U.S. patent application number 15/267352 was filed with the patent office on 2017-08-10 for formulations of enzalutamide.
The applicant listed for this patent is Astellas Pharma Inc., Bend Research, Inc., Medivation Prostate Therapeutics, Inc.. Invention is credited to Jason A. Everett, Ryousuke Irie, Atsushi Kanbayashi, Sanjay Konagurthu, Douglas Alan Lorenz, Sheila Matz, Koji Nishimura, Shinsuke Oba, Toshiro Sakai, Yuuki Takaishi, Hiroyasu Toyota, Randy J. Wald.
Application Number | 20170224624 15/267352 |
Document ID | / |
Family ID | 49231627 |
Filed Date | 2017-08-10 |
United States Patent
Application |
20170224624 |
Kind Code |
A1 |
Lorenz; Douglas Alan ; et
al. |
August 10, 2017 |
FORMULATIONS OF ENZALUTAMIDE
Abstract
This disclosure provides formulations of enzalutamide and their
use for treating hyperproliferative disorders.
Inventors: |
Lorenz; Douglas Alan; (Bend,
OR) ; Konagurthu; Sanjay; (Bend, OR) ; Wald;
Randy J.; (Bend, OR) ; Everett; Jason A.;
(Bend, OR) ; Matz; Sheila; (San Francisco, CA)
; Takaishi; Yuuki; (Tokyo, JP) ; Sakai;
Toshiro; (Tokyo, JP) ; Irie; Ryousuke; (Tokyo,
JP) ; Oba; Shinsuke; (Tokyo, JP) ; Toyota;
Hiroyasu; (Tokyo, JP) ; Nishimura; Koji;
(Tokyo, JP) ; Kanbayashi; Atsushi; (Tokyo,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bend Research, Inc.
Medivation Prostate Therapeutics, Inc.
Astellas Pharma Inc. |
Bend
San Francisco
Tokyo |
OR
CA |
US
US
JP |
|
|
Family ID: |
49231627 |
Appl. No.: |
15/267352 |
Filed: |
September 16, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14023878 |
Sep 11, 2013 |
|
|
|
15267352 |
|
|
|
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61699351 |
Sep 11, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 13/08 20180101;
A61K 31/4166 20130101; A61K 9/1652 20130101; A61K 9/16 20130101;
A61P 15/14 20180101; A61K 9/1635 20130101; A61P 15/08 20180101;
A61K 9/2054 20130101; C07D 233/86 20130101; A61P 15/00 20180101;
A61K 47/32 20130101; A61K 9/2095 20130101; A61K 9/10 20130101; A61P
43/00 20180101; A61K 47/38 20130101; A61K 31/4164 20130101; A61P
35/00 20180101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/10 20060101 A61K009/10; C07D 233/86 20060101
C07D233/86 |
Claims
1. Amorphous enzalutamide.
2. The amorphous enzalutamide of claim 1, which contains less than
20% crystalline enzalutamide.
3. The amorphous enzalutamide of claim 1, which contains less than
10% crystalline enzalutamide.
4. The amorphous enzalutamide of claim 1, characterized by a powder
x-ray diffraction pattern with two broad peaks centered at
16.5.+-.1 and 24.+-.1 degrees 2-.theta..
5. A pharmaceutical composition comprising amorphous
enzalutamide.
6. The pharmaceutical composition of claim 5, wherein at least
about 80 wt % of the total amount of enzalutamide present is in an
amorphous form.
7. The pharmaceutical composition of claim 5, further comprising a
concentration enhancing polymer.
8. The pharmaceutical composition of claim 7, that when
administered to an aqueous use environment, provides a maximum
dissolved concentration of enzalutamide in the use environment that
is at least 5-fold that provided by a control composition
consisting essentially of an equivalent quantity of the
enzalutamide in crystalline form alone.
9-12. (canceled)
13. The pharmaceutical composition of claim 7, wherein at least
about 80 wt % of the total amount of enzalutamide present is in an
amorphous form.
14. The pharmaceutical composition of claim 7, wherein the
concentration enhancing polymer is selected from the group
consisting of an ionizable cellulosic polymer, a nonionizable
cellulosic polymer, and a noncellulosic polymer.
15. The pharmaceutical composition of claim 14, wherein the
concentration enhancing polymer is the ionizable cellulosic polymer
and the ionizable cellulosic polymer is selected from the group
consisting of hydroxypropyl methyl cellulose acetate succinate,
carboxymethyl ethyl cellulose, cellulose acetate phthalate,
hydroxypropyl methyl cellulose phthalate, methyl cellulose acetate
phthalate, cellulose acetate trimellitate, hydroxypropyl cellulose
acetate phthalate, hydroxypropyl methyl cellulose acetate
phthalate, cellulose acetate terephthalate, and cellulose acetate
isophthalate.
16. The pharmaceutical composition of claim 14, wherein the
concentration enhancing polymer is the nonionizable cellulosic
polymer and the nonionizable cellulosic polymer is selected from
the group consisting of hydroxypropyl methyl cellulose acetate,
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl
cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose
acetate, and hydroxyethyl ethyl cellulose.
17. The pharmaceutical composition of claim 14, wherein the
concentration enhancing polymer is the noncellulosic polymer and
the noncellulosic polymer is selected from the group consisting of
carboxylic acid functionalized polymethacrylates; carboxylic acid
functionalized polyacrylates; amine-functionalized polyacrylates;
amine-functionalized polymethacrylates; proteins; carboxylic acid
functionalized starches; vinyl polymers and copolymers having at
least one substituent selected from the group consisting of
hydroxyl, alkylacyloxy, and cyclicamido; vinyl copolymers of at
least one hydrophilic, hydroxyl-containing repeat unit and at least
one hydrophobic, alkyl- or aryl-containing repeat unit; polyvinyl
alcohols that have at least a portion of their repeat units in the
unhydrolyzed form; polyvinyl alcohol polyvinyl acetate copolymers;
polyethylene glycol polypropylene glycol copolymers; polyvinyl
pyrrolidone; polyvinyl pyrrolidone polyvinyl acetate copolymers,
also called PVP-VA; polyethylene polyvinyl alcohol copolymers;
polyoxyethylene-polyoxypropylene block copolymers; and graft
copolymers of polyethyleneglycol, polyvinylcaprolactam and
polyvinylacetate.
18. (canceled)
19. The pharmaceutical composition of claim 7, wherein the
composition is in the form of a solid amorphous dispersion of
enzalutamide and a concentration-enhancing polymer.
20-25. (canceled)
26. The pharmaceutical composition of claim 19, wherein at least
about 80 wt % of the total amount of enzalutamide present is in an
amorphous form.
27. The pharmaceutical composition of claim 19, wherein the
concentration-enhancing polymer is selected from the group
consisting of hydroxypropylmethylcellulose acetate succinate
(HPMCAS); hydroxypropylmethylcellulose (HPMC);
hydroxypropylmethylcellulosephthalate (HPMCP);
polyvinylpyrrolidonevinylacetate (PVP-VA); copolymers of
methacrylic acid and methylmethacrylate in approximately a 1:1
ratio; and graft copolymers of polyethyleneglycol,
polyvinylcaprolactam, and polyvinylacetate.
28. The pharmaceutical composition of claim 19, comprising 60 wt %
enzalutamide and hydroxypropylmethylcellulose acetate
succinate.
29. A tablet comprising 45-70 wt % of a solid amorphous dispersion
of claim 19, the dispersion comprising 55-65 wt % enzalutamide and
hydroxypropylmethylcellulose acetate succinate.
30-82. (canceled)
83. A pharmaceutical composition comprising a solid dispersion
containing enzalutamide and a polymer.
84. The pharmaceutical composition according to claim 83, wherein
enzalutamide is an amorphous state.
85. The pharmaceutical composition according to claim 83, wherein
the polymer is a polymer or two or more polymers selected from the
group consisting of polyvinyl pyrrolidone, polyethyleneoxide,
poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates,
polyoxyethylene alkyl ethers, polyoxyethylene castor oils,
polycaprolactam, polylactic acid, polyglycolic acid,
poly(lactic-glycolic)acid, lipids, cellulose, pullulan, dextran,
maltodextrin, hyaluronic acid, polysialic acid, chondroitin
sulfate, heparin, fucoidan, pentosan polysulfate, spirulan,
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, 10
carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate
succinate, cellulose acetate phthalate, cellulose acetate
trimellitate, ethyl cellulose, cellulose acetate, cellulose
butyrate, cellulose acetate butyrate, and dextran polymer
derivative.
86. The pharmaceutical composition according to claim 85, wherein
the polymer is hydroxypropyl methylcellulose acetate succinate.
87. The pharmaceutical composition according to claim 83, wherein
the amount of the polymer is 0.5 to 3 parts by weight, with respect
to 1 part by weight of the enzalutamide.
88. The pharmaceutical composition according to claim 83, wherein
the amount of the polymer is 3 parts by weight, with respect to 1
part by weight of the enzalutamide.
89. The pharmaceutical composition according to claim 83, which the
solubility of enzalutamide is twice or more compared to that of
enzalutamide.
90. The pharmaceutical composition according to claim 83, prepared
by a process comprising: dissolving and/or suspending the compound
of enzalutamide and the polymer in a pharmaceutically acceptable
solvent, and removing the solvent by spray drying to prepare the
solid dispersion.
91. A process of manufacturing the pharmaceutical composition of
claim 83, comprising: (1) preparing the solid dispersion of
enzalutamide and the polymer (2) mixing and/or granulating the
solid dispersion, and (3) tableting the solid dispersion.
92. A process of manufacturing a pharmaceutical composition
according to claim 91, comprising: (1) preparing a solid dispersion
of enzalutamide and a polymer, (2) mixing the solid dispersion with
one additive or two or more additives and granulating the mixture,
and (3) tableting the granules.
93. The pharmaceutical composition of claim 5, which is a tablet.
Description
[0001] This application is a continuation of Ser. No. 14/023,878
filed on Sep. 11, 2013, which claims priority to and incorporates
by reference Ser. No. 61/699,351 filed on Sep. 11, 2012.
[0002] All documents cited in this disclosure are incorporated
herein by reference in their entireties.
TECHNICAL FIELD
[0003] This disclosure relates to solid formulations of
enzalutamide.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIG. 1. PXRD Diffractograms of amorphous enzalutamide, three
spray-dried dispersions of enzalutamide with
concentration-enhancing polymers, and crystalline enzalutamide. See
Example 3.
[0005] FIGS. 2A-H. Scanning Electron Micrograph (SEM) images of
amorphous enzalutamide (100% A Spray-dried) and spray-dried
dispersions (SDDs) comprising enzalutamide and HPMCAS or PVPVA.
FIG. 2A, 60% A:HPMCAS-MG Dispersion D6 before exposure to a
50.degree. C./75% RH environment. FIG. 2B, 60% A:HPMCAS-MG
Dispersion D6 after 1 day exposure to a 50.degree. C./75% RH
environment. FIG. 2C, 80% A:HPMCAS-MG Dispersion D7 before exposure
to a 50.degree. C./75% RH environment. FIG. 2D, 80% A:HPMCAS-MG
Dispersion D7 after 1 day exposure to a 50.degree. C./75% RH
environment. FIG. 2E, 40% A:PVPVA Dispersion D10 before exposure to
a 50.degree. C./75% RH environment. FIG. 2F, 40% A:PVPVA Dispersion
D10 after 1 day exposure to a 50.degree. C./75% RH environment.
FIG. 2G, 100% spray dried amorphous MDV3100 before exposure to a
50.degree. C./75% RH environment. FIG. 2H, 100% spray dried
amorphous MDV3100 after 1 day exposure to a 50.degree. C./75% RH
environment. See Example 6.
[0006] FIG. 3 is a dissolution profile of the solid dispersions
obtained by Example 17 (1:3), 18 (1:2), 19 (1:1.5), 20 (1:1), and
21 (1:0.67) in Example 23.
[0007] FIG. 4 is a dissolution profile of the tablets obtained by
Example 16 (1:3), 18 (1:2), and 21 (1:0.67) in Example 23.
[0008] FIG. 5 is a dissolution profile of the initial tablet
obtained by Example 17 and the tablet stored at 40.degree. C. and
75% relative humidity for 1 month in Example 24.
[0009] FIG. 6 is an X-ray diffraction spectrum of the solid
dispersions prepared in Example 16 (1:3), 18 (1:2), and crystalline
drug substance obtained by measuring it immediately after its
preparation.
[0010] FIG. 7A and FIG. 7B are X-ray diffraction spectra of the
solid dispersion which was prepared in Example 17 and stored at
40.degree. C. and 75% relative humidity for 1 month in Example
26.
DETAILED DESCRIPTION
[0011] Enzalutamide is an androgen receptor signaling inhibitor.
The chemical name is
4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylide-
neimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. The structural
formula is:
##STR00001##
[0012] Enzalutamide is used as an agent for treating
castration-resistant prostate cancer who have received docetaxel
therapy; enzalutamide also is disclosed for treating breast cancer,
prostate cancer, benign prostate hyperplasia and ovarian cancer;
See, e.g., U.S. Pat. No. 7,709,517.
[0013] The present disclosure provides a solid dispersion having
the properties such as improvement solubility and absorption of
enzalutamide, and a pharmaceutical composition containing the solid
dispersion which has dissolution stability.
[0014] Further, the present disclosure provides a method for making
pharmaceutical composition which has dissolution stability of
enzalutamide.
[0015] According to the present disclosure, (1) a pharmaceutical
composition which improves solubility and absorption of
enzalutamide, (2) a pharmaceutical composition which has rapid
disintegrating property and dispersibility of enzalutamide when
said pharmaceutical composition (tablet and the like)is used, and
(3) a process of manufacturing the pharmaceutical composition which
has said effect, can be provided.
[0016] These dosage forms provide unusually large enhancements in
aqueous concentration in an environment of use. These compositions
also provide the opportunity to dose the entire daily therapeutic
dose of enzalutamide in a single dosage unit, by improving the oral
bioavailability of the drug.
Amorphous Enzalutamide
[0017] In some embodiments, enzalutamide is amorphous (i.e., in a
non-crystalline state). Amorphous enzalutamide dissolves more
quickly and to a greater extent than crystalline enzalutamide in an
aqueous use environment, such as an aqueous dissolution medium of
an in vitro dissolution test (e.g., phosphate buffered saline or
model fasted duodenal fluid or simulated gastric fluid) or the in
vivo environment of the stomach or small intestine. This enhanced
dissolution results in higher enzalutamide oral bioavailability,
compared to crystalline drug. An example of a crystalline form of
enzalutamide is Form A, characterized by the powder x-ray
diffraction pattern designated `Bulk Crystalline Drug` in FIG.
1.
[0018] In some embodiments, enzalutamide is greater than 80%
amorphous (i.e., containing less than 20% crystalline
enzalutamide). In some embodiments, enzalutamide is greater than
90% amorphous (i.e., containing less than 10% crystalline
enzalutamide). In some embodiments, enzalutamide is greater than
95% amorphous (i.e., containing less than 5% crystalline
enzalutamide). In some embodiments, enzalutamide exhibits no
crystalline character when measured by powder x-ray diffraction, by
low angle x-ray scattering, by .sup.13C-NMR, or by
.sup.19F-NMR.
[0019] Amorphous enzalutamide may be prepared by any known means,
including spray-drying, hot melt extrusion, and precipitation from
solution on addition of a non-solvent.
Pharmaceutical Compositions
[0020] The exact amount (effective dose) of enzalutamide will vary
from subject to subject, depending on, for example, the species,
age, weight and general or clinical condition of the subject, the
severity or mechanism of any disorder being treated, the particular
agent or vehicle used, the method and scheduling of administration,
and the like.
[0021] The particular mode of administration and the dosage regimen
will be selected by the attending clinician, taking into account
the particulars of the case (e.g., the subject, the disease, the
disease state involved, and whether the treatment is prophylactic).
Treatment may involve daily or multi-daily doses of compound(s)
over a period of a few days to months, or even years.
[0022] In general, however, a suitable dose will be in the range of
from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about
100 mg/kg of body weight per day, such as above about 0.1 mg per
kilogram, or in a range of from about 1 to about 10 mg per kilogram
body weight of the recipient per day. For example, a suitable dose
may be about 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per
day.
[0023] Enzalutamide conveniently administered in unit dosage form;
for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to
1000 mg, 10 to 200 mg, or 40 to 160 mg of enzalutamide per unit
dosage form.
[0024] Enzalutamide may conveniently be presented in a single dose
or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator.
[0025] In some embodiments, compositions comprise amorphous
enzalutamide and a concentration-enhancing polymer. In some
embodiments, compositions comprise amorphous enzalutamide and more
than one concentration-enhancing polymer.
[0026] Amorphous enzalutamide and a concentration-enhancing polymer
may be physically mixed, that is the two materials, as separate
powders, may be blended by methods known in the pharmaceutical
arts, including dry-blending, dry-granulation, and wet
granulation.
[0027] In some embodiments, compositions comprise solid amorphous
dispersions of enzalutamide and a concentration-enhancing polymer.
In some embodiments, at least a major portion of the enzalutamide
in the composition is amorphous. As used herein, the term "a major
portion" of the enzalutamide means that at least 60% of the
enzalutamide in the composition is in the amorphous form, rather
than the crystalline form. In some embodiments, the enzalutamide in
the dispersion is substantially amorphous. As used herein,
"substantially amorphous" means that the amount of the enzalutamide
in crystalline form does not exceed about 20%. In some embodiments,
the enzalutamide in the dispersion is "almost completely amorphous,
meaning that the amount of enzalutamide in the crystalline form
does not exceed about 10%. Amounts of crystalline enzalutamide may
be measured by powder X-ray diffraction, low angle x-ray
scattering, differential scanning calorimetry (DSC), solid state
19F-NMR, solid state 13C-NMR, or any other standard quantitative
measurement.
[0028] Compositions may contain from about 1 to about 80 wt %
enzalutamide, depending on the dose of the drug and the
effectiveness of the concentration-enhancing polymer. Enhancement
of aqueous enzalutamide concentrations and relative bioavailability
are typically best at low enzalutamide levels in the dispersion,
typically less than about 75 wt %. In some embodiments, dispersions
comprise greater than 20wt % and less than 75wt % enzalutamide. In
some embodiments, dispersions comprise greater than 25wt % and less
than 75wt % enzalutamide. In some embodiments, dispersions comprise
greater than 50wt % and less than 70wt % enzalutamide.
[0029] Amorphous enzalutamide can exist within the solid amorphous
dispersion as a pure phase, as a solid solution of enzalutamide
homogeneously distributed throughout the polymer, or any
combination of these states or states that lie intermediate between
them.
[0030] In some embodiments, the dispersion is substantially
homogeneous so that the amorphous enzalutamide is dispersed as
homogeneously as possible throughout the polymer. "Substantially
homogeneous" means that the fraction of enzalutamide that is
present in relatively pure amorphous domains within the solid
dispersion is relatively small, on the order of less than 20%, and
in some embodiments, less than 10% of the total amount of
enzalutamide.
[0031] In some embodiments, the solid amorphous dispersion may have
some enzalutamide-rich domains. In some embodiments, the dispersion
itself has a single glass transition temperature (Tg) which
demonstrates that the dispersion is substantially homogeneous. This
contrasts with a simple physical mixture of pure amorphous
enzalutamide particles and pure amorphous polymer particles which
generally displays two distinct Tgs, one that of the enzalutamide
and one that of the polymer. Tg as used herein is the
characteristic temperature where a glassy material, upon gradual
heating, undergoes a relatively rapid (e.g., 10 to 100 seconds)
physical change from a glass state to a rubber state. The Tg of an
amorphous material such as a polymer, drug or dispersion can be
measured by several techniques, including by a dynamic mechanical
analyzer (DMA), a dilatometer, dielectric analyzer, and by a
differential scanning calorimeter (DSC). The exact values measured
by each technique can vary somewhat but usually fall within
10.degree. to 30.degree. C. of each other. Regardless of the
technique used, when an amorphous dispersion exhibits a single Tg,
this indicates that the dispersion is substantially homogenous.
