U.S. patent application number 15/533188 was filed with the patent office on 2017-12-21 for anticancer compositions.
The applicant listed for this patent is Aragon Pharmaceuticals, Inc.. Invention is credited to Dennis Martin Hester, Jason Michael Vaughn.
Application Number | 20170360754 15/533188 |
Document ID | / |
Family ID | 52006906 |
Filed Date | 2017-12-21 |
United States Patent
Application |
20170360754 |
Kind Code |
A1 |
Hester; Dennis Martin ; et
al. |
December 21, 2017 |
ANTICANCER COMPOSITIONS
Abstract
The present invention concerns pharmaceutical formulations of
ARN-509, which can be administered to a mammal, in particular a
human, suffering from an androgen receptor (AR)-related disease or
condition, in particular cancer, more in particular prostate
cancer, including but not limited to castration-resistant prostate
cancer, metastatic castration resistant prostate cancer,
chemotherapy-naive metastatic castration resistant prostate cancer,
biochemically relapsed hormone sensitive prostate cancer, or
high-risk, non-metastatic castration-resistant prostate cancer. In
one aspect, these formulations comprise a solid dispersion of
ARN-509 and HPMCAS. In one aspect, the solid dispersion of ARN-509
and HPMCAS is obtainable, in particular is obtained, by
melt-extruding a mixture comprising ARN-509 and HPMCAS and
optionally subsequently milling said melt-extruded mixture. In one
aspect, the solid dispersion of ARN-509 and HPMCAS is obtainable,
in particular is obtained, by spray drying a mixture comprising
ARN-509 and HPMCAS in a suitable solvent.
Inventors: |
Hester; Dennis Martin; (San
Diego, CA) ; Vaughn; Jason Michael; (High Point,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Aragon Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
52006906 |
Appl. No.: |
15/533188 |
Filed: |
December 3, 2015 |
PCT Filed: |
December 3, 2015 |
PCT NO: |
PCT/US2015/063661 |
371 Date: |
June 5, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4184 20130101;
A61K 9/141 20130101; A61K 9/16 20130101; A61K 9/1652 20130101; A61K
9/0053 20130101; A61K 9/1682 20130101; A61P 35/00 20180101; A61K
9/2077 20130101; A61K 9/2054 20130101 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61K 9/00 20060101 A61K009/00; A61K 9/16 20060101
A61K009/16; A61K 9/20 20060101 A61K009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 5, 2014 |
EP |
14196594.7 |
Claims
1. A solid dispersion comprising ARN-509 and HPMCAS.
2. A solid dispersion according to claim 1 wherein the dispersion
consists of ARN-509 and HPMCAS.
3. A solid dispersion according to claim 1 wherein the
weight-by-weight ratio of ARN-509:HPMCAS in the solid dispersion is
in the range from 1:1 to 1:5.
4. A solid dispersion according to claim 3 wherein the
weight-by-weight ratio of ARN-509:HPMCAS in the solid dispersion is
1:3.
5. A solid dispersion according to claim 1 wherein ARN-509 is
present in amorphous form.
6. A solid dispersion according to claim 1 wherein the dispersion
is a solid solution.
7. A solid dispersion according to claim 1 wherein the HPMCAS is
HPMCAS LG.
8. A solid dispersion according to claim 1 obtainable by spray
drying.
9. A solid dispersion according to claim 1 obtainable by hot melt
extrusion.
10. A particle consisting of a solid dispersion as defined in claim
1.
11. A particle comprising a solid dispersion as defined claim
2.
12. A pharmaceutical formulation comprising a pharmaceutically
acceptable carrier and a solid dispersion according to claim 1.
13. A pharmaceutical formulation comprising a pharmaceutically
acceptable carrier and particles according to claim 10.
14. A formulation according to claim 12 wherein the formulation is
a tablet.
15. A formulation according to claim 14 which is suitable for oral
administration.
16. A process for preparing the solid dispersion according to claim
8 comprising the steps of mixing ARN-509 and HPMCAS in a suitable
solvent and spray drying said mixture.
17. A process according to claim 16 wherein the suitable solvent is
a mixture of dichloromethane and methanol.
18. A process according to claim 17 wherein the weight:weight ratio
of dichloromethane to methanol in the mixture is 4:6.
19.-20. (canceled)
Description
[0001] The present invention concerns pharmaceutical formulations
of ARN-509, which can be administered to a mammal, in particular a
human, suffering from an androgen receptor (AR)-related disease or
condition, in particular cancer, more in particular prostate
cancer, including but not limited to castration-resistant prostate
cancer, metastatic castration resistant prostate cancer,
chemotherapy-naive metastatic castration resistant prostate cancer,
biochemically relapsed hormone sensitive prostate cancer, or
high-risk, non-metastatic castration-resistant prostate cancer. In
one aspect, these formulations comprise a solid dispersion of
ARN-509 and HPMCAS. In one aspect, the solid dispersion of ARN-509
and HPMCAS is obtainable, in particular is obtained, by
melt-extruding a mixture comprising ARN-509 and HPMCAS and
optionally subsequently milling said melt-extruded mixture. In one
aspect, the solid dispersion of ARN-509 and HPMCAS is obtainable,
in particular is obtained, by spray drying a mixture comprising
ARN-509 and HPMCAS in a suitable solvent.
[0002] The solid dispersion of ARN-509 and HPMCAS may be further
formulated with a pharmaceutically acceptable carrier into a
pharmaceutical formulation, such formulation providing improved
stability or improved shelf life. With the formulation of the
present invention the pill burden for the patient, in particular
the cancer patient, can be reduced, and hence therapy adherence and
therapy efficiency can be improved.
FIGURES
[0003] FIG. 1: XRD pattern of ARN-509 Form B.
[0004] FIG. 2: IR spectrum of ARN-509 Form B.
[0005] FIG. 3: DSC curve of ARN-509 Form B.
DETAILED DESCRIPTION
[0006] ARN-509 is a potent and specific antagonist of the androgen
receptor (AR). ARN-509's mechanism of action is antagonism of
androgen receptor signaling through inhibition of AR nuclear
translocation and DNA binding to androgen response elements.
[0007] The actions of androgens with androgen receptors have been
implicated in a number of diseases or conditions, such as androgen
dependent cancers, virilization in women, and acne, among others.
Compounds that diminish the effects of androgens with androgen
receptors and/or lower the concentrations of androgen receptors
find use in the treatment of diseases or conditions in which
androgen receptors play a role.
[0008] AR-related diseases or conditions include, but are not
limited to, benign prostate hyperplasia, hirsutism, acne, adenomas
and neoplasias of the prostate, benign or malignant tumor cells
containing the androgen receptor, hyperpilosity, seborrhea,
endometriosis, polycystic ovary syndrome, androgenic alopecia,
hypogonadism, osteoporosis, suppression of spermatogenesis, libido,
cachexia, anorexia, androgen supplementation for age related
decreased testosterone levels, prostate cancer, breast cancer,
endometrial cancer, uterine cancer, hot flashes, Kennedy's disease
muscle atrophy and weakness, skin atrophy, bone loss, anemia,
arteriosclerosis, cardiovascular disease, loss of energy, loss of
well-being, type 2 diabetes, and abdominal fat accumulation. Given
the central role of AR in prostate cancer development and
progression, ARN-509 is useful for the treatment of cancer, in
particular prostate cancer, including but not limited to
castration-resistant prostate cancer, metastatic castration
resistant prostate cancer, chemotherapy-naive metastatic castration
resistant prostate cancer, biochemically relapsed hormone sensitive
prostate cancer, or high-risk, non-metastatic castration-resistant
prostate cancer.
[0009] The chemical structure of ARN-509 is:
##STR00001##
[0010] ARN-509 or
4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspir-
o[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is currently in clinical
development as a nonaqueous, lipid-based solution that is filled
into softgel capsules, each containing 30 mg ARN-509. The daily
dose being studied is 240 mg/day by oral administration (or 8
softgel capsules). It has been found that in use, the softgel
capsules containing ARN-509 have a shelf life of only 6 months and
need cold chain storage.
[0011] An aspect of the invention relates to pharmaceutical
formulations, in particular solid pharmaceutical formulations, more
in particular solid pharmaceutical formulations for oral
administration of ARN-509, where such formulations have an improved
stability, a longer shelf life, or provide for a reduced pill
burden for the patient, in particular the cancer patient. The
pharmaceutical formulations of the present invention provide a
means to increase therapy adherence and therapy efficiency.
[0012] An aspect of the invention is a solid dispersion comprising
ARN-509 and HPMCAS.
[0013] HPMCAS or hydroxypropyl methylcellulose acetate succinate or
hypromellose acetate succinate (CAS number 71138-97-1) is a mixture
of acetic acid and monosuccinic acid esters of hydroxypropylmethyl
cellulose (IUPAC name: cellulose, 2-hydroxypropyl methyl ether,
acetate, hydrogen butanedioate). Different grades are available
differentiated based on degree/ratio of substitution (acetyl
content, succinoyl content) and particle size (micronized and
granular). In an aspect of the invention, the HPMCAS in the
dispersions with ARN-509 is HPMCAS LG (granular grade) or HPMCAS LF
(micronized grade) (Shin-Etsu Chemical Co., Ltd), in particular
HPMCAS LG.
[0014] An aspect of the invention is a solid dispersion comprising
ARN-509 and HPMCAS LG.
[0015] An aspect of the invention is a solid dispersion comprising
ARN-509 and HPMCAS LF.
[0016] An aspect of the invention is a solid dispersion consisting
of ARN-509 and HPMCAS.
[0017] An aspect of the invention is a solid dispersion consisting
of ARN-509 and HPMCAS LG.
[0018] An aspect of the invention is a solid dispersion consisting
of ARN-509 and HPMCAS LF.
[0019] A preferred grade of HPMCAS in the solid dispersions of the
invention is HPMCAS LG, because of its better and safer handling
properties.
[0020] In an aspect of the invention, the weight-by-weight ratio of
ARN-509:HPMCAS in the solid dispersion as described herein is in
the range from 1:1 to 1:10, preferably from 1:1 to 1:5, more
preferably from 1:1 to 1:3 or from 1:2 to 1:3. In an aspect of the
invention, the weight-by-weight ratio of ARN-509:HPMCAS is 1:2. In
an aspect of the invention, the weight-by-weight ratio of
ARN-509:HPMCAS is 1:3. In an aspect of the invention, the
weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2. In an aspect of
the invention, the weight-by-weight ratio of ARN-509:HPMCAS LG is
1:3. In an aspect of the invention, the weight-by-weight ratio of
ARN-509:HPMCAS LF is 1:2. In an aspect of the invention, the
weight-by-weight ratio of ARN-509:HPMCAS LF is 1:3.
[0021] An aspect of the invention is a particle consisting of a
solid dispersion as described herein.
[0022] An aspect of the invention is a particle consisting of a
solid dispersion comprising ARN-509 and HPMCAS, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or
1:3.
[0023] An aspect of the invention is a particle consisting of a
solid dispersion comprising ARN-509 and HPMCAS LG, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or
1:3.
[0024] An aspect of the invention is a particle consisting of a
solid dispersion comprising ARN-509 and HPMCAS LF, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or
1:3.
