U.S. patent application number 14/707922 was filed with the patent office on 2015-09-03 for abiraterone acetate formulation and methods of use.
The applicant listed for this patent is iCeutica Inc.. Invention is credited to Satya Bhamidipati, H. William Bosch, Matthew Callahan, Jason Coleman, Christopher Hill, Maura Murphy, Paul Nemeth.
Application Number | 20150246060 14/707922 |
Document ID | / |
Family ID | 54006256 |
Filed Date | 2015-09-03 |
United States Patent
Application |
20150246060 |
Kind Code |
A1 |
Murphy; Maura ; et
al. |
September 3, 2015 |
Abiraterone Acetate Formulation and Methods of Use
Abstract
Pharmaceutical compositions, including unit dosage forms,
comprising abiraterone acetate and methods for producing and using
such compositions are described.
Inventors: |
Murphy; Maura;
(Philadelphia, PA) ; Nemeth; Paul; (Philadelphia,
PA) ; Bosch; H. William; (Philadelphia, PA) ;
Callahan; Matthew; (Philadelphia, PA) ; Bhamidipati;
Satya; (Philadelphia, PA) ; Coleman; Jason;
(Philadelphia, PA) ; Hill; Christopher;
(Philadelphia, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
iCeutica Inc. |
Philadelphia |
PA |
US |
|
|
Family ID: |
54006256 |
Appl. No.: |
14/707922 |
Filed: |
May 8, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2014/030642 |
Mar 17, 2014 |
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14707922 |
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14282535 |
May 20, 2014 |
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PCT/US2014/030642 |
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61789141 |
Mar 15, 2013 |
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61883941 |
Sep 27, 2013 |
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61883941 |
Sep 27, 2013 |
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62052294 |
Sep 18, 2014 |
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Current U.S.
Class: |
514/170 ;
428/402; 514/171; 540/95 |
Current CPC
Class: |
A61K 31/58 20130101;
A61K 31/573 20130101; A61K 9/2054 20130101; A61K 9/145 20130101;
A61K 31/573 20130101; A61K 31/58 20130101; Y10T 428/2982 20150115;
A61K 31/19 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 31/19 20060101 A61K031/19; A61K 31/573 20060101
A61K031/573 |
Claims
1. A unit dosage form of abiraterone acetate, wherein a 500 mg dose
of the unit dosage form is bioequivalent to a 1000 mg dose of
Zytiga.RTM. in healthy male subjects in the fasted state.
2. The unit dosage form of abiraterone acetate of claim 1, wherein
the ratio of the log of the geometric mean of the
AUC.sub.(0-.infin.) for a 500 mg dose administered to healthy male
subjects in the fasted state compared to a 1000 mg dose of
Zytiga.RTM. administered to healthy male subjects in the fasted
state is selected from: 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2 and 0.9
to 1.1.
3. The unit dosage form of abiraterone acetate of claim 1, wherein
the ratio of the log of the geometric mean of the C(max) for a 500
mg dose administered to healthy male subjects in the fasted state
compared to a 1000 mg dose of Zytiga.RTM. administered to healthy
male subjects in the fasted state is selected from: 0.6 to 1.4, 0.7
to 1.3, 0.8 to 1.2 and 0.9 to 1.1.
4. The unit dosage form of abiraterone acetate of claim 1, wherein
the [D90] of the abiraterone acetate is greater than 300 nm and
less than one of: 7500 nm, 7000 nm, 6000 nm, 5000 nm, 4500 nm, 4000
nm, 3000 nm, 2000 nm, 900 nm, 800 nm, and 700 nm.
5. The unit dosage form of abiraterone acetate of claim 1, wherein
the [D50] of the abiraterone acetate greater than 100 nm and is
less than one of: 3500 nm, 3000 nm, 2500 nm, 1600 nm, 1400 nm, 1200
nm, 1000 nm, 800 nm, 500 nm, 400 nm, and 300 nm.
6. The unit dosage form of abiraterone acetate of claim 1, wherein
the [D4,3] of the abiraterone acetate is greater than 300 nm and
less than one of: 7000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nm, 2500
nm, 2400 nm, 2200 nm, 2000 nm, 1900 nm, 1700 nm, 1500 nm, 1300 nm,
1100 nm, 900 nm, and 800 nm.
7. The unit dosage form of abiraterone acetate of claim 1, wherein
the dissolution rate of the abiraterone acetate in the unit dosage
form is such that when a sample containing 100 mg of abiraterone
acetate is tested in 900 ml of pH 4.5 phosphate buffer with 0.1%
sodium lauryl sulfate using USP Apparatus II at 75 rpm, at least
70% of the abiraterone acetate dissolves in between 5 and 15 min or
between 5 and 10 min.
8. The unit dosage form of abiraterone acetate of claim 1, wherein
the dissolution rate of the abiraterone acetate in the unit dosage
form is such that when a sample containing 125 mg of abiraterone
acetate is tested in 900 ml of pH 4.5 phosphate buffer with 0.12%
sodium lauryl sulfate using USP Apparatus II at 75 rpm, at least
70% of the abiraterone acetate dissolves in between 5 and 15 min or
between 5 and 10 min.
9. The unit dosage form of abiraterone acetate of claim 1
containing 125 mg of abiraterone acetate.
10. The unit dosage form of abiraterone acetate of claim 1, wherein
a 500 mg dose, upon oral administration to a population of healthy
male subjects in the fasted state, provides a mean blood plasma
Cmax of 50-120 ng/ml.
11. The unit dosage form of claim 10, wherein a 500 mg dose, upon
oral administration to a population of healthy male subjects in the
fasted state, provides a median blood plasma tmax of 1 to 2.5
hrs.
12. The unit dosage form of abiraterone acetate of claim 1, wherein
a 500 mg dose, upon oral administration to a population of healthy
male subjects in the fasted state, provides a mean blood plasma AUC
(0-.infin.) of 240-650 h*ng/ml.
13. The unit dosage form of claim 1 containing 125 mg of
abiraterone acetate.
14. The unit dosage form of abiraterone acetate of claim 1, wherein
the 90% confidence interval of the mean blood plasma Cmax is a
value between 50 and 120 ng/ml when a 500 mg dose is administered
to healthy male subjects in the fasted state.
15. The unit dosage form of abiraterone acetate of claim 1, wherein
the 90% confidence interval of the mean blood plasma AUC
(0-.infin.) is a value between 240 and 650 h*ng/ml when a 500 mg
dose is administered to healthy male subjects in the fasted
state.
16. The unit dosage form of claim 14 containing 125 mg of
abiraterone acetate.
17. The unit dosage form of any of claim 1 further comprising an
antioxidant.
18. A unit dosage form of abiraterone acetate containing 125 mg of
abiraterone acetate, wherein the median particle size of the
abiraterone acetate, on a particle volume basis, is between 2000 nm
and 100 nm.
19. The unit dosage from of claim 18, wherein the dissolution rate
of the abiraterone acetate in the unit dosage form is such that
when a sample containing 125 mg of abiraterone acetate is tested in
900 ml of pH 4.5 phosphate buffer with 0.12% sodium lauryl sulfate
using USP Apparatus II at 75 rpm, at least 70% of the abiraterone
acetate dissolves in between 5 and 15 min or between 5 and 10
min.
20. The unit dosage form of claim 18, wherein the 90% confidence
interval of the mean blood plasma AUC (0-.infin.) is a value
between 240 and 650 h*ng/ml when a 500 mg dose is administered to
healthy male subjects in the fasted state.
21. The unit dosage form of claim 18, wherein the 90% confidence
interval of the mean blood plasma Cmax is a value between 50 and
120 ng/ml when a 500 mg dose is administered to healthy male
subjects in the fasted state.
22. A method for treating castration resistant prostate cancer
comprising administering to a patient in need thereof a daily 500
mg dose of a dosage form abiraterone acetate, wherein the 500 mg
dose is bioequivalent to a 1000 mg dose of Zytiga.RTM. in healthy
male subjects in the fasted state and a glucocorticoid.
23. The method of claim 22 wherein the glucocorticoid is selected
from the group consisting of prednisone, prednisolone and
methylprednisolone.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part and claims
priority to Application Serial Number PCT/US2014/030642, filed on
Mar. 17, 2014, which claims priority under 35 USC .sctn.119(e) to
provisional U.S. Patent Application 61/789,141, filed on Mar. 15,
2013, and 61/883,941, filed on Sep. 27, 2013. This application is
also a continuation-in-part and claims priority to application Ser.
No. 14/282,535, filed on May 20, 2014, which claims priority under
35 USC .sctn.119(e) to provisional U.S. Patent Application
61/883,941, filed on Sep. 27, 2013, the entire contents of which is
hereby incorporated by reference.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to methods for producing
particles of abiraterone acetate as well as compositions containing
abiraterone acetate and methods of treatment using compositions
containing abiraterone acetate.
BACKGROUND
[0003] Abiraterone ((3.beta.)-17-(pyridin-3-yl)
androsta-5,16-dien-3-ol; CAS #: 154229-19-3; Formula:
C.sub.24H.sub.31NO; Mol. Weight: 349.5 g/mol) is an inhibitor of
CYP17 and thus interferes with the synthesis of androgens in the
testes, adrenal glands and prostate tumor tissue. Abiraterone
acetate (17-(3-Pyridyl) androsta-5, acetate; CAS #154229-18-2), a
prodrug of abiraterone, is approved in the United States for
treatment of castration-resistant prostate cancer. Abiraterone
acetate is considered poorly water soluble.
[0004] Zytiga.RTM. Tablets (250 mg; National Drug Code Number
57894-150; NDA 202379) are approved in the United States in
combination with prednisone for the treatment of patients with
metastatic castration-resistant prostate cancer. The prescribing
information for Zytiga.RTM. tablets recommends 1,000 mg
(4.times.250 mg tablets) administered orally once daily in
combination with prednisone (5 mg) administered orally twice daily.
The European approval of Zytiga.RTM. is for administration in
combination with either prednisone or prednisolone.
[0005] Prescribing information for Zytiga.RTM. states that it must
be taken on an empty stomach and that no food should be consumed
for at least two hours before the dose is taken and for and for at
least one hour after the dose is taken. The prescribing information
explains that at a dose of 1,000 mg daily in patients with
metastatic, castration resistant prostate cancer the steady-state
values (mean.+-.SD) of Cmax were 226.+-.178 ng/mL and of AUC were
1173.+-.690 nghr/mL. A single dose (1000 mg) cross-over study of
Zytiga.RTM. in healthy subjects found that systemic exposure of
abiraterone is increased when Zytgia.RTM. is administered with
food. Specifically, abiraterone C.sub.max and AUC.sub.0-.infin.
were approximately 7- and 5-fold higher, respectively, when
Zytiga.RTM. was administered with a low-fat meal (7% fat, 300
calories) compared to administration in the fasted state.
Abiraterone C.sub.max and AUC.sub.0-.infin. were approximately 17-
and 10-fold higher, respectively, when Zytiga.RTM. was administered
with a high-fat (57% fat, 825 calories) meal compared to
administration in the fasted state.
SUMMARY
[0006] The present disclosure features pharmaceutical compositions,
including unit dosage forms, comprising abiraterone acetate as well
as methods for producing and using such compositions.
[0007] Described herein is unit dosage form of abiraterone acetate,
wherein a 500 mg dose of the unit dosage form is bioequivalent to a
1000 mg dose of Zytiga.RTM. in healthy male subjects in the fasted
state. Also described is: a unit dosage form of abiraterone
acetate, wherein the ratio of the log of the geometric mean of the
AUC.sub.(0-.infin.) for a 500 mg dose administered to healthy male
subjects in the fasted state compared to a 1000 mg dose of
Zytiga.RTM. administered to healthy male subjects in the fasted
state is selected from: 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2 and 0.9
to 1.1; a unit dosage form of abiraterone acetate, wherein the
ratio of the log of the geometric mean of the C(max) for a 500 mg
dose administered to healthy male subjects in the fasted state
compared to a 1000 mg dose of Zytiga.RTM. administered to healthy
male subjects in the fasted state is selected from: 0.6 to 1.4, 0.7
to 1.3, 0.8 to 1.2 and 0.9 to 1.1.
[0008] In some cases: the [D90] of the abiraterone acetate is
greater than 300 nm and less than one of: 7500 nm, 7000 nm, 6000
nm, 5000 nm, 4500 nm, 4000 nm, 3000 nm, 2000 nm, 900 nm, 800 nm,
and 700 nm; the [D50] of the abiraterone acetate greater than 100
nm and is less than one of: 3500 nm, 3000 nm, 2500 nm, 1600 nm,
1400 nm, 1200 nm, 1000 nm, 800 nm, 500 nm, 400 nm, and 300 nm; the
[D4,3] of the abiraterone acetate is greater than 300 nm and less
than one of: 7000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nm, 2500 nm,
2400 nm, 2200 nm, 2000 nm, 1900 nm, 1700 nm, 1500 nm, 1300 nm, 1100
nm, 900 nm, and 800 nm; the dissolution rate of the abiraterone
acetate in the unit dosage form is such that when a sample
containing 100 mg of abiraterone acetate is tested in 900 ml of pH
4.5 phosphate buffer with 0.1% sodium lauryl sulfate using USP
Apparatus II at 75 rpm, at least 70% of the abiraterone acetate
dissolves in between 5 and 15 min or between 5 and 10 min; the
dissolution rate of the abiraterone acetate in the unit dosage form
is such that when a sample containing 125 mg of fine particle
abiraterone acetate is tested in 900 ml of pH 4.5 phosphate buffer
with 0.12% sodium lauryl sulfate using USP Apparatus II at 75 rpm,
at least 70% of the abiraterone acetate dissolves in between 5 and
15 min or between 5 and 10 min; the unit dosage form contains 125
mg of abiraterone acetate.
[0009] Also described is a unit dosage form of a pharmaceutical
composition comprising abiraterone acetate, wherein a 500 mg dose,
upon oral administration to a population of healthy male subjects
in the fasted state, provides a mean blood plasma Cmax of 50-120
ng/ml. In some cases: a 500 mg dose, upon oral administration to a
population of healthy male subjects in the fasted state, provides a
median blood plasma tmax of 1 to 2.5 hrs. Described herein is a
unit dosage form of a pharmaceutical composition comprising
abiraterone acetate, wherein a 500 mg dose, upon oral
administration to a population of healthy male subjects in the
fasted state, provides a mean blood plasma AUC (0-.infin.) of
240-650 h*ng/ml. In some case the unit dosage form contains 125 mg
of abiraterone acetate.
[0010] Also described is: a unit dosage form of a pharmaceutical
composition comprising of abiraterone acetate, wherein the 90%
confidence interval of the mean blood plasma Cmax is a value
between 50 and 120 ng/ml when a 500 mg dose is administered to
healthy male subjects in the fasted state; and a unit dosage form
of a pharmaceutical composition comprising of abiraterone acetate,
wherein the 90% confidence interval of the mean blood plasma AUC
(0-.infin.) is a value between 240 and 650 h*ng/ml when a 500 mg
dose is administered to healthy male subjects in the fasted
state.
[0011] The unit dosage forms described herein can contain an
antioxidant (e.g., one or both of BHA and BHT).
