NZ717230B2 - Sustained release dosage forms for a jak1 inhibitor - Google Patents
Sustained release dosage forms for a jak1 inhibitor Download PDFInfo
- Publication number
- NZ717230B2 NZ717230B2 NZ717230A NZ71723014A NZ717230B2 NZ 717230 B2 NZ717230 B2 NZ 717230B2 NZ 717230 A NZ717230 A NZ 717230A NZ 71723014 A NZ71723014 A NZ 71723014A NZ 717230 B2 NZ717230 B2 NZ 717230B2
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- NZ
- New Zealand
- Prior art keywords
- dosage forms
- release dosage
- pyrrolo
- fluoro
- isonicotinoyl
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Abstract
This invention relates to the use of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (also known as itacitinib / INCB039110) , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease selected from graft versus host disease, psoriasis, rheumatoid arthritis, primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis, wherein the medicament is provided in the form of one or more sustained release dosage forms comprising a once-daily oral dose of about 400 mg to about 600 mg on a free base basis. icament for the treatment of a disease selected from graft versus host disease, psoriasis, rheumatoid arthritis, primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis, wherein the medicament is provided in the form of one or more sustained release dosage forms comprising a once-daily oral dose of about 400 mg to about 600 mg on a free base basis.
Description
SUSTAINED RELEASE DOSAGE FORMS FORAJAKl INHIBITOR
This application claims the benefit of priority of U.S. Prov. Appl. No.
61/863,325, filed August 7, 2013, and U.S. Prov. Appl. No. 61/913,066, filed
er 6, 2013, each of which is incorporated herein by reference in its ty.
TECHNICAL FIELD
This application relates to a sustained release dosage form comprising {1- {1-
[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidin—4-yl} -3 -[4-(7H-pyrrolo [2,3 -
d]pyrimidinyl)—1H—pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically
acceptable salt f, and doses and methods related thereto.
BACKGROUND
Protein kinases (PKs) regulate diverse biological processes ing cell
growth, survival, differentiation, organ formation, morphogenesis, neovascularization,
tissue repair, and regeneration, among others. Protein kinases also play specialized
roles in a host ofhuman diseases ing cancer. nes, low-molecular weight
polypeptides or glycoproteins, regulate many pathways involved in the host
inflammatory response to sepsis. nes influence cell differentiation,
proliferation and activation, and can modulate both pro—inflammatory and anti—
inflammatory ses to allow the host to react appropriately to pathogens.
Signaling of a wide range of cytokines es the Janus kinase family (JAKs) of
protein tyrosine kinases and Signal Transducers and Activators of Transcription
(STATS). There are four known mammalian JAKs: JAKl (Janus -l), JAK2,
JAK3 (also known as Janus kinase, leukocyte; JAKL; and L-JAK), and TYK2
(protein—tyrosine kinase 2).
Cytokine—stimulated immune and inflammatory responses contribute to
pathogenesis of diseases: pathologies such as severe combined immunodeficiency
(SCID) arise from suppression of the immune system, while a hyperactive or
inappropriate immune/inflammatory response contributes to the pathology of
autoimmune es (e.g., asthma, systemic lupus erythematosus, thyroiditis,
myocarditis), and illnesses such as scleroderma and osteoarthritis nn, R. A., T.
Cheng, et al. (2000) Arthritis Res 2(1): 16—32).
Deficiencies in expression of JAKs are associated with many disease states.
For example, Jakl-/— mice are runted at birth, fail to nurse, and die perinatally (Rodig,
S. J., M. A. Meraz, et al. (1998) Cell 93(3): ). Jak2—/— mouse embryos are
anemic and die around day 12.5 postcoitum due to the absence of definitive
erythropoiesis.
The AT pathway, and in particular all four JAKs, are believed to play
a role in the pathogenesis of asthmatic response, chronic obstructive pulmonary
e, bronchitis, and other related inflammatory diseases of the lower respiratory
tract. Multiple cytokines that signal through JAKs have been linked to inflammatory
diseases/conditions of the upper respiratory tract, such as those affecting the nose and
sinuses (e. g., rhinitis and tis) r classically allergic reactions or not. The
JAK/STAT pathway has also been implicated in atory es/conditions of
the eye and c allergic responses.
Activation of JAK/STAT in cancers may occur by cytokine stimulation (e.g.
IL—6 or GM—CSF) or by a reduction in the nous suppressors of JAK signaling
such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of
activated STAT) (Boudny, V., and Kovarik, J
., Neoplasm. 49:349—355, 2002).
Activation of STAT signaling, as well as other pathways downstream of JAKS (e.g.,
Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et
al. Oncogene 19:2474—2488, 2000). Elevated levels of circulating cytokines that
signal h JAK/STAT play a causal role in cachexia and/or chronic fatigue. As
such, JAK inhibition may be beneficial to cancer patients for reasons that extend
beyond potential anti-tumor activity.
JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative
disorders, e. g., themia vera (PV), essential thrombocythemia (ET), myeloid
metaplasia with myelofibrosis (MMM) (Levin, et al, Cancer Cell, vol. 7, 2005: 387—
397). Inhibition of the JAK2V617F kinase decreases proliferation of hematopoietic
cells, suggesting JAK2 as a potential target for pharmacologic inhibition in patients
with PV, ET, and MMM.
Inhibition of the JAKs may benefit patients suffering from skin immune
disorders such as psoriasis, and skin sensitization. The maintenance of psoriasis is
believed to depend on a number of inflammatory cytokines in addition to various
chemokines and growth factors (JCI, 11321664—1675), many of which signal through
JAKs (Adv Pharmacol. 2000;47:113—74).
Due to the ness of compounds which inhibit JAK in targeting
tation or suppression of the immune and atory pathways (such as
immunosuppressive agents for organ transplants), as well as the treatment of
autoimmune es, es involving a hyperactive inflammatory response (e.g.,
eczema), allergies, cancer (e. g., prostate, leukemia, multiple myeloma), and some
immune reactions (e.g., skin rash or contact dermatitis or diarrhea) caused by other
therapeutics, there is a need for improved formulations for administering JAK
kinases. The dosages forms bed herein, as well as the doses and methods
described supra are directed toward this need and other ends.
SUMMARY
JAK inhibitors are described in US. Serial No. 13/043,986 (US
2011/0224190), filed March 9, 2011, which is incorporated herein by reference in its
entirety, including { l- { l - [3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -
[4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— 1 H-pyrazol- l etidin—3 -yl} acetonitrile,
which is depicted below as Formula I.
NC”\
N N
2014/049940
The present application provides, inter alia, sustained—release dosage forms
comprising about 25 mg to about 600 mg (e. g., 25 mg, 100 mg, 200 mg, 300 mg, or
600 mg) on a free base basis of {l— { uoro-2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof.
The present invention further provides one or more sustained release dosage
forms each sing [3-fluoro(trifluoromethy1)isonicotinoyl]piperidin
yl} -3 -[4-(7H-pyrrolo [2,3 imidinyl)- l zol- l -yl]azetidin
yl}acetonitrile, or a pharmaceutically acceptable salt thereof; wherein said one or
more sustained release dosage forms together provide a once—daily oral dosage of
about 400 mg to about 600 mg on a free base basis of {l-{ l—[3 —fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— azol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The present invention also provides a dose, comprising one or more sustained
release dosage forms each comprising {1—{ l—[3—fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—1H—pyrazol—l-yl]azetidin-3—yl}acetonitrile, or a pharmaceutically acceptable salt
thereof; wherein said dose provides a once—daily oral dosage of about 400 mg to about
600 mg on a free base basis of {l—{ 1-[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)-lH-pyrazol-l-yl]azetidin-3 -y1}acetonitrile, or a pharmaceutically acceptable salt
thereof, to a t.
The present application further provides one or more sustained release dosage
forms as described herein, which together provide a once—daily oral dosage of about
600 mg on a free base basis of {l—{ 1—[3-fluoro—2-
oromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The present application also provides a dose comprising one or more sustained
release dosage forms as described herein, which together provide a once—daily oral
WO 21153
dosage of about 600 mg on a free base basis of {l—{l—[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The t application further provides methods of treating an mune
disease, a cancer, a myeloproliferative disorder, an atory disease, a bone
tion e, or organ transplant rejection in a patient in need thereof,
comprising orally administering to said patient one or more ned release dosage
forms as described herein.
The present application also provides methods of treating an autoimmune
disease, a cancer, a myeloproliferative disorder, an inflammatory e, a bone
resorption disease, or organ transplant rejection in a patient in need thereof,
comprising orally administering to said patient a once-daily dose of about 400 mg to
about 600 mg on a free base basis of {l— { 1-[3 —fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} itrile, or a pharmaceutically acceptable salt
thereof, wherein the dose comprises one or more sustained release dosage forms each
comprising { l- { l -[3-fluoro-2—(trifluoromethyl)isonicotinoyl]piperidinyl} [4-
(7H-pyrrolo[2,3 imidin-4—yl)— lH—pyrazol— l -yl]azetidiny1} acetonitrile, or a
pharmaceutically acceptable salt thereof.
The present application further provides methods of treating an autoimmune
disease, a cancer, a roliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a patient in need thereof,
comprising orally administering to said patient one or more ned release dosage
as described herein.
The present application also es methods of treating an autoimmune
disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a patient in need thereof, wherein
the method comprises orally administering to said patient the one or more sustained
release dosage forms as a once—daily dosage of about 600 mg on a free base basis of
{ l- { l—[3 -fluoro(trifluoromethyl)isonicotinoy1]piperidiny1} -3 -[4-(7H—
pyrrolo [2,3 -d]pyrimidinyl)— l H—pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically acceptable salt thereof.
DESCRIPTION OF DRAWINGS
FIG. lA-C depicts plasma concentrations for the compound of Formula I
(Mean 1 SE) in healthy subjects receiving single doses of 300 mg IR capsules (1A:
Cohorts l-4, fasted), SRl, SR2, SR3, and SR4 tablets (2B: Cohorts l-4, fasted; and
2C: s 1—4, fed a high-fat meal).
—B s —dose 300 mg SR3 PK profiles (Mean i SE) (2A:
Cohort 3, SR3, fasted versus high-fat meal; and 2B: Cohort 5, SR3, fasted versus
-fat meal).
s a comparison of PK s (mean i SE) between the 25 mg
and 100 mg SR3 tablets (treatment A vs C) and the food effect of a high—fat meal on
the 25 mg SR3 tablet (treatment B vs A).
depicts the percent change from baseline for hemoglobin for several
dosing regimens for sustained release tablets versus placebo.
a) depicts the percentage of patients having a 2 50% reduction in total
m score (TSS) at week 12 by dose cohort (100 mg BID, 200 mg BID, and 600
mg QD).
b) depicts the percent change in total symptom score (TSS) from
baseline at week 12 by dose cohort (100 mg BID, 200 mg BID, and 600 mg QD).
a) depicts mean hemoglobin levels over time by dose cohort (100 mg
BID, 200 mg BID, and 600 mg QD).
b) depicts mean hemoglobin levels (g/dL) over time by dose cohort
(100 mg BID, 200 mg BID, and 600 mg QD) at 48 weeks.
c) depicts mean hemoglobin levels (g/dL) over time by dose cohort at
48 weeks as an average for three dose cohorts as compared to individuals dosed with
placebo or ruxolitinib.
DETAILED PTION
The present application provides sustained—release dosage forms comprising
{ l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-
pyrrolo[2,3-d]pyrimidin—4-yl)- l H—pyrazol- 1 etidin—3-yl} acetonitrile, or a
pharmaceutically acceptable salt thereof. In some embodiments, the present
application provides a sustained—release dosage form sing about 25 mg to
about 600 mg on a free base basis of {1— { l-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl} [4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof.
In some embodiments, the sustained—release dosage form comprises about 300
mg on a free base basis of {l—{ l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
4-yl} -3 - [4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— lH-pyrazol- l -yl]azetidin—3 -
yl}acetonitrile, or a pharmaceutically able salt thereof.
In some embodiments, the sustained—release dosage form comprises about 200
mg on a free base basis of {l- { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
4-yl} -3 - [4-(7H—pyrrolo[2,3 -d]pyrimidin—4-yl)- lH-pyrazol- l -yl]azetidin—3 -
yl}acetonitrile, or a pharmaceutically acceptable salt thereof.
In some ments, the sustained—release dosage form comprises about 100
mg on a free base basis of {l- { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
4-yl} -3—[4-(7H—pyrrolo[2,3 -d]pyrimidin—4-yl)- 1 H—pyrazolyl]azetidin—3 —
yl}acetonitrile, or a pharmaceutically acceptable salt f.
In some embodiments, the sustained-release dosage form comprises about 300
mg on a free base basis of {l- { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
4-y1} [4-(7H-pyrrolo[2,3 -d]pyrimidinyl)—lH-pyrazolyl]azetidin-3 -
yl}acetonitrile adipic acid salt.
In some embodiments, the sustained—release dosage form comprises about 200
mg on a free base basis of {l- { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
4-yl} —3 - [4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— l H—pyrazolyl]azetidin—3 -
tonitrile adipic acid salt.
In some embodiments, the ned—release dosage form comprises about 100
mg on a free base basis of {l- { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
WO 21153
4-yl} —3 - [4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— 1 H—pyrazol- l -yl]azetidin—3 -
yl}acetonitrile adipic acid salt.
In some embodiments of the sustained—release dosage form sing about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean peak plasma tration (Cmax) of {1- { l-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)—lH-pyrazol-l-yl]azetidinyl}acetonitrile of about 100 nM to about 1000 nM. As
used in this context, oral administration means that a single dose is administered to
the individual (in this case, 3 x 100 mg) and the PK parameter is calculated from the
measurements of plasma concentration over time. In this context, the PK parameter
(in this case, Cmax) is being used to characterize the single sustained release dosage
form (i.e., the claims are directed to a single dosage form, not three dosage forms).
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean peak plasma concentration (Cmax) of {1-{1-[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrile of about 400 nM to about 700 nM.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean time to peak plasma tration (Tmax) of {l- {l-[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)—lH—pyrazol—l—yl]azetidin—3-yl}acetonitrile of about 0.5 hours to about 3 hours.
In some embodiments of the sustained-release dosage form sing about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean time to peak plasma concentration (Tmax) of {1- {1-[3-fluoro
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin—3—yl}acetonitrile of at least 0.5 hours.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral stration of three of said dosage forms to a fasted individual
provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma
concentration (C1211) of { l— { l—[3 -fluoro(trifluoromethyl)isonicotinoy1]piperidin
yl} -3 —[4-(7H—pyrrolo [2,3 -d]pyrimidin—4-yl)- l H—pyrazol- l -yl]azetidin-3—
yl}acetonitrile of about 5 to about 50.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma
concentration (Cizh) of {l—{l-[3—fluoro—2—(trifluoromethyl)isonicotinoyl]piperidin—4-
yl} -3 H-pyrrolo [2,3 imidinyl)- l H-pyrazol- l -yl]azetidin-3—
tonitrile of about 9 to about 40.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma
tration (C1211) of {1—{1—[3-fluoro—2—(trifluoromethy1)isonicotinoy1]piperidin-4—
yl} -3 -[4-(7H-pyrrolo [2,3 imidinyl)- l H—pyrazol— l -yl]azetidin
yl}acetonitrile of about 15 to about 30.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean half-life (ti/2) of {l—{ 1—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—1H—pyrazol—1—y1]azetidin-3—yl}acetonitrile of about 5 hours to about 15 hours.
In some embodiments of the sustained—release dosage form sing about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean half—life (ti/2) of {1-{1-[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl} [4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)—lH—pyrazol—l—yl]azetidin—3-yl}acetonitrile of about 7 hours to about 12 hours.
