NZ756084A - Sustained release dosage forms for a jak1 inhibitor - Google Patents
Sustained release dosage forms for a jak1 inhibitor Download PDFInfo
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- NZ756084A NZ756084A NZ756084A NZ75608414A NZ756084A NZ 756084 A NZ756084 A NZ 756084A NZ 756084 A NZ756084 A NZ 756084A NZ 75608414 A NZ75608414 A NZ 75608414A NZ 756084 A NZ756084 A NZ 756084A
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Abstract
This invention relates to a sustained release composition, comprising: (i) { 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, or a pharmaceutically acceptable salt thereof; (ii) a first hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of about 80 cP to about 120 cP; (iii) a second hypromellose, characterized by having an apparent viscosity at a concentration of 2% in water of about 3000 cP to about 5600 cP, wherein the composition comprises about 8% to about 20% of the first and second hypromelloses; (iv) about 16% to about 22% by weight of microcrystalline cellulose; and (v) about 45% to about 55% by weight of lactose monohydrate.
Description
SUSTAINED E DOSAGE FORMS FOR A JAK1 INHIBITOR
The present Application is a Divisional Application from New d Patent
Application No. 717230. The entire disclosures of New Zealand Patent Application No.
717230 and its corresponding International Patent Application No. ,
are incorporated herein by reference. 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 December 6, 2013, each of which is incorporated herein by reference in
its entirety.
TECHNICAL FIELD
This application relates to a sustained release dosage form comprising [3-
fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[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 including cell
growth, survival, differentiation, organ formation, morphogenesis, neovascularization,
tissue repair, and regeneration, among others. Protein kinases also play specialized
roles in a host of human diseases including cancer. nes, low-molecular weight
polypeptides or glycoproteins, regulate many pathways involved in the host
inflammatory response to . Cytokines influence cell differentiation, eration
and activation, and can modulate both flammatory and anti-inflammatory
responses to allow the host to react appropriately to pathogens. Signaling of a wide
range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases
and Signal ucers and Activators of Transcription (STATs). There are four
known mammalian JAKs: JAK1 (Janus kinase-1), 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: ogies such as severe combined immunodeficiency
(SCID) arise from suppression of the immune system, while a hyperactive or
inappropriate immune/inflammatory se contributes to the pathology of
autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis
myocarditis), and illnesses such as scleroderma and osteoarthritis (Ortmann, 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): 373—83). Jak2—/— mouse embryos are
anemic and die around day 12.5 postcoitum due to the absence of definitive
erythropoiesis.
The JAK/STAT pathway, and in particular all four JAKs, are ed to play
a role in the pathogenesis of asthmatic se, chronic obstructive pulmonary
disease, itis, 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 sinusitis) whether classically allergic reactions or not. The
JAK/STAT pathway has also been implicated in inflammatory diseases/conditions of
the eye and chronic 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 endogenous suppressors of JAK signaling
such as SOCS essor or cytokine signaling) or PIAS (protein tor of
activated STAT) y, V., and k, J
., Neoplasm. —355, 2002).
Activation of STAT signaling, as well as other pathways downstream of JAKS (e.g.,
Akt), has been ated with poor prognosis in many cancer types (Bowman, T., et
al. Oncogene 19:2474—2488, 2000). Elevated levels of circulating nes that
signal through 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., polycythemia vera (PV), essential ocythemia (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 ial 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 ization. The maintenance of psoriasis is
believed to depend on a number of inflammatory cytokines in addition to various
chemokines and growth factors (JCI, 64—1675), many of which signal through
JAKs (Adv Pharmacol. 7:113—74).
Due to the usefulness of compounds which inhibit JAK in targeting
augmentation or suppression of the immune and inflammatory pathways (such as
immunosuppressive agents for organ transplants), as well as the treatment of
autoimmune diseases, diseases involving a hyperactive inflammatory se (e.g.,
eczema), allergies, cancer (e. g., te, 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 s forms described 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 -yl]azetidin—3 -yl} acetonitrile,
which is ed below as Formula I.
NC”\
N N
The present application provides, inter alia, ned—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— { l—[3—fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)— azol-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 comprising {1-{1-[3-fluoro(trifluoromethy1)isonicotinoyl]piperidin
yl} -3 -[4-(7H-pyrrolo [2,3 -d]pyrimidinyl)- l H-pyrazol- l -yl]azetidin
yl}acetonitrile, or a pharmaceutically acceptable salt thereof; wherein said one or
more sustained release dosage forms together e 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—{ uoro-2—
oromethyl)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 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]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 er e 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 ceutically acceptable salt
thereof, to a patient.
The present application further provides s of treating an mune
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
forms as described herein.
The present application also provides s 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 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} acetonitrile, or a pharmaceutically acceptable salt
f, 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 -d]pyrimidin-4—yl)— lH—pyrazol— l -yl]azetidiny1} acetonitrile, or a
pharmaceutically acceptable salt thereof.
The present application further provides methods of treating an mune
disease, a cancer, a roliferative disorder, an inflammatory disease, a bone
resorption e, or organ transplant rejection in a patient in need f,
comprising orally administering to said patient one or more sustained release dosage
as described herein.
The t 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, wherein
the method comprises orally administering to said t the one or more sustained
release dosage forms as a aily 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: Cohorts 1—4, fed a high-fat meal).
—B depicts single—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
medium-fat meal).
depicts a comparison of PK profiles (mean i SE) n 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) s the tage of patients having a 2 50% reduction in total
symptom 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
ne 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) s mean hemoglobin levels (g/dL) over time by dose cohort at
48 weeks as an average for three dose cohorts as ed to individuals dosed with
placebo or ruxolitinib.
DETAILED DESCRIPTION
The present application provides sustained—release dosage forms sing
{ l- { l—[3 -fluoro(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-
pyrrolo[2,3-d]pyrimidin—4-yl)- l H—pyrazolyl]azetidin—3-yl} acetonitrile, or a
pharmaceutically acceptable salt thereof. In some embodiments, the present
application provides a sustained—release dosage form comprising 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 ments, 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 f.
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 - —pyrrolo[2,3 -d]pyrimidin—4-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 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 zolyl]azetidin—3 —
yl}acetonitrile, or a ceutically 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-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 -
yl}acetonitrile adipic acid salt.
In some embodiments, 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 imidinyl)— 1 H—pyrazol- l -yl]azetidin—3 -
yl}acetonitrile adipic acid salt.
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- { l-[3 —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 t, 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 ments 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 ments 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 concentration (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 comprising 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
-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 etidin-3—
yl}acetonitrile of about 5 to about 50.
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 (Cizh) of {l—{l-[3—fluoro—2—(trifluoromethyl)isonicotinoyl]piperidin—4-
yl} -3 H-pyrrolo [2,3 -d]pyrimidinyl)- l H-pyrazol- l -yl]azetidin-3—
yl}acetonitrile of about 9 to about 40.