[0012] Also described herein is a method for treating castration
resistant prostate cancer comprising administering to a patient in
need thereof a therapeutically effective dose (e.g., 500 mg) of the
unit dosage form of abiraterone acetate described herein and a
glucocorticoid. In various embodiments: the glucocorticoid is
selected from the group consisting of prednisone, prednisolone and
methylprednisolone; the therapeutically effective dose is 500
mg/day; the therapeutically effective dose is administered using
dosage forms containing: 100 mg, 125 mg, or 150 mg of abiraterone
acetate; the 500 mg dose is administered using 1, 2, 3, 4, 5, or 6
unit dosage forms.
[0013] Described herein is a method for producing a composition
comprising abiraterone acetate, the method comprising: dry milling
a composition comprising abiraterone acetate, a millable grinding
compound, a facilitating agent and one or both of an antioxidant
and a sequestering agent in a mill, for a time period sufficient to
produce a composition comprising milled abiraterone acetate,
wherein the particle size of the abiraterone acetate is reduced by
dry milling.
[0014] In some cases of the method for production: the [D90] of the
abiraterone acetate in the milled composition is greater than 400
nm and less than one of: 7500, 7000, 6000 nm, 5000 nm, 4500 nm,
4000 nm, 3000 nm, 2000 nm, 900 nm, 800 nm, and 700 nm; the [D50] of
the abiraterone acetate in the milled composition is greater than
100 nm and is less than 3500 nm, 3000 nm, 2500 nm, less than 1600
nm, less than 1400 nm, less than 1200 nm, less than 1000 nm, less
than 800 nm, less than 500 nm, less than 400 nm, less than 300 nm;
the dissolution rate of the abiraterone acetate in the milled
composition is such that when a sample containing 100 mg of
abiraterone acetate is tested in 900 ml of pH 4.5 phosphate buffer
with 0.1% sodium lauryl sulfate using USP Apparatus II at 75 rpm,
at least 70% of the abiraterone acetate dissolves in between 5 and
15 min or between 5 and 10 min; the dissolution rate of the
abiraterone acetate in the milled composition is such that when a
sample containing 125 mg of abiraterone acetate is tested in 900 ml
of pH 4.5 phosphate buffer with 0.12% sodium lauryl sulfate using
USP Apparatus II at 75 rpm, at least 70% of the abiraterone acetate
dissolves in between 5 and 15 min or between 5 and 10 min; the
[D50] of the abiraterone acetate in the milled composition is
greater than 200 nm and is less than 6500 nm, 6000 nm, 5500 nm,
less than 5000 nm, less than 4000 nm, less than 3000 nm, or less
than 2000 nm; and method the method further comprises: combining
the composition comprising fine particles of abiraterone acetate
with one or more pharmaceutically acceptable diluents,
disintegrants, lubricants, glidants or dispersants to prepare unit
dosage form.
[0015] In various embodiments, the particles of abiraterone acetate
in the pharmaceutical compositions (or used to prepared the
pharmaceutical composition) have a median particle size, determined
on a particle volume basis ([D.sub.50] or D.sub.[50] or [D50]),
equal or less than a size selected from the group consisting of:
5000 nm, 4000 nm, 3000 nm, 2500 nm, 2400 nm, 2300 nm, 2200 nm, 2200
nm, 2100 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm,
1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700
nm, 600 nm, 500 nm, 400 nm, 300 nm and 200 nm. In some embodiments,
the [D50] is equal to or greater than 25 nm or 100 nm or even 500
nm. In various embodiments the [D50] is between: 5000 nm and 100
nm, 3500 nm and 100 nm, 2500 nm and 100 nm, 1500 nm and 100 nm,
1200 nm and 100 nm, 1100 nm and 100 nm, 1000 nm and 100 nm, 800 nm
and 100 nm, 700 nm and 100 nm, 600 nm and 100 nm, 500 nm and 100
nm. The D[4,3] (volume mean diameter) in various embodiments is:
less than 7000 nm, less than 5000 nm, less than 3500 nm, less than
3000 nm, less than 2000 nm, less than 1000 or less than 300 nm. In
various cases, such as those described previously, the D[4,3] is
greater than 100 nm or greater than 200 nm. In some cases the
D[4,3] (volume mean diameter) is between: 7000 nm and 1000 nm, 6000
nm and 200 nm, 5000 nm and 1000 nm, 4000 nm and 1000 nm, 3000 nm
and 1000 nm, 2000 nm and 1000 nm, 1800 nm and 1000 nm, 1600 nm and
1000 nm, 1500 nm and 1000 nm, 1500 nm and 500 nm, 4000 nm and 2000
nm, 4000 nm and 100 nm, 25000 nm and 500 nm, 700 nm and 100 nm, 600
nm and 100 nm, 500 nm and 100 nm 1000 nm and 200 nm, 900 nm and 200
nm, 800 nm and 200 nm, 700 nm and 200 nm. The [D90] ([D.sub.90] or
D.sub.[90]) in various embodiments is: less than 8000 nm, less than
7500 nm, less than 7000 nm, less than 6000 nm, less than 4000 nm,
less than 2000 nm, less than 1000 nm, less than 500 nm. In some
cases, the D90 is between: 5500 nm and 300 nm, 5000 nm and 500 nm,
4500 nm and 500 nm, 4000 nm and 200 nm, 4500 nm and 750 nm, and
3500 nm and 500 nm. In various embodiments described herein the
[D90] of the abiraterone acetate is less than 5000 nm or less than
4000 nm. In some embodiments the [D.sub.90] is: 6000 nm-500 nm,
5500 nm-500 nm, or 5000 nm-500 nm, and 4000-400 nm.
[0016] In another embodiment, the crystallinity profile of the
abiraterone acetate is selected from the group consisting of: at
least 20% of the abiraterone acetate is crystalline, at least 30%
of the abiraterone acetate is crystalline, at least 40% of the
abiraterone acetate is crystalline, at least 50% of the abiraterone
acetate is crystalline, at least 60% of the abiraterone acetate is
crystalline, at least 70% of the abiraterone acetate is
crystalline, at least 75% of the abiraterone acetate is
crystalline, at least 85% of the abiraterone acetate is
crystalline, at least 90% of the abiraterone acetate is
crystalline, at least 95% of the abiraterone acetate is crystalline
and at least 98% of the abiraterone acetate is crystalline. In some
embodiments, the crystallinity profile of the abiraterone acetate
is substantially equal to the crystallinity profile of the
abiraterone acetate before the material was subjected to the method
as described herein.
[0017] In another embodiment, the amorphous content of the
abiraterone acetate is selected from the group consisting of: less
than 80% of the abiraterone acetate is amorphous, less than 70% of
the abiraterone acetate is amorphous, less than 60% of the
abiraterone acetate is amorphous, less than 50% of the abiraterone
acetate is amorphous, less than 40% of the abiraterone acetate is
amorphous, less than 30% of the abiraterone acetate is amorphous,
less than 25% of the abiraterone acetate is amorphous, less than
15% of the abiraterone acetate is amorphous, less than 10% of the
abiraterone acetate is amorphous, less than 5% of the abiraterone
acetate is amorphous and less than 2% of the abiraterone acetate is
amorphous. In some embodiments, the abiraterone acetate has no
significant increase in amorphous content after subjecting the
material to the dry milling method described herein.
[0018] In some embodiments, the particles of abiraterone acetate
are prepared by dry milling abiraterone acetate with a millable
grinding compound and a facilitating agent in the presence of
milling bodies. Additional components can be present during the
milling and together the various components present during milling
(with the exception of abiraterone acetate and the milling bodies)
are referred to as a grinding matrix. In some cases, the milling
produces particles of abiraterone acetate that are significantly
reduced in size dispersed in grinding matrix. Because all of the
components in the grinding matrix are pharmaceutically acceptable,
pharmaceutical compositions can be prepared using the mixture of
abiraterone acetate and grinding matrix produced by the milling. In
some cases some or all of the components of the grinding matrix are
reduced in size during milling. In some cases additional
pharmaceutically acceptable components can be added to the mixture
of abiraterone acetate and grinding matrix subsequent to milling.
In some embodiments, the dry milling takes place in the presence of
milling bodies; in other cases the particles are produced by
milling in the absence of milling bodies, for example, by milling
in jet mill or another type of mill, for example a mill that can
reduce the particle size and/or increase the solubility of
abiraterone acetate when the abiraterone acetate is milling in
presence of millable grinding compound, which itself may or may not
be reduced in particle size.
[0019] In some cases abiraterone acetate is milled with one or more
millable grinding compounds selected from: lactose (e.g., lactose
monohydrate or lactose anhydrous) and mannitol and one or more
facilitating agents selected from sodium lauryl sulfate and
povidone. In some cases, the milling, in addition to reducing the
particle size of the abiraterone acetate, reduces the particle size
of one or more components of the grinding matrix. Thus, in some
cases, the milling reduces the particles of one or more of the
materials (e.g., lactose) used as the millable grinding compound.
In some cases, abiraterone acetate is milled with lactose (e.g.,
lactose monohydrate) and sodium lauryl sulfate. In some cases
during dry milling the abiraterone acetate can be present at 20-60%
(w/w) the lactose at up to 80% (w/w) the mannitol at up to 80%
(w/w) and the povidone and sodium lauryl sulfate each (or both) at
1-10% (w/w).
[0020] In some embodiments, the abiraterone acetate is dry milled
in the presence of one or more antioxidants and/or one or more
sequestering agents (i.e., an agent that can sequester ions, e.g,
metal ions) in addition to at least one millable grinding compound
and at least one facilitating agent. Thus, one or more of:
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
ascorbic acid, fumaric acid, tartaric acid and citric acid (e.g,
anhydrous citric acid) or mixtures thereof can be present during
the dry milling. In some cases, both at least one antioxidant and
at least one sequestering agent are present during milling. During
milling, the ascorbic acid, fumaric acid, tartaric acid and citric
acid (e.g, anhydrous citric acid) can be present at 8% or less on a
w/w basis (e.g., 7%-0.1%, 1%-0.1%, or 0.2% each or in combination)
and the BHT and BHA can be present at 0.5% or less (e.g.,
0.5%-0.01%, 0.2%-0.08%, 0.15%-0.05%, or 0.1% each or in
combination). One or more additional antioxidants and/or one or
more additional sequestering agents can be added to the milled
material after milling is completed.
[0021] The pharmaceutical composition can be a unit dosage form
such as a capsule or tablet containing 50-500 mg of abiraterone
acetate (e.g, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110,
115, 120, 125, 130, 135, 140, 145, 150, 175, 200, 225, 250, 275,
300, 325, 350, 375, 400, 425, 450, 475 or 500 mg), wherein the
abiraterone acetate has a size profile described herein and/or the
dosage form has a dissolution profile described herein.
[0022] Also described herein is a method for treating a patient
comprising administering a daily dose of 1000 mg to 50 mg of
abiraterone acetate (e.g, 900, 850, 800, 750, 700, 650, 600, 550,
525, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225,
200, 150, 100, 90, 80, 70, 60, or 50 mg) in the form of a
pharmaceutical composition described herein (e.g, by administering
one or more units of a unit dosage form described herein comprising
abiraterone acetate), wherein the abiraterone acetate has a size
profile described herein and/or the dosage form has a dissolution
profile described herein. The patient can also be treated with a
glucocorticoid such as prednisone, prednisolone, or dexamethasone.
Alternatively, the patient can also be treated with
methylprednisolone, for example at 5-15 mg/day (e.g., 5, 6, 7, 8,
9, 10 mg/day, for example two 4 mg doses/day). In some cases a
patient, e.g., a patient not suffering from hepatic impairment, is
treated at 500 mg/daily by administering four 125 mg unit dosage
forms of abiraterone acetate as described herein.
[0023] In some cases, for the dosage forms described herein, the
AUC.sub.0-.infin. for a single dose of a unit dosage form described
herein (or an effective dose thereof, e.g., 4.times.125 mg) when
administered with a low-fat meal (7% fat, 300 calories) is 4-fold
or less (3-fold or less, 2-fold or less, 1.5-fold or less) higher
than when administered in the fasted state.
[0024] In some cases, for the dosage forms described herein, the
AUC.sub.0-.infin. (or AUC.sub.0-t) for a single dose of a unit
dosage form described herein (or an effective dose thereof, e.g.,
4.times.125 mg) when administered with a high-fat meal (57% fat,
825 calories) is 8-fold or less (7-fold or less, 5-fold or less,
3-fold or less, 2-fold or less, 1.5-fold or less) higher than when
administered in the fasted state.
[0025] In some cases, for the dosage forms described herein, the
Cmax for a single dose of a unit dosage form described herein (or
an effective dose thereof, e.g., 4.times.125 mg) when administered
with a high-fat meal (57% fat, 825 calories) is 15-fold or less
(13-fold or less or, 12-fold or less, 11-fold or less, 10-fold or
less, 9-fold or less, 8-fold or less, 7-fold or less, 6-fold or
less, 5-fold or less) higher than when administered in the fasted
state.
[0026] In some cases, for the dosage forms described herein, the
Cmax for a single dose of a unit dosage form described herein (or
an approved dose thereof, e.g., 4.times.125 mg) when administered
with a low-fat meal (7% fat, 300 calories) is 6-fold or less
(5-fold or less or 4-fold or less, 3-fold or less, 2-fold or less,
1.5-fold or less) higher than when administered in the fasted
state.
[0027] The dissolution rate of a tablet containing 100 mg or 125 mg
of abiraterone acetate when tested in 900 ml of pH 4.5 phosphate
buffer with 0.1%-0.12% sodium lauryl sulfate (respectively) using
USP Apparatus II at 75 rpm, is such that at least 90% or at least
95% of the abiraterone acetate dissolves in 20 min or less (e.g, 19
min or less, 18 min or less, 17 min or less, 16 min or less, 15 min
or less, 14 min or less, 13 min or less, 11 min or less, 9 min or
less). For example, 90% can dissolve in 9-19 minutes. In cases
where the tablet contains more than 125 mg or less than 100 mg of
abiraterone acetate, the dissolution rate given is for a fraction
of a larger tablet (or multiple of a smaller tablet) providing
100-125 mg of abiraterone acetate. In some cases, at least 80% or
at least 85% of the abiraterone acetate dissolves in 15 min or less
(e.g, 14 min or less, 13 min or less, 12 min or less, 11 min or
less, 10 min or less, 9 min or less, 8 min or less, or 7 min or
less). For example, 85% can dissolve in 7-14 minutes.
[0028] In some cases, at least 80% or at least 85% of the
abiraterone acetate in a 125 mg unit dosage form dissolves in 15
min or less (e.g, 14 min or less, 13 min or less, 12 min or less,
11 min or less, 10 min or less, 9 min or less, 8 min or less, or 7
min or less) after storage at 4 weeks or more (e.g., 8 weeks or 12
weeks) at 25.degree. C. at 60% RH. In some cases, at least 95% of
the abiraterone acetate dissolves in 15 min or less (e.g, 14 min or
less, 13 min or less, 11 min or less, 9 min or less) after storage
at 3 weeks or more (e.g., 6 weeks or 9 weeks) at 40.degree. C. at
75% RH. For example, 95% can dissolve in 8-14 min. Here too, in
cases where the tablet contains more than 125 mg or less than 100
mg of abiraterone acetate, the dissolution rate given is for a
fraction of a larger tablet (or multiple of a smaller tablet)
providing 100-125 mg of abiraterone acetate.