In some embodiments of the sustained-release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted individual
provides a mean half—life (ti/2) of {1-{1-[3—fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—1H-pyrazol-1—yl]azetidin—3—y1}acetonitrile of about 1 hour to about 20 hours.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted dual
provides a mean bioavailability (AUCO—oo) of {1—{1-[3-fluoro—2—
2014/049940
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrile of about 1000 nM*h to about 4000
nM*h.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to a fasted dual
provides a mean bioavailability (AUCO-oo) of {1—{1-[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—1H-pyrazoly1]azetidinyl}acetonitrile of about 1500 nM*h to about 3100
nM*h.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high—fat meal provides a mean peak plasma concentration (Cmax) of {1— { 1-[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin-3—y1}acetonitrile of about 200 nM to about 2000 nM.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a mean peak plasma concentration (Cmax) of [3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrile of about 500 nM to about 1500 nM.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a mean time to peak plasma concentration (Tmax) of {l— {1-[3-
fluoro(trifluoromethyl)isonicotinoy1]piperidiny1}[4-(7H-pyrrolo[2,3-
d]pyrimidinyl)—lH-pyrazol-l-yl]azetidinyl}acetonitrile of about 1 hour to about
9 hours.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral stration of three of said dosage forms to an individual after a
high-fat meal provides a mean time to peak plasma tration (Tmax) of {1- {1-[3-
fluoro—2-(trifluoromethyl)isonicotinoy1]piperidinyl}—3-[4-(7H—pyrrolo[2,3-
d]pyrimidin-4—yl)-lH-pyrazol-l-yl]azetidin-3 -y1}acetonitrile of at least 1.5 hours.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a ratio of mean peak plasma concentration (Cmax) to mean 12-
hour plasma concentration (Cizh) of { 1—{1-[3-fluoro—2-
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrile of about 10 to about 70.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a ratio of mean peak plasma concentration (Cmax) to mean 12-
hour plasma concentration (Cizh) of {1- {1-[3-fluoro
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—1H-pyrazoly1]azetidin—3—y1}acetonitrile of about 15 to about 50.
In some embodiments of the sustained—release dosage form sing about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a ratio of mean peak plasma concentration (Cmax) to mean 12-
hour plasma concentration (Cizh) of {l— {l-[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
-pyrazol-l-yl]azetidin-3—yl}acetonitrile of about 25 to about 45.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a mean half-life (ti/2) of {l— { l-[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—1H—pyrazol—1—yl]azetidin-3—yl}acetonitrile of about 1 hour to about 7 hours.
In some ments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a mean half-life (ti/2) of {l- { l-[3-fluoro—2—
(trifluoromethy1)isonicotinoy1]piperidinyl}[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)—lH—pyrazol—l—yl]azetidin—3—yl}acetonitrile of about 2 hours to about 5 hours.
In some ments of the sustained—release dosage form sing about
100 mg, oral administration of three of said dosage forms to an individual after a
high—fat meal provides a mean bioavailability (AUCO—oo) of {l- {1-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)—lH-pyrazol-l-yl]azetidin-3—yl}acetonitrile of about 2000 nM*h to about 5000
nM*h.
In some embodiments of the sustained—release dosage form comprising about
100 mg, oral administration of three of said dosage forms to an individual after a
high-fat meal provides a mean ilability (AUCO—oo) of {l- {1-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)—lH-pyrazol-l-yl]azetidinyl}acetonitrile of about 3000 nM*h to about 4000
nM*h.
In some embodiments, the percent geometric mean ratio of the sustained
release dosage form relative to an immediate release dosage form for Cmax is about
% to about 30%, wherein one or more ate release dosage forms and one or
more sustained release dosage forms are independently orally administered to fasted
individuals as a single dose, wherein the same size dose of {l—{ 1—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin-3—yl}acetonitrile, or a pharmaceutically acceptable salt,
is administered.
In some embodiments, the percent geometric mean ratio of the sustained
release dosage form relative to an immediate release dosage form for Cmax is about
% to about 30%, wherein one or more immediate release dosage forms and one or
more sustained release dosage forms are ndently orally administered to fasted
individuals as a single dose, wherein the same size dose of {l-{ l—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrile, or a ceutically acceptable salt,
is administered.
In some embodiments, the percent geometric mean ratio of the sustained
release dosage form ve to an immediate e dosage form for AUCO—oo is about
40% to about 55%, wherein one or more immediate release dosage forms and one or
more sustained e dosage forms are independently orally administered to fasted
individuals as a single dose, wherein the same size dose of {l—{ 1-[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin-3—yl}acetonitrile, or a pharmaceutically acceptable salt,
is administered.
In some embodiments, the percent ric mean ratio for Cmax of the
sustained release dosage form orally administered to an individual after a high-fat
meal relative to the sustained e dosage form orally administered to a fasted
individual is about 150% to about 250%.
In some embodiments, the percent geometric mean ratio for AUCO—oo of the
sustained release dosage form orally administered to an individual after a high-fat
meal relative to the sustained release dosage form orally administered to a fasted
individual is about 125% to about 170%.
In some embodiments, the sustained—release dosage forms of the invention
may include a sustained-release matrix former. Example sustained-release matrix
s include cellulosic ethers such as hydroxypropyl methylcellulose (HPMC,
hypromellose) which is a high ity polymer, and methyl celluloses. Example
hydroxypropyl methylcelluloses include MethocelTM K15M, MethocelTM K4M,
MethocelTM KIOOLV, MethocelTM E3, MethocelTM E5, elTM E6, MethocelTM
E15, MethocelTM E50, MethocelTM E10M, MethocelTM E4M, and elTM E10M.
In some ments, the sustained release dosage form comprises one or more
hypromelloses. In some embodiments, the sustained release dosage form comprises a
first hypromellose characterized by having an apparent viscosity at a concentration of
2% in water of about 80 CF to about 120 cP and a second hypromellose characterized
by having an apparent viscosity at a tration of 2% in water of about 3000 CF to
about 5600 CR In some embodiments, the sustained release dosage form comprises
about 8% to about 20% by weight of one or more hypromelloses. In some
embodiments, the sustained release dosage form comprises about 10% to about 15%
by weight of one or more hypromelloses.
In some embodiments, the sustained-release dosage forms of the invention can
further include one or more , glidants, disintegrants, binders, or lubricants as
inactive ingredients. In some embodiments, the filler comprises microcrystalline
cellulose, lactose monohydrate, or both. In some embodiments, the sustained release
dosage form comprises about 16% to about 22% by weight of microcrystalline
cellulose. In some embodiments, the sustained release dosage form comprises about
45% to about 55% by weight of lactose monohydrate,
In some embodiments, ants can be present in the dosage forms of the
ion in an amount of 0 to about 5% by weight. Non-limiting examples of
lubricants include ium stearate, stearic acid (stearin), hydrogenated oil,
polyethylene glycol, sodium stearyl te, and glyceryl behenate. In some
embodiments, the formulations include magnesium stearate, stearic acid, or both. In
some embodiments, the sustained release dosage form comprises about 0.3% to about
0.7% by weight of ium stearate.
In some embodiments, glidants may be present in the dosage forms. In some
embodiments, glidants can be present in the dosage forms of the invention in an
amount of 0 to about 5% by weight. Non-limiting examples of glidants include talc,
dal silicon dioxide, and cornstarch. In some embodiments, the t is
colloidal silicon dioxide.
In some ments, film—coating agents can be present in an amount of 0 to
about 5% by weight. Non-limiting illustrative examples of film-coating agents
include hypromellose or polyvinyl alcohol based coating with titanium dioxide, talc
and optionally colorants available in several commercially available complete coating
systems.
In some ments, the sustained release dosage form comprises
pregelatinized starch.
In some embodiments, the sustained release dosage form is a tablet.
In some embodiments, the sustained release dosage form is prepared by
process comprising wet granulation.
In some embodiments, the sustained release dosage form comprises one or
more excipients independently ed from hypromelloses and microcrystalline
celluloses.
In some embodiments, the sustained release dosage form comprises one or
more ents independently selected from hypromelloses, microcrystalline
celluloses, magnesium stearate, e, and lactose monohydrate.
In some embodiments, the sustained release dosage form comprises one or
more excipients independently selected from hypromelloses, microcrystalline
celluloses, magnesium stearate, lactose, lactose monohydrate, and pregelatinized
starch.
The present invention further provides one or more ned release dosage
forms each sing {1-{ uoro(trifluoromethyl)isonicotinoyl]piperidin
yl} -3 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4—yl)- l H—pyrazol— l -yl]azetidin-3—
yl}acetonitrile, or a pharmaceutically acceptable salt thereof; wherein said one or
more sustained release dosage forms er e a once—daily oral dosage of
about 400 mg to about 600 mg on a free base basis of {l—{ l—[3 —2—
oromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The present invention also provides a dose, sing one or more ned
release dosage forms each comprising {1-{1-[3-fluoro
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-y1]azetidin—3 —y1} acetonitrile, or a pharmaceutically acceptable salt
thereof; wherein said dose provides a once—daily oral dosage of about 400 mg to about
600 mg on a free base basis of {1—{1—[3-fluoro—2-
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
f, to a patient.
The present application further provides one or more sustained release dosage
forms as described herein, which together provide a once—daily oral dosage of about
600 mg on a free base basis of {l—{ 1-[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The present application further provides one or more sustained release dosage
forms as described herein, which together provide a once-daily oral dosage of about
500 mg on a free base basis of {l— {l—[3-fluoro—2—
oromethy1)isonicotinoyl]piperidiny1}[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The t application further provides one or more sustained release dosage
forms as described herein, which together provide a once—daily oral dosage of about
400 mg on a free base basis of {1—{1—[3—fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
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yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
In some embodiments, the one or more sustained release dosage forms are six
dosage forms of about 100 mg on a free base basis of {1—{1—[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—1H—pyrazol—l-yl]azetidin-3 etonitrile, or a pharmaceutically acceptable salt
thereof, are provided. In some embodiments, the one or more sustained e
dosage forms are three dosage forms of about 200 mg on a free base basis of {1-{1-
[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 - [4-(7H-pyrrolo [2,3-
d]pyrimidin—4—yl)—1H—pyrazol—1-yl]azetidin—3—y1}acetonitrile, or a pharmaceutically
able salt thereof, are provided. In some embodiments, the one or more
sustained release dosage forms are two dosage forms of about 300 mg on a free base
basis of {l-{ l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 H-
pyrrolo [2,3 -d]pyrimidinyl)— l H—pyrazol- l -y1]azetidin-3 etonitri1e, or a
pharmaceutically acceptable salt thereof, are provided. In some embodiments, the one
or more sustained release dosage forms is one dosage form of about 600 mg on a free
base basis of {l- { l—[3 —fluoro-2—(trifluoromethyl)isonicotinoyl]piperidin—4-yl} -3—[4-
(7H-pyrrolo[2,3 -d]pyrimidinyl)- lH—pyrazol— l etidinyl} acetonitrile, or a
pharmaceutically acceptable salt thereof, is provided.
The present application also provides a dose comprising one or more sustained
e dosage forms as described herein, which provide a once—daily oral dosage of
about 600 mg on a free base basis of {1— { l-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl} [4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The present application also provides a dose comprising one or more sustained
e dosage forms as described herein, which provide a once—daily oral dosage of
about 500 mg on a free base basis of {l—{l-[3-fluoro
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
The present application also provides a dose comprising one or more sustained
release dosage forms as described herein, which provide a once—daily oral dosage of
about 400 mg on a free base basis of {1— { l—[3 —fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a patient.
In some embodiments, the dose comprises six dosage forms of about 100 mg
on a free base basis of {1- {1-[3-fluoro(trifluoromethyl)isonicotinoy1]piperidin
yl} -3 -[4-(7H-pyrrolo [2,3 -d]pyrimidinyl)- l H-pyrazol- l -yl]azetidin
yl}acetonitrile, or a pharmaceutically acceptable salt f. In some embodiments,
the dose comprises three dosage forms of about 200 mg on a free base basis of { l—{l—
[3 o(trifluoromethyl)isonicotinoyl]piperidin-4—yl} -3 - [4—(7H—pyrrolo [2,3—
d]pyrimidin-4—yl)— lH-pyrazol-l-yl]azetidinyl} acetonitrile, or a pharmaceutically
acceptable salt thereof. In some embodiments, the dose comprises two dosage forms
of about 300 mg on a free base basis of {l— {l—[3-fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidiny1}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH—pyrazol—l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically able salt
thereof. In some embodiments, the dose comprises one dosage form of about 600 mg
on a free base basis of {1— { l—[3—fluoro—2—(trifluoromethy1)isonicotinoy1]piperidin—4—
yl} -3 —[4-(7H-pyrrolo [2,3 -d]pyrimidinyl)- l H-pyrazol- l -yl]azetidin-3—
yl}acetonitrile, or a pharmaceutically acceptable salt thereof
The present application further provides a kit sing one or more
sustained release dosage forms as bed herein, which er provide a once-
daily oral dosage of about 400 mg to about 600 mg on a free base basis of {l— { 1—[3—
fluoro(trifluoromethyl)isonicotinoyl]piperidiny1}[4-(7H-pyrrolo[2,3-
d]pyrimidin-4—yl)— lH-pyrazol-l-yl]azetidinyl} acetonitrile, or a ceutically
acceptable salt thereof, to a patient. In some embodiments, the kit further comprises
an instruction to ster the one or more sustained release dosage forms as a once—
daily dose of about 400 mg to about 600 mg on a free base basis of {1—{ uoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof.
The present application further provides a kit comprising one or more
sustained e dosage forms as described herein, which together provide a once—
daily oral dosage of about 600 mg on a free base basis of {l— { l—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, to a t. In some embodiments, the kit further comprises an instruction to
administer the one or more sustained release dosage forms as a once—daily dose of
about 600 mg on a free base basis of {1-{1-[3-fluoro
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-y1]azetidin—3 —y1} acetonitrile, or a pharmaceutically acceptable salt
thereof.
The t application further provides a kit comprising one or more
sustained release dosage forms as described , which together provide a once—
daily oral dosage of about 500 mg on a free base basis of {l—{l—[3—fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
f, to a patient. In some embodiments, the kit further comprises an instruction to
administer the one or more sustained e dosage forms as a once—daily dose of
about 600 mg on a free base basis of {1— { 1-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3 —yl}acetonitrile, or a pharmaceutically acceptable salt
thereof.
The present application further provides a kit comprising one or more
sustained release dosage forms as described herein, which er e a once—
daily oral dosage of about 400 mg on a free base basis of {1-{1-[3-fluoro
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin—3 —yl} acetonitrile, or a ceutically acceptable salt
thereof, to a patient. In some embodiments, the kit further comprises an instruction to
administer the one or more sustained release dosage forms as a once—daily dose of
about 600 mg on a free base basis of {l— { l-[3 -fluoro—2-
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof.
In some ments, the kit comprises six dosage forms of about 100 mg on
a free base basis of {1—{1—[3-fluoro—2-(trifluoromethyl)isonicotinoyl]piperidin-4—yl}—
3 -[4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— lH-pyrazol- l -yl] azetidin-3 -yl} acetonitrile, or
a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises
three dosage forms of about 200 mg on a free base basis of {l—{ l—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl} [4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)— azol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof. In some embodiments, the kit comprises two dosage forms of about 300 mg
on a free base basis of {l- { l —[3 —fluoro-2—(trifluoromethyl)isonicotinoyl]piperidin-4—
yl} -3 —[4-(7H—pyrrolo [2,3 -d]pyrimidin—4-yl)- l H—pyrazol- l etidin-3—
yl}acetonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments,
the kit comprises one dosage form of about 600 mg on a free base basis of {l- { 1-[3—
2-(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H-pyrrolo[2,3-
d]pyrimidin-4—yl)— azol—l-yl]azetidinyl} acetonitrile, or a pharmaceutically
acceptable salt thereof.