In some embodiments of the sustained—release dosage form sing about
100 mg, oral administration of three of said dosage forms to a fasted dual
provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma
concentration (C1211) of {1— { 1—[3-fluoro—2—(trifluoromethy1)isonicotinoy1]piperidin-4—
yl} -3 -[4-(7H-pyrrolo [2,3 -d]pyrimidinyl)- 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—
(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 individual
provides a mean bioavailability 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
at 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 ments 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 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—yl}acetonitrile of about 500 nM to about 1500 nM.
In some embodiments of the sustained—release dosage form sing about
100 mg, oral administration of three of said dosage forms to an dual 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 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 {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 tration (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 es 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 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 tration (Cizh) 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 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 es 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 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—
(trifluoromethy1)isonicotinoy1]piperidinyl}[4-(7H-pyrrolo[2,3 -d]pyrimidin
—pyrazol—l—yl]azetidin—3—yl}acetonitrile of about 2 hours to about 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 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 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 es a mean bioavailability (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 immediate 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 ments, the percent geometric mean ratio of the ned
release dosage form relative to an immediate e dosage form for Cmax is about
% to about 30%, wherein one or more immediate e dosage forms and one or
more sustained release dosage forms are independently orally stered 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 pharmaceutically acceptable salt,
is administered.
In some ments, the percent geometric mean ratio of the sustained
release dosage form relative to an immediate release dosage form for AUCO—oo is about
40% to about 55%, wherein one or more immediate release dosage forms and one or
more sustained release dosage forms are independently orally administered to fasted
individuals as a single dose, n 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 geometric mean ratio for Cmax of the
sustained release dosage form orally administered to an individual after a high-fat
meal relative to the sustained release dosage form orally stered to a fasted
individual is about 150% to about 250%.
In some embodiments, the percent geometric mean ratio for o 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
formers include cellulosic ethers such as hydroxypropyl cellulose (HPMC,
hypromellose) which is a high viscosity polymer, and methyl celluloses. Example
ypropyl methylcelluloses include MethocelTM K15M, MethocelTM K4M,
elTM KIOOLV, MethocelTM E3, MethocelTM E5, MethocelTM E6, MethocelTM
E15, MethocelTM E50, MethocelTM E10M, MethocelTM E4M, and elTM E10M.
In some embodiments, 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 nt 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 ses 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 fillers, glidants, egrants, binders, or ants 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, lubricants can be present in the dosage forms of the
invention in an amount of 0 to about 5% by weight. Non-limiting examples of
lubricants include magnesium stearate, c acid (stearin), hydrogenated oil,
polyethylene glycol, sodium stearyl fumarate, and glyceryl te. In some
embodiments, the ations 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 magnesium stearate.
In some embodiments, ts may be present in the dosage forms. In some
ments, 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,
colloidal silicon dioxide, and cornstarch. In some ments, the glidant is
colloidal silicon dioxide.
In some embodiments, film—coating agents can be present in an amount of 0 to
about 5% by weight. miting illustrative examples of film-coating agents
include hypromellose or polyvinyl alcohol based g with um dioxide, talc
and optionally colorants available in several commercially available complete g
systems.
In some embodiments, 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 ation.
In some embodiments, the sustained release dosage form ses one or
more excipients independently selected from hypromelloses and microcrystalline
oses.
In some embodiments, the sustained release dosage form comprises one or
more excipients independently selected from hypromelloses, microcrystalline
celluloses, magnesium te, lactose, 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 sustained release dosage
forms each comprising {1-{ l—[3-fluoro(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 able salt thereof; wherein said one or
more sustained release dosage forms together e 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]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
f, to a patient.
The present invention also provides a dose, comprising one or more sustained
release dosage forms each comprising [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
f; wherein said dose provides a once—daily oral dosage of about 400 mg to about
600 mg on a free base basis of [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 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} itrile, 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—
(trifluoromethy1)isonicotinoyl]piperidiny1}[4-(7H-pyrrolo[2,3 imidin
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
400 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 ceutically 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 —yl}acetonitrile, or a pharmaceutically able 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 {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
acceptable salt thereof, are provided. In some ments, the one or more
ned release dosage forms are two dosage forms of about 300 mg on a free base
basis of {l-{ l—[3 o(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-
pyrrolo [2,3 -d]pyrimidinyl)— l H—pyrazol- l -y1]azetidin-3 -yl}acetonitri1e, or a
ceutically 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-
rrolo[2,3 -d]pyrimidinyl)- lH—pyrazol— l -yl]azetidinyl} acetonitrile, or a
pharmaceutically acceptable salt thereof, is provided.
The present application also provides a dose sing one or more sustained
release 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)— azol-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 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 e a aily 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 ses 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 ceutically acceptable salt thereof. In some embodiments,
the dose comprises three dosage forms of 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]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} itrile, or a pharmaceutically acceptable salt
thereof. In some ments, 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 able 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 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 pharmaceutically
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 400 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—4-
yl)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
thereof.
The present application further es a kit comprising 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— { 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, to a patient. In some embodiments, the kit further comprises an instruction to
administer the one or more ned 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
The present application further provides a kit comprising 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—
(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, 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 {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 t application further provides a kit sing 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
(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. In some embodiments, the kit r comprises an instruction to
administer the one or more ned release dosage forms as a aily 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 embodiments, 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] in-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)— lH-pyrazol-l-yl]azetidin-3 -yl} acetonitrile, or a ceutically able 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 imidin—4-yl)- l H—pyrazol- l -yl]azetidin-3—
tonitrile, 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—
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.
As used herein, “sustained—release” is used as generally understood in the art
and refers to a formulation designed to slowly release the active ient into a
patient after oral administration.
As used herein, “dose” refers to the total amount of the compound of Formula
I orally administered 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 aneously.
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 , "Cmax" means the maximum observed plasma concentration.
As used herein, ” refers to the plasma tration measured at 12 hours
from administration.
As used herein, "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, "AUCo-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 tration-
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 described herein. As used herein, "pharmaceutically acceptable salts"
refers to derivatives of the disclosed compounds wherein the parent nd is
modified by converting an existing acid or base moiety to its salt form. Examples of
pharmaceutically acceptable salts include, but are not limited to, mineral or organic
acid salts of basic residues such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the
present invention include the non-toxic salts of the parent compound , for
example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable
salts of the present invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional al 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, ueous media like ether, ethyl
acetate, alcohols (e. g., methanol, ethanol, opanol, or l) or acetonitrile
(ACN) are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical
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.
Methods
The present application r 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,
comprising orally administering to said patient one or more ned release dosage
forms as described herein.