[0029] In certain embodiments, the coefficient of variation
observed for a pharmaceutical composition described herein in one
or more of Cmax, AUC(0-t), and AUC(0-.infin.) will be less than
60%, less than 50%, less than 40%, less than 30%, less than 25%, or
less than 20% when administered to healthy patients in the fasted
state. In some embodiments, a pharmaceutical composition described
herein (125 mg unit dosage form or a 500 mg dose of a unit dosage
form, e.g., 4.times.125 mg) shows less variability in one or more
of Cmax, AUC(0-t), and AUC(0-.infin.) relative to, e.g., a 250 mg
dosage form of Zytiga.RTM. (or a 1000 dose of a 250 mg dosage form
of Zytiga.RTM.) in comparative pharmacokinetic testing.
[0030] In some cases, the hardness of abiraterone tablets is
between 100N and 190N (e.g., 110N to 180N).
[0031] The drug product intermediate can be prepared by dry milling
the following materials: (A) abiraterone acetate at 5-60 weight
percent, lactose (e.g., lactose monohydrate) at 30-95 weight
percent, sodium lauryl sulfate at 0.1-15 weight percent; BHA at
0.001-1 weight percent, and BHT at 0.001-1 weight percent; (B)
abiraterone acetate at 10-50 weight percent, lactose (e.g., lactose
monohydrate) at 40-80 weight percent, sodium lauryl sulfate at
0.5-10 weight percent; BHA at 0.01-0.8 weight percent, and BHT at
0.01-0.8 weight percent; (C) abiraterone acetate at 20-40 weight
percent, lactose (e.g., lactose monohydrate) at 50-70 weight
percent, sodium lauryl sulfate at 2-8 weight percent; BHA at
0.05-0.5 weight percent, and BHT at 0.05-0.5 weight percent; (D)
abiraterone acetate at 25-35 weight percent, lactose (e.g., lactose
monohydrate) at -60-70 weight percent, sodium lauryl sulfate at 4-8
weight percent; BHA at 0.05-0.15 weight percent, and BHT at
0.05-0.15 weight percent; and (E) abiraterone acetate at 30 weight
percent, lactose (e.g., lactose monohydrate) at 63.8 weight
percent, sodium lauryl sulfate at 6 weight percent; BHA at 0.1
weight percent, and BHT at 0.1 weight percent.
[0032] Drug product intermediate described above can be processed
into tablets having the following materials: (A) abiraterone
acetate at 5-50 weight percent, lactose (e.g., lactose monohydrate)
at 5-80 weight percent, sodium lauryl sulfate at 0.1-10 weight
percent, BHA at 0.001-1 weight percent, BHT at 0.001-1 weight
percent, microcrystalline cellulose at 5-80 weight percent
croscarmellose sodium at 0.5-20 weight percent, and sodium stearyl
fumarate at 0.01-10 weight percent; (B) abiraterone acetate at 8-40
weight percent, lactose (e.g., lactose monohydrate) at 10-60 weight
percent, sodium lauryl sulfate at 0.5-8 weight percent, BHA at
0.01-0.05 weight percent, BHT at 0.01-0.5 weight percent,
microcrystalline cellulose at 10-70 weight percent, croscarmellose
sodium at 1-15 weight percent, and sodium stearyl fumarate at
0.05-5 weight percent; (C) abiraterone acetate at 10-30 weight
percent, lactose (e.g., lactose monohydrate) at 20-40 weight
percent, sodium lauryl sulfate at 1-5 weight percent; BHA at
0.01-0.2 weight percent, BHT at 0.01-0.2 weight percent,
microcrystalline cellulose at 20-60 weight percent, croscarmellose
sodium at 2-10 weight percent, and sodium stearyl fumarate at 0.1-2
weight percent; (D) abiraterone acetate at 12-17 weight percent,
lactose (e.g., lactose monohydrate) at 25-35 weight percent, sodium
lauryl sulfate at 2-5 weight percent; BHA at 0.01-0.2 weight
percent, BHT at 0.01-0.2 weight percent, microcrystalline cellulose
at 35-50 weight percent, croscarmellose sodium at 5-9 weight
percent, and sodium stearyl fumarate at 0.2-0.8 weight percent; and
(E) abiraterone acetate at 14.29 weight percent, lactose (e.g.,
lactose monohydrate) at 30.38 weight percent, sodium lauryl sulfate
at 3.21 weight percent; BHA at 0.05 weight percent, BHT at 0.05
weight percent, microcrystalline cellulose at 44-53 weight percent,
croscarmellose sodium at 7 weight percent, and sodium stearyl
fumarate at 0.5 weight percent.
[0033] In some embodiments, the dry milling apparatus used to dry
mill abiraterone acetate is a mill selected from the group
consisting of: attritor mills (horizontal or vertical), nutating
mills, tower mills, pearl mills, planetary mills, vibratory mills,
eccentric vibratory mills, gravity-dependent-type ball mills, rod
mills, roller mills and crusher mills. In some embodiments, the dry
milling apparatus used to dry mill abiraterone acetate is a mill
selected from the group consisting of: jet mills, spiral jet mills,
micronisers or pulverizers. Preferably, the method is configured to
produce the abiraterone acetate in a swing batch or continuous
fashion.
[0034] In some embodiments, where a mill uses milling bodies, the
milling bodies within the milling apparatus are mechanically
agitated by 1, 2 or 3 rotating shafts. The milling bodies can be
formed of a material selected from the group consisting of:
ceramics, glasses, steels, polymers, ferromagnetics and metals and
other suitable materials. In some embodiments, the milling bodies
are steel balls having a diameter selected from the group
consisting of: between 1 and 20 mm, between 2 and 15 mm and between
3 and 10 mm. In various embodiments of the dry milling method, the
milling bodies are zirconium oxide balls having a diameter selected
from the group consisting of: between 1 and 20 mm, between 2 and 15
mm and between 3 and 10 mm.
[0035] In another embodiment, the milling time period is a range
selected from the group consisting of: between 10 minutes and 6
hours, between 10 minutes and 2 hours, between 10 minutes and 90
minutes, between 10 minutes and 1 hour, between 10 minutes and 45
minutes, between 10 minutes and 30 minutes, between 5 minutes and
30 minutes, between 5 minutes and 20 minutes, between 2 minutes and
10 minutes, between 2 minutes and 5 minutes, between 1 minutes and
2 minutes.
Additional Milling Matrixes and Facilitating Agents
[0036] In embodiments, the grinding matrix is a single material or
is a mixture of two or more materials in any proportion. In some
embodiments, the single material or a mixture of two or more
materials is selected from the group consisting of: mannitol,
sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol,
arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous
lactose, lactose monohydrate, sucrose, maltose, trehalose, and
maltodextrins. In some embodiments the single material or mixture
of two or more materials is selected from the group consisting of:
dextrin, inulin, dextrates, polydextrose, starch, wheat flour, corn
flour, rice flour, rice starch, tapioca flour, tapioca starch,
potato flour, potato starch, other flours and starches, milk
powder, skim milk powders, other milk solids and derivatives, soy
flour, soy meal or other soy products, cellulose, microcrystalline
cellulose, microcrystalline cellulose based co-blended materials,
pregelatinized (or partially gelatinized) starch, hypromellose,
carboxymethyl cellulose, hydroxypropyl cellulose, citric acid,
tartaric acid, malic acid, maleic acid, fumaric acid, ascorbic
acid, succinic acid, sodium citrate, sodium tartrate, sodium
malate, sodium ascorbate, potassium citrate, potassium tartrate,
potassium malate, sodium acetate, potassium ascorbate, sodium
carbonate, potassium carbonate, magnesium carbonate, sodium
bicarbonate, potassium bicarbonate, calcium carbonate, dibasic
calcium phosphate, tribasic calcium phosphate, sodium sulfate,
sodium chloride, sodium metabisulphite, sodium thiosulfate,
ammonium chloride, glauber's salt, ammonium carbonate, sodium
bisulfate, magnesium sulfate, potash alum, potassium chloride,
sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides,
hydrogen carbonates, ammonium chloride, methylamine hydrochloride,
ammonium bromide, silica, thermal silica, alumina, titanium
dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium
trisilicate, clay based materials or aluminium silicates, sodium
lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate,
sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate,
N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol
distearate glyceryl palmitostearate, glyceryl behenate, glyceryl
caprylate, glyceryl oleate, benzalkonium chloride, cetrimonium
bromide, cetrimonium chloride, cetrimide, cetylpyridinium chloride,
cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate,
PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407
polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20
stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether,
polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61,
polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40
castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil,
polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil,
polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated
castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl
alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate,
sorbitan monostearate, sorbitan trioleate, sucrose palmitate,
sucrose stearate, sucrose distearate, sucrose laurate, glycocholic
acid, sodium glycholate, cholic acid, sodium cholate, sodium
deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic
acid, sodium taurodeoxycholate, taurodeoxycholic acid, soy
lecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000,
PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend, calcium dodecylbenzene sulfonate,
sodium dodecylbenzene sulfonate, diisopropyl naphthaenesulphonate,
erythritol distearate, naphthalene sulfonate formaldehyde
condensate, nonylphenol ethoxylate (poe-30), tristyrylphenol
ethoxylate, polyoxyethylene (15) tallowalkylamines, sodium alkyl
naphthalene sulfonate, sodium alkyl naphthalene sulfonate
condensate, sodium alkylbenzene sulfonate, sodium isopropyl
naphthalene sulfonate, sodium methyl naphthalene formaldehyde
sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol
ethoxylate (poe-18), triethanolamine isodecanol phosphate ester,
triethanolamine tristyrylphosphate ester, tristyrylphenol
ethoxylate sulfate, bis(2-hydroxyethyl)tallowalkylamines.
[0037] In some embodiments, the concentration of the single (or
first) component of the grinding matrix is selected from the group
consisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w,
25-75% w/w, 30-60% w/w, 40-50% w/w. In some embodiments, the
concentration of the second or subsequent component of the grinding
matrix is selected from the group consisting of: 5-50% w/w, 5-40%
w/w, 5-30% w/w, of 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w,
20-40% w/w, or 20-30% w/w or if the second or subsequent material
is a surfactant or water soluble polymer the concentration is
selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w,
0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w,
of 0.75-1.25% w/w, 0.75-1% and 1% w/w.
[0038] In some embodiments, abiraterone acetate is milled in the
presence of: [0039] (a) Lactose monohydrate or lactose monohydrate
combined with at least one material selected from the group
consisting of: xylitol; lactose anhydrous; microcrystalline
cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid;
sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100
stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl
sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate;
hydrophobic collodial silica; sodium lauryl sulfate or other alkyl
sulfate surfactants with a chain length between C5 to C18;
polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene
glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol
100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl
sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium
lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl
100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium
lauryl sulfate and poloxamer 338, sodium lauryl sulfate and
poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl
naphthalene sulfonate condensate/lignosulfonate blend; calcium
dodecylbenzene sulfonate (branched); diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; naphthalene sulfonate formaldehyde
condensate; nonylphenol ethoxylate, POE-30; phosphate esters,
tristyrylphenol ethoxylate, free acid; polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene;
formaldehyde sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; triethanolamine
isodecanol phosphate ester; triethanolamine tristyrylphosphate
ester; tristyrylphenol ethoxylate sulfate; bis(2-hydroxyethyl)
tallowalkylamines. [0040] (b) Lactose anhydrous or lactose
anhydrous combined with at least one material selected from the
group consisting of: lactose monohydrate; xylitol; microcrystalline
cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid;
sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100
stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl
sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate;
hydrophobic collodial silica; sodium lauryl sulfate or other alkyl
sulfate surfactants with a chain length between C5 to C18;
polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene
glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol
100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl
sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium
lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl
100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium
lauryl sulfate and poloxamer 338, sodium lauryl sulfate and
poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl
naphthalene sulfonate condensate/Lignosulfonate blend; calcium
dodecylbenzene sulfonate (branched); diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; naphthalene sulfonate formaldehyde
condensate; nonylphenol ethoxylate, POE-30; phosphate esters,
tristyrylphenol ethoxylate, free acid; polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene;
formaldehyde sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; triethanolamine
isodecanol phosphate ester; triethanolamine tristyrylphosphate
ester; tristyrylphenol ethoxylate sulfate; bis(2-hydroxyethyl)
tallowalkylamines. [0041] (c) Mannitol or mannitol combined with at
least one material selected from the group consisting of: lactose
monohydrate; xylitol; lactose anhydrous; microcrystalline
cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; trisodium citrate dihydrate; D,L-malic acid;
sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100
stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl
sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate;
hydrophobic collodial silica; sodium lauryl sulfate or other alkyl
sulfate surfactants with a chain length between C5 to C18;
polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene
glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol
100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl
sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium
lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl
100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium
lauryl sulfate and poloxamer 338, sodium lauryl sulfate and
poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl
naphthalene sulfonate condensate/lignosulfonate blend; calcium
dodecylbenzene sulfonate (branched); diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; naphthalene sulfonate formaldehyde
condensate; nonylphenol ethoxylate, POE-30; phosphate esters,
tristyrylphenol ethoxylate, free acid; polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene;
formaldehyde sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; triethanolamine
isodecanol phosphate ester; triethanolamine tristyrylphosphate
ester; tristyrylphenol ethoxylate sulfate; bis(2-hydroxyethyl)
tallowalkylamines. [0042] (d) Sucrose or sucrose combined with at
least one material selected from the group consisting of: lactose
monohydrate; lactose anhydrous; mannitol; microcrystalline
cellulose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; tartaric acid; trisodium citrate dihydrate;
D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate;
polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium
n-lauroyl sacrosine; lecithin; docusate sodium;
polyoxyl-40-stearate; hydrophobic collodial silica; sodium lauryl
sulfate or other alkyl sulfate surfactants with a chain length
between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and
polyethylene glycol 40 stearate, sodium lauryl sulfate and
polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and
PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl
sulfate and polyoxyl 100 stearyl ether, sodium lauryl sulfate and
poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium
lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338,
poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl)tallowalkylamines [0043] (e)
Glucose or glucose combined with at least one material selected
from the group consisting of: lactose monohydrate; lactose
anhydrous; mannitol; microcrystalline cellulose; sucrose; sodium
chloride; talc; kaolin; calcium carbonate; malic acid; tartaric
acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether;
polyoxyl 10 stearyl ether; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; hydrophobic collodial
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium
lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000,
sodium lauryl sulfate and polyoxyl 100 stearyl ether, sodium lauryl
sulfate and poloxamer 407, sodium lauryl sulfate and Poloxamer 338,
sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer
338, poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl)tallowalkylamines [0044] (f)
Sodium chloride or sodium chloride combined with at least one
material selected from the group consisting of: lactose
monohydrate; lactose anhydrous; mannitol; microcrystalline
cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic
acid; tartaric acid; trisodium citrate dihydrate; D,L-malic acid;
sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100
stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl
sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate;
hydrophobic collodial silica; sodium lauryl sulfate or other alkyl
sulfate surfactants with a chain length between C5 to C18;
polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene
glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol
100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl
sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium
lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl
100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium
lauryl sulfate and poloxamer 338, sodium lauryl sulfate and
poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl
naphthalene sulfonate condensate/lignosulfonate blend; calcium
dodecylbenzene sulfonate (branched); diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; naphthalene sulfonate formaldehyde
condensate; nonylphenol ethoxylate, POE-30; phosphate esters,
tristyrylphenol ethoxylate, free acid; polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene;
formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; triethanolamine
isodecanol phosphate ester; triethanolamine tristyrylphosphate
ester; tristyrylphenol ethoxylate sulfate;
bis(2-hydroxyethyl)tallowalkylamines [0045] (g) Xylitol or xylitol
combined with at least one material selected from the group
consisting of: lactose monohydrate; lactose anhydrous; mannitol;
microcrystalline cellulose; sucrose; glucose; sodium chloride;
talc; kaolin; calcium carbonate; malic acid; tartaric acid;
trisodium citrate dihydrate; D,L-malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether;
polyoxyl 10 stearyl ether; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; hydrophobic collodial
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium
lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000,
sodium lauryl sulfate and polyoxyl 100 stearyl ether, sodium lauryl
sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338,
sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer
338, poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl)tallowalkylamines [0046] (h)
Tartaric acid or tartaric acid combined with at least one material
selected from the group consisting of: lactose monohydrate; lactose
anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose;
sodium chloride; talc; kaolin; calcium carbonate; malic acid;
trisodium citrate dihydrate; D,L-malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether;
polyoxyl 10 stearyl ether; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; hydrophobic collodial
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium
lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000,
sodium lauryl sulfate and Polyoxyl 100 stearyl ether, sodium lauryl
sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338,
sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer
338, poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; Phosphate Esters, tristyrylphenol Ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl)tallowalkylamines
[0047] (i) Microcrystalline cellulose or microcrystalline cellulose
combined with at least one material selected from the group
consisting of: lactose monohydrate; xylitol; lactose anhydrous;
mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; tartaric acid; trisodium citrate dihydrate;
D,L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate;
polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium
n-lauroyl sacrosine; lecithin; docusate sodium;
polyoxyl-40-stearate; hydrophobic collodial silica; sodium lauryl
sulfate or other alkyl sulfate surfactants with a chain length
between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and
polyethylene glycol 40 stearate, sodium lauryl sulfate and
polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and
PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl
sulfate and Polyoxyl 100 stearyl ether, sodium lauryl sulfate and
poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium
lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338,
poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl)tallowalkylamines [0048] (j)
Kaolin combined with at least one material selected from the group
consisting of: lactose monohydrate; xylitol; lactose anhydrous;
mannitol; microcrystalline cellulose; sucrose; glucose; sodium
chloride; talc; kaolin; calcium carbonate; malic acid; tartaric
acid; trisodium citrate dihydrate; D,L-malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; Polyoxyl 100 stearyl ether;
Polyoxyl 10 stearyl ether; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; Hydrophobic collodial
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium
lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000,
sodium lauryl sulfate and polyoxyl 100 stearyl ether, sodium lauryl
sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338,
sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer
338, poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; briethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl)tallowalkylamines [0049] (k)
Talc combined with at least one material selected from the group
consisting of: lactose monohydrate; xylitol; lactose anhydrous;
mannitol; microcrystalline cellulose; sucrose; glucose; sodium
chloride; kaolin; calcium carbonate; malic acid; tartaric acid;
trisodium citrate dihydrate; D,L-malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether;
polyoxyl 10 stearyl ether; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; hydrophobic collodial
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium
lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000,
sodium lauryl sulfate and polyoxyl 100 stearyl ether, sodium lauryl
sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338,
sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer
338, poloxamer 188, alkyl naphthalene sulfonate
condensate/lignosulfonate blend; calcium dodecylbenzene sulfonate
(branched); diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
naphthalene sulfonate formaldehyde condensate; nonylphenol
ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate,
free acid; polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; sodium methyl naphthalene; formaldehyde
sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol
ethoxylate sulfate; bis(2-hydroxyethyl) tallowalkylamines.