As used herein, ined—release” is used as generally understood in the art
and refers to a formulation designed to slowly release the active ingredient into a
patient after oral administration.
As used herein, “dose” refers to the total amount of the compound of Formula
I orally stered to the individual or patient. The dose may be in a single dosage
form, or a plurality of dosage forms (e.g., a 600 mg dose may be one 600 mg dosage
form, two 300 mg dosage forms, three 200 mg dosage forms, six 100 mg dosage
forms, etc.). Hence, a dose can refer to a plurality of pills to be taken by a patient at
nearly simultaneously.
As used herein, “a fasted individual” means an individual who has fasted for at
least 10 hours prior to administration of the dose.
As used herein, "mean" when preceding a pharmacokinetic value (e. g. mean
Cmax) represents the arithmetic mean value of the pharmacokinetic value taken from a
population of patients unless otherwise specified.
As used herein, "Cmax" means the maximum observed plasma concentration.
WO 21153
As used herein, “C1211” refers to the plasma concentration measured at 12 hours
from administration.
As used , "Tmax" refers to the time at which the maximum blood plasma
concentration is observed.
As used herein, “Ti/2” refers to the time at which the plasma concentration is
half of the observed maximum.
As used herein, "AUC" refers to the area under the plasma concentration-time
curve which is a measure of total bioavailability.
As used herein, oo" refers to the area under the plasma concentration-
time curve extrapolated to infinity.
As used herein, "AUCo-t" refers to the area under the plasma concentration-
time curve from time 0 to the last time point with a quantifiable plasma concentration,
usually about 12—36 hours.
As used herein, "AUCoJ' refers to the area under the plasma concentration-
time curve from time 0 to the time of the next dose.
As used herein, “Cl/F” refers to oral clearance.
The present invention also includes pharmaceutically acceptable salts of the
compounds bed herein. As used herein, "pharmaceutically acceptable salts"
refers to derivatives of the disclosed compounds wherein the parent compound is
modified by ting an existing acid or base moiety to its salt form. Examples of
pharmaceutically acceptable salts include, but are not limited to, l or organic
acid salts of basic es such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the
t invention include the non-toxic salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable
salts of the present ion can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of these compounds with
a stoichiometric amount of the appropriate base or acid in water or in an organic
solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl
acetate, alcohols (e. g., methanol, ethanol, iso-propanol, or butanol) or itrile
(ACN) are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical
2014/049940
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and
Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporated herein
by reference in its entirety. In some embodiments, the compounds described herein
include the N—oxide forms.
The present application further provides methods of treating an autoimmune
disease, a , a myeloproliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a patient in need thereof,
comprising orally administering to said patient one or more sustained release dosage
forms as bed herein.
The present application also provides a method of ng an autoimmune
disease, a , a myeloproliferative disorder, an inflammatory disease, a bone
resorption e, or organ transplant rejection in a patient in need thereof,
comprising orally administering to said patient a aily dose of about 400 mg to
about 600 mg on a free base basis of {l- { 1-[3 —fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)—1H-pyrazolyl]azetidin-3—yl}acetonitrile, or a pharmaceutically acceptable salt
thereof, n the dose comprises one or more sustained release dosage forms each
comprising { 1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4-
(7H-pyrrolo[2,3 —d]pyrimidin-4—yl)- lH—pyrazol— 1 —yl]azetidiny1} acetonitrile, or a
pharmaceutically acceptable salt thereof. The present application further provides
a method of treating an autoimmune disease, a cancer, a myeloproliferative disorder,
an inflammatory disease, a bone resorption disease, or organ transplant rejection in a
patient in need thereof, comprising orally administering to said patient one or more
sustained release dosage as described herein.
The present application also provides a method of ng an autoimmune
disease, a cancer, a roliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a patient in need f, n
the method comprises orally administering to said patient the one or more sustained
release dosage forms as a once-daily dosage of about 600 mg on a free base basis of
{ 1-{1—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} —3 -[4-(7H-
WO 21153
o [2,3 -d]pyrimidinyl)— l H—pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically able salt thereof.
The present application also provides a method of ng an autoimmune
disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a t in need f, wherein
the method comprises orally administering to said patient the one or more sustained
release dosage forms as a once—daily dosage of about 500 mg on a free base basis of
{1-{1-[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}-3 -[4-(7H-
pyrrolo [2,3 -d]pyrimidinyl)- 1 H-pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
ceutically acceptable salt thereof.
The present ation also provides a method of treating an autoimmune
disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a patient in need f, wherein
the method comprises orally administering to said patient the one or more sustained
release dosage forms as a once—daily dosage of about 400 mg on a free base basis of
{ l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H—
pyrrolo [2,3 -d]pyrimidinyl)- l H-pyrazol- l -yl]azetidin—3 -yl} acetonitrile, or a
pharmaceutically acceptable salt thereof.
In some embodiments of the methods in the ing three paragraphs, the
one or more sustained release dosage forms are six dosage forms of about 100 mg on
a free base basis of {1—{1—[3-fluoro—2-(trifluoromethyl)isonicotinoyl]piperidin-4—yl}—
3 -[4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— lH-pyrazol- l -yl] azetidin-3 -yl} acetonitrile, or
a pharmaceutically acceptable salt thereof, are provided. In some embodiments of the
methods in the preceding three paragraphs, the one or more sustained release dosage
forms are three dosage forms of about 200 mg on a free base basis of {1-{1-[3 -fluoro-
2-(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin—3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, are provided. In some embodiments of the methods in the preceding three
paragraphs, the one or more sustained release dosage forms are two dosage forms of
about 300 mg on a free base basis of {1— { l-[3 -fluoro—2-
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH—pyrazol—l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, are provided. In some ments of the methods in the preceding three
paragraphs, the one or more sustained e dosage forms is one dosage form of
about 600 mg on a free base basis of {1— { l-[3 -fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, is provided.
In some embodiments, oral administration of one or more sustained e
dosage forms to a fasted individual provides a mean time to peak plasma
concentration (Tmax) of {l- { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin
yl} —3 —[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—lH-pyrazolyl]azetidin—3—
tonitrileof about 0.5 hours to about 3 hours.
In some embodiments,oral administration of one or more sustained release
dosage forms to a fasted individual provides a mean time to peak plasma
concentration (Tmax) of {l-{l—[3-fluoro(trifluoromethyl)isonicotinoy1]piperidin
yl} -3 -[4-(7H-pyrrolo [2,3 -d]pyrimidinyl)- lH—pyrazol— l -yl]azetidin-3—
yl}acetonitrile of at least 0.5 hours.
In some embodiments,oral administration of one or more sustained release
dosage forms to a fasted dual provides a ratio of mean peak plasma
concentration (Cmax) to mean 12—hour plasma concentration (Cm) of {l—{ l-[3-fluoro—
2-(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrile of about 5 to about 50.
In some embodiments,oral administration of one or more sustained release
dosage forms to a fasted individual provides a ratio of mean peak plasma
concentration (Cmax) to mean r plasma concentration (Cizh) of {l-{ l-[3-fluoro—
2-(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin-3—yl}acetonitrile of about 9 to about 40.
In some embodiments,oral stration of one or more sustained e
dosage forms to a fasted individual provides a ratio of mean peak plasma
concentration (Cmax) to mean 12-hour plasma concentration (Cizh) of {l—{ l-[3-fluoro—
2-(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin-3—yl}acetonitrile of about 15 to about 30.
In some embodiments, oral administration of one or more sustained release
dosage forms to a fasted individual es a mean half-life (ha) of {l—{ l-[3-fluoro—
2-(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)—lH—pyrazol—l-yl]azetidin-3—yl}acetonitrileof about 1 hour to about 20 hours.
In some embodiments, oral administration of one or more sustained release
dosage forms to an individual after a high-fat meal es a mean time to peak
plasma concentration (Tmax) of {l-{ l-[3-fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidiny1}[4-(7H-pyrrolo[2,3 -d]pyrimidin
-pyrazol-l-yl]azetidinyl}acetonitrileof about 1 hour to about 9 hours.
In some embodiments, oral administration of one or more ned release
dosage forms to an individual after a high-fat meal provides a mean time to peak
plasma concentration (Tmax) of {l-{ 1—[3-fluoro—2-
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidin-3—yl}acetonitrile of at least 1.5 hours.
In some embodiments, oral administration of one or more sustained release
dosage forms to an individual after a high-fat meal provides a ratio of mean peak
plasma concentration (Cmax) to mean 12—hour plasma concentration (Cizh) of {l- { l-[3-
fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H-pyrrolo[2,3-
d]pyrimidin-4—yl)—lH-pyrazol-l—yl]azetidin-3 -yl}acetonitrile of about 10 to about 70.
In some embodiments, oral administration of one or more ned release
dosage forms to an dual after a high-fat meal provides a ratio of mean peak
plasma concentration (Cmax) to mean 12-hour plasma concentration (C12h)0f {l—{ l-[3-
2-(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-
d]pyrimidinyl)-lH-pyrazol-l-yl]azetidin-3 -yl}acetonitrile of about 15 to about 50.
In some embodiments, oral administration of one or more sustained release
dosage forms to an individual after a high-fat meal provides a ratio of mean peak
plasma concentration (Cmax) to mean 12-hour plasma concentration (C12h) of {1—{ l-[3—
fluoro—2-(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-
d]pyrimidin-4—yl)-lH—pyrazol—l-yl]azetidin-3 —yl}acetonitrile of about 25 to about 45.
In some embodiments, oral administration of one or more sustained e
dosage forms to an individual after a high-fat meal provides a mean half-life (ti/2) of
{ l- { l —[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} —3 -[4-(7H-
pyrrolo[2,3-d]pyrimidinyl)—lH—pyrazol-l-yl]azetidinyl}acetonitrile of about 1
hour to about 7 hours.
In some embodiments, oral administration of one or more sustained release
dosage forms to an individual after a high-fat meal provides a mean half—life (he) of
{ l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-
pyrrolo[2,3-d]pyrimidin—4-yl)-lH—pyrazol-l-yl]azetidin—3—yl}acetonitrile of about 2
hours to about 5 hours.
In some embodiments, the one or more ned release dosage forms are
each a tablet. In some embodiments, the one or more sustained release dosage forms
are ed by process comprising wet granulation.
In some embodiments, the one or more ned release dosage forms each
comprises one or more hypromelloses. In some embodiments, the one or more
sustained release dosage forms each comprises one or more excipients independently
selected from hypromelloses and microcrystalline celluloses. In some embodiments,
the one or more sustained release dosage forms each ses one or more
excipients ndently selected from hypromelloses, microcrystalline oses,
magnesium stearate, lactose, and lactose monohydrate. In some embodiments, the
one or more sustained release dosage forms each comprises a first hypromellose
characterized by having an apparent viscosity at a tration of 2% in water of
about 80 CF to about 120 cP and a second hypromellose characterized by having an
apparent viscosity at a concentration of 2% in water of about 3000 CF to about 5600
In some embodiments, the one or more ned release dosage forms each
comprises about 10% to about 15% by weight of one or more hypromelloses. In some
embodiments, the one or more sustained e dosage forms each comprises about
16% to about 22% by weight of microcrystalline cellulose. In some embodiments, the
one or more sustained release dosage forms each comprises about 45% to about 55%
by weight of lactose monohydrate. In some embodiments, the one or more sustained
release dosage forms each comprises about 0.3% to about 0.7% by weight of
magnesium stearate.
In some embodiments, the present application provides a method of treating
myelofibrosis in a patient, comprising orally administering to said t a once—daily
dose of about 400 mg to about 600 mg on a free base basis of {1- {l—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, wherein the dose comprises one or more sustained release dosage forms each
comprising { l- { l -[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} [4-
(7H-pyrrolo[2,3 —d]pyrimidin-4—yl)-lH—pyrazol—l—yl]azetidiny1}acetonitrile, or a
pharmaceutically acceptable salt thereof; wherein the method results in a reduced total
symptom score (TSS) of said patient compared with baseline. In some ments,
the present application provides a method of treating myelofibrosis in a patient,
comprising orally administering to said patient the one or more ned release
dosage forms as a once—daily dosage of about 600 mg on a free base basis of {l—{ l-
[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidin-4—yl} -3 - [4—(7H—pyrrolo [2,3—
midin-4—yl)—lH-pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically
acceptable salt thereof; wherein the method results in a reduced total m score
(TSS) of said patient compared with baseline.
In some embodiments, the present application provides a method of treating
myeloflbrosis in a t, comprising orally administering to said patient the one or
more sustained release dosage forms as a once—daily dosage of about 500 mg on a free
base basis of {l- { l—[3 —fluoro-2—(trifluoromethy1)isonicotinoyl]piperidin—4-yl} -3—[4-
(7H-pyrrolo[2,3 imidinyl)- azol— l -yl]azetidinyl} acetonitrile, or a
pharmaceutically acceptable salt thereof; wherein the method results in a reduced total
symptom score (TSS) of said patient compared with baseline.
In some embodiments, the present ation provides a method of ng
myelofibrosis in a t, comprising orally administering to said patient the one or
more sustained release dosage forms as a once-daily dosage of about 400 mg on a free
base basis of {l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidin—4-yl} -3—[4-
(7H—pyrrolo[2,3 -d]pyrimidin—4-yl)-lH—pyrazol—l-yl]azetidin-3—y1}acetonitrile, or a
pharmaceutically acceptable salt thereof; n the method results in a reduced total
symptom score (TSS) of said patient compared with baseline.
In some embodiments of the methods in the preceding three paragraphs, the
one or more sustained release dosage forms are six dosage forms of about 100 mg on
a free base basis of {1—{ l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-4—yl} [4-(7H—pyrrolo[2,3 —d]pyrimidinyl)— lH—pyrazol- l -yl] azetidin-3 -yl} acetonitrile, or
a pharmaceutically acceptable salt thereof, are ed. In some embodiments of the
methods in the preceding three paragraphs, the one or more sustained release dosage
forms are three dosage forms of about 200 mg on a free base basis of {l- {l—[3 —fluoro—
2-(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-pyrrolo[2,3 -d]pyrimidin
—pyrazol—l-yl]azetidin-3 —yl}acetonitrile, or a pharmaceutically acceptable salt
thereof, are provided. In some embodiments of the methods in the preceding three
paragraphs, the one or more sustained e dosage forms are two dosage forms of
about 300 mg on a free base basis of {l- { l—[3—fluoro—2—
(trifluoromethy1)isonicotinoyl]piperidin-4—y1}—3-[4—(7H—pyrrolo[2,3 —d]pyrimidin
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, are provided. In some embodiments of the methods in the preceding three
paragraphs, the one or more sustained release dosage forms is one dosage form of
about 600 mg on a free base basis of {l— { l-[3 —fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, is provided.
In some embodiments, “total symptom score (TS S)” refers to the TSS derived
from the modified Myelofibrosis m Assessment Form (MFSAF) (e.g., v3.0)
electronic diary as compared with baseline (baseline is the patient’s baseline TSS
before treatment). In some ments, ibrosis is primary myelofibrosis
(PMF), post-polycythemia vera MF, or post-essential thrombocythemia MP.
The present application also provides a method of treating an autoimmune
disease, a cancer, a roliferative disorder, an inflammatory disease, a bone
resorption disease, or organ transplant ion in a patient in need thereof,
comprising orally administering to said patient a once-daily dose of about 400 mg to
about 600 mg on a free base basis of {l— { 1-[3 —fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— azol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof, wherein the dose ses one or more sustained release dosage forms each
comprising { l- { l -[3-fluoro-2—(trifluoromethyl)isonicotinoyl]piperidin—4-yl} [4-
(7H-pyrrolo[2,3 imidin-4—yl)— lH—pyrazol— l -yl]azetidinyl} acetonitrile, or a
pharmaceutically acceptable salt thereof; wherein said method results in reduced
anemia.