The present application also provides 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,
sing 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]piperidin—4-yl}-3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4-
yl)—1H-pyrazolyl]azetidin-3—yl}acetonitrile, or a ceutically acceptable salt
thereof, n the dose comprises one or more sustained release dosage forms each
sing { 1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4-
rrolo[2,3 —d]pyrimidin-4—yl)- lH—pyrazol— 1 —yl]azetidiny1} acetonitrile, or a
pharmaceutically acceptable salt f. 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 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 t 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-
pyrrolo [2,3 imidinyl)— l H—pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically acceptable salt thereof.
The present application also es a method of treating an mune
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 ses orally stering 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
pharmaceutically acceptable salt thereof.
The present application 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 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 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} itrile, or a
pharmaceutically acceptable salt thereof.
In some embodiments of the methods in the preceding three paragraphs, the
one or more ned 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 ing 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 H-pyrrolo[2,3 imidin
yl)— azol-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 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 {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 release
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 imidinyl)- lH—pyrazol— l -yl]azetidin-3—
yl}acetonitrile of at least 0.5 hours.
In some embodiments,oral stration of one or more sustained release
dosage forms to a fasted individual 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
—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 12-hour 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 provides 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 provides a mean time to peak
plasma concentration (Tmax) of {l-{ l-[3-fluoro-2—
(trifluoromethyl)isonicotinoyl]piperidiny1}[4-(7H-pyrrolo[2,3 -d]pyrimidin
yl)—lH-pyrazol-l-yl]azetidinyl}acetonitrileof about 1 hour to about 9 hours.
In some embodiments, oral administration of one or more sustained release
dosage forms to an dual after a at meal provides a mean time to peak
plasma tration (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 ments, 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 tration (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 e
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)0f {l—{ l-[3-
fluoro(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 r 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 release
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-
o[2,3-d]pyrimidin—4-yl)-lH—pyrazol-l-yl]azetidin—3—yl}acetonitrile of about 2
hours to about 5 hours.
In some ments, the one or more sustained release dosage forms are
each a tablet. In some embodiments, the one or more sustained e dosage forms
are prepared by process comprising wet granulation.
In some embodiments, the one or more sustained 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
ed from hypromelloses and microcrystalline celluloses. In some embodiments,
the one or more sustained release dosage forms each comprises one or more
excipients independently selected from hypromelloses, microcrystalline oses,
magnesium te, 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 concentration of 2% in water of
about 80 CF to about 120 cP and a second hypromellose characterized by having an
apparent ity at a concentration of 2% in water of about 3000 CF to about 5600
In some embodiments, the one or more sustained release dosage forms each
comprises about 10% to about 15% by weight of one or more hypromelloses. In some
embodiments, the one or more ned release dosage forms each comprises about
16% to about 22% by weight of rystalline 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 patient 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)— azol-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 t compared with baseline. In some embodiments,
the present application provides a method of treating myelofibrosis in a patient,
comprising 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)isonicotinoyl]piperidin-4—yl} -3 - [4—(7H—pyrrolo [2,3—
d]pyrimidin-4—yl)—lH-pyrazolyl]azetidinyl}acetonitrile, or a ceutically
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 application provides a method of treating
lbrosis in a patient, comprising orally administering to said patient the one or
more sustained release dosage forms as a aily 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)- lH—pyrazol— l -yl]azetidinyl} 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, the present ation provides a method of treating
myelofibrosis in a patient, 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; wherein the method results in a reduced total
symptom score (TSS) of said t compared with baseline.
In some embodiments of the s in the preceding three paragraphs, the
one or more ned 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 f, 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 {l- {l—[3 —fluoro—
2-(trifluoromethyl)isonicotinoyl]piperidinyl} -3 -[4-(7H-pyrrolo[2,3 imidin
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 {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 e dosage forms is one dosage form of
about 600 mg on a free base basis of {l— { l-[3 —fluoro—2—
oromethyl)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 embodiments, myelofibrosis is primary myelofibrosis
(PMF), post-polycythemia vera MF, or post-essential thrombocythemia MP.
The present ation also provides a method of treating an autoimmune
e, 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 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)— lH-pyrazol-l-yl]azetidin-3 —yl} acetonitrile, or a pharmaceutically acceptable salt
f, wherein the dose comprises one or more sustained release dosage forms each
comprising { l- { l -[3-fluoro-2—(trifluoromethyl)isonicotinoyl]piperidin—4-yl} [4-
rrolo[2,3 -d]pyrimidin-4—yl)— lH—pyrazol— l etidinyl} acetonitrile, or a
pharmaceutically acceptable salt thereof; n said method s in reduced
anemia.
The present application also provides a method of treating an autoimmune
disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone
tion 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(trifluoromethy1)isonicotinoyl]piperidinyl}-3 -[4-(7H-
pyrrolo [2,3 -d]pyrimidinyl)- l H-pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
pharmaceutically able salt thereof; wherein said method results in d
anemia.
The present application also provides a method of treating an autoimmune
disease, a cancer, a myeloproliferative disorder, an inflammatory e, a bone
resorption e, 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 500 mg on a free base basis of
{ l- { l —[3 (trifluoromethyl)isonicotinoyl]piperidinyl} —3 -[4-(7H-
o [2,3 -d]pyrimidinyl)— l H-pyrazol- l -yl]azetidin-3 -yl} acetonitrile, or a
ceutically acceptable salt thereof; wherein said method results in reduced
.
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 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 400 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]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 pharmaceutically 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 -[4-(7H-
pyrrolo[2,3-d]pyrimidinyl)- l H-pyrazol- l -yl]azetidinyl} acetonitrile, or a
ceutically 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(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 f, is provided.
Reduced anemia is relative to that experienced for a twice—daily dose of 200
mg on a free base basis of {l— { uoro(trifluoromethyl)isonicotinoyl]piperidin-
4-yl} —3 - [4-(7H-pyrrolo[2,3 -d]pyrimidinyl)— l zol- 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 {1— {1—[3-
fluoro—2-(trifluoromethyl)isonicotinoyl]piperidinyl}—3-[4-(7H—pyrrolo[2,3-
midin-4—yl)— azol—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 ing pathways
that, when ulated, can result in or contribute to disease 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 h JAKl inhibition is expected to provide clinical benefit
(Guschin, D., N., et al Embo J 1, 1995; Smolen, J. S., et a1. Lancet 371:987,
2008). er, in some cancers JAKl is mutated resulting in constitutive
undesirable tumor cell growth and survival (Mullighan CG, Proc Natl Acad Sci U S
A. 14—8, 2009; Flex E., et all Exp Med. 205:751—8, 2008). In other
autoimmune diseases and cancers elevated systemic levels of inflammatory cytokines
that te JAKl may also contribute to the disease and/or ated symptoms.