[0032] Dispersions that are substantially homogeneous generally are
more physically stable and have improved concentration-enhancing
properties and, in turn, improved bioavailability, relative to
nonhomogeneous dispersions.
[0033] Compositions comprising the enzalutamide and a
concentration-enhancing polymer provide enhanced concentration of
the dissolved enzalutamide in in vitro dissolution tests. It has
been determined that enhanced drug concentration in in vitro
dissolution tests in Model Fasted Duodenal (MFD) solution (MFDS) or
Phosphate Buffered Saline (PBS) is a good indicator of in vivo
performance and bioavailability. An appropriate PBS solution is an
aqueous solution comprising 20 mM sodium phosphate (Na2HPO4), 47 mM
potassium phosphate (KH2PO4), 87 mM NaCl, and 0.2 mM KCl, adjusted
to pH 6.5 with NaOH. An appropriate MFD solution is the same PBS
solution wherein additionally is present 7.3 mM sodium taurocholic
acid and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. A
composition can be dissolution-tested by adding it to MFD or PBS
solution and agitating to promote dissolution. Generally, the
amount of composition added to the solution in such a test is an
amount that, if all the drug in the composition dissolved, would
produce an enzalutamide concentration that is at least about 2-fold
and, in some embodiments, at least 5-fold the equilibrium
solubility of the crystalline enzalutamide alone in the test
solution.
[0034] In some embodiments, compositions provide a Maximum Drug
Concentration (MDC) that is at least about 2-fold the maximum
concentration of a control composition comprising an equivalent
quantity of crystalline enzalutamide but free from the
concentration-enhancing polymer, during the first 90 minutes after
dosing the dispersion into the in vitro medium. In other words, if
the maximum concentration provided by the control composition is 10
.mu.g/mL, then a composition provides an MDC of at least about 20
.mu.g/mL. The comparison composition is conventionally crystalline
enzalutamide. In some embodiments, the MDC of enzalutamide achieved
with the compositions is at least about 5-fold the maximum
concentration of the control composition. In some embodiments, the
MDC of enzalutamide achieved with the compositions is at least
about 10-fold the maximum concentration of the control
composition.
[0035] In some embodiments, compositions, when tested in the in
vitro test described above, exhibit a enzalutamide concentration
one hour after reaching C.sub.max which is at least 80% of the
C.sub.max concentration, where Cmax is the maximum enzalutamide
concentration achieved in the in vitro test.
[0036] In some embodiments, compositions provide in an aqueous use
environment a enzalutamide concentration versus time Area Under The
Curve (AUC.sub.90), for any period of at least 90 minutes between
the time of introduction into the use environment and about 270
minutes following introduction to the use environment, that is at
least 2-fold the AUC.sub.90 of a control composition comprising an
equivalent quantity of undispersed crystalline enzalutamide. In
some embodiments, the compositions provide in an aqueous use
environment a concentration versus time AUC.sub.90, for any period
of at least 90 minutes between the time of introduction into the
use environment and about 270 minutes following introduction to the
use environment, that is at least about 5-fold, in some embodiments
at least about 10-fold, that of a control composition as described
above. Such large enhancements in aqueous concentration versus time
AUC.sub.90 values are surprising given the extremely low aqueous
solubility and hydrophobicity of enzalutamide.
[0037] In some embodiments, compositions meet both the C.sub.max
and AUC.sub.90 criteria when tested in vitro. The in vitro test to
evaluate enhanced drug concentration in aqueous solution can be
conducted by (1) adding with agitation a sufficient quantity of
control composition, that is, the crystalline enzalutamide alone,
to the in vitro test medium, typically MFD or PBS solution, to
determine the maximum concentration of the enzalutamide achieved
under the conditions of the test; (2) adding with agitation a
sufficient quantity of test composition (e.g., the enzalutamide and
polymer) in an equivalent test medium, such that if all the
enzalutamide dissolved, the theoretical concentration of
enzalutamide would exceed the observed maximum concentration of
enzalutamide by a factor of about 20; and (3) comparing the
measured MDC and/or aqueous concentration versus time AUC.sub.90 of
the test composition in the test medium with the maximum
concentration, and/or the aqueous concentration versus time
AUC.sub.90 of the control composition. In conducting such a
dissolution test, the amount of test composition or control
composition used is an amount such that if all of the enzalutamide
dissolved, the test enzalutamide concentration would be at least
about 20-fold that of the control enzalutamide concentration.
[0038] The concentration of dissolved enzalutamide is typically
measured as a function of time by sampling the test medium and
plotting enzalutamide concentration in the test medium vs. time so
that the MDC can be ascertained. The MDC is taken to be the maximum
value of dissolved enzalutamide measured over the duration of the
test. The aqueous concentration of the enzalutamide versus time
AUC.sub.90 is calculated by integrating the concentration versus
time curve over any 90-minute time period between the time of
introduction of the composition into the aqueous use environment
(time equals zero) and 270 minutes following introduction to the
use environment (time equals 270 minutes). Typically, when the
composition reaches its MDC rapidly, in less than about 30 minutes,
the time interval used to calculate AUC.sub.90 is from time equals
zero to time equals 90 minutes. However, if the AUC.sub.90 over any
90-minute time period described above of a composition meets this
criterion, it is encompassed within the compositions described in
this disclosure. The time period 270 min is chosen because of its
physiological relevance. Drug absorption in mammals generally
occurs in the small intestine, and the small intestinal transit
time in humans is approximately 4.5 hr, or 270 min. In the in vivo
situation, for example after oral dosing to a human, it is
important that undissolved enzalutamide/polymer dispersion be
capable of dissolving and resupplying the gastrointestinal fluid
with dissolved drug as drug is removed from the system by
absorption through the gastrointestinal wall into the bloodstream.
The capacity of a dispersion to carry on this resupply function may
be tested in vitro in a so-called "membrane test." In some
embodiments, enzalutamide/polymer dispersions have high capacity to
support transmembrane flux in the in vitro membrane test.
[0039] In some embodiments, when dosed orally to a human or other
mammal, compositions provide an area under the plasma enzalutamide
concentration versus time curve (AUC) that is at least about
1.25-fold that observed when a control composition comprising an
equivalent quantity of crystalline drug is dosed. It is noted that
such compositions can also be said to have a relative
bioavailability of at least about 1.25. In some embodiments,
compositions dosed orally to a human or other animal provide a
plasma enzalutamide AUC that is at least about 2-fold that observed
when a control composition comprising an equivalent quantity of
crystalline drug is dosed. In some embodiments, the in vivo AUC is
AUC.sub.0-7 days, as described below. Thus, the compositions can be
evaluated in either in vitro or in vivo tests, or both.
[0040] Relative bioavailability of enzalutamide in the dispersions
can be tested in vivo in animals or humans using conventional
methods for making such a determination. An in vivo test, such as a
crossover pharmacokinetic study, may be used to determine whether a
composition of enzalutamide and concentration-enhancing polymer (or
a composition comprised of amorphous enzalutamide without a
concentration-enhancing polymer) provides an enhanced relative
bioavailability compared with a control composition comprised of
crystalline enzalutamide but no polymer as described above. In an
in vivo crossover study a "test composition" of enzalutamide and
polymer is dosed to half a group of test subjects and, after an
appropriate washout period (at least 42 days) the same subjects are
dosed with a "control composition" that comprises an equivalent
quantity of crystalline enzalutamide with no
concentration-enhancing polymer present. The other half of the
group is dosed with the control composition first, followed by the
test composition. The relative bioavailability is measured as the
area under the plasma drug concentration versus time curve (AUC)
determined for the test group divided by the plasma AUC provided by
the control composition. In some embodiments, this test/control
ratio is determined for each subject, and then the ratios are
averaged over all subjects in the study. In vivo determinations of
AUC can be made by plotting the plasma concentration of drug along
the ordinate (y-axis) against time along the abscissa (x-axis), and
using the trapezoidal rule method.
[0041] Thus, as noted above, one embodiment is one in which the
relative bioavailability of the test composition is at least about
1.25 relative to a control composition comprised of crystalline
enzalutamide but with no concentration-enhancing polymer as
described above. (That is, the in vivo AUC provided by the test
composition is at least about 1.25-fold the in vivo AUC provided by
the control composition.) In some embodiments, the relative
bioavailability of the test composition is at least about 2,
relative to a control composition composed of crystalline
enzalutamide but with no concentration-enhancing polymer present,
as described above. The determination of AUCs is a well-known
procedure and is described, for example, in Welling,
"Pharmacokinetics Processes and Mathematics," ACS Monograph 185
(1986).
[0042] To carry out the in vivo AUC measurements for enzalutamide,
the enzalutamide test and control compositions should be dosed at a
160 mg dose to a cohort of at least 24 subjects in the fasted
state. Blood samples should be collected at 0 time (pre-dose), and
at post-dose times 15, 30, and 45 minutes; and at 1, 2, 3, 4, 6, 8,
and 12 hours; and at 0 and 12 hours on day 2; and at 0 hours on
days 3, 5, and 7 (where 0 hours on days 2, 3, 5, and 7 correspond
to the time of day when dosing occurred on day 1).
[0043] Relative bioavailability is measured using AUC.sub.0-7 days.
The absolute value of the AUC.sub.0-7 days is also used to
determine if a dispersion formulation falls within compositions of
this disclosure; i.e., pharmaceutical compositions comprising a
solid amorphous dispersion of enzalutamide and a
concentration-enhancing polymer, which when dosed to a cohort of 24
or more humans at a dose of 160 mg provides a mean area under the
plasma enzalutamide concentration vs. time curve from the time of
dosing to 7 days after dosing, AUC.sub.0-7 days, which is greater
than 150 .mu.ghr/ml. This constraint applies to other doses as
well, providing a plasma AUC.sub.0-7 days which is greater than
(150 .mu.ghr/ml)/(160 mg) or more generally greater than 0.94
.mu.ghr/mlmg, where mg refers to the weight of the enzalutamide
dose.
[0044] Inspection of the plasma enzalutamide concentration versus
time curves for the dosed subjects will give the maximum
enzalutamide concentration C.sub.max achieved during the post-dose
period. A mean C.sub.max can be calculated for the cohort of
subjects. This disclosure provides a pharmaceutical composition
comprising a solid amorphous dispersion of enzalutamide and a
concentration-enhancing polymer, said dispersion when dosed to a
cohort of 24 or more humans at a dose of 160 mg providing a mean
maximum plasma enzalutamide concentration C.sub.max which is
greater than 2 .mu.g/ml. In some embodiments, greater than 2.5
.mu.g/ml. This constraint applies to other doses as well, providing
a C.sub.max greater than (2 .mu.g/ml)/(160 mg), where mg refers to
the weight of the enzalutamide dose. In some embodiments, C.sub.max
is greater than (2.5 .mu.g/ml)/(160 mg); this constraint can be
expressed as providing a C.sub.max greater than 12.5 ng/mlmg. In
some embodiments, C.sub.max is greater than 15.6 ng/mlmg.
Concentration-Enhancing Polymers
[0045] Concentration-enhancing polymers suitable for use in the
compositions are be inert, in the sense that they do not chemically
react with enzalutamide, are pharmaceutically acceptable (i.e. are
non-toxic), and have at least some solubility in aqueous solution
at physiologically relevant pHs (e.g. 1-8). The
concentration-enhancing polymer can be neutral or ionizable, and
should have an aqueous-solubility of at least 0.1 mg/mL over at
least a portion of the pH range of 1-8.
[0046] A polymer is a "concentration-enhancing polymer" if it meets
at least one, or, in some embodiments, both, of the following
conditions. The first condition is that the concentration-enhancing
polymer increases the in vitro MDC of enzalutamide in the
environment of use relative to a control composition consisting of
an equivalent amount of crystalline enzalutamide but no polymer.
That is, once the composition is introduced into an environment of
use, the polymer increases the aqueous concentration of
enzalutamide relative to the control composition. In some
embodiments, the polymer increases the MDC of enzalutamide in
aqueous solution by at least 2-fold relative to a control
composition; in some embodiments, by at least 5-fold; in some
embodiments, by at least 10-fold. The second condition is that the
concentration-enhancing polymer increases the AUC.sub.90 of the
enzalutamide in the in vitro environment of use relative to a
control composition consisting of enzalutamide but no polymer as
described above. That is, in the environment of use, the
composition comprising the enzalutamide and the
concentration-enhancing polymer provides an area under the
concentration versus time curve (AUC.sub.90) for any period of 90
minutes between the time of introduction into the use environment
and about 270 minutes following introduction to the use environment
that is at least 2-fold that of a control composition comprising an
equivalent quantity of enzalutamide but no polymer. In some
embodiments, the AUC provided by the composition is at least
5-fold; in some embodiments, at least 10-fold that of the control
composition.
[0047] Concentration-enhancing polymers may be cellulosic or
non-cellulosic. The polymers may be neutral or ionizable in aqueous
solution. In some embodiments, polymers are ionizable and
cellulosic. In some embodiments, polymers are ionizable cellulosic
polymers.
[0048] In some embodiments, polymers are "amphiphilic" in nature,
meaning that the polymer has hydrophobic and hydrophilic portions.
The hydrophobic portion may comprise groups such as aliphatic or
aromatic hydrocarbon groups. The hydrophilic portion may comprise
either ionizable or non-ionizable groups that are capable of
hydrogen bonding such as hydroxyls, carboxylic acids, esters,
amines or amides. The relative contents of hydrophobic, ionizable
hydrophilic, and non-ionizable hydrophilic groups in the polymer
can be optimized to provide improved functionality as a
concentration-enhancing polymer.
[0049] Amphiphilic polymers may have relatively strong interactions
with enzalutamide and may promote the formation of various types of
polymer/drug assemblies in the use environment. In addition, the
repulsion of the like charges of ionized groups of such polymers
may serve to limit the size of the polymer/drug assemblies to the
nanometer or submicron scale. For example, while not wishing to be
bound by a particular theory, such polymer/drug assemblies may
comprise hydrophobic enzalutamide clusters surrounded by the
polymer with the polymer's hydrophobic regions turned inward
towards the enzalutamide and the hydrophilic regions of the polymer
turned outward toward the aqueous environment. Alternatively, the
polar functional groups of the polymer may associate, for example,
via hydrogen bonds, with polar groups of the enzalutamide. In the
case of ionizable polymers, the hydrophilic regions of the polymer
would include the ionized functional groups. Such polymer/drug
assemblies in solution may well resemble charged polymeric
micellar-like structures. In any case, regardless of the mechanism
of action, the inventors have observed that such amphiphilic
polymers, particularly ionizable cellulosic polymers, have been
shown to improve the MDC and/or AUC.sub.90 of enzalutamide in
aqueous solution in vitro relative to crystalline control
compositions free from such polymers.
[0050] Surprisingly, such amphiphilic polymers can greatly enhance
the maximum concentration of enzalutamide obtained when
enzalutamide is dosed to a use environment. In addition, such
amphiphilic polymers interact with enzalutamide to prevent the
precipitation or crystallization of the enzalutamide from solution
despite its concentration being substantially above its equilibrium
concentration. In some embodiments, when the compositions are solid
amorphous dispersions of enzalutamide and the
concentration-enhancing polymer, the compositions provide a greatly
enhanced drug concentration, particularly when the dispersions are
substantially homogeneous. The maximum drug concentration may be
5-fold and often more than 10-fold the equilibrium concentration of
the crystalline enzalutamide. Such enhanced enzalutamide
concentrations in turn lead to substantially enhanced relative
bioavailability for enzalutamide.
[0051] One class of polymers comprises neutral non-cellulosic
polymers, including, but not limited to, vinyl polymers and
copolymers having substituents of hydroxyl, alkylacyloxy, and
cyclicamido polyvinyl alcohols that have at least a portion of
their repeat units in the unhydrolyzed (vinyl acetate) form;
polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl
pyrrolidone; polyvinylpyrrolidone vinyl acetate; and polyethylene
polyvinyl alcohol copolymers.
[0052] Another class of polymers comprises ionizable non-cellulosic
polymers, including, but not limited to, carboxylic
acid-functionalized vinyl polymers, such as the carboxylic acid
functionalized polymethacrylates and carboxylic acid functionalized
polyacrylates such as the EUDRAGITS.RTM. manufactured by Rohm Tech
Inc., of Malden, Mass.; amine-functionalized polyacrylates and
polymethacrylates; proteins; and carboxylic acid functionalized
starches such as starch glycolate.
[0053] Non-cellulosic polymers that are amphiphilic are copolymers
of a relatively hydrophilic and a relatively hydrophobic monomer.
Examples include acrylate and methacrylate copolymers. Commercial
grades of such copolymers include the EUDRAGITS.RTM., which are
copolymers of methacrylates and acrylates; and graft copolymers of
polyethyleneglycol, polyvinylcaprolactam, and polyvinylacetate, one
commercially available version of a graft copolymer known as
SOLUPLUS.RTM..
[0054] Other polymers comprise ionizable and neutral cellulosic
polymers with at least one ester- and/or ether-linked substituent,
in which the polymer has a degree of substitution of at least 0.1
for each substituent. In the polymer nomenclature used herein,
ether-linked substituents are recited prior to "cellulose" as the
moiety attached to the ether group; for example, "ethylbenzoic acid
cellulose" has ethoxybenzoic acid substituents. Analogously,
ester-linked substituents are recited after "cellulose" as the
carboxylate; for example, "cellulose phthalate" has one carboxylic
acid of each phthalate moiety ester-linked to the polymer and the
other carboxylic acid unreacted.
[0055] As used herein, a polymer name such as "cellulose acetate
phthalate" (CAP) refers to any of the family of cellulosic polymers
that have acetate and phthalate groups attached via ester linkages
to a significant fraction of the cellulosic polymer's hydroxyl
groups. Generally, the degree of substitution of each substituent
group can range from 0.1 to 2.9 as long as the other criteria of
the polymer are met. "Degree of substitution" refers to the average
number of the three hydroxyls per saccharide repeat unit on the
cellulose chain that have been substituted. For example, if all of
the hydroxyls on the cellulose chain have been phthalate
substituted, the phthalate degree of substitution is 3. Also
included within each polymer family type are cellulosic polymers
that have additional substituents added in relatively small amounts
that do not substantially alter the performance of the polymer.
[0056] Amphiphilic cellulosics may be prepared by substituting the
cellulose at any or all of the 3 hydroxyl substituents present on
each saccharide repeat unit with at least one relatively
hydrophobic substituent. Hydrophobic substituents may be
essentially any substituent that, if substituted to a high enough
level or degree of substitution, can render the cellulosic polymer
essentially aqueous insoluble. Hydrophilic regions of the polymer
can be either those portions that are relatively unsubstituted,
since the unsubstituted hydroxyls are themselves relatively
hydrophilic, or those regions that are substituted with hydrophilic
substituents. Examples of hydrophobic substitutents include
ether-linked alkyl groups such as methyl, ethyl, propyl, butyl,
etc.; or ester-linked alkyl groups such as acetate, propionate,
butyrate, etc.; and ether- and/or ester-linked aryl groups such as
phenyl, benzoate, or phenylate. Hydrophilic groups include ether-
or ester-linked nonionizable groups such as the hydroxy alkyl
substituents hydroxyethyl, hydroxypropyl, and the alkyl ether
groups such as ethoxyethoxy or methoxyethoxy. In some embodiments,
hydrophilic substituents are those that are ether- or ester-linked
ionizable groups such as carboxylic acids, thiocarboxylic acids,
substituted phenoxy groups, amines, phosphates or sulfonates.