The present application also es a method of treating an autoimmune
disease, a , a myeloproliferative disorder, an inflammatory disease, a bone
resorption e, or organ transplant rejection in a patient in need thereof, wherein
the method ses orally administering to said patient the one or more sustained
release dosage forms as a once—daily dosage of about 600 mg on a free base basis of
{l— { l -[3 -fluoro(trifluoromethy1)isonicotinoyl]piperidinyl}-3 -[4-(7H-
pyrrolo [2,3 -d]pyrimidinyl)- l zol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically acceptable salt thereof; wherein said method results in reduced
anemia.
The present application also es a method of treating an autoimmune
disease, a cancer, a myeloproliferative er, an inflammatory disease, a bone
resorption disease, or organ transplant rejection in a patient in need thereof, wherein
the method ses orally administering to said patient the one or more sustained
release dosage forms as a once-daily dosage of about 500 mg on a free base basis of
{ l- { l —[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} —3 -[4-(7H-
pyrrolo [2,3 -d]pyrimidinyl)— l zol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically acceptable salt thereof; wherein said method s in reduced
anemia.
The present application also provides a method of treating an autoimmune
disease, a , a myeloproliferative disorder, an inflammatory disease, a bone
resorption disease, or organ tranSplant rejection in a patient in need thereof, wherein
the method ses orally administering to said patient the one or more sustained
release dosage forms as a once-daily dosage of about 400 mg on a free base basis of
{ l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-
pyrrolo [2,3 -d]pyrimidinyl)— l H—pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically acceptable salt thereof; wherein said method results in reduced
anemia. In some embodiments, the one or more sustained release dosage forms are
six dosage forms of about 100 mg on a free base basis of {l—{ l—[3—fluoro—2—
(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-d]pyrimidin
yl)— lH—pyrazol—l-yl]azetidin-3 —yl} acetonitrile, or a ceutically acceptable salt
thereof, are provided. In some embodiments, the one or more sustained release
dosage forms are three dosage forms of about 200 mg on a free base basis of {l—{ l—
[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 - [4—(7H-pyrrolo [2,3—
d]pyrimidin-4—yl)— lH-pyrazol-l—yl]azetidinyl} acetonitrile, or a pharmaceutically
acceptable salt thereof, are provided. In some embodiments, the one or more
sustained release dosage forms are two dosage forms of about 300 mg on a free base
basis of {l-{ l-[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 H-
pyrrolo[2,3-d]pyrimidinyl)- l H-pyrazol- l -yl]azetidinyl} acetonitrile, or a
pharmaceutically acceptable salt thereof, are provided. In some ments, the one
or more sustained release dosage forms is one dosage form of about 600 mg on a free
base basis of {l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidin—4-yl} -3—[4-
(7H—pyrrolo[2,3 -d]pyrimidin—4-yl)- azol— l -yl]azetidin-3—yl} acetonitrile, or a
ceutically able salt thereof, is provided.
Reduced anemia is relative to that experienced for a twice—daily dose of 200
mg on a free base basis of {l— { l-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin-
4-yl} —3 - -pyrrolo[2,3 -d]pyrimidinyl)— l H—pyrazol- l -yl]azetidin—3 -
yl}acetonitrile, or a pharmaceutically acceptable salt thereof, n the dose
comprises one or more sustained release dosage forms each comprising {1— {1—[3-
fluoro—2-(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-
d]pyrimidin-4—yl)— lH-pyrazol—l-yl]azetidinyl} acetonitrile, or a pharmaceutically
acceptable salt thereof.
The compound of Formula I is a JAK inhibitor. A JAKl selective inhibitor is
a compound that inhibits JAKl activity preferentially over other Janus kinases. JAKl
plays a central role in a number of cytokine and growth factor signaling pathways
that, when dysregulated, can result in or contribute to e states. For example, IL-
6 levels are elevated in rheumatoid arthritis, a disease in which it has been suggested
to have detrimental effects (Fonesca, J.E. et al., Autoimmunity Reviews, 8:53 8—42,
2009). Because IL-6 signals, at least in part, through JAKl, antagonizing IL-6
directly or indirectly through JAKl inhibition is expected to provide clinical benefit
(Guschin, D., N., et al Embo J 14:1421, 1995; Smolen, J. S., et a1. Lancet 371:987,
2008). Moreover, in some s JAKl is d resulting in constitutive
undesirable tumor cell growth and survival (Mullighan CG, Proc Natl Acad Sci U S
A. 10629414—8, 2009; Flex E., et all Exp Med. 205:751—8, 2008). In other
mune diseases and cancers elevated systemic levels of inflammatory cytokines
that te JAKl may also contribute to the disease and/or associated symptoms.
Therefore, patients with such diseases may benefit from JAKl inhibition. Selective
inhibitors of JAKl may be efficacious while avoiding unnecessary and potentially
undesirable effects of inhibiting other JAK kinases.
Selective inhibitors of JAKl, relative to other JAK kinases, may have multiple
therapeutic advantages over less selective inhibitors. With respect to ivity
against JAK2, a number of ant cytokines and growth s signal through
JAK2 including, for example, erythropoietin (Epo) and thrombopoietin (Tpo)
nas E, et al. Cell. 93:3 85—95, 1998). Epo is a key growth factor for red blood
cells production; hence a paucity of Epo-dependent signaling can result in reduced
s of red blood cells and anemia ansky K, NEJM 354:2034—45, 2006).
Tpo, another example of a JAK2-dependent growth factor, plays a central role in
controlling the proliferation and maturation of megakaryocytes — the cells from which
platelets are produced (Kaushansky K, NEJM 354:2034-45, 2006). As such, d
Tpo signaling would decrease megakaryocyte numbers (megakaryocytopenia) and
lower circulating platelet counts (thrombocytopenia). This can result in undesirable
and/or uncontrollable ng. Reduced inhibition of other JAKs, such as JAK3 and
Tyk2, may also be desirable as humans lacking functional version of these kinases
have been shown to suffer from numerous maladies such as severe—combined
immunodeficiency or mmunoglobulin E syndrome (Minegishi, Y, et al.
Immunity 25:745-55, 2006; Macchi P, et al. Nature. 377:65-8, 1995). Therefore a
JAKl inhibitor with reduced affinity for other JAKs would have significant
advantages over a less-selective inhibitor with respect to reduced side effects
involving immune suppression, anemia and thrombocytopenia.
Another aspect of the present invention pertains to methods of treating a JAK-
associated disease or disorder in an individual (e. g., t) by administering to the
individual in need of such treatment a sustained-release dosage form of the ion.
A JAK—associated disease can include any disease, disorder or condition that is
directly or indirectly linked to expression or activity of the JAK, including
overexpression and/or abnormal activity levels. A JAK—associated disease can also
include any disease, disorder or condition that can be prevented, ameliorated, or cured
by modulating JAK activity.
Examples of JAK—associated diseases include diseases involving the immune
system including, for example, organ transplant rejection (e. g., aft rejection and
graft versus host disease).
Further examples of JAK—associated diseases include autoimmune diseases
such as le sclerosis, rheumatoid arthritis, le arthritis, psoriatic arthritis,
type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis,
Crohn’s e, myasthenia gravis, immunoglobulin nephropathies, myocarditis,
autoimmune thyroid ers, chronic obstructive pulmonary disease (COPD), and
the like. In some embodiments, the autoimmune disease is an autoimmune bullous
skin er such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).
Further examples of JAK—associated es include allergic conditions such
as asthma, food allergies, eszematous dermatitis, contact dermatitis, atopic dermatitis
(atropic eczema), and rhinitis. Further examples of JAK—associated diseases e
viral diseases such as n Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV,
HTLV l, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).
Further examples of JAK—associated disease include diseases associated with
cartilage turnover, for example, gouty tis, septic or infectious arthritis, reactive
arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome, costal
athropathy, osteoarthritis deformans endemica, Mseleni disease, Handigodu e,
degeneration resulting from fibromyalgia, systemic lupus matosus, scleroderma,
or ankylosing spondylitis.
Further examples of JAK-associated disease include congenital cartilage
malformations, including hereditary chrondrolysis, chrondrodysplasias, and
pseudochrondrodysplasias (e.g., microtia, enotia, and metaphyseal
chrondrodysplasia).
Further examples of JAK—associated diseases or ions include skin
disorders such as psoriasis (for example, psoriasis vulgaris), atopic itis, skin
rash, skin irritation, skin ization (e. g., contact dermatitis or allergic contact
dermatitis). For example, certain substances including some pharmaceuticals when
lly applied can cause skin sensitization. In some embodiments, co—
administration or sequential administration of at least one JAK inhibitor of the
invention together with the agent causing unwanted sensitization can be helpful in
treating such unwanted sensitization or itis. In some embodiments, the skin
disorder is treated by topical administration of at least one JAK inhibitor of the
ion.
In further embodiments, the JAK—associated disease is cancer including those
characterized by solid tumors (e. g., prostate cancer, renal , hepatic cancer,
pancreatic cancer, gastric cancer, breast cancer, lung cancer, s of the head and
neck, thyroid cancer, glioblastoma, Kaposi’s sarcoma, Castleman’s disease, uterine
leiomyosarcoma, melanoma etc), hematological cancers (e.g., lymphoma, leukemia
such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or
multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and
cutaneous B—cell lymphoma. Example CTCLs include Sezary syndrome and mycosis
fungoides.
In some embodiments, the dosage forms described herein, or in combination
with other JAK inhibitors, such as those reported in US. Ser. No. 11/637,545, which
is orated herein by reference in its ty, can be used to treat inflammation-
associated cancers. In some embodiments, the cancer is associated with inflammatory
bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative
colitis. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In
some embodiments, the inflammation-associated cancer is colitis—associated .
In some embodiments, the inflammation-associated cancer is colon cancer or
colorectal cancer. In some embodiments, the cancer is gastric cancer, gastrointestinal
carcinoid tumor, gastrointestinal stromal tumor (GIST), adenocarcinoma, small
intestine cancer, or rectal .
JAK—associated es can further include those characterized by sion
of: JAK2 mutants such as those having at least one on in the -kinase
domain (e.g., JAK2V617F); JAKZ mutants having at least one mutation outside of
the pseudo-kinase domain; JAKl mutants; JAK3 mutants; erythropoietin receptor
(EPOR) mutants; or deregulated expression of CRLF2.
JAK—associated diseases can further e myeloproliferative disorders
(MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET),
myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF),
chronic myelogenous leukemia (CML), c myelomonocytic leukemia (CMML),
hypereosinophilic syndrome (HES), systemic mast cell disease , and the like.
In some embodiments, the myeloproliferative disorder is myelofibrosis (e.g., primary
myelofibrosis (PMF) or post polycythemia vera/essential thrombocythemia
myelofibrosis (Post-PV/ET MF)). In some embodiments, the myeloproliferative
er is post— essential thrombocythemia myeloflbrosis ET). In some
embodiments, the myeloproliferative disorder is post polycythemia vera myelofibrosis
(Post-PV MF).
In some embodiments, dosage forms described herein can be used to treat
pulmonary arterial hypertension.
The present invention further provides a method of treating dermatological
side effects of other pharmaceuticals by administration of the dosage forms of the
invention. For example, numerous pharmaceutical agents result in unwanted allergic
reactions which can st as acneiform rash or related dermatitis. Example
pharmaceutical agents that have such undesirable side effects include anti—cancer
drugs such as gefltinib, cetuximab, erlotinib, and the like. The dosage forms of the
invention can be administered systemically in combination with (e.g., simultaneously
or sequentially) the pharmaceutical agent having the undesirable dermatological side
effect.
Further JAK-associated diseases e inflammation and atory
diseases. Example inflammatory diseases include sarcoidosis, inflammatory diseases
of the eye (e. g., , uveitis, scleritis, conjunctivitis, or related disease),
inflammatory diseases of the respiratory tract (e. g., the upper respiratory tract
including the nose and sinuses such as is or sinusitis or the lower respiratory
tract including bronchitis, chronic obstructive pulmonary disease, and the like),
atory myopathy such as myocarditis, and other inflammatory diseases. In
some embodiments, the inflammation disease of the eye is ritis.
The dosage forms described herein can further be used to treat ischemia
reperfusion injuries or a disease or condition related to an inflammatory ischemic
event such as stroke or cardiac arrest. The dosage forms described herein can further
be used to treat xin—driven disease state (e. g., complications after bypass
surgery or chronic endotoxin states contributing to chronic cardiac failure). The
dosage forms described herein can further be used to treat anorexia, cachexia, or
fatigue such as that resulting from or associated with cancer. The dosage forms
bed herein can further be used to treat osis, sclerodermitis, or fibrosis.
The dosage forms bed herein can further be used to treat conditions associated
with hypoxia or astrogliosis such as, for example, ic retinopathy, cancer, or
egeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427—36
and Sriram, K. et a]. J. Biol. Chem. 2004, 279(19):19936-47. Epub 2004 Mar 2, both
of which are incorporated herein by reference in their ty. The JAK inhibitors
described herein can be used to treat Alzheimer’s e.
The dosage forms bed herein can further be used to treat other
inflammatory diseases such as systemic inflammatory response syndrome (SIRS) and
septic shock.
The dosage forms described herein can further be used to treat gout and
increased prostate size due to, e.g., benign prostatic hypertrophy or benign prostatic
hyperplasia.
Further JAK—associated diseases include bone resorption es such as
osteoporosis, osteoarthritis. Bone resorption can also be associated with other
conditions such as hormonal imbalance and/or hormonal therapy, autoimmune disease
(e.g. osseous sarcoidosis), or cancer (e.g. myeloma). The reduction of the bone
resorption due to the the compound of Formula I can be about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
In some embodiments, the dosage forms described herein can further be used
to treat a dry eye disorder. As used herein, “dry eye disorder” is intended to
encompass the disease states summarized in a recent official report of the Dry Eye
Workshop (DEWS), which defined dry eye as “a multifactorial disease of the tears
and ocular surface that results in symptoms of discomfort, Visual disturbance, and tear
film instability with potential damage to the ocular surface. It is anied by
increased osmolarity of the tear film and inflammation of the ocular surface.” Lemp,
“The Definition and fication of Dry Eye Disease: Report of the Definition and
Classification Subcommittee of the International Dry Eye Workshop”, The Ocular
Surface, 5(2), 75—92 April 2007, which is incorporated herein by reference in its
entirety. In some embodiments, the dry eye disorder is selected from aqueous tear—
deficient dry eye (ADDE) or evaporative dry eye disorder, or appropriate
combinations thereof. In some ments, the dry eye er is Sjogren
syndrome dry eye (SSDE). In some embodiments, the dry eye disorder is non—
Sjogren syndrome dry eye (NSSDE).
In a r aspect, the present ion provides a method of treating
conjunctivitis, s (including chronic uveitis), chorioditis, retinitis, cyclitis,
itis, episcleritis, or iritis; treating inflammation or pain related to corneal
transplant, LASIK (laser assisted in situ keratomileusis), photorefractive keratectomy,
or LASEK (laser assisted ithelial keratomileusis); inhibiting loss of visual
acuity related to corneal transplant, LASIK, photorefractive keratectomy, or LASEK;
or inhibiting lant rejection in a t in need thereof, comprising administering
to the patient a dosage form of the invention.
Additionally, the dosage forms of the invention, or in combination with other
JAK inhibitors, such as those reported in US. Ser. No. 11/637,545, which is
incorporated herein by reference in its entirety, can be used to treat respiratory
dysfunction or failure associated with viral ion, such as influenza and SARS.
In some embodiments, the present invention provides a dosage form as
described in any of the embodiments herein, for use in a method of treating any of the
diseases or disorders described herein. In some embodiments, the present invention
provides the use of a dosage form as described in any of the embodiments herein, for
the preparation of a medicament for use in a method of ng any of the diseases or
disorders described herein.