Therefore, patients with such diseases may benefit from JAKl inhibition. Selective
inhibitors of JAKl may be cious 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 tors. With respect to selectivity
against JAK2, a number of important cytokines and growth factors signal through
JAK2 including, for example, erythropoietin (Epo) and thrombopoietin (Tpo)
(Parganas 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
numbers 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 ed (Kaushansky K, NEJM 354:2034-45, 2006). As such, reduced
Tpo signaling would decrease megakaryocyte numbers (megakaryocytopenia) and
lower circulating platelet counts (thrombocytopenia). This can result in undesirable
and/or uncontrollable bleeding. d inhibition of other JAKs, such as JAK3 and
Tyk2, may also be desirable as humans lacking functional version of these s
have been shown to suffer from numerous maladies such as severe—combined
immunodeficiency or hyperimmunoglobulin E syndrome (Minegishi, Y, et al.
ty 25:745-55, 2006; Macchi P, et al. Nature. 377:65-8, 1995). Therefore a
JAKl tor with reduced affinity for other JAKs would have significant
advantages over a less-selective inhibitor with respect to d side effects
involving immune suppression, anemia and thrombocytopenia.
Another aspect of the present invention ns to methods of treating a JAK-
associated disease or disorder in an individual (e. g., patient) by administering to the
individual in need of such treatment a sustained-release dosage form of the invention.
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 ion that can be prevented, rated, or cured
by modulating JAK activity.
Examples of JAK—associated diseases include diseases involving the immune
system ing, for example, organ transplant rejection (e. g., allograft rejection and
graft versus host disease).
Further examples of JAK—associated diseases include autoimmune diseases
such as multiple sclerosis, toid arthritis, juvenile arthritis, psoriatic arthritis,
type I diabetes, lupus, psoriasis, atory bowel disease, ulcerative colitis,
Crohn’s disease, myasthenia gravis, immunoglobulin pathies, myocarditis,
autoimmune thyroid ers, chronic obstructive pulmonary disease (COPD), and
the like. In some embodiments, the autoimmune disease is an autoimmune s
skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).
Further examples of JAK—associated diseases include allergic conditions such
as asthma, food allergies, eszematous itis, contact dermatitis, atopic dermatitis
(atropic eczema), and rhinitis. Further examples of JAK—associated diseases include
viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV,
HTLV l, Varicella-Zoster Virus (VZV) and Human oma Virus (HPV).
Further examples of JAK—associated e include diseases associated with
cartilage turnover, for example, gouty arthritis, septic or infectious arthritis, reactive
arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome, costal
athy, rthritis deformans endemica, Mseleni e, Handigodu disease,
degeneration resulting from fibromyalgia, systemic lupus erythematosus, 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 es of JAK—associated diseases or conditions include skin
disorders such as psoriasis (for e, psoriasis vulgaris), atopic itis, skin
rash, skin irritation, skin sensitization (e. g., contact dermatitis or allergic contact
dermatitis). For example, certain substances including some pharmaceuticals when
topically applied can cause skin sensitization. In some embodiments, co—
stration 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 ed sensitization or dermatitis. In some embodiments, the skin
er is treated by topical administration of at least one JAK inhibitor of the
ion.
In further embodiments, the JAK—associated e is cancer including those
characterized by solid tumors (e. g., prostate cancer, renal cancer, hepatic cancer,
pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers 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 ma. Example CTCLs include Sezary syndrome and mycosis
des.
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 incorporated herein by reference in its entirety, can be used to treat inflammation-
associated cancers. In some embodiments, the cancer is associated with inflammatory
bowel e. In some embodiments, the inflammatory bowel disease is ulcerative
colitis. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In
some ments, 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
oid tumor, intestinal stromal tumor (GIST), adenocarcinoma, small
intestine , or rectal cancer.
JAK—associated diseases can further include those characterized by expression
of: JAK2 mutants such as those having at least one mutation in the pseudo-kinase
domain (e.g., JAK2V617F); JAKZ mutants having at least one mutation outside of
the pseudo-kinase domain; JAKl mutants; JAK3 s; erythropoietin receptor
(EPOR) mutants; or deregulated expression of CRLF2.
JAK—associated diseases can further include myeloproliferative disorders
(MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET),
myelofibrosis with d asia (MMM), primary myelofibrosis (PMF),
chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia ,
hypereosinophilic syndrome (HES), ic 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
disorder 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 ion further provides a method of treating ological
side effects of other pharmaceuticals by stration of the dosage forms of the
invention. For example, numerous pharmaceutical agents result in unwanted allergic
reactions which can manifest 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
.
r JAK-associated diseases include inflammation and inflammatory
diseases. e inflammatory diseases include sarcoidosis, atory es
of the eye (e. g., iritis, 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 rhinitis or sinusitis or the lower respiratory
tract including bronchitis, chronic obstructive pulmonary disease, and the like),
inflammatory myopathy such as myocarditis, and other inflammatory diseases. In
some embodiments, the inflammation disease of the eye is blepharitis.
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 endotoxin—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 ia, cachexia, or
fatigue such as that resulting from or associated with cancer. The dosage forms
described herein can further be used to treat restenosis, sclerodermitis, or fibrosis.
The dosage forms described herein can further be used to treat conditions associated
with hypoxia or astrogliosis such as, for example, diabetic retinopathy, cancer, or
neurodegeneration. 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 nce in their entirety. The JAK inhibitors
described herein can be used to treat Alzheimer’s disease.
The dosage forms described herein can further be used to treat other
inflammatory diseases such as systemic inflammatory response me (SIRS) and
septic shock.
The dosage forms described herein can further be used to treat gout and
increased te size due to, e.g., benign prostatic hypertrophy or benign prostatic
hyperplasia.
Further JAK—associated diseases include bone tion diseases 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. s 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 er. 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 e of the tears
and ocular surface that results in symptoms of discomfort, Visual disturbance, and tear
film ility with potential damage to the ocular surface. It is accompanied by
increased rity of the tear film and inflammation of the ocular surface.” Lemp,
“The Definition and Classification of Dry Eye e: 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 s tear—
deficient dry eye (ADDE) or evaporative dry eye disorder, or appropriate
combinations f. In some embodiments, the dry eye disorder is n
syndrome dry eye (SSDE). In some embodiments, the dry eye disorder is non—
Sjogren syndrome dry eye ).
In a r aspect, the present invention provides a method of treating
conjunctivitis, uveitis (including chronic uveitis), chorioditis, retinitis, cyclitis,
sclieritis, episcleritis, or iritis; treating inflammation or pain related to corneal
transplant, LASIK (laser assisted in situ keratomileusis), photorefractive keratectomy,
or LASEK (laser assisted sub—epithelial keratomileusis); inhibiting loss of visual
acuity related to l transplant, LASIK, photorefractive keratectomy, or LASEK;
or inhibiting transplant rejection in a patient 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 nce in its entirety, can be used to treat respiratory
dysfunction or failure associated with viral infection, 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 bed 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 treating any of the es or
disorders described .