[0057] One class of cellulosic polymers comprises neutral polymers,
meaning that the polymers are substantially non-ionizable in
aqueous solution. Such polymers contain non-ionizable substituents,
which may be either ether-linked or ester-linked. Exemplary
ether-linked non-ionizable substituents include: alkyl groups, such
as methyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such as
hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups
such as phenyl. Exemplary ester-linked non-ionizable groups
include: alkyl groups, such as acetate, propionate, butyrate, etc.;
and aryl groups such as phenylate. However, when aryl groups are
included, the polymer may need to include a sufficient amount of a
hydrophilic substituent so that the polymer has at least some water
solubility at any physiologically relevant pH of from 1 to 8.
[0058] Exemplary non-ionizable polymers that may be used as the
polymer include: hydroxypropyl methyl cellulose acetate,
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl
cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose
acetate, and hydroxyethyl ethyl cellulose.
[0059] In some embodiments, neutral cellulosic polymers are those
that are amphiphilic. Exemplary polymers include hydroxypropyl
methyl cellulose and hydroxypropyl cellulose acetate, where
cellulosic repeat units that have relatively high numbers of methyl
or acetate substituents relative to the unsubstituted hydroxyl or
hydroxypropyl substituents constitute hydrophobic regions relative
to other repeat units on the polymer.
[0060] In some embodiments, cellulosic polymers comprise polymers
that are at least partially ionizable at physiologically relevant
pH and include at least one ionizable substituent, which may be
either ether-linked or ester-linked. Exemplary ether-linked
ionizable substituents include: carboxylic acids, such as acetic
acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic
acids such as ethoxybenzoic acid or propoxybenzoic acid, the
various isomers of alkoxyphthalic acid such as ethoxyphthalic acid
and ethoxyisophthalic acid, the various isomers of alkoxynicotinic
acid such as ethoxynicotinic acid, and the various isomers of
picolinic acid such as ethoxypicolinic acid, etc.; thiocarboxylic
acids, such as thioacetic acid; substituted phenoxy groups, such as
hydroxyphenoxy, etc.; amines, such as aminoethoxy,
diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such as
phosphate ethoxy; and sulfonates, such as sulphonate ethoxy.
Exemplary ester linked ionizable substituents include: carboxylic
acids, such as succinate, citrate, phthalate, terephthalate,
isophthalate, trimellitate, and the various isomers of
pyridinedicarboxylic acid, etc.; thiocarboxylic acids, such as
thiosuccinate; substituted phenoxy groups, such as amino salicylic
acid; amines, such as natural or synthetic amino acids, such as
alanine or phenylalanine; phosphates, such as acetyl phosphate; and
sulfonates, such as acetyl sulfonate. For aromatic-substituted
polymers to also have the requisite aqueous solubility, it is also
desirable that sufficient hydrophilic groups such as hydroxypropyl
or carboxylic acid functional groups be attached to the polymer to
render the polymer aqueous soluble at least at pH values where any
ionizable groups are ionized. In some cases, the aromatic group may
itself be ionizable, such as phthalate or trimellitate
substituents.
[0061] Exemplary cellulosic polymers that are at least partially
ionized at physiologically relevant pHs include: hydroxypropyl
methyl cellulose acetate succinate, hydroxypropyl methyl cellulose
succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl
methyl cellulose succinate, hydroxyethyl cellulose acetate
succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl
methyl cellulose acetate succinate, hydroxyethyl methyl cellulose
acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose,
cellulose acetate phthalate, methyl cellulose acetate phthalate,
ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate
phthalate, hydroxypropyl methyl cellulose acetate phthalate,
hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl
methyl cellulose acetate succinate phthalate, hydroxypropyl methyl
cellulose succinate phthalate, cellulose propionate phthalate,
hydroxypropyl cellulose butyrate phthalate, cellulose acetate
trimellitate, methyl cellulose acetate trimellitate, ethyl
cellulose acetate trimellitate, hydroxypropyl cellulose acetate
trimellitate, hydroxypropyl methyl cellulose acetate trimellitate,
hydroxypropyl cellulose acetate trimellitate succinate, cellulose
propionate trimellitate, cellulose butyrate trimellitate, cellulose
acetate terephthalate, cellulose acetate isophthalate, cellulose
acetate pyridinedicarboxylate, salicylic acid cellulose acetate,
hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid
cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose
acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic
acid cellulose acetate, and ethyl picolinic acid cellulose
acetate.
[0062] A particularly desirable subset of cellulosic ionizable
polymers are those that possess both a carboxylic acid functional
aromatic substituent and an alkylate substituent and thus are
amphiphilic. Exemplary polymers include cellulose acetate phthalate
(CAP), methyl cellulose acetate phthalate, ethyl cellulose acetate
phthalate, hydroxypropyl cellulose acetate phthalate,
hydroxylpropyl methyl cellulose phthalate (HPMCP), hydroxypropyl
methyl cellulose acetate phthalate (HPMCAP), hydroxypropyl
cellulose acetate phthalate succinate, cellulose propionate
phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose
acetate trimellitate, methyl cellulose acetate trimellitate, ethyl
cellulose acetate trimellitate, hydroxypropyl cellulose acetate
trimellitate, hydroxypropyl methyl cellulose acetate trimellitate,
hydroxypropyl cellulose acetate trimellitate succinate, cellulose
propionate trimellitate, cellulose butyrate trimellitate, cellulose
acetate terephthalate, cellulose acetate isophthalate, cellulose
acetate pyridinedicarboxylate, salicylic acid cellulose acetate,
hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid
cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose
acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic
acid cellulose acetate, and ethyl picolinic acid cellulose
acetate.
[0063] In some embodiments, cellulosic ionizable polymers are those
that possess a non-aromatic carboxylate substituent. Exemplary
polymers include hydroxypropyl methyl cellulose acetate succinate,
hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose
acetate succinate, hydroxyethyl methyl cellulose acetate succinate,
hydroxyethyl methyl cellulose succinate, and hydroxyethyl cellulose
acetate succinate.
[0064] While, as listed above, a wide range of polymers may be used
to form dispersions of enzalutamide, the inventors have found that
relatively hydrophobic polymers have shown the best performance as
demonstrated by high MDC and AUC.sub.90 in vitro dissolution
values. In particular, cellulosic polymers that are aqueous
insoluble in their nonionized state but are aqueous soluble in
their ionized state perform particularly well. A particular
subclass of such polymers are the so-called "enteric" polymers
which include, for example, hydroxypropylmethylcellulose acetate
succinate (HPMCAS) and certain grades of hydroxypropyl methyl
cellulose acetate phthalate (HPMCAP) and cellulose acetate
trimellitate (CAT). Dispersions formed from such polymers generally
show very large enhancements in the maximum drug concentration
achieved in dissolution tests relative to that for a crystalline
drug control.
[0065] In some embodiments, concentration-enhancing polymers for
use in dispersions with enzalutamide are
hydroxypropylmethylcellulose acetate succinate (HPMCAS),
hydroxypropylmethylcellulose (HPMC),
hydroxypropylmethylcellulosephthalate (HPMCP),
polyvinylpyrrolidonevinylacetate (PVP-VA), copolymers of
methacrylic acid and methylmethacrylate (approximate 1:1 ratio)
available as EUDRAGIT L-100.RTM., and graft copolymers of
polyethyleneglycol, polyvinylcaprolactam, and polyvinylacetate, one
commercially available version of a graft copolymer is known as
SOLUPLUS.RTM..
[0066] In some embodiments, the enzalutamide/polymer dispersion,
regardless of preparation method, may contain one or more
lipophilic microphase-forming materials, comprising surfactants and
lipidic mesophase-forming materials, or mixtures thereof. Examples
of lipophilic microphase-forming materials are sulfonated
hydrocarbons and their salts, such as dioctylsodiumsulfocuccinate
and sodium laurylsulfate; polyoxyethylene sorbitan fatty acid
esters, such as polysorbate-80 and polysorbate-20; polyoxyethylene
alkyl ethers; polyoxyethylene castor oil; polyoxyethylene (-40 or
-60) hydrogenated castor oil; tocopheryl polyethyleneglycol 1000
succinate; glyceryl polyethyleneglycol-8 caprylate/caprate;
polyoxyethylene-32 glyceryl laurate; polyoxyethylene fatty acid
esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglycolized glycerides; long-chain fatty acids such as palmitic
and stearic and oleic and ricinoleic acids; medium-chain and
long-chain saturated and unsaturated mono-, di- and tri-glycerides
and mixtures thereof; fractionated coconut oils; mono- and
di-glycerides of capric and caprylic acids; bile salts such as
sodium taurocholate; and phospholipids such as egg lecithin, soy
lecithin, 1,2-diacyl-sn-glycerophosphorylcholines such as
1-palmitoyl-2-oleyl-sn-glycerophosphorylcholine,
dipalmitoyl-sn-glycerophosphorylcholine,
distearoyl-sn-glycerophosphorylcholine, and
1-palmitoyl-2-stearoyl-sn-glycerophosphorylcholine.
[0067] In some embodiments, the enzalutamide/polymer dispersion
contains less than 30% by weight of lipophilic microphase-forming
materials. In some embodiments, the enzalutamide/polymer dispersion
contains less than 20% by weight of lipophilic microphase-forming
materials. In some embodiments, the enzalutamide/polymer dispersion
contains less than 10% by weight of lipophilic microphase-forming
materials. In some embodiments, the enzalutamide/polymer dispersion
contains less than 5% by weight of lipophilic microphase-forming
materials.
[0068] To obtain the best performance, particularly upon storage
for long times prior to use, it is preferred that the enzalutamide
remain, to the extent possible, in the amorphous state. The
inventors have found that this is best achieved when the
glass-transition temperature, Tg, of the solid amorphous dispersion
is substantially above the storage temperature of the composition.
In particular, it is preferable that the Tg of the amorphous state
of the dispersion be at least 40.degree. C. In some embodiments,
the Tg of the amorphous state of the dispersion is at least
60.degree. C. To achieve a high Tg for an enzalutamide/polymer
dispersion, it is desirable that the polymer have a high Tg.
Exemplary high Tg concentration-enhancing polymers are HPMCAS,
HPMCP, CAP, CAT.
[0069] The polymer is not particularly limited, so long as
enzalutamide can be carried as the solid dispersion. In some
embodiments, the polymer is not particularly limited, so long as
enzalutamide can be an amorphous state. Examples of the polymer
include polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), 5
poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates,
polyoxyethylene alkyl ethers, polyoxyethylene castor oils,
polycaprolactam, polylactic acid, polyglycolic acid,
poly(lactic-glycolic)acid, lipids, cellulose, pullulan, dextran,
maltodextrin, hyaluronic acid, polysialic acid, chondroitin
sulfate, heparin, fucoidan, pentosan polysulfate, spirulan,
hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose
(HPC), carboxymethyl ethylcellulose (CMEC), hydroxypropyl
methylcellulose acetate succinate (HPMCAS), cellulose acetate
phthalate (CAP), cellulose acetate trimellitate (CAT), ethyl
cellulose, cellulose acetate, cellulose butyrate, cellulose acetate
butyrate, dextran polymer derivatives, and pharmaceutically
acceptable forms, derivatives. In some embodiments, the polymer is
hydroxypropyl methylcellulose acetate succinate (HPMCAS).
Preparation of Compositions
[0070] Dispersions of enzalutamide and concentration-enhancing
polymer may be made according to any known process which results in
at least a major portion (at least 60%) of the enzalutamide being
in the amorphous state. Exemplary mechanical processes include
milling and hot-melt extrusion; melt processes include high
temperature fusion, solvent modified fusion and melt-congeal
processes; and solvent processes include non-solvent precipitation,
spray coating and spray-drying. Although the dispersions may be
made by any of these processes, the dispersions generally have
their maximum bioavailability and stability when the enzalutamide
is dispersed in the polymer such that it is substantially amorphous
and substantially homogeneously distributed throughout the
polymer.
[0071] Particularly effective methods for forming solid amorphous
dispersions of enzalutamide and concentration-enhancing polymers
are solvent processing and hot melt extrusion.
[0072] In general, as the degree of homogeneity of the dispersion
increases, the enhancement in the aqueous concentration of
enzalutamide and relative bioavailability increases as well. Given
the low aqueous solubility and bioavailability of crystalline
enzalutamide, it is highly preferred for the dispersions to be as
homogeneous as possible. Thus, most preferred are dispersions
having a single glass transition temperature, which indicates a
high degree of homogeneity.
[0073] In some embodiments, substantially amorphous and
substantially homogeneous dispersions are made by any of the
methods described above. In some embodiments, dispersions are
formed by "solvent processing," in which enzalutamide and a polymer
are dissolved in a common solvent. "Common" here means that the
solvent, which can be a mixture of compounds, will simultaneously
dissolve the drug and the polymer(s). After both the enzalutamide
and the polymer have been dissolved, the solvent is rapidly removed
by evaporation or by mixing with a non-solvent. Exemplary processes
are spray-drying, spray-coating (pan-coating, fluidized bed
coating, etc.), and precipitation by rapid mixing of the polymer
and drug solution with CO.sub.2, water, or some other non-solvent.
In some embodiments, removal of the solvent results in a solid
dispersion which is substantially homogeneous. As described
previously, in such substantially homogeneous dispersions, the
enzalutamide is dispersed as homogeneously as possible throughout
the polymer and can be thought of as a solid solution of
enzalutamide in the polymer(s). When the resulting dispersion
constitutes a solid solution of enzalutamide in polymer, the
dispersion may be thermodynamically stable, meaning that the
concentration of enzalutamide in the polymer is at or below its
equilibrium value. Alternatively, the composition may be a
supersaturated solid solution where the enzalutamide concentration
in the dispersion polymer(s) is above its equilibrium value.
[0074] The solvent may be removed through the process of
spray-drying. The term spray-drying is used conventionally and
broadly refers to processes involving breaking up liquid mixtures
into small droplets (atomization) and rapidly removing solvent from
the mixture in a container (spray-drying apparatus) where there is
a strong driving force for evaporation of solvent from the
droplets. The strong driving force for solvent evaporation is
generally provided by maintaining the partial pressure of solvent
in the spray-drying apparatus well below the vapor pressure of the
solvent at the temperature of the drying droplets. This is
accomplished by either (1) maintaining the pressure in the
spray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50
atm); (2) mixing the liquid droplets with a warm drying gas; or (3)
both. In addition, at least a portion of the heat required for
evaporation of solvent may be provided by heating the spray
solution.
[0075] Solvents suitable for spray-drying can be any organic
compound in which enzalutamide and polymer are mutually soluble. In
some embodiments, the solvent is also volatile with a boiling point
of 150.degree. C. or less. In addition, the solvent should have
relatively low toxicity and be removed from the dispersion to a
level that is acceptable according to The International Committee
on Harmonization (ICH) guidelines. Removal of solvent to this level
may require a processing step such as tray-drying subsequent to the
spray-drying or spray-coating process. Solvents include alcohols
such as methanol, ethanol, n-propanol, iso-propanol, and butanol;
ketones such as acetone, methyl ethyl ketone and methyl iso-butyl
ketone; esters such as ethyl acetate and propylacetate; and various
other solvents such as acetonitrile, methylene chloride, toluene,
and 1,1,1-trichloroethane. Lower volatility solvents such as
dimethyl acetamide or dimethylsulfoxide can also be used. Mixtures
of solvents, such as 50% methanol and 50% acetone, can also be
used, as can mixtures with water as long as the polymer and
enzalutamide are sufficiently soluble to make the spray-drying
process practicable. Generally, due to the hydrophobic nature of
enzalutamide, non-aqueous solvents used. Non-aqueous solvents
comprise less than about 10 wt % water; in some embodiments, less
than 1 wt % water.
[0076] In some embodiments, solvents for spray drying
enzalutamide/polymer solutions are acetone, ethanol, methanol,
mixtures thereof, and mixtures with water.
[0077] Generally, the temperature and flow rate of the drying gas
is chosen so that the polymer/drug-solution droplets are dry enough
by the time they reach the wall of the apparatus that they are
essentially solid, and so that they form a fine powder and do not
stick to the apparatus wall. The actual length of time to achieve
this level of dryness depends on the size of the droplets. Droplet
sizes generally range from 1 .mu.m to 500 .mu.m in diameter, with 5
to 100 .mu.m being more typical. The large surface-to-volume ratio
of the droplets and the large driving force for evaporation of
solvent leads to actual drying times of a few seconds or less, and
more typically less than 0.1 second. This rapid drying is often
critical to the particles maintaining a uniform, homogeneous
dispersion instead of separating into drug-rich and polymer-rich
phases. As above, to get large enhancements in concentration and
bioavailability it is often necessary to obtain as homogeneous a
dispersion as possible. Solidification times should be less than
100 seconds. In some embodiments, solidification time is less than
a few seconds. In some embodiments, solidification time is less
than 1 second. In general, to achieve this rapid solidification of
the enzalutamide/polymer solution, the size of droplets formed
during the spray-drying process is less than about 100 .mu.m in
diameter. The resultant solid particles thus formed are generally
less than about 100 .mu.m in diameter.
[0078] Following solidification, the solid powder typically stays
in the spray-drying chamber for about 5 to 60 seconds, further
evaporating solvent from the solid powder. The final solvent
content of the solid dispersion as it exits the dryer should be
low, since this reduces the mobility of enzalutamide molecules in
the dispersion, thereby improving its stability. Generally, the
solvent content of the dispersion as it leaves the spray-drying
chamber should be less than 10 wt %. In some embodiments, the
solvent content of the dispersion as it leaves the spray-drying
chamber is less than 2 wt %. In some cases, it may be preferable to
spray a solvent or a solution of a polymer or other excipient into
the spray-drying chamber to form granules, so long as the
dispersion is not adversely affected.
[0079] Spray-drying processes and spray-drying equipment are
described generally in Perry's Chemical Engineers' Handbook, Sixth
Edition (R. H. Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill
Book Co. 1984, pages 2054 to 20 57. More details on spray-drying
processes and equipment are reviewed by Marshall "Atomization and
Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954).
[0080] The spray drying equipment used in the Examples below
were:
[0081] Mini Spray Dryer. This bench-top spray dryer is an atomizer
in the top cap of a vertically oriented 10-cm diameter stainless
steel pipe. The atomizer was a two-fluid nozzle (Spraying Systems
Co. 1650 fluid cap and 64 air cap). Atomizing gas (nitrogen) was
delivered to the nozzle at 100.degree. C. at a flow rate of 15
gm/min, and the spray solution was delivered to the nozzle at room
temperature and at a flow rate of 1.0 gm/min using a syringe pump
(Harvard Apparatus, Syringe Infusion Pump. Filter paper attached to
a supporting screen was clamped to the bottom end of the pipe to
collect the solid spray-dried material and allow the nitrogen and
evaporated solvent to escape.
[0082] Bend Laboratory Spray Drier (BLD). The BLD is a custom-made
spray drier manufactured at Bend Research, Inc. The spray solution
is delivered to an atomizer located in the spray drying chamber.
The chamber consists of three sections: a top section, a
straight-side section, and a cone section. The top section contains
a perforated plate to create an organized co-current flow of drying
gas and the atomized spray solution within the drying chamber. The
drying gas enters the top section through the drying-gas inlet and
passes through the perforated plate. The drying gas then enters the
straight side section of the spray-drying chamber. The atomizer
slightly protrudes from the perforated plate. The spray solution is
sprayed into the straight-side section of the spray-drying chamber.
