Note: Descriptions are shown in the official language in which they were submitted.
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DISPERSIBLE FORMULATIONS OF N-((R)-2,3 -DIHYDROXYPROPDXY)-
3 ,4-DIFLUOR0-2-(2-FLUOR0-4-IODO-PHENYLAMINO)-BENZAMIDE AND
USES THEREOF
FIELD OF THE INVENTION
[0001] The present disclosure relates to dispersible formulations of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide for
use in
administration to patients in need thereof, and methods of producing such
dispersible
formulations. The present disclosure further relates to dispersible
formulations
comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; methods of producing dispersible formulations
comprising N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
and methods and uses of treating a tumor, a cancer, or a Rasopathy disorder by
administering N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide to a subject in need thereof.
BACKGROUND
[0002] Neurofibromatosis Type 1 ("NF I") is characterized by diverse,
progressive
cutaneous, neurological, skeletal and neoplastic manifestations with no
standard drug
treatment options available. Neurofibromas are benign peripheral nerve sheath
tumors
comprised of a mixture of Schwann cells, fibroblasts, perineuri al cells, and
mast cells and
occur in 20 to 50% of NFI patients (Tucker, et al. (2011) J. Histochem.
Cytochem.
59(6).584-590). When a neurofibroma extends longitudinally along a nerve and
involves
multiple fascicles, it is classified as a plexiform neurofibroma (PN).
Plexiform
neurofibromas rarely regress spontaneously, and in many patients their growth
is
relentless. Plexiform neurofibromas represent a major cause of morbidity and
disfigurement in individuals with NF1, and when symptomatic, are associated
with
increased mortality (Rasmussen, et al. (2001) Am. J. Hum. Genet. 68(5):1110-
1118;
Prada, et al. (2012) J. Pediat. 160(3):461-467). As tumor growth progresses,
such lesions
produce dysfunction, pain, and cosmetic disfigurement and can compress the
airway or
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spinal cord. Furthermore, PNs have the potential to undergo malignant
transformation
producing malignant peripheral nerve sheath tumors (MPNSTs).
[0003] Previous longitudinal retrospective studies have demonstrated
age dependent
differences in plexiform neurofibromas, with high inverse correlation of PN
growth to
patient age (Dombi, et al. (2007) Neurology. 68(9):643-647; Nguyen, et al.
(2012)
Orphanet J. rare Dis. 7(75); Tucker, et al. (2008) Am. J. Med. Genet. 46:81-
85). In a
retrospective review, Tucker et al. analyzed serial MRIs of 34 patients
(median 10 years
of age, range 1 to 47 years) with a measurable PN for a median follow-up
length of 6
years (range 1 to 15 years). This study observed that the difference between
the initial and
final two-dimensional estimated tumor size was significantly greater in
younger
individuals compared to older individuals; 3.2 cm2 vs 0.2 cm2., respectively
(p = 0.031). In
addition, the growth rate of tumors in patients < 10 years of age (0.7
cm2/year) was
significantly greater than that of tumors in patients > 10 years of age (0.03
cm2/year, p =
0.014). Similarly, in an observational study of 49 patients 3 to 25 years of
age (median
8.3 years), Dombi et al. observed that PN volume increased more rapidly than
body
weight over time (p = 0.026). Furthermore, there was a tendency for patients
younger
than the median age of 8.3 years to have a greater increase in PN volume per
year vs
older children; 21.1% vs 8.4% volume change per year, respectively (p =
0.001). This
trend holds true when PN growth rate is expressed relative to the rate of
increase in body
size.
[0004] Based on the findings of Tucker and Dombi, Nguyen et al.
conducted a
retrospective study of 71 patients with an evaluable PN for a median follow-up
of 2.2
years (range 1.1 to 4.9 years). The rate of growth of the individual tumors
was inversely
correlated with age at initial examination (Spearman's rho = -0.33, p <
0.001), but not
with the tumor volume on initial MRI examination. Also, tumors that grew more
than
20% per year were significantly more frequent among children than among adults
(p <
0.001). In summation, findings from three independent retrospective reviews of
PN
volume clearly show that the growth rate of PNs in NF1 patients is inversely
correlated
with age, indicating discrete age dependent tumor differences and an unmet
need in the
pediatric population.
[0005] These observations suggest that the youngest patients could
receive the greatest
clinical benefit from therapy. However, the youngest potential patients with
an urgent
medical need for treatment may struggle to receive treatment due to the
inability to
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swallow a whole capsule or tablet. Therefore, there is a need for an age-
appropriate
pediatric formulation that permits accurate dosing and enhanced adherence to
optimize
efficacy and safety in this population.
[0006] Moreover, any patient in need of treatment but who experiences
difficulty
swallowing ("dysphasia") would benefit from a non-capsule or tablet
formulation which
can be orally administered. Dysphagia can be caused by a variety of
circumstances
affecting one or more components of the swallowing process. These can include
but are
not limited to: physical damage to the tongue, pharynx, larynx, esophagus, or
trachea
caused by trauma, infection, proliferative disease; treatment for a such a
condition;
congenital anatomical defects such as cleft palate; underdevelopment at young
age;
weakening at old age; dementia, memory loss, or cognitive decline; or any
condition
which otherwise weakens or damages the muscles or nerves used in the
swallowing
process, such as Parkinson's disease, stroke, or nervous system disease.
[0007] N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide ("mirdametinib", or "PD-0325901") is a small molecule drug which has
been
designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1") and
mitogen-
activated protein kinase kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that
play key
roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The
MAPK
pathway is critical for cell survival and proliferation, and overactivation of
this pathway
has been shown to lead to tumor development and growth. Mirdametinib is a
highly
potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2.
By
virtue of its mechanism of action, mirdametinib leads to significantly
inhibited
phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2,
thereby
leading to impaired growth of tumor cells both in vitro and in vivo In
addition, evidence
indicates that inflammatory cytokine-induced increases in MEK/ERK activity
contribute
to the inflammation, pain, and tissue destruction associated with rheumatoid
arthritis and
other inflammatory diseases.
[0008] Crystal forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-
phenylamino)-benzamide have been described previously. W02002/006213 describes
crystalline Forms I and II, and is incorporated by reference. Form I is
characterized by an
XRF'D containing peaks at one or more of 10.6, 13.7, 19.0, and 23.7 degrees
20; Form II
is characterized by an XRPD containing peaks at 5.5 and/or 19.6 degrees 20.
Form I is
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characterized by a melting point at about 117 C-118 C, and Form II is
characterized as
melting at 89 C-90 C, as determined by DSC.
[0009] U. S . Patent No. 7,060,856 ("the '856 patent") describes a
method of producing
Form IV, and is incorporated by reference. The '856 patent indicates that the
material
produced by this method was greater than 90% Form IV (The '856 patent, Example
1).
The '856 patent also states that the differential scanning calorimetry ("DSC")
of the
material produced shows an onset of melting at 110 C, as well as a small peak
with an
onset at 117 C, consistent with the material being a mixture of two forms.
Compositions
containing more than one polymorphic form are generally undesirable because of
the
potential of interconversion of one polymorphic form to another. Polymorphic
interconversion can lead to differences in the effective dose or physical
properties
affecting processability of a drug, caused by differences in solubility or
bioavailability.
