Note: Descriptions are shown in the official language in which they were submitted.
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Abiraterone Acetate Formulation and Methods of Use
Background
Abiraterone ((313)-17-(pyridin-3-y1) androsta-5, 16-dien-3-ol; CAS #: 154229-
19-3; Formula:
C24H31N0: 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.
Zytiga0 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 Zytiga0
tablets
recommends 1,000 mg (4 x 250 mg tablets) administered orally once daily in
combination with
prednisone (5 mg) administered orally twice daily. The European approval of
Zytiga0 is for
administration in combination with either prednisone or prednisolone.
Prescribing information for Zytiga0 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 ng.hr/mL.
A single
dose (1000 mg) cross-over study of Zytiga0 in healthy subjects found that
systemic exposure of
abiraterone is increased when Zytgia0 is administered with food. Specifically,
abiraterone Cmax
and AUC o, were approximately 7- and 5-fold higher, respectively, when Zytiga0
was
administered with a low-fat meal (7% fat, 300 calories) compared to
administration in the fasted
state. Abiraterone C. and AUC o, were approximately 17- and 10-fold higher,
respectively,
when Zytiga0 was administered with a high-fat (57% fat, 825 calories) meal
compared to
administration in the fasted state.
Summary
The present disclosure features pharmaceutical compositions, including unit
dosage forms,
comprising abiraterone acetate as well as methods for producing and using such
compositions.
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Described herein is unit dosage form of abiraterone acetate, wherein a 500mg
dose of the unit
dosage form is bioequivalent to a 1000mg dose of Zytiga0 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(0_0,) for a 500mg dose administered to healthy
male subjects in
the fasted state compared to a 1000mg dose of Zytiga0 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 500mg dose administered to healthy male subjects in the fasted state
compared to a 1000mg
dose of Zytiga0 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.
In some cases: the [D90] of the abiraterone acetate is greater than 300nm and
less than one of:
7500nm, 7000nm, 6000nm, 5000nm, 4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm,
and
700nm; the [D50] of the abiraterone acetate greater than 100nm and is less
than one of: 3500nm,
3000nm, 2500nm, 1600nm, 1400nm, 1200nm, 1000nm, 800nm, 500nm, 400nm, and
300nm; the
[D4,3] of the abiraterone acetate is greater than 300nm and less than one of:
7000nm, 6000nm,
5000nm, 4000nm, 3000nm, 2500nm, 2400nm, 2200nm, 2000nm, 1900nm, 1700nm,
1500nm,
1300nm, 1100nm, 900nm, and 800nm; the dissolution rate of the abiraterone
acetate in the unit
dosage form is such that when a sample containing 100mg 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
min; the dissolution rate of the abiraterone acetate in the unit dosage form
is such that when a
sample containing 125mg 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 contains125mg of abiraterone acetate.
Also described is a unit dosage form of a pharmaceutical composition
comprising abiraterone
acetate, wherein a 500mg 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
500mg 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 500mg
dose, upon oral
administration to a population of healthy male subjects in the fasted state,
provides a mean blood
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plasma AUC (0-0o) of 240-650 h*ng/ml. In some case the unit dosage form
contains 125mg of
abiraterone acetate.
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 500mg 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-Go) is a
value between
240 and 650 h*ng/m1 when a 500mg dose is administered to healthy male subjects
in the fasted
state.
The unit dosage forms described herein can contain an antioxidant (e.g., one
or both of BHA and
BHT).
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., 500mg) 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
500mg/day; the
therapeutically effective dose is administered using dosage forms containing:
100mg, 125mg, or
150mg of abiraterone acetate; the 500mg dose is administered using 1, 2, 3, 4,
5, or 6 unit
dosage forms.
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.