In some embodiments, the present invention provides a dosage form as
described herein, or a pharmaceutically acceptable salt thereof, for use in a method of
modulating JAKl. In some embodiments, the present invention also provides use of a
dosage form as described herein, or a ceutically acceptable salt thereof, for the
preparation of a medicament for use in a method of modulating JAKl.
As used herein, the term “individual” is a human. In some embodiments, the
human is an adult subject.
As used herein, the term ing” or “treatment” refers to one or more of (l)
inhibiting the disease; for example, inhibiting a disease, condition or disorder in an
individual who is experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further pment of the ogy
and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating
a disease, condition or disorder in an dual who is experiencing or ying the
pathology or symptomatology of the disease, condition or disorder (i.e., reversing the
pathology and/or symptomatology) such as decreasing the severity of disease.
Combination Therapies
One or more additional pharmaceutical agents such as, for example,
chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, as well
as Bcr—Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those
described in WC 2006/0563 99, which is orated herein by reference in its
entirety, or other agents can be used in combination with the dosage forms bed
herein for treatment of JAK—associated diseases, disorders or conditions. The one or
more additional pharmaceutical agents can be administered to a patient
simultaneously or sequentially.
Example herapeutics include proteosome inhibitors (e.g., bortezomib),
thalidomide, revlimid, and maging agents such as melphalan, doxorubicin,
cyclophosphamide, vincristine, etoposide, carmustine, and the like.
Example steroids include coriticosteroids such as dexamethasone or
prednisone.
Example Bcr-Abl inhibitors include the compounds, and pharmaceutically
acceptable salts thereof, of the genera and species disclosed in US. Pat. No.
,521,184, WO 04/005281, and US. Ser. No. 60/578,491, all ofwhich are
incorporated herein by reference in their entirety.
e suitable Flt-3 inhibitors include compounds, and their
pharmaceutically able salts, as disclosed in WC 03/037347, WO 03/099771,
and WO 04/046120, all of which are incorporated herein by reference in their entirety.
Example suitable RAF inhibitors include compounds, and their
pharmaceutically acceptable salts, as sed in WO 00/09495 and WO 05/028444,
both of which are incorporated herein by reference in their entirety.
Example le FAK inhibitors include nds, and their
pharmaceutically acceptable salts, as disclosed in WC 04/080980, WO 04/056786,
WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402, all ofwhich
are incorporated herein by reference in their ty.
In some embodiments, one or more of the dosage forms of the invention can
be used in combination with one or more other kinase inhibitors including imatinib,
particularly for treating patients ant to imatinib or other kinase inhibitors.
In some embodiments, one or more dosage forms of the invention can be used
in combination with a chemotherapeutic in the treatment of cancer, such as multiple
myeloma, and may improve the treatment response as compared to the response to the
chemotherapeutic agent alone, without exacerbation of its toxic effects. es of
additional pharmaceutical agents used in the treatment of multiple a, for
e, can include, without limitation, melphalan, melphalan plus prednisone
[MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further onal
agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and
FAK kinase inhibitors. Additive or synergistic s are desirable outcomes of
combining a dosage form of the present invention with an additional agent.
Furthermore, resistance of multiple a cells to agents such as dexamethasone
may be reversible upon treatment with a dosage form of the present invention. The
agents can be combined with the present compounds in a single or continuous dosage
form, or the agents can be administered simultaneously or sequentially as separate
dosage forms.
In some embodiments, a corticosteroid such as dexamethasone is administered
to a patient in ation with at the dosage form of the ion where the
dexamethasone is administered intermittently as opposed to continuously.
In some further embodiments, combinations of one or more IAK tors of
the invention with other therapeutic agents can be administered to a patient prior to,
during, and/or after a bone marrow transplant or stem cell transplant.
In some embodiments, the additional therapeutic agent is fluocinolone
acetonide (Retisert®), or rimexolone (AL-2178, Vexol, Alcon).
In some embodiments, the additional therapeutic agent is cyclosporine
(Restasis®).
In some embodiments, the additional therapeutic agent is a corticosteroid. In
some embodiments, the corticosteroid is triamcinolone, dexamethasone, fluocinolone,
cortisone, prednisolone, or flumetholone.
In some embodiments, the additional therapeutic agent is selected from
DehydrexTM (Holles Labs), Civamide (Opko), sodium onate (Vismed,
io/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T)
(testosterone, Argentis), AGR1012(P) tis), ecabet sodium (Senju-Ista),
gefarnate (Santen), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,
doxycycline 0501, Alacrity), minocycline, iDestrinTM (NP50301, Nascent
Pharmaceuticals), porine A (Nova22007, li), oxytetracycline
(Duramycin, MOLI1901, Lantibio), CF101 (2S,3S,4R,5R)—3,4—dihydroxy—5—[6—[(3—
iodophenyl)methylamino]purinyl]—N—methy1-oxolanecarbamyl, Can-Fite
Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Agentis),
45 (synthetic resolvin analog, Resolvyx), DYN15 (Dyanmis Therapeutics),
rivoglitazone (DEOl 1, Daiichi Sanko), TB4 (RegeneRx), OPH-Ol (Ophtalmis
Monaco), PCSlOl (Pericor Science), REV1—31 (Evolutec), Lacritin (Senju),
rebamipide (Otsuka—Novartis), OT-551 a), PAI-2 (University of Pennsylvania
and Temple University), pilocarpine, imus, pimecrolimus (AMS981, Novartis),
loteprednol etabonate, rituximab, osol tetrasodium (INS365, Inspire), KLS—
0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,
mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267
(TorreyPines Therapeutics), actemra, gemcitabine, oxaliplatin, L-asparaginase, or
thalidomide.
In some embodiments, the additional therapeutic agent is an ngiogenic
agent, cholinergic agonist, TRP-l receptor modulator, a calcium channel blocker, a
mucin secretagogue, MUCl stimulant, a calcineurin inhibitor, a corticosteroid, a
P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, r
JAK inhibitor, Ber-Ab] kinase inhibitor, Flt-3 kinase inhibitor, RAF kinase tor,
and FAK kinase inhibitor such as, for example, those described in WO 56399,
which is incorporated herein by reference in its entirety. In some embodiments, the
additional therapeutic agent is a tetracycline derivative (e.g., minocycline or
doxycline). In some embodiments, the additional therapeutic agent binds to FKBP12.
In some embodiments, the additional therapeutic agent is an alkylating agent
or DNA cross—linking agent; an anti-metabolite/demethylating agent (e.g., 5-
flurouracil, capecitabine or azacitidine); an anti-hormone therapy (e. g., hormone
receptor antagonists, SERMs, or aromotase inhibitor); a c tor (e. g.
Vincristine or paclitaxel); an topoisomerase (I or II) inhibitor (e.g. mitoxantrone and
irinotecan); an apoptotic inducers (e. g. ABT—737); a c acid therapy (e. g.
antisense or RNAi); nuclear receptor ligands (e.g., agonists and/or antagonists: all-
trans retinoic acid or bexarotene); epigenetic ing agents such as histone
deacetylase inhibitors (e. g. vorinostat), hypomethylating agents (e.g. bine);
tors of protein stability such as Hsp90 inhibitors, ubiquitin and/or ubiquitin like
conjugating or deconjugating molecules; or an EGFR inhibitor (erlotinib).
In some embodiments, the additional therapeutic s) are demulcent eye
drops (also known as “artificial tears”), which include, but are not limited to,
compositions containing polyvinylalcohol, hydroxypropyl methylcellulose, glycerin,
polyethylene glycol (e.g. PEG400), or carboxymethyl ose. Artificial tears can
help in the treatment of dry eye by compensating for d moistening and
lubricating capacity of the tear film. In some embodiments, the additional therapeutic
agent is a mucolytic drug, such as N-acetyl-cysteine, which can interact with the
mucoproteins and, therefore, to decrease the viscosity of the tear film.
In some embodiments, the additional therapeutic agent includes an antibiotic,
antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non-
steroidal nflammatories, and anti-allergic agents. Examples of suitable
medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin,
streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin,
acin, in, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;
naphthyridine; sulfonamides; xin; chloramphenicol; neomycin; paramomycin;
imethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives
(“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericins; zole;
flucytosine; natamycin; miconazole; ketoconazole; osteroids; diclofenac;
flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;
antazoline; pheniramine; or azalide antibiotic.
It is further appreciated that certain features of the invention, which are, for
clarity, described in the context of separate embodiments, can also be provided in
combination in a single embodiment (as if the embodiments of the specification are
written as multiply dependent claims).
Example 1. Preparation of Sustained Release Formulations
Sustained release tablets were prepared with the excipients being in the
amounts shown in the table below. Protocol A was used for the SR1 tablets, protocol
B was used for the SR2 tablets, ol C was used for the SR3 tablets and the 25
mg SR s, and Protocol D was used for the SR4 tablets.
Protocol A:
Step 1. Individually screen the adipic acid salt of the compound of
Formula I, microcrystalline cellulose, hypromelloses (Methocel K100 LV and
Methocel K4M), and lactose monohydrate.
Step 2. Transfer the screened material from Step 1 to a suitable blender
and mix.
Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.
Step 4. Add purified water while .
Step 5. Transfer the granules from Step 4 into a suitable dryer and dry
until LCD is less than 3%.
Step 6. Screen the granules from Step 5.
Step 7. Mix ed Magnesium Stearate with granules in Step 6 in a
suitable blender.
Step 8. ss the final blend in Step 7 on a le rotary tablet
press.
ol B:
Step 1. Individually screen the adipic acid salt of the compound of
Formula I, microcrystalline ose, hypromellose and pregelatinized starch.
Step 2. Transfer the screened material from Step 1 to a suitable blender
and mix.
Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.
Step 4. Add purified water while mixing.
Step 5. Transfer the granules from Step 4 into a suitable dryer and dry
until LCD is less than 3%.
Step 6. Screen the granules from Step 5.
Step 7. Individually screened polyox, butylated hydroxytoluene and
colloidal silicone dioxide.
Step 8. Transfer the es from Step 6 and al from Step 7 into
a le blender and mix.
Step 9. Add screened Magnesium Stearate to the material in Step 8 and
continue blending.
Step 10. Compress the final blend in Step 9 on a suitable rotary tablet
press.
Protocol C:
Step 1. Individually screen lactose monohydrate, the adipic acid salt of
the compound of Formula I, microcrystalline cellulose and hypromelloses h a
suitable screen.
Step 2. Transfer the screened material from Step 1 to a suitable blender
and mix.
Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.
Step 4. Add d water while mixing.
Step 5. Screen wet granules h a suitable screen.
Step 6. Transfer the granules from Step 5 into a suitable dryer and dry
until LCD is less than 3%.
Step 7. Mill the granules from Step 6.
Step 8. Mix screened magnesium stearate with granules in Step 7 in a
le blender.
Step 9. Compress the final blend in Step 8 on a suitable rotary tablet
press.
Protocol D:
Step 1. Individually screen pregelatinized starch, the adipic acid salt of
the compound of Formula I, hypromellose, and a portion of required microcrystalline
cellulose through a suitable screen.
Step 2. Transfer the screened material from Step 1 to a le blender
and mix.
Step 3. Transfer the blend from Step 2 to a suitable granulator and mix.
Step 4. Add purified water while mixing.
Step 5. Screen wet granules h a suitable screen.
Step 6. Transfer the granules from Step 5 into a suitable dryer and dry
until LOD is less than 3%.
Step 7. Mill the granules from Step 6.
Step 8. Screen the remaining portion of microcrystalline cellulose and
half of the sodium bicarbonate.
Step 9. Transfer the milled granules from Step 7 and screened
materials from Step 8 into a suitable r and mix.
Step 10. Screen the remaining portion of sodium bicarbonate and mix
with blend in Step 9.
Step 11. Screen magnesium stearate and mix with blend in Step 10.
Step 12. Compress the final blend in Step 11 on a suitable rotary tablet
press.
SR1: Composition of 100 mg Sustained Release Tablets
ent Function Weight (mg/tablet) Composition
(wt%)
Adipic acid salt of the Active 126.422 21.1
compound of Formula I a
l'ystalllne Cellulose"m
ellose
Release Control 10.0
(Methocel K100LV)
Hypromellose
Release l 10.0
(Methocel K4M)
Component Function Weight (mg/tablet) Composition
(wt%)
e Monohydrate 290.5 8
Purified Water c Granulating q.s.
Liquid
a Conversion factor for adipate salt to free base is 0.7911
b Added after granulation
c Removed during processing
SR2: Composition of 100 mg Sustained e Tablets
Component Function Weight Composition
(mg/tablet) (wt%)
Adipic acid salt of the Active
126.4 a 21.1
compound of Formula Ia
Microcrystalline Cellulose 180.0
ellose .
(MethoceleOLw "n
hylene Oxide
Release Control 180.0
(Polyox WRS 1105) b
Pregelatinized Starch 101.6
Butylated Hydroxytoluene b 0.012 0.002
Purified Water ° Granulating
‘1' s
Liquid '
a Conversion factor for adipate salt to free base is 0.7911
b Added after granulation
c Removed during processing
SR3 (100 mg): Composition of 100 mg Sustained Release Tablets
Component Function Weight Composition
(mg/tablet) (wt%)
Adipic acid salt of the Active
126.4 a 21.1
compound of Formula I21
Mlcrocrystalllne Flller
108.0 18.0
Cellulose
Hypromellose
e Control 42 0 7 0
(Methocel KIOOLV) ' '
Hypromellose
Rdeasecmtml
<Methoce1K4M>
d Water C Granulating
Liquid
a Conversion factor for adipate salt to free base is 0.7911
b Added after granulation
c d during sing
SR4: Composition of 100 mg Sustained Release Tablets
Excipient Function Weight (mg/tablet) Composition
(wt%)
AdlplC ac1d salt of the Actlve
126.4 a 21.1
compound of Formula 121
Microcrystalline .
Hypromellose
R 1 C t 1 210.0 35.0
(MethoceIKwOLw ---
————
WO 21153
a Conversion factor for adipate salt to free base is 0.7911
b Added after granulation
c Removed during sing
d Partial added before and partial added after granulation
25mg SR: Composition of 25 mg Sustained Release Tablets
Component Function Weight Composition
(mg/tablet) (wt%)
Adlpic ac1d salt of the Active
31.6 a 12.6
compound of Formula Ial
Microcrystamnecaulose 105.0
Hypromellose,
Hypromellose,
Release l 25.0 10.0
(Methocel K4M)
C Granulating
a Conversion factor for adipate salt to free base is 0.7911
b Added after granulation
c Removed during processing
Example 2. Preparation of the IR Formulation of the Compound of Formula I
The IR formulation used in the studies in Example 3 was prepared as 50 mg
capsules with the composition shown in the table below according to Protocol E
below.
Protocol E:
Step 1. Pre-mix the required amount of the adipic acid salt of the compound of
Formula I and an imately equal amount of fied microcrystalline cellulose
(SMCC).
Step 2. Pass the e in Step 1 through a suitable screen (for example 40
mesh).
Step 3. Screen the remaining SMCC through the same screen used in Step 2.
Step 4. Blend the ed SMCC from Step 3 along with mixture from Step 2
in a suitable blender (for e Turbula blender) for approximately 5 minutes.
Step 5. Fill the blend into capsules to desired fill weight.
INGREDIENT WEIGHT QUANTITY
COMPOSITION PER UNIT
(0%) (mg)
Adipic acid salt of the nd of
.11 6320*
Formula I
Silicified Microcrystalline Cellulose, NF
64.89
(Prosolv SMCC HD 90)
TOTAL 100.00 %
#2 Capsules, Hard Gelatin, White
Opaque
* Adipic acid salt of the nd of Formula I with salt conversion factor of 0.7911
Example 3. Relative Bioavailability Study of Sustained Release Dosage Forms
A total of 72 healthy adult subjects were enrolled in 6 cohorts (12 subjects per
cohort) and randomized to ent sequences within each cohort according to a
randomization schedule. All treatments were single-dose administrations of the
compound of Formula I. There was a washout period of 7 days between the treatment
periods.