[0010] There is a need for a dispersible formulation of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide which is safely
administrable to
patients who have difficulty swallowing full capsules or tablets (e.g.,
pediatric patients or
patients suffering from dysphagia), for use in treatment of a tumor, a cancer,
or a
Rasopathy disorder. Given the apparent mixture of forms in previously
disclosed Form
IV, there is a need for dispersible formulations containing essentially pure
Form IV of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide to
limit polymorphic interconversion between forms which may affect solubility
and
bioavailability.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. lA is a X-ray powder diffraction pattern ("XM3D")
corresponding to
essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide.
[0012] FIG. 1B is a thermogravimetric analysis thermogram ("TGA'') and
a differential
scanning calorimetry thermogram ("DSC") corresponding to essentially pure
crystalline
Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-b enzamide.
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100131 FIG. 2 is an XRPD corresponding to a batch of essentially pure
Form IV of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide as
initially prepared and an XRPD of a known reference standard of Form IV.
[0014] FIG. 3A is an XRPD corresponding to essentially pure Form IV of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after
storage for 68 months after production at 25 C and <65% relative humidity.
[0015] FIG. 3B is an XRPD corresponding to essentially pure Form IV of
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide after
storage for 140 months after production at 25 C and <65% relative humidity.
BRIEF SUMMARY OF THE INVENTION
[0016] The present disclosure features useful compositions for treating
disorders whereby
aberrant MEK1 or 1VIEK2 activity is implicated, e.g., a tumor, a cancer, or a
Rasopathy
disorder, such as neurofibromatosis type 1, in a subject in need thereof. In
some aspects,
the methods and compositions described herein are useful in treating patients
who
struggle to swallow whole capsules or tablets, e.g., pediatric patients or
subjects suffering
from dysphagia, such as patients with esophageal cancer, Parkinson's disease,
amyotrophic lateral sclerosis, stroke, achalasia, or esophageal narrowing. In
some aspects,
the compositions comprise Form I, Form II, or Form IV of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
Pharmaceutical Composition
[0017] In some aspects, the present disclosure is directed to a
pharmaceutical
composition comprising an amount of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide of Formula (I)
HOO N
OH
õ
r- -F
(I),
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wherein the pharmaceutical composition is dispersible in a potable liquid.
(e.g., water) or
orodispersible in a subject's saliva.
[0018] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide in the pharmaceutical compositions described
herein is
crystalline. In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is selected from the group
consisting of: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having
peaks
at 4.6 0.2, 7.3 0.2, and 14.6 0.2 degrees two theta; (b) a crystalline
form of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
characterized by an XRPD pattern having peaks at 10.6 0.2, 13.7 0.2, 19.0
0.2, and
23.7 + 0.2 degrees two theta; and (c) a crystalline form of N#R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an
XRPD
pattern having peaks at 5.5 0.2 and 19.6 0.2 degrees two theta.
[0019] In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 4.6 0.2, 7.3 0.2, and 14.6 0.2 degrees two
theta. In some
aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks
at 4.6
0.2, 7.3 0.2, 14.6 0.2, and 25.0 0.2 degrees two theta.
[0020] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern substantially as shown in FIG. 1A.
[0021] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC
profile
which does not include an endotherm with an onset at about 117 C.
[0022] In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by one or
both of:
(a) a TGA profile substantially as shown in FIG. 1B; and/or (b) a DSC profile
substantially as shown in FIG. 1B.
[0023] In some aspects, the crystalline form of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide does not contain any amount
of
Form 1 or Form 11 detectable by XRPD and/or DSC.
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100241 In some aspects, the crystalline form N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-iodo-phenyl amino)-benzami de is anhydrous.
[0025] In some aspects, the crystalline form N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IV. In some aspects, the
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is essentially pure Form IV.
[0026] In some aspects, the essentially pure Form IV of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD
pattern
and/or DSC profile which is substantially unchanged after storage for 3 months
at
standard warehouse conditions (15 C-25 C and <65% relative humidity). In some
aspects, the essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC
profile
which is substantially unchanged after storage for 6 months at standard
warehouse
conditions (15 C-25 C and <65% relative humidity). In some aspects, the
essentially pure
Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for 1 year at standard warehouse
conditions (15 C-
25 C and <65% relative humidity). In some aspects, the essentially pure Form
IV of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
exhibits an XRPD pattern and/or DSC profile which is substantially unchanged
after
storage for 68 months at standard warehouse conditions (15 C-25 C and <65%
relative
humidity). In some aspects, the essentially pure Form IV of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits an
XRPD pattern and/or DSC profile which is substantially unchanged after storage
for >140
months at standard warehouse conditions (15 C-25 C and <65% relative
humidity). In
some aspects, the essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern
and/or
DSC profile which is substantially unchanged after storage for >14 years at
standard
warehouse conditions (15 C-25 C and <65% relative humidity).
[0027] In some aspects, the XRPD pattern is generated using a
PANALYTICAL X'Pert
Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step
size of
0.03 20 with a X'CELERATOR Real Time Multi-Strip detector, configured (a) on
the
incidental beam side as follows: variable divergence slits (10 mm irradiated
length), 0.04
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rad Soller slits, fixed anti-scatter slit (0.500), and 10 mm beam mask, and
(b) on the
diffracted beam side as follows: variable anti-scatter slit (10 mm observed
length) and
0.04 rad Soller slit or a BRUKEle D8 ADVANCETM system using Cu Ka (40 kV/40
mA) radiation and a step size of 0.03 20 with a LYNXEYE" detector, configured
(a) on
the incidental beam side as follows: Goebel mirror, mirror exit slit (0.2 mm),
2.5 Soller
slit, beam knife, and (b) on the diffracted beam side as follows: anti-scatter
slit (8 mm)
and 2.5 Soller slit; wherein samples are mounted flat on zero-background Si
wafers. In
some aspects, the DSC pattern is generated using a TA Instruments Q100 or
Q2000
differential scanning calorimeter at a rate of temperature increase of about
15 C/min.
[0028] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.6 0.2, 13.7 0.2, 19.0 0.2, and 23.7 0.2
degrees two
theta In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 10.6 0.2, 13.7 0.2, 14.6 0.2, 17.3 0.2, 18.0
0.2, 18.2
0.2, 19.0 0.2, 19.3 0.2, 20.1 0.2, 21.0 0.2, 21.9 0.2, 22.4 0.2,
23.7 0.2, 24.0
0.2, 24.9 0.2, 26.3 0.2, 27.6 0.2, 28.0 0.2, 30.1 0.2, 32.1 0.2,
32.3 0.2,
32.9 0.2, 35.8 0.2, and 37.7 0.2 degrees two theta.
[0029] In some aspects, the crystalline form N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by a DSC profile
with an
endotherm with onset at about 117 C.
[0030] In some aspects, the crystalline form N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form I.
[0031] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.5 0.2 and 19.6 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5
0.2,
10.7 0.2, 16.5 0.2, 19.6 0.2, 22.0 0.2, 22.5 0.2, 23.6 0.2, 24.1
0.2, 25.0
0.2, 26.2 0.2, 27.6 0.2, 29.1 0.2, 30.5 0.2, 31.7 0.2, 33.3 0.2,
and 39.0 0.2
degrees two theta.
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100321 In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
di fluoro-2-(2-fluoro-4-i odo-phenylamino)-benzamide is characterized by a DSC
profile
with an endotherm with onset at about 87 C.
[0033] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form II.
[0034] In some aspects, the pharmaceutical composition further
comprises one or more
pharmaceutically acceptable carriers.