[0025] An aspect of the invention is a particle consisting of a
solid dispersion consisting of ARN-509 and HPMCAS, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or
1:3.
[0026] An aspect of the invention is a particle consisting of a
solid dispersion consisting of ARN-509 and HPMCAS LG, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or
1:3.
[0027] An aspect of the invention is a particle consisting of a
solid dispersion consisting of ARN-509 and HPMCAS LF, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or
1:3.
[0028] An aspect of the invention is a particle comprising a solid
dispersion as described hereinabove.
[0029] An aspect of the invention is a particle comprising a solid
dispersion comprising ARN-509 and HPMCAS, in particular wherein the
weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or 1:3.
[0030] An aspect of the invention is a particle comprising a solid
dispersion comprising ARN-509 and HPMCAS LG, in particular wherein
the weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or 1:3.
[0031] An aspect of the invention is a particle comprising a solid
dispersion comprising ARN-509 and HPMCAS LF, in particular wherein
the weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or 1:3.
[0032] An aspect of the invention is a particle comprising a solid
dispersion consisting of ARN-509 and HPMCAS, in particular wherein
the weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or 1:3.
[0033] An aspect of the invention is a particle comprising a solid
dispersion consisting of ARN-509 and HPMCAS LG, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or
1:3.
[0034] An aspect of the invention is a particle comprising a solid
dispersion consisting of ARN-509 and HPMCAS LF, in particular
wherein the weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or
1:3.
[0035] In an aspect of the invention, the particles as described
herein are obtainable, in particular are obtained, by
melt-extruding a mixture comprising ARN-509 and HPMCAS and
subsequently milling said melt-extruded mixture. In an aspect, the
particles as described herein are obtainable, in particular are
obtained, by melt-extruding a mixture consisting of ARN-509 and
HPMCAS and subsequently milling said melt-extruded mixture. In an
aspect, the weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or
1:3.
[0036] In an aspect of the invention, the particles as described
herein are obtainable, in particular are obtained, by
melt-extruding a mixture comprising ARN-509 and HPMCAS LG and
subsequently milling said melt-extruded mixture. In an aspect, the
particles as described herein are obtainable, in particular are
obtained, by melt-extruding a mixture consisting of ARN-509 and
HPMCAS LG and subsequently milling said melt-extruded mixture. In
an aspect, the weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2
or 1:3.
[0037] In an aspect of the invention, the particles as described
herein are obtainable, in particular are obtained, by
melt-extruding a mixture comprising ARN-509 and HPMCAS LF and
subsequently milling said melt-extruded mixture. In an aspect, the
particles as described herein are obtainable, in particular are
obtained, by melt-extruding a mixture consisting of ARN-509 and
HPMCAS LF and subsequently milling said melt-extruded mixture. In
an aspect, the weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2
or 1:3.
[0038] In an aspect of the invention, the particles as described
herein are obtainable, in particular are obtained, by spray drying
a mixture comprising ARN-509 and HPMCAS in a suitable solvent. In
an aspect, the particles as described herein are obtainable, in
particular are obtained, by spray drying a mixture consisting of
ARN-509 and HPMCAS in a suitable solvent. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or 1:3.
[0039] In an aspect of the invention, the particles as described
herein are obtainable, in particular are obtained, by spray drying
a mixture comprising ARN-509 and HPMCAS LG in a suitable solvent.
In an aspect, the particles as described herein are obtainable, in
particular are obtained, by spray drying a mixture consisting of
ARN-509 and HPMCAS LG in a suitable solvent. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or 1:3.
[0040] In an aspect of the invention, the particles as described
herein are obtainable, in particular are obtained, by spray drying
a mixture comprising ARN-509 and HPMCAS LF in a suitable solvent.
In an aspect, the particles as described herein are obtainable, in
particular are obtained, by spray drying a mixture consisting of
ARN-509 and HPMCAS LF in a suitable solvent. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or 1:3.
[0041] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and a solid
dispersion as described herein.
[0042] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles as
described herein.
[0043] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and a solid
dispersion, said solid dispersion comprising ARN-509 and HPMCAS. An
aspect of the invention is a pharmaceutical formulation comprising
a pharmaceutically acceptable carrier and a solid dispersion, said
solid dispersion consisting of ARN-509 and HPMCAS. In an aspect,
the weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or 1:3.
[0044] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and a solid
dispersion, said solid dispersion comprising ARN-509 and HPMCAS LG.
An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and a solid
dispersion, said solid dispersion consisting of ARN-509 and HPMCAS
LG. In an aspect, the weight-by-weight ratio of ARN-509:HPMCAS LG
is 1:2 or 1:3.
[0045] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and a solid
dispersion, said solid dispersion comprising ARN-509 and HPMCAS LF.
An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and a solid
dispersion, said solid dispersion consisting of ARN-509 and HPMCAS
LF. In an aspect, the weight-by-weight ratio of ARN-509:HPMCAS LF
is 1:2 or 1:3.
[0046] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles
comprising a solid dispersion, said solid dispersion comprising
ARN-509 and HPMCAS. An aspect of the invention is a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and
particles comprising a solid dispersion, said solid dispersion
consisting of ARN-509 and HPMCAS. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS is 1:2 or 1:3. In an
aspect, the particles are obtainable, in particular are obtained,
by spray drying as described herein. In an aspect, the particles
are obtainable, in particular are obtained, by melt extrusion as
described herein.
[0047] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles
consisting of a solid dispersion, said solid dispersion comprising
ARN-509 and HPMCAS. An aspect of the invention is a pharmaceutical
formulation comprising a pharmaceutically acceptable carrier and
particles consisting of a solid dispersion, said solid dispersion
consisting of ARN-509 and HPMCAS. In an aspect, the particles are
obtainable, in particular are obtained, by spray drying as
described herein. In an aspect, the particles are obtainable, in
particular are obtained, by melt extrusion as described herein.
[0048] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles
comprising a solid dispersion, said solid dispersion comprising
ARN-509 and HPMCAS LG. An aspect of the invention is a
pharmaceutical formulation comprising a pharmaceutically acceptable
carrier and particles comprising a solid dispersion, said solid
dispersion consisting of ARN-509 and HPMCAS LG. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or 1:3. In an
aspect, the particles are obtainable, in particular are obtained,
by spray drying as described herein. In an aspect, the particles
are obtainable, in particular are obtained, by melt extrusion as
described herein.
[0049] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles
comprising a solid dispersion, said solid dispersion comprising
ARN-509 and HPMCAS LF. An aspect of the invention is a
pharmaceutical formulation comprising a pharmaceutically acceptable
carrier and particles comprising a solid dispersion, said solid
dispersion consisting of ARN-509 and HPMCAS LF. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or 1:3. In an
aspect, the particles are obtainable, in particular are obtained,
by spray drying as described herein. In an aspect, the particles
are obtainable, in particular are obtained, by melt extrusion as
described herein.
[0050] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles
consisting of a solid dispersion, said solid dispersion comprising
ARN-509 and HPMCAS LG. An aspect of the invention is a
pharmaceutical formulation comprising a pharmaceutically acceptable
carrier and particles consisting of a solid dispersion, said solid
dispersion consisting of ARN-509 and HPMCAS LG. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS LG is 1:2 or 1:3. In an
aspect, the particles are obtainable, in particular are obtained,
by spray drying as described herein. In an aspect, the particles
are obtainable, in particular are obtained, by melt extrusion as
described herein.
[0051] An aspect of the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable carrier and particles
consisting of a solid dispersion, said solid dispersion comprising
ARN-509 and HPMCAS LF. An aspect of the invention is a
pharmaceutical formulation comprising a pharmaceutically acceptable
carrier and particles consisting of a solid dispersion, said solid
dispersion consisting of ARN-509 and HPMCAS LF. In an aspect, the
weight-by-weight ratio of ARN-509:HPMCAS LF is 1:2 or 1:3. In an
aspect, the particles are obtainable, in particular are obtained,
by spray drying as described herein. In an aspect, the particles
are obtainable, in particular are obtained, by melt extrusion as
described herein.
[0052] An aspect of the invention is a solid dispersion as
described herein wherein no surfactant is present.
[0053] An aspect of the invention is a particle as described herein
wherein no surfactant is present.
[0054] An aspect of the invention is a pharmaceutical formulation
as described herein wherein no surfactant is present.
[0055] An aspect of the invention is a solid dispersion as
described herein wherein ARN-509 is the only active pharmaceutical
ingredient.
[0056] An aspect of the invention is a particle as described herein
wherein ARN-509 is the only active pharmaceutical ingredient.
[0057] An aspect of the invention is a pharmaceutical formulation
as described herein wherein ARN-509 is the only active
pharmaceutical ingredient.
[0058] In the solid dispersions or particles or pharmaceutical
formulations as described herein ARN-509 is present in base form or
as a pharmaceutically acceptable addition salt, in particular as a
pharmaceutically acceptable acid addition salt. Preferably, ARN-509
is present in base form.
[0059] The pharmaceutically acceptable addition salts are meant to
comprise the therapeutically active non-toxic salt forms. The acid
addition salt forms can be obtained by treating the base form of
ARN-509 with an appropriate acid, such as inorganic acids,
including but not limited to, hydrohalic acids, e.g. hydrochloric
acid, hydrobromic acid and the like acids; sulfuric acid; nitric
acid; phosphoric acid; metaphosphoric acid and the like acids; or
organic acids, including but not limited to, acetic acid,
trifluoroacetic acid, trimethylacetic acid, propanoic acid,
hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid,
glycolic acid, oxalic acid, malonic acid, succinic acid, maleic
acid, fumaric acid, malic acid, mandelic acid, tartaric acid,
2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid,
ethanesulfonic acid, 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzoic acid, cinnamic acid,
hydrocinnamic acid, benzenesulfonic acid, 4-methylbenzene-sulfonic
acid, 2-naphthalenesulfonic acid, cyclohexanesulfamic acid,
2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, hexanoic
acid, cyclopentanepropionic acid, 3-(4-hydroxybenzoyl)benzoic acid,
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic
acid, glutamic acid, hydroxynaphthoic acid, stearic acid, muconic
acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic
acid, and the like acids.
[0060] Conversely said salt forms can be converted by treatment
with an appropriate base into the free base form.
[0061] Also included are the hydrates, the solvent addition forms
and mixtures thereof which ARN-509 and its salts are able to form.
Examples of such forms are e.g. hydrates, alcoholates and the like,
for instance an ethanolate.