The flow rate of drying gas and spray solution are selected such
that the atomized spray solution forms solid particles, which are
collected in the cone section of the spray-drying chamber. The
spray-dried particles, evaporated solvent, and drying gas are
removed from the spray-drying chamber through an outlet port and
sent to a cyclone separator where the spray-dried particles are
collected. The evaporated solvent and drying gas are then sent to a
filter for removal of any remaining particles before discharge.
[0083] PSD-1 Spray Drier. This spray drying apparatus is a type XP
Portable Spray-Dryer with a Liquid Feed Process Vessel Model No.
PSD-1 (Niro A/S, Soeborg, Denmark). The PSD-1 is equipped with a
pressure nozzle. Heated drying gas (nitrogen, typically at
100.degree. C.) is delivered to the drying chamber through an inlet
duct and a DPH gas disperser (Niro) that surrounds the nozzle. The
resulting SDD exits the chamber with the drying gas and evaporates
solvents through transport ducts and into a cyclone. At the top of
the cyclone is an exhaust vent that allowed the nitrogen and
evaporated solvent to escape. The SDD is collected in a
canister.
[0084] In some embodiments, formation of enzalutamide/polymer
amorphous dispersions is achieved using hot-melt extrusion. Powder
mixtures of enzalutamide and concentration-enhancing polymer are
heated and passed through an extruder such as a 7.5 mm MP&R
extruder, which is capable of reaching 210.degree. C. and is
equipped with a 1/8 inch cylindrical die. After the extruded
enzalutamide/polymer mass exits the extruder, it is milled. In some
embodiments, for the purpose of enhancing the in vitro C.sub.max
and AUC.sub.90 in an enzalutamide dissolution test, a
enzalutamide/polymer dispersion has a mean particle size less than
150 .mu.m. In some embodiments, mean particle size is less than 50
.mu.m. In some embodiments, concentration-enhancing polymers for
use in hot-melt extruded enzalutamide/polymer solid amorphous
dispersions are hydroxypropylmethylcellulose acetate succinate
(HPMCAS) and polyvinylpyrrolidonevinylacetate (PVP-VA).
[0085] The amount of concentration-enhancing polymer relative to
the amount of enzalutamide present in the dispersions may vary
widely. The composition of enzalutamide/polymer dispersions is
expressed, for example, as 25% A:HPMCAS-M, where 25% A means "25%
active" and the dispersion contains 25% (by weight) enzalutamide
and 75% (by weight) hydroxypropylmethlycellulose acetate succinate
M-grade. In enzalutamide dispersions described herein, the
enzalutamide content is generally greater than 20% A; in some
embodiments, from 25% A to 75% A; in some embodiments, from 50% A
to 70% A. For a specific concentration-enhancing polymer, the
enzalutamide/polymer ratio that yields optimum results is best
determined in in vitro dissolution tests and/or in vivo
bioavailability tests.
[0086] The ratio of the polymer to enzalutamide is not particularly
limited, so long as enzalutamide can be formed the solid
dispersion. In some embodiments, the ratio of the polymer to
enzalutamide is not particularly limited, so long as enzalutamide
can be an amorphous state. The ratio of the polymer is specifically
0.5 to 3 parts by weight, 1 to 3 parts by weight in other
embodiments, and 2 to 3 parts by weight in still other embodiments,
with respect to 1 part by weight of enzalutamide.
[0087] In addition, the amount of concentration-enhancing polymer
that can be used in a dosage form is often limited by the total
mass requirements of the dosage form. For example, when oral dosing
to a human is desired, at low enzalutamide-to-polymer ratios the
total mass of drug and polymer may be unacceptably large for
delivery of the desired dose in a single tablet or capsule. Thus,
it is often necessary to use enzalutamide-to-polymer ratios that
are less than optimum in specific dosage forms to provide a
sufficient enzalutamide dose in a dosage form that is small enough
to be easily swallowed by a human.
[0088] Solid amorphous dispersions having fine particles, such as
less than 50 .mu.m in average particle diameter, can have poor flow
characteristics. Poor flowability of a solid amorphous dispersion
can lead to difficulties in handling and compressing the solid
amorphous dispersion. For example, poor flowability of the solid
amorphous dispersion can lead to inconsistent flow through
processing equipment and/or inconsistent or incomplete filling of
tablet or capsule dies, which can lead to delivery of inconsistent
dosages.
[0089] In addition to particle size, the flow characteristics of
the solid amorphous dispersion can also be dependent on the bulk
specific volume of the solid amorphous dispersion. The bulk
specific volume of a powder is the inverse of the bulk density of a
powder and can be measured as the volume occupied by a unit mass of
the powder, such as in cubic centimeters per gram, when the powder
is poured into a container, such as a graduated cylinder.
Generally, the lower the bulk specific volume of a powder, the
better the flowability of the particles. Improving the flowability
of the solid amorphous dispersion can therefore be more desirable
for a solid amorphous dispersion having a higher bulk specific
volume. For example, in some exemplary methods, the solid amorphous
dispersion can have a bulk specific volume greater than or equal to
3 cc/g, greater than or equal to 5 cc/g, greater than or equal to 8
cc/g, from 3 to 5 cc/g, and/or from 3 to 8 cc/g.
[0090] High-shear mixing of the solid amorphous dispersion and a
glidant can increase the uniformity of the mixed particles, such as
producing an ordered mixture and/or an interactive mixture. As used
herein, the term "glidant" means a substance that, when added to a
powder, improves the flowability of the powder, such as by reducing
inter-particle friction. Exemplary glidants include but are not
limited to colloidal silicas, colloidal silicon dioxide, fumed
silica, CAB-O-SIL.RTM. M-5P, AEROSIL.RTM., talc, starch, and
magnesium aluminum silicates.
[0091] A blend of the solid amorphous dispersion and the glidant
using high-shear mixing can have improved flowability, as measured
by Carr's Index, compared to the flowability of the solid amorphous
dispersion alone. In general, the lower the Carr's Index, the
better the flowability of the substance. As used herein, the term
"Carr's Index" means a dimensionless parameter "C" used to
characterize the flowability of a substance, such as a powder,
where C=1-(B/T), B is the bulk density of the substance and T is
the tapped density of the substance. The Carr's Index can be
expressed as a percentage, e.g., if C=0.5, the Carr's Index can be
expressed as 50%. The bulk density is equal to mass per volume
(g/cc) of a sample before being tapped and the tapped density is
equal to the mass of a sample divided by the volume of the sample
after the sample is tapped for 2000 cycles in a Vankel Tap density
instrument.
[0092] A powder having a lower Carr's Index can also be easier to
compress into a tablet. In some exemplary methods, a mixture having
a Carr's Index greater than 40%, for example, can be difficult to
compress into a tablet. For example, a tablet formed from a mixture
having a high Carr's Index can be more likely to crack, fracture,
or otherwise fail to stick together or maintain a tablet form after
compression. Adding a glidant to the solid amorphous dispersion
with high-shear mixing can produce a mixture having a low Carr's
Index, such as below 40% and/or 35%, that is suitable for direct
compression. This allows direct compression of the solid amorphous
dispersion without the need to include an intermediate granulation
process to decrease the Carr's Index of the mixture to a suitable
level.
[0093] An exemplary method for forming a pharmaceutical dosage form
comprises: providing a solid amorphous dispersion comprising
particles wherein the particles comprise enzalutamide and a
polymer, the solid amorphous dispersion having an average particle
diameter of less than 50 .mu.m; forming an ordered mixture by
high-shear mixing a blend comprising the solid amorphous dispersion
and a powdered glidant, the glidant having an average particle
diameter of less than or equal to one-fifth the average particle
diameter of the solid amorphous dispersion after high-shear mixing;
and forming the pharmaceutical dosage form by at least one of
directly compressing the ordered mixture to form a tablet and
encapsulating the ordered mixture to form a capsule.
[0094] Another exemplary method of preparing a pharmaceutical
dosage form comprises: providing a solid amorphous dispersion
comprising particles wherein the particles comprise enzalutamide
and a polymer, the solid amorphous dispersion having an average
particle diameter of less than 50 .mu.m; forming an ordered mixture
comprising the solid amorphous dispersion and a glidant using
high-shear mixing, the ordered mixture having a Carr's Index of
less than 40%; and forming the pharmaceutical dosage form by
directly compressing the ordered mixture to form a tablet or
encapsulating the ordered mixture to form a capsule.
[0095] Another exemplary method for forming a pharmaceutical dosage
form comprises: providing a solid amorphous dispersion comprising
particles, the particles comprising enzalutamide and a polymer, the
solid amorphous dispersion having an average particle diameter of
less than 50 .mu.m; forming a blend comprising the solid amorphous
dispersion and a powdered glidant using high-shear mixing, the
high-shear mixing having a Froude Number greater than 0.2; and
forming the pharmaceutical dosage form by at least one of directly
compressing the blend to form a tablet and encapsulating the blend
to form a capsule.
[0096] As used herein, the term "Froude Number" means a
dimensionless parameter "Fr" used to characterize a mixing process,
such that Fr=V.sup.2/gD.sub.c, where V is the characteristic
velocity of the particles in a mixing chamber, D.sub.c is the
characteristic diameter of the chamber, and g is the acceleration
due to Earth's gravity. For a rotating agitator, such as an
impeller, the characteristic velocity may be defined as
V=.pi.D.sub.aN, where D.sub.a is the diameter of the agitator and N
is the agitator rotation rate in revolutions per unit time.
[0097] As used herein, the term "high-shear mixing" means a powder
mixing process characterized by a Froude Number within a specified
range, such as greater than 0.01, greater than 0.1, greater than
0.2, greater than 0.5, greater than 1, greater than 10, and/or
greater than 20, for example. Where the Froude Number is not
specified, the term "high-shear mixing" means a powder mixing
process characterized by a Froude Number of at least 1. The term
"high-shear mixing" does not include high-shear granulation using a
liquid, or dissolving or dispersing a solid in a liquid.
[0098] As used herein, the term "low-shear mixing" means a
conventional mixing process that is not high-shear mixing.
[0099] As used herein, the term "ordered mixture" means a mixture
of powders having a level of uniformity that is greater than a
level achievable by random mixing.
[0100] As used herein, the term "interactive mixture" means a
mixture of a first powder having a first average particle size and
a second powder having a second average particle size that is
larger than the first average particle size, wherein all,
substantially all or at least 90% of the particles of the first
powder interact with and adhere to at least one of the plurality of
the particles of the second powder. In some embodiments, an ordered
mixture is also an interactive mixture.
[0101] As used herein, the term "average particle size" means the
D.sub.50. The term D.sub.50 means that 50 vol % of the particles
have a diameter that is smaller than this, and 50 vol % of the
particles have a diameter that is larger than this. The average
particle size may be measured using standard laser diffraction
particle sizing techniques known in the art. One example of an
instrument to measure the particle size of the dry powders is the
Masteresizer 2000, manufactured by Malvern Instruments Ltd
(Worcestershire, UK). In some embodiments, the average particle
diameter of the glidant after high-shear mixing is less than that
of the dispersion particles. This can be determined by
scanning-electron microscopy analysis of the blend. A comparison of
the dispersion particles before high-shear mixing with the glidant
and after high-shear mixing will show small particles of glidant on
the surfaces of the dispersion particles.
Excipients and Dosage Forms
[0102] Although the key ingredients present in the compositions are
simply the enzalutamide to be delivered and the
concentration-enhancing polymer(s), the inclusion of other
excipients in the composition may be useful. These excipients may
be utilized with the enzalutamide and polymer composition in order
to formulate the composition into tablets, capsules, suspensions,
powders for suspension, creams, transdermal patches, depots, and
the like. The composition of enzalutamide and polymer can be added
to other dosage form ingredients in essentially any manner that
does not substantially alter the enzalutamide. The excipients may
be either physically mixed with the dispersion and/or included
within the dispersion.
[0103] The solid dispersion comprising enzalutamide and the polymer
is further mixed with one or more pharmaceutically acceptable
additives to prepare a pharmaceutical composition.
[0104] The additives are not particularly limited, so long as they
are pharmaceutically acceptable. Examples of the additives include
a filler, a binder, a disintegrator, an acidulant, an effervescent
agent, an artificial sweetener, a flavor, a lubricant, a coloring
agent, a stabilizing agent, a buffer, an antioxidant, a glidant,
and the like.
[0105] The filler may be selected from, for example, mannitol,
lactose, starch, corn starch, calcium hydrogen phosphate hydrate,
magnesium carbonate, calcium carbonate, purified sucrose, glucose,
and the like.
[0106] The binder may be selected from, for example,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl
alcohol, methyl cellulose, gum arabic, and the like.
[0107] The disintegrator may be selected from, for example, corn
starch, starches, crystalline cellulose, carmellose calcium,
carmellose sodium, croscarmellose sodium, light anhydrous silicic
acid, calcium silicate, low-substituted hydroxypropyl cellulose,
partially pregelatinized starch, sodium carboxymethyl starch, agar
powder, crospovidone, synthetic aluminum silicate, sucrose fatty
acid esters, lactose hydrate, D-mannitol, anhydrous citric acid,
and the like.
[0108] The acidulant may be selected from, for example, citric
acid, tartaric acid, malic acid, and the like.
[0109] The effervescent agent may be selected from, for example,
sodium bicarbonate and the like.
[0110] The artificial sweetener may be selected from, for example,
saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia,
thaumatin, and the like.
[0111] The flavor may be selected from, for example, lemon,
lemon-lime, orange, menthol, and the like.
[0112] The lubricant may be selected from, for example, magnesium
stearate, calcium stearate, sucrose fatty acid esters, sodium
stearyl fumarate, polyethylene glycol, talc, stearic acid, and the
like.
[0113] The coloring agent may be selected from, for example, yellow
ferric oxide, red ferric oxide, food yellow No. 4, food yellow No.
5, food red No. 3, food red No. 102, food blue No. 3, and the
like.
[0114] The buffer may be selected from, for example, citric acid,
succinic acid, fumaric acid, tartaric acid, ascorbic acid, or salts
thereof; glutamic acid, glutamine, glycine, aspartic acid, alanine,
arginine, or salts thereof; magnesium oxide, zinc oxide, magnesium
hydroxide, phosphoric acid, boric acid, or their salts; and the
like.
[0115] The antioxidant may be selected from, for example, ascorbic
acid, dibutyl hydroxytoluene, propyl gallate, and the like.
[0116] The glidant may be selected from, for example, light
anhydrous silicic acid, titanium oxide, stearic acid, colloidal
silica, colloidal 20 silicon dioxide, fumed silica, CAB-O-SIL.RTM.
M-5P, AEROSIL.RTM., talc, starch, and magnesium aluminum silicates
and the like.
[0117] These additives may be added alone in an appropriate amount,
or as a combination of two or more thereof in appropriate
amounts.
[0118] One very useful class of excipients to be added to the
formulation after formation of the enzalutamide/polymer dispersion
comprises surfactants and surface-active agents. Suitable
surfactants and surface-active agents are sulfonated hydrocarbons
and their salts, such as dioctylsodiumsulfocuccinate and sodium
laurylsulfate; polyoxyethylene sorbitan fatty acid esters, such as
polysorbate-80 and polysorbate-20; polyoxyethylene alkyl ethers;
polyoxyethylene castor oil; polyoxyethylene (-40 or -60)
hydrogenated castor oil; tocopheryl polyethyleneglycol 1000
succinate; glyceryl polyethyleneglycol-8 caprylate/caprate;
polyoxyethylene-32 glyceryl laurate; polyoxyethylene fatty acid
esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglycolized glycerides; long-chain fatty acids such as palmitic
and stearic and oleic and ricinoleic acids; medium-chain and
long-chain saturated and unsaturated mono-, di- and tri-glycerides
and mixtures thereof; fractionated coconut oils; mono- and
di-glycerides of capric and caprylic acids; bile salts such as
sodium taurocholate; and phospholipids such as egg lecithin, soy
lecithin, 1,2-diacyl-sn-glycerophosphorylcholines such as
1-palmitoyl-2-oleyl-sn-glycerophosphorylcholine,
dipalmitoyl-sn-glycerophosphorylcholine,
distearoyl-sn-glycerophosphorylcholine, and
1-palmitoyl-2-stearoyl-sn-glycerophosphorylcholine. Such materials
can be advantageously be employed to increase the rate of
dissolution by facilitating wetting, thereby increasing the maximum
dissolved concentration, and also to inhibit crystallization or
precipitation of drug by interacting with the dissolved drug by
mechanisms such as complexation, formation of inclusion complexes,
formation of micelles or adsorbing to the surface of solid drug,
crystalline or amorphous. These surfactants may comprise up to 5%
of the composition.
[0119] The addition of pH modifiers such as acids, bases, or
buffers may also be beneficial, retarding the dissolution of the
composition (e.g., acids such as citric acid or succinic acid when
the concentration-enhancing polymer is anionic) or, alternatively,
enhancing the rate of dissolution of the composition (e.g., bases
such as sodium acetate or amines when the polymer is anionic).
[0120] Conventional matrix materials, complexing agents,
solubilizers, fillers, disintegrating agents (disintegrants), or
binders may also be added as part of the composition itself or
added by granulation via wet or mechanical or other means. These
materials may comprise up to 90 wt % of the composition.
[0121] Examples of matrix materials, fillers, or diluents include
lactose, mannitol, xylitol, microcrystalline cellulose, calcium
diphosphate, and starch.
[0122] Examples of disintegrants include sodium starch glycolate,
sodium alginate, carboxy methyl cellulose sodium, methyl cellulose,
and croscarmellose sodium.
[0123] Examples of binders include methyl cellulose,
microcrystalline cellulose, starch, and gums such as guar gum, and
tragacanth.
[0124] Examples of lubricants include magnesium stearate and
calcium stearate.
[0125] Other conventional excipients may be employed, including
those excipients well-known in the art. Generally, excipients such
as pigments, lubricants, flavorants, and so forth may be used for
customary purposes and in typical amounts without adversely
affecting the properties of the compositions. These excipients may
be utilized in order to formulate the composition into tablets,
capsules, suspensions, powders for suspension, creams, transdermal
patches, and the like.
[0126] The compositions may be delivered by a wide variety of
routes, including, but not limited to, oral, nasal, rectal, and
pulmonary. In some embodiments, compositions are delivered by the
oral route.
[0127] The pharmaceutical compositions comprising the solid
dispersion, can be formulated into various dosage forms, including
tablets, powders, fine granules, granules, dry syrups, capsules and
the like as well as the solid dispersion itself. In some
embodiments, the solid pharmaceutical composition is in tablet
form.
[0128] Compositions disclosed herein may also be used in a wide
variety of dosage forms for administration of enzalutamide.
Exemplary dosage forms are powders or granules that may be taken
orally either dry or reconstituted by addition of water or other
liquids to form a paste, slurry, suspension or solution; tablets;
capsules; multiparticulates; and pills. Various additives may be
mixed, ground, or granulated with the compositions disclosed herein
to form a material suitable for the above dosage forms.
[0129] The compositions may be formulated in various forms such
that they are delivered as a suspension of particles in a liquid
vehicle. Such suspensions may be formulated as a liquid or paste at
the time of manufacture, or they may be formulated as a dry powder
with a liquid, typically water, added at a later time but prior to
oral administration. Such powders that are constituted into a
suspension are often termed sachets or oral powder for constitution
(OPC) formulations. Such dosage forms can be formulated and
reconstituted via any known procedure. The simplest approach is to
formulate the dosage form as a dry powder that is reconstituted by
simply adding water and agitating.