In some cases of the method for production: the [D90] of the abiraterone
acetate in the milled
composition is greater than 400nm and less than one of: 7500, 7000, 6000nm,
5000nm,
4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm, and 700nm; the [D50] of the
abiraterone
acetate in the milled composition is greater than 100nm and is less than
3500nm, 3000nm,
2500nm, less than 1600nm, less than 1400nm, less than 1200nm, less than
1000nm, less than
800nm, less than 500nm, less than 400nm, less than 300nm; the dissolution rate
of the
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abiraterone acetate in the milled composition is such that when a sample
containing 100mg 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 125mg 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 200nm and is less than 6500nm, 6000nm, 5500nm, less than 5000nm,
less than
4000nm, less than 3000nm, or less than 2000nm; 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.
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 ([D5o] or D[so] or [D50]), equal or less than a size
selected from the group
consisting of: 5000nm, 4000nm, 3000 nm, 2500nm, 2400 nm, 2300nm, 2200nm,
2200nm,
2100nm, 2000nm, 1900nm, 1800nm, 1700nm, 1600nm, 1500nm, 1400nm, 1300nm,
1200nm,
1100nm, 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400 nm, 300nm and 200nm. In
some
embodiments, the [D50] is equal to or greater than 25nm or 100nm or even
500nm. In various
embodiments the [D50] is between: 5000nm and 100nm, 3500nm and 100nm, 2500nm
and
100nm, 1500nm and 100nm, 1200nm and 100nm, 1100nm and 100nm, 1000nm and 100nm,
800nm and 100nm, 700nm and 100nm, 600nm and 100nm, 500nm and 100nm. The D[4,3]
(volume mean diameter) in various embodiments is: less than 7000nm, less than
5000nm, less
than 3500nm, less than 3000 nm, less than 2000 nm, less than 1000 or less than
300nm. In
various cases, such as those described previously, the D[4,3] is greater than
100nm or greater
than 200nm. In some cases the D[4,3] (volume mean diameter) is between: 7000nm
and
1000nm, 6000nm and 200nm, 5000nm and 1000nm, 4000nm and 1000nm, 3000nm and
1000nm, 2000nm and 1000nm, 1800nm and 1000nm, 1600nm and 1000nm, 1500nm and
1000nm, 1500nm and 500nm, 4000nm and 2000nm, 4000nm and 100nm, 25000nm and
500nm,
700nm and 100nm, 600nm and 100nm, 500nm and 100nm 1000nm and 200nm, 900nm and
200nm, 800nm and 200nm, 700nm and 200nm. The [D90] ([D90] or D[9o]) in various
embodiments is: less than 8000nm, less than 7500nm, less than 7000nm, less
than 6000nm, less
than 4000 nm, less than 2000nm, less than 1000nm, less than 500nm. In some
cases, the D90 is
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between: 5500nm and 300nm, 5000nm and 500nm, 4500nm and 500nm, 4000nm and
200nm,
4500nm and 750nm, and 3500nm and 500nm. In various embodiments described
herein the
[D90] of the abiraterone acetate is less than 5000nm or less than 4000nm. In
some embodiments
the [D90] is: 6000nm-500nm, 5500nm-500nm, or 5000nm-500nm, and 4000-400nm.
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.
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.
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
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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 solublity 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.
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).
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.
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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.
Also described herein is a method for treating a patient comprising
administering a daily dose of
1000mg to 50mg 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
4mg doses/day). In some cases a patient, e.g., a patient not suffering from
hepatic impairment, is
treated at 500mg/daily by administering four 125mg unit dosage forms of
abiraterone acetate as
described herein.
In some cases, for the dosage forms described herein, the AUC o-. for a single
dose of a unit
dosage form described herein (or an effective dose thereof, e.g., 4 x 125mg)
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.
In some cases, for the dosage forms described herein, the AUC (or AUC
o-t) for a single dose
of a unit dosage form described herein (or an effective dose thereof, e.g., 4
x 125mg) 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.
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 x 125mg)
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.
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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 x 125mg)
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.