[0062] In general, doses employed for adult human treatment are
typically in the range from 0.01 mg to 5000 mg per day. In one
aspect, doses employed for adult human treatment are from about 1
mg to about 1000 mg per day. In another aspect, doses employed for
adult human treatment are from about 100 mg to about 500 mg per
day. In another aspect, the dose employed for adult human treatment
is 240 mg per day. The exact dosage and frequency of administration
of ARN-509 may depend on the particular condition being treated,
the severity of the condition being treated, the age, weight and
general physical condition of the particular patient as well as
other medication the individual may be taking, as is known to those
skilled in the art. Furthermore, it is evident that said daily
amounts may be lowered or increased depending on the response of
the treated subject and/or depending on the evaluation of the
physician prescribing ARN-509. The doses mentioned herein are
therefore only a guideline and are not intended to limit the scope
or use of the invention to any extent. In an aspect of the
invention, the daily dose is conveniently presented in a single
dose or in divided doses administered simultaneously (or over a
short period of time) or at appropriate intervals, for example as
two, three, four or more sub-doses per day. In an aspect of the
invention, the daily dose is administered in 4 divided doses. In an
aspect of the invention, the daily dose is administered in 4
divided doses administered simultaneously (or over a short period
of time). In an aspect of the invention, the daily dose is
administered in 3 divided doses. In an aspect of the invention, the
daily dose is administered in 3 divided doses administered
simultaneously (or over a short period of time). In an aspect of
the invention, the daily dose is administered in 2 divided doses.
In an aspect of the invention, the daily dose is administered in 2
divided doses administered simultaneously (or over a short period
of time).
[0063] In an aspect of the invention, the pharmaceutical
formulation comprises 240 mg of ARN-509.
[0064] In an aspect of the invention, the pharmaceutical
formulation comprises 120 mg of ARN-509.
[0065] In an aspect of the invention, the pharmaceutical
formulation comprises 60 mg of ARN-509.
[0066] In an aspect of the invention, the pharmaceutical
formulation comprises 240 mg of ARN-509. The pharmaceutical
formulation is administered once daily.
[0067] In an aspect of the invention, the pharmaceutical
formulation comprises 120 mg of ARN-509. Two of said formulations
are administered daily, preferably simultaneously (or over a short
period of time).
[0068] In an aspect of the invention, the pharmaceutical
formulation comprises 60 mg of ARN-509. Four of said formulations
are administered daily, preferably simultaneously (or over a short
period of time).
[0069] The formulation of the present invention can also be used in
combination with another anticancer agent, in particular with
another anti prostate cancer agent, more in particular with an
androgen biosynthesis inhibitor, that inhibits
17.alpha.-hydroxylase/C17,20-lyase (CYP17), in particular
abiraterone acetate. The formulation of the present invention can
further be combined with prednisone.
[0070] Thus, the present invention also relates to a combination of
a pharmaceutical formulation according to the invention and another
anticancer agent, in particular another anti prostate cancer agent,
more in particular an androgen biosynthesis inhibitor, that
inhibits 17.alpha.-hydroxylase/C17,20-lyase (CYP17), in particular
abiraterone acetate.
[0071] Said combination may further comprise prednisone.
[0072] The term "a solid dispersion" means a system in a solid
state (as opposed to a liquid or gaseous state) comprising at least
two components, wherein one component is dispersed more or less
evenly throughout the other component or components. When said
dispersion of the components is such that the system is chemically
and physically uniform or homogenous throughout or consists of one
phase as defined in thermo-dynamics, such a solid dispersion will
be called "a solid solution" herein. Solid solutions are preferred
physical systems because the components therein are usually readily
bioavailable to the organisms to which they are administered. This
advantage can probably be explained by the ease with which said
solid solutions can form liquid solutions when contacted with a
liquid medium such as gastric juice. The ease of dissolution may be
attributed at least in part to the fact that the energy required
for dissolution of the components from a solid solution is less
than that required for the dissolution of components from a
crystalline or microcrystalline solid phase.
[0073] The term "a solid dispersion" also comprises dispersions
which are less homogenous throughout than solid solutions. Such
dispersions are not chemically and physically uniform throughout or
comprise more than one phase. For example, the term "a solid
dispersion" also relates to a system in a solid state comprising at
least two components (a) and (b) and having domains or small
regions wherein amorphous, microcrystalline or crystalline (a), or
amorphous, microcrystalline or crystalline (b), or both, are
dispersed more or less evenly in another phase comprising (b), or
(a), or a solid solution comprising (a) and (b). Said domains are
regions distinctively marked by some physical feature, small in
size compared to the size of the system as a whole, and evenly and
randomly distributed throughout the system.
[0074] Preferred are solid dispersions or particles as described
herein wherein ARN-509 is in a non-crystalline phase as these have
an intrinsically faster dissolution rate than those wherein part or
all of ARN-509 is in a microcrystalline or crystalline form.
[0075] Alternatively, the solid dispersions may be in the form of a
dispersion wherein amorphous or microcrystalline ARN-509 or
amorphous or microcrystalline HPMCAS is dispersed more or less
evenly in a solid solution comprising ARN-509 and HPMCAS.
[0076] In an aspect of the invention ARN-509 is present in the
solid dispersions as described herein in amorphous form.
[0077] In an aspect of the invention the solid dispersion as
described herein is a solid solution.
[0078] Various techniques exist for preparing the solid dispersions
of the invention including melt-extrusion (e.g. hot melt
extrusion), spray-drying and solution-evaporation, in particular
hot melt-extrusion and spray-drying, spray-drying being
preferred.
[0079] The particles according to the invention can be prepared by
first preparing a solid dispersion of the components, and then
optionally grinding or milling said dispersion.
[0080] The melt-extrusion process comprises the following
steps:
[0081] a) mixing ARN-509 and HPMCAS,
[0082] b) optionally blending additives with the thus obtained
mixture,
[0083] c) heating the thus obtained blend until one obtains a
homogenous melt,
[0084] d) forcing the thus obtained melt through one or more
nozzles; and
[0085] e) cooling the melt till it solidifies.
[0086] The terms "melt" and "melting" do not only mean the
alteration from a solid state to a liquid state, but can also refer
to a transition to a glassy state or a rubbery state, and in which
it is possible for one component of the mixture to get embedded
more or less homogeneously into the other. In particular cases, one
component will melt and the other component(s) will dissolve in the
melt thus forming a solution, which upon cooling may form a solid
solution having advantageous dissolution properties.
[0087] One important parameter of melt extrusion is the temperature
at which the melt-extruder is operating. For the melt extrusion
process of the present invention, the operating temperature
preferably ranges between about 160.degree. C. and about
190.degree. C., more preferably ranges between about 160.degree. C.
and 175.degree. C. The lower temperature limit is defined by the
point at which ARN-509 is still melting during extrusion with a
given set of extrusion conditions. When ARN-509 is not completely
molten, the extrudate may not provide the desired bioavailability.
When the viscosity of the mixture is too high, the process of melt
extrusion will be difficult. At higher temperatures the components
may decompose to an unacceptable level. A person skilled in the art
will recognize the most appropriate temperature range to be
used.
[0088] The throughput rate is also of importance because the
components may start to decompose when they remain too long in
contact with the heating element.
[0089] It will be appreciated that the person skilled in the art
will be able to optimize the parameters of the melt extrusion
process within the above given ranges. The working temperatures
will also be determined by the kind of extruder or the kind of
configuration within the extruder that is used. Most of the energy
needed to melt, mix and dissolve the components in the extruder can
be provided by the heating elements. However, the friction of the
material within the extruder may also provide a substantial amount
of energy to the mixture and aid in the formation of a homogenous
melt of the components.
[0090] A person skilled in the art will recognize the most
appropriate extruder, such as, for example, a single screw, a twin
screw extruder or a multi-screw extruder, for the preparation of
the subject-matter of the present invention.
[0091] Spray-drying of a mixture of the components in a suitable
solvent also yields a solid dispersion of said components or
particles comprising or consisting of a solid dispersion of said
components and may be a useful alternative to the melt-extrusion
process, particularly in those cases where the HPMCAS is not
sufficiently stable to withstand the extrusion conditions and where
residual solvent can effectively be removed from the solid
dispersion. Yet another possible preparation consists of preparing
a mixture of the components in a suitable solvent, pouring said
mixture onto a large surface so as to form a thin film, and
evaporating the solvent therefrom.
[0092] Solvents suitable for spray-drying can be any organic
solvent in which ARN-509 and HPMCAS, in particular HPMCAS LG or
HPMCAS LF, are miscable. In an aspect of the invention, the boiling
point of the solvent is lower than the Tg (glass transition
temperature) of the solid dispersion. 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 post drying step such as for
instance tray-drying, subsequent to the spray-drying process.
Solvents include alcohols such as methanol, ethanol, n-propanol,
iso-propanol, and butanol, in particular methanol; 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, dichloromethane, toluene, and
1,1,1-trichloroethane. Lower volatility solvents such as dimethyl
acetamide or dimethylsulfoxide can also be used. In an aspect of
the invention, the solvent suitable for spray drying is a mixture
of solvents. In an aspect of the invention the solvent for spray
drying is a mixture of an alcohol and dichloromethane, in
particular a mixture of methanol and dichloromethane, more in
particular a mixture of methanol and dichloromethane 6:4 (w:w) or
5:5 (w/w), 6:4 (w:w) being preferred.
[0093] The particles as described herein have a d.sup.50 of about
1500 .mu.m, of about 1000 .mu.m, of about 500 .mu.m, of about 400
.mu.m, of about 250 .mu.m, of about 200 .mu.m, of about 150 .mu.m,
of about 125 .mu.m, of about 100 .mu.m, of about 70 .mu.m, of about
65 .mu.m, of about 60 .mu.m, of about 55 .mu.m, of about 50 .mu.m,
of about 45 .mu.m, of about 40 .mu.m, of about 35 .mu.m, of about
30 .mu.m, of about 25 .mu.m, or of about 20 .mu.m. Particles
obtained by spray drying have preferably a d.sup.50-value falling
in the range from about 20 .mu.m to about 100 .mu.m, in particular
a d.sup.50-value falling in the range from about 20 .mu.m to about
70 .mu.m, more in particular a d.sup.50-value of about 20 .mu.m, of
about 25 .mu.m, of about 30 .mu.m, of about 35 .mu.m, of about 40
.mu.m, of about 45 .mu.m, of about 50 .mu.m, of about 55 .mu.m, of
about 60 .mu.m, of about 65 .mu.m, or of about 70 .mu.m.
[0094] As used herein, the term d.sup.50 has its conventional
meaning as known to the person skilled in the art and can be
measured by art-known particle size measuring techniques such as,
for example, sedimentation field flow fractionation, photon
correlation spectroscopy, laser diffraction or disk centrifugation.
The d.sup.50 mentioned herein may be related to volume
distributions of the particles. In that instance, by "a d.sup.50 of
50 .mu.m" it is meant that at least 50% of the volume of the
particles has a particle size of less than 50 .mu.m. The same
applies to the other particle sizes mentioned. In a similar manner,
the d.sup.50 particle size may be related to weight distributions
of the particles. In that instance, by "d.sup.50 of 50 .mu.m" it is
meant that at least 50% of the weight of the particles has a
particle size of less than 50 .mu.m. The same applies to the other
particle sizes mentioned. Usually volume and weight distribution
result in the same or about the same value for the average particle
size.
[0095] The particle size can be an important factor determining the
tabletting speed, in particular the flowability and therefore the
manufacturability on a large scale of a particular dosage form or
formulation, and the quality of the final product. For instance,
for capsules, the particle size may range preferably from about 100
to about 1500 .mu.m (d.sup.50); for tablets the particle size is
preferably less than 250 .mu.m, more preferably less than 100 .mu.m
(d.sup.50). Too small particles (<10-20 .mu.m) often cause
sticking on the tablet punches and manufacturability issues.