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 es use of a
dosage form as bed herein, or a pharmaceutically acceptable salt thereof, for the
preparation of a medicament for use in a method of modulating JAKl.
As used herein, the term idual” is a human. In some embodiments, the
human is an adult subject.
As used herein, the term “treating” 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 matology of the
e, condition or disorder (i.e., arresting further development of the ogy
and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating
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., reversing the
pathology and/or symptomatology) such as decreasing the severity of disease.
Combination ies
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 incorporated 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 es, disorders or conditions. The one or
more additional pharmaceutical agents can be administered to a patient
simultaneously or sequentially.
Example chemotherapeutics include proteosome tors (e.g., bortezomib),
thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin,
cyclophosphamide, vincristine, etoposide, carmustine, and the like.
Example steroids include costeroids such as thasone or
prednisone.
Example Bcr-Abl inhibitors include the nds, and pharmaceutically
acceptable salts thereof, of the genera and species sed 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.
Example suitable Flt-3 inhibitors include compounds, and their
pharmaceutically acceptable 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.
e suitable RAF inhibitors include compounds, and their
pharmaceutically able salts, as disclosed in WO 00/09495 and WO 05/028444,
both of which are incorporated herein by reference in their entirety.
Example suitable FAK inhibitors include compounds, 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 ments, one or more of the dosage forms of the invention can
be used in combination with one or more other kinase tors including imatinib,
ularly for treating patients resistant 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 ent of cancer, such as multiple
myeloma, and may improve the treatment response as compared to the response to the
chemotherapeutic agent alone, t exacerbation of its toxic effects. Examples of
additional pharmaceutical agents used in the treatment of multiple myeloma, for
example, can include, without limitation, melphalan, melphalan plus prednisone
[MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional
agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and
FAK kinase inhibitors. Additive or istic effects are desirable outcomes of
combining a dosage form of the present invention with an additional agent.
rmore, resistance of multiple myeloma 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 nds in a single or continuous dosage
form, or the agents can be administered simultaneously or sequentially as separate
dosage forms.
In some embodiments, a osteroid such as dexamethasone is administered
to a patient in combination with at the dosage form of the invention where the
dexamethasone is administered ittently as opposed to continuously.
In some further embodiments, combinations of one or more IAK inhibitors 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, .
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 olone.
In some embodiments, the additional therapeutic agent is selected from
DehydrexTM (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed,
Lantibio/TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), ARG101(T)
(testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium -Ista),
gefarnate (Santen), -hydroxyeicosatetraenoic acid -HETE), cevilemine,
doxycycline (ALTY-0501, Alacrity), minocycline, iDestrinTM (NP50301, Nascent
Pharmaceuticals), cyclosporine A (Nova22007, Novagali), 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),
RX-10045 (synthetic in , 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 (Othera), PAI-2 rsity of Pennsylvania
and Temple University), pilocarpine, tacrolimus, olimus (AMS981, Novartis),
loteprednol etabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS—
0611 (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,
mycophenolate sodium, etanercept (Embrel®), ychloroquine, NGX267
(TorreyPines Therapeutics), actemra, abine, oxaliplatin, L-asparaginase, or
thalidomide.
In some embodiments, the onal therapeutic agent is an anti-angiogenic
agent, ergic agonist, TRP-l receptor modulator, a calcium channel r, a
mucin secretagogue, MUCl stimulant, a calcineurin inhibitor, a corticosteroid, a
P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another
JAK inhibitor, Ber-Ab] kinase tor, Flt-3 kinase inhibitor, RAF kinase inhibitor,
and FAK kinase inhibitor such as, for example, those described in ,
which is incorporated herein by nce 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 onal 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 mitotic inhibitor (e. g.
Vincristine or paclitaxel); an topoisomerase (I or II) inhibitor (e.g. mitoxantrone and
irinotecan); an apoptotic inducers (e. g. 7); a nucleic acid therapy (e. g.
nse or RNAi); nuclear receptor ligands (e.g., agonists and/or antagonists: all-
trans retinoic acid or bexarotene); epigenetic targeting agents such as histone
deacetylase tors (e. g. vorinostat), hypomethylating agents (e.g. decitabine);
regulators of protein stability such as Hsp90 inhibitors, ubiquitin and/or tin like
conjugating or deconjugating molecules; or an EGFR inhibitor (erlotinib).
In some embodiments, the additional therapeutic agent(s) are demulcent eye
drops (also known as “artificial tears”), which include, but are not limited to,
itions ning polyvinylalcohol, hydroxypropyl methylcellulose, glycerin,
polyethylene glycol (e.g. PEG400), or carboxymethyl cellulose. Artificial tears can
help in the treatment of dry eye by compensating for reduced moistening and
lubricating capacity of the tear film. In some embodiments, the additional eutic
agent is a mucolytic drug, such as N-acetyl-cysteine, which can interact with the
oteins 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 anti-inflammatories, and anti-allergic agents. Examples of suitable
ments include aminoglycosides such as amikacin, gentamycin, ycin,
streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin,
norfloxacin, in, oxacin, lomefloxacin, levofloxacin, and enoxacin;
naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin;
colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives
(“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole;
flucytosine; natamycin; miconazole; ketoconazole; osteroids; diclofenac;
flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; bastin; naphazoline;
antazoline; pheniramine; or e 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 s, protocol
B was used for the SR2 s, Protocol C was used for the SR3 s and the 25
mg SR tablets, 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
el 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 screened ium Stearate with granules in Step 6 in a
suitable blender.
Step 8. Compress the final blend in Step 7 on a suitable rotary tablet
press.
Protocol B:
Step 1. Individually screen the adipic acid salt of the compound of
Formula I, microcrystalline cellulose, hypromellose and atinized starch.
Step 2. Transfer the screened material from Step 1 to a le blender
and mix.
Step 3. er 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. Individually screened polyox, butylated hydroxytoluene and
colloidal silicone dioxide.
Step 8. Transfer the granules from Step 6 and material from Step 7 into
a suitable blender and mix.
Step 9. Add screened Magnesium Stearate to the material in Step 8 and
ue blending.
Step 10. Compress the final blend in Step 9 on a suitable rotary tablet
press.
Protocol C:
Step 1. dually screen lactose monohydrate, the adipic acid salt of
the compound of Formula I, microcrystalline cellulose and hypromelloses through 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 purified water while .