[0130] In some embodiments, dispersions of enzalutamide are
formulated for long-term storage in the dry state as this promotes
the chemical and physical stability of the enzalutamide. Various
excipients and additives are combined with the compositions to form
the dosage form. For example, it may be desirable to add some or
all of the following: preservatives such as sulfites (an
antioxidant), benzalkonium chloride, methyl paraben, propyl
paraben, benzyl alcohol or sodium benzoate; suspending agents or
thickeners such as xanthan gum, starch, guar gum, sodium alginate,
carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl
cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, silica
gel, aluminum silicate, magnesium silicate, or titanium dioxide;
anticaking agents or fillers such as silicon oxide, or lactose;
flavorants such as natural or artificial flavors; sweeteners such
as sugars such as sucrose, lactose, or sorbitol as well as
artificial sweeteners such as aspartame or saccharin; wetting
agents or surfactants such as various grades of polysorbate,
docusate sodium, or sodium lauryl sulfate; solubilizers such as
ethanol propylene glycol or polyethylene glycol; coloring agents
such as FD and C Red No. 3 or FD and C Blue No. 1; and pH modifiers
or buffers such as carboxylic acids (including citric acid,
ascorbic acid, lactic acid, and succinic acid), various salts of
carboxylic acids, amino acids such as glycine or alanine, various
phosphate, sulfate and carbonate salts such as trisodium phosphate,
sodium bicarbonate or potassium bisulfate, and bases such as amino
glucose or triethanol amine.
[0131] In some embodiments, an additional concentration-enhancing
polymer may be added. An additional concentration-enhancing polymer
may act as a thickener or suspending agent in formulations which
are constituted with a liquid before dosing, and which may provide
additional precipitation inhibition for all dosage forms after
dosing to an aqueous use environment.
[0132] In some cases, the overall dosage form or particles,
granules or beads that make up the dosage form may have superior
performance if coated with an enteric polymer to prevent or retard
dissolution until the dosage form leaves the stomach. Exemplary
enteric coating materials include hydroxypropyl methyl cellulose
acetate succinate, hydroxypropyl methyl cellulose phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate,
carboxylic acid-functionalized polymethacrylates, and carboxylic
acid-functionalized polyacrylate.
[0133] Compositions may be administered in a controlled release
dosage form. In one such dosage form, the composition of the
enzalutamide and polymer is incorporated into an erodible polymeric
matrix device. By an erodible matrix is meant aqueous-erodible or
water-swellable or aqueous-soluble in the sense of being either
erodible or swellable or dissolvable in pure water or requiring the
presence of an acid or base to ionize the polymeric matrix
sufficiently to cause erosion or dissolution. When contacted with
the aqueous environment of use, the erodible polymeric matrix
imbibes water and forms an aqueous-swollen gel or "matrix" that
entraps the dispersion of enzalutamide and polymer. The
aqueous-swollen matrix gradually erodes, swells, disintegrates or
dissolves in the environment of use, thereby controlling the
release of the dispersion to the environment of use.
[0134] In some embodiments, compositions are administered by or
incorporated into a non-erodible matrix device.
[0135] In some embodiments, compositions are delivered using a
coated osmotic controlled release dosage form. This dosage form has
two components: (a) the core which contains an osmotic agent and
the dispersion of enzalutamide and concentration-enhancing polymer;
and (b) a non-dissolving and non-eroding coating surrounding the
core, the coating controlling the influx of water to the core from
an aqueous environment of use so as to cause drug release by
extrusion of some or all of the core to the environment of use. The
osmotic agent contained in the core of this device may be an
aqueous-swellable hydrophilic polymer, osmogen, or osmagent. The
coating is in some embodiments, polymeric, aqueous-permeable, and
has at least one delivery port.
[0136] In some embodiments, compositions are delivered via a coated
hydrogel controlled release form having at least two components:
(a) a core comprising the dispersion and a hydrogel, and (b) a
coating through which the dispersion has passage when the dosage
form is exposed to a use environment.
[0137] In some embodiments, a drug mixture is delivered via a
coated hydrogel controlled release dosage form having at least
three components: (a) a composition containing the dispersion, (b)
a water-swellable composition wherein the water-swellable
composition is in a separate region within a core formed by the
drug-containing composition and the water-swellable composition,
and (c) a coating around the core that is water-permeable,
water-insoluble, and has at least one delivery port therethrough.
In use, the core imbibes water through the coating, swelling the
water-swellable composition and increasing the pressure within the
core, and fluidizing the dispersion-containing composition. Because
the coating remains intact, the dispersion-containing composition
is extruded out of the delivery port into an environment of
use.
[0138] In some embodiments, compositions may be administered as
multiparticulates. Multiparticulates generally refer to dosage
forms that comprise a multiplicity of particles that may range in
size from about 10 .mu.m to about 2 mm, more typically about 100
.mu.m to 1 mm in diameter. Such multiparticulates may be packaged,
for example, in a capsule such as a gelatin capsule or a capsule
formed from an aqueous-soluble polymer such as HPMCAS, HPMC or
starch or they may be dosed as a suspension or slurry in a
liquid.
[0139] Such multiparticulates may be made by any known process,
such as wet- and dry-granulation processes,
extrusion/spheronization, roller-compaction, or by spray-coating
seed cores. For example, in wet- and dry-granulation processes, the
composition of enzalutamide and concentration-enhancing polymer is
prepared as described above. This composition is then granulated to
form multiparticulates of the desired size. Other excipients, such
as a binder (e.g., microcrystalline cellulose), may be blended with
the composition to aid in processing and forming the
multiparticulates. In the case of wet granulation, a binder such as
microcryscalline cellulose may be included in the granulation fluid
to aid in forming a suitable multiparticulate.
[0140] In any case, the resulting particles may themselves
constitute the multiparticulate dosage form or they may be coated
by various film-forming materials such as enteric polymers or
water-swellable or water-soluble polymers, or they may be combined
with other excipients or vehicles to aid in dosing to patients.
[0141] The solid dispersion can be prepared by dissolving and/or
suspending enzalutamide and the polymer in a pharmaceutically
acceptable solvent, and removing the solvent. Pharmaceutically
acceptable additives can be added to the solvent which dissolved
and/or suspended enzalutamide.
[0142] The pharmaceutically acceptable solvent is not particularly
limited, so long as enzalutamide can be an amorphous state in the
presence of the polymer. Examples of the pharmaceutically
acceptable solvent include ketones such as acetone, alcohols such
as methanol, ethanol, or propanol, a mixture thereof, and a mixed
solvent of water with one or more of these solvents. These
pharmaceutically acceptable solvents may be used alone or as an
appropriate combination of two or more thereof.
[0143] The amount of the pharmaceutically acceptable solvent is not
particularly limited, so long as it can be dissolved and/or
suspended enzalutamide. A 1- to 100-fold amount (w/w) of the
pharmaceutically acceptable solvent, or a 5- to 20-fold amount
(w/w) of the pharmaceutically acceptable solvent in other
embodiments may be contained, with respect to the total weight of
enzalutamide and the polymer.
[0144] A method of removing the pharmaceutically acceptable solvent
is not particularly limited, so long as the solvent can be removed
from the liquid in which enzalutamide and the polymer are dissolved
and/or suspended. Examples of the method include spray drying,
drying under reduced pressure, forced-air drying, and the like, and
spray drying may be used in other embodiments.
[0145] The process of manufacturing the pharmaceutical composition
or its pharmaceutical formulation is not particularly limited, so
long as it can produce the desired pharmaceutical formulation by
using an appropriate combination of the above methods or known
methods per se. Specifically, for example, the solid dispersion is
mixed with one additive, or two or more additives, and known
methods per se are carried out to obtain tablets, powders, fine
granules, granules, dry syrups, or capsules.
[0146] The process of manufacturing the pharmaceutical composition
or its pharmaceutical formulation is not particularly limited, so
long as it can produce the desired pharmaceutical formulation by
using an appropriate combination of the above methods or known
methods per se.
[0147] The pharmaceutical composition can be produced, for example,
by any known process including the steps of blending, granulation,
specific size controlling, tableting, film coating and the
like.
[0148] For example, the solid pharmaceutical composition in the
form of powders, fine granules, granules or dry syrups can be
produced by a process including the steps of (1) mixing the solid
dispersion with one additive or two or more additives using
blender, and (2) granulating the resulting mixture by dry
granulation using dry granulator. In a case where the above various
pharmaceutical additives are used as needed, these pharmaceutical
additives may be added at any stage, e.g., during step (1), between
steps (1) and (2), or during step (2).
[0149] The specific size controlling method can be adjusted the
particle size of the granules. For example, the size may be
adjusted 50 .mu.m to 500 .mu.m, 100 .mu.m to 300 .mu.m in another
embodiment, 100 .mu.m to 250 .mu.m in still another embodiment
using a sizing machine.
[0150] The granules may each be adjusted to any suitable size by
being subjected to a grinding step prior to the mixing step. In the
grinding step, any apparatus or means may be used as long as it
generally allows pharmaceutical grinding of the drug and/or the
pharmaceutical additive(s). In the mixing step of the individual
components, which is subsequent to grinding, any apparatus or means
may be used as long as it generally allows pharmaceutical mixing of
the individual components into a uniform state.
[0151] The granulated product is then tabulated to produce tablets.
Any tableting technique may be used for this purpose as long as it
generally allows pharmaceutical production of compression molded
products. Examples include techniques in which a granulated product
is tabulated in admixture with one additive, or two or more
additives. Any type of tablet machine may be used for this purpose
as long as it generally allows pharmaceutical production of
compression molded products. Examples include a rotary tablet
machine, a single-shot tablet machine and the like. The tablet
hardness is set to, for example, 50 to 300 N, or alternatively, 80
to 250 N, taking into consideration handling in production,
distribution, and the like of medicaments.
[0152] After tableting, the tablet surface may be coated with a
film coating. Any technique may be used for this purpose as long as
it generally allows pharmaceutical tablet coating. Examples include
pan coating processes and the like. Any type of film coating agent
may be used for this purpose as long as it is generally used as a
pharmaceutical additive for pharmaceutical tablet coating. Film
coating agents may be added alone or in combination as appropriate
in suitable amounts.
[0153] In general, the coating rate is not limited in any way as
long as the tablet surface can be coated.
[0154] Any method may be used to produce the pharmaceutical
compositions disclosed herein or a pharmaceutical formulation
thereof, as long as it allows production of pharmaceutical
formulations having the desired effects by the method described
above or an appropriate combination of methods known per se.
Tablet Formulations
[0155] In some embodiments, for manufacture of a tablet dosage form
of an enzalutamide/polymer dispersion, an enzalutamide/polymer
dispersion containing 55-65 wt % enzalutamide is used. In some
embodiments, a 60% A:HPMCAS-M dispersion is used. A useful tablet
contains approximately 70% of its total weight as 60% A:HPMCAS-M
dispersion, with the remainder inactive excipients, including a
disintegrant. In some embodiments, a tablet comprises sodium starch
glycolate (e.g., EXPLOTAB.RTM.) as a disintegrant. In some
embodiments, a tablet comprises croscarmellose sodium (e.g.,
AC-DI-SOL.RTM.) as a disintegrant. In some embodiments, such
tablets comprise 6 to 10 wt % disintegrant. In some embodiments, a
tablet comprises 266.67 mg 60% A:HPMCAS-M dispersion, and 30.5 mg
croscarmellose sodium, in a 381 mg tablet; this corresponds to a
dispersion content of 70 wt % and a disintegrant content of 8 wt
%.
[0156] In some embodiments, a tablet contains approximately 55-65%
of its total weight as 60% A:HPMCAS-M dispersion, with the
remainder inactive excipients, including a disintegrant. In some
embodiments, sodium starch glycolate (e.g., EXPLOTAB.RTM.) as a
disintegrant. In some embodiments, tablets contain croscarmellose
sodium (e.g., AC-DI-SOL.RTM.) as a disintegrant. In some
embodiments, such tablets comprise 6 to 10 wt % disintegrant. For
example, in some embodiments, a tablet of this type may comprise
266.67 mg 60% A:HPMCAS-M dispersion, and 34 mg croscarmellose
sodium, in a 425 mg tablet. This corresponds to a dispersion
content of 62.7 wt % and a disintegrant content of 8 wt %.
[0157] In some embodiments, a tablet contains approximately 45-55%
of its total weight as 60% A:HPMCAS-M dispersion, with the
remainder inactive excipients, including a disintegrant. In some
embodiments, sodium starch glycolate (e.g., EXPLOTAB.RTM.) or
croscarmellose sodium (e.g., AC-DI-SOL.RTM.), is used. In some
embodiments, a tablet comprises 6 to 10 wt % disintegrant. For
example, in some embodiments a tablet of this type may comprise
266.67 mg 60% A:HPMCAS-M dispersion, and 40 mg croscarmellose
sodium, in a 500 mg tablet. This corresponds to a dispersion
content of 53.3 wt % and a disintegrant content of 8 wt %. Larger
tablets may be made, providing they contain 266.67 mg 60%
A:HPMCAS-M dispersion, and at least 6 wt % disintegrant; in some
embodiments, 8 wt % disintegrant.
[0158] Tablets comprising enzalutamide/polymer dispersions may be
prepared using wet granulation, dry granulation, or direct
compression. In some embodiments, dry granulation or direct
compression is used.
[0159] In some embodiments, tablets comprise 60% A:HPMCAS-M
dispersion, the disintegrant croscarmellose sodium, and
microcrystalline cellulose (e.g., AVICEL.RTM. PH102). In some
embodiments, tablets comprise 60% A:HPMCAS-M dispersion, the
disintegrant croscarmellose sodium, microcrystalline cellulose
(e.g., AVICEL.RTM. PH102), and lactose 318 Fast-Flo. In some
embodiments, tablets comprise 60% A:HPMCAS-M dispersion, the
disintegrant croscarmellose sodium, microcrystalline cellulose
(e.g., AVICEL.RTM. PH102), lactose 318 Fast-Flo, and silica (e.g.,
CAB-O-SIL.RTM.). An example of a 500 mg tablet formulation,
manufactured by direct compression, comprises: [0160] 53.3 wt % 60%
A:HPMCAS-M dispersion; [0161] 8.0 wt % croscarmellose sodium;
[0162] 19.0 wt % microcrystalline cellulose; [0163] 19.0 wt %
fast-flo lactose; [0164] 0.5 wt % silica; and [0165] 0.25 wt %
magnesium stearate.
[0166] It will be apparent that said exemplary tablet may be made
larger or smaller, without significant effect on performance, by
making small variations in the amount of each excipient, providing
that the tablet contains sufficient 60% A:HPMCAS-M dispersion to
provide a 160 mg dose of enzalutamide. In some embodiments of
larger or smaller tables, the relative ratios of the five listed
excipients remains approximately constant.
[0167] Compositions disclosed herein may be used to treat any
condition which is subject to treatment by administering
enzalutamide. Accordingly, compositions can be used to treat
hyperproliferative disorders, such as prostate cancer (e.g.,
hormone-refractory prostate cancer, hormone-sensitive prostate
cancer), breast cancer, and ovarian cancer, in a mammal (including
a human being) by administering to a mammal in need of such
treatment a therapeutically effective amount of a composition
disclosed herein.
[0168] The in vitro dissolution test to evaluate enhanced drug
concentration in aqueous solution can be conducted by (1) adding
with agitation a sufficient quantity of control composition, that
is, the crystalline enzalutamide alone, to the in vitro test
medium, typically MFD or PBS solution, to determine the maximum
concentration of the enzalutamide achieved under the conditions of
the test; (2) adding with agitation a sufficient quantity of test
composition (e.g., the enzalutamide and polymer) in an equivalent
test medium, such that if all the enzalutamide dissolved, the
theoretical concentration of enzalutamide would exceed the observed
maximum concentration of enzalutamide by a factor of about 20; and
(3) comparing the measured MDC and/or aqueous concentration versus
time AUC.sub.90 of the test composition in the test medium with the
maximum concentration, and/or the aqueous concentration versus time
AUC.sub.90 of the control composition. In conducting such a
dissolution test, the amount of test composition or control
composition used is an amount such that if all of the enzalutamide
dissolved, the test enzalutamide concentration would be at least
about 20-fold that of the control enzalutamide concentration.
[0169] The concentration of dissolved enzalutamide is typically
measured as a function of time by sampling the test medium and
plotting enzalutamide concentration in the test medium vs. time so
that the MDC can be ascertained. The MDC is taken to be the maximum
value of dissolved enzalutamide measured over the duration of the
test. The enzalutamide concentration versus time AUC.sub.90 is
calculated by integrating the concentration versus time curve over
any 90-minute time period between the time of introduction of the
composition into the aqueous use environment (time equals zero) and
270 minutes following introduction to the use environment (time
equals 270 minutes). Typically, when the composition reaches its
MDC rapidly, in less than about 30 minutes, the time interval used
to calculate AUC.sub.90 is from time equals zero to time equals 90
minutes. However, if the AUC.sub.90 over any 90-minute time period
described above of a composition meets the criteria of compositions
described herein, then the composition is included in compositions
of this disclosure. The time period 270 min is chosen because of
its physiological relevance. Drug absorption in mammals generally
occurs in the small intestine, and the small intestinal transit
time in humans is approximately 4.5 hr, or 270 min.
[0170] To avoid large enzalutamide particulates which would give an
erroneous determination, the test solution is either filtered or
centrifuged. "Dissolved enzalutamide" is typically taken as that
material that either passes a 0.45 micron syringe filter or,
alternatively, the material that remains in the supernatant
following centrifugation. Filtration can be conducted using a 13
mm, 0.45 micron polyvinylidine difluoride syringe filter, such as
the filter sold by Scientific Resources under the trademark
TITAN.TM.. Centrifugation is typically carried out in a
polypropylene microcentrifuge tube by centrifuging at 13,000 G for
60 seconds. Other similar filtration or centrifugation methods can
be employed and useful results obtained. For example, using other
types of microfilters may yield values somewhat higher or lower
(+/-10-40%) than that obtained with the filter specified above but
will still allow identification of dispersions. It is recognized
that this definition of "dissolved enzalutamide" encompasses not
only monomeric solvated enzalutamide molecules but also a wide
range of species such as polymer/enzalutamide assemblies that have
submicron dimensions such as enzalutamide aggregates, aggregates of
mixtures of polymer and enzalutamide, micelles, polymeric micelles,
colloidal particles, polymer/enzalutamide complexes, and other such
enzalutamide-containing species that are present in the filtrate or
supernatant in the specified dissolution test.
[0171] The membrane permeability test described in the Examples
below is carried out as follows. A drug-permeable membrane is
placed between feed and permeate reservoirs. A sufficient quantity
of test composition is added to a feed test medium and placed in
the feed reservoir, while a water immiscible organic solution, such
as a 60/40 mixture of decanol/decane, is placed in the permeate
reservoir. Samples are removed from the permeate reservoir and
analyzed for the concentration of drug as a function of time. From
these data the maximum flux of drug across the membrane is
determined, as is the total drug recovery, defined as the
percentage of the amount of drug which has crossed the membrane
after 240 minutes. Further details of this membrane permeation test
are disclosed in U.S. Pat. No. 7,611,630 B2.
[0172] Nothing in this specification should be considered as
limiting the scope of this disclosure. All examples presented are
representative and non-limiting. The above-described embodiments
can be modified or varied, as appreciated by those skilled in the
art in light of the above teachings. It is therefore to be
understood that, within the scope of the claims and their
equivalents, the embodiments disclosed herein can be practiced
otherwise than as specifically described.
[0173] In the examples below, "Control 1" is crystalline
enzalutamide, obtained as described in U.S. Pat. No. 7,709,517B2,
in which this compound is called RD162'; and "Control 2" is a 4.23
mg/ml solution of enzalutamide in LABRASOL.RTM. (Caprylocaproyl
polyoxylglycerides).