[0035] In some aspects, the pharmaceutical composition is for oral
administration. In
some aspects, the pharmaceutical composition is dispersible. In some aspects,
the
pharmaceutical composition is orodispersible.
[0036] In some aspects, the pharmaceutical composition is a tablet, a
powder, granules,
minitablets, or pellets (also called beads).
[0037] In some aspects, the pharmaceutical composition is a powder. In
some aspects,
the pharmaceutical composition is a dispersible powder. In some aspects, a
capsule or
sachet comprises the dispersible powder.
[0038] In some aspects, the pharmaceutical composition is in the form
of granules. In
some aspects, the granules are dispersible granules. In some aspects, a
capsule or sachet
comprises the dispersible granules.
[0039] In some aspects, the pharmaceutical composition is in the form
of minitablets. In
some aspects, the minitablets are dispersible minitablets. In some aspects, a
capsule or
sachet comprises the dispersible minitablets.
[0040] In some aspects, the pharmaceutical composition is in the form
of pellets. In some
aspects, the pellets are dispersible pellets. In some aspects, a capsule or
sachet comprises
the dispersible pellets
[0041] In some aspects, the pharmaceutical composition is a tablet. In
some aspects, the
tablet is a dispersible tablet. In some aspects, the tablet is an
orodispersible tablet.
[0042] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7
wt/wt% of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1
wt/wt% to
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about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners; and
(0 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0043] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.2 wt/wt% to about 1.5
wt/wt% of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 75 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 3
wt/wt% to
about 8 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of
one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners; and
(0 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0044] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2
wt/wt% of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5
wt/wt% to
about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more
sweeteners; and
(0 about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
[0045] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition
comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 2 mg of N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
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dispersible minitablets, or dispersible pellets comprises about 3 mg of N-((R)-
2,3-
di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de.
In some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 4 mg
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide.
[0046] In some aspects, at least one of the diluents is selected from
the group consisting
of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose,
starch,
pregelatinized starch, calcium sulfate, calcium carbonate and dibasic calcium
phosphate.
In some aspects, at least one of the diluents is microcrystalline cellulose.
[0047] In some aspects, at least one of the disintegrants is selected
from the group
consisting of croscarmellose sodium, sodium starch glycolate, crospovidone,
microcrystalline cellulose, starch, pregelatinized starch, low substituted
hydroxypropyl
cellulose, and alginic acid. In some aspects, at least one of the
disintegrants is
croscarmellose sodium.
[0048] In some aspects, at least one of the flavoring agents is
selected from the group
consisting of natural or synthetic flavors including but not limited to, grape
flavoring,
bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring,
strawberry
flavoring, raspberry flavoring, mint flavoring, peppermint flavoring,
grapefruit flavoring,
pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring,
banana flavoring,
or cherry flavoring. In some aspects, at least one of the flavoring agents is
grape
flavoring.
[0049] In some aspects, at least one of the sweeteners is selected from
the group
consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol,
sorbitol,
glucose, fructose, and aspartame. In some aspects, at least one of the
sweeteners is
sucralose.
[0050] In some aspects, at least one of the lubricants is selected from
the group consisting
of magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax,
colloidal
silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glycerol
dibehenate,
and talc. In some aspects, at least one of the lubricants is magnesium
stearate.
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Methods of Treatment
[0051] In some aspects, the present disclosure provides a method of
treating a tumor, a
cancer, or a Rasopathy disorder comprising administering to a subject in need
of such
treatment a pharmaceutical composition (e.g., a dispersible tablet, a
dispersible powder,
dispersible granules, dispersible mintablets, or dispersible pellets)
described herein.
[0052] In some aspects, the present disclosure provides use of a
pharmaceutical
composition (e.g., a dispersible tablet, a dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets) described herein for the
manufacture of a
medicament for treating a tumor, a cancer, or a Rasopathy disorder.
[0053] In some aspects, the tumor is a neurofibroma. In some aspects,
the tumor is a
neurofibroma associated with Neurofibromatosis Type 1. In some aspects, the
tumor is
selected from the group consisting of cutaneous neurofibroma, plexiform
neurofibroma,
optic pathway glioma, low-grade glioma, high-grade glioma, or malignant
peripheral
nerve sheath tumor. In some aspects, the tumor is plexiform neurofibroma.
[0054] In some aspects, the subject has been diagnosed with a Rasopathy
disorder
selected from the group consisting of neurofibromatosis type 1,
neurofibromatosis type 2,
cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan
syndrome, and Noonan syndrome with multiple lentigines.
[0055] In some aspects, the cancer is selected from the group
consisting of skin cancer,
malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic
neoplasm,
lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer,
thyroid cancer,
cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,
sarcoma, bladder
cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid
cystic
carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer,
pancreatic
cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous
carcinoma of the
peritoneum. In some aspects, the leukemia is selected from the group
consisting of acute
lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic
leukemia, and
chronic myelogenous leukemia. In some aspects, the lymphoma is selected from
the
group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,
follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the
lung
cancer is selected from the group consisting of lung adenocarcinoma, squamous
non-
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small cell lung cancer, non-squamous non-small cell lung cancer, and small
cell lung
cancer,
[0056] In some aspects, the subject bears a mutation or other
aberration in one or more
genes for which the mutation or other aberration causes a gain or loss of
function
characteristic of certain cancers, wherein the mutation or other aberration in
one or more
genes is a mutation or other aberration in one or more of KRAS, NRAS, BRAS,
BRAF,
MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0057] In some aspects, an individual dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more
than one
dispersible tablet, more than one dose of dispersible powder, more than one
dose of
dispersible granules, more than one dose of dispersible minitablets, more than
one dose of
dispersible pellets, or a combination thereof. For example, a dose of 3 mg of
the N-((R)-
2,3-dihydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-iodo-phenyl amino)-benzami
de can be
administered as two dispersible tablets ¨ one containing 2 mg and the other
containing 1
mg or as three dispersible tablets each containing 1 mg. As another example, a
dose of 1.5
mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide can be administered as two dispersible dosage forms ¨ one
dispersible tablet
containing 1 mg and a separate unit of dispersible powder containing 0.5 mg or
as three
units of dispersible powder each containing 0.5 mg.
[0058] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
mg In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed 8
mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 6 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 2 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 1 mg.
[0059] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a)
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21 days in which the total daily dose is administered; and (b) 7 days in which
no N-((R)-
2,3 -di hydroxypropoxy)-3 ,4-di fluoro-2-(2-fluoro-4-iodo-phenyl amino)-
benzami de is
administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising (a) 21 consecutive days in which the total daily dose is
administered;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. In some
aspects,
the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day
periods
each comprising (i) 5 days in which the total daily dose is administered and
(ii) 2 days in
which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered. In some aspects, the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) three 7-day periods each
comprising (i) 5 consecutive days in which the total daily dose is
administered and (ii) 2
consecutive days in which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0060] In some aspects, the 28-day dosing cycle is repeated up to a
total of 24
consecutive 28-day dosing cycles.
[0061] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising 28
days in which the total daily dose is administered.
[0062] In some aspects, the subject experiences dysphagia. In some
aspects, the subject
experiences dysphagia caused by one or more of: disease of the nervous system,
muscle
weakening, developmental disability, stroke, injury, anatomical defect,
cancer, treatment
for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
[0063] In some aspects, the subject is a pediatric subject.
[0064] In some aspects, the total daily dose of N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times
daily. In
some aspects, the total daily dose of the N -((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
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fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
0.1 mg to about 10 mg each. In some aspects, the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.25 mg each. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 0.5
mg each.