[0050] In some embodiments, the abiraterone acetate is dry milled
with one or more additional materials is selected from the group
consisting of: a material considered to be `Generally Regarded as
Safe` (GRAS) for pharmaceutical products.
[0051] In some embodiments, the dry milling of abiraterone acetate
takes place in the presence of a facilitating agent or combination
of facilitating agents. In some embodiments, the facilitating agent
is selected from the group consisting of: a glidant, a surfactant,
a polymer, and/or a lubricant. In some embodiments, the
facilitating agent is selected from the group consisting of:
colloidal silicon dioxide, sodium stearate and talc. In some
embodiments, the facilitating agent is selected from the group
consisting of: benzethonium chloride, docusate sodium, polyethylene
alkyl ethers, sodium lauryl sulfate, tricaprylin, alpha tocopherol,
glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene
alkyl ethers, polyoxyethylene stearates, polyoxyethylene castor oil
derivatives, polyoxyl 15 hydroxystearate, polyoxylglycerides,
polysorbates, propylene glycol dilaurate, sorbitan esters, sucrose
palmitate, vitamin E polyethylene glycol succinate, polyethylene
glycols (PEG), poloxamers, poloxamines, sarcosine based
surfactants, polysorbates, aliphatic alcohols, alkyl and aryl
sulfates, alkyl and aryl polyether sulfonates and other sulfate
surfactants, trimethyl ammonium based surfactants, lecithin and
other phospholipids, bile salts, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan
fatty acid esters sucrose fatty acid esters, alkyl
glucopyranosides, alkyl maltopyranosides, glycerol fatty acid
esters, alkyl benzene sulphonic acids, alkyl ether carboxylic
acids, alkyl and aryl phosphate esters, alkyl and aryl sulfate
esters, alkyl and aryl sulphonic acids, alkyl phenol phosphates
esters, alkyl phenol sulfates esters, alkyl and aryl phosphates,
alkyl polysaccharides, alkylamine ethoxylates, alkyl-naphthalene
sulphonates formaldehyde condensates, sulfosuccinates,
lignosulfonates, ceto-oleyl alcohol ethoxylates, condensed
naphthalene sulphonates, dialkyl and alkyl naphthalene sulphonates,
di-alkyl sulphosuccinates, ethoxylated nonylphenols, ethylene
glycol esters, fatty alcohol alkoxylates, hydrogenated
tallowalkylamines, mono-alkyl sulphosuccinamates, nonyl phenol
ethoxylates, sodium oleyl N-methyl taurate, tallowalkylamines,
linear and branched dodecylbenzene sulfonic acids.
[0052] In some embodiments, the facilitating agent is selected from
the group consisting of sodium stearyl sulfate, sodium stearyl
fumarate, magnesium stearate, talc, myristic acid, sodium cetyl
sulfate, sodium cetostearyl sulfate, sodium docusate, sodium
deoxycholate, N-lauroylsarcosine sodium salt, glyceryl
monostearate, glycerol distearate glyceryl palmitostearate,
glyceryl behenate, glyceryl caprylate, glyceryl oleate,
benzalkonium chloride, cetyl trimethylammonium bromide, cetyl
trimethylammonium chloride, cetrimide, cetylpyridinium chloride,
cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate,
PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407
polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20
stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether,
polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61,
polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40
castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil,
polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil,
polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated
castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl
alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate,
sorbitan monostearate, sorbitan trioleate, sucrose palmitate,
sucrose stearate, sucrose distearate, sucrose laurate, glycocholic
acid, sodium glycholate, cholic acid, sodium cholate, sodium
deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic
acid, sodium taurodeoxycholate, taurodeoxycholic acid, soy
lecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000,
PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate
condensate/lignosulfonate blend, calcium dodecylbenzene sulfonate,
sodium dodecylbenzene sulfonate, diisopropyl naphthaenesulphonate,
erythritol distearate, naphthalene sulfonate formaldehyde
condensate, nonylphenol ethoxylate (POE-30), tristyrylphenol
ethoxylate, polyoxyethylene (15) tallowalkylamines, sodium alkyl
naphthalene sulfonate, sodium alkyl naphthalene sulfonate
condensate, sodium alkylbenzene sulfonate, sodium isopropyl
naphthalene sulfonate, sodium methyl naphthalene formaldehyde
sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol
ethoxylate (poe-18), triethanolamine isodecanol phosphate ester,
triethanolamine tristyrylphosphate ester, tristyrylphenol
ethoxylate sulfate, bis(2) hydroxyethyl)tallowalkylamines.
[0053] In some embodiments the facilitating agent is selected from
the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, acrylic
acid based polymers and copolymers of acrylic acid.
[0054] In some embodiments, the facilitating agent has a
concentration during dry milling selected from the group consisting
of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%,
0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of
0.75-1.25% w/w, 0.75-1% and 1% w/w.
[0055] In some embodiments, a facilitating agent is used or
combination of facilitating agents is used during dry milling. In
some embodiments, the facilitating agent is added during dry
milling. In some embodiments, the facilitating agent is added to
the dry milling at a time selected from the group consisting of:
with 1-5% of the total milling time remaining, with 1-10% of the
total milling time remaining, with 1-20% of the total milling time
remaining, with 1-30% of the total milling time remaining, with
2-5% of the total milling time remaining, with 2-10% of the total
milling time remaining, with 5-20% of the total milling time
remaining and with 5-20% of the total milling time remaining.
[0056] The reasons for including facilitating agents include, but
are not limited to providing better dispersibility, control of
agglomeration, the release or retention of the active particles
from the delivery matrix. Examples of facilitating agents include,
but are not limited to: sodium lauryl sulfate, cross-linked PVP
(crospovidone), cross linked sodium carboxymethylcellulose
(croscarmellose sodium), sodium starch glycolate, povidone (PVP),
povidone K12, povidone K17, povidone K25, povidone K29/32 and
povidone K30, stearic acid, magnesium stearate, calcium stearate,
sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate,
sodium stearate or lithium stearate, other solid state fatty acids
such as oleic acid, lauric acid, palmitic acid, erucic acid,
behenic acid, or derivatives (such as esters and salts), amino
acids such as leucine, isoleucine, lysine, valine, methionine,
phenylalanine, aspartame or acesulfame K.
[0057] In another aspect the disclosure includes a method of
treating a human in need of such treatment comprising the step of
administering to the human an effective amount of a pharmaceutical
composition as described herein for treatment of castration
resistant prostate cancer. The treatment can include administering
500 mg of abiraterone acetate daily (e.g., in 1 or 2 or 4 equal
doses (e.g., one unit dose containing 500 mg, two unit doses
containing 250 mg of abiraterone acetate each, or four unit doses
containing 125 mg of abiraterone acetate each). The patient can
also be treated with a glucocorticoid, e.g, prednisone,
dexamethasone or prednisolone (e.g., at 5 mg, twice daily).
Alternatively, the patient can be treated with methylprednisolone
(e.g. at 4 mg twice daily). The patient can also be treated with
other chemotherapeutic agents or other agents for the treatment of
cancer (e.g., prostate cancer).
[0058] The disclosure also includes a method for treating breast
cancer (e.g., metastatic breast cancer) and ovarian cancer (e.g.,
epithelial ovarian cancer) using a composition described
herein.
[0059] In another aspect, the disclosure comprises the use of a
pharmaceutical composition as described herein in the manufacture
of a medicament for the treatment of a human in need of such
treatment.
[0060] In another aspect the disclosure comprises a method for
manufacturing a pharmaceutical composition as described herein
comprising the step of combining a composition comprising
abiraterone acetate prepared by a method described herein or a
composition as described herein, together with one of a diluent,
lubricant, excipient, disintegrant, wetting agent, to produce a
pharmaceutically acceptable dosage form.
[0061] The disclosure described herein may include one or more
ranges of values (e.g. size, concentration etc.). A range of values
will be understood to include all values within the range,
including the values defining the range, and values adjacent to the
range that lead to the same or substantially the same outcome as
the values immediately adjacent to that value which defines the
boundary to the range.
[0062] The entire disclosures of all publications (including
patents, patent applications, journal articles, laboratory manuals,
books, or other documents) cited herein are hereby incorporated by
reference. Inclusion does not constitute an admission is made that
any of the references constitute prior art or are part of the
common general knowledge of those working in the field to which
this disclosure relates.
[0063] Throughout this specification, unless the context requires
otherwise, the word "comprise" or variations, such as "comprises"
or "comprising" will be understood to imply the inclusion of a
stated integer, or group of integers, but not the exclusion of any
other integers or group of integers. It is also noted that in this
disclosure, and particularly in the claims and/or paragraphs, terms
such as "comprises", "comprised", "comprising" and the like can
have the meaning attributed to it in US Patent law; e.g., they can
mean "includes", "included", "including", and the like.
[0064] "Therapeutically effective amount" as used herein with
respect to methods of treatment and in particular drug dosage,
shall mean that dosage that provides the specific pharmacological
response for which the drug is administered in a significant number
of subjects in need of such treatment. It is emphasized that
"therapeutically effective amount," administered to a particular
subject in a particular instance will not always be effective in
treating the diseases described herein, even though such dosage is
deemed a "therapeutically effective amount" by those skilled in the
art. It is to be further understood that drug dosages are, in
particular instances, measured as oral dosages, or with reference
to drug levels as measured in blood.
[0065] Throughout this specification, unless the context requires
otherwise, the phrase "dry mill" or variations, such as "dry
milling," should be understood to refer to milling in at least the
substantial absence of liquids. If liquids are present, they are
present in such amounts that the contents of the mill retain the
characteristics of a dry powder.
[0066] The term "millable" means that the grinding matrix is
capable of being reduced in size under the dry milling conditions
of the method of the disclosure. In one embodiment of the
disclosure, the milled grinding matrix is of a comparable particle
size to the abiraterone acetate. In another embodiment of the
disclosure the particle size of the matrix is substantially reduced
but not as small as the abiraterone acetate.
[0067] Those skilled in the art will appreciate that the disclosure
described herein is susceptible to variations and modifications
other than those specifically described. It is to be understood
that the disclosure includes all such variations and modifications.
The disclosure also includes all of the steps, features,
compositions and materials referred to or indicated in the
specification, individually or collectively and any and all
combinations or any two or more of the steps or features.
[0068] The present disclosure is not to be limited in scope by the
specific embodiments described herein, which are intended for the
purpose of exemplification only. Functionally equivalent products,
compositions and methods are clearly within the scope of the
disclosure as described herein.
[0069] Other aspects and advantages of the disclosure will become
apparent to those skilled in the art from a review of the ensuing
description.
DRAWINGS
[0070] FIG. 1 is a graph of the results of particle size analysis
of unmilled abiraterone acetate and abiraterone acetate in formula
1 and formula 2 of Example 1.
[0071] FIG. 2 is a graph of the results of dissolution rate
measurements for abiraterone acetate tablets as described in
Example 3.
[0072] FIGS. 3A and 3B are graphs depicting the results of
stability studies described in Example 6.
DETAILED DESCRIPTION OF THE DISCLOSURE
Particle Size
[0073] For measurements made using a laser diffraction the term
"median particle size" is defined as the median particle diameter
as determined on an equivalent spherical particle volume basis.
Where the term median is used, it is understood to describe the
particle size that divides the population in half such that 50% of
the population on a volume basis is greater than or less than this
size. The median particle size is written as: [D.sub.50] or
D.sub.[50] or [D50], D50, D(0.50) or D[0.5] or similar. As used
herein [D.sub.50] or D.sub.[50] or [D50], D50, D(0.50) or D[0.5] or
similar shall be taken to mean median particle size.