The dissolution rate of a tablet containing 100mg 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 mm or less, 18 min or less, 17 mm
or less, 16 min or
less, 15 min or less, 14 min or less, 13 min or less, 11 min or less, 9 mm or
less). For example,
90% can dissolve in 9-19 minutes. In cases where the tablet contains more than
125mg or less
than 100mg of abiraterone acetate, the dissolution rate given is for a
fraction of a larger tablet (or
multiple of a smaller tablet) providing 100-125mg 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 mm or less, 9 min or less, 8
min or less, or 7 min
or less). For example, 85% can dissolve in 7-14 minutes.
In some cases, at least 80% or at least 85% of the abiraterone acetate in a
125mg unit dosage
form dissolves in 15 mm or less (e.g, 14 mm or less, 13 mm or less, 12 min or
less, 11 mm or
less, 10 min or less, 9 min or less, 8 mm or less, or 7 min or less) after
storage at 4 weeks or
more (e.g., 8 weeks or 12 weeks) at 25 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 C at 75% RH.
For example, 95% can dissolve in 8-14 min. Here too, in cases where the tablet
contains more
than 125mg or less than 100mg of abiraterone acetate, the dissolution rate
given is for a fraction
of a larger tablet (or multiple of a smaller tablet) providing 100-125mg of
abiraterone acetate.
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-Go) 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 (125mg unit dosage form or a 500mg dose of a unit dosage
form, e.g., 4 x
125mg) shows less variability in one or more of Cmax, AUC(0-t), and AUC(0-Do)
relative to,
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e.g., a 250mg dosage form of Zytiga0 (or a 1000 dose of a a 250mg dosage form
of Zytiga0) in
comparative pharmacokinetic testing.
In some cases, the hardness of abiraterone tablets is between 100N and 190N
(e.g., 110N to
180N).
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.
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
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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.
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.
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.
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
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
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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,
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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.
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.
In some embodiments, abiraterone acetate is milled in the presence of:
(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
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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.
(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,
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POE-18; triethanolamine isodecanol phosphate ester; triethanolamine
tristyrylphosphate ester; tristyrylphenol ethoxylate sulfate; bis(2-
hydroxyethyl)
tallowalkylamines.
(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.
(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
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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.
(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
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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.
(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.
(g) Xylitol or xylitol combined with at least one material selected from the
group
consisting of: lactose monohydrate; lactose anhydrous; mannitol;
microcrystalline
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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.
(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
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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.
(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
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sulfonate; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol
phosphate
ester; triethanolamine tristyrylphosphate ester; tristyrylphenol ethoxylate
sulfate;
bis(2-hydroxyethyl)tallowalkylamines.
(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.
(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
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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.
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.
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
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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.
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
188õ 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
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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.
In some embodiments the facilitating agent is selected from the list of:
polyvinylpyrrolidones
(PVP), polyvinylalcohol, acrylic acid based polymers and copolymers of acrylic
acid.
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.
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.
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.
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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 500mg of abiraterone acetate daily (e.g.,
in 1 or 2 or 4 equal
doses (e.g., one unit dose containing 500mg, two unit doses containing 250mg
of abiraterone
acetate each, or four unit doses containing 125mg 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).
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.
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.
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.
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.
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
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constitute prior art or are part of the common general knowledge of those
working in the field to
which this disclosure relates.
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.
"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.
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.
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.
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,
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individually or collectively and any and all combinations or any two or more
of the steps or
features.
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.
Other aspects and advantages of the disclosure will become apparent to those
skilled in the art
from a review of the ensuing description.
Drawings
Figure 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.
Figure 2 is a graph of the results of dissolution rate measurements for
abiraterone acetate tablets
as described in Example 3.
Figures 3A and 3B are graphs depicting the results of stability studies
described in Example 6.
Detailed Description of the Disclosure
Particle Size
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: [D5o] or D[501 or [D50],
D50, D(0.50) or D[0.5]
or similar. As used herein [D5o] or D[so] or [D50], D50, D(0.50) or D[0.5] or
similar shall be
taken to mean median particle size.
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 90th percentile, D95 refers to the 95th
percentile, and so
forth. Taking D90 as an example this can often be written as, [D9o] or D[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
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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).