[0096] The particles or solid dispersions as described herein may
further comprise one or more pharmaceutically acceptable excipients
such as, for example, plasticizers, flavors, colorants,
preservatives and the like. Especially in case of preparation by
hot melt extrusion, said excipients should not be heat-sensitive,
in other words, they should not show any appreciable degradation or
decomposition at the working temperature of the melt-extruder.
[0097] Suitable plasticizers are pharmaceutically acceptable and
include low molecular weight polyalcohols such as ethylene glycol,
propylene glycol, 1,2 butylene glycol, 2,3-butylene glycol, styrene
glycol; polyethylene glycols such as diethylene glycol, triethylene
glycol, tetraethylene glycol; other polyethylene glycols having a
molecular weight lower than 1,000 g/mol; polypropylene glycols
having a molecular weight lower than 200 g/mol; glycol ethers such
as monopropylene glycol monoisopropyl ether; propylene glycol
monoethyl ether; diethylene glycol monoethyl ether; ester type
plasticizers such as triethyl citrate, sorbitol lactate, ethyl
lactate, butyl lactate, ethyl glycolate, allyl glycollate; and
amines such as monoethanolamine, diethanolamine, triethanolamine,
monoisopropanolamine; triethylenetetramine,
2-amino-2-methyl-1,3-propanediol and the like. Of these, the low
molecular weight polyethylene glycols, ethylene glycol, low
molecular weight polypropylene glycols and especially propylene
glycol are preferred.
[0098] In an aspect of the invention, the particles or solid
dispersions as described herein do not contain a plasticizer.
[0099] The solid dispersions or the particles of the present
invention can be formulated into pharmaceutical formulations
comprising a therapeutically effective amount of ARN-509. Although,
at first instance, pharmaceutical formulations for oral
administration such as tablets and capsules are envisaged, the
solid dispersions or the particles of the present invention can
also be used to prepare pharmaceutical formulations e.g. for rectal
administration. Preferred formulations are those adapted for oral
administration shaped as a tablet. They can be produced by
conventional tabletting techniques with conventional ingredients or
excipients (pharmaceutically acceptable carrier) and with
conventional tabletting machines. In order to facilitate the
swallowing of such a formulation by a mammal, it is advantageous to
give the formulations, in particular tablets, an appropriate shape.
A film coat on the tablet may further contribute to the ease with
which it can be swallowed.
[0100] The formulations of the invention, in particular the
tablets, may include one or more conventional excipients
(pharmaceutically acceptable carrier) such as disintegrants,
diluents, fillers, binders, buffering agents, lubricants, glidants,
thickening agents, sweetening agents, flavors, and colors. Some
excipients can serve multiple purposes. Preferably, the
formulations of the present invention include a disintegrant, a
diluent or filler, a lubricant and glidant.
[0101] Suitable disintegrants are those that have a large
coefficient of expansion. Examples thereof are hydrophilic,
insoluble or poorly water-soluble crosslinked polymers such as
crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose
sodium (crosslinked sodium carboxymethylcellulose). The amount of
disintegrant in the tablets according to the present invention may
conveniently range from about 3 to about 15% (w/w) and preferably
range from about 3 to 7%, in particular is about 5% (w/w). Because
disintegrants by their nature yield sustained release formulations
when employed in bulk, it is advantageous to dilute them with an
inert substance called a diluent or filler.
[0102] A variety of materials may be used as diluents or fillers.
Examples are lactose monohydrate, anhydrous lactose, sucrose,
dextrose, mannitol, sorbitol, starch, cellulose (e.g.
micro-crystalline cellulose (Avicel.TM.), silicified
microcrystalline cellulose), dihydrated or anhydrous dibasic
calcium phosphate, and others known in the art, and mixtures
thereof (e.g. spray-dried mixture of lactose monohydrate (75%) with
microcrystalline cellulose (25%) which is commercially available as
Microcelac.TM.) Preferred is microcrystalline cellulose and
silicified microcrystalline cellulose. The amount of diluent or
filler in the tablets may conveniently range from about 20% to
about 70% (w/w) and preferably ranges from about 55% to about 60%
(w/w).
[0103] Lubricants and glidants can be employed in the manufacture
of certain dosage forms, and will usually be employed when
producing tablets. Examples of lubricants and glidants are
hydrogenated vegetable oils, e.g hydrogenated Cottonseed oil,
magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium
lauryl sulfate, colloidal silica, colloidal anhydrous silica talc,
mixtures thereof, and others known in the art.
[0104] Interesting lubricants are magnesium stearate, and mixtures
of magnesium stearate with colloidal silica. A preferred lubricant
is magnesium stearate. A preferred glidant is colloidal anhydrous
silica.
[0105] Glidants generally comprise 0.2 to 7.0% of the total tablet
weight, in particular 0.5 to 1.5%, more in particular 1 to 1.5%
(w/w).
[0106] Lubricants generally comprise 0.2 to 7.0% of the total
tablet weight, in particular 0.2 to 1%, more in particular 0.5 to
1% (w/w).
[0107] Other excipients such as coloring agents and pigments may
also be added to the formulations of the invention. Coloring agents
and pigments include titanium dioxide and dyes suitable for food. A
coloring agent is an optional ingredient in the formulation of the
invention, but when used the coloring agent can be present in an
amount up to 3.5% based on the total tablet weight.
[0108] Flavors are optional in the formulation and may be chosen
from synthetic flavor oils and flavoring aromatics or natural oils,
extracts from plants leaves, flowers, fruits and so forth and
combinations thereof. These may include cinnamon oil, oil of
wintergreen, peppermint oils, bay oil, anise oil, eucalyptus, thyme
oil. Also useful as flavors are vanilla, citrus oil, including
lemon, orange, grape, lime and grapefruit, and fruit essences,
including apple, banana, pear, peach, strawberry, raspberry,
cherry, plum, pineapple, apricot and so forth, The amount of flavor
may depend on a number of factors including the organoleptic effect
desired. Generally the flavor will be present in an amount from
about 0% to about 3% (w/w).
[0109] As known in the art, tablet blends may be dry-granulated or
wet-granulated before tabletting. The tabletting process itself is
otherwise standard and readily practised by forming a tablet from
desired blend or mixture of ingredients into the appropriate shape
using a conventional tablet press.
[0110] Tablets of the present invention may further be film-coated
e.g. to improve taste, to provide ease of swallowing and an elegant
appearance. Many suitable polymeric film-coating materials are
known in the art. A preferred film-coating material is Opadry II
85F210036 Green. Other suitable film-forming polymers also may be
used herein, including, hydroxypropylcellulose, hydroxypropyl
methylcellulose (HPMC), especially HPMC 2910 5 mPas, and
acrylate-methacrylate copolymers. Besides a film-forming polymer,
the film coat may further comprise a plasticizer (e.g. propylene
glycol) and optionally a pigment (e.g. titanium dioxide). The
film-coating suspension also may contain talc as an anti-adhesive.
In tablets according to the invention, the film coat in terms of
weight preferably accounts for about 3% (w/w) or less of the total
tablet weight.
[0111] Preferred formulations are those wherein the weight of the
particles or solid dispersions as described herein ranges from 20
to 40%, in particular from 30 to 40% of the total weight of the
formulation.
[0112] The present invention further concerns a process of
preparing solid dispersions as described herein, comprising
blending ARN-509 and HPMCAS and extruding said blend at a
temperature in the range from about 160.degree. C. to about
190.degree. C.
[0113] The present invention further concerns a process of
preparing particles as described herein, comprising blending
ARN-509 and HPMCAS, extruding said blend at a temperature in the
range from about 160.degree. C. to about 190.degree. C., grinding
the extrudate, and optionally sieving the particles.
[0114] Suitable extruders that may be used are the Haake
mini-extruder, Leistritz 18 mm extruder, and the Leistritz 27 mm
extruder.
[0115] The present invention further concerns a process of
preparing particles or solid dispersions as described herein
comprising mixing ARN-509 and HPMCAS in a suitable solvent and
spray drying said mixture. In an aspect, the suitable solvent is a
mixture of dichloromethane and methanol. In an aspect, the suitable
solvent is a mixture of dichloromethane and methanol wherein the
weight:weight ratio of dichloromethane to methanol in the mixture
is 4:6 or 5:5, 4:6 being preferred.
[0116] A preferred crystalline form of ARN-509 for preparing the
solid dispersions or particles as described herein is Form B, which
is an anhydrous crystalline form (see hereinafter and reference is
also made to WO2013/184681, which is incorporated herein by
reference).
[0117] It is another object of the invention to provide a process
of preparing a pharmaceutical formulation as described herein, in
particular in the form of a tablet or a capsule, characterized by
blending a therapeutically effective amount of a solid dispersion
or particles as described herein, with a pharmaceutically
acceptable carrier and compressing said blend into tablets or
filling said blend in capsules.
[0118] Further, this invention concerns a solid dispersion or
particles as described herein, for use in preparing a
pharmaceutical formulation for administration, in particular oral
administration, to a mammal, in particular a human, suffering from
an androgen receptor (AR)-related disease or condition, in
particular cancer, more in particular prostate cancer, including
but not limited to castration-resistant prostate cancer, metastatic
castration resistant prostate cancer, chemotherapy-naive metastatic
castration resistant prostate cancer, biochemically relapsed
hormone sensitive prostate cancer, or high-risk, non-metastatic
castration-resistant prostate cancer.
[0119] The present invention also concerns the use of a solid
dispersion or particles as described herein, for the preparation of
a pharmaceutical formulation for administration, in particular oral
administration, to a mammal, in particular a human, suffering from
an androgen receptor (AR)-related disease or condition, in
particular cancer, more in particular prostate cancer, including
but not limited to castration-resistant prostate cancer, metastatic
castration resistant prostate cancer, chemotherapy-naive metastatic
castration resistant prostate cancer, biochemically relapsed
hormone sensitive prostate cancer, or high-risk, non-metastatic
castration-resistant prostate cancer.
[0120] The invention also relates to a method of treating an
androgen receptor (AR)-related disease or condition, in particular
cancer, more in particular prostate cancer, including but not
limited to castration-resistant prostate cancer, metastatic
castration resistant prostate cancer, chemotherapy-naive metastatic
castration resistant prostate cancer, biochemically relapsed
hormone sensitive prostate cancer, or high-risk, non-metastatic
castration-resistant prostate cancer, in a mammal, in particular a
human, which comprises administering, in particular orally, to said
mammal, in particular human, an effective anticancer amount of a
pharmaceutical formulation as described herein.
[0121] The invention further concerns the use of a pharmaceutical
formulation as specified herein, for the manufacture of a
medicament for treating an androgen receptor (AR)-related disease
or condition, in particular cancer, more in particular prostate
cancer, including but not limited to castration-resistant prostate
cancer, metastatic castration resistant prostate cancer,
chemotherapy-naive metastatic castration resistant prostate cancer,
biochemically relapsed hormone sensitive prostate cancer, or
high-risk, non-metastatic castration-resistant prostate cancer. Or,
alternatively, the invention concerns a pharmaceutical formulation
as specified herein for use in the treatment of an androgen
receptor (AR)-related disease or condition, in particular cancer,
more in particular prostate cancer, including but not limited to
castration-resistant prostate cancer, metastatic castration
resistant prostate cancer, chemotherapy-naive metastatic castration
resistant prostate cancer, biochemically relapsed hormone sensitive
prostate cancer, or high-risk, non-metastatic castration-resistant
prostate cancer.