[0074] The term "Dx of the particle size distribution" refers to
the xth percentile of the distribution on a volume basis; thus, D90
refers to the 90.sup.th percentile, D95 refers to the 95.sup.th
percentile, and so forth. Taking D90 as an example this can often
be written as, [D.sub.90] or D.sub.[90] or [D90], D(0.90) or D[0.9]
or similar. With respect to the median particle size and Dx an
upper case D or lowercase d are interchangeable and have the same
meaning. Another commonly used way of describing a particle size
distribution measured by laser diffraction, or an equivalent method
known in the art, is to describe what % of a distribution is under
or over a nominated size. The term "percentage less than" also
written as "%<" is defined as the percentage, by volume, of a
particle size distribution under a nominated size--for example the
%<1000 nm. The term "percentage greater than" also written as
"%>" is defined as the percentage, by volume, of a particle size
distribution over a nominated size--for example the %>1000 nm.
The term D(3,2) is referred to as the area-weighted mean size or
the Sauter diameter; the term D(4,3) is referred to as the
volume-weighted mean size. Detailed descriptions of how these
values are calculated are known in the art and can be found in, for
example, ISO 9276-2:2014(E).
[0075] For many of the materials subject to the methods of this
disclosure the particle size can be easily measured. Where the
active material has poor water solubility and the matrix it is
milled in has good water solubility the powder can simply be
dispersed in an aqueous solvent. In this scenario the matrix
dissolves leaving the active material dispersed in the solvent.
This suspension can then be measured by techniques such as PCS or
laser diffraction.
[0076] Suitable methods to measure an accurate particle size where
the active material has substantive aqueous solubility or the
matrix has low solubility in a water based dispersant are outlined
below. [0077] 1. In the circumstance where an insoluble matrix such
as microcrystalline cellulose prevents the measurement of the
active material separation techniques such as filtration or
centrifugation could be used to separate the insoluble matrix from
the active material particles. Other ancillary techniques would
also be required to determine if any active material was removed by
the separation technique so that this could be taken into account.
[0078] 2. In the case where the active material is too soluble in
water, other solvents could be evaluated for the measurement of
particle size. Where a solvent could be found that active material
is poorly soluble in but is a good solvent for the matrix a
measurement would be relatively straight forward. If such a solvent
is difficult to find another approach would be to measure the
ensemble of matrix and active material in a solvent (such as
iso-octane) which both are insoluble in. Then the powder would be
measured in another solvent where the active material is soluble
but the matrix is not. Thus with a measurement of the matrix
particle size and a measurement of the size of the matrix and
active material together an understanding of the active material
particle size can be obtained. [0079] 3. In some circumstances
image analysis could be used to obtain information about the
particle size distribution of the active material. Suitable image
measurement techniques might include transmission electron
microscopy (TEM), scanning electron microscopy (SEM), optical
microscopy and confocal microscopy. In addition to these standard
techniques some additional technique would be required to be used
in parallel to differentiate the active material and matrix
particles. Depending on the chemical makeup of the materials
involved possible techniques could be elemental analysis, Raman
spectroscopy, FTIR spectroscopy or fluorescence spectroscopy.
Improving the Dissolution Profile
[0080] The process results in the abiraterone acetate having an
improved dissolution profile. An improved dissolution profile has
significant advantages including, in some cases, the improvement of
bioavailability of the abiraterone acetate in vivo. Standard
methods for determining the dissolution profile of a material in
vitro are available in the art. A suitable method to determine an
improved dissolution profile in vitro may include determining the
concentration of the sample material in a solution over a period of
time and comparing the results from the sample material to a
control sample. An observation that peak solution concentration for
the sample material was achieved in less time than the control
sample would indicate that the sample material has an improved
dissolution profile. The test sample can be the unit dosage form
containing abiraterone acetate with grinding matrix and/or other
additives that has been subject to the processes of the disclosure
described here, as well as excipients to manufacture the final
dosage form. Herein a control sample can be as a physical of the
components in the measurement sample with the same relative
proportions of active, matrix and/or additive as the measurement
sample. The control sample can also be the commercially available
dosage form, Zytiga.RTM. tablets, cut to represent an equivalent
quantity of abirateratone acetate as the test sample. Standard
methods for determining the improved dissolution profile of a
material in vivo are available in the art.
Crystallization Profile
[0081] Methods for determining the crystallinity profile of the
abiraterone acetate are widely available in the art. Suitable
methods may include X-ray diffraction, differential scanning
calorimetry, and Raman or IR spectroscopy.
Amorphicity Profile
[0082] Methods for determining the amorphous content of the
abiraterone acetate are widely available in the art. Suitable
methods may include X-ray diffraction, differential scanning
calorimetry, and Raman or IR spectroscopy.
Grinding Matrix
[0083] As will be described subsequently, selection of an
appropriate grinding matrix affords particular advantageous
applications of the method of the present disclosure. Again, as
will be described subsequently, a highly advantageous aspect of the
present disclosure is that certain grinding matrixes appropriate
for use in the method of the disclosure are also appropriate for
use in a medicament. The present disclosure encompasses methods for
the production of a medicament incorporating both the abiraterone
acetate and the grinding matrix or in some cases the abiraterone
acetate and a portion of the grinding matrix, medicaments so
produced, and methods of treatment using the medicament. The
medicament may include only the milled abiraterone acetate together
with the milled grinding matrix or, more preferably, the milled
abiraterone acetate and milled grinding matrix may be combined with
one or more pharmaceutically acceptable carriers, as well as any
desired excipients or other like agents commonly used in the
preparation of medicaments.
[0084] In some cases at least one component of the grinding matrix
is harder than the abiraterone acetate, and is thus capable of
reducing the particle size of the abiraterone acetate under the dry
milling conditions of the disclosure. Again without wishing to be
bound by theory, under these circumstances it is believed that the
millable grinding matrix affords the advantage of the present
disclosure through a second route, with the smaller particles of
grinding matrix produced under the dry milling conditions enabling
greater interaction with the abiraterone acetate. The quantity of
the grinding matrix relative to the quantity of abiraterone
acetate, and the extent of physical degradation of the grinding
matrix, is sufficient to inhibit re-agglomeration of the particles
of the active material In some embodiments, the quantity of the
grinding matrix relative to the quantity of abiraterone acetate,
and the extent of size reduction of the grinding matrix, is
sufficient to inhibit re-agglomeration of the particles of the
active material. As detailed above, the grinding matrix can include
one or more anti-oxidants and/or one or more sequestering
agents.
[0085] In some embodiments, the grinding matrix has a low tendency
to agglomerate during dry milling. While it is difficult to
objectively quantify the tendency to agglomerate during milling, it
is possible to obtain a subjective measure by observing the level
of "caking" of the grinding matrix in the milling chamber of the
mill as dry milling progresses.
[0086] The grinding matrix may be an inorganic or organic
substance.
Milling Bodies
[0087] In the method of the present disclosure, where milling
bodies are utilized, the milling bodies are preferably chemically
inert and rigid. The term "chemically-inert", as used herein, means
that the milling bodies do not react chemically with the
abiraterone acetate or the grinding matrix.
[0088] As described above, the milling bodies are essentially
resistant to fracture and erosion in the milling process.
[0089] The milling bodies are desirably provided in the form of
bodies which may have any of a variety of smooth, regular shapes,
flat or curved surfaces, and lacking sharp or raised edges. For
example, suitable milling bodies can be in the form of bodies
having ellipsoidal, ovoid, spherical or right cylindrical shapes.
In some embodiments, the milling bodies are provided in the form of
one or more of beads, balls, spheres, rods, right cylinders, drums
or radius-end right cylinders (i.e., right cylinders having
hemispherical bases with the same radius as the cylinder).
[0090] Depending on the nature of the abiraterone acetate and the
grinding matrix, the milling bodies desirably have an effective
mean diameter between about 0.1 and 30 mm, more preferably between
about 1 and about 15 mm, still more preferably between about 3 and
10 mm.
[0091] The milling bodies may comprise various substances such as
ceramic, glass, metal or polymeric compositions, in a particulate
form. Suitable metal milling bodies are typically spherical and
generally have good hardness (i.e. RHC 60-70), roundness, high wear
resistance, and narrow size distribution and can include, for
example, balls fabricated from type 52100 chrome steel, type 304,
316 or 440C stainless steel or type 1065 high carbon steel.
[0092] Ceramics, for example, can be selected from a wide array of
ceramics desirably having sufficient hardness and resistance to
fracture to enable them to avoid being chipped or crushed during
milling and also having sufficiently high density. Suitable
densities for milling bodies can range from about 1 to 15
g/cm.sup.3, preferably from about 1 to 8 g/cm.sup.3. Ceramics can
be selected from steatite, aluminum oxide, zirconium oxide,
zirconia-silica, yttria-stabilized zirconium oxide,
magnesia-stabilized zirconium oxide, silicon nitride, silicon
carbide, cobalt-stabilized tungsten carbide, and the like, as well
as mixtures thereof.
[0093] Glass milling bodies are spherical (e.g. beads), have a
narrow size distribution, are durable, and include, for example,
lead-free soda lime glass and borosilicate glass. Polymeric milling
bodies are preferably substantially spherical and can be selected
from a wide array of polymeric resins having sufficient hardness
and friability to enable them to avoid being chipped or crushed
during milling, abrasion-resistance to minimize attrition resulting
in contamination of the product, and freedom from impurities such
as metals, solvents, and residual monomers.
[0094] Milling bodies can be formed from polymeric resins.
Polymeric resins, for example, can be selected from crosslinked
polystyrenes, such as polystyrene crosslinked with divinylbenzene,
styrene copolymers, polyacrylates such as polymethylmethacrylate,
polycarbonates, polyacetals, vinyl chloride polymers and
copolymers, polyurethanes, polyamides, high density polyethylenes,
polypropylenes, and the like. The use of polymeric milling bodies
to grind materials down to a very small particle size (as opposed
to mechanochemical synthesis) is disclosed, for example, in U.S.
Pat. Nos. 5,478,705 and 5,500,331. Polymeric resins typically can
have densities ranging from about 0.8 to 3.0 g/cm.sup.3. Higher
density polymeric resins are generally preferred. Alternatively,
the milling bodies can be composite bodies comprising dense core
bodies having a polymeric resin adhered thereon. Core particles can
be selected from substances known to be useful as milling bodies,
for example, glass, alumina, zirconia silica, zirconium oxide,
stainless steel, and the like. Core substances have densities
greater than about 2.5 g/cm.sup.3.
[0095] In one embodiment of the disclosure, the milling bodies are
formed from a ferromagnetic substance, thereby facilitating removal
of contaminants arising from wear of the milling bodies by the use
of magnetic separation techniques.
[0096] Each type of milling body has its own advantages. For
example, metals have the highest specific gravities, which increase
grinding efficiency due to increased impact energy. Metal costs
range from low to high, but metal contamination of final product
can be an issue. Glasses are advantageous from the standpoint of
low cost and the availability of small bead sizes as low as 0.004
mm. However, the specific gravity of glasses is lower than other
bodies and significantly more milling time is required. Finally,
ceramics are advantageous from the standpoint of low wear and
contamination, ease of cleaning, and high hardness.
Dry Milling
[0097] In the dry milling process of the present disclosure, the
abiraterone acetate and grinding matrix, in the form of crystals,
powders, or the like, are combined in suitable proportions with or
without a plurality of milling bodies in a milling chamber that is
mechanically agitated for a predetermined period of time at a
predetermined intensity of agitation. Typically, a milling
apparatus is used to impart motion to contents of the mill
including any milling bodies by the external application of
agitation, a stream of dry gas or other force, whereby various
translational, rotational or inversion motions or combinations
thereof are applied to the milling chamber and its contents, or by
the internal application of agitation through a rotating shaft
terminating in a blade, propeller, impeller or paddle or by a
combination of both actions.
[0098] During milling, motion imparted to the milling bodies or gas
flowing through the milling system can result in application of
shearing forces as well as multiple impacts or collisions having
significant intensity between the mill components, any milling
bodies utilized and the particles of abiraterone acetate and the
grinding matrix. The nature and intensity of the forces applied to
the abiraterone acetate and the grinding matrix is influenced by a
wide variety of processing parameters including: the type of
milling apparatus; the intensity of the forces generated, the
kinematic aspects of the process; the size, density, shape, and
composition of any milling bodies used; the weight ratio of the
abiraterone acetate and grinding matrix mixture to any milling
bodies used; the duration of milling; the physical properties of
both the abiraterone acetate and the grinding matrix; the
atmosphere present during milling; and other factors.
[0099] Advantageously, the mill is capable of repeatedly or
continuously applying mechanical compressive forces and shear
stress to the abiraterone acetate and the grinding matrix.
Throughout the remainder of the specification reference will be
made to dry milling being carried out by way of a ball mill.
Examples of this type of mill are attritor mills, nutating mills,
tower mills, planetary mills, vibratory mills,
gravity-dependent-type ball mills, jet mills, rod mills, roller
mills or crusher mills, jet mills and pulverizing mills. It will be
appreciated that dry milling in accordance with the method of the
disclosure may also be achieved by any suitable milling method or
means.
[0100] In some cases, the particle size of the abiraterone acetate
prior to dry milling according to the methods described herein is
less than about 1000 .mu.m, as determined by sieve analysis. If the
particle size of the abiraterone acetate is greater than about 1000
.mu.m, then it is preferred that the particles of the abiraterone
acetate substrate be reduced in size to less than 1000 .mu.m using
another particle size reduction method prior to dry milling
according to the methods described herein.
Agglomerates of Abiraterone Acetate after Processing
[0101] Agglomerates comprising particles of abiraterone acetate
having a particle size within the ranges specified herein, should
be understood to fall within the scope of the present disclosure,
regardless of whether the agglomerates exceed the ranges specified
above.
Processing Time
[0102] In some embodiments, the abiraterone acetate and the
grinding matrix are dry milled for the shortest time necessary to
minimize any possible contamination from the mill process and/or
any milling bodies utilized. This time varies greatly, depending on
the abiraterone acetate and the grinding matrix, and may range from
as short as 1 minute to several hours.
[0103] Suitable rates of agitation and total milling times are
adjusted for the type and size of milling apparatus, the type and
size of any milling media utilized, the weight ratio of the
abiraterone acetate and grinding matrix mixture to the plurality of
milling bodies that may be utilized, the chemical and physical
properties of the abiraterone acetate and grinding matrix, and
other parameters that may be optimized empirically.
[0104] In some embodiments, the grinding matrix (the materials
milled together with abiraterone acetate) is not separated from the
abiraterone acetate but is maintained with the abiraterone acetate
in the final product. In some embodiments the grinding matrix is
considered to be Generally Regarded as Safe (GRAS) for
pharmaceutical products.
[0105] In an alternative aspect, the grinding matrix is separated
from the abiraterone acetate. In one aspect, where the grinding
matrix is not fully milled, the unmilled grinding matrix is
separated from the abiraterone acetate. In a further aspect, at
least a portion of the milled grinding matrix is separated from the
abiraterone acetate.
[0106] Any portion of the grinding matrix may be removed, including
but not limited to 10%, 25%, 50%, 75%, or substantially all of the
grinding matrix.