The SR1, SR2, SR3, and SR4 formulations were evaluated in Cohort l, Cohort
2, Cohort 3, and Cohort 4, respectively (see Example 1 for SR1, SR2, SR3, SR4, and
mg SR tablets used in study). The subjects received the IR and SR treatments
according to a 3—way crossover design:
Treatment A: 300 mg (6 X 50 mg capsule) IR formulation of the compound of
Formula 1 administered orally after an overnight fast of at least 10 hours.
Treatment B: 300 mg (3 X 100 mg tablets) SR formulation of the compound
of Formula 1 administered orally after an overnight fast of at least 10 hours.
Treatment C: 300 mg (3 X 100 mg s) SR formulation of the compound
of Formula I administered orally after a high-fat meal.
The subjects in Cohort 5 received the following treatments in a 2—way
crossover design:
Treatment A: 300 mg (3 X 100 mg tablets of the compound of Formula I) SR3
administered orally after an overnight fast of at least 10 hours.
Treatment B: 300 mg (3 X 100 mg tablets of the compound of Formula I) SR3
administered orally after a medium—fat meal.
The subjects in Cohort 6 received the following treatments in a 3—way
crossover design:
Treatment A: 50 mg (2 X 25 mg tablets of the nd of al (25 mg
SR tablets from e 1)) administered orally after an overnight fast of at least 10
hours.
Treatment B: 50 mg (2 X 25 mg s of the compound of Formula I (25 mg
SR tablets from Example 1)) stered orally after a high-fat meal.
Treatment C: 100 mg (l X 100 mg tablets) SR3 administered orally after an
ght fast of at least 10 hours.
Blood samples for determination of plasma concentrations of the compound of
Formula I were collected using lavender top (K2EDTA) Vacutainer® tubes at 0, 0.25,
0.5, l, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours post dose.
Plasma samples were assayed by a validated, GLP, LC/MS/MS method with a
linear range of 5.0 to 5000 nM. Table 1 summarizes the accuracy and precision (CV
%) of the assay quality l samples during the analysis of the plasma samples
from this study.
2014/049940
Table 1: Accuracy and Precision of the Plasma Assay y Control
Samples
-------- Low QC --------- - Middle QC ------- —-------- High QC --------
Analyte CV CV CV
Theo Accuracy Theo Accuracy Theo Accuracy
(Unit). % % %
Compound
of 15.0 99.0% 4.6% 250 101% 4.2% 4000 99.5% 2.2%
Formula I
CV% =percent coefficient of variability; QC = quality l; Theo = theoretical or nominal
concentration.
For the PK analysis, the actual sample collection times were used. For any
sample with missing actual collection time, the led time was used provided that
there was no protocol deviation noted for the collection of these samples.
Standard partmental PK methods were used to analyze the data for the
plasma concentration of the compound of Formula using Phoenix WinNonlin version
6.0 (Pharsight Corporation, Mountain View, CA). Thus, Cmax and Tmax were taken
directly from the observed plasma concentration data. The terminal-phase disposition
rate constant (M) was estimated using a log-linear regression of the concentration data
in the terminal disposition phase, and W. was estimated as 2tz. AUCO-t was
estimated using the linear trapezoidal rule for increasing concentrations and the log-
oidal rule for decreasing concentrations, and the total AUCo.oo was calculated as
AUCO—t + Ct/kz. The oral—dose clearance (CL/F) was estimated as Dose/AUCo-oo, and
the terminal-phase volume of distribution (Vz/F) was estimated as Dose/[AUCo—oo*?tz].
The log—transformed Cmax and AUC values (after dose normalization, where
the doses were different) were compared between the fasted and fed dosing
treatments, and between the SR and IR dosing treatments, using a ver ANOVA
(fixed factor = treatment, sequence and , random effect = subject (sequence)).
The ed geometric mean ratios of Cmax and AUC between the treatments
(reference = IR or fasted administration of SR) and the corresponding 90% confidence
intervals (CIs) were determined. In addition, the correlation between the observed
food effect of a at meal on AUCo.00 and the relative bioavailability of the SR
formulations (with reference to the IR capsule) were explored by a quantile plot using
the data from all subjects who completed Treatment A, B, and C in Cohorts l to 4.
The tical analysis was performed using Phoenix lin version 6.0.
presents plasma concentrations of the compound of Formula I (mean :
SE) for the subjects in Cohorts 1 to 4 following Treatment A (300 mg IR
administration in fasted state), Treatment B (300 mg SR administration in fasted
state), and Treatment C (300 mg SR administration with a at meal).
compares the effect of a high-fat meal and medium-fat meal on the mean PK profile
following a single-dose 300 mg (3 X 100mg) administration of the compound of
Formula I SR3 tablets. presents plasma concentrations of the compound of
Formula I (mean :: SE) for the subjects in Cohort 6 following Treatment A (2 X 25 mg
SR tablet administration in fasted , Treatment B (2 X 25 mg SR tablet with a
high—fat meal), and Treatment C (l X 100 mg SR3 administration in fasted state).
Tables 2A, 2B, 3A and 3B summarize mean PK parameters for subjects in
Cohorts l to 4, the relative ilability (reference = IR capsule) and food effect
(high-fat meal) for the 100 mg strength SRl-SR4 tablets. Table 4A and 4B
summarize mean PK parameters for subjects in Cohort 5, and food effect (medium—fat
meal) for the 100 mg strength SR3 . Table 5A and 5B summarizes mean PK
parameters for subjects in Cohort 6, the ormalized relative bioavailability
(reference = 100 mg SR3 tablet), and the food effect (high-fat meal) for the 25 mg SR
tablet.
Table 2A
Cmax TmaX tl/z
Cohort/Treatment 11 CmaX/Cl2h
(HM) (h) (h
Cohort 1
12 2.29 i 1 0
300 mg IR 197 :: 147 2.0 :: 0.27
0.50 (0.50—
(fasted) 159 2.0
2.24 2.0)
12 0 341 4 1 3
300 mg SR1 13.2 :: 7.8 9.2 :: 4.5
0 13 (0.50—
d) 11.6
0.317 3.0)
12 0.610 d:
300 mg SR1 4'0 18.0 :: 6.4 3.2 :: 1.4
0.14
(high-fat meal) (2.0—8.0) 16.8 3.0
0.595
Cohort 2
12 2.05 i 1.0
300 mg IR 130 i: 72.9 2.1 3: 0.34
0.67 (0.50—
(fasted) 112 2.1
1.92 3.0)
12 0.191 i
300 mg SR2 2‘5 11.4 :1: 9.9 11 d: 8.4
0.10
(fasted) (1.040) 8.60 9.23
0172
12 0.470 i
300 mg SR2 6‘0 11.0 :1: 4.0 3.5 3:26
0.16
(high-fat meal) (1.5-6.0) 10.4 3.0
0443
Cohort 3
11 2.35 i 1.0
300 mg IR 136 :: 70.8 2.2 :: 0.53
0.41 (0.50—
(fasted) 120 2.2
2.31 2.0)
11 0.553 4 1.5
300 mg SR3 22.9 :: 13.4 9.8 :: 8.5
0.24 (0.50—
(fasted)
0.502 3.0)
12 1.05 i
300 mg SR3 4'0 34.92: 15.8 3.3 :: 1.2
0.47
(high-fat meal) (1.5-8.0) 30.8 3.1
0.968
Cohort 4
12 2.94 i 1.0
300 mg IR 170 i 58.6 2.1i0.58
0.98 (0.25-
(fasted) 162 2.1
2.78 1.5)
12 0.321 i
300 mg SR4 2'0 10.3 i 6.0 7.3 i 5.3
0.27
(fasted) .1) 8.92 6.0
0249
12 0.549 i
300 mg SR4 4'0 12.8 i 14.8 4.9 i 2.6
0.28
(high—fat meal) (2.0-16) 6.06 4.4
0.481
Table 2B
Cohort/Treatment (1:512:13 ; 8417141;
Cohort 1
300 mg IR 4148;: 4.45 1.00 127 27.1
(fasted) 4:33 4.35 124
300 mg SR1 10555: 1.65 0.54 359 106
(fasted) 1:47 1.57 345
300 mg SR1 268:: 2.91 0.65 194 39.9
(high-fat meal) 2:82 2.85 190
Cohort 2
300 mg IR 414356* 4.47 :1: 1.36 134 :1: 50.1
(fasted) 4:24 4.27 127
300 mg SR2 1.004037 1.17: 0.43 510: 148
d) 0.95 1.11 488
300 mg SR2 204:; 2.52 0.72 235 83.5
(high-fat meal) 2:38 2.42 224
Cohort 3
300 mg IR 55);); 5.03 :l: 1.34 115 :1: 32.4
(fasted) 4:83 4.87 111
300 mg SR3 20273: 2.39 :l: 0.70 248 i— 82.8
(fasted) 2:17 2.29 236
300 mg SR3 3i5153i 3.59 :l: 1.13 165 i: 50.2
(high-fat meal) 3:40 3.44 158
Cohort 4
300 mg IR 52213;: 5.25 2.15 117 39.8
(fasted) 4:88 4.90 111
300 mg SR4 2621: 1 70 1.25 456 259
(fasted) 1:31 1.40 387
300 mg SR4 20?: 3.13 1.20 200 80.0
(high-fat meal) 2:78 2.92 186
Table 3A
Cmax Tmax t1/2
Cohort/Treatment CmaX/C12h
(HM) (h) (h)
SR1 fasted vs IR 14.2%
(11.4%-17.5%)
SR1 fed vs fasted 188%
(152%-232%)
SR2 fasted vs IR 8.9%
(6.7%-11.9%)
SR2 fed vs fasted 258%
(193%—344%)
SR3 fasted vs IR 22.3%
(17.4%-28.6%)
SR3 fed vs fasted 191%
(150%—244%)
SR4 fasted vs IR 9.0%
(6.8%-11.9%)
SR4 fed vs fasted 193%
(146%-256%)
PK parameter values are mean :: SD and geometric mean except for Tmax, Where median
(90%
confidence al) is reported.
Table 3B
Cohort/Treatment $113133]; 311103110; 841;]:
Geometric Mean Relative Bioavailability and the 90% Confidence Intervals
SR1 fasted vs IR 34.1% 36.1%
(31.3%-37.0%) (33.3%—39.2%)
SR1 fed vs fasted 191% 181%
(176%-208%) (167%-196%)
SR2 fasted vs IR 22.4% 26.0%
-27.4%) (21.6%-31.3%)
SR2 fed vs fasted 250% 218%
(204%-306%) (181%-262%)
SR3 fasted vs IR 45.4% 47.5%
(39.6%-52.0%) (41.9%-53.9%)
SR3 fed vs fasted 151% 145%
(132%-173%) (128%-164%)
SR4 fasted vs IR 26.9% 28.5%
(21.6%-33.4%) (23.2%-35.1%)
SR4 fed vs fasted 213% 215%
264%) (172%-268%)
PK parameter values are mean :: SD and geometric mean except for Tmax, Where median
(90% confidence interval) is reported.
wo 20151021153
Table 4A
Cohort/Tl‘e Cmax Tmax t‘/2
’1 Cmax/C12“
atment (uM) (h) (h)
Cohort 5
300 mg SR3 12 0.619i0.41 1.75 22.8 i: 16.7 7.71:5.2
(fasted) 0.523 (0.5040) 17.8 6.2
ffiiifgfifi 12
0.875 i 0.47 2.5 40.6 :1: 22.7 3.6 2.0
0.764 (156.0) 31.2 3.3
meal)
Geometric Mean Relative ilability and the 90% Confidence Intervals
146%
SR3 fed vs fasted
(105%—202%)
Pharmacokinetic parameter values are mean i SD and geometric mean except for Tm“, where median
(90% confidence interval) is reported.
Table 4B
Cohort/Tre AUCO-t AUCO-au CL/F
atment (HM*h) (HM*h) (L/h)
Cohort 5
300 mg SR3 1.13 2.58i1.12 251 :: 105
(fasted) 2.23 2.36 230
300 mg SR3
2.98 d: 1.34 3.02 d: 1.35 215d:94.2
(medium-fat
2.72 2.76 196
meal)
Geometric Mean Relative Bioavailability and the 90% Confidence Intervals
SR3 fed vs (112:;0
fasted (102A;146A>)0 0 . 0-
137%)
Pharmacokinetic ter values are mean :: SD and ric mean except for Tmax,
where median
(90% confidence interval) is reported.
Table 5A
Cmax Tmax CmaX/C12 tl/z
Cohort/Treatment 11
(nM) (h) h (h)
Cohort 6
2 X 25 mg SR3 12 55.1 i 30.3 1.3 4.0 :: 2.6
(fasted) 48.0 (0.50-4.0) 3.4
2 X 25 mg SR3 12 80.3 d: 27.3 3.0 2.2 i 0.4
(hlgh-fat meal) 76.7 (1.5-6.0) 2.2
1X 100mg SR3 11 .5 1.8 3.0i1.3
d) 161 (050-40) 2.7
Geometric Mean Relative Bioavailability and the 90% Confidence
Intervals
2 X 25 mg SR3 fed 160%
vs fasted (129%-199%)
2 x 25 mg SR3 vs 1 x 58.7%”
100 mg SR3 (fasted) (46.9%-73.5%)
NC = not calculated because of significant numbers of mismatching Tlast within the subjects
between treatments; NR = not reported e significant numbers of C1211 values were BQL.
PK parameter values are mean i SD and geometric mean except for Tm, where median (90%
confidence al) is reported.
i) Statistical comparison
was dose-normalized.
Table 5B
Cohort/Treatme AUC0-t AUCMo CL/F
nt (nM*h) (nM*h) (L/h)
Cohort 6
2 X 25 mg SR3 205 i 103 243 d: 99.9 429 :: 167
d) 183 226 400
2 X 25 mg SR3 333 :: 104 376 :: 94.6 253 :: 57.7
(high-fat meal) 319 366 247
1X 100 mg SR3 671 i230 704i230 280::815
(fasted) 639 673 268
Geometric Mean ve Bioavailability and the 90% Confidence
Intervals
2 X 25 mg SR3 fed 174% 158%
vs fasted (150%-202%) (138%-182%
2 X 25 mg SR3 vs 1 X 661%”
100 mg SR3 (fasted) (57.5%-75.9‘%
NC = not calculated because of significant numbers of mismatching Tm within the subjects
n treatments; NR = not reported because significant numbers of C12h values were BQL.
PK parameter values are mean fl: SD and geometric mean except for Tmax, where median (90%
confidence interval) is reported.
0 Statistical comparison
was dose-normalized.
The mean PK profiles following the fasting single-dose administration of 300
mg IR capsules were similar among the subjects in Cohorts l to 4 (.
Compared to the IR formulation, following g single-dose stration of the
SR1-SR4 formulations (3 X 100 mg tablets), the observed plasma median Tmax values
were moderately prolonged (by 0.3 to 1.5 hours) with icantly d mean Cmax
values (the upper bounds of the 90% CI for the geometric mean Cmax ratios were
< 30%), suggesting decreased absorption rate of the compound of Formula I for the
SR tablets. The apparent mean disposition tI/z observed in the terminal phase was
significantly longer, ranging from 7.3 to 11 hours for SR1-SR4, as compared to about
2 hours for the IR capsule, indicating that the ic elimination of the compound
of Formula I was likely imited by its absorption, which was sustained in the
terminal disposition phase. As a result of lower Cmax and longer disposition tI/z, the
Cmax/ C1211 ratios were significantly lower for the SR tablets compared to the IR
capsule for the same ts studied. The geometric mean Cmax/Cth ratios were
11.6—, 8.6—, 19.3—, and 89—fold, respectively, for SR1, SR2, SR3, and SR4 tablets, as
compared to 112- to l62-fold for the IR capsules administered in the fasted state.