EXAMPLE 1
Preparation of Amorphous Enzalutamide
[0174] Amorphous enzalutamide was prepared by spray-drying a 3 wt %
solution of enzalutamide dissolved in acetone using a lab-scale
spray drier. The lab-scale drier consisted of a 27.6-cm diameter
spray drier having a diameter-to-height ratio of greater than 3.
The lab-scale drier was equipped with a Schlick 2.0 pressure
nozzle. Heated drying gas (nitrogen) was delivered to the drying
chamber through a perforated plate to provide a uniform flow of
drying gas through the drying chamber. To form amorphous
enzalutamide, the spray solution was delivered to the nozzle at a
flow rate of 20 g/min and a pressure of 110 psig. In the drying
chamber, the atomized droplets were combined with the nitrogen
drying gas, which entered the system at a flow rate of 470 g/min
and a temperature of 100.degree. C. The spray-dried particles,
evaporated solvent, and drying gas were removed from the
spray-drying chamber at a temperature of 45.degree. C. through an
outlet port and sent to a high-efficiency cyclone separator where
the spray-dried particles were collected. The evaporated solvent
and drying gas were then sent to a filter for removal of any
remaining particles before discharge.
EXAMPLE 2
Preparation of Enzalutamide Dispersions with Concentration
Enhancing Polymers
[0175] A solid amorphous dispersion of 25 wt % enzalutamide and 75
wt % HPMCAS was prepared using a spray drying process as follows. A
spray solution was prepared by dissolving 1 wt % enzalutamide and 3
wt % HPMCAS-M in acetone. This solution was spray-dried using the
lab-scale spray drier described in Example 1. The solution was
delivered to a Schlick 2.0 pressure nozzle atomizer at a pressure
of 114 psig. The spray solution was delivered to the spray drier at
a flow rate of 20 gm/min. The nitrogen drying gas was delivered to
the nozzle at 102.degree. C. and at a flow rate of 470 g/min. The
outlet temperature of the spray dryer was 46.degree. C. The
resulting spray dried particles were removed using a cyclone
separator. The spray drying parameters are summarized in Table
2.1.
[0176] Additional dispersions were made using various polymers and
formulations, as summarized in Table 2.1.
TABLE-US-00001 TABLE 2.1 Preparation conditions for spray-dried
dispersions (SDDs) of enzalutamide with polymers. Solids Drying
Spray SDD in Gas Solution Composition Spray Run Drying Gas Flow
Feed Nozzle and (Dispersion Spray Soln. Size T.sub.in T.sub.out
Rate Rate Spray Pressure Number) Dryer (%) (gA) (C..degree.)
(C..degree.) (g/min) (g/min) Nozzle (psi) 25% A lab- 4.0 6.4 102 46
470 20 Schlick 114 HPMCAS-M scale 2.0 SDD drier (D1) 25% A PVP-
lab- 4.0 1.5 112 46 470 20 Schlick 111 VA64 SDD scale 2.0 (D2)
drier 60% A lab- 8.0 9.0 109 47 470 25 Schlick 109 HPMCAS-M scale
2.0 SDD (D3) drier 25% A mini 2.0 50 mg 100 23 20 0.65 2-fluid*
HPMCAS-M SDD (D4) 40% A mini 1.5 50 mg 100 23 20 0.65 2-fluid
HPMCAS-M SDD (D5) 60% A mini 1.0 50 mg 100 23 20 0.65 2-fluid
HPMCAS-M SDD (D6) 80% A mini 1.0 50 mg 100 23 20 0.65 2-fluid
HPMCAS-M SDD (D7) 25% A mini 2.0 50 mg 100 23 20 0.65 2-fluid
HPMCAS-H SDD (D8) 40% A mini 1.5 50 mg 100 23 20 0.65 2-fluid
HPMCAS-H SDD (D9) 40% A PVP mini 1.0 50 mg 100 23 20 0.65 2-fluid
VA64 SDD (D10) 25% A lab- 8.0 10 107 44 510 22 Schlick 106
HPMCAS-MG scale 2.0 SDD (D11) drier 60% A lab- 8.0 20 109 55 490 22
Schlick 104 HPMCAS-MG scale 2.0 SDD (D12) drier 60% A PSD-1 18.0
900 99 30 1750 230 Spray 330-370 HPMCAS-MG Systems SDD (D13)
SK79-16 60% A HPMC- mini 1.5 100 mg 105 23 20 0.65 2-fluid E3Prem
SDD (D14) 60% A HPMCP- mini 1.5 100 mg 105 23 20 0.65 2-fluid 55
SDD (D15) 60% A Eudragit- mini 1.5 100 mg 105 23 20 0.65 2-fluid
L100 SDD (D16) *2-fluid nozzle is a Spraying Systems 1650 liquid,
64 air cap, available from Spraying Systems Co. .RTM., Wheaton, IL
The "mini" spray-dryer consisted of an atomizer in the top cap of a
vertically oriented 11-cm diameter stainless steel pipe. The PSD-1
spray dryer is a Niro type XP Portable Spray-Dryer with a
Liquid-Feed Process Vessel.
EXAMPLE 3
PXRD Diffractograms of Spray-Dried Amorphous Drug and
Enzalutamide/Polymer Dispersions, and Bulk Crystalline Drug
[0177] The dispersions were analyzed by powder X-ray diffraction
(PXRD) using an AXS D8 Advance PXRD measuring device (Bruker, Inc.
of Madison, Wis.) using the following procedure. Samples
(approximately 30 to 100 mg) were packed in Lucite sample cups
fitted with Si (511) plates as the bottom of the cup to give no
background signal. Samples were spun in the .phi. plane at a rate
of 30 rpm to minimize crystal orientation effects. The x-ray source
(KCu.sub..alpha., .lamda.=1.54 .ANG.) was operated at a voltage of
45 kV and a current of 3 mA. Data for each sample were collected
over a period of 120 minutes in continuous detector scan mode at a
scan speed of 8 seconds/step and a step size of 0.04.degree./step.
Diffractograms were collected over the 2.theta. range of 4.degree.
to 40.degree..
[0178] The diffractograms in FIG. 1 demonstrate that spray-dried
enzalutamide, a 25% A:PVP-VA64 SDD, a 25% A:HPMCAS-M SDD, and a 60%
A:HPMCAS-MG SDD all are completely amorphous, characterized by the
absence of sharp crystallographic x-ray peaks.
EXAMPLE 4
In Vitro Dissolution of Enzalutamide Formulations and Controls
[0179] In vitro dissolution studies were carried out for a subset
of the formulations whose manufacture is described in Example 2.
These dissolution studies utilized the Microcentrifuge Dissolution
Test described above. The formulations tested were amorphous
enzalutamide, various enzalutamide/Polymer spray-dried dispersions
(SDDs), and Controls 1 and 2. A dose of 200 .mu.g/ml enzalutamide
was chosen, in order to be 10 to 20 times higher than the
solubility of crystalline enzalutamide, in order to evaluate the
ability of formulations to achieve enzalutamide supersaturation and
sustainment of supersaturation relative to crystalline drug. The
dissolution medium was Model Fasted Duodenal Solution (MFDS), which
consisted of an aqueous solution comprising 20 mM Na2HPO4, 47 mM
KH2PO4, 87 mM NaCl, 0.2 mM KCl, at pH 6.5 and 290 mOsm/kg,
additionally containing 7.3 mM sodium taurocholic acid and 1.4 mM
of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.
TABLE-US-00002 TABLE 4.1 Microcentrifuge dissolution test data for
enzalutamide spray-dried dispersions (SDDs), amorphous
enzalutamide, and controls. Enzalutamide Concentration (.mu.g/ml)
Formulation (Dispersion #) 0 min 4 min 10 min 20 min 40 min 90 min
1200 min 25% A HPMCAS-M SDD (D4) 0.0 150 150 150 160 160 100 40% A
HPMCAS-M SDD (D5) 0.0 110 86 93 110 120 100 60% A HPMCAS-M SDD (D6)
0.0 75 78 93 100 110 100 80% A HPMCAS-M SDD (D7) 0.0 87 100 130 130
130 40 25% A HPMCAS-H SDD (D8) 0.0 110 110 110 110 110 110 40% A
HPMCAS-H SDD (D9) 0.0 100 110 110 110 110 110 25% A PVP VA64 SDD
(D2) 0.19 110 110 110 110 110 Not Done 40% A PVP VA64 SDD (D10) 0.0
100 100 110 110 110 40 Amorphous (spray-dried) 0.0 61 100 100 110
120 30 enzalutamide - BREC-0035-09B(V) Crystalline enzalutamide 0.0
1 3 5 6 7 9 (Control 1) 4.23 mgA/mL enzalutamide in 0.0 170 180 170
170 170 190 Labrasol (Control 2)
TABLE-US-00003 TABLE 4.2 Microcentrifuge dissolution data
(C.sub.max and AUC.sub.90) for enzalutamide spray-dried dispersions
(SDDs), amorphous enzalutamide, and controls. C.sub.max,90.sup.a
AUC.sub.90.sup.b Sample Tested (Dispersion #) (.mu.g/mL) (min *
.mu.g/mL) 25% A HPMCAS-M SDD (D4) 160 13,600 40% A HPMCAS-M SDD
(D5) 120 9,200 60% A HPMCAS-M SDD (D6) 110 8,500 80% A HPMCAS-M SDD
(D7) 130 11,200 25% A HPMCAS-H SDD (D8) 110 9,800 40% A HPMCAS-H
SDD (D9) 110 9,700 25% A PVP VA64 SDD (D2) 110 9,700 40% A PVP VA64
SDD (D10) 110 9,800 Amorphous (spray-dried) enzalutamide - 120
9,500 BREC-0035-09B(V) Crystalline enzalutamide (Control 1) 7 500
4.23 mgA/mL enzalutamide in Labrasol 180 15,200 (Control 2)
.sup.aC.sub.max, 90 min = maximum drug concentration through 90
minutes. .sup.bAUC.sub.90 min = area under the curve at 90
minutes.
[0180] The data in Tables 4.1 and 4.2 demonstrate that amorphous
enzalutamide, a Labrasol solution of enzalutamide, and various
spray-dried dispersions (SDDs) of enzalutamide with the polymers
HPMCAS and PVP-VA64 all exhibit a large enzalutamide
supersaturation when dissolved, relative to crystalline
enzalutamide, in addition to the ability to maintain this
supersaturation.
[0181] The AUC.sub.90 values for the SDDs in Table 4.2 are all
greater than 5 times the AUC.sub.90 for crystalline enzalutamide
(Control 1). The C.sub.max 90 values for the SDDs in Table 4.2 are
all greater than 5 times the C.sub.max 90 for crystalline
enzalutamide (Control 1).
EXAMPLE 5
Glass Transition Temperatures (Tgs) as a Function of Relative
Humidity
[0182] Below Tg, an amorphous material is said to be in a "glassy"
state in which molecular mobility is severely restricted. Above Tg,
an amorphous material is in a state in which molecular mobility is
increased significantly relative to the "glassy" state. Glass
transition temperatures Tg were determined for amorphous
enzalutamide, and for spray-dried dispersions (SDDs) of
enzalutamide with HPMCAS-M or PVP-VA64, at <5% and 75% relative
humidity (RH). Tgs were determined by modulated differential
scanning calorimetry (mDSC), utilizing the following protocol.
Samples (about 5 mg) were equilibrated at the desired RH overnight
in an environmental chamber at ambient temperature. The samples
were then loaded into pans and sealed inside the environmental
chamber. The samples were analyzed on a Q1000 mDSC (TA Instruments,
New Castle, Del.). Samples were typically scanned over the
temperature range of -40.degree. C. to 180.degree. C., at a scan
rate of 2.5.degree. C./min, and a modulation rate of
.+-.1.5.degree. C./min. The data sampling interval was 0.20
sec/point. The Tg was calculated based on half height.
[0183] Tg data are presented in Table 5.1. As is generally
observed, Tg decreases with increasing RH because the amorphous
material is plasticized by incorporated water vapor as the % RH
increases. Generally, Tg decreases approximately linearly as % RH
increases.
TABLE-US-00004 TABLE 5.1 T.sub.g as a Function of Relative Humidity
(RH) for enzalutamide SDDs SDD Formulation T.sub.g (.degree. C.)
(Dispersion #) <5% RH 75% RH Amorphous (spray-dried) 88.5 64.0
MDV-3100 80% A HPMCAS-M (D7) 90.4 59.3 60% A HPMCAS-M (D6) 87.1
52.0 25% A HPMCAS-M (D4) 93.1 50.7 40% A HPMCAS-M (D5) 91.3 51.9
25% A HPMCAS-H (D8) 94.0 51.2 40% A HPMCAS-H (D9) 91.1 51.2 40% A
PVP VA64 (D10) 103.3 34.9 25% A PVP VA64 (D2) 105.5 30.8
[0184] In order to assure that a dispersion will maintain its
amorphous character (and thus its capacity to supersaturate a
solution), it is desirable to choose a dispersion composition whose
Tg is above the temperatures at which the product may be stored. If
the product is stored at a temperature above its Tg, the amorphous
drug within the dispersion will be relatively mobile and can
diffuse into drug-rich patches and can crystallize. This is
undesirable. Typical storage challenge conditions dictated by the
US Food and Drug Administration are 40.degree. C./25% RH,
50.degree. C./20% RH, 30.degree. C./60% RH, and 40.degree. C./75%
RH. At 75% RH, 100% A spray-dried enzalutamide (pure amorphous
enzalutamide) and the enzalutamide/HPMCAS SDDs exhibit Tgs which
are above each of the FDA challenge conditions (30.degree. C.,
40.degree. C., 50.degree. C.). This is highly desirable, and these
materials will not need protective packaging to protect them in
high humidity environments.
[0185] The 25% A and 40% A enzalutamide dispersions with the
concentration-enhancing polymer PVP-VA64 exhibit Tgs at
30.8.degree. C. and 34.9.degree. C., respectively. If
enzalutamide/PVP-VA dispersions encounter storage conditions above
their Tgs (such as 40.degree. C.), they can possibly undergo
undesirable change. Thus enzalutamide/PVP-VA dispersions should be
stored in protective packaging (such as foil-foil blisters) which
prevents ingress of water vapor into the dispersion.
[0186] Amorphous enzalutamide and MCV3100/HPMCAS dispersions have
high Tgs.
EXAMPLE 6
Particle Morphology of Amorphous Enzalutamide, and SDDs of
Enzalutamide with HPMCAS and PVP-VA
[0187] Scanning electron micrographs (SEMs) were obtained for
samples before and after 1 day exposure to a 50.degree. C./75% RH
environment. These SEMs are presented in FIG. 2. After exposure of
these samples to this challenging storage environment, no crystals
were seen, indicative of the ability of these samples to maintain
the amorphous character of enzalutamide. For three of the four
samples, the 1 day storage challenge resulted in fusion of
particles to form larger particles (100% A Spray-dried, 80%
A:HPMCAS-MG, 40% A:PVPVA), with this effect being extreme for 40%
A:PVPVA. Thus these three embodiments would require controlled
storage conditions to maintain their efficacy. The 60% A:HPMCAS-MG
SDD did not undergo fusion to larger particles over the 1 day
storage challenge, and would not require controlled storage
conditions to maintain efficacy.
[0188] In some embodiments, enzalutamide/HPMCAS SDDs have a drug
content less than 80%.
EXAMPLE 7
Capacity of Enzalutamide SDDs to Maintain Supersaturation After
Suspension in Aqueous Media
[0189] Drugs and drug formulations are sometimes dosed as aqueous
suspensions, particularly for pediatric patients. The ability of
various enzalutamide SDDs to retain their ability to maintain drug
supersaturation in vitro was assessed by using the microcentrifuge
dissolution test to measure drug dissolution after suspension in
0.5% methylcellulose in water for 2 hours. Methylcellulose is a
standard viscosifying suspending agent which is used to maintain
drug particles in suspension in oral suspension dosage forms. The
table below presents in vitro dissolution performance before and
after suspension in 0.5% methylcellulose.
TABLE-US-00005 TABLE 7.1 In vitro dissolution behavior of SDDs
before and after suspension for 2 hr in aqueous 0.5%
methylcellulose. C.sub.max 90 AUC.sub.90% (mcg/ AUC.sub.90 of 0 Hr
Sample (Dispersion #) ml) (min mcg/ml) Value 25% A:PVPVA64 (D2), 0
hr 130 9,600 -- 25% A:PVPVA64 (D2), 2 hr 130 7,100 74 25%
A:HPMCAS-MG (D17), 0 hr 140 12,200 -- 25% A:HPMCAS-MG (D17), 2 hr
140 12,400 102 60% A:HPMCAS-MG (D3), 0 hr 120 9,500 -- 60%
A:HPMCAS-MG (D3), 2 hr 120 9,600 101 Amorphous enzalutamide, 0 hr
110 8,900 -- Amorphous enzalutamide, 2 hr 100 8,800 99
[0190] Amorphous enzalutamide and the SDDs with HPMCAS-MG
maintained their ability to effect sustained supersaturation after
suspension for 2 hr in aqueous methylcellulose. Incubation of a 25%
A:PVPVA64 SDD for 2 hr in aqueous methylcellulose resulted in a 26%
loss in supersaturation capacity, as measured by AUC.sub.90.\
EXAMPLE 8
Membrane-Permeation (MP) Dissolution Test
[0191] The MP-dissolution test, whose details are described above,
measures a capability of low solubility drug formulations which is
not measured in the microcentrifuge dissolution test utilized in
Examples 4 and 7. This test mimics an aspect of the in vivo
situation in the GI tract. In the in vivo situation, it is
generally accepted that free drug in solution (i.e. individual drug
molecules dissolved in the GI medium without association with
formulation components) is the species which is absorbed across the
gastrointestinal wall into the bloodstream. As free drug is
absorbed, the formulation must be capable of supplying more free
drug for absorption. The membrane permeation test measures the
amount of drug which crosses a polymeric membrane (as a model of
the GI wall) over time, and thus reflects the ability of the
formulation to resupply free drug in solution to be further
passively transported across the polymeric membrane. In Table 8.1
below, Maximum Flux is the maximum observed rate of permeation
across the polymeric membrane, based on the slope of the absorption
curve over any period within the 240 minute duration of the
experiment, normalized for membrane area. Total drug recovery is
the % of the initial drug dose which has crossed the membrane when
the test ended at 240 minutes.
TABLE-US-00006 TABLE 8.1 Membrane permeation tests for various
enzalutamide SDDs and controls. Total Drug Recovery Maximum Flux
Sample (Dispersion #) (%) (.mu.g/cm.sup.2 .times. min) 25% A
HPMCAS-M SDD (D4) 87 3.3 40% A HPMCAS-M SDD (D5) 83 2.8 60% A
HPMCAS-M SDD (D6) 87 2.8 80% A HPMCAS-M SDD (D7) 69 2.0 25% A
HPMCAS-H SDD (D8) 91 3.3 40% A HPMCAS-H SDD (D9) 86 2.6 25%
A:PVP-VA64 SDD (D2) 94 4.8 40% A PVP VA64 SDD (D10) 85 2.8
Amorphous (spray-dried) enzalutamide 56 1.3 Crystalline
enzalutamide (Control 1) 28 0.4
[0192] These data (Table 8.1) demonstrate that amorphous
enzalutamide and the SDDs with PVP-VA64 and HPMCAS are able to
resupply free drug as free drug is transported across the polymeric
membrane, at a rate (flux) and an extent superior to crystalline
enzalutamide (Control 1). The SDDs perform better than amorphous
enzalutamide in this respect. The lesser capacity of amorphous
enzalutamide is likely due to slower dissolution than the SDDs, due
to higher hydrophobicity. The data in Table 8.1 also indicate that
HPMCAS-SDDs at 25% A, 40% A, and 60% A are superior to HPMCAS-SDDs
at 80% A. Accordingly, in some embodiments enzalutamide/HPMCAS SDDs
have an enzalutamide content less than 80% A. The data in Table 8.1
also indicate that enzalutamide SDDs with the M- and H-grades of
HPMCAS perform equally well.