[0107] In some embodiments of the disclosure, a significant portion
of the milled grinding matrix may comprise particles of a size
similar to and/or smaller than the particles comprising the
abiraterone acetate. Where the portion of the milled grinding
matrix to be separated from the particles comprising the
abiraterone acetate comprises particles of a size similar to and/or
smaller than the particles comprising the abiraterone acetate,
separation techniques based on size distribution are inapplicable.
In these circumstances, the method of the present disclosure may
involve separation of at least a portion of the milled grinding
matrix from the abiraterone acetate by techniques including, but
not limited to, electrostatic separation, magnetic separation,
centrifugation (density separation), hydrodynamic separation, and
froth flotation. Advantageously, the step of removing at least a
portion of the milled grinding matrix from the abiraterone acetate
may be performed through means such as selective dissolution,
washing, or sublimation.
[0108] In some cases grinding matrix that has two or more
components where at least one component is water soluble and at
least one component has low solubility in water can be used. In
this case washing can be used to remove the matrix component
soluble in water leaving the abiraterone acetate dispersed in the
remaining matrix components. In a highly advantageous aspect of the
disclosure the matrix with low solubility is a functional
excipient.
[0109] In some cases the grinding matrix is appropriate for use in
the method of the disclosure are also pharmaceutically acceptable
and thus appropriate for use in a medicament. Where the method of
the present disclosure does not involve complete separation of the
grinding matrix from the abiraterone acetate, the present
disclosure encompasses methods for the production of a medicament
incorporating both the abiraterone acetate and at least a portion
of the milled grinding matrix, medicaments so produced and methods
of treatment of an animal, including man, using a therapeutically
effective amount of said abiraterone acetate by way of said
medicaments.
Abiraterone Acetate and Compositions
[0110] The present disclosure encompasses pharmaceutically
acceptable materials produced according to the methods of the
present disclosure, compositions including such materials,
including compositions comprising such materials together with the
grinding matrix with or without milling aids, facilitating agents,
with at least a portion of the grinding matrix or separated from
the grinding matrix.
Medicaments
[0111] The medicaments of the present disclosure may include the
pharmaceutically acceptable material, optionally together with the
grinding matrix or at least a portion of the grinding matrix, with
or without milling aids, facilitating agents, combined with one or
more pharmaceutically acceptable carriers, as well as other agents
commonly used in the preparation of pharmaceutically acceptable
compositions.
[0112] As used herein "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, and the like that are physiologically compatible.
In some embodiments, the carrier is suitable for parenteral
administration, intravenous, intraperitoneal, intramuscular,
sublingual, pulmonary, transdermal or oral administration.
Pharmaceutically acceptable carriers include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous
preparation of sterile injectable solutions or dispersion. The use
of such media and agents for the manufacture of medicaments is well
known in the art. Except insofar as any conventional media or agent
is incompatible with the pharmaceutically acceptable material, use
thereof in the manufacture of a pharmaceutical composition
according to the disclosure is contemplated.
[0113] Pharmaceutical acceptable carriers according to the
disclosure may include one or more of the following examples:
[0114] (1) surfactants and polymers including, but not limited to
polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium
lauryl sulfate, polyvinylalcohol, crospovidone,
polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose
derivatives, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl
cellulose phthalate, polyacrylates and polymethacrylates, urea,
sugars, polyols, and their polymers, emulsifiers, sugar gum,
starch, organic acids and their salts, vinyl pyrrolidone and vinyl
acetate [0115] (2) binding agents such as various celluloses and
cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and
or [0116] (3) filling agents such as lactose monohydrate, lactose
anhydrous, microcrystalline cellulose and various starches; and or
[0117] (4) lubricating agents such as agents that act on the
flowability of the powder to be compressed, including colloidal
silicon dioxide, talc, stearic acid, magnesium stearate, calcium
stearate, silica gel; and or [0118] (5) sweeteners such as any
natural or artificial sweetener including sucrose, xylitol, sodium
saccharin, cyclamate, aspartame, and acesulfame K; and or [0119]
(6) flavoring agents; and or [0120] (7) preservatives such as
potassium sorbate, methylparaben, propylparaben, benzoic acid and
its salts, other esters of parahydroxybenzoic acid such as
butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic
chemicals such as phenol, or quarternary compounds such as
benzalkonium chloride; and or [0121] (8) buffers; and or [0122] (9)
Diluents such as pharmaceutically acceptable inert fillers, such as
microcrystalline cellulose, lactose, dibasic calcium phosphate,
saccharides, and/or mixtures of any of the foregoing; and or [0123]
(10) wetting agents such as corn starch, potato starch, maize
starch, and modified starches, and mixtures thereof; and or [0124]
(11) disintegrants; such as croscarmellose sodium, crospovidone,
sodium starch glycolate, and or [0125] (12) effervescent agents
such as effervescent couples such as an organic acid (e.g., citric,
tartaric, malic, fumaric, adipic, succinic, and alginic acids and
anhydrides and acid salts), or a carbonate (e.g. sodium carbonate,
potassium carbonate, magnesium carbonate, sodium glycine carbonate,
L-lysine carbonate, and arginine carbonate) or bicarbonate (e.g.
sodium bicarbonate or potassium bicarbonate); and or [0126] (13)
other pharmaceutically acceptable excipients.
[0127] Actual dosage levels of abiraterone acetate disclosure may
be varied in accordance with the nature of the abiraterone acetate,
as well as the potential increased efficacy due to the advantages
of providing and administering the abiraterone acetate (e.g.,
increased solubility, more rapid dissolution, increased surface
area of the abiraterone acetate, etc.). Thus as used herein
"therapeutically effective amount" will refer to an amount of
abiraterone acetate required to effect a therapeutic response in an
animal. Amounts effective for such a use will depend on: the
desired therapeutic effect; the route of administration; the
potency of the abiraterone acetate; the desired duration of
treatment; the stage and severity of the disease being treated; the
weight and general state of health of the patient; and the judgment
of the prescribing physician.
Pharmacokinetic Properties of Abiraterone Acetate Compositions
Fast Onset of Absorbtion
[0128] In some embodiments, the abiraterone acetate compositions of
the disclosure are rapidly absorbed. In one example, the
abiraterone acetate compositions of the disclosure have a
T.sub.max, when administered to an adult male in the fasted state,
of less than about 2.5 hours (about 3 hours to about 2 hours), less
than about 2.0 hours, less than about 1.75 hours, less than about
1.5 hours, less than about 1.25 hours, and more than about 1.0
hour, for example between 1.5 and 2.0 hrs
Increased Bioavailability
[0129] The abiraterone acetate compositions of the disclosure
exhibit increased bioavailability (AUC) and require smaller doses
as compared to prior conventional compositions administered at the
same dose (e.g., Zytiga.RTM.). In some cases an AUC and/or a Cmax
similar to Zytiga.RTM. can be achieved at lower dose than for
Zytiga.RTM.. Thus, in some cases the pharmaceutical compositions
described herein administered at a lower dose than Zytiga provide
comparable systemic exposure. For example, a 500 mg dose can be
bioequivalent to a 1,000 mg dose of Zytiga.RTM.. Any drug
composition can have adverse side effects. Thus, lower doses of
drugs which can achieve the same or better therapeutic effect as
those observed with larger doses of conventional compositions are
desired. Such lower doses can be realized with the compositions of
the disclosure because the greater bioavailability observed with
the compositions as compared to conventional drug formulations
means that smaller doses of drug are required to obtain the desired
therapeutic effect.
The Pharmacokinetic Profiles of the Compositions of the Disclosure
May be Less Affected by the Fed or Fasted State of the Subject
Ingesting the Compositions
[0130] The disclosure encompasses abiraterone acetate compositions
wherein the pharmacokinetic profile of the composition is less
affected by the fed or fasted state of a subject ingesting the
composition compared to Zytiga.RTM.. This means that there is a
less difference in the quantity of composition or the rate of
composition absorption when the compositions are administered in
the fed versus the fasted state. Thus, in some cases the
compositions of the disclosure reduce the effect of food on the
pharmacokinetics of the composition compared to Zytiga.RTM..
The Pharmacokinetic Profiles of the Compositions of the Disclosure
May Exhibit Reduced Inter-Patient Variability
[0131] In some cases, the geometric mean coefficient of variation
in one or more of Cmax, AUC0-t and AUC0-.infin. may be less for an
abiraterone acetate dosage form described herein than for
Zytiga.RTM.. Thus, the geometric mean coefficient of variation in
one or more of Cmax, AUC0-t and AUC0-.infin. can be 10%-50% less
(at least 10% less, 10%-30% less, or 10%-20% less) than for
Zytiga.RTM.. (Calculated as CV (Zytiga.RTM.)-CV (present dosage
form)/CV (Zytiga.RTM.).times.100%).
Pharmacokinetic Protocol
[0132] Any standard pharmacokinetic protocol can be used to
determine blood plasma concentration profile in humans following
administration of a composition, and thereby establish whether that
composition meets the pharmacokinetic criteria set out herein. For
example, a randomized single-dose crossover study can be performed
using a group of healthy adult human subjects. The number of
subjects should be sufficient to provide adequate control of
variation in a statistical analysis, and is typically about 10 or
greater, although for certain purposes a smaller group can suffice.
Each subject receives by oral administration at time zero a single
dose (e.g., 100 mg) of a test formulation of composition, normally
at around 8 am following an overnight fast. The subjects continue
to fast and remain in an upright position for about 4 hours after
administration of the composition. Blood samples are collected from
each subject prior to administration (e.g., 15 minutes) and at
several intervals after administration. For the present purpose it
is to take several samples within the first hour, and to sample
less frequently thereafter. Illustratively, blood samples could be
collected at 15, 30, 45, 60, and 90 minutes after administration,
then every hour from 2 to 10 hours after administration. Additional
blood samples may also be taken later, for example at 12, 24, 36
and 48 hours after administration. If the same subjects are to be
used for study of a second test formulation, a period of at least 7
days should elapse before administration of the second formulation.
Plasma is separated from the blood samples by centrifugation and
the separated plasma is analyzed for composition by a validated
high performance liquid chromatography (HPLC) or liquid
chromatography mass spectrometry (LCMS) procedure. Plasma
concentrations of composition referenced herein are intended to
mean total concentrations including both free and bound
composition.
Modes of Administration of Medicaments Comprising Abiraterone
Acetates
[0133] Medicaments of the disclosure can be administered to
animals, including man, in any pharmaceutically acceptable manner,
such as orally, rectally, pulmonary, intravaginally, locally
(powders, ointments or drops), transdermal, parenteral
administration, intravenous, intraperitoneal, intramuscular,
sublingual or as a buccal or nasal spray.
[0134] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, pellets, and granules. Further,
incorporating any of the normally employed excipients, such as
those previously listed, and generally 5-95% of the biologically
active agent, and more preferably at a concentration of 10%-75%
will form a pharmaceutically acceptable non-toxic oral
composition.
[0135] However, if the abiraterone acetate is to be utilized in a
liquid suspension, the particles comprising the abiraterone acetate
may require further stabilization once the solid carrier has been
substantially removed to ensure the elimination, or at least
minimization of particle agglomeration.
Example 1
Preparation of Fine Particle Abiraterone Acetate Powder Blend
[0136] Abiraterone acetate was dry milled in the presence of
lactose monohydrate and sodium lauryl sulfate in the percentages
shown in Table 1 to prepare a drug product intermediate for use in
the preparation of tablets. Both lots of material were milled in a
Union Process 1S attritor mill with a 0.5 gallon jacket-cooled
tank. 200 g batches were milled with milling bodies for 40
minutes.
TABLE-US-00001 TABLE 1 Drug Product Intermediate for Preparation of
Tablets Ingredient Name and Formula 1 Formula 2 Grade % w/w % w/w
Abiraterone Acetate 20.00 30.00 Lactose Monohydrate, USP 78.50
67.75 Sodium Lauryl Sulfate, NF 1.50 2.25 Total 100.00 100.00
Example 2
Particle Size Analysis of Milled and Unmilled Abiraterone
Acetate
[0137] The particle size distribution of the abiraterone acetate in
the two drug product intermediate lots described in Example 1 were
measured by light scattering using a Malvern Mastersizer 3000 model
MAZ3000 particle size analyzer configured with a Hydro MV wet
sample dispersion unit. Additionally, an unmilled blend of
abiraterone acetate, lactose monohydrate and sodium lauryl sulfate
was measured. All three samples were measured using the method as
follows: the dispersant used was an aqueous solution of 0.1%
povidone K30. Approximately 20 mg of sample powder and 5 mL of
dispersant was added to a plastic centrifuge tube. The tube was
swirled to disperse the powder and then sonicated (Branson Digital
Sonifier 250 with sonic probe model 102C) for 1 minute at 20%
amplitude with a sonication cycle of 5 seconds on and 15 seconds
off. The particle size analyzer sample dispersion unit was filled
with the dispersant and the sample was pipetted into the reservoir
until the target obscuration of 5-15% was reached and remained
constant. The stirrer was run at 1500 rpm, and data were collected
for 10 seconds. Three measurements were made and the average values
of each particle size parameter were reported. Table 2 and FIG. 1
show the particle size distributions; the data shows over a 10-fold
reduction in particle size.
TABLE-US-00002 TABLE 2 Particle size Distribution of Unmilled and
Milled Abiraterone Acetate Formula 1 Formula 2 Unmilled (20% AA)
(30% AA) D.sub.10 3.41 0.087 0.095 (micron) D.sub.50 8.50 0.199
0.225 (micron) D.sub.90 16.4 0.463 0.538 (micron) D.sub.4, 3 9.32
0.254 0.280 (micron) D.sub.3, 2 6.46 0.164 0.183 (micron)
Example 3
Preparation of Tablets and Comparative Dissolution Studies
[0138] The milled drug product intermediate was combined with
intragranular excipients and dry granulated using roller compaction
and milling. The granulation was blended with extragranular
excipients and compressed in a rotary tablet press to produce 100
mg abiraterone acetate tablets having the composition shown in
Table 3.
TABLE-US-00003 TABLE 3 Abiraterone Acetate 100 mg Tablet
Composition Formula 1 Formula 2 mg/ mg/ Ingredient % w/w tablet %
w/w tablet Abiraterone Acetate DPI 58.82 500.0 Formula 1 (20% AA)
Abiraterone Acetate DPI 47.62 333.3 Formula 2 (30% AA)
Microcrystalline Cellulose, 33.38 283.7 44.53 311.7 NF Sodium
Lauryl Sulfate, NF 0.3 2.6 0.35 2.5 Croscarmellose Sodium, NF 7
59.5 7 49.0 Sodium Stearyl Fumarate, NF 0.5 4.3 0.5 3.5 Total 100
850.0 100 700.0
[0139] The dissolution rates of the tablets prepared as described
above were measured using the method listed on the FDA website for
abiraterone acetate tablets, 250 mg; USP Apparatus II, 50 rpm in
900 mL of pH 4.5 buffer with 0.25% sodium lauryl sulfate. Samples
were analyzed by UV at 270 nm. Additionally, for comparison
purposes, Zytiga.RTM. tablets were tested with the same dissolution
conditions. The results of this analysis are shown in Table 4 and
FIG. 2. Full dissolution (>85% dissolved) was achieve in 10-20
minutes for the two tablet formulations contained milled
abiraterone acetate, compared to Zytiga.RTM. which had full
dissolution (>85% dissolved) in 60 minutes.