For administration in the fasted state, the 4 SR tablets showed reduced relative
bioavailability compared to the IR capsule dosed in the same subjects. The percent
geometric mean ratios (90% CI) of Cmax were 14.2 % (11.4%—l7.5%), 8.9% (6.7%—
11.9%), 22.3% (17.4%—28.6%) and 9.0% (6.8%—11.9%) for SR1, SR2, SR3, and SR4,
respectively. The percent geometric mean ratios (90% CI) of AUCo-oo were 36.1 %
(33.3%—39.2%), 26.0% (21.6%—31.3%), 47.5% (41.9%—53.9%), and 28.5% (23.2%—
.1%) for SR1, SR2, SR3, and SR4, reSpectively. SR3 and SR1 demonstrated the
best and second best relative bioavailability, tively, among the SR formulations
tested.
Dosed in the fasted state, the intersubj ect variability as measured by percent
cient of variability (CV%) in plasma exposure was icantly higher for the
gastroretentive formulation SR4, but comparable among the 3 regular SR tablets
designed for intestinal release. The ubj ect CV% for the 100 mg SR1 tablet was
39% and 33% for Cmax and AUCO—oo, respectively. The intersubject CV% for the 100
mg SR2 tablet was 50% and 37% for Cmax and AUCO—oo, respectively. The intersubject
CV% for the 100 mg SR3 tablet was 43% and 29% for Cmax and AUC0_oo,
respectively. The ubject CV% for the 100 mg SR4 tablet was 83% and 73% for
Cmax and AUCo-oo, respectively. Pooling all ts in Cohorts 1—5 (n = 59) who were
administered 300 mg IR in the fasted state, the intersubj ect CV% was 49% and 39%
for Cmax and AUCO—oo, respectively, comparable to the CV% values observed for SR1,
SR2, and SR3.
A positive food effect was observed for all SR formulations studied at the
300 mg (3 X 100 mg) dose level. Administered after a high-fat meal, geometric mean
Cmax and AUCO-oo values increased by 88% and 81%, respectively, for SR1; by 158%
and 118%, respectively; for SR2; by 91% and 45%; respectively; for SR3; and by
93% and 115%; respectively; for SR4. The food effect was moderate for a medium—
fat meal as compared to a high—fat meal, as suggested by the data for SR3 in Cohort 5.
For SR3, Cmax and o values increased by 46% and 17%, respectively, when it
was administered following a standardized medium-fat meal. Administration with
food did not significantly change the intersubj ect CV% in compound of al
plasma exposure for SR1, SR2, and SR3, which are SR formulations designed for
intra—intestinal release. For SR4, which is a retentive SR ation, the
intersubj ect CV% in plasma exposures appeared to be significantly reduced with a
concomitant high-fat meal.
This study also explored the dose-normalized relative bioavailability of the
25 mg SR tablet in reference to the 100 mg SR3 tablet. For the subjects in Cohort 6,
the dose—normalized Cmax and AUCO-oo percent geometric mean ratio for the 2 X 25 mg
SR3 treatment was 59% and 66%, respectively, versus the 1 X 100 mg SR3
administration in the fasted state. However, due to the supralinear dose-exposure
relationship for the compound of Formula I, the ve bioavailability of the 25 mg
SR tablet may be underestimated. For the 2 X 25 mg SR dose, a high-fat meal
increased compound of Formula I Cmax and o by 60% and 58%, respectively.
For the four SR formulations evaluated, the observed apparent disposition tvz
was comparable, and the Cmax/Cth ratios from a fasting single—dose administration
(which is used as a proxy for P/T ratio from twice-daily administration) were r
among SR1, SR2, and SR4 (~10-fold) and moderately higher for SR3 (~20-fold).
Overall, all 4 SR formulations demonstrated a cantly flatter PK profile
compared the IR capsule, meeting an important ive for sustained release.
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Bioavailability of orally administered drug products may be defined by the rate and
extent of the drug absorption into systemic circulation. A reduction in drug
absorption rate by limiting the drug release rate from drug products is a design
requirement in ned release formulations. ore, for SR formulations, the
extent of the compound of Formula 1 absorption as measured by the plasma AUCO—oo is
used as the primary endpoint to assess the relative bioavailability. Thus, the mean
relative bioavailability is similar between SR2 (26%) and SR4 (29%), which was
slightly lower than that of SR1 (36%). The best relative bioavailability was observed
for SR3 (48%). The results are in line with the in vitro dissolution profiles obtained
before conducting this study.
There was an apparent inverse correlation between the food effect and relative
bioavailability for the SR formulations. On average, dosed with a at meal, the
food—effect measured by the increase in AUCO—oo was the greatest for SR2 (118%) and
SR4 (115%), which was lower than that for SR1 (81%). The smallest food effect was
observed for SR3 (45%). This ation was also apparent when the data from all
the subjects were pooled together. A quantile plot using the pooled individual data
(divided into 5 bins with 9 subjects per bin) suggests that the food effect was more
significant (> 2-fold increase in AUC) for the subjects with relative bioavailability
less than 35%, regardless of the formulation. The food effect was moderate (~50% or
less increase in AUC) for the subjects with ve ilability greater than 40%,
regardless of formulation. SR3 delivered a mean relative bioavailability of 48% and
is likely to be associated with a moderate food effect. In fact, when the SR3 tablet (3
X 100 mg) was dosed with a medium-fat meal (which is a more typical daily diet), the
observed increase in geometric mean AUCO—oo was only 17%, suggesting that this
formulation may be administered without regard to medium- or low-fat meals. From
the perspective of avoiding significant food , SR3 is superior to the other
formulations.
Example 4. Clinical Results in Phase 2a in patients with active rheumatoid
arthritis (RA)
An l 28 day part of the study was conducted in order to select doses
moving forward, guiding dose selection for the 3 month second part of the study. Part
2 of the study was randomized, double—blind, placebo controlled (sponsor unblinded)
with treatment for 84 days. Sixty subjects to be randomized, using the same
population as in Part 1: single cohort, five parallel treatment groups, 12 subjects each:
100 mg SR3 s BID; 300 mg (3 x 100 mg SR3 tablets) QD; 200 mg (2 x 100 mg
SR3 tablets) BID; 600 mg (6 x 100 mg SR3 tablets) QD; and placebo. Interim data
was submitted to ACR (American College of Rheumatology) 2013 (n=40 subjects
who completed day 84). The ACR scores at 3 months re shown in Table 6. The
ACR scores for the 600 mg QD are unprecedented as ed to other JAK
inhibitors that are approved for ent of RA. For example, the approved product
for tofacitinib citrate (5 mg BID) showed much lower ACR scores at 3 months: 59%
(ACR20), 31% ), and 15% (ACR70) (Table 5 of XELJANZ® — tofacitinib
citrate tablet — label).
Table 6
Placebo 100 mg 300 mg QD 200 mg 600 mg QD
BID BID
The percent change from baseline for hemoglobin was also studied for each of
the dosing regimens (. As can be seen in the 200 mg BID dose showed
a drop away from the baseline compared to the other doses which tended to stay Close
to the placebo levels. For example, the 600 mg QD dose did not show the same
downward trend as shown for the BID dose. However, as can be seen in Table 6, the
once—daily dosing (600 mg QD) did not mise efficacy compared with the BID
doses. This indicates that the once-daily dosing (such as 600 mg QD) may e
maximal y without inducing side-effects such anemia. As shown in and
Table 6, the 600 mg QD dose has robust efficacy with trivial change in hemoglobin
levels.
It is believed that this efficacy/side—effect profile may be due to the QD dose
achieving l JAKl signaling (tied to cy) with low JAK2 tion at the
trough, as JAK2 signaling is tied to hematopoiesis. This hypothesis is supported by
the PK derived JAKl (IL-6) and JAK2 (TPO) inhibition data for the compound of
Formula at various doses (Table 7). In particular, the 600 mg QD dose showed
similar average IL-6 inhibition to the 200 mg BID and 400 mg BID doses (61%
versus 64% and 69%), but lower trough TPO inhibition in comparison to the 200 mg
BID and 400 mg BID doses (4% versus 13% and 16%). The trough IL-6 inhibition
for the 600 mg QD dose is also lower than the trough IL-6 tion for the 200 mg
BID and 400 mg BID doses, which suggests that there may be a ion in infection
from the QD dose.
Table 7
Dose regimen Average IL-6 Trough IL-6 Average TPO Trough TPO
inhibition inhibition inhibition inhibition
100 mg QD 30% 7% 7% <1%
200 mg QD 39% 11% 11% <1%
300 mg QD
600 mg QD
100 mg BID
200 mg BID
400 mg BID
Example 5. Clinical Results in Patients with Plaque Psoriasis
A double—blind (sponsor unblinded), randomized, placebo controlled study
was conducted in approximately 48 subjects treated for 28 days. Eligibility
requirements included: active plaque psoriasis for at least 6 months at screening;
body surface area (BSA) of plaque psoriasis of 2 5%; sis area and severity
index (PASI) score of 2 5; static physician’s global assessment (sPGA) score of Z 3;
inadequate response to topical therapies; innovative design allowing rapid progress
between doses, with conservative safety assessment. Four staggered dose groups of
12 subjects each (9 active and 3 PBO) progressing from 100 mg QD to 200 mg QD to
200 mg BID to 600 mg QD. Once the 4th subject (block of 3 active 1 PBO)
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completed 28 days administration without a Grade 3 or higher AE, the next group of
12 subjects initiated treatment with the next highest dose; while the first 4 subjects in
this group are d for 28 days, the 1st group is filled
60 subjects with moderate to severe psoriasis were randomized. There were five
treatment groups: placebo, 100 mg QD, 200 mg QD, 200 mg BID and 600 mg QD. A
tial method of tment was used, increasing from the lowest dose to the
highest, each after the completion of 28 days for the first four subjects in the previous
dose. The results at 28 days are show in Table 8 (PASI 50 is Psoriasis Area and
Severity Index). These PASI 50 score of 81.8% for the 600 mg QD dose are
unprecedented as compared to other JAK inhibitors that are in development for
treatment of psoriasis. For example, 5 mg tofacitinib (also known as tasocitinib)
showed lower PASI 50 score of 65.3% at 12 weeks (published on
/press.pfizer.com on 10/7/2010). The 5 mg tofacitinib dose is the approved
dosage level for RA for safety reasons in the US.
Table 8
Placebo 100 mg 200 mg QD 200 mg 600 mg QD
BID BID
Mean % —l2.5% —35.2% —42.4%
change
sPGA
% sPGA 0 33.3% 45.5%
(clear or
minimal)
% PASI 50 8.3% 22.2% 66.7% 44.4% 81.8%
Example 6. Open-Label Phase 11 Study in Patients with Myelofibrosis
In this study, patients with age 218 years, a diagnosis of primary myelofibrosis
(PMF) or post—polycythemia vera MF or post-essential thrombocythemia MF
(JAK2V617F positive or negative on status), platelet counts 2 50 X lO9/L,
hemoglobin levels 2 8.0 g/dL (transfusions permitted to achieve these levels),
intermediate-l or higher per DIPSS criteria, and palpable spleen or prior splenectomy
were enrolled. Three different dose cohorts were assessed: (1) 100 mg SR3 tablets
BID) (2) 200 mg (2 x 100 mg SR3 tablets) BID; and (3) 600 mg (6 X 100 mg SR3
tablets) QD. a)-(b) show interim s with respect to proportion of subjects
with 2 50% reduction in total symptom score (TSS) in each dose group per the
modified Myelofibrosis Symptom ment Form (MFSAF) V3.0 electronic diary
at week 12 compared with baseline (The modified MFSAF V3.0 comprises 19
questions assessing MF—related symptoms on a scale of 0 (absent) to 10 (worst
imaginable». a) s the percentage of patients having a 2 50% reduction
in TSS at week 12 by dose cohort (100 mg BID, 200 mg BID, and 600 mg QD)
(patients who discontinued prior to the week 12 visit were considered nonresponders).
b) depicts the t change in TSS from baseline at week 12 by dose cohort
(100 mg BID, 200 mg BID, and 600 mg QD) (only patients with baseline and week
12 data were included). a) depicts mean obin levels (g/dL) over time
by dose cohort (100 mg BID, 200 mg BID, and 600 mg QD) (interim results of study
for all patients). b) depicts mean hemoglobin levels (g/dL) over time by dose
cohort (100 mg BID, 200 mg BID, and 600 mg QD) at 48 weeks. c) s
mean hemoglobin levels (g/dL) over time by dose cohort at 48 weeks as an average
for three dose cohorts as compared to duals dosed with placebo or ruxolitinib
(ruxolitinib was dosed according to the label for Jakafi®). The data show an increase
in hemoglobin levels for the 600 mg QD dose. Finally, Table 9 below show interim
hematology laboratory results (new and worsening) for each dose cohort. Table 9a
shows the hematology laboratory results (new and worsening) for each dose cohort
after long exposure.
Table 9
Days of Exposure, 102.5 169.0 16.0
median (range) (23.0, 376.0) (22.0, 339.0) (1.0, 196.0)
Anemia, Grade 3 3/9 (33.3) 12/42 (28.6) 2/29 (6.9)
Thrombocytopenia
Grade 3 4/9 (44.4) 12/44 (27.3) 1/29 (3.4)
Grade 4 0/9 (0) 2/45 (4.4) 0/29 (0)
Table 93
Event n/N % 100 mg BID 200 mg BID 600 mg QD
Days of re, 102.0 254.0 192.0
median (range) (23,519) (28,343)
Anemia, Grade 3 3/10 (30.0) 19/45 (42.2) 8/32 (25.0)
Thrombocytopenia
Grade 3 4/10 (40.0) 13/45 (28.9) 4/32 (12.5)
Grade 4 0/10 (0.0) 3/45 (6.7) l/32 (3.1)
Example A: In vitro JAK Kinase Assay
The compound of Formula 1 herein was tested for inhibitory activity of JAK
targets according to the following in vitro assay described in Park et al, Analytical
Biochemistry 1999, 269, 94—104. The catalytic s of human JAK] (a.a. 837-
1142) and JAK2 (a.a. 828-1132) with an N—terminal His tag were expressed using
baculovirus in insect cells and purified. The catalytic activity of JAKl and JAK2 was
assayed by ing the phosphorylation of a biotinylated peptide. The
phosphorylated peptide was detected by homogenous time resolved fluorescence
(HTRF). ICsos of compounds were measured for each kinase in the 40 microL
reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8)
buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM
leo measurements, ATP concentration in the reactions was 1 mM. Reactions were
carried out at room temperature for 1 hr and then stopped with 20 uL 45 mM EDTA,
300 nM SA-APC, 6 nM Eu-Py20 in assay buffer n Elmer, Boston, MA).
Binding to the Europium d antibody took place for 40 minutes and HTRF signal
was measured on a Fusion plate reader n Elmer, Boston, MA). The nd
of Formula I and the adipic acid salt had an leo at JAKl of S 5 nM (measured at 1
mM ATP) with a JAK2/JAK1 ratio of > 10 (measured at 1 mM ATP).
Example B: Cellular Assays
Cancer cell lines dependent on cytokines and hence AT signal
transduction, for growth, can be plated at 6000 cells per well (96 well plate format) in
RPMI 1640, 10% FBS, and l nG/mL of appropriate cytokine. nds can be
added to the cells in DMSO/media (final concentration 0.2% DMSO) and incubated
for 72 hours at 37 OC, 5% C02. The effect of compound on cell viability is assessed
using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) followed by
TopCount (Perkin Elmer, Boston, MA) quantitation. Potential off-target effects of
compounds are measured in parallel using a non-JAK driven cell line with the same
assay readout. All experiments are typically performed in duplicate.