In some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a
dose of
about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each. In some aspects,
the total daily
dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzami de is administered two times daily at a dose of about 4
mg each. In
some aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two
times daily
at a dose of about 10 mg each.
[0065] In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily.
In some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 0.1
mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.5 mg. In some aspects, the total
daily dose of
the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered once daily at a dose of about 1 mg. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 4
mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
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of about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de is administered once
daily at a
dose of about 10 mg In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 20 mg.
[0066] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
20 mg. In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed
mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed 8
mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 6 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 4 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 2 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is administered in a total daily dose that does not
exceed 1 mg.
Method of Manufacturing a Pharmaceutical Composition
[0067] In some aspects, the present disclosure provides a method of
manufacturing a
pharmaceutical composition, the method comprising forming a pharmaceutical
composition described herein.
Definitions
[0068] To facilitate understanding of the disclosure set forth herein,
a number of terms
are defined below.
[0069] Generally, the nomenclature used herein and the laboratory
procedures in organic
chemistry, medicinal chemistry, and pharmacology described herein are those
well-
known and commonly employed in the art. Unless defined otherwise, all
technical and
scientific terms used herein generally have the same meaning as commonly
understood by
one of ordinary skill in the art to which this disclosure belongs
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[0070] In this specification and the appended claims, the singular
forms "a," "an" and
"the" include plural referents unless the context clearly dictates otherwise.
The terms ''a"
(or "an"), as well as the terms "one or more," and "at least one" can be used
interchangeably herein. In certain aspects, the term "a" or "an" means
"single." In other
aspects, the term "a" or "an" includes "two or more" or "multiple."
[0071] Furthermore, "and/or" where used herein is to be taken as
specific disclosure of
each of the two specified features or components with or without the other.
Thus, the term
"and/or" as used in a phrase such as "A and/or B" herein is intended to
include "A and B,"
"A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in
a phrase
such as "A, B, and/or C" is intended to encompass each of the following
aspects: A, B,
and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A
(alone); B
(alone); and C (alone).
[0072] The terms "mirdametinib- and "PD-0325901" refer to the single
enantiomer N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide.
[0073] The term "subject" refers to an animal, including, but not
limited to, a primate
(e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The
terms "subject"
and "patient" are used interchangeably herein in reference, for example, to a
mammalian
subject, such as a human subject.
[0074] The term "pediatric" refers to a human subject under the age of
21 years at the
time of treatment. The term "pediatric" can be further divided into various
subpopulations
including: neonates (from birth through the first 28 days of life); infants
(29 days of age
to less than two years of age); children (two years of age to less than 12
years of age); and
adolescents (12 years of age through 21 years of age (up to, but not
including, the twenty-
second birthday)). See, e.g., Berhman R E, Kliegman R, Arvin AM, Nelson W E.
Nelson
Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996;
Rudolph
A M, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and
Avery M
D, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
Younger
pediatric patients in particular, such as neonates, infants and young
children, can have
difficulty swallowing whole capsules or tablets.
[0075] The term "dispersible" as used herein refers to a composition
(e.g., a tablet,
powder, granules, minitablets, or pellets) which disintegrates and/or
dissolves when
combined with water or another potable liquid (e.g., a non-water beverage), or
a subject's
own saliva when placed in the subject's mouth, with or without the addition of
agitation
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or temperature modification. In some aspects, the dispersible composition
disintegrates or
dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5
minutes, 4
minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or
another
potable liquid. Such disintegration or dissolution need not be complete. For
example, a
dispersible tablet may dissolve almost entirely, but some undissolved
particulate matter
may remain.
[0076] The term "orodispersible" refers to a composition which is
capable of dissolving
or disintegrating in a subject's mouth (i.e., dissolving or disintegrating in
a subject's
saliva) if administered orally, without a requirement of first dissolving or
disintegrating in
a separate container.
[0077] As used herein, the terms "treat," "treated," and "treating"
mean both therapeutic
treatment and prophylactic or preventative measures wherein the object is to
prevent or
slow down (lessen) an undesired physiological condition, disorder, or disease,
or obtain
beneficial or desired clinical results. Thus, those in need of treatment
include those
already diagnosed with or suspected of having the disorder. Beneficial or
desired clinical
results include, but are not limited to, alleviation of symptoms, diminishment
of the
extent of a condition, disorder, or disease; stabilized (i.e., not worsening)
state of
condition, disorder, or disease; delay in onset or slowing of condition,
disorder, or disease
progression; amelioration of the condition, disorder, or disease state or
remission
(whether partial or total), whether detectable or undetectable; an
amelioration of at least
one measurable physical parameter, not necessarily discernible by the patient;
or
enhancement or improvement of condition, disorder, or disease. Treatment
includes
eliciting a clinically significant response without excessive levels of side
effects.
Treatment also includes prolonging survival as compared to expected survival
if not
receiving treatment. The term "therapeutically effective amount" is meant to
include the
amount of a compound that, when administered, is sufficient to prevent
development of,
or alleviate to some extent, one or more of the symptoms of a disorder,
disease, or
condition being treated. The term "therapeutically effective amount" also
refers to the
amount of a compound that is sufficient to elicit the biological or medical
response of a
cell, tissue, system, animal, or human, which is being sought by a researcher,
veterinarian,
medical doctor, or clinician.
[0078] In certain aspects, a subject is successfully "treated" for a
tumor, according to the
methods described herein if the patient shows one or more of the following: a
reduction in
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the size of the tumor; relief of one or more symptoms associated with the
specific tumor;
a reduction in the volume of the tumor; improvement in quality of life;
increased
progression-free survival (PFS), disease-free survival (DFS), overall survival
(OS),
metastasis-free survival (MFS), complete response (CR), minimal residual
disease
(MRD), partial response (PR), stable disease (SD), a decrease in progressive
disease
(PD), an increased time to progression (TTP), or any combination thereof In
some
aspects, nationally or internationally accepted standards of treatment
outcomes in a given
tumor can be used to determine whether an effective amount of mirdametinib
meets any
of these particular endpoints (e.g., CR, PFS, PR).
[0079] In certain aspects, a subject is successfully "treated" for
cancer, e.g., lung cancer
or ovarian cancer, according to the methods described herein if the patient
shows one or
more of the following: a reduction in the number of or complete absence of
cancer cells;
relief of one or more symptoms associated with the specific cancer; reduced
morbidity
and mortality; improvement in quality of life; increased progression-free
survival (PFS),
disease-free survival (DFS), overall survival (OS), metastasis-free survival
(MFS),
complete response (CR), minimal residual disease (MRD), partial response (PR),
stable
disease (SD), a decrease in progressive disease (PD), an increased time to
progression
(TTP), or any combination thereof In some aspects, nationally or
internationally accepted
standards of treatment outcomes in a given cancer can be used to determine
whether an
effective amount of mirdametinib meets any of these particular endpoints
(e.g., CR, PFS,
PR).