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.
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.
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.
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
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active material together an understanding of the active material particle size
can be
obtained.
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
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, ZytigaCD 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
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.
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A morphicity Profile
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
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.
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.
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,
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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.
The grinding matrix may be an inorganic or organic substance.
Milling bodies
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.
As described above, the milling bodies are essentially resistant to fracture
and erosion in the
milling process.
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).
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.
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.
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/cm3, preferably from about 1 to 8 g/cm3. Ceramics can be
selected from
steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized
zirconium oxide,
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magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-
stabilized tungsten
carbide, and the like, as well as mixtures thereof.
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.
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. patents 5,478,705 and 5,500,331. Polymeric resins typically can have
densities ranging
from about 0.8 to 3.0 g/cm3. 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/cm3.
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.
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.
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Dry Milling
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.
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.
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.
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 pm, as determined by sieve
analysis. If the
particle size of the abiraterone acetate is greater than about 1000 p.m, then
it is preferred that the
particles of the abiraterone acetate substrate be reduced in size to less than
1000 p.m using
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another particle size reduction method prior to dry milling according to the
methods described
herein.
Agglomerates of abiraterone acetate after processing
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
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.
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.
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.
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.
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.
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
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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.
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.
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
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.
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Medicaments
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.
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.
Pharmaceutical acceptable carriers according to the disclosure may include one
or more of the
following examples:
(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
(2) binding agents such as various celluloses and cross-linked
polyvinylpyrrolidone,
microcrystalline cellulose; and or
(3) filling agents such as lactose monohydrate, lactose anhydrous,
microcrystalline
cellulose and various starches; and or
(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
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(5) sweeteners such as any natural or artificial sweetener including
sucrose, xylitol, sodium
saccharin, cyclamate, aspartame, and acesulfame K; and or
(6) flavoring agents; and or
(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
(8) buffers; and or
(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
(10) wetting agents such as corn starch, potato starch, maize starch, and
modified starches,
and mixtures thereof; and or
(11) disintegrants; such as croscarmellose sodium, crospovidone, sodium starch
glycolate,
and or
(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
(13) other pharmaceutically acceptable excipients.
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
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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 Tmax ,
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
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., Zytigag). In some cases an AUC and/or a Cmax similar to
Zytiga0 can be
achieved at lower dose than for Zytiga0. Thus, in some cases the
pharmaceutical compositions
described herein administered at a lower dose than Zytiga provide comparable
systemic
exposure. For example, a 500mg dose can be bioequivalent to a 1,000mg dose of
Zytiga0.
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
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 Zytiga0. 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 Zytiga0.
The Pharmacokinetic Profiles of the Compositions of the Disclosure May Exhibit
Reduced Inter-
patient Variability
In some cases, the geometric mean coefficient of variation in one or more of
Cmax, AUCO-t and
AUCO-00 may be less for an abiraterone acetate dosage form described herein
than for Zytiga0.
Thus, the geometric mean coefficient of variation in one or more of Cmax, AUCO-
t and AUCO-
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Do can be 10%-50% less (at least 10% less, 10%-30% less, or 10%-20% less) than
for Zytiga0.
(Calculated as CV (Zytiga0)-CV (present dosage form)/CV (Zytiga0) x 100%).
Pharmacokinetic Protocol
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
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.
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
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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.
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
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. 200g batches were milled with milling bodies
for 40 minutes.
Table 1: Drug Product Intermediate for Preparation of Tablets
Ingredient Name and Formula 1 Formula 2
Grade (1/0w/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
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
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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 Figure 1 show the particle size distributions; the data
shows over a 10-fold
reduction in particle size.
Table 2. Particle size Distribution of Unmilled and Milled Abiraterone Acetate
Formula 1 Formula 2
Unmilled
(20% AA) (30% AA)
Dio
3.41 0.087 0.095
(micron)
Dso
8.50 0.199 0.225
(micron)
D90
16.4 0.463 0.538
(micron)
1)4,3
9.32 0.254 0.280
(micron)
D3,2
6.46 0.164 0.183
(micron)
Example 3: Preparation of Tablets and Comparative Dissolution Studies
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 100mg
abiraterone acetate tablets
having the composition shown in Table 3.