The above cell lines can also be used to examine the effects of compounds on
phosphorylation of JAK s or potential downstream substrates such as STAT
proteins, Akt, Shp2, or Erk. These experiments can be performed ing an
overnight cytokine starvation, followed by a brief preincubation with compound (2
hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are
then extracted from cells and analyzed by techniques familiar to those schooled in the
art including Western blotting or ELISAs using antibodies that can differentiate
between orylated and total protein. These experiments can utilize normal or
cancer cells to investigate the activity of compounds on tumor cell survival biology or
on mediators of inflammatory e. For example, with regards to the latter,
cytokines such as IL-6, IL-12, IL-23, or IFN can be used to stimulate JAK activation
resulting in phosphorylation of STAT protein(s) and potentially in transcriptional
profiles (assessed by array or qPCR technology) or production and/or secretion of
proteins, such as lL-l7. The ability of compounds to t these cytokine mediated
effects can be measured using techniques common to those schooled in the art.
Compounds herein can also be tested in cellular models ed to te
their potency and activity against mutant JAKs, for example, the JAK2V617F
mutation found in myeloid proliferative disorders. These experiments often utilize
cytokine dependent cells of hematological lineage (e. g. BaF/3) into which the wild-
type or mutant JAK kinases are cally expressed , C., et al. Nature
434:1144—1148; Staerk, J., et a3. JBC 280:41893—41899). Endpoints include the
effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT,
Akt, or Erk ns.
Certain compounds herein can be evaluated for their ty inhibiting T-cell
proliferation. Such as assay can be considered a second cytokine (226. JAK) driven
proliferation assay and also a simplistic assay of immune suppression or tion of
immune activation. The following is a brief outline of how such experiments can be
performed. Peripheral blood mononuclear cells (PBMCs) are prepared from human
whole blood samples using Ficoll Hypaque tion method and T-cells (fraction
2000) can be obtained from PBMCs by elutriation. Freshly isolated human T-cells can
be maintained in culture medium (RPMI 1640 supplemented with10% fetal bovine
serum, 100 U/ml penicillin, 100 ug/ml streptomycin) at a density of 2 x 106 cells/ml at
37 °C for up to 2 days. For IL—2 stimulated cell proliferation analysis, T—cells are first
treated with Phytohemagglutinin (PHA) at a final concentration of 10 ug/mL for 72h.
After washing once with PBS, 6000 cells/well are plated in l plates and d
with compounds at different concentrations in the culture medium in the presence of
100 U/mL human IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates are
incubated at 37 °C for 72h and the proliferation index is assessed using ter—Glo
Luminescent reagents following the manufactory suggested protocol (Promega;
Madison, WI).
Example C: In vivo anti-tumor efficacy
Compounds herein can be evaluated in human tumor xenograft models in
immune compromised mice. For example, a tumorigenic variant of the INA-6
plasmacytoma cell line can be used to inoculate SCID mice subcutaneously (Burger,
R., et a]. Hematol J. 2:42—53, 2001). Tumor bearing s can then be randomized
into drug or vehicle treatment groups and different doses of compounds can be
administered by any number of the usual routes including oral, i.p., or uous
infusion using implantable pumps. Tumor growth is followed over time using
calipers. Further, tumor s can be harvested at any time after the initiation of
treatment for analysis as described above (Example B) to te compound s
on JAK activity and downstream signaling pathways. In addition, selectivity of the
compound(s) can be assessed using xenograft tumor models that are driven by other
know kinases (e.g. Bcr—Abl) such as the K562 tumor model.
Example D: Murine Skin Contact d Hypersensitivity se Test
nds herein can also be tested for their efficacies (of inhibiting JAK
targets) in the T—cell driven murine delayed ensitivity test model. The murine
skin contact delayed—type hypersensitivity (DTH) response is considered to be a valid
model of clinical contact dermatitis, and other T-lymphocyte mediated immune
disorders of the skin, such as psoriasis (Immunol Today. 1998 Jan;l9(l):37—44).
Murine DTH shares multiple characteristics with psoriasis, including the immune
ate, the accompanying increase in inflammatory cytokines, and keratinocyte
hyperproliferation. Furthermore, many classes of agents that are efficacious in
ng psoriasis in the clinic are also effective inhibitors of the DTH response in
mice (Agents Actions. 1993 Jan;38(l—2): 1 16-21).
On Day 0 and l, Balb/c mice are sensitized with a topical application, to their
shaved abdomen with the n 2,4,dinitro-fluorobenzene (DNFB). On day 5, ears
are measured for thickness using an engineer’s micrometer. This measurement is
recorded and used as a baseline. Both of the animals’ ears are then nged by a
topical ation of DNFB in a total of 20 uL (10 uL on the internal pinna and 10
uL on the external pinna) at a concentration of 0.2%. Twenty—four to y—two
hours after the challenge, ears are measured again. Treatment with the test
compounds is given throughout the sensitization and challenge phases (day -l to day
7) or prior to and throughout the challenge phase (usually afternoon of day 4 to day
7). Treatment of the test compounds (in different concentration) is administered
either systemically or topically (topical application of the ent to the ears).
Efficacies of the test compounds are indicated by a reduction in ear swelling
ing to the situation without the treatment. nds causing a reduction of
% or more were considered efficacious. In some experiments, the mice are
challenged but not sensitized (negative control).
The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the
test compounds can be confirmed by immunohistochemical analysis. Activation of
the JAK-STAT pathway(s) results in the formation and translocation of functional
transcription s. Further, the influx of immune cells and the increased
proliferation of keratinocytes should also provide unique expression profile changes
in the ear that can be investigated and quantified. Formalin fixed and paraffin
embedded ear sections (harvested after the challenge phase in the DTH model) are
subjected to immunohistochemical analysis using an antibody that specifically
interacts with phosphorylated STAT3 (clone 58El2, Cell Signaling Technologies).
The mouse ears are treated with test compounds, vehicle, or dexamethasone (a
clinically efficacious treatment for psoriasis), or without any treatment, in the DTH
model for comparisons. Test nds and the dexamethasone can produce similar
transcriptional changes both qualitatively and quantitatively, and both the test
compounds and dexamethasone can reduce the number of infiltrating cells. Both
systemically and topical administration of the test compounds can produce inhibitive
effects, i.e., reduction in the number of infiltrating cells and inhibition of the
transcriptional changes.
Example E: In vivo anti-inflammatory activity
nds herein can be evaluated in rodent or non—rodent models designed
to replicate a single or complex ation response. For instance, rodent models
of arthritis can be used to evaluate the therapeutic potential of compounds dosed
preventatively or therapeutically. These models include but are not d to mouse
or rat collagen—induced arthritis, rat adjuvant-induced arthritis, and collagen antibody-
induced arthritis. Autoimmune diseases including, but not limited to, multiple
sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, enia gravis,
immunoglobulin nephropathies, myocarditis, airway sensitization a), lupus, or
colitis may also be used to evaluate the therapeutic ial of compounds herein.
These models are well ished in the research community and are familiar to those
schooled in the art (Current ols in logy, Vol 3., Coligan, J.E. et a1,
Wiley Press; Methods in Molecular Biology: Vol. 225, Inflammation Protocols,
Winyard, PG. and Willoughby, D.A., Humana Press, 2003.).
Example F: Animal Models for the Treatment of Dry Eye, Uveitis, and
Conjunctivitis
Agents may be evaluated in one or more nical models of dry eye known
to those schooled in the art including, but not limited to, the rabbit concanavalin A
(ConA) lacrimal gland model, the scopolamine mouse model (subcutaneous or
transdermal), the Botulinumn mouse lacrimal gland model, or any of a number of
spontaneous rodent auto-immune models that result in ocular gland dysfunction (e.g.
NOD-SCID, MRL/lpr, or NZB/NZW) (Barabino et al., mental Eye Research
2004, 79, 613—621 and er et al., Developmental Opthalmology, Karger 2008,
41, 298-312, each of which is incorporated herein by reference in its entirety).
Endpoints in these models may include histopathology of the ocular glands and eye
(cornea, etc.) and possibly the classic Schirmer test or modified versions thereof
(Barabino et al.) which measure tear production. Activity may be assessed by dosing
via multiple routes of administration (eg. systemic or topical) which may begin prior
to or after measurable disease exists.
Agents may be evaluated in one or more nical models of uveitis known
to those schooled in the art. These include, but are not limited to, models of
experimental mune uveitis (EAU) and endotoxin induced uveitis (EIU). EAU
experiements may be performed in the , rat, or mouse and may involve passive
or activate zation. For instance, any of a number or retinal ns may be
used to sensitize animals to a relevant immunogen after which animals may be
challenged y with the same antigen. The EIU model is more acute and involves
local or ic administration of lipopolysaccaride at sublethal doses. Endpoints
for both the EIU and EAU models may include fundoscopic exam, histopathology
amongst others. These models are reviewed by Smith et a1. (Immunology and Cell
Biology 1998, 76, 497—512, which is incorporated herein by reference in its entirety).
Activity is assessed by dosing via multiple routes of stration (e. g. systemic or
topical) which may begin prior to or after measurable disease exists. Some models
listed above may also develop scleritis/episcleritis, chorioditis, cyclitis, or iritis and
are therefore useful in investigating the potential activity of compounds for the
therapeutic treatment of these diseases.
Agents may also be evaluated in one or more nical models of
conjunctivitis known those schooled in the art. These include, but are not limited to,
rodent models utilizing guinea—pig, rat, or mouse. The guinea-pig models include
those utilizing active or passive immunization and/or immune challenge protocols
with antigens such as ovalbumin or d wed in Groneberg, D.A., et al.,
Allergy 2003, 58, 1101—1113, which is incorporated herein by reference in its
entirety). Rat and mouse models are similar in general design to those in the guinea-
pig (also reviewed by Groneberg). Activity may be assessed by dosing via multiple
routes of administration (e. g. ic or topical) which may begin prior to or after
measurable disease exists. Endpoints for such s may include, for example,
histological, immunological, biochemical, or molecular analysis of ocular tissues such
as the conjunctiva.
Example G: In vivo protection of bone
Compounds may be evaluated in s preclinical models of osteopenia,
osteoporosis, or bone resorption known to those schooled in the art. For example,
ovariectomized rodents may be used to evaluate the ability of compounds to affect
signs and markers of bone remodeling and/or density (W.S.S. Jee and W. Yao, J
Musculoskel. Nueron. Interact, 2001, 1(3), 193—207, which is incorporated herein by
reference in its entirety). Alternatively, bone density and ecture may be
evaluated in control or compound treated rodents in models of therapy (e.g.
glucocorticoid) d enia (Yao, et a1. Arthritis and Rheumatism, 2008,
58(6), 3485-3497; and id. 58(11), 1674-1686, both of which are incorporated herein
by nce in its entirety). In addition, the effects of compounds on bone resorption
and density may be evaluable in the rodent models of arthritis discussed above
(Example E). Endpoints for all these models may vary but often include histological
and radiological ments as well as immunohisotology and appropriate
biochemical markers of bone remodeling.
Claims (28)
1. Use of {1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4- (7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease selected from graft versus host disease, psoriasis, rheumatoid arthritis, primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis, and post-essential thrombocythemia ibrosis, wherein the medicament is provided in the form of one or more sustained e dosage forms each comprising a aily oral dose of about 400 mg to about 600 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a ceutically acceptable salt thereof.
2. The use according to claim 1, wherein the medicament is provided in the form of one or more sustained release dosage forms each comprising a once-daily oral dosage of about 600 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin -pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically acceptable salt thereof.
3. The use according to claim 1, wherein the medicament is provided in the form of six oral dosage forms of about 100 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically acceptable salt thereof.
4. The use according to claim 1, wherein the ment is provided in the form of three oral dosage forms of about 200 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically acceptable salt thereof.
5. The use ing to claim 1, wherein the medicament is provided in the form of two oral dosage forms of about 300 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically acceptable salt thereof.
6. The use according to claim 1, wherein the medicament is provided in the form of one oral dosage form of about 600 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a pharmaceutically acceptable salt thereof.
7. The use according to any one of claims 1 to 6, wherein said disease is rheumatoid arthritis.
8. The use according to claim 7, wherein the ACR70 score of said patient is to be greater than about 40%.
9. The use according to claim 7, wherein the ACR70 score of said patient is to be greater than about 50%.
10. The use ing to any one of claims 1 to 6, wherein said disease is psoriasis.
11. The use according to claim 10, n the PASI 50 score is to be greater than about 70%.
12. The use according to any one of claims 1 to 6, wherein said e is primary myelofibrosis (PMF).
13. The use according to claim 12, wherein the use results in a reduced total symptom score (TSS) of said patient ed with baseline.
14. The use according to claim 12, n said use results in reduced anemia.
15. The use according to any one of claims 1 to 6, wherein said disease is postpolycythemia vera myelofibrosis.
16. The use according to any one of claims 1 to 6, wherein said disease is postessential ocythemia myelofibrosis.
17. The use ing to any one of claims 1 to 6, wherein said disease is graft versus host disease.
18. The use according to any one of claims 1 to 17, wherein the one or more sustained release dosage forms are each formulated as a .
19. The use according to any one of claims 1 to 18, wherein the one or more sustained release dosage forms are ed by process sing wet granulation.
20. The use according to any one of claims 1 to 19, wherein the one or more sustained release dosage forms each comprises one or more hypromelloses.
21. The use according to any one of claims 1 to 19, wherein the one or more sustained release dosage forms each comprises one or more excipients independently selected from hypromelloses and microcrystalline celluloses.
22. The use according to any one of claims 1 to 19, wherein the one or more sustained release dosage forms each comprises one or more excipients independently selected from hypromelloses, microcrystalline celluloses, magnesium stearate, lactose, and lactose monohydrate.
23. The use ing to any one of claims 1 to 19, wherein the one or more sustained release dosage forms each comprises a first hypromellose characterized by having an nt viscosity at a concentration of 2% in water of about 80 cP to about 120 cP and a second hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of about 3000 cP to about 5600 cP.
24. The use according to any one of claims 1 to 19, wherein the one or more sustained release dosage forms each comprises about 10% to about 15% by weight of one or more hypromelloses.
25. The use according to any one of claims 1 to 19 and 24, wherein the one or more sustained release dosage forms each ses about 16% to about 22% by weight of microcrystalline cellulose.
26. The use according to any one of claims 1 to 19 and 24 to 25, wherein the one or more sustained release dosage forms each comprises about 45% to about 55% by weight of lactose monohydrate.
27. The use according to any one of claims 1 to 19 and 24 to 26, wherein the one or more sustained release dosage forms each comprises about 0.3% to about 0.7% by weight of magnesium stearate.
28. The use according to any one of claims 1 to 27, wherein said salt is {1-{1-[3- fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3- d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile adipic acid salt.
Priority Applications (2)
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NZ756084A NZ756084B2 (en) | 2013-08-07 | 2014-08-06 | Sustained release dosage forms for a jak1 inhibitor |
NZ756083A NZ756083B2 (en) | 2013-08-07 | 2014-08-06 | Sustained release dosage forms for a jak1 inhibitor |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US201361863325P | 2013-08-07 | 2013-08-07 | |
US61/863,325 | 2013-08-07 | ||
US201361913066P | 2013-12-06 | 2013-12-06 | |
US61/913,066 | 2013-12-06 | ||
PCT/US2014/049940 WO2015021153A1 (en) | 2013-08-07 | 2014-08-06 | Sustained release dosage forms for a jak1 inhibitor |
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NZ717230A NZ717230A (en) | 2021-05-28 |
NZ717230B2 true NZ717230B2 (en) | 2021-08-31 |
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