[0080] The terms "pharmaceutically acceptable carrier,"
"pharmaceutically acceptable
excipient," "physiologically acceptable carrier," or "physiologically
acceptable excipient"
refer to a pharmaceutically acceptable material, composition, or vehicle, such
as a liquid
or solid excipient, solvent, or encapsulating material. In one aspect, each
component is
"pharmaceutically acceptable" in the sense of being compatible with the other
ingredients
of a pharmaceutical formulation, and suitable for use in contact with the
tissue or organ of
humans and animals without excessive toxicity, irritation, allergic response,
immunogenicity, or other problems or complications, commensurate with a
reasonable
benefit/risk ratio. See Remington: The Science and Practice of Pharmacy, 21st
Edition,
Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of
Pharmaceutical
Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the
American
Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives,
3rd
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Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical
Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL,
2004
(incorporated herein by reference). Excipients can include, for example:
antiadherents,
antioxidants, binders, coatings, compression aids, disintegrants, dyes
(colors), emollients,
emulsifiers, fillers (diluents), film formers or coatings, flavors,
fragrances, glidants (flow
enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or
dispersing
agents, sweeteners, and waters of hydration. Exemplary excipients include, but
are not
limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium
phosphate
(dibasic), calcium stearate, calcium sulfate, croscarmellose, crosslinked
polyvinyl
pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin,
hydroxypropyl
cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate,
maltitol,
mannitol, methionine, methylcellulose, methyl paraben, microcrystalline
cellulose,
polyethylene glycol, polyvinyl pyrrolidone, povi done, pregelatinized starch,
propyl
paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl
cellulose,
sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic
acid, sucrose, talc,
titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
[0081] The term "pharmaceutical composition," as used herein,
represents a composition
containing a compound described herein formulated with a pharmaceutically
acceptable
excipient or a combination of multiple pharmaceutically acceptable excipients,
and can be
manufactured or sold with the approval of a governmental regulatory agency as
part of a
therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical
compositions can be formulated, for example, for oral administration in unit
dosage form
(e.g., a tablet (e.g., dispersible tablet), powder (e.g., dispersible powder)
capsule,
granules, minitablets, pellets, caplet, gelcap, or syrup)
[0082] The terms "about" or "approximately" means within a range of an
acceptable error
for a particular value as determined by one of ordinary skill in the art,
which depends in
part on how the value is measured or determined. In some aspects, the term
"about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In some
aspects, the term
"about" or "approximately" means a quantity, level, value, number, frequency,
percentage, dimension, size, amount, weight or length that varies by as much
as 30, 25,
20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level,
value, number,
frequency, percentage, dimension, size, amount, weight or length.
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[0083] As used herein, the term "administration" refers to the
administration of a
composition (e.g., a compound or a preparation that includes a compound as
described
herein) to a subject or system. Administration to an animal subject (e.g., to
a human) can
be by any appropriate route, such as one described herein.
[0084] The term "crystalline," as used herein, refers to a solid state
form which consists
of orderly arrangement of structural units. Different crystalline forms of the
same
compound, or a salt, hydrate, or solvate thereof, arise from different packing
of the
molecules in the solid state, which results in different crystal symmetries
and/or unit cell
parameter. Different crystalline forms usually have different X-ray
diffraction patterns,
infrared spectra, melting points, density, hardness, crystal shape, optical
and electrical
properties, stability, and solubility. See, e.g., Remington's Pharmaceutical
Sciences, 18"
ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia,
23rd ed.,
1843-1844 (1995) (incorporated herein by reference).
[0085] Crystalline forms are commonly characterized by X-ray powder
diffraction
(XRPD). An XRPD pattern of reflections (peaks, typically expressed in degrees
2-theta)
is commonly considered a fingerprint of a particular crystalline form. The
relative
intensities of the XRPD peaks can widely vary depending on, inter alia, the
sample
preparation technique, crystal size distribution, filters, the sample mounting
procedure,
and the particular instrument employed. In some instances, new peaks may be
observed
or existing peaks may disappear, depending on the type of instrument or the
settings. In
some instances, any particular peak in an XRPD pattern may appear as a
singlet, doublet,
triplet, quartet, or multiplet, depending on the type of instrument or the
settings, the
sensitivity of the instrument, measuring conditions, and/or purity of the
crystalline form.
In some instances, any particular peak in an XRPD may appear in a symmetric
shape or
in an asymmetric shape, e.g., having a shoulder. Moreover, instrument
variation and other
factors can affect the 2-theta values. A skilled artisan understanding these
variations is
capable of discriminating or ascertaining the defining features or
characteristics of a
particular crystal form using XRPD, as well as using other known
physicochemical
techniques.
[0086] The term "anhydrate" as applied to a compound refers to a
crystalline form
wherein the compound contains no structural water within the crystal lattice.
[0087] As used herein, the term "essentially pure" with respect to Form
IV means that the
composition comprising Form IV contains no detectable amount of another
polymorphic
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form (e.g., Form I or Form II), as determined by observing no detectable
differences in an
XRPD and/or DSC pattern between a single Form IV crystal and the crystalline
composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide. However, "essentially pure" Form IV of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can
include
impurities, such as, but not limited to, synthetic reactants or by-products
generated during
the chemical synthesis.
[0088] As used herein, the term "aberration" as applied to a gene
refers to a mutation,
chromosomal loss or fusion, epigenetic chemical modification, or other event
which alters
the sequence, level of expression, or processed mRNA sequence associated with
a gene
relative to the sequence, level of expression, or processed mRNA sequence
associated
with the wild-type gene.
[0089] It is understood that wherever aspects are described herein with
the language
"comprising," otherwise analogous aspects described in terms of "consisting
of' and/or
"consisting essentially of" are also provided.
[0090] The details of one or more aspects are set forth in the
description below. Other
features, objects, and advantages will be apparent from the description and
from the
claims.
DETAILED DESCRIPTION OF THE INVENTION
[0091] Dispersible formulations (e.g., dispersible tablets, dispersible
powders, dispersible
granules, dispersible minitablets, or dispersible pellets) of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide which are safely
administrable
to a patient who has difficulty swallowing (e.g., a pediatric patient or a
patient suffering
from dysphagia) are described herein.
10092] As with all pharmaceutical compounds and compositions, the
chemical and
physical properties of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide are important in its commercial development. These
properties
include, but are not limited to: (1) packing properties such as molar volume,
bulk density
and hygroscopicity, (2) thermodynamic properties such as melting temperature,
vapor
pressure and solubility, (3) kinetic properties such as dissolution rate and
stability
(including stability at ambient conditions, especially to moisture and under
storage
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conditions), (4) surface properties such as surface area, wettability,
interfacial tension and
shape, (5) mechanical properties such as hardness, tensile strength,
compactibility,
handling, flow and blend; and (6) filtration properties. These properties can
affect, for
example, the processing and storage of the compound and pharmaceutical
compositions
comprising the compound. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as Form I, Form II,
or Form
IV (e.g., essentially pure Form IV) of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide in addition to pharmaceutically
acceptable
carriers or excipients.
Pharmaceutical Composition
[0093] In some aspects, the present disclosure provides a
pharmaceutical composition
comprising an amount of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide of Formula (I)
N
HO----"":-
OH ,N
F '1
(I),
wherein the pharmaceutical composition is dispersible in a potable liquid
(e.g., water) or
orodispersible in a subject's saliva.
[0094] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide included in the pharmaceutical compositions
described
herein is crystalline. In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
selected
from the group consisting of: (a) a crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD
pattern
having peaks at 4.6 0.2, 7.3 0.2, and 14.6 0.2 degrees two theta; (b) a
crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide characterized by an XRPD pattern having peaks at 10.6 0.2, 13.7
0.2, 19.0
+ 0.2, and 23.7 + 0.2 degrees two theta; and (c) a crystalline form of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
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characterized by an XRPD pattern haying peaks at 5.5 0.2 and 19.6 0.2
degrees two
theta.