Table 3. Abiraterone Acetate 100 mg Tablet Composition
Formula 1 Formula 2
Ingredient % w/w mg/tablet % w/w mg/tablet
Abiraterone Acetate DPI
58.82 500.0
Formula 1 (20% AA)
Abiraterone Acetate DPI
333.3
Formula 2 (30% AA) :]'! 47.62
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
The dissolution rates of the tablets prepared as described above were measured
using the method
listed on the FDA website for abiraterone acetate tablets, 250mg; USP
Apparatus II, 50 rpm in
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900mL of pH 4.5 buffer with 0.25% sodium lauryl sulfate. Samples were analyzed
by UV at
270nm. Additionally, for comparison purposes, Zytiga0 tablets were tested with
the same
dissolution conditions. The results of this analysis are shown in Table 4 and
Figure 2. Full
dissolution (>85% dissolved) was achieve in 10-20 minutes for the two tablet
formulations
contained milled abiraterone acetate, compared to Zytiga0 which had full
dissolution (>85%
dissolved) in 60 minutes.
Table 4. Dissolution of Abiraterone Acetate Tablets
Formula 1 (100mg Formula 2 (100 mg Zytiga0 (250mg
abiraterone acetate) abiraterone acetate) abiraterone acetate)
Avg % Std Avg % Std % Std
Time[min] dissolved Deviation dissolved Deviation dissolved Deviation
0 0 0 0 0 0 0
50.9 14.3 63.8 12.4 16.3 1.8
81.9 10.9 87.4 6.4 30.2 2.8
88.3 2.9 92.4 4.8 52.6 3.3
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
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 1S
attritor mill with a 1.5 gallon jacket-cooled tank. The material was milled
with milling bodies
for 40 minutes.
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
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
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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 135W, 42KHz) 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 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 6: Milled Abiraterone Acetate Particle Size
Particle Size Parameter Result (micron)
Di 0.105
Dso 0.387
D90 1.308
D4,3 0.588
D3,2 0.247
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 100mg
abiraterone acetate tablets
having the composition shown in Table 7.
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
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The dissolution rates of the tablets prepared as described above were measured
in USP
Apparatus II, 75 rpm in 900mL of pH 4.5 buffer with 0.1% SLS. Samples were
analyzed by
HPLC. Additionally, for comparison purposes, Zytiga tablets were tested with
the same
dissolution conditions. Because Zytiga tablets are 250mg which is approaching
the solubility
limit of the dissolution media, the tablets were cut to a weight equivalent to
100mg of
abiraterone acetate. Zytiga samples were measured using UV at 270nm. The
results of this
analysis are shown in Table 8; full dissolution (>85% dissolved) of the
prepared tablets was
achieved in 5 minutes, wheras the Zytiga tablets dissolution was achieved in
20 minutes.
Table 8: Dissolution of Abiraterone Acetate Tablets 100 mg
100mg Tablets for Phase 1 Zytiga
tablets (cut to
Clinical testing 100mg)
Average (1/0 Average ')/0
Time (minutes) dissolved 'YoRSD dissolved (YoRSD
88 7.2 32.7 27.1
99 1.8 59.0 21.3
99 1.1 78.2 9.6
91.6 6.7
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 1 Study of 100, 200, and 400 mg Doses of Abiraterone Acetate
Formulation Compared to Zytiga 1000 mg
The abiraterone acetate 100 mg tablet formulation prepared as described in
Example 4 was
tested in healthy male patients under fasting conditions at 100mg, 200mg, and
400mg doses (1,
2, or 4 x 100 mg tablets respectively). In the same study, a 1000mg dose of
Zytiga was tested
(4 x 250mg tablets). The results of this study are shown in Table 9.