EXAMPLE 9
Enzalutamide SDDs with the Polymers HPMC, HPMCP, and
EUDRAGIT-L100.RTM.
[0193] A 60% A enzalutamide SDD was prepared with each of three
polymers: hydroxypropylmethylcellulose (E3 Prem grade) (HPMC E3
Prem); hydroxymethylcellulose phthalate (grade with nominal
phthalate content of 31%) (HPMCP-55); anionic 1:1 copolymer of
methacrylic acid and methylmethacrylate (EUDRAGIT L100.RTM.). 60% A
SDDs were prepared with these three polymers, using the mini spray
drier, and the conditions shown in Table 2. Each of the three 60% A
SDDs exhibited no sharp features in their PXRD diffactograms, and
were thus amorphous.
[0194] The three 60% SDDs were tested in the in vitro
microcentrifuge dissolution test, in addition to a 60% A HPMCAS-M
dispersion and Control 1 (crystalline enzalutamide). Table 9.1
presents the dissolution data, and Table 9.2 presents C.sub.max and
AUC.sub.90 values derived from these dissolution data. All four
SDDs exhibited enzalutamide supersaturation (.sub.Cmax) and
sustained supersaturation (AUC.sub.90), relative to crystalline
drug (Tables 9.1 and 9.2).
[0195] Table 9.1 shows that the enzalutamide SDDs with HPMCP-55 and
with EUDRAGIT L100.RTM. exhibit decreased enzalutamide
concentration in solution after the 40 minute time point, while
SDDs with HPMCAS and HPMC E3 Prem do not. This is reflected in the
in vitro AUC.sub.90 data shown in Table 9.2.
TABLE-US-00007 TABLE 9.1 In vitro dissolution (microcentrifuge
dissolution test) of various enzalutamide SDDs and crystalline
enzalutamide. Average .mu.g/mL 60% A: 60% A: HPMCAS- HPMC 60% A:
60% A: Time M (Disp (Disp HPMCP Eudragit Crystalline (min) D12)
D14) (Disp D15) (Disp D16) enzalutamide 0 0.00 0.00 0.00 0.00 0.32
4 77.69 108.33 90.21 57.80 5.23 10 84.96 108.65 88.19 68.93 8.04 20
93.53 109.16 100.48 81.42 7.69 40 102.73 109.70 109.37 91.94 8.65
90 108.32 104.10 36.07 34.19 9.14 1200 58.82 36.29 21.75 23.66
12.12
TABLE-US-00008 TABLE 9.2 C.sub.max and AUC.sub.90 values for
various enzalutamide SDDs and crystalline enzalutamide
(microcentrifuge dissolution test). C.sub.max,90 min.sup.a
AUC.sub.90 min.sup.b Sample (Dispersion #) (.mu.g/mL) (min *
.mu.g/mL) 60% A HPMCAS-M SDD (D12) 110 8,800 60% A HPMC E3 Prem SDD
(D14) 110 9,500 60% A HPMCP-55 SDD (D15) 110 7,400 60% A
Eudragit-L100 SDD (D16) 90 6,100 Crystalline enzalutamide (Control
1) 10 740 .sup.aC.sub.max,90 min = maximum drug concentration
through 90 minutes. .sup.bAUC.sub.90 min = area under the curve at
90 minutes.
[0196] The membrane permeation test was carried out for 60% A
enzalutamide SDDs with HPMCAS-M, HPMC E3 Prem, HPMCP-55, and
Eudragit-L100, as described in Example 8. The data in Table 9.3
demonstrate that each of the four SDDs exhibit higher transmembrane
flux than crystalline enzalutamide, and have the capacity to
replace absorbed free drug. The data in Table 9.3 also demonstrate
that the SDDs with HPMCAS-M and HPMC E3 Prem have greater
transmembrane flux and thus greater capacity to replace absorbed
free drug than do SDDs with HPMCP-55 and Eudragit-L100.
TABLE-US-00009 TABLE 9.3 Membrane-Permeation Test Results for SDDs
and Crystalline enzalutamide Maximum Flux Total Drug Formulation
(Dispersion #) (.mu.g/cm.sup.2-min) Recovery (%) 60% A: HPMCAS-MG
SDD (D12) 3.7 81 60% A: HPMC E3 Prem SDD (D14) 2.1 75 60% A: HPMCP
HP55 SDD (D15) 1.6 62 60% A: Eudragit L100 SDD (D16) 1.7 55
Crystalline enzalutamide (Control 1) 0.4 35
EXAMPLE 10
[0197] One Kilo-scale Batch of 60% A:HPMCAS-M SDD (Dispersion D18).
A large batch of 60% A:HPMCAS-M SDD was prepared using a PSD-1
Spray-drier. Spray-drying conditions are presented in Table 10.1
(and in Table 2.1). Powder properties for the spray-dried material
after tray-drying are also presented in Table 10.1.
TABLE-US-00010 TABLE 10.1 Spray-drying conditions and powder
properties for 1 kilo-scale lot of 60% A: HPMCAS-M enzalutamide SDD
(Dispersion D18). SPRAY-DRYING CONDITIONS Solids in spray solution
18.0% Run size 900 g enzalutamide Run time 36 min Drying gas
T.sub.in 100 .+-. 10.degree. C. Drying gas T.sub.out 30 .+-.
5.degree. C. Drying gas flow rate 1750 .+-. 300 g/min Spray
solution feed rate 230 .+-. 30 g/min Spray Systems SK79-16 nozzle
pressure 370 .+-. 100 psi SDD PARTICLE PROPERTIES Powder bulk
density 0.33 g/cc Powder tapped density 0.42 g/cc Volume Mean
Diameter 30 .mu.m DV10 9 .mu.m DV50 25 .mu.m DV90 59 .mu.m Span
[(DV90 - DV10)/DV50] 2.0 (unit-less)
EXAMPLE 11
Preparation of Enzalutamide Drug/Polymer Dispersions By Hot Melt
Extrusion (HME)
[0198] HME dispersions were produced using dry-powder blends of
enzalutamide and HPMCAS-M or PVP VA at three different drug
loadings: 25% A, 40% A, and 60% A. Using a volumetric powder
feeder, the blends were fed at a controlled rate to a 7.5-mm
MP&R2.TM. Model ME7.5 Twin-Screw Extruder (MP&R,
Hackensack, N.J.). The extruder is capable of reaching 210.degree.
C. and is equipped with a 1/8-inch cylindrical die. Extrudates were
milled by hand using a mortar and pestle for subsequent testing.
For a variety of extrusion runs, Table 11.1 presents the extrusion
temperature, the crystallinity of the dispersion (amorphous is
desired), and the glass transition temperature (Tg) measured by
DSC.
TABLE-US-00011 TABLE 11.1 Extrusion temperature, and extrudate
properties after milling with mortar and pestle Control
Crystallinity by PXRD & Formulation Temp..sup.a Differential
Scanning T.sub.g (Dispersion #) (.degree. C.) Calorimetry (.degree.
C.) 25% A: PVP-VA64 (D19) 150 Amorphous 104 25% A: PVP-VA64 (D20)
195 Amorphous 104 40% A: PVP-VA64 (D21) 195 Amorphous 103 60% A:
PVP-VA64 (D22) 170 Crystalline 103 60% A: PVP-VA64 (D23) 190
Amorphous 99 25% A: HPMCAS-M 170 Partially Crystalline* 93 (D24)
25% A: HPMCAS-M 190 Partially Crystalline 95 (D25) 25% A: HPMCAS-M
195 Partially Crystalline 95 (D26) 40% A: HPMCAS-M 195 Partially
Crystalline 90 (D28) 40% A: HPMCAS-M 220 Amorphous 88 (hot
plate).sup.b (D29) 60% A: HPMCAS-M 170 Crystalline -- (D30)
*Partially Crystalline means that while a Tg was observed, a
crystalline drug melt peak was also observed. The PXRD showed
evidence that some crystals were present. Controls were not
performed to identify the amount of drug that was amorphous or
crystalline. .sup.aThis is the control temperature for the terminal
extruder barrels and the die. The actual product temperature is
higher in the extruder due to additional frictional heat. It is
difficult to measure the actual product temperature but was done
using a temperature probe during the preparation of Dispersion D26.
In that case, the extruder control temperature was 195.degree. C.
and the product temperature was measured at approximately
215.degree. C. .sup.bThis sample was prepared on a hot plate at a
temperature higher than was possible using the MP&R
extruder.
[0199] The results in Table 11.1 demonstrate that amorphous
enzalutamide: PVP-VA64 dispersions can be prepared by HME at 25% A
and 40% A. Amorphous 60% A:PVP-VA64 dispersions can also be
prepared if the temperature is held at 190.degree. C. enzalutamide
dispersions with HPMCAS-M were crystalline or partially
crystalline, when prepared at the temperatures possible on the
extruder used. Preparation at 220.degree. C. on a hot plate
resulted in an amorphous 40% A:HPMCAS-M dispersion. Preparation of
HME dispersions of MDC3100 with HPMCAS at temperatures above
200.degree. C. is non-optimal because HPMCAS degrades in this
temperature range.
[0200] Dissolution of enzalutamide/polymer dispersions prepared by
HME was evaluated using the microcentrifuge dissolution test, after
dispersions were sieved to give various particle size ranges.
Dissolution results are presented in Table 11.2.
TABLE-US-00012 TABLE 11.2 Microcentrifuge dissolution test results
for enzalutamide dispersions prepared by hot melt extrusion. The
total amount of sample dosed was 200 mcg per ml of dissolution
medium. The dissolution medium was Model Fasted Duodenal Solution
(MFDS) (0.5 wt % NaTC/POPC in PBS, pH 6.5, 290 mOsm). Results for
SDDs of similar composition are presented for comparison.
C.sub.max90.sup.a Sample (Dispersion #) (.mu.g/mL) AUC.sub.90.sup.b
(min * .mu.g/mL) 25% A HPMCAS-M SDD (D11) 130 11,000 25% A HPMCAS-M
HME dispersion (150 to 355 .mu.m) 110 6,000 (D26) 25% A HPMCAS-M
HME dispersion (50 to 150 .mu.m) 140 10,700 (D26) 25% A HPMCAS-M
HME dispersion (<50 .mu.m) 140 11,600 (D26) 40% A HPMCAS-MG SDD
(D31) 110 9,100 40% A HPMCAS-MG HME dispersion (150 to 355 .mu.m)
40 2,300 (D28) 40% A HPMCAS-MG HME dispersion (50 to 150 .mu.m) 80
6,200 (D28) 40% A HPMCAS-MG HME dispersion (<50 .mu.m) 110 8,800
(D28) 25% A PVP VA SDD (D2) 130 9,700 25% A PVP VA HME dispersion
(150 to 355 .mu.m) 90 6,400 (D20) 25% A PVP VA HME dispersion (50
to 150 .mu.m) 110 7,900 (D20) 25% A PVP VA HME dispersion (<50
.mu.m) (D20) 130 9,000 40% A PVP VA SDD (D10) 110 7,500 40% A PVP
VA HME dispersion (150 to 355 .mu.m) 60 4,700 (D21) 40% A PVP VA
HME dispersion (50 to 150 .mu.m) 100 8,200 (D21) 40% A PVP VA HME
dispersion (<50 .mu.m) (D21) 130 8,500 .sup.aC.sub.max90 =
maximum drug concentration through 90 minutes .sup.bAUC.sub.90 =
area under the time/concentration curve at 90 minutes
[0201] The data in Table 11.2 demonstrate that there is a particle
size effect for supersaturation using HME-prepared dispersions of
enzalutamide. HME dispersions with HPMCAS or PVP-VA, with a
particle size <50 .mu.m, are as efficacious as SDDs of identical
composition. In some cases, HME dispersions with particle size
50-150 .mu.m are also similar in efficacy to SDDs of identical
composition. HME dispersions with particle size 150-355 .mu.m are
generally less efficacious than SDDs in achieving and maintaining
supersaturation of enzalutamide.
EXAMPLE 12
Relative Bioavailability of Enzalutamide Amorphous Drug and
Spray-Dried Dispersion Formulations in Rats
[0202] Five groups of jugular vein-cannulated CD.RTM. rats (n=6 per
group) were dosed five enzalutamide formulations by oral gavage, at
a dose of 20 mg/kg, in a volume of 2 ml/kg. Blood samples were
obtained at 1, 3, 6, 12, 24, 36, 48, 60, and 72 hr post-dose.
[0203] The analytes, enzalutamide, MDPC0002, and MDPC0001 and
internal standards (IS), N-.sup.13CD.sub.3-enzalutamide,
MDPC0002-.sup.13CD.sub.3, and MDPC0001-.sup.13CD.sub.3 were
extracted from 0.050 .mu.L of rat plasma by a liquid-liquid
extraction procedure. Internal standard working solution (25.0
.mu.L) was added to all wells except the matrix blank. A 25.0-.mu.L
volume of acetonitrile was added all matrix blank samples. After
adding 200 .mu.L of 5% sodium bicarbonate in water buffer solution,
the plate was vortexed for approximately 10 seconds. A Tomtec
Quadra 96-well pipettor was used to add 1.050 mL of methyl
tert-butyl ether (MTBE) to all wells, mixed, and approximately 1.00
mL of the organic layer was transferred to a clean 96-well plate.
The samples were evaporated under heated nitrogen and reconstituted
with 250 .mu.L of 0.1% formic acid in methanol/water (40:60, v/v).
The plate was covered and gently vortexed for approximately 10
seconds. The extracts were chromatographed under reverse phase
conditions on an ACE 5 C18 HPLC 5 .mu.m, 2.1.times.30 mm column.
The compounds were detected and quantified by tandem mass
spectrometry in positive ion mode on an MDS Sciex API 3000 equipped
with a Turbo IONSPRAY.RTM. probe. Calibration curves were obtained
by performing a linear regression (weighted 1/x.sup.2) of the data
from the calibration standards.
[0204] Plasma enzalutamide concentration vs. time curves were
prepared, and values for the following parameters were determined.
C.sub.max is the highest enzalutamide concentration observed for
each rat. Tmax is the time that C.sub.max is first achieved.
AUC.sub.0-72 is the area under the plasma enzalutamide
concentration vs. time plot out to 72 hr post-dosing.
Pharmacokinetic data for the formulations studied are presented in
Table 12.1.
TABLE-US-00013 TABLE 12.1 Mean pharmacokinetic parameters
(.+-.standard deviation) in rats for enzalutamide formulations.
Crystalline drug, amorphous drug, and SDDs were dosed in suspension
in a 0.5% methylcellulose vehicle. C.sub.max Tmax AUC.sub.0-72
enzalutamide Formulation (.mu.g/ml) (hr) (.mu.g hr/ml) Crystalline
drug (Control 1) 3.53 .+-. 0.66 6.05 .+-. 0.92 72.7 .+-. 18.4
Solution in Labrasol 10.1 .+-. 1.38 5.86 .+-. 0.99 201 .+-. 42.9
(4.23 mg/ml) (Control 2) Spray-dried amorphous drug 7.14 .+-. 0.97
2.55 .+-. 0.57 121 .+-. 16.4 25% A: HPMCAS-M 10.8 .+-. 1.63 2.96
.+-. 0.65 171 .+-. 40.2 60% A: HPMCAS-M 10.3 .+-. 1.66 3.30 .+-.
0.77 196 .+-. 39.6
[0205] These data demonstrate that dosing a suspension of amorphous
enzalutamide results in a higher C.sub.max and AUC than after
dosing a suspension of crystalline drug (Control 1). Even greater
improvement is observed after dosing a Labrasol solution, a 25%
A:HPMCAS-M SDD, or a 60% A:HPMCAS-M SDD.
[0206] The AUC.sub.0-72 data demonstrate that the 25% A:HPMCAS-M
and 60% A:HPMCAS-M dispersions give higher bioavailability than the
spray-dried amorphous drug. The 60% A:HPMCAS-M dispersion is
equivalent in C.sub.max and AUC.sub.0-72 to the Labrasol
solution.
EXAMPLE 13
Relative Bioavailability of Enzalutamide Amorphous Drug and Hot
Melt Extrusion (HME) Dispersion Formulations in Rats
[0207] Six groups of jugular vein-cannulated CD.RTM. rats (n=6 per
group) were dosed six enzalutamide formulations by oral gavage, at
a dose of 20 mg/kg, in a volume of 2 ml/kg, with the exception of
one group which was dosed intravenously via tail vein. Blood
samples were obtained at 1, 3, 6, 12, 24, 36, 48, 60, and 72 hr
post-dose.
[0208] The analytes, enzalutamide, MDPC0002, and MDPC0001 and
internal standards (IS), N-.sup.13CD.sub.3-enzalutamide,
MDPC0002-.sup.13CD.sub.3, and MDPC0001-.sup.13CD.sub.3 were
extracted from 0.050 .mu.L of rat plasma by a liquid-liquid
extraction procedure. Internal standard working solution (25.0
.mu.L) was added to all wells except the matrix blank. A 25.0-.mu.L
volume of acetonitrile was added all matrix blank samples. After
adding 200 .mu.L of 5% sodium bicarbonate in water buffer solution,
the plate was vortexed for approximately 10 seconds. A Tomtec
Quadra 96-well pipettor was used to add 1.050 mL of methyl
tert-butyl ether (MTBE) to all wells, mixed, and approximately 1.00
mL of the organic layer was transferred to a clean 96-well plate.
The samples were evaporated under heated nitrogen and reconstituted
with 250 .mu.L of 0.1% formic acid in methanol/water (40:60, v/v).
The plate was covered and gently vortexed for approximately 10
seconds. The extracts were chromatographed under reverse phase
conditions on an ACE 5 C18 HPLC 5 .mu.m, 2.1.times.30 mm column.
The compounds were detected and quantified by tandem mass
spectrometry in positive ion mode on an MDS Sciex API 3000 equipped
with a Turbo IONSPRAY.RTM. probe. Calibration curves were obtained
by performing a linear regression (weighted 1/x.sup.2) of the data
from the calibration standards.
[0209] Plasma enzalutamide concentration vs. time curves were
prepared, and values for the following parameters were determined.
C.sub.max is the highest enzalutamide concentration observed for
each rat. Tmax is the time that C.sub.max is first achieved.
AUC.sub.0-72 is the area under the plasma enzalutamide
concentration vs. time plot out to 72 hr post-dosing.
Pharmacokinetic data for the formulations studied are presented in
Table 13.1.
TABLE-US-00014 TABLE 13.1 Mean AUC.sub.0-inf and % Bioavailability
in rats for enzalutamide formulations. Crystalline drug, amorphous
drug, and HME dispersion formulations were dosed in suspension in a
0.5% methylcellulose vehicle. For intravenous dosing, enzalutamide
was dissolved in 50% polyethyleneglycol-400/20% ethanol (200
proof)/30% sterile water for injection (USP), and was dosed via
tail vein. Mean AUC.sub.0-inf Bioavailability enzalutamide
Formulation (.mu.g hr/ml) (%)* Intravenous (IV) 231 -- Crystalline
drug (Control 1) 62.6 27.1 Solution in Labrasol (4.23 mg/ml) 225
97.4 (Control 2) Spray-dried amorphous drug 132 57.1 25% A:
PVP-VA64 HME dispersion 167 72.3 60% A: PVP-VA64 HME dispersion 142
61.5 25% A: HPMCAS HME dispersion 187 81.0 *Bioavailability = Mean
AUC.sub.0-inf/IV Mean AUC.sub.0-inf. For example, 62.6/231 =
27.1%
[0210] These data demonstrate that dosing a suspension of amorphous
enzalutamide results in a higher AUC than after dosing a suspension
of crystalline drug (Control 1). Even greater improvement is
observed after dosing HME dispersions of enzalutamide with the
polymers PVP-VA64 and HPMCAS. The HME dispersion with HPMCAS gave a
higher bioavailability than the dispersions with PVP-VA64.