[0095] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by an XRPD pattern having peaks
at 4.6 +
0.2, 7.3 0.2, and 14.6 0.2 degrees two theta. In some aspects, the
crystalline form of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is characterized by an XRPD pattern having peaks at 4.6 0.2, 7.3 0.2, 14.6
0.2, and
25.0 0.2 degrees two theta.
[0096] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by an XRPD pattern
substantially as
shown in FIG. 1A.
[0097] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by one or both of: (a) a TGA
profile
substantially as shown in FIG. 1B; and/or (b) a DSC profile substantially as
shown in
FIG. 1B.
[0098] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by a DSC profile which does not
include
an endotherm with an onset at about 117 C.
[0099] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein does not contain any amount of Form I or Form II
detectable by XRPD and/or DSC.
[0100] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is anhydrous.
[0101] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is Form IV. In some aspects, the crystalline
form of of N-
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((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fiuoro-4-iodo-phenylamino)-
benzamide is
essentially pure Form IV.
[0102] In some aspects, the crystalline Form IV composition included in
the
pharmaceutical compositions described herein is stable, as demonstrated by a
substantially unchanged XRPD pattern and/or DSC profile over time. In some
aspects, the
crystalline Form IV composition exhibits an XRPD pattern and/or DSC profile
which is
substantially unchanged after storage for 1 month, 2 months, 3 months, 4
months, 5
months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3
years, 4
years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11
years, 140
months, 12 years, 13 years, 14 years, or 15 years at standard warehouse
conditions (15 C-
25 C and <65% relative humidity). In some aspects, the crystalline Form IV
composition
of N-((R)-2,3 -dihydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl
amino)-
benzami de exhibits an XRPD pattern and/or DSC profile which is substantially
unchanged after storage for 3 months at standard warehouse conditions (15 C-25
C and
<65% relative humidity). In some aspects, the crystalline Form IV composition
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits an XRPD pattern and/or DSC profile which is substantially unchanged
after
storage for 6 months at standard warehouse conditions (15 C-25 C and <65%
relative
humidity). In some aspects, the crystalline Form IV composition of NAR)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
exhibits an
XRPD pattern and/or DSC profile which is substantially unchanged after storage
for 1
year at standard warehouse conditions (15 C-25 C and <65% relative humidity).
In some
aspects, the crystalline Form IV composition of NAR)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern
and/or
DSC profile which is substantially unchanged after storage for 5 years at
standard
warehouse conditions (15 C-25 C and <65% relative humidity). In some aspects,
the
crystalline Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide exhibits an XRPD pattern and/or DSC
profile
which is substantially unchanged after storage for 68 months at standard
warehouse
conditions (15 C-25 C and <65% relative humidity). In some aspects, the
crystalline
Form IV composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for >140 months at standard warehouse
conditions
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(15 C-25 C and <65% relative humidity). In some aspects, the crystalline Form
IV
composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for >14 years at standard warehouse
conditions
(15 C-25 C and <65% relative humidity).
[0103] In some aspects, the XRPD pattern for Form IV of N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
included in
the pharmaceutical compositions described herein is generated using a
PANALYTICAL'
X'Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and
a step
size of 0.03 20 with a X'CELERATOR Real Time Multi-Strip detector,
configured (a)
on the incidental beam side as follows: variable divergence slits (10 mm
irradiated
length), 0.04 rad Soller slits, fixed anti-scatter slit (0.500), and 10 mm
beam mask, and (b)
on the diffracted beam side as follows: variable anti-scatter slit (10 mm
observed length)
and 0.04 rad Soller slit or a BRUKER D8 ADVANCETM system using Cu Ka (40
kV/40 mA) radiation and a step size of 0.03 20 with a LYNXEYETM detector,
configured (a) on the incidental beam side as follows. Goebel mirror, mirror
exit slit (0.2
mm), 2.5 Soller slit, beam knife, and (b) on the diffracted beam side as
follows: anti-
scatter slit (8 mm) and 2.5 Soller slit; wherein samples are mounted flat on
zero-
background Si wafers.
[0104] In some aspects, the DSC pattern is generated using a TA
Instruments Q100 or
Q2000 differential scanning calorimeter at a rate of temperature increase of
about
15 C/min.
[0105] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by an XRPD pattern having peaks
at 10.6
0.2, 13.7 0.2, 19.0 0.2, and 23.7 0.2 degrees two theta. In some
aspects, the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern having one or more
peaks
at 10.6 0.2, 13.7 0.2, 14.6 0.2, 17.3 0.2, 18.0 0.2, 18.2 0.2,
19.0 0.2, 19.3
0.2, 20.1 0.2, 21.0 0.2, 21.9 0.2, 22.4 0.2, 23.7 0.2, 24.0 0.2,
24.9 0.2, 26.3
0.2, 27.6 0.2, 28.0 0.2, 30.1 0.2, 32.1 0.2, 32.3 0.2, 32.9 0.2,
35.8 0.2, and
37.7 0.2 degrees two theta.
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[0106] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by a DSC profile with an
endotherm with
onset at about 117 'C.
[0107] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is Form I.
[0108] In some aspects, the crystalline form of N#R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by an XRPD pattern having peaks
at 5.5
0.2 and/or 19.6 0.2 degrees two theta. In some aspects, the crystalline form
of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
characterized by an XRPD pattern having peaks at 5.5 0.2, 10.7 0.2, 16.5
0.2, 19.6
0.2, 22.0 0.2, 22.5 0.2, 23.6 0.2, 24.1 0.2, 25.0 0.2, 26.2 0.2,
27.6 0.2,
29.1 0.2, 30.5 0.2, 31.7 0.2, 33.3 0.2, and 39.0 0.2 degrees two
theta.
[0109] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is characterized by a DSC profile with an
endotherm with
onset at about 87 C.
[0110] In some aspects, the crystalline form of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide included in the
pharmaceutical
compositions described herein is Form II.
[0111] In some aspects, the present disclosure provides a
pharmaceutical composition
(e.g., a dispersible tablet, dispersible powder, dispersible granules,
dispersible minitablets,
or dispersible pellets) comprising N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition
(e.g., a dispersible tablet, dispersible powder, dispersible granules,
dispersible minitablets,
or dispersible pellets) further comprises one or more pharmaceutically
acceptable carriers.
[0112] In some aspects, the pharmaceutical composition is for oral
administration. In
some aspects, the pharmaceutical composition is orodispersible.
[0113] In some aspects, the potable liquid is water, milk or a juice
(e.g., orange juice or
apple juice). In some aspects, the potable liquid is water. In some aspects,
the potable
liquid is a juice.
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[0114] In some aspects, the pharmaceutical composition is a tablet, a
powder, granules,
minitablets, or pellets.
[0115] In some aspects, the pharmaceutical composition is a powder. In
some aspects,
the powder is a dispersible powder. In some aspects, a capsule or sachet
comprises the
dispersible powder.
[0116] In some aspects, the pharmaceutical composition is in the form
of granules. In
some aspects, the granules are dispersible granules. In some aspects, a
capsule or sachet
comprises the dispersible granules.
[0117] In some aspects, the pharmaceutical composition is in the form
of minitablets. In
some aspects, the minitablets are dispersible minitablets. In some aspects, a
capsule or
sachet comprises the dispersible minitablets.