[0122] The invention also relates to a pharmaceutical package
suitable for commercial sale comprising a container, a
pharmaceutical formulation as described herein, and associated with
said package written matter.
[0123] The term "about" as used herein in connection with a
numerical value is meant to have its usual meaning in the context
of the numerical value. Where necessary the word "about" may be
replaced by the numerical value.+-.10%, or .+-.5%, or .+-.2%, or
.+-.1%. All documents cited herein are incorporated by reference in
their entirety.
[0124] The following examples are intended to illustrate the
present invention.
Example 1: ARN-509 Forms
[0125] For the preparation of different (crystalline) forms of
ARN-509, reference is made to WO2013/184681, which is incorporated
herein by reference. Different (crystalline or amorphous) forms of
ARN-509 can be used to prepare the solid dispersions, particles or
formulations according to the present invention.
[0126] A preferred form of ARN-509 for use in the preparation of
the solid dispersions, particles or formulations according to the
present invention is ARN-509 Form B, which is an anhydrous crystal.
It was prepared by suspending ARN-509 Form A (reference is made to
WO2013/184681, including for the diffraction data) in USP water and
heating the slurry to 55.+-.5.degree. C., holding at said
temperature for at least 24 hours, followed by cooling the slurry
to 25.+-.5.degree. C. The resulting slurry was filtered, and the
wet cake washed once with USP water. The wet cake was unloaded from
the filter and dried under vacuum to afford ARN-509 Form B.
Reference is also made to Example 2 below.
[0127] Solubility of Form A: 0.01 mg/ml in water.
[0128] Solubility of Form B: 0.004 mg/ml in water.
Example 2
[0129] Characterisation of ARN-509 Form B
[0130] Powder XRD
[0131] X-ray powder diffraction (XRPD) analyses were carried out on
a PANalytical (Philips) X'PertPRO MPD diffractometer. The
instrument is equipped with a Cu LFF X-ray tube.
[0132] The compound was spread on a zero background sample
holder.
[0133] Instrument Parameters
TABLE-US-00001 generator voltage: 45 kV generator amperage: 40 mA
geometry: Bragg-Brentano stage: spinner stage
[0134] Measurement Conditions
TABLE-US-00002 scan mode: continuous scan range: 3 to 50.degree.
2.theta. step size: 0.02.degree./step counting time: 30 sec/step
spinner revolution time: 1 sec radiation type: CuK.alpha.
[0135] Incident Beam Path Diffracted Beam Path
TABLE-US-00003 program. divergence slit: 15 mm Soller slit: 0.04
rad beam mask: 15 mm anti scatter slit: 1.degree. beam knife: +
TABLE-US-00004 long anti scatter shield: + Soller slit: 0.04 rad Ni
filter: + detector: X'Celerator
[0136] The X-ray powder diffraction pattern of ARN-509 Form B shows
diffraction peaks without the presence of a halo, indicating that
this compound is present as a crystalline product. The XRD pattern
of ARN-509 Form B is shown in FIG. 1.
[0137] Infrared Spectrometry (Micro ATR-IR)
[0138] The samples were analyzed using a suitable microATR
accessory.
TABLE-US-00005 apparatus: Thermo Nexus 670 FTIR spectrometer number
of scans: 32 resolution: 1 cm.sup.-1 wavelength range: 4000 to 400
cm.sup.-1 detector: DTGS with KBr windows beamsplitter: Ge on KBr
micro ATR accessory: Harrick Split Pea with Si crystal
[0139] The spectrum of ARN-509 Form B is shown in FIG. 2.
[0140] Differential Scanning Calorimetry (DSC)
[0141] The compound was transferred into a standard aluminum
TA-Instrument sample pan. The sample pan was closed with the
appropriate cover and the DSC curve was recorded on a
TA-Instruments Q1000 MTDSC equipped with a RCS cooling unit, using
the following parameters:
TABLE-US-00006 initial temperature: 25.degree. C. heating rate:
10.degree. C./min final temperature: 250.degree. C.
[0142] The DSC curve of ARN-509 Form B shows the melting of the
product at 194.9.degree. C. with a heat of fusion of 73 J/g. See
FIG. 3.
Example 3.1: Preparation of a Solid Dispersion of ARN-509:HPMCAS LG
1:3
TABLE-US-00007 [0143] ARN-509 2,500 g HPMC-AS LG 7,500 g
Dichloromethane, .sup.a 76,000 g Methanol .sup.a 114,000 g .sup.a
Removed during processing
[0144] The dichloromethane and methanol were transferred into a
suitable container and stirring was started. Under continuous
stirring ARN-509 Form B was added to the solvent mixture and
stirred until dissolved. HPMCAS was added to the solution and
stirred overnight. A yellowish viscous turbid mixture was obtained.
The mixture was filtered inline through a GRID filter. The mixture
was spray dried using a suitable spray dryer, e.g. Niro A/S PSD3
with a high pressure nozzle with the following parameters: feed
flow of 75 kg/hour, outlet temperature of 46.degree. C. and a
condenser temperature of -9.degree. C.
[0145] The spray dried product (SDP) was dried in a suitable dryer,
e.g. tray dryer using vacuum, nitrogen flow and a drying
temperature of 40.degree. C.
Example 3.2: Preparation of Tablets Comprising a Solid Dispersion
of ARN-509:HPMCAS 1:3
TABLE-US-00008 [0146] Spray dried powder (SDP) of Example 3.1 7,200
g Colloidal Anhydrous Silica 273 g Croscarmellose sodium 1,050 g
Microcrystalline Cellulose 8,865 g Silicified Microcrystalline
Cellulose 3,507 g Magnesium stearate .sup.a 105 g .sup.a Vegetable
grade for 30,000 tablets
[0147] The SDP was sieved and mixed with part (10/13) of the
colloidal anhydrous silica to a homogeneous blend using a suitable
blender. Part (1/2) of the croscarmellose sodium and the
microcrystalline cellulose (all) were sieved and added to the blend
and mixed using a suitable blender. A dry granulate was made by
using a suitable compaction technique, e.g. roller compaction. The
silicified microcrystalline cellulose, remainder of the
croscarmellose sodium (1/2) and colloidal anhydrous silica (3/13)
were sieved and added to the dry granulate and mixed using a
suitable blender. The magnesium stearate was sieved, added to the
blend and mixed using a suitable blender. The blend was compressed
into tablets (containing 60 mg of ARN 509) using a suitable tablet
press.
Example 3.3: Preparation of Coated Tablets
TABLE-US-00009 [0148] ARN-509 (60 mg) Tablets (see Example 3.2)
599.9 g Opadry II 85F210036 Green 17.997 g Purified Water .sup.a
71.988 g .sup.a Removed during processing per batch of 857
tablets
[0149] The purified water was transferred into a suitable
container. The coating powder was added and mixed with a suitable
mixer. The core tablets were film coated with the coating
suspension using a suitable coater.
Example 4.1: Preparation of a Solid Dispersion of ARN-509:HPMCAS LF
1:2
TABLE-US-00010 [0150] ARN-509 333.33 mg HPMCAS LF 666.67 mg Acetone
.sup.a 19000 mg .sup.a Removed during processing (the reported
amounts are for 1 g of SDP (spray dried product))
[0151] The acetone was transferred into a suitable container, and
HPMCAS and ARN-509 Form B were added. After mixing the ingredients
using a suitable mixer, the mixture was spray dried using a
suitable spray dryer, e.g. Buchi mini spray dryer with the
following parameters: spray rate in the range from 6.2-6.7
gram/minute, outlet temperature in the range from 46.degree.
C.-49.degree. C. and a condenser temperature in the range from
-18.degree. C. to -21.degree. C.
[0152] The spray dried product (SDP) was dried in a suitable dryer,
e.g. tray dryer using vacuum, nitrogen flow and a drying
temperature of 40.degree. C.
Example 4.2: Preparation of Tablets Comprising a Solid Dispersion
of ARN-509:HPMCAS 1:2
TABLE-US-00011 [0153] Spray dried powder of 4.1 (SDP) 360.0 mg
Colloidal Anhydrous Silica 18.2 mg Croscarmellose sodium 70.0 mg
Silicified Microcrystalline Cellulose 944.8 mg Magnesium stearate
7.0 mg (amounts for 1 tablet)
[0154] The SDP, part (7110/9448) of the silicified microcrystalline
cellulose, part (10/13) of the colloidal anhydrous silica and part
(1/2) of the croscarmellose sodium were sieved and mixed to a
homogenous blend using a suitable blender. A dry granulate was made
by using a suitable compaction technique. The remainder of the
silicified microcrystalline cellulose (2338/9448), colloidal
anhydrous silica (3/13) and croscarmellose sodium (1/2) were sieved
and added to the dry granulate and further mixed using a suitable
blender. Magnesium stearate was sieved and added to the blend and
mixed further using a suitable blender. The blend was compressed
into tablets using a suitable tablet press.
Example 5.1: Preparation of a Solid Dispersion of ARN-509:HPMCAS LF
1:3 by Hot Melt Extrusion (HME)
TABLE-US-00012 [0155] ARN-509 250 mg HPMCAS LF 750 mg (the reported
amounts are for 1 g of HME product)
[0156] The HPMCAS and ARN-509 Form B were blended in a suitable
recipient using a suitable blender. Hot melt extrusion was
performed in a Haake extruder, flush mode, maximum temperature
180.degree. C., screw speed 50 rpm. The hot melt extrudate was
collected and milled in a suitable mill. The milled hot melt
extrudate was sieved using a suitable sieve (250 .mu.m).
Example 5.2: Preparation of Tablets Comprising a Solid Dispersion
of ARN-509:HPMCAS LF 1:3 (HME)
TABLE-US-00013 [0157] HME powder of 5.1 240.0 mg Colloidal
Anhydrous Silica 9.1 mg Croscarmellose sodium 35.0 mg Silicified
Microcrystalline Cellulose 412.4 mg Magnesium stearate 3.5 mg
(amounts for 1 tablet) HME powder of 5.1 480.0 mg Colloidal
Anhydrous Silica 18.2 mg Croscarmellose sodium 70.0 mg Silicified
Microcrystalline Cellulose 824.8 mg Magnesium stearate 7.0 mg
(amounts for 1 tablet)
[0158] The silicified microcrystalline cellulose, croscarmellose
sodium and colloidal anhydrous silica were sieved and mixed with
the hot melt extrudate to a homogenous blend using a suitable
blender. Magnesium stearate was sieved and added to the blend and
mixed further using a suitable blender. The blend was compressed
into tablets using an eccentric tableting press.
Example 6.1: Preparation of a Solid Dispersion of ARN-509:HPMCAS LF
1:3 SDP
TABLE-US-00014 [0159] ARN-509 250.0 mg HPMCAS LF 750.0 mg Acetone
.sup.a 19000.0 mg .sup.a Removed during processing (the reported
amounts are for 1 g of SDP (spray dried product))
[0160] The acetone was transferred into a suitable container and
HPMCAS LF and ARN-509 Form B were added. After mixing the
ingredients using a suitable mixer, the mixture was spray dried
using a suitable spray dryer, e.g. Buchi mini spray dryer with the
following parameters: spray rate in the range from 5.9-6.6
gram/minute, outlet temperature in the range from 46.degree.