EXAMPLE 14
Tablets Containing Enzalutamide/Polymer Spray-Dried Dispersions
[0211] Enzalutamide tablets were prepared by direct compression,
from the formulation in Table 14.1.
TABLE-US-00015 TABLE 14.1 Tablet composition. Component Quantity
(mg/tablet) 60% A enzalutamide/HPMCAS-M SDD 266.7 Colloid silicon
dioxide (Cab-O-Sil M5P) 2.5 Microcrystalline cellulose (Avicel
PH102) 94.8 Lactose monohydrate, spray-dried (Fast Flo 316) 94.7
Croscarmellose sodium (Ac-Di-Sol) 40.0 Magnesium stearate 1.3 TOTAL
500.0
[0212] The following procedure was used to form the tablets. First,
the solid amorphous dispersion was added to an appropriate
container. A portion of the solid amorphous dispersion
(approximately 3 to 10 times the weight of colloidal silicon
dioxide) was added to an LDPE bag containing the colloidal silicon
dioxide. The SDD was manually mixed with the silicon dioxide for
approximately 2 minutes. The mixture was passed through a No. 30
mesh screen, and added to the container. The mixture was blended
for 15 minutes at 12 rpm using a Turbula mixer. Microcrystalline
cellulose, lactose monohydrate, and croscarmellose sodium were
added to the container, and the mixture was blended for 15
minutes.
[0213] Next, the mixture was subjected to high-shear mixing by
passing it through a Comil 197 equipped with a 0.032-inch screen
and 1601 impeller (impeller speed 1000 rpm). Since the Comil has a
chamber diameter of 2.2 inches, the Froude Number for this
high-shear mixing is about 125. The milled material was added to a
container. A portion (approximately 3 to 10 times the weight of
magnesium stearate) was added to an LDPE bag containing the
magnesium stearate. The material was manually mixed with the
magnesium stearate for approximately 30 seconds to 2 minutes,
passed through a No. 20 mesh screen, and added to the container.
The mixture was blended for 5 minutes at 12 rpm using a Turbula
mixer.
[0214] Tablets were compressed using a rotary single-layer press,
with 13/32'' standard round convex tooling. Tablets weighed 500 mg
each, with a hardness of 12 to 16 kP.
[0215] Carr's Index Testing
[0216] The flowability for Example 14 tablet blend, and for the
dispersion alone, was evaluated using the Carr's index calculated
from bulk and tap density. First, bulk density is measured using a
graduated cylinder. The empty cylinder is weighed, the material is
added, the final weight and volume are measured, and bulk density
is calculated as shown below.
Bulk Density=Weight of Sample (g)/Volume of Sample (cc)
[0217] To measure the tapped density, the sample in the cylinder
above is placed in a VanKel tap density instrument, set for 2000
cycles. The ending volume is recorded, and the tapped density is
calculated as shown below.
Tapped Density=Weight of Sample (g)/Volume of Sample after 2000 Tap
Cycles (cc)
[0218] Carr's index was determined using the following equation
C = 100 .times. ( 1 - .rho. B .rho. T ) ##EQU00001##
[0219] where .rho..sub.B is equal to the bulk density and
.rho..sub.T is equal to the tapped density. The results are shown
below in Table A.
TABLE-US-00016 TABLE A Carr's Index Formulation Carr's Index 60%
enzalutamide:HPMCAS-M SDD 33.3% Example 14 tablet blend (made with
colloidal 24.2% silicon dioxide and high-shear mixing)
[0220] The lower Carr's index of the formulation of Example 14
demonstrates improved flow properties of the dispersion, which
enables tablet formation using a direct compression Process.
EXAMPLE 15
Human Pharmacokinetics Study
[0221] A randomized, two-period crossover pilot bioequivalence and
food effect study was carried out in humans. This study compared
two formulations. The reference formulation was a liquid-filled,
soft gelatin capsule containing 40 mg enzalutamide dissolved in
Labrasol; four such capsules are required to deliver a 160 mg dose.
The test formulation was a tablet containing 160 mg enzalutamide in
the form of a 60% A:HPMCAS-M spray-dried dispersion. The
liquid-filled capsule formulation had previously been used in
clinical studies in castration-resistant prostate cancer. The
four-capsule regimen is inconvenient because of the number of
capsules that must be taken, particularly in the light of the fact
that cancer patients have to take multiple drugs. The objectives of
the human pharmacokinetics study were as follows: [0222] 1. To
evaluate the bioequivalence of two oral formulations of
enzalutamide following a single 160 mg dose in healthy male
subjects under fasted conditions; [0223] 2. To evaluate the
bioequivalence of two oral formulations of enzalutamide following a
single 160 mg dose in healthy male subjects under fed conditions;
[0224] 3. To assess the effects of food on the rate and extent of
absorption of two oral formulations following a single 160 mg dose
in healthy male subjects; [0225] 4. To evaluate the safety and
tolerability of two oral formulations of enzalutamide following a
single 160 mg dose in healthy male subjects under fasted or fed
conditions. Sixty healthy adult male subjects were divided into
four cohorts as follows.
TABLE-US-00017 ##STR00002## [0225] ##STR00003##
[0226] The fasted conditions involved an overnight fast from food
(minimum 10 hours) prior to dosing, and the fed conditions involved
a standard high-fat, high-calorie meal that was ingested within 30
minutes prior to dosing. The high-fat, high-calorie meal was
described in "US FDA Guidance for Industry: Food Effect
Bioavailability and Fed Bioequivalence Studies (December 2002)." In
both the fasted and fed conditions, the clinical research personnel
administered the study medication at approximately 0800 hours with
ambient temperature water to a total volume of about 240 mL.
Subjects were required to swallow the study medication whole and
not chew the medication prior to swallowing. The subjects were
required to refrain from drinking beverages other than water during
the first 4 hours after dosing. Water was allowed except 1 hour pre
and post dose. Lunch was served .about.4 hours post dose, and
dinner was served .about.9 to 10 hours post dose.
[0227] Blood samples for pharmacokinetics determinations were
collected in each period as follows: [0228] Day 1: pre-dose (0 hr)
and post-dose 15, 30, and 45 minutes; and at 1, 2, 3, 4, 6, 8, and
12 hours; [0229] Day 2: 0 and 12 hours; [0230] Days 3, 5, 7, 14,
21, 28, 35, and 42: 0 hours.
[0231] Plasma isolated from the whole blood samples was analyzed
for concentrations of enzalutamide and its metabolites MDPC0001 and
MDPC0002 using a sensitive, specific, and validated assay based on
liquid chromatography and tandem mass spectroscopy (LC/MS/MS). The
analytes, enzalutamide, MDPC0002, and MDPC0001 and internal
standards (IS), N 13CD3 enzalutamide, MDPC0002 13CD3, and
MDPC0001-13CD3 were extracted from 0.050 .mu.L of plasma by a
liquid extraction procedure. Internal standard working solution
(25.0 .mu.L) was added to all wells except the matrix blank. A
25.0-.mu.L volume of acetonitrile was added all matrix blank
samples. After adding 200 .mu.L of 5% sodium bicarbonate in water
buffer solution, the plate was vortexed for approximately 10
seconds. A Tomtec Quadra 96-well pipettor was used to add 1.050 mL
of methyl tert-butyl ether (MTBE) to all wells, mixed, and
approximately 1.00 mL of the organic layer was transferred to a
clean 96-well plate. The samples were evaporated under heated
nitrogen and reconstituted with 250 .mu.L of 0.1% formic acid in
methanol/water (40:60, v/v). The plate was covered and gently
vortexed for approximately 10 seconds. The extracts were
chromatographed under reverse phase conditions on an ACE 5 C18 HPLC
5 .mu.m, 2.1.times.30 mm column. The compounds were detected and
quantified by tandem mass spectrometry in positive ion mode on an
MDS Sciex API 3000 equipped with a Turbo IONSPRAY.RTM. probe.
Calibration curves were obtained by performing a linear regression
(weighted 1/x2) of the data from the calibration standards.
[0232] A summary of pharmacokinetic parameters is presented in
Table 15.1.
TABLE-US-00018 TABLE 15.1 Analysis of Formulation Bioequivalence:
Geometric Mean (CV %) Plasma Enzalutamide Pharmacokinetic Parameter
Values by Treatment and Food Condition A. Comparison of Tablet and
Capsule Formulations under Fasted Conditions Liquid-Filled Soft
Gelatin Tablet Capsule Formulation, Formulation, Fasted Fasted 90%
Confidence Pharmacokinetic Conditions Conditions Ratio.sup.b
Interval (%) Parameters (Units).sup.a (Test) (Reference) (%) Lower
Upper n 28 29 -- -- -- AUC.sub.Day1-7 (.mu.g h/mL) 177 (24) 185
(25) 95 92 97 AUC.sub.0-t (.mu.g h/mL) 255 (29) 269 (30) 95 92 97
AUC.sub.0-inf (.mu.g h/mL) 263 (28) 278 (29) 94 92 97 C.sub.max
(.mu.g/mL) 2.98 (24) 5.16 (20) 57 54 62 t.sub.max.sup.c (h) 4.00
(2.00-6.00) 1.00 (0.75-3.00) -- -- -- t.sub.1/2 (days) 3.45 (36)
3.67 (32) -- -- -- B. Comparison of Tablet and Capsule Formulations
under Fed Conditions Liquid-Filled Soft Gelatin Tablet Capsule
Formulation, Formulation, 90% Confidence Pharmacokinetic Fed
Conditions Fed Conditions Ratio.sup.d Interval (%) Parameters
(units) (Test) (Reference (%) Lower Upper n 15 15 -- -- --
AUC.sub.Day1-7 (.mu.g h/mL) 191 (20) 187 (19) 102 91 114 C.sub.max
(.mu.g/mL) 2.96 (25) 3.86 (35) 77 65 91 t.sub.max.sup.c (h) 1.00
(4.00-24.00) 2.00 (0.50-6.00) -- -- -- n = total number of subjects
contributing to the summary statistics for PK parameters .sup.aArea
under the plasma concentration-time profile from time zero to Day 7
(AUC.sub.Day1-7), AUC from time zero to the last measurable
concentration (AUC.sub.0-t), AUC from time zero to infinity
(AUC.sub.0-inf), maximum plasma concentration (C.sub.max), and time
to maximum plasma concentration (t.sub.max). .sup.bRatio of least
squares means (Test/Reference) based on crossover-treatment
bioequivalence statistical tests. .sup.cMedian (range). .sup.dRatio
of least squares means (Test/Reference) based on parallel-treatment
bioequivalence statistical tests.
[0233] The analysis showed the extent of oral bioavailability for
the Test and Reference formulations to be equivalent, the AUCs for
the two formulations being essentially the same regardless of food
conditions (fasted or fed).
EXAMPLE 16
[0234] After 1 part by weight of enzalutamide and 3 parts by weight
of hydroxypropylmethylcellulose acetate succinate (HPMCAS-MG,
Shin-Etsu Chemical Co., Ltd) were dissolved in acetone, a spray
dryer (QSD-0.8-CC, GEA) was used to obtain a solid dispersion.
[0235] After the solid dispersion was mixed with calcium hydrogen
phosphate hydrate, croscarmellose sodium and magnesium stearate by
mortar and pestle, the mixture was formed into tablets by using an
oil press tableting machine to obtain a tablet containing the solid
dispersion at 12kN of tableting pressure. The formulation is shown
in Table 16.
EXAMPLE 17
[0236] After 1 part by weight of enzalutamide and 3 parts by weight
of hydroxypropylmethylcellulose acetate succinate were dissolved in
acetone, a spray dryer (QSD-0.8-CC, GEA) was used to obtain a solid
dispersion.
[0237] After the solid dispersion was mixed with calcium hydrogen
phosphate hydrate, croscarmellose sodium and magnesium stearate,
the mixture was formed into granules using dry granulation machine
(roller compactor, TF-MINI, FREUND). After the resulting granules
were mixed with croscarmellose sodium and magnesium stearate, the
mixture was formed into tablets using a rotary tableting machine to
obtain a tablet containing the solid dispersion. After tableting,
the tablet was filmcoated by using filmcoating machine (HCT-30 Hi
coater 30, FREUND). The formulation is shown in Table 16.
TABLE-US-00019 TABLE 16 component Example 16 Example 17 Example 18
Example 21 enzalutamide 80.0 80.0 80.0 160
hydroxypropylmethylcellolose 240.0 240.0 160.0 106.7 acetate
succinate calcium hydrogen phosphate 160.6 160.6 240.6 -- hydrate
colloidal silicon dioxide -- -- -- 2.5 microcrystalline cellulose
-- -- -- 94.8 lactose monohydrate -- -- -- 94.7 croscarmellose
sodium 54.0 54.0 54.0 40.0 magnesium stearate 5.4 5.4 5.4 1.30
filmcoating agent -- 16.2 17.5 total (mg) 540.0 556.2 540.0 517.5
tablet size 14.8 mm .times. 7.8 mm -- --
EXAMPLE 18
[0238] After 1 part by weight of enzalutamide and 2 parts by weight
of hydroxypropylmethylcellulose acetate succinate were dissolved in
acetone, a spray dryer (QSD-0.8-CC, GEA) was used to obtain a solid
dispersion. Further, a tablet was prepared as the same method as
Example 16. The formulation is shown in Table 16.
EXAMPLE 19
[0239] A solid dispersion, which comprises 1 part by weight of
enzalutamide and 1.5 part by weight of hydroxypropylmethylcellulose
acetate succinate, was prepared as the same method as Example
18.
EXAMPLE 20
[0240] A solid dispersion, which comprises 1 part by weight of
enzalutamide and 1 part by weight of hydroxypropylmethylcellulose
acetate succinate, was prepared as the same method as Example
18.
EXAMPLE 21
[0241] A solid dispersion, which comprises 1 part by weight of
enzalutamide and 0.67 part by weight of
hydroxypropylmethylcellulose acetate succinate, was prepared as the
same method as Example 18.
[0242] The solid dispersion was mixed with colloidal silicon
dioxide. Microcrystalline cellulose, lactose monohydrate, and
croscarmellose sodium are added to the mixture and blending is
continued. The mixture is then milled. After magnesium stearate is
mixed with the milled mixture, core tablets are compressed on a
tablet press. The tablet was filmcoated by using filmcoating
machine.
EXAMPLE 22
Solubility Test
[0243] Enzalutamide and the polymer were dissolved in 2 mL of 50%
acetone and 50% USP 6.8 buffer. The polymer was used each of
hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co.,
Ltd.), hydroxypropylmethylcellulose 2910 (TC-5R, Shin-Etsu Chemical
Co., Ltd.), polyvinylpyrrolidone (Kollidon, BASF), copolyvidone
(Kollidon VA-64, BASF), hydroxypropylmethylcellulose acetate
succinate (HPMCAS-MG, Shin-Etsu Chemical Co., Ltd) and was
dissolved in 500 mL of a second fluid for disintegrating test used
in a dissolution test described in the Japanese Pharmacopoeia
fifteenth edition. For comparison, 2 mL of 50% acetone and 50% USP
6.8 buffer dispersed enzalutamide without such polymers was
prepared.
[0244] To each vessel, 2 mL of a solution of enzalutamide was
added, and the solubility of enzalutamide was measured after 5
minutes. The test was carried out using 900 mL of a USP phosphate
buffer (pH 6.8) as a test solution.
[0245] Each solubility is shown in Table 17.
TABLE-US-00020 TABLE 17 polymer solubility (.mu.g/mL)
hydroxypropylmethylcellulose 2910 (TC-5E) 42.7
hydroxypropylmethylcellulose 2910 (TC-5R) 39.2 polyvinylpyrrolidone
40.1 copolyvidone 47.4 hydroxypropylmethylcellulose acetate
succinate 31.1 without polymer 29.0
EXAMPLE 23
Dissolution Test
[0246] A drug release property from each of the solid dispersion
prepared in Examples 1 to 6 or each of the tablet prepared in
Examples 1, 3 and 6 was evaluated by a liquid-replacement
dissolution test, in which a paddle method (50 rpm) was started
using 300 mL of 0.03N hydrochloric acid (pH1.2), and the liquid
conditions for the dissolution test were changed to pH6.8 and 900
mL 30 minutes after the beginning of the USP 34-NF 29. The drug
release property was evaluated. The dissolution profiles of the
enzalutamide from the solid dispersion and the tablet are shown in
FIG. 3, FIG. 4, respectively.
EXAMPLE 24
Evaluation of Dissolution Stability
[0247] The tablet obtained in Example 17 was subjected to a
dissolution test to study their dissolution immediately after
formulation (at the start of storage) and after storage at
40.degree. C. and 75% relative humidity for 1 month. The
dissolution test was accomplished by the paddle method described
the United States Pharmacopoeia. A liquid-replacement dissolution
test, in which a paddle method (50 rpm) was started using 300 mL of
0.03N hydrochloric acid (pH1.2), and the liquid conditions for the
dissolution test were changed to pH6.8 and 900 mL 30 minutes after
the beginning of the USP 34-NF 29. The drug release property was
evaluated. The dissolution profile is shown in FIG. 5.
EXAMPLE 25
Dog Absorption Test
[0248] The tablets prepared in Examples 16, 18, and 21 and a soft
capsule for control were orally administered to dogs. The
formulation of the soft capsule is shown in Table 18. Percentage of
blood exposure of enzalutamide compared to the soft capsule, % AUC
and % C.sub.max, were evaluated.
[0249] The test formulations were administered with 50 mL water to
dogs had been fasted over night. The test formulations were used
one tablet in case of the tablet comprised 160 mg enzalutamide
(Example 21), two tablets in case of the tablet comprised 80 mg
enzalutamide (Example 16 and 17), or 4 capsules comprised 40 mg
enzalutamide for control.
[0250] After orally administered the test formulations, blood
samples were collected with time. A drug concentration in the
plasma (ng/mL) was measured and calculated maximum drug
concentration(Cmax) and AUC for 168 hr (AUC 0-168 h:ng*h/mL). The
dogs adjusted acid condition in the stomach were used in this test
on the assumption of healthy individuals.
[0251] % AUC and % Cmax of each formulation are shown in Table
19.
TABLE-US-00021 TABLE 18 soft capsule enzalutamide 40.000
caprylocaproyl polyoxylglycerides 904.96 BHA 0.946 BHT 0.095 total
(mg) 946.0
TABLE-US-00022 TABLE 19 Dog PK results % Cmax % AUC Example 6 102
99 Example 8 92 84 Example 21 72 70 Soft Capsule 100 100
EXAMPLE 26
X-Ray Analysis
[0252] The solid dispersions prepared in Examples 16 and 18, and
crystalline enzalutamide were evaluated for crystallinity using X
rays. In addition, the initial tablet prepared in Example 17 and
the tablet after stored at 40.degree. C. and 75% relative humidity
for 1 month in Test Example 18.
[0253] As shown in FIG. 6, the solid dispersions prepared in
Examples 16 and 18 were amorphous. As shown in FIG. 7, the tablet
obtained by storing the solid dispersion prepared in Example 17 at
40.degree. C. and 75% relative humidity for 1 month in Test Example
19 was also amorphous.
* * * * *