[0118] In some aspects, the pharmaceutical composition is in the form
of pellets. In some
aspects, the pellets are dispersible pellets In some aspects, a capsule or
sachet comprises
the dispersible pellets.
[0119] In some aspects, the pharmaceutical composition is a tablet. In
some aspects, the
tablet is a dispersible tablet. In some aspects, the dispersible tablet is an
orodispersible
tablet.
[0120] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide wherein each component of the
pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7
wt/wt% of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 50 wt/wt% to about 98 wt/w0/0 of one or more diluents; (c) about 1
wt/wt% to
about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners, and
(0 about 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0121] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide wherein each component of the
pharmaceutical composition is as follows: (a) about 0.2 wt/wt% to about 1.5 -
wt/wt% of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
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(b) about 75 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 3
wt/wt% to
about 8 wt/wt% of one or more di sintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more
sweeteners; and
(f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0122] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the
pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2
wt/wt% of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide;
(b) about 85 wt/wt% to about 95 wt/w0/0 of one or more diluents; (c) about 3.5
wt/wt% to
about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt%
of one or
more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more
sweeteners; and
(f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
[0123] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5
mg, about
0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg,
about 2 mg,
about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg,
about 5.5
mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5
mg,
about 9 mg, about 9.5 mg, or about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 0.5 mg of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 1 mg
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 2 mg of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
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dispersible pellets comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 4 mg of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 5 mg
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 6 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 7 mg of N#R)-2,3-clihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 8 mg of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 9 mg
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-
iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition
that is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 11 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 12 mg of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 13 mg
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of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzami de. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 14 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-
iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition
that is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 15 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 16 mg of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 17 mg
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 18 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-
iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition
that is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 19 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-
2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 20 mg of N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
[0124] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 0.1 wt/wt% to about 7 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises about 0.1
wt/wt% to
about 5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
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dispersible pellets comprises about 0.1 wt/wt"/0, about 0.2 wt/wt%, about 0.3
wt/wt%,
about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about
0.75
wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%,
about
1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6
wt/wt%,
about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about
2.1
wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5
wt/wt%,
about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about
3
wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4
wt/wt%,
about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about
3.9
wt/wt%, about 4 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%,
about
4.4 wt/vv-t%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/vvf)/0, about
4.8 wt/wt%,
about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about
5.3
wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7
wt/wt%,
about 5.8 wt/wt%, about 5.9 wt/wt%, about 6 wt/wt%, about 6.1 wt/wt%, about
6.2
wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6
wt/wt%,
about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, or about 7 wt/wt% of N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
In
some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 0.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 0.8 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
[0125] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises one or more diluents. In some aspects, the pharmaceutical
composition that is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 50 wt/wt% to about 98 wt/wt% of one or
more
diluents. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible disgranules, dispersible minitablets, or
dispersible pellets
comprises about 75 wt/wt% to about 98 wt/wt% of one or more diluents. In some
aspects,
the pharmaceutical composition comprises about 85 wt/wt% to about 95 wt/wt% of
one
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or more diluents. In some aspects, the pharmaceutical composition that is a
dispersible
tablet, dispersible powder, dispersible granules, dispersible minitablets, or
dispersible
pellets comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53
wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%,
about
58 wt/wt%, about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%,
about 63 wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67
wt/wt%, about 68 wt/wt%, about 69 wt/wt%, about 70 wt/wt%, about 71 wt/wt%,
about
72 wt/wt%, about 73 wt/wt%, about 74 wt/wt%, about 75 wt/wt%, about 76 wt/wt%,
about 77 wt/wt%, about 78 wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81
wt/wt%, about 82 wt/wt%, about 83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%,
about
86 wt/wt%, about 87 wt/wt%, about 88 wt/wt%, about 89 wt/wt%, about 90
wt/we/o,
about 91 wt/wt%, about 92 wt/w0/0, about 93 wt/wt%, about 94 wt/wt%, about 95
wt/wt%, about 96 wt/wt%, about 97 wt/wt%, or about 98 wt/wt% of one or more
diluents.
In some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 90 wt/wt% of one or more diluents. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 91 wt/wt% of
one or more
diluents. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 92 wt/wt% of one or more diluents. In some aspects, the
pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 93 wt/wt% of
one or more
diluents
[0126] In some aspects, at least one of the diluents is selected from
the group consisting
of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose,
pregelatinized
starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium
phosphate. In some
aspects, at least one of the diluents is microcrystalline cellulose. In some
aspects, the
pharmaceutical composition comprises about 50 wt/wt% to about 98 wt/wt%
microcrystalline cellulose. In some aspects, the pharmaceutical composition
comprises
about 75 wt/wt% to about 98 wt/wt% microcrystalline cellulose. In some
aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises about 85
wt/wt % to
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about 95 wt/wt % microcrystalline cellulose. In some aspects, the
pharmaceutical
composition comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about
53
wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%,
about
58 wt/wt%, about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%,
about 63 wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67
wt/wt%, about 68 wt/wt%, about 69 wt/wt%, about 70 wt/wt %, about 71 wt/wt %,
about
72 wt/wt %, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76
wt/wt %,
about 77 wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt %, about
81
wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt %, about 85 wt/wt
%,
about 86 wt/wt %, about 87 wt/wt %, about 88 wt/wt %, about 89 wt/wt %, about
90
wt/wt %, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt/0, about 94 wt/wt%,
about
95 wt/wt, about 96 wt/wt%, about 97 wt/wt%, or about 98 wt/wt% %
microcrystalline
cellulose. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 90 wt/wt% microcrystalline cellulose. In some aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises about 91
wt/wt%
microcrystalline cellulose. In some aspects, the pharmaceutical composition
that is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 92 wt/wt% microcrystalline cellulose. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 93
wt/wt% microcrystalline cellulose.
[0127] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises about 1.0 wt/wt% to about 10 wt/wt% of one or more disintegrants. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 3.5
wt/wt% to about 6 wt/wt% of one or more disintegrants. In some aspects, the
pharmaceutical composition comprises about 1.0 wt/wt%, about 1.1 wt/wt%, about
1.2
wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6
wt/wt%,
about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2.0 wt/wt%, about
2.1
wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5
wt/wt%,
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about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about
3.0
wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4
wt/wt%,
about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about
3.9
wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3
wt/wt%,
about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about
4.8
wt/wt%, about 4.9 wt/wt%, about 5.0 wt/wt%, about 5.1 wt/wt%, about 5.2
wt/wt%,
about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about
5.7
wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt%, about 6.0 wt/wt%, about 6.1
wt/wt%,
about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about
6.6
wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, about 7.0
wt/wt%,
about 7.1 wt/wt%, about 7.2 wt/wt%, about 7.3 wt/wt%, about 7.4 wt/wt%, about
7.5
wt/wt%, about 7.6 wt/w0/0, about 7.7 wt/wt%, about 7.8 wt/wt%, about 7.9
wt/wt%,
about 8.0 wt/wt%, about 8.1 wt/wt%, about 8.2 wt/wt%, about 8.3 wt/wt%, about
8.4
wt/wt%, about 8.5 wt/wt%, about 8.6 wt/wt%, about 8.7 wt/wt%, about 8.8
wt/wt%,
about 8.9 wt/wt%, about 9.0 wt/wt%, about 9.1 wt/wt%, about 9.2 wt/wt%, about
9.3
wt/wt%, about 9.4 wt/wt%, about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7
wt/wt%,
about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% of one or more
disintegrants.
In some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 5 wt/wt% of one or more disintegrants.