C.-49.degree. C. and a condenser temperature in the range from
-15.degree. C. to -21.degree. C.
[0161] The spray dried product (SDP) was dried in a suitable dryer,
e.g. tray dryer using vacuum, nitrogen flow and a drying
temperature of 40.degree. C.
Example 6.2: Preparation of Tablets Comprising a Solid Dispersion
of ARN-509:HPMCAS 1:3
TABLE-US-00015 [0162] Spray dried powder of 6.1 (SDP) 240.0 mg
Colloidal Anhydrous Silica 9.1 mg Croscarmellose sodium 35.0 mg
Silicified Microcrystalline Cellulose 412.4 mg Magnesium stearate
3.5 mg (amounts for 1 tablet) Spray dried powder of 6.1 (SDP) 480.0
mg Colloidal Anhydrous Silica 18.2 mg Croscarmellose sodium 70.0 mg
Silicified Microcrystalline Cellulose 824.8 mg Magnesium stearate
7.0 mg (amounts for 1 tablet)
[0163] The SDP, part (2955/4124) of the silicified microcrystalline
cellulose, part (10/13) of the colloidal anhydrous silica and part
(1/2) of the croscarmellose sodium were sieved and mixed to a
homogenous blend using a suitable blender. A dry granulate was made
by using a suitable compaction technique. The remainder of the
silicified microcrystalline cellulose (1169/4124), colloidal
anhydrous silica (3/13) and croscarmellose sodium (1/2) were sieved
and added to the dry granulate and further mixed using a suitable
blender. Magnesium stearate was sieved and added to the blend and
mixed further using a suitable blender. The blend was compressed
into tablets using an eccentric tabletting press.
[0164] Bioavailability Study
[0165] Test System
[0166] Species: Marshall beagle dogs
[0167] Supplier: Marshall Farms, Italy/USA
[0168] Gender and age: male (n=12), approximately 1-7 years
[0169] Body weights: 8-13 kg at the start of the experimental
phase
[0170] Diet and Water Supply: [0171] Continuous access to water
[0172] Dosing: fasted for about 21 hours before dosing till .+-.2
hours after dosing. [0173] Afterwards, dogs had free access to food
until the late afternoon.
[0174] Test Compound and Formulations
[0175] Formulation 1: 60 mg tablet containing ARN-509-HPMC AS-LF
ratio 1/3 SDP
[0176] Formulation 2: 60 mg tablet containing ARN-509-HPMC AS-LF
ratio 1/3 HME
[0177] Formulation 3: a nonaqueous, lipid-based solution filled
into softgel capsules, each containing 30 mg ARN-509
[0178] Blood Sampling and Plasma Preparation
[0179] Blood samples (2 ml on EDTA) were taken from a jugular vein.
Within 1 hour of sampling, the blood samples were centrifuged and
within 2 hours after the start of centrifugation, plasma was stored
in the freezer.
[0180] Dose Administration
TABLE-US-00016 Day of Dose Tablet Dosing Formulation Route (mg/dog)
(pcs) Dog Nos. Day 0 Formulation 1 PO 60 1 n = 4 (gavage)
Formulation 2 PO 60 1 n = 4 (gavage) Formulation 3 PO 60 2 n = 4
(gavage)
[0181] Bioanalysis
[0182] All study samples were analyzed using a qualified LC-MS/MS
method. The samples were subjected to a selective sample cleanup,
followed by HPLC-MS/MS. HPLC separation was done using non-chiral
reversed phase liquid chromatography. Subsequent MS/MS analysis was
performed using triple quadrupole mass spectrometry in the Multiple
Reaction Monitoring (MRM) mode, optimized for the compound. Samples
were quantified against calibration curves prepared to cover the
concentration range of the study samples. The curves were prepared
in the same matrix as the study samples. For each analytical batch,
independent quality control samples, prepared in the same matrix as
the samples, were analyzed together with the study samples and
calibration curve. All analytical batches were accepted based on
calibration curve and QC acceptance criteria in line with the
current FDA guidelines.
[0183] Data Analysis
[0184] Individual plasma concentration-time profiles were subjected
to a pharmacokinetic analysis using validated Phoenix software. A
non-compartmental analysis using the linear up/log down trapezoidal
rule was used for all data.
[0185] Results
[0186] The mean C.sub.max, T.sub.max, AUC and F.sub.rel values of
ARN-509 in male beagle dogs after single oral administration of the
3 formulations are presented below:
TABLE-US-00017 Formulation 1 2 3 C.sub.max (ng/ml) 3900 2630 4110
T.sub.max (h) 0.5-1 1-2 1-2 AUC.sub.last (ng h/ml) .sup.1) 183000
159000 157000 AUC.sub.0-inf (ng h/ml) 183000 151000.sup.2) 167000
Frel (AUC.sub.last ratios) 117% 101% .sup.1) T.sub.last in majority
of animals was 168 h; .sup.2)n = 3
[0187] Formulation 1: HPMC AS-LF ratio 1/3 (SDP)
[0188] Formulation 2: HPMC AS-LF ratio 1/3 (HME)
[0189] Formulation 3: softgel reference capsule
[0190] Stability Tests Performed on Powders of Example 3.1 and
5.1
[0191] The tests were performed on the powders packed in LDPE/Alu
bags.
[0192] 1. Appearance Testing
[0193] A visual examination was performed on the powder of Example
3.1 and Example 5.1 stored under different storage conditions as
indicated in table a1 and a2 below.
[0194] The results are reported in the table a1 and a2 below.
[0195] 2. Water Content
[0196] The water content was determined by means of a vaporized
coulometric Karl Fischer determination in accordance with USP/Ph.
Eur.
[0197] Powder of Example 3.1 or Example 5.1 was stored as indicated
in table a1 or a2 below.
[0198] About 50.00 mg (.+-.5.00 mg) of the sample was weighted
accurately into a vial and the vial was crimped securely.
[0199] The results are reported in table a1 and a2 below.
[0200] The following instrumentation, reagents and solutions and
parameters were used.
[0201] Instrumentation
[0202] Coulometer: 831 KF Coulometer Metrohm
[0203] Oven: 774 Sample Oven Processor Metrohm
[0204] Generator electrode: Electrode with diaphragm Metrohm
6.0344.100
[0205] Indicator electrode: Double Pt-wire electrode Metrohm
6.0341.100
[0206] Reagents and Solutions
[0207] Anode solution: Hydranal Coulomat AG Oven (Fluka 34739)
[0208] Cathode solution: Hydranal Coulomat CG (Fluka 34840)
[0209] Water standard: Hydranal Water Standard 1.00 (Fluka
34828)
[0210] Oven Parameters
[0211] Carrier gas: N.sub.2
[0212] Flow rate: Setpoint 60 mL/min [0213] Read out value minimum
20 mL/min
[0214] Oven temperature: 120.degree. C.
[0215] Coulometer Parameters
[0216] Titration Parameters
[0217] Extr. time: 60 s
[0218] Drift correction: Auto
[0219] Start Conditions
[0220] Pause: 60 s
[0221] Start drift: maximum 12 .mu.g/min
[0222] Time cond. OK: 10 s
[0223] Stop Parameters
[0224] Rel. drift: 5 .mu.g/min
[0225] Alternative coulometer parameters may be used provided
system suitability requirements are met
[0226] 3. pXRD Testing for the Detection of Crystalline ARN-509
[0227] The physical stability of powder of Example 3.1 and Example
5.1 stored under different storage conditions was followed up using
powder X-Ray diffraction. The XRD pattern of the powder was
compared to the XRD pattern of the corresponding powder measured at
time zero (amorphous product).
[0228] The powder was brought on to the zero background sample
holder. A X-ray measurement of the sample was performed.
[0229] The results are reported in table a1 and a2 below.
[0230] The following instrumentation and parameters were used.
[0231] Instrumentation
[0232] Pananalytical X'Pert PRO MPD diffractometer PW3050/60
[0233] X-ray tube Cu LFF PW3373/10
[0234] Detector: X'Celerator
[0235] Sample stage: spinner
[0236] Sample holder: zero background sample holder
[0237] Instrument Settings
[0238] Spinner revolution time: 1 rps
[0239] Generator voltage: 45 kV
[0240] Generator current: 40 mA
[0241] Optical components in X-ray beam path
[0242] Incident beam path:
[0243] Programmable divergence slit: irradiated length 15 mm
[0244] Soller slit: 0.04 rad
[0245] Beam mask: 15 mm
[0246] Anti-scatter slit: 1.degree.
[0247] Beam knife+
[0248] Diffracted beam path:
[0249] Programmable Anti-scatter slit: 1.degree.
[0250] Soller slit: 0.04 rad
[0251] Filter: Ni
[0252] Instrument Parameters
[0253] Geometry: Bragg-Brentano
[0254] Radiation: CuK.alpha.
[0255] Step size: 0.02.degree.
[0256] Scan range: from 3.degree. 2.theta. to 50.degree.
2.theta.
[0257] Counting time per step: 60 sec
TABLE-US-00018 TABLE a1 Test conditions and results for powders of
Example 3.1 stored in LDPE/Alu Bags -appearance and water content
and crystallinity results Parameter Storage Appearance .sup.a Water
Storage time Visual content condition (months) examination (%)
Crystallinity Initial Pass 0.6 Amorphous product 30.degree. C./75%
RH 6 Pass 1.0 Amorphous product 9 Pass 1.0 Amorphous product 12
Pass 1.7 Amorphous product .sup.a Pass: White to light yellow, fine
to granular powder
TABLE-US-00019 TABLE a2 Test conditions and results for powders of
Example 5.1 stored in LDPE/Alu Bags -appearance and water content
and crystallinity results Parameter Storage Appearance .sup.a Water
Storage time Visual content condition (months) examination (%)
Crystallinity Initial Pass 2.3 Amorphous product 30.degree. C./75%
RH 6 Pass 2.0 Amorphous product .sup.a Pass: White to light
yellow-brownish, fine to granular powder
[0258] For the appearance, no substantial stability related changes
were observed during storage of the drug product intermediate
powder at the different storage conditions.
[0259] For the water content, no substantial stability related
changes were observed during storage of the drug product
intermediate powder at the different storage conditions.
[0260] For the crystallinity, no substantial stability related
changes were observed during storage of the drug product at the
different storage conditions.
[0261] 4. Assay of ARN-509-Chromatographic Purity
[0262] The concentration of ARN-509 and its degradation products in
powders of Example 3.1 and Example 5.1 stored under different
storage conditions were determined by gradient Reversed-Phase UHPLC
with UV Detection.
[0263] Powders were stored as indicated in table b1 and b2
below.
[0264] Approximately 240.00 mg powder was weighted accurately into
a 250-mL volumetric flask. Approximately 125 mL acetonitrile was
added by graduated cylinder and the whole was shaken mechanically
for 30 minutes and diluted to volume with water till approximately
1 cm under the marker. The whole was shaked up manually vigorously.
