table 3.
Example 3
Large Scale Preparation of a Suspension Containing Ibrutinib
Preparation of 4L Batch
[0131] Purified water (480 g) was added to a vessel and warmed to
about 83.degree. C. at a stirring rate of about 400 rpm for about
60 minutes. HPMC (10.002 g) was slowly added to the vessel and the
mixture stirred at a rate of about 7600 rpm for about 4 minutes
until the mixture was homogenized. To this vessel was added
purified water (480 g) and then mixture was stirred for about 5
minutes at a rate of about 500 rpm at room temperature until the
mixture was solubilized. Ibrutinib (278.6 g) was added to the
mixture and it was stirred at 600 rpm for about 2 h until it was
homogenous. The mixture was monitored using a microscope for
agglomerates.
[0132] Purified water (2400 g) was then added to a second vessel.
At a rate of about 500 rpm, MCC (51.74 g; Avicel) was added to the
second vessel over a period of 3 minutes, followed by stirring at a
rate of about 400 rpm for about 60 minutes. This mixture was then
homogenized using a stirring speed of about 7600 tr/min over a
period of about 4 minutes. The mixture was monitored using a
microscope for agglomerates.
[0133] The mixture in the first vessel was then added to the
mixture in the second vessel and the combined contents stirred for
about 5 minutes at a speed of about 500 rpm. The first vessel was
then rinsed using purified water (200 ml) and the same added to the
second vessel. Under moderate stirring conditions, sucralose
(4.0038 g), sodium methyl parahydroxybenzoate (4.5838 g), and
sodium ethyl parahydroxybenzoate (2.300 g) were sequentially added
to the second vessel and the mixture stirred for about 11 minutes
until the solids solubilized. Citric acid monohydrate (6.052 g) was
then added to the second vessel and the mixture stirred for about
10 minutes. Anhydrous disodium hydrogen phosphate (5.521 g) was
then added and the mixture was stirred for about 10 minutes until
the contents solubilized. The pH of the solution was measured and
found to be about 5.94, thereby eliminating the need to adjust the
pH.
[0134] The mixture was then diluted using purified water (4064 g)
until a final weight of 4084 g. This mixture was then homogenized.
The pH was again measured and found to be about 5.98. Aliquots (8
ml) of the mixture were then removed under constant stirring at a
speed of about 500 to about 1300 rpm over a period of about 75
minutes. Each aliquot was added to a an amber, glass vial (10 ml),
a Flurotec coated rubber injection stopper (20 mm) then inserted
into the vial, and the stopper affixed with an aluminum tear-off
cap (20 mm). See, FIG. 3.
Example 4
Stability Studies of Ibrutinib Formulations
[0135] The stability of the solid composition described herein was
evaluated in 3 liquids. Specifically, the contents of 4 sprinkle
capsules described herein (each containing 140 mg of solid
composition) were dissolved in water (100 mL), milk (100 mL), and
orange juice (100 mL) at room temperature. After about 6 hours, the
colors of the milk and orange juice solutions remained unchanged,
while the water solution turned milky white.
[0136] It was found using liquid chromatography that the three
Ibrutinib formulations were stable. Specifically, most of the
Ibrutinib active agent with minor amounts of impurities was
recovered from these formulations after sitting for 6 hours.
Example 5
Feeding Tube Studies Using Ibrutinib Formulations
[0137] Feasibility studies were conducted on feeding tubes using a
composition described herein. Specifically, two formulations were
prepared, each formulation containing water (20 mL) and the
contents of 4 sprinkle capsules described herein (total of 560 mg
of active equivalent granules). Upon passing the formulations
through size 2.2 mm and 2.7 mm ID feeding tubes, it was observed
that the formulations (containing the water and composition) passed
through the tubes by gravity force and without clogging.
[0138] It was also found that the tubes could be re-used before the
introduction of another formulation. Specifically, air was blown
through the tubes by applying a small amount of pressure using a
syringe. Additional formulations could then be passed through the
tubes without any interruption. It is to be understood that while
the invention has been described in conjunction with the preferred
specific embodiments thereof, that the foregoing description and
the examples that follow are intended to illustrate and not limit
the scope of the invention. It will be understood by those skilled
in the art that various changes may be made and equivalents may be
substituted without departing from the scope of the invention, and
further that other aspects, advantages and modifications will be
apparent to those skilled in the art to which the invention
pertains. In addition to the embodiments described herein, the
present invention contemplates and claims those inventions
resulting from the combination of features of the invention cited
herein and those of the cited prior art references which complement
the features of the present invention. Similarly, it will be
appreciated that any described material, feature, or article may be
used in combination with any other material, feature, or article,
and such combinations are considered within the scope of this
invention.
[0139] The disclosures of each patent, patent application, and
publication cited or described in this document are hereby
incorporated herein by reference, each in its entirety, for all
purposes.
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