TABLE-US-00004 TABLE 4 Dissolution of Abiraterone Acetate Tablets
Formula 1 (100 Formula 2 (100 Zytiga .RTM. (250 mg abiraterone mg
abiraterone mg abiraterone acetate) acetate) acetate) Avg % Std Avg
% Std % Std Time dis- Devi- dis- Devi- dis- Devi- [min] solved
ation solved ation solved ation 0 0 0 0 0 0 0 5 50.9 14.3 63.8 12.4
16.3 1.8 10 81.9 10.9 87.4 6.4 30.2 2.8 20 88.3 2.9 92.4 4.8 52.6
3.3 30 93 9.1 93.7 4.8 80.2 9.7 60 95.5 7.1 94.9 4.4 95.5 1.2
Example 4
Abiraterone Acetate Tablets for Initial Phase I Study
[0140] Abiraterone acetate was dry milled in the presence of
lactose monohydrate and sodium lauryl sulfate in the amounts shown
in Table 5 to prepare a drug product intermediate for use in the
preparation of tablets for use in Phase I testing. The material was
milled in a Union Process is attritor mill with a 1.5 gallon
jacket-cooled tank. The material was milled with milling bodies for
40 minutes.
TABLE-US-00005 TABLE 5 Drug Product Intermediate for Preparation of
Tablets for Phase I Testing Ingredient Name and Weight Quantity per
Grade percent batch (g) Abiraterone Acetate 30.00 300.0 Lactose
Monohydrate, USP 67.75 677.5 Sodium Lauryl Sulfate, NF 2.25 22.5
Total 100.00 1000.0
[0141] The particle size distribution of the abiraterone acetate in
the milled drug product intermediate was measured with a
Micromeritics Saturn DigiSizer II 5205 particle size analyzer
configured with an AquaPrep II sample cell. The instrument sample
reservoir was filled with dispersant solution (0.1% povidone K30).
The sample was prepared by adding 100 mg of milled powder and 20 mL
of dispersant to a 30 mL glass bottle. The particles were dispersed
by agitation with a pipette, and then the capped bottle was placed
in an ultrasonic water bath (Branson Ultrasonic bath, Model
5510-MT, output 135 W, 42 KHz) such that the bath water level was
half way up the side of the bottle. The sample was then sonicated
for 30 minutes. The dispersed sample was added dropwise to the
reservoir of the liquid sample handling unit until an obscuration
value of approximately 7% was reached. The internal sonic probe was
run at 100% intensity for 300 seconds, and then the sample was
circulated for 120 seconds before data collection. Data were
collected at a beam angle setting of 65.degree. when the
obscuration value was between 5 and 10%. Each measurement was
repeated in triplicate and the average of three measurements was
reported. Particle size data from the milled powder are reported in
Table 6.
TABLE-US-00006 TABLE 6 Milled Abiraterone Acetate Particle Size
Particle Size Parameter Result (micron) D.sub.10 0.105 D.sub.50
0.387 D.sub.90 1.308 D.sub.4, 3 0.588 D.sub.3, 2 0.247
[0142] The milled drug product intermediate was combined with
intragranular excipients and dry granulated using roller compaction
and milling. The granulation was blended with extragranular
excipients and compressed in a rotary tablet press to produce 100
mg abiraterone acetate tablets having the composition shown in
Table 7.
TABLE-US-00007 TABLE 7 Abiraterone Acetate 100 mg Tablet
Composition for Initial Phase 1 Testing Ingredient % w/w mg/tablet
Abiraterone Acetate 14.29 100.0 Lactose Monohydrate, NF 32.26 225.8
Sodium Lauryl Sulfate, NF 1.42 10.0 Microcrystalline Cellulose, NF
44.53 311.7 Croscarmellose Sodium, NF 7.00 49.0 Sodium Stearyl
Fumarate, NF 0.50 3.5 Total 100.00 700.0
[0143] The dissolution rates of the tablets prepared as described
above were measured in USP Apparatus II, 75 rpm in 900 mL of pH 4.5
buffer with 0.1% SLS. Samples were analyzed by HPLC. Additionally,
for comparison purposes, Zytiga.RTM. tablets were tested with the
same dissolution conditions. Because Zytiga.RTM. tablets are 250 mg
which is approaching the solubility limit of the dissolution media,
the tablets were cut to a weight equivalent to 100 mg of
abiraterone acetate. Zytiga.RTM. samples were measured using UV at
270 nm. The results of this analysis are shown in Table 8; full
dissolution (>85% dissolved) of the prepared tablets was
achieved in 5 minutes, whereas the Zytiga.RTM. tablets dissolution
was achieved in 20 minutes.
TABLE-US-00008 TABLE 8 Dissolution of Abiraterone Acetate Tablets
100 mg 100 mg Tablets for Phase 1 Zytiga .RTM. tablets (cut to
Clinical testing 100 mg) Average % Average % Time (minutes)
dissolved % RSD dissolved % RSD 5 88 7.2 32.7 27.1 10 99 1.8 59.0
21.3 15 99 1.1 78.2 9.6 20 -- -- 91.6 6.7 30 100 1.1 97.1 4.0 45
100 1.2 97.6 3.8 60 100 1.2 97.7 3.8
Example 5
Phase I Study of 100, 200, and 400 mg Doses of Abiraterone Acetate
Formulation Compared to Zytiga.RTM. 1000 mg
[0144] The abiraterone acetate 100 mg tablet formulation prepared
as described in Example 4 was tested in healthy male patients under
fasting conditions at 100 mg, 200 mg, and 400 mg doses (1, 2, or
4.times.100 mg tablets respectively). In the same study, a 1000 mg
dose of Zytiga.RTM. was tested (4.times.250 mg tablets). The
results of this study are shown in Table 9.
TABLE-US-00009 TABLE 9 Abiraterone Acetate Tablets 100 mg
Pharmacokinetic Data (Arithmetic Means) Milled Abiraterone Acetate
Zytiga .RTM. PK Parameters Statistics 100 mg 200 mg 400 mg 1,000 mg
AUC.sub.0-inf N 19 18 19 19 (ng hr/mL) Mean* 74.49 183.34 319.92
421.23 S.D. 42.22 86.7 140.74 183.83 CV (%) 56.68 47.29 43.99 43.64
AUC.sub.0-t N 19 18 19 19 (ng hr/mL) Mean* 67.55 169.99 302.9
387.34 S.D. 39.37 83.73 137.17 168.67 CV (%) 58.28 49.25 45.29
43.55 C.sub.max (ng/mL) N 19 18 19 19 Mean* 17.28 39.11 65.42 79.46
S.D. 10.41 21.69 35.58 39.56 CV (%) 60.29 55.46 54.39 49.78
T.sub.max (hour) N 19 18 19 19 Mean 1.55 1.78 2.32 2.16 S.D. 0.57
0.77 1.33 0.78 CV (%) 37.02 43.38 57.22 36.27 t.sub.1/2 (hr) N 19
18 19 19 Mean* 4.72 7.83 8.84 14.48 S.D. 2.57 3.88 2.96 5.11 CV (%)
54.35 49.51 33.45 35.32 Ke (hr.sup.-1) N 19 18 19 19 Mean 0.18 0.11
0.09 0.05 S.D. 0.08 0.05 0.03 0.02 CV (%) 43.38 45.27 30.8 36.98
*Observed differences were highly significant (p < 0.0001,
ANOVA) among the four treatments. {circumflex over ( )} Observed
differences were significant (p < 0.05, Wilcoxon signed rank
test), compared to Zytiga .RTM. 1,000 mg.
Example 6
Stability of Abiraterone Acetate Powder Blends and Tablets
[0145] Total impurity growth of 0.2-0.6% AUC was detected by HPLC
after abiraterone acetate was dry milled with lactose monohydrate
and sodium lauryl sulfate. When the milled abiraterone acetate
powder blend (or drug product intermediate; "DPI") was further
processed into tablets, the level of impurities was found to be
higher, about 0.5-1.1%. Stability testing showed that the
impurities grew at 25.degree. C./60% RH and at 40.degree. C./75%
RH, but did not grow at 2-8.degree. C. In addition, impurity growth
in the tablets was faster than that in the milled DPI. Table 10 and
FIGS. 3A and 3B (diamonds, 5.degree. C.; squares, 25.degree. C./60%
RH; and triangles, 40.degree. C./75% RH) provide an overview of the
impurity levels in lots of milled DPI and tablets upon accelerated
stability testing. Tablets stored refrigerated had an acceptably
low level of impurities, but it is desirable to have formulation
that can be stored under ambient conditions.
TABLE-US-00010 TABLE 10 Abiraterone Acetate Stability (total
impurities) Abiraterone Acetate DPI Abiraterone Acetate tablets,
(contains milled API) 100 mg (contains milled API) 25.degree. C./
40.degree. C./ 25.degree. C./ 40.degree. C./ Time 60% 75% 60% 75%
(months) 5.degree. C. RH RH 5.degree. C. RH RH 0 0.20 0.44 0.44
0.73 0.48 0.48 1 0.33 0.65 0.65 0.77 0.78 3.02 2 0.34 0.65 1.21
0.77 1.86 3.34 3 0.28 0.8 1.71 0.72 2.25 4.49
[0146] The impurity growth in the DPI and tablets containing fine
particle abiraterone acetate is due to oxidative degradation of
abiraterone acetate. Aged Zytiga.RTM. (abiraterone acetate) tablets
were tested for purity, and the impurity levels were found to be
much lower than aged tablets containing fine particle abiraterone
acetate. The faster degradation in tablets containing fine particle
abiraterone acetate could arise from a number of sources,
including, but not limited to: greater surface area of the API,
higher proportion of excipient relative to the API, and differences
in excipients. Further studies found that the API has some
degradation in the presence of the excipients, but the degradation
is greatly accelerated once the mixture is milled. Data are
provided in Table 11.
TABLE-US-00011 TABLE 11 Abiraterone Acetate Stability Total
impurities by HPLC Product Milling Stability (% AUC) Abiraterone
Acetate (API) none 80.degree. C., 4 hrs 0.23 SPEX 80.degree. C., 4
hrs 0.17 shaker mill Drug Product Intermediate none 80.degree. C.,
4 hrs 0.28 (API, SLS, lactose SPEX 80.degree. C., 4 hrs 3.90
monohydrate) shaker mill Tablet formulation (API, none 80.degree.
C., 4 hrs 0.76 SLS, lactose monohydrate, SPEX 105.degree. C., 4 hrs
10.00 microcrystalline cellulose, shaker croscarmellose sodium,
mill sodium stearyl fumarate) Zytiga .RTM. (abiraterone None Stored
room 0.20 acetate) tablet temperature until expiry
Example 7
Milling of Abiraterone with Antioxidant or Sequestering Agent
[0147] Dry milling of abiraterone acetate was carried out in the
presence of lactose monohydrate and sodium lauryl sulfate and
various antioxidants and/or sequestering agents. In one study the
dry milling included a combination of ascorbic acid and fumaric
acid or a combination of butylated hydroxyanisole (BHA) and
butylated hydroxytoluene (BHT): the formulations are shown in Table
12. Each lot was milled in a Union Process 1S attritor mill with a
0.5 gallon jacket-cooled tank. 200 g batches were milled with
milling bodies for 40 minutes. Both DPI Formulas contained
abiraterone acetate having a D90 below 1,000 nm, when tested per
the light scattering method described in Example 2.
TABLE-US-00012 TABLE 12 DPI Formulation Containing Antioxidant or
Sequestering Agent DPI DPI Formulation Formulation Ascorbic/
BHA/BHT Ingredient Function Fumaric % w/w % w/w Abiraterone Acetate
Active 30.00 30.00 Lactose Monohydrate Grinding 67.35 67.65
compound Sodium lauryl sulfate Facilitating 2.25 2.25 agent
Ascorbic acid Antioxidant 0.20 Fumaric acid Sequestering 0.20 agent
Butylated Hydroxy- Antioxidant 0.05 anisole (BHA) Butylated
Hydroxy- Antioxidant 0.05 toluene (BHT) TOTAL 100.00 100.00
[0148] The two different DPI Formulations were used to prepare two
different corresponding tablet Formulation as detailed in Table 13
by adding the indicated excipients to the DPI Formulations, dry
granulating and tableting.
TABLE-US-00013 TABLE 13 Tablet Formulations Containing Antioxidant
or Sequestering Agent Tablet Tablet Formu- Formu- lation lation
Ascorbic/ BHA/BHT Function Fumaric % w/w % w/w DPI Formulation
Ascorbic/ 47.62 Fumaric (abiraterone acetate, lactose mono-
hydrate, SLS, ascorbic acid, fumaric acid) DPI Formulation BHA/
47.62 BHT (abiraterone acetate, lactose monohydrate, SLS, BHA, BHT)
Microcrystalline cellulose Diluent 44.53 44.53 Sodium lauryl
sulfate Wetting 0.35 0.35 agent Croscarmellose sodium Disintegrant
7.0 7.0 Sodium stearyl fumarate Lubricant 0.5 0.5 Total 100 100
[0149] The stability of the two tablet formulations was tested
under accelerated conditions. Table 14 contains data demonstrating
that both tablet formulations with antioxidant had dramatically
improved stability after 3 months storage at 40.degree. C./75% RH
compared to the formulation without antioxidant, with the BHA/BHT
formulation nearly halting all degradation. This demonstrates that
the addition of antioxidants and/or sequestering agents during
milling can dramatically improve stability.
TABLE-US-00014 TABLE 14 Tablet Stability data with and without
Antioxidant Formulation Ascorbic Acid Formulation No antioxidant
and Fumaric Acid BHA&BHT Total Total Total Assay (% impurities
Assay (% Impurities Assay (% Impurities condition label claim) (%
AUC) label claim) (% AUC) label claim) (% AUC) Initial 98.6 0.48
101.5 0.31 101.6 0.16 1 month, 98.1 0.78 100.9 0.89 101.1 0.15
25.degree. C./60%RH 1 month, 92.4 3.02 96.8 1.13 100.7 0.19
40.degree. C./75%RH 2 month, 97.5 1.86 95.5 1.26 96.7 0.13
25.degree. C./60%RH 2 month, 92.8 3.36 97.5 1.46 97.4 0.16
40.degree. C./75%RH 3 months, 95.2 2.25 97.8 1.75 95.5 0.45
25.degree. C./60%RH 3 months, 92.5 4.49 96.0 1.90 98.6 0.70
40.degree. C./75%RH
[0150] The dissolution rate of the abiraterone acetate in the
Tablet Formulation Ascorbic/Fumaric and Tablet Formulation BHA/BHT
was tested using USP Apparatus II at 75 rpm in 900 ml of pH 4.5
phosphate buffer with 0.1% SLS. Tablets for all three types of
tablets had full dissolution (>85% of the abiraterone acetate
dissolved) within 10 minutes.
Example 8
Abiraterone Acetate Tablets for Additional Phase I Studies
[0151] An additional drug product intermediate formulation was
prepared by dry milling abiraterone acetate, lactose monohydrate,
sodium lauryl sulfate, BHA and BHT. The composition of the material
milled to form this intermediate is shown in Table 15. The
formulation was milled in a custom jacket-cooled 62 gallon attritor
mill; the powder blend was milled with milling bodies for 72
minutes.