Table 9: Abiraterone Acetate Tablets 100 mg Pharmacokinetic Data (Arithmetic
Means)
Milled Abiraterone Acetate w Zytiga R
i]]Pk Parameters Statistics
100 mg 200 mg 400 mg õõ 1,000 mg
19 18 19 19
AUCo-in( (ng-hr/mL) Mean* 74.49 183.34 319.92 421.23
S.D. 42.22 86.7 140.74 183.83
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CV (%) 56.68 47.29 43.99 43.64
N 19 18 19 19
Mean* 67.55 169.99 302.9 387.34
AUCot (ng=hr/mL)
S.D. 39.37 83.73 137.17 168.67
CV (`)/0) 58.28 49.25 45.29 43.55
N 19 18 19 19
Mean* 17.28 39.11 65.42 79.46
C. (ng/mL)
S.D. 10.41 21.69 35.58 39.56
CV (%) 60.29 55.46 54.39 49.78
N 19 18 19 19
Mean 1.55 1.78 2.32 2.16
imax (hour)
S.D. 0.57 0.77 1.33 0.78
CV (%) 37.02 43.38 57.22 36.27
N 19 18 19 19
Mean* 4.72 7.83 8.84 14.48
t,A r)
(h
S.D. 2.57 3.88 2.96 5.11
CV (%) 54.35 49.51 33.45 35.32
N 19 18 19 19
K (h r-1 Mean 0.18 0.11 0.09 0.05
e )
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.
A Observed differences were significant (p<0.05, Wilcoxon signed rank test),
compared to
Zytiga0 1,000 mg.
Example 6: Stability of Abiraterone Acetate Powder Blends and Tablets
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 C/60%RH and at 40 C/75%RH, but did not grow at 2-8 C. In
addition,
impurity growth in the tablets was faster than that in the milled DPI. Table
10 and Figures 3A
and 3B (diamonds, 5 C; squares, 25 C/60% RH; and triangles, 40 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 10. Abiraterone Acetate Stability (total impurities)
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Abiraterone Acetate DPI Abiraterone Acetate tablets, 100mg
(contains milled API) (contains milled API)
Time 25 C/60 % 40 C/75% 25 C/60% 40 C/75%
5oc 5oc
(months) RH RH 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
The impurity growth in the DPI and tablets containing fine particle
abiraterone acetate is due to
oxidative degradation of abiraterone acetate. Aged Zytigag (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.
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Table 11. Abiraterone Acetate Stability
Total impurities
Product Milling Stability by HPLC (%
AUC)
Abiraterone Acetate (API) none 80 C, 4 hrs 0.23
SPEX shaker mill 80 C, 4 hrs 0.17
Drug Product Intermediate none 80 C, 4 hrs 0.28
(API, SLS, lactose
monohydrate) SPEX shaker mill 80 C, 4 hrs 3.90
Tablet formulation (API, SLS,
lactose monohydrate, none 80 C, 4 hrs 0.76
microcrystalline cellulose,
croscarmellose sodium, sodium SPEX shaker mill 105 C, 4 hrs
10.00
stearyl fiimarate)
Stored room
Zytiga0 (abiraterone
None temperature until 0.20
acetate) tablet
expiry
Example 7: Milling of Abiraterone with Antioxidant or Sequestering Agent
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. 200g 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.
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Table 12: DPI Formulation Containing Antioxidant or Sequestering Agent
DPI Formulation DPI
Ascorbic/Fumari Formulation
c BHA/BHT
Ingredient Function A w/w % w/w
Abiraterone Acetate Active 30.00 30.00
Lactose Monohydrate Grinding compound 67.35 67.65
Sodium lauryl sulfate Facilitating agent 2.25 2.25
Ascorbic acid Antioxidant 0.20
ffiliMaiffiiMaiMM
Fumaric acid Sequestering agent 0.20 ¨
.,
õ ., ...õ..