Step 5. Screen wet granules through 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 ium stearate with granules in Step 7 in a
suitable 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, ellose, and a portion of required microcrystalline
cellulose through a suitable screen.
Step 2. er 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. Screen wet granules through a le 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 le blender 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: ition of 100 mg Sustained Release Tablets
Component Function Weight (mg/tablet) Composition
(wt%)
Adipic acid salt of the Active 126.422 21.1
compound of Formula I a
MlClOCl'ystalllne Cellulose"m
Hypromellose
Release Control 10.0
(Methocel K100LV)
ellose
Release Control 10.0
(Methocel K4M)
Component on 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 Release Tablets
Component Function Weight Composition
(mg/tablet) (wt%)
Adipic acid salt of the Active
126.4 a 21.1
compound of Formula Ia
rystalline Cellulose 180.0
Hypromellose .
(MethoceleOLw "n
Polyethylene Oxide
Release Control 1800
(Polyox WRS 1105) b
Pregelatinized Starch 101.6
Butylated Hydroxytoluene b 0.012 0.002
Purified Water ° ating
‘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
blet) (wt%)
Adipic acid salt of the Active
126.4 a 21.1
compound of Formula I21
Mlcrocrystalllne Flller
108.0 18.0
Cellulose
Hypromellose
Release Control 42 0 7 0
(Methocel KIOOLV) ' '
Hypromellose
Rdeasecmtml
<Methoce1K4M>
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
SR4: Composition of 100 mg Sustained e Tablets
ent on Weight (mg/tablet) Composition
(wt%)
AdlplC ac1d salt of the Actlve
126.4 a 21.1
compound of Formula I21
Microcrystalline .
Hyprome11056
Release Control 210.0 35.0
(Methocel KIOOLV)
————
a sion factor for adipate salt to free base is 0.7911
b Added after granulation
c Removed during processing
d Partial added before and partial added after granulation
25mg SR: Composition of 25 mg Sustained Release s
Component Function Weight Composition
blet) (wt%)
Adlpic ac1d salt of the Active
31.6 a 12.6
compound of Formula Ial
Microcrystamnecaulose 105.0
Hypromellose,
Hypromellose,
Release Control 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 ing 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 silicified microcrystalline cellulose
(SMCC).
Step 2. Pass the mixture in Step 1 through a le screen (for example 40
mesh).
Step 3. Screen the remaining SMCC h the same screen used in Step 2.
Step 4. Blend the screened SMCC from Step 3 along with mixture from Step 2
in a suitable blender (for example Turbula r) 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 compound of
.11 6320*
Silicified Microcrystalline Cellulose, NF
64.89
(Prosolv SMCC HD 90)
TOTAL 100.00 %
#2 Capsules, Hard Gelatin, White
Opaque
* Adipic acid salt of the compound of Formula I with salt sion 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 treatment 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 :
Treatment A: 300 mg (6 X 50 mg capsule) IR formulation of the nd 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 tablets) SR formulation of the compound
of Formula I administered orally after a high-fat meal.
The subjects in Cohort 5 received the ing 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 Formulal (25 mg
SR tablets from Example 1)) administered orally after an overnight fast of at least 10
hours.
ent B: 50 mg (2 X 25 mg tablets 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
overnight fast of at least 10 hours.
Blood samples for determination of plasma concentrations of the nd of
a 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.
Table 1: Accuracy and Precision of the Plasma Assay Quality Control
Samples
-------- Low QC --------- -—----- Middle QC ------- —-------- High QC --------
Analyte CV CV CV
Theo Accuracy Theo cy 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 control; 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 scheduled time was used ed that
there was no protocol ion noted for the collection of these samples.
Standard noncompartmental 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 ition
rate constant (M) was estimated using a near regression of the concentration data
in the terminal ition phase, and W. was estimated as ln(2)/?tz. AUCO-t was
estimated using the linear trapezoidal rule for sing concentrations and the log-
trapezoidal 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 UCo-oo, and
the al-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 crossover ANOVA
(fixed factor = treatment, sequence and period, random effect = subject (sequence)).
The adjusted 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 e) 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 statistical analysis was performed using Phoenix WinNonlin version 6.0.
presents plasma trations of the compound of Formula I (mean :
SE) for the subjects in Cohorts 1 to 4 ing 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 high-fat 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. ts 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 state), Treatment B (2 X 25 mg SR tablet with a
at 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 bioavailability (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 tablet. Table 5A and 5B summarizes mean PK
parameters for subjects in Cohort 6, the dose—normalized relative bioavailability
(reference = 100 mg SR3 tablet), and the food effect 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—
(fasted) 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 d: 1.0
300 mg IR 130 i: 72.9 2.1 4: 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
d) (1.040) 8.60 9.23
0.172
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 2.14:0.58
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
0.249
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 83/31:; 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 41435;: 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
(fasted) 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 :1: 1.34 115 :1: 32.4
d) 4:83 4.87 111
300 mg SR3 20273: 2.39 :1: 0.70 248 i— 82.8
(fasted) 2:17 2.29 236
300 mg SR3 3i5153i 3.59 :1: 1.13 165 :1: 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
d) 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
/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 Tm“, Where median
(90%
confidence interval) is reported.
Table 3B
Cohort/Treatment (1:{15/1311) (Eli/13:10) 841;]:
Geometric Mean Relative ilability 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%
(18.3%-27.4%) (21.6%-31.3%)
SR2 fed vs fasted 250% 218%
(204%-306%) (181%-262%)
SR3 fasted vs IR 45.4% 47.5%
-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.l%)
SR4 fed vs fasted 213% 215%
(171%-264%) (172%-268%)
PK ter values are mean :: SD and geometric mean except for Tm“, where median
(90% confidence interval) is reported.
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 7.73:5.2
d) 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 (1.560) 31.2 3.3
meal)
Geometric Mean Relative Bioavailability 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 (11M*h) (11M*h) (L/h)
Cohort 5
300 mg SR3 2.46d:1.13 .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 ve Bioavailability and the 90% nce Intervals
SR3 fed vs (111:;0
fasted (102A;146A>)0 0 . 0-
137%)
Pharmacokinetic parameter values are mean :: SD and geometric 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
(high-fat meal) 76.7 (1.5-6.0) 2.2
1X 100mg SR3 11 .5 1.8 3.0i1.3
(fasted) 161 (050-40) 2.7
Geometric Mean ve 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 ching Tlast within the ts
between treatments; NR = not reported because significant numbers of C1211 values were BQL.
PK parameter values are mean i SD and geometric mean except for Tm, where median (90%
confidence interval) is reported.
i) tical 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
(fasted) 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 Relative 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 66.1%”
100 mg SR3 (fasted) (57.5%-75.9‘%
NC = not calculated because of significant s of mismatching Tm within the subjects
between 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 es were similar among the subjects in Cohorts l to 4 (.