The sample solution was allowed to equilibrate to ambient
temperature and was diluted to volume with water. Just before
filtering, the volumetric flask was shaked up manually vigorously.
The sample solution was filtered through a chemical resistant 0.2
.mu.m filter. The first 3 mL filtrate were discarded into a waste
container, not back into the volumetric flask.
[0265] The sample solution is stable for 4 days, if stored in
refrigerator, protected from light (closed cabinet).
[0266] The results are reported in table b1 and b2 below.
[0267] The following solutions and instrumentation and parameters
were used.
[0268] Mobile Phases
[0269] Mobile Phase A
[0270] 10 mM NH.sub.4Ac+0.1% TFA/Acetonitrile (90/10, v/v).
[0271] Mobile Phase B
[0272] Acetonitrile
[0273] UHPLC Conditions for Identification, Assay and
Chromatographic Purity
[0274] Column: Acquity BEH C18, 150 mm length.times.2.1 mm i.d.,
1.7 .mu.m particle size
[0275] Column Temperature: 45.degree. C.
[0276] Auto-Sampler Temperature: 5.degree. C.
[0277] Flow Rate: 0.40 mL/min
[0278] Detection: UV
[0279] Wavelength: 268 nm
[0280] Injection Volume: 3 .mu.L
[0281] Data Collection Time: 35 minutes
[0282] Analysis Run Time: 40 minutes
[0283] A linear gradient was programmed as demonstrated in the
below table.
[0284] Linear Gradient Program
TABLE-US-00020 Time (min) A (% vol) B (% vol) 0 100 0 35 30 70 36
100 0 40 100 0
TABLE-US-00021 TABLE b1 Test conditions and results for powders of
Example 3.1 stored in LDPE/Alu Bags-assay and degradation products
results Degradation products (%) Total degradation products
Parameter (sum of all degradation Storage products .gtoreq.0.05%
(totals Storage time Assay(%) are calculated on condition (months)
ARN-509 unrounded results) Initial 99.3 0.066 30.degree. C./75% RH
6 98.9 0.11 9 98.0 0.07 12 98.2 0.06
TABLE-US-00022 TABLE b2 Test conditions and results for powders of
Example 5.1 stored in LDPE/Alu Bags-assay and degradation products
results Degradation products (%) Total degradation products
Parameter (sum of all degradation Storage products .gtoreq.0.05%
(totals Storage time Assay(%) are calculated on condition (months)
ARN-509 unrounded results) Initial 96.4 0.11 30.degree. C./75% RH 6
96.3 0.08
[0285] No substantial stability related changes were observed
during storage of the drug product intermediate powders at the
different storage conditions.
[0286] 5. Water Activity
[0287] The water activity was determined with a Novasina
a.sub.w-meter.
[0288] The test was performed on powders of Example 3.1 and Example
5.1.
[0289] The results are reported in table c1 and c2 below.
TABLE-US-00023 TABLE c1 Test conditions and results for powders of
Example 3.1 stored in LDPE/Alu Bags -Water activity results
Parameter Storage Storage time condition (months) Water activity
Initial 0.21 30.degree. C./75% RH 12 0.38
TABLE-US-00024 TABLE c2 Test conditions and results for powders of
Example 5.1 stored in LDPE/Alu Bags -Water activity results
Parameter Storage Storage time condition (months) Water activity
Initial 0.44
[0290] Stability Tests Performed on Tablets of Example 3.3
[0291] Tests were performed on tablets stored in HDPE Bottles with
Desiccant (silica gel).
[0292] 1. Appearance Testing
[0293] A visual examination was performed on the tablets of Example
3.3 stored under different storage conditions as indicated in table
1 below.
[0294] The results are reported in table 1 below.
[0295] 2. Water Content
[0296] The water content was determined by means of a vaporized
coulometric Karl Fischer determination in accordance with USP/Ph.
Eur.
[0297] Tablets of Example 3.3 were stored as indicated in table 1
below.
[0298] Tablets were grinded using a Retsch Mixer Mill. Immediately
after grinding, about 50.00 mg (.+-.5.00 mg) of the sample was
weighted accurately into a vial and the vial was crimped
securely.
[0299] The results are reported in table 1 below.
[0300] The following instrumentation, reagents and solutions and
parameters were used.
[0301] Instrumentation
[0302] Coulometer: 831 KF Coulometer Metrohm
[0303] Oven: 774 Sample Oven Processor Metrohm
[0304] Generator electrode: Electrode with diaphragm Metrohm
6.0344.100
[0305] Indicator electrode: Double Pt-wire electrode Metrohm
6.0341.100
[0306] Reagents and Solutions
[0307] Anode solution: Hydranal Coulomat AG Oven (Fluka 34739)
[0308] Cathode solution: Hydranal Coulomat CG (Fluka 34840)
[0309] Water standard: Hydranal Water Standard 1.00 (Fluka
34828)
[0310] Oven Parameters
[0311] Carrier gas: N.sub.2
[0312] Flow rate: Setpoint 60 mL/min [0313] Read out value minimum
20 mL/min
[0314] Oven temperature: 120.degree. C.
[0315] Coulometer Parameters
[0316] Titration Parameters
[0317] Extr. time: 60 s
[0318] Drift correction: Auto
[0319] Start Conditions
[0320] Pause: 60 s
[0321] Start drift: maximum 12 .mu.g/min
[0322] Time cond. OK: 10 s
[0323] Stop Parameters
[0324] Rel. drift: 5 .mu.g/min
[0325] Alternative coulometer parameters may be used provided
system suitability requirements are met
TABLE-US-00025 TABLE 1 Test conditions and results for tablets of
Example 3.3 stored in HDPE Bottles with Desiccant (silica gel)
-appearance and water content results Parameter Storage Storage
time Appearance .sup.a condition (months) Visual examination Water
content (%) Initial Pass 3.8 -20.degree. C. 1 Pass 2.4 5.degree. C.
3 Pass 2.9 6 Pass 2.2 12 Pass 3.2 25.degree. C./60% RH 6 Pass 2.4
12 Pass 3.7 30.degree. C./75% RH 1 Pass 2.4 3 Pass 3.0 6 Pass 2.5 9
Pass 3.2 12 Pass 3.7 40.degree. C./75% RH 1 Pass 2.5 3 Pass 3.3 6
Pass 3.2 50.degree. C. 1 Pass 2.2 3 Pass 2.9 Light ICH Pass 2.3
.sup.a Pass: Greenish colored, oblong tablet Light ICH: integrated
near UV energy not less than 200 W h/m.sup.2, overall illumination
not less than 1200 klux h
[0326] For the appearance, no substantial stability related changes
were observed during storage of the drug product at the different
storage conditions.
[0327] A slight increase in water content was observed.
[0328] 3. pXRD Testing for the Detection of Crystalline ARN-509
[0329] The physical stability of different tablets of Example 3.3
stored under different storage conditions was followed up using
powder X-Ray diffraction. The XRD pattern of the tablets was
compared to the XRD pattern of the corresponding tablets at time
zero (amorphous product).
[0330] One tablet was gently grinded to a fine powder using a
mortar and pestle. The powder was loaded into the 16 mm sample
holder using the back loading technique. A X-ray measurement of the
sample was performed.
[0331] The results are reported in table 2 below.
[0332] The following instrumentation and parameters were used.
[0333] Instrumentation
[0334] Philips X'Pert PRO MPD diffractometer PW3050/60
[0335] X-ray tube Cu LFF PW3373/10
[0336] Detector: X'Celerator
[0337] Sample stage: spinner
[0338] Sample holder: cavity diameter 16 mm, cavity depth 2.5
mm
[0339] Instrument Settings
[0340] Spinner revolution time: 1 rps
[0341] Generator voltage: 45 kV
[0342] Generator current: 40 mA
[0343] Optical components in X-ray beam path
[0344] Incident beam path:
[0345] Programmable divergence slit: irradiated length 10 mm
[0346] Soller slit: 0.04 rad
[0347] Beam mask: 10 mm
[0348] Anti-scatter slit: 1.degree.
[0349] Beam knife+
[0350] Diffracted beam path:
[0351] Programmable Anti-scatter slit: 1.degree.
[0352] Soller slit: 0.04 rad
[0353] Filter: Ni
[0354] Instrument Parameters
[0355] Geometry: Bragg-Brentano
[0356] Radiation: CuK.alpha.
[0357] Step size: 0.02.degree.
[0358] Scan range: from 3.degree. 2.theta. to 50.degree.
2.theta.
[0359] Counting time per step: 100 sec
TABLE-US-00026 TABLE 2 Test conditions and results for tablets of
Example 3.3 stored in HDPE Bottles with Desiccant (silica
gel)-crystallinity results Parameter Storage Storage time condition
(months) Crystallinity Initial Amorphous drug substance in drug
product -20.degree. C. 1 Amorphous drug substance in drug product
5.degree. C. 3 Amorphous drug substance in drug product 6 Amorphous
drug substance in drug product 12 Amorphous drug substance in drug
product 25.degree. C./ 6 Amorphous drug substance in drug product
60% RH 12 Amorphous drug substance in drug product 30.degree. C./ 1
Amorphous drug substance in drug product 75% RH 3 Amorphous drug
substance in drug product 6 Amorphous drug substance in drug
product 9 Not Tested 12 Amorphous drug substance in drug product
40.degree. C./ 1 Amorphous drug substance in drug product 75% RH 3
Amorphous drug substance in drug product 6 Amorphous drug substance
in drug product 50.degree. C. 1 Amorphous drug substance in drug
product 3 Amorphous drug substance in drug product Light ICH
Amorphous drug substance in drug product Light ICH: integrated near
UV energy not less than 200 W h/m.sup.2, overall illumination not
less than 1200 klux h
[0360] No substantial stability related changes were observed
during storage of the drug product at the different storage
conditions.
[0361] 4. Assay of ARN-509-Chromatographic Purity
[0362] The concentration of ARN-509 and its degradation products in
tablets of Example 3.3 stored under different storage conditions
were determined by gradient Reversed-Phase UHPLC with UV
Detection.
[0363] Tablets were stored as indicated in table 3 below.
[0364] Five tablets were weighted accurately. Mean tablet weight
was determined. Tablets were grinded to a fine powder. An amount of
homogenized powder equivalent to the mean tablet weight was
accurately weighted into a 250-mL volumetric flask. Approximately
125 mL acetonitrile was added by graduated cylinder and the whole
was shaken mechanically for 30 minutes and diluted to volume with
water till approximately 1 cm under the marker. The whole was
shaked up manually vigorously. The sample solution was allowed to
equilibrate to ambient temperature and was diluted to volume with
water. Just before filtering, the volumetric flask was shaked up
manually vigorously. The sample solution was filtered through a
chemical resistant 0.45 .mu.m filter. The first 3 mL filtrate was
discarded into a waste container, not back into the volumetric
flask.
[0365] The sample solution is stable for 4 days, if stored in
refrigerator, protected from light (closed cabinet).
[0366] The results are reported in table 3 below.
[0367] The following solutions and instrumentation and parameters
were used.