Butylated Hydroxyanisole
emoimimimimimin3 0.05
Antioxidant
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
::i:::::::::
(BHA)
.::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
::::::::::::
Butylated Hydroxytoluene
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
::::::::::::
Antioxidant .. 0.05
(BHT)
TOTAL 100.00 100.00
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 13: Tablet Formulations Containing Antioxidant or Sequestering Agent
Tablet Tablet
Formulation Formulation
Ascorbic/Fumaric BHA/BHT
Function % w/w % w/w
DPI Formulation Ascorbic/Fumaric
(abiraterone acetate, lactose ,
,=
47.62 mi s m
monohydrate, SLS, ascorbic acid, :: ]i]] m
fumaric acid) .:. , =
=
DPI Formulation BHA/BHT
(abiraterone acetate, lactose
. 47.62
monohydrate, SLS, BHA, BHT)
Microcrystalline cellulose Diluent 44.53 44.53
Sodium lauryl sulfate Wetting agent 0.35 0.35
Croscarmellose sodium Disintegrant 7.0 7.0
Sodium stearyl fumarate Lubricant 0.5 0.5
Total 100 100
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 C/75%RH compared to the
formulation without
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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 14. Tablet Stability data with and without Antioxidant
Formulation Ascorbic Formulation
No antioxidant Acid 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,
25 C/60%RH 98.1 0.78 100.9 0.89 101.1 0.15
1 month,
40 C/75%RH 92.4 3.02 96.8 1.13 100.7 0.19
2 month,
25 C/60%RH 97.5 1.86 95.5 1.26 96.7 0.13
2 month,
40 C/75%RH 92.8 3.36 97.5 1.46 97.4 0.16
3 months,
25 C/60%RH 95.2 2.25 97.8 1.75 95.5 0.45
3 months,
40 C/75%RH 92.5 4.49 96.0 1.90 98.6 0.70
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
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.
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Table 15: Milled Drug Product Intermediate Containing BHA and BHT for Phase 1
clinical
studies
Quantity per batch
Component
Weight percent (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
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:
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.
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 um 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 P3OH
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 37kHz 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
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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.
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 16: Particle Size Distribution Data for Abiraterone Acetate DPI
Containing BHA and
BHT
Particle Size (}tm)
Parameter
Unmilled Milled Milled
Method 1 Method 1 Method 2
Dio 1.64 0.153 0.124
Dso 3.07 0.747 0.286
D90 5.79 3.250 0.937
D4,3 3.44 1.300 0.479
D3,2 2.75 0.390 0.241
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 125mg
abiraterone acetate tablets
having the composition shown in Table 17.
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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
The dissolution rate of these tablets was measured in at USP Apparatus II,
75rpm 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 18: Dissolution of Abiraterone Acetate Tablets
Time % abiraterone
(minutes) acetate dissolved "ZoRSD
53 6.6
86 3.4
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 1000 mg
The abiraterone acetate 125mg tablet formulation prepared as described in
Example 10 was
tested in healthy male patients under fasting conditions at 125mg, 500mg, and
625mg doses (1,
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4, or 5 x 125 mg tablets respectively). In the same study, a 1000mg dose of
Zytiga0 was tested
(4 x 250mg tablets). The results of this study are shown in Table 19.
Table 19: Abiraterone Acetate Tablets 125 mg Pharmacokinetic Data (Arithmetic
Means)
Milled Abiraterone Acetate Zytiga it
rK Parametert !: Statistics
:.m 0
125 mg: ,,,, 500 rrkg ::: 625 m,6,,. : : 1,000 mo
N 33 34 34 33
Mean* 112.12 438.02 473.31 453.18
AUCo-ini. (ng=hr/mL)
S.D. 65.94 249.43 247.19 219.07
CV (%) 58.81 56.94 52.23 48.34
N 33 34 34 34
Mean* 102.55 416.23 450.19 415.91
AUCot (ng-hr/mL)
S.D. 63.27 245.73 241.85 210.67
CV (%) 61.7 59.04 53.72 50.65
N 33 34 34 34
Mean* 28.22 84.16 100.76 83.4
C. (ng/mL)
S.D. 16.46 44.05 63.75 57.4
CV (%) 58.34 52.34 63.27 68.83
N 33 34 34 34
Mean 1.61 1.79 1.84 2.21
T. (hour)
S.D. 0.98 1.12 0.97 1.44
CV (%) 61.16 62.55 52.61 65.34
N 33 34 34 33
r) Mean* 7.2 14.2 14.54 20.64
tv2(h
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
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.