Compared to the IR formulation, following fasting single-dose administration 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 significantly reduced 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
cantly longer, ranging from 7.3 to 11 hours for 4, as compared to about
2 hours for the IR capsule, indicating that the systemic elimination of the compound
of Formula I was likely rate-limited by its absorption, which was ned 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 subjects 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 es administered in the fasted state.
For administration in the fasted state, the 4 SR tablets showed reduced relative
ilability 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 o were 36.1 %
—39.2%), 26.0% (21.6%—31.3%), 47.5% —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, respectively, among the SR formulations
tested.
Dosed in the fasted state, the intersubj ect variability as measured by percent
coefficient of variability (CV%) in plasma exposure was significantly higher for the
gastroretentive formulation SR4, but comparable among the 3 regular SR tablets
ed for intestinal release. The intersubj 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 intersubject CV% for the 100 mg SR4 tablet was 83% and 73% for
Cmax and AUCo-oo, respectively. Pooling all subjects 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 ations studied at the
300 mg (3 X 100 mg) dose level. Administered after a high-fat meal, ric mean
Cmax and o values increased by 88% and 81%, respectively, for SR1; by 158%
and 118%, tively; 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 AUCo-oo 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 Formulal
plasma exposure for SR1, SR2, and SR3, which are SR ations designed for
intra—intestinal release. For SR4, which is a gastroretentive SR formulation, 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 ormalized 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 xposure
onship for the compound of Formula I, the relative bioavailability of the 25 mg
SR tablet may be underestimated. For the 2 X 25 mg SR dose, a high-fat meal
increased nd of Formula I Cmax and AUCO—oo by 60% and 58%, respectively.
For the four SR formulations evaluated, the observed apparent disposition tvz
was able, 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 similar
among SR1, SR2, and SR4 (~10-fold) and tely higher for SR3 (~20-fold).
Overall, all 4 SR formulations demonstrated a significantly flatter PK profile
compared the IR capsule, meeting an important objective for sustained release.
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 sustained release formulations. Therefore, for SR formulations, the
extent of the compound of Formula 1 absorption as measured by the plasma AUCO—oo is
used as the primary nt to assess the relative ilability. Thus, the mean
ve 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 ations. 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 correlation 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
cant (> 2-fold increase in AUC) for the ts 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 relative 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 effect, SR3 is superior to the other
formulations.
Example 4. al Results in Phase 2a in patients with active rheumatoid
arthritis (RA)
An initial 28 day part of the study was conducted in order to select doses
moving forward, g 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
tion as in Part 1: single cohort, five parallel treatment groups, 12 subjects each:
100 mg SR3 tablets 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. m 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 compared to other JAK
inhibitors that are approved for treatment of RA. For example, the approved product
for tinib citrate (5 mg BID) showed much lower ACR scores at 3 months: 59%
(ACR20), 31% (ACR50), 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 d 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
aily dosing (600 mg QD) did not compromise efficacy compared with the BID
doses. This indicates that the once-daily dosing (such as 600 mg QD) may achieve
maximal efficacy without inducing side-effects such anemia. As shown in and
Table 6, the 600 mg QD dose has robust efficacy with l change in hemoglobin
levels.
It is believed that this efficacy/side—effect profile may be due to the QD dose
ing maximal JAKl signaling (tied to efficacy) with low JAK2 inhibition at the
trough, as JAK2 signaling is tied to hematopoiesis. This hypothesis is ted by
the PK derived JAKl (IL-6) and JAK2 (TPO) inhibition data for the nd 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 inhibition for the 200 mg
BID and 400 mg BID doses, which suggests that there may be a reduction in infection
from the QD dose.
Table 7
Dose regimen e 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 imately 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%; psoriasis area and severity
index (PASI) score of 2 5; static ian’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) ssing 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)
ted 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 treated for 28 days, the 1st group is filled
60 subjects with moderate to severe psoriasis were randomized. There were five
treatment : placebo, 100 mg QD, 200 mg QD, 200 mg BID and 600 mg QD. A
sequential method of recruitment 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 tinib (also known as tasocitinib)
showed lower PASI 50 score of 65.3% at 12 weeks (published on
http://press.pfizer.com on 10/7/2010). The 5 mg tofacitinib dose is the ed
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 % —12.5% —35.2% —42.4%
change
sPGA
% sPGA 0 33.3% 45.5%
(clear or
% 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 ssential ocythemia MF
(JAK2V617F positive or negative mutation status), platelet counts 2 50 X 109/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 m results with respect to proportion of subjects
with 2 50% reduction in total m score (TSS) in each dose group per the
modified Myelofibrosis Symptom Assessment Form ) V3.0 electronic diary
at week 12 compared with baseline (The modified MFSAF V3.0 comprises 19
ons assessing ated symptoms on a scale of 0 (absent) to 10 (worst
imaginable». a) depicts 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 percent 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 obin 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
(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 ing) 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 Exposure, 102.0 254.0 192.0
median (range) (23,519) 3)
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) 1/32 (3.1)
Example A: In vitro JAK Kinase Assay
The compound of Formula 1 herein was tested for inhibitory activity of JAK
s according to the ing in vitro assay bed in Park et al, Analytical
Biochemistry 1999, 269, 94—104. The catalytic domains 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 measuring the orylation of a biotinylated peptide. The
phosphorylated peptide was detected by homogenous time resolved fluorescence
(HTRF). ICsos of compounds were ed for each kinase in the 40 microL
ons 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 (Perkin Elmer, Boston, MA).
Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal
was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). The compound
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. Compounds can be
added to the cells in DMSO/media (final concentration 0.2% DMSO) and ted
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 kinases or potential downstream substrates such as STAT
proteins, Akt, Shp2, or Erk. These experiments can be performed following an
overnight cytokine starvation, followed by a brief ubation with compound (2
hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are
then extracted from cells and ed by techniques ar to those ed in the
art including Western blotting or ELISAs using antibodies that can differentiate
between orylated and total protein. These ments can utilize normal or
cancer cells to investigate the ty of compounds on tumor cell survival biology or
on mediators of inflammatory disease. For example, with regards to the latter,
nes 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 ially 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 inhibit these ne mediated
effects can be measured using techniques common to those schooled in the art.
Compounds herein can also be tested in cellular models designed to evaluate
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 ectopically expressed (James, C., et al. Nature
434:1144—1148; , J., et a3. JBC 280:41893—41899). Endpoints include the
effects of compounds on cell al, proliferation, and phosphorylated JAK, STAT,
Akt, or Erk proteins.