[0368] Mobile Phases
[0369] Mobile Phase A
[0370] 10 mM NH.sub.4Ac (aqueous ammonium acetate)+0.1% TFA
(trifluoroacetic acid)/Acetonitrile (90/10, v/v).
[0371] Mobile Phase B
[0372] Acetonitrile
[0373] UHPLC Conditions for Identification, Assay and
Chromatographic Purity
[0374] Column: Acquity BEH C18, 150 mm length.times.2.1 mm i.d.,
1.7 .mu.m particle size
[0375] Column Temperature: 45.degree. C.
[0376] Auto-Sampler Temperature: 5.degree. C.
[0377] Flow Rate: 0.40 mL/min
[0378] Detection: UV
[0379] Wavelength: 268 nm
[0380] Injection Volume: 3 .mu.L
[0381] Data Collection Time: 35 minutes
[0382] Analysis Run Time: 40 minutes
[0383] A linear gradient was programmed as demonstrated in the
below table.
[0384] Linear Gradient Program
TABLE-US-00027 Time (min) A (% vol) B (% vol) 0 100 0 35 30 70 36
100 0 40 100 0
TABLE-US-00028 TABLE 3 Test conditions and results for tablets of
Example 3.3 stored in HDPE Bottles with Desiccant (silica
gel)-assay and degradation products results Degradation products
(%) Total degradation products Parameter (sum of all degradation
Storage products .gtoreq.0.05% (totals Storage time Assay(%) are
calculated on condition (months) ARN-509 unrounded results) Initial
102.3 0.11 -20.degree. C. 1 97.7 0.06 5.degree. C. 3 100.5 0.12 6
99.7 0.07 12 98.6 0.07 25.degree. C./60% RH 6 100.5 0.07 12 101.3
0.11 30.degree. C./75% RH 1 98.8 0.11 3 98.7 0.12 6 100.4 0.07 9
100.1 0.11 12 99.5 0.07 40.degree. C./75% RH 1 96.2 0.06 3 98.5
0.12 6 101.4 0.12 50.degree. C. 1 100.1 0.11 3 100.6 0.07 Light ICH
97.5 0.07 Light ICH: integrated near UV energy not less than 200 W
h/m.sup.2, overall illumination not less than 1200 klux h
[0385] No substantial stability related changes were observed
during storage of the drug product at the different storage
conditions.
[0386] 5. Dissolution
[0387] The dissolution test was performed using Paddle Apparatus
(USP type 2, Ph. Eur., JP.) at 75 rpm in 900 mL of 0.5% (w/v)
cetyltrimethylammonium bromide (CTAB) in 0.05 M sodium phosphate
buffer pH 4.5.
[0388] Samples were taken by Distek.RTM. sample needles with solid
housing and samples were filtered with Whatman.RTM. Spartan.RTM.
0.45 .mu.m RC (regenerated cellulose) membrane 30 mm diameter
filters.
[0389] The determination of the quantity of ARN-509 present in the
dissolution samples was based upon an isocratic ultra high
performance liquid chromatographic (UHPLC) method with UV
detection.
[0390] The test was performed on tablets of Example 3.3 stored
under different storage conditions as indicated in table 4
below.
[0391] The following instrumentation, reagents and solutions and
parameters were used.
[0392] Instrumentation
[0393] Dissolution Instrument: Paddle apparatus (USP type 2, Ph.
Eur., JP).
[0394] UHPLC Instrument: Waters Acquity H-Class with UV
detector.
[0395] Data Acquisition System: Waters Empower.
[0396] Analytical Balance: Sensitive to 0.01 g.
[0397] Analytical Balance: Sensitive to 0.01 mg.
[0398] pH Meter: Sensitive to 0.01 pH units.
[0399] Thermometer: Sensitive to 0.1.degree. C.
[0400] Reagents and Solutions
[0401] Reagents
[0402] Cetrimonium bromide, cetyltrimethylammonium bromide,
[0403] hexadecyltrimethylammonium bromide, (CTAB): Pro Analysis,
99.0% Purity.
[0404] Sodium phosphate monobasic monohydrate
(NaH.sub.2PO.sub.4.H.sub.2O): ACS Grade.
[0405] Trifluoroacetic acid: HPLC Grade, 99.0% Purity.
[0406] Acetonitrile: HPLC Grade.
[0407] Mobile Phase
[0408] Mobile Phase A: 0.1% (v/v) TFA in water
[0409] Mobile Phase B: Acetonitrile
[0410] Procedure
[0411] Dissolution Parameters
[0412] Apparatus: Paddle Apparatus (USP type 2, Ph. Eur, JP.).
[0413] Vessels: 1-L glass.
[0414] Rotation Speed: 75 rpm.
[0415] Dissolution Medium: 0.5% (w/v) CTAB in 0.05 M Phosphate
Buffer pH 4.5.
[0416] Volume of Medium: 900 mL.
[0417] Medium Degassing: Not Required.
[0418] Medium Replacement: Not Required.
[0419] Temperature: 37.0.+-.0.5.degree. C.
[0420] Sinker: Use no sinker.
[0421] Sample Introduction: Transfer 1 tablet into each dissolution
vessel.
[0422] Analytical Finish--UHPLC Parameters
[0423] Conditions
[0424] Column: Acquity UHPLC.RTM. CSH C18 1.7-.mu.m particle size,
2.1.times.50 mm i.d.
[0425] Column Temperature: 60.+-.5.degree. C.
[0426] Sample Temperature: Ambient.
[0427] Flow Rate: 0.6 mL/min.
[0428] Detection: UV at 242 nm.
[0429] Injection Volume: 3 .mu.L.
[0430] Elution Mode: Isocratic.
[0431] Mobile Phase: 50/50 (v:v), 0.1% TFA in water: Acetonitrile.
[0432] Degas using suitable means.
[0433] Run Time (guide): 1.5 minutes.
[0434] Retention Time (guide): Approximately 0.7 minutes for
ARN-509
[0435] Wash Solvent: Acetonitrile.
[0436] Needle Wash: Acetonitrile.
[0437] Seal Wash Solvent: 90/10 (v:v), Water:Acetonitrile.
[0438] Purge Solvent: 90/10 (v:v), Water:Acetonitrile.
[0439] Sampling Rate: 20 points/sec with filter constant
normal.
TABLE-US-00029 TABLE 4 Test conditions and results for tablets of
Example 3.3 stored in HDPE Bottles with Desiccant (silica
gel)-Dissolution results Parameter Storage Storage time Dissolution
mean (%) (min-max) condition (months) 5 min 10 min 15 min 20 min 30
min 45 min 60 min Initial 65 87 94 97 99 100 100 (64-65) (86-88)
(93-96) (96-100) (97-102) (97-102) (98-103) -20.degree. C. 1 64 85
92 95 97 97 97 (63-66) (84-87) (91-93) (94-97) (95-99) (95-99)
(95-100) 5.degree. C. 3 65 87 94 97 99 99 99 (63-66) (85-88)
(92-96) (95-99) (97-101) (97-101) (97-101) 6 63 84 92 95 96 97 97
(61-64) (83-86) (91-94) (93-97) (94-100) (95-100) (95-100) 12 60 83
90 93 95 95 95 (57-62) (82-84) (89-93) (92-96) (93-98) (93-99)
(93-99) 25.degree. C./ 6 68 84 92 95 97 97 97 60% RH (67-70)
(83-86) (90-93) (93-96) (94-99) (95-99) (95-99) 12 63 85 93 96 98
99 99 (62-65) (84-86) (92-94) (95-98) (97-99) (97-100) (97-100)
30.degree. C./ 1 63 85 93 96 98 98 98 75% RH (60-64) (84-86)
(91-94) (94-97) (95-99) (95-100) (96-100) 3 65 86 94 97 99 99 99
(64-66) (85-86) (93-95) (96-98) (97-100) (98-100) (98-100) 6 64 86
94 97 99 99 99 (63-67) (85-87) (93-94) (95-98) (97-100) (97-101)
(97-101) 9 62 85 92 95 98 98 98 (61-64) (84-86) (91-93) (94-97)
(95-99) (96-99) (96-99) 12 65 86 93 96 97 98 98 (62-66) (85-87)
(92-94) (93-98) (95-100) (95-100) (95-100) 40.degree. C./ 1 63 86
93 96 99 99 99 75% RH (62-65) (84-87) (91-94) (93-98) (94-101)
(94-102) (95-101) 3 65 86 93 96 98 99 99 (64-67) (85-87) (92-96)
(95-99) (96-101) (97-102) (97-101) 6 66 86 93 96 97 97 97 (65-67)
(85-88) (92-95) (94-98) (95-100) (96-100) (96-101) 50.degree. C. 1
64 86 94 97 99 100 100 (63-64) (84-87) (92-96) (95-99) (97-101)
(97-102) (98-103) 3 65 86 94 97 99 100 100 (64-65) (85-87) (93-96)
(95-100) (97-102) (97-103) (97-103) Light ICH 64 85 93 96 98 98 98
(63-65) (85-86) (92-94) (95-97) (97-99) (96-99) (97-99) Light ICH:
integrated near UV energy not less than 200 W h/m.sup.2, overall
illumination not less than 1200 klux h
[0440] No substantial stability related changes were observed
during storage of the drug product at the different storage
conditions.
[0441] 6. Water Activity
[0442] The water activity was determined with a Novasina
a.sub.w-meter.
[0443] The test was performed on tablets of Example 3.3.
[0444] The results are reported in table 5 below.
TABLE-US-00030 TABLE 5 Test conditions and results for tablets of
Example 3.3 stored in HDPE Bottles with Desiccant (silica
gel)-Water activity results Parameter Storage Storage time
condition (months) Water activity Initial 0.50 5.degree. C. 12 0.14
25.degree. C./60% RH 12 0.22 30.degree. C./75% RH 12 0.27
[0445] A slight decrease in water activity was observed after 12
months storage at the tested conditions.
[0446] 7. Microbiological Purity
[0447] The microbiological purity of the tablets of Example 3.3 was
tested according to USP <61> and <62>, and Ph. Eur.
2.6.12 and 2.6.13.
[0448] Results are reported in table 6 below.
TABLE-US-00031 TABLE 6 Test conditions and results for tablets of
Example 3.3 stored in HDPE Bottles with Desiccant (silica
gel)-Microbiological Purity Results Total Total combined Aerobic
Molds and Microbial Yeasts Count Pathogens: Parameter Storage count
(cfu/g) (cfu/g) E. Coli Storage time USP <61>/ USP
<61>/ USP <62>/ condition (months) Ph. Eur. 2.6.12 Ph.
Eur. 2.6.12 Ph. Eur. 2.6.13 Initial <50 <50 Absent in 1 g
5.degree. C. 12 <50 <50 Absent in 1 g 25.degree. C./ 12
<50 <50 Absent in 1 g 60% RH 30.degree. C./ 12 <50 <50
Absent in 1 g 75% RH
[0449] No substantial stability related changes were observed
during storage of the drug product at the different storage
conditions.
[0450] It is within the knowledge of the skilled person to
recognize equivalent conditions, solutions, reagents, parameters
and instrumentation to the ones described above. It is within the
knowledge of the skilled person to recognize appropriate reference
solutions, calculation methods, suitability tests.
* * * * *