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Table 16: Additional Milled Drug Product Intermediate
Ingredient Weight percent Quantity per 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
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 17: Additional Particle Size Distribution Data for Abiraterone Acetate
DPI
Particle Size (ftm)
Parameter
Unmilled Batch 1, Milled Batch 2,
Milled
Di 1.69 1.17 1.36
Dso 3.55 2.13 2.46
D90 7.58 4.17 4.64
D4,3 5.94 5.45 4.46
D3,2 3.02 1.95 2.25
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
100mg abiraterone
acetate tablets having the composition shown in Table 18.
Table 18: Milled Abiraterone Acetate Tablets 100 mg Composition
Component A) 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
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The dissolution rate of these tablets was measured in at USP Apparatus II,
75rpm in pH 4.5
buffer with 0.1% SLS. Samples were analyzed by UV at 270nm. The results of
this analysis are
shown in Table 19; full dissolution (>85% dissolved) was achieved in 10
minutes.
Table 19: Dissolution of Abiraterone Acetate Tablets, 100mg
Time A abiraterone
(minutes) acetate dissolved ')/oRSD
60.2 7.1
94.3 4.0
97.6 3.4
30 98.8 2.1
45 98.2 2.3
60 98.3 2.3
Example 13: Stability of Tablets
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 20: Milled Drug Product Intermediate Containing BHA and BHT
IngredientQuantity per batch
Weight percent
(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
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.
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Table 21: Additional Particle Size Distribution Data for Abiraterone Acetate
DPI Containing
BHA and BHT
Particle Size (!lm)
Parameter
Unmilled Milled
Di 1.69 0.184
D50 3.55 1.20
D90 7.58 3.57
D4,3 5.94 1.56
D3,2 3.02 0.49
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 125mg
abiraterone acetate tablets
having the composition shown in Table 22.
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
Tablets were packaged and mounted on accelerated stability at 40 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, 75rpm 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 C/75%RH,
and the dissolution remained unchanged with full dissolution (>85% dissolved)
within 10
minutes over 3 months at 40 C/75%RH.
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Table 23. Stability of Abiraterone Acetate Tablets, 125mg
Abiraterone Acetate Tablets, 125mg
1 month 2 month 3 month
Initial
40 C/75%RH 40 C/75%RH 40 C/75%RH
Total Impurities
(%AUC) 0.05 <0.05 0.05 <0.05
Avg % Avg % Avg %
Time dissolv Avg % dissolve dissolved
(minutes ed %RS dissolve %R d (n=3) %RS (n=3)
) (n=6) D d (n=3) SD D %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
93.9 1.2 93.6 2.9 95.5 0.8 95.3 0.6
95.0 1.4 97.4 1.9 97.4 0.6 97.4 0.4
95.3 1.4 97.7 0.6 98.0 0.3 97.3 0.8
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
The effect of a high fat meal on the oral bioavailability of a 500mg dose of
125mg 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 (AUCo-., AUCo-t, and
Cmax) for each
subject and treatment. The geometric mean values for AUCo-o,, AUCo-t, and Cmax
when the test
article was administered in the fed state were 1444.1 ng-h/mL, 1393.4 ng-h/mL,
and 443.7
ng/mL respectively, while the geometric mean values for those same parameters
were 322.7
ng=h/mL, 301.0 ng=h/mL, and 67.9 ng/mL when the drug was administered in the
fasted state.
The ratios (fed/fasted) for AUCo-., AUCo-t, and C. were 4.48, 4.63, and 6.53,
respectively.