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 stic assay of immune suppression or inhibition 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 separation method and T-cells (fraction
2000) can be obtained from PBMCs by ation. Freshly isolated human s 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 96—well plates and treated
with compounds at different trations 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 CellTiter—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 genic 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 animals 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
on using implantable pumps. Tumor growth is followed over time using
calipers. Further, tumor samples can be harvested at any time after the tion of
treatment for is as described above (Example B) to evaluate compound effects
on JAK activity and downstream signaling pathways. In on, 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 Delayed Hypersensitivity Response Test
Compounds herein can also be tested for their efficacies (of inhibiting JAK
s) in the T—cell driven murine delayed hypersensitivity test model. The murine
skin contact d—type hypersensitivity (DTH) response is considered to be a valid
model of al 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
infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte
hyperproliferation. Furthermore, many classes of agents that are efficacious in
treating sis 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 antigen nitro-fluorobenzene (DNFB). On day 5, ears
are measured for thickness using an engineer’s micrometer. This ement is
recorded and used as a baseline. Both of the animals’ ears are then challenged by a
topical application 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 seventy—two
hours after the challenge, ears are measured again. ent with the test
nds is given throughout the sensitization and challenge phases (day -l to day
7) or prior to and throughout the challenge phase ly afternoon of day 4 to day
7). Treatment of the test compounds (in ent 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
comparing to the situation without the ent. Compounds 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 histochemical analysis. Activation of
the JAK-STAT pathway(s) results in the formation and translocation of functional
transcription factors. r, the influx of immune cells and the increased
eration of keratinocytes should also provide unique expression profile changes
in the ear that can be investigated and quantified. in fixed and n
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 compounds and the dexamethasone can e similar
transcriptional changes both qualitatively and quantitatively, and both the test
nds and dexamethasone can reduce the number of infiltrating cells. Both
systemically and l 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 inflammation response. For instance, rodent models
of tis can be used to te the therapeutic potential of compounds dosed
preventatively or therapeutically. These models include but are not limited to mouse
or rat collagen—induced arthritis, rat nt-induced arthritis, and collagen antibody-
induced arthritis. Autoimmune diseases including, but not limited to, multiple
sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis,
immunoglobulin nephropathies, myocarditis, airway sensitization (asthma), lupus, or
colitis may also be used to evaluate the therapeutic potential of compounds herein.
These models are well ished in the research community and are familiar to those
schooled in the art (Current Protocols in Immunology, 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 preclinical 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 amine mouse model (subcutaneous or
transdermal), the numn 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., Experimental Eye Research
2004, 79, 613—621 and Schrader 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 e tear tion. ty 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 autoimmune uveitis (EAU) and endotoxin induced uveitis (EIU). EAU
experiements may be performed in the rabbit, rat, or mouse and may involve passive
or activate immunization. For instance, any of a number or retinal ns may be
used to ize animals to a nt immunogen after which animals may be
challenged ocuarly with the same antigen. The EIU model is more acute and involves
local or systemic 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 tis/episcleritis, chorioditis, cyclitis, or iritis and
are therefore useful in igating the potential activity of compounds for the
therapeutic treatment of these diseases.
Agents may also be evaluated in one or more preclinical 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 ragweed (reviewed 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 r 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. systemic or topical) which may begin prior to or after
measurable disease exists. Endpoints for such studies may include, for e,
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 various 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 ling and/or density (W.S.S. Jee and W. Yao, J
oskel. Nueron. ct, 2001, 1(3), 193—207, which is incorporated herein by
reference in its entirety). Alternatively, bone y and architecture may be
evaluated in control or compound treated rodents in models of therapy (e.g.
glucocorticoid) induced osteopenia (Yao, et a1. Arthritis and tism, 2008,
58(6), 3485-3497; and id. 58(11), 1674-1686, both of which are incorporated herein
by reference in its entirety). In addition, the effects of nds on bone resorption
and density may be ble in the rodent models of arthritis discussed above
(Example E). Endpoints for all these models may vary but often include histological
and radiological assessments as well as immunohisotology and riate
biochemical markers of bone remodeling.
Claims (9)
1. A sustained release composition, sing: (i) {1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H- pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a ceutically acceptable salt thereof; (ii) a first hypromellose characterized by having an apparent viscosity at a concentration of 2% in water of 80 cP to 120 cP; (iii) a second hypromellose, characterized by having an apparent viscosity at a concentration of 2% in water of 3000 cP to 5600 cP, wherein the composition comprises 8% to 20% of the first and second hypromelloses; (iv) 16% to 22% by weight of microcrystalline cellulose; and (v) 45% to 55% by weight of lactose monohydrate.
2. The sustained release composition according to claim 1, wherein the composition comprises 10% to 15% by weight of the one or more hypromelloses.
3. The sustained release composition according to claim 1 or claim 2, wherein the ition comprises 0.3% to 0.7% by weight of magnesium stearate.
4. A sustained release composition, comprising: (i) 100 mg on a free base basis of {1-{1-[3-fluoro (trifluoromethyl)isonicotinoyl]piperidinyl}[4-(7H-pyrrolo[2,3- midinyl)-1H-pyrazolyl]azetidinyl}acetonitrile, or a ceutically acceptable salt thereof; (ii) a first ellose characterized by having an apparent viscosity at a concentration of 2% in water of 80 cP to 120 cP; (iii) a second hypromellose, characterized by having an apparent viscosity at a concentration of 2% in water of 3000 cP to 5600 cP, wherein the composition comprises 10% to 15% of the first and second hypromelloses; (iv) 16% to 22% by weight of microcrystalline cellulose; and (v) 45% to 55% by weight of e monohydrate.
5. The sustained release composition according to any one of claims 1 to 4, wherein oral administration of one or more of the sustained release compositions to a fasted dual provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma concentration (C12h) of {1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4- (7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile of 9 to 40.
6. The ned e composition according to any one of claims 1 to 4, wherein oral administration of one or more of the sustained release compositions to a fasted individual provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma tration (C12h) of {1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidinyl}[4- (7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile of 15 to 30.
7. The ned release composition according to any one of claims 1 to 6, wherein oral administration of one or more of the sustained release compositions to an individual after a at meal provides a ratio of mean peak plasma concentration (Cmax) to mean 12-hour plasma concentration (C12h) of {1-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin [4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile of 10 to 70.
8. The sustained release composition according to any one of claims 1 to 6, wherein oral administration of one or more of the sustained release compositions 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-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin yl}[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile of 15 to 50.
9. The sustained release composition ing to any one of claims 1 to 6, wherein oral administration of one or more of the sustained release compositions 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-{1-[3-fluoro(trifluoromethyl)isonicotinoyl]piperidin yl}[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]azetidinyl}acetonitrile of 25 to 45.
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NZ717230A NZ717230B2 (en) | 2013-08-07 | 2014-08-06 | Sustained release dosage forms for a jak1 inhibitor |
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