TABLE-US-00015 TABLE 15 Milled Drug Product Intermediate Containing
BHA and BHT for Phase 1 clinical studies Weight Quantity per
Component percent batch (g) Abiraterone Acetate 30.0 8.400 Lactose
Monohydrate, USP 63.8 17.886 Sodium Lauryl Sulfate, NF 6.0 1.680
BHA 0.1 0.028 BHT 0.1 0.028 Total 100 28.000
[0152] The particle size distribution of the abiraterone acetate in
this drug product intermediate was measured by light scattering
using a Malvern Mastersizer 3000 model MAZ3000 particle size
analyzer configured with a Hydro MV wet sample dispersion unit. Two
different methods were used to measure the particle size
distributions, as described below:
[0153] Method 1: The dispersant used was an aqueous solution of
0.1% povidone K30. Approximately 20 mg of sample powder and 5 mL of
dispersant was added to a plastic centrifuge tube. The tube was
swirled to disperse the powder and then sonicated (Branson Digital
Sonifier 250 with sonic probe model 102C) for 1 minute at 20%
amplitude with a sonication cycle of 5 seconds on and 15 seconds
off. The particle size analyzer sample dispersion unit was filled
with the dispersant and the sample was pipetted into the reservoir
until the target obscuration of 5-15% was reached and remained
constant. The stirrer was run at 1500 rpm, and data were collected
for 10 seconds. Three measurements were made and the average values
of each particle size parameter were reported.
[0154] Method 2: The dispersant used was an aqueous solution
comprising 0.1% of poloxamer 338 and 0.1% calcium chloride which
was filtered through a 0.2 .mu.m nylon filter prior to use.
Approximately 20 mg of sample powder and 5 mL of dispersant
solution was added to a glass vial. The vial was capped and swirled
to disperse the powder particles. The vial cap was then loosened
and the vial placed in the center of a sonic bath (Elma Elmsonic
P30H ultrasonic bath). The vial was immersed such that the bath
liquid level was above the level of the dispersant in the vial, but
the vial was not touching the bottom of the bath. The sample was
sonicated at 37 kHz at 100% power for ten minutes. The particle
size analyzer sample dispersion unit was filled with dispersant and
the sample was pipetted into the reservoir until an obscuration of
5-15% was obtained and remained constant. The stirrer was run at
1500 rpm, and data were collected for 10 seconds. Three
measurements were made and the average values of each particle size
parameter were reported.
[0155] Table 16 presents a comparison of the particle size values
for abiraterone acetate in the drug product intermediate (DPI)
described in Table 15 before and after milling, using Methods 1 and
2 described above.
TABLE-US-00016 TABLE 16 Particle Size Distribution Data for
Abiraterone Acetate DPI Containing BHA and BHT Particle Size
(.mu.m) Unmilled Milled Milled Parameter Method 1 Method 1 Method 2
D.sub.10 1.64 0.153 0.124 D.sub.50 3.07 0.747 0.286 D.sub.90 5.79
3.250 0.937 D.sub.4, 3 3.44 1.300 0.479 D.sub.3, 2 2.75 0.390
0.241
[0156] The milled drug product intermediate was combined with
intragranular excipients and dry granulated using roller compaction
and milling. The granulation was blended with extragranular
excipients and compressed in a rotary tablet press to produce 125
mg abiraterone acetate tablets having the composition shown in
Table 17.
TABLE-US-00017 TABLE 17 Milled Abiraterone Acetate Tablets 125 mg
Composition Component % w/w mg/tablet Abiraterone Acetate 14.37
125.00 Lactose Monhydrate, NF 30.56 265.83 Sodium Lauryl Sulfate,
NF 2.87 25.00 BHA (butylated hydroxyanisole), NF 0.05 0.42 BHT
(butylated hydroxytoluene), NF 0.05 0.42 Microcrystalline
Cellulose, NF 44.60 388.06 Croscarmellose Sodium, NF 7.00 60.90
Sodium Stearyl Fumarate, NF 0.50 4.38 Total 100.00 870.00
[0157] The dissolution rate of these tablets was measured in at USP
Apparatus II, 75 rpm in pH 4.5 buffer with 0.12% SLS. Samples were
analyzed by HPLC. The results of this analysis are shown in Table
18; full dissolution (>85% dissolved) was achieved in 10
minutes.
TABLE-US-00018 TABLE 18 Dissolution of Abiraterone Acetate Tablets
Time % abiraterone (minutes) acetate dissolved % RSD 5 53 6.6 10 86
3.4 15 93 3.5 30 95 2.9 45 95 3.1 60 95 3.0
Example 11
Phase I Study of 125, 500, and 625 mg Doses of Abiraterone Acetate
Formulation Compared to Zytiga.RTM. 1000 mg
[0158] The abiraterone acetate 125 mg tablet formulation prepared
as described in Example 10 was tested in healthy male patients
under fasting conditions at 125 mg, 500 mg, and 625 mg doses (1, 4,
or 5.times.125 mg tablets respectively). In the same study, a 1000
mg dose of Zytiga.RTM. was tested (4.times.250 mg tablets). The
results of this study are shown in Table 19.
TABLE-US-00019 TABLE 19 Abiraterone Acetate Tablets 125 mg
Pharmacokinetic Data (Arithmetic Means) Milled Abiraterone Acetate
Zytiga .RTM. PK Parameters Statistics 125 mg 500 mg 625 mg 1,000 mg
AUC.sub.0-inf N 33 34 34 33 (ng hr/mL) Mean* 112.12 438.02 473.31
453.18 S.D. 65.94 249.43 247.19 219.07 CV (%) 58.81 56.94 52.23
48.34 AUC.sub.0-t N 33 34 34 34 (ng hr/mL) Mean* 102.55 416.23
450.19 415.91 S.D. 63.27 245.73 241.85 210.67 CV (%) 61.7 59.04
53.72 50.65 C.sub.max (ng/mL) N 33 34 34 34 Mean* 28.22 84.16
100.76 83.4 S.D. 16.46 44.05 63.75 57.4 CV (%) 58.34 52.34 63.27
68.83 T.sub.max (hour) N 33 34 34 34 Mean 1.61 1.79 1.84 2.21 S.D.
0.98 1.12 0.97 1.44 CV (%) 61.16 62.55 52.61 65.34 t.sub.1/2 (hr) N
33 34 34 33 Mean* 7.2 14.2 14.54 20.64 S.D. 3.47 6.44 5.54 9.03 CV
(%) 48.28 45.61 38.07 43.75 Ke (/hr) N 33 34 34 33 Mean 0.13 0.06
0.05 0.04 S.D. 0.09 0.05 0.02 0.02 CV (%) 65.7 71.26 36.1 46.69
Example 12
Additional Abiraterone Acetate Powder and Tablets
[0159] An additional drug product intermediate formulation was
prepared by dry milling abiraterone acetate, lactose monohydrate,
sodium lauryl sulfate, BHA and BHT. The composition of the material
milled to form this intermediate is shown in Table 16. Two batches
were milled with varying processing conditions, yielding slightly
different particle size.
TABLE-US-00020 TABLE 16 Additional Milled Drug Product Intermediate
Weight Quantity per Ingredient percent batch (g) Abiraterone
Acetate 30.00 450.00 Lactose Monohydrate, USP 67.55 1013.25 Sodium
Lauryl Sulfate, NF 2.25 33.75 Butylated Hydroxytoluene (BHT) 0.10
1.50 Butylated Hydroxyanisole (BHA) 0.10 1.50 total 100.00
1500.0
[0160] The particle size distribution of the abiraterone acetate in
both lots of drug product intermediate were measured by light
scattering using a Malvern Mastersizer 3000 model MAZ3000 particle
size analyzer configured with a Hydro MV wet sample dispersion
unit. Method 1 described in example 8 was utilized to obtain the
particle size distribution shown in Table 17.
TABLE-US-00021 TABLE 17 Additional Particle Size Distribution Data
for Abiraterone Acetate DPI Particle Size (.mu.m) Parameter
Unmilled Batch 1, Milled Batch 2, Milled D.sub.10 1.69 1.17 1.36
D.sub.50 3.55 2.13 2.46 D.sub.90 7.58 4.17 4.64 D.sub.4, 3 5.94
5.45 4.46 D.sub.3, 2 3.02 1.95 2.25
[0161] The milled drug product intermediate from Batch 1 was
combined with intragranular excipients and dry granulated using
roller compaction and milling. The granulation was blended with
extragranular excipients and compressed in a rotary tablet press to
produce 100 mg abiraterone acetate tablets having the composition
shown in Table 18.
TABLE-US-00022 TABLE 18 Milled Abiraterone Acetate Tablets 100 mg
Composition Component % w/w mg/tablet Abiraterone Acetate 14.29
100.0 Lactose Monhydrate, NF 32.17 10.0 Sodium Lauryl Sulfate, NF
1.42 0.3 BHA (butylated hydroxyanisole), NF 0.05 0.3 BHT (butylated
hydroxytoluene), NF 0.05 225.2 Microcrystalline Cellulose, NF 44.53
311.7 Croscarmellose Sodium, NF 7.00 49.0 Sodium Stearyl Fumarate,
NF 0.50 3.5 Total 100.0 700.0
[0162] The dissolution rate of these tablets was measured in at USP
Apparatus II, 75 rpm in pH 4.5 buffer with 0.1% SLS. Samples were
analyzed by UV at 270 nm. The results of this analysis are shown in
Table 19; full dissolution (>85% dissolved) was achieved in 10
minutes.
TABLE-US-00023 TABLE 19 Dissolution of Abiraterone Acetate Tablets,
100 mg Time % abiraterone (minutes) acetate dissolved % RSD 5 60.2
7.1 10 94.3 4.0 15 97.6 3.4 30 98.8 2.1 45 98.2 2.3 60 98.3 2.3
Example 13
Stability of Tablets
[0163] An additional drug product intermediate formulation was
prepared by dry milling abiraterone acetate, lactose monohydrate,
sodium lauryl sulfate, BHA and BHT. The composition of the material
milled to form this intermediate is shown in Table 20.
TABLE-US-00024 TABLE 20 Milled Drug Product Intermediate Containing
BHA and BHT Weight Quantity per Ingredient percent batch (kg)
Abiraterone Acetate 30.00 7.44 Lactose Monohydrate, USP 63.8 15.82
Sodium Lauryl Sulfate, NF 6.0 1.49 Butylated Hydroxytoluene (BHT)
0.10 0.025 Butylated Hydroxyanisole (BHA) 0.10 0.025 total 100.00
24.80
[0164] The particle size distribution of the abiraterone acetate in
this drug product intermediate was measured by light scattering
using a Malvern Mastersizer 3000 model MAZ3000 particle size
analyzer configured with a Hydro MV wet sample dispersion unit.
Method 1 described in example 8 was utilized to obtain the particle
size distribution shown in Table 21.
TABLE-US-00025 TABLE 21 Additional Particle Size Distribution Data
for Abiraterone Acetate DPI Containing BHA and BHT Particle Size
(.mu.m) Parameter Unmilled Milled D.sub.10 1.69 0.184 D.sub.50 3.55
1.20 D.sub.90 7.58 3.57 D.sub.4, 3 5.94 1.56 D.sub.3, 2 3.02
0.49
[0165] The milled drug product intermediate was combined with
intragranular excipients and dry granulated using roller compaction
and milling. The granulation was blended with extragranular
excipients and compressed in a rotary tablet press to produce 125
mg abiraterone acetate tablets having the composition shown in
Table 22.
TABLE-US-00026 TABLE 22 Milled Abiraterone Acetate Tablets 125 mg
Composition Ingredient % w/w mg/tablet Abiraterone acetate 14.34
125.00 Lactose monohydrate, USP 30.49 265.83 Butylated
Hydroxytoluene (BHT) 0.05 0.42 Butylated Hydroxyanisole (BHA) 0.05
0.42 sodium lauryl sulfate, NF 2.87 25.00 Microcrystalline
cellulose, NF 44.69 389.63 Croscarmellose sodium, NF 7.02 61.25
Sodium stearyl fumarate, NF 0.50 4.38 total 100.00 871.92
[0166] Tablets were packaged and mounted on accelerated stability
at 40.degree. C. and 75% relative humidity. Impurities were
measured by a stability-indicating HPLC method. The dissolution
rate of these tablets was measured in at USP Apparatus II, 75 rpm
in pH 4.5 buffer with 0.12% SLS. The results are shown in Table 23;
no impurity growth was observed over 3 months at 40.degree. C./75%
RH, and the dissolution remained unchanged with full dissolution
(>85% dissolved) within 10 minutes over 3 months at 40.degree.
C./75% RH.
TABLE-US-00027 TABLE 23 Stability of Abiraterone Acetate Tablets,
125 mg Abiraterone Acetate Tablets, 125 mg 1 month 2 month 3 month
Initial 40.degree. C./75%RH 40.degree. C./75%RH 40.degree. C./75%RH
Total Impurities (% AUC) 0.05 <0.05 0.05 <0.05 Avg % Avg %
Avg % Avg % Time dissolved dissolved dissolved dissolved (minutes)
(n = 6) % RSD (n = 3) % RSD (n = 3) % RSD (n = 3) % RSD 4 60.8 10.2
60.3 8.3 63.4 8.0 65.3 8.6 6 81.3 8.3 80.0 5.0 87.2 3.0 85.8 2.9 8
92.1 1.5 91.6 4.2 94.2 1.2 93.8 0.7 10 93.9 1.2 93.6 2.9 95.5 0.8
95.3 0.6 20 95.0 1.4 97.4 1.9 97.4 0.6 97.4 0.4 30 95.3 1.4 97.7
0.6 98.0 0.3 97.3 0.8 40 95.4 1.9 98.0 0.1 99.3 2.9 97.0 1.2 60
98.1 4.7 97.4 0.7 99.0 1.2 97.2 0.7
Example 14
Effect of Fed or Fasted State
[0167] The effect of a high fat meal on the oral bioavailability of
a 500 mg dose of 125 mg milled abiraterone mg tablets was evaluated
in a single-center, single-dose, randomized, open-label, 2-period,
2-treatment crossover pharmacokinetic study. During the first
dosing period, approximately half of the subjects were administered
the test article with 240 mL of water, after a 10 hour fast. The
remaining subjects were given the test article approximately 30
minutes after consuming a standard FDA high fat breakfast. After a
seven day washout period, each subject was crossed over to the
other treatment. Plasma samples were taken immediately prior to
dosing and at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0,
18.0, 24.0, and 48.0 hours after administration of the test
article. Samples were analyzed for abiraterone concentration, and
the results were used to calculate pharmacokinetic parameters
(AUC.sub.0-.infin., AUC.sub.0-t, and C.sub.max) for each subject
and treatment. The geometric mean values for AUC.sub.0-.infin.,
AUC.sub.0-t, and C.sub.max when the test article was administered
in the fed state were 1444.1 ngh/mL, 1393.4 ngh/mL, and 443.7 ng/mL
respectively, while the geometric mean values for those same
parameters were 322.7 ngh/mL, 301.0 ngh/mL, and 67.9 ng/mL when the
drug was administered in the fasted state. The ratios (fed/fasted)
for AUC.sub.0-.infin., AUC.sub.0-t, and C.sub.max were 4.48, 4.63,
and 6.53, respectively.
* * * * *