[0128] In some aspects, at least one of the disintegrants is selected
from the group
consisting of croscarmellose sodium, sodium starch glycolate, crospovidone,
microcrystalline cellulose, starch, pregelatinized starch, low substituted
hydroxypropyl
cellulose, and alginic acid. In some aspects, at least one of the
disintegrants is
croscarmellose sodium. In some aspects, the disintegrant is croscarmellose
sodium. In
some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 1.0 wt/wt % to about 10 wt/wt % croscarmellose sodium. In some aspects,
the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises about 3.5
wt/wt % to
about 6 wt/wt % croscarmellose sodium. In some aspects, the pharmaceutical
composition comprises about about 1.0 wt/wt%, about 1.1 wt/wt%, about 1.2
wt/wt%,
about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about
1.7
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wt/w0/0, about 1.8 wt/w0/0, about 1.9 wt/wt%, about 2.0 wt/wt%, about 2.1
wt/wt%,
about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about
2.6
wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0
wt/wt%,
about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, 3.5
wt/wt %
about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %,
about 4.0
wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4
wt/wt%,
about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %,
about 4.9
wt/wt%, about 5 wt/wt %, about 5.1 wt/wt%, about 5.2 wt/wt %, about 5.3
wt/wt%,
about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7 wt/wt %,
about 5.8
wt/wt %, about 5.9 wt/wt %, about 6.0 wt/wt %, about 6.1 wt/wt%, about 6.2
wt/wt%,
about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6 wt/wt%, about
6.7
wt/wt%, about 6.8 wt/w0/0, about 6.9 wt/wt%, about 7.0 wt/wt%, about 7.1
wt/wt%,
about 7.2 wt/wt%, about 7.3 wt/wt%, about 7.4 wt/wt%, about 7.5 wt/wt%, about
7.6
wt/wt%, about 7.7 wt/wt%, about 7.8 wt/wt%, about 7.9 wt/wt%, about 8.0
wt/wt%,
about 8.1 wt/wt%, about 8.2 wt/wt%, about 8.3 wt/wt%, about 8.4 wt/wt%, about
8.5
wt/wt%, about 8.6 wt/wt%, about 8.7 wt/wt%, about 8.8 wt/wt%, about 8.9
wt/wt%,
about 9.0 wt/wt%, about 9.1 wt/wt%, about 9.2 wt/wt%, about 9.3 wt/wt%, about
9.4
wt/wt%, about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7 wt/wt%, about 9.8
wt/wt%,
about 9.9 wt/wt%, or about 10.0 wt/wt% croscarmellose sodium. In some aspects,
In
some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 5 wt/wt % croscarmellose sodium.
101291 In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents. In some
aspects,
the pharmaceutical composition that is a dispersible tablet, dispersible
powder, dispersible
granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%
to about 2.5
wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical
composition
that is a dispersible tablet, dispersible powder, dispersible granules,
dispersible
minitablets, or dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%,
about 0.2
wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6
wt/wt%,
about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about
1.1
wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5
wt/wt%, 1.6
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wt/w0/0, about 1.7 wt/w0/0, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2
wt/wt%, about
2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5
wt/wt%,
about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about
3.0
wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 vvt/wt%, about 3.4
wt/wt%,
about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %,
about 3.9
wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3
wt/wt %,
about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %,
about 4.8
wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % of one or more flavoring
agents. In
some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 2 wt/wt% of one or more flavoring agents.
[0130] In some aspects, at least one of the flavoring agents is
selected from the group
consisting of natural or synthetic flavors including but not limited to, grape
flavoring,
bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring,
strawberry
flavoring, raspberry flavoring, mint flavoring, peppermint flavoring,
grapefruit flavoring,
pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring,
banana flavoring,
or cherry flavoring. In some aspects, at least one of the flavoring agents is
grape
flavoring. In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises 0 wt/wt% to about 5.0 wt/wt% grape flavoring. In some aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%
to about 2.5
wt/wt% grape flavoring. In some aspects, the pharmaceutical composition that
is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%,
about 0.3
wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7
wt/wt%,
about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about
1.2
wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%,
about 1.7
wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%,
about
2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6
wt/wt%,
about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about
3.1
wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt
%,
about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %,
about 4.0
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wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4
wt/w0/0,
about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %,
about 4.9
wt/wt %, or about 5.0 wt/wt % grape flavoring. In some aspects, the
pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 2 wt/wt% grape
flavoring.
[0131] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises 0 wt/wt% to about 5 wt/wt% of one or more sweeteners. In some
aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%
to about 2
wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical
composition that
is a dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%,
about 0.3
wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7
wt/wt%,
about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about
1.2
wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%,
about 1.7
wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%,
about
2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6
wt/wt%,
about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about
3.1
wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt
%,
about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %,
about 4.0
wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4
wt/wt%,
about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %,
about 4.9
wt/wt %, or about 5.0 wt/wt % of one or more sweeteners. In some aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises about 1
wt/wt% of one
or more sweeteners.
[0132] In some aspects, at least one of the sweeteners is selected from
the group
consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol,
sorbitol,
glucose, fructose, and aspartame. In some aspects, at least one of the
sweeteners is
sucralose. In some aspects, the sweetener is sucralose. In some aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%
to about 5
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wt/w0/0 sucralose. In some aspects, the pharmaceutical composition that is a
dispersible
tablet, dispersible powder, dispersible granules, dispersible minitablets, or
dispersible
pellets comprises 0 wt/wt% to about 2 wt/wt% sucralose In some aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises 0 wt/wt%,
about 0.1
wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5
wt/wt%,
about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about
1
wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4
wt/wt%,
about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9
wt/wt%,
about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about
2.4
wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8
wt/wt%,
about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about
3.3
wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7
wt/wt %,
about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %,
about 4.2
wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6
wt/wt %,
about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5 wt/wt %
sucralose.
In some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises
about 1 wt/wt% sucralose.
[0133] In some aspects, the pharmaceutical composition that is a
dispersible tablet,
dispersible powder, dispersible granules, dispersible minitablets, or
dispersible pellets
comprises 0 wt/wt% to about 5 wt/wt% of one or more lubricants. In some
aspects, the
pharmaceutical composition that is a dispersible tablet, dispersible powder,
dispersible
granules, dispersible minitablets, or dispersible pellets comprises about 0.1
wt/wt% to
about 5 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 0.5 wt/wt% to
about 2
wt/wt% of one or more lubricants. In some aspects, the pharmaceutical
composition
comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%,
about 0.4
wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8
wt/wt%,
about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about
1.3
wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%,
about 1.8
wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%,
about
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2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7
wt/wt%,
about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about
3.2
wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt %, about 3.6 wt/wt
%,
about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %,
about 4.1
wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5
wt/wt %,
about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or
about 5
wt/wt % of one or more lubricants. In some aspects, the pharmaceutical
composition that
is a dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 1 wt/wt% of one or more lubricants.
[0134] In some aspects, at least one of the lubricants is selected from
the group consisting
of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic
acid,
hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax,
colloidal silicon
dioxide, and talc. In some aspects, at least one of the lubricants is
magnesium stearate. In
some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises 0
wt/wt% to about 5 wt/wt% magnesium stearate. In some aspects, the
pharmaceutical
composition that is a dispersible tablet, dispersible powder, dispersible
granules,
dispersible minitablets, or dispersible pellets comprises about 0.1 wt/wt% to
about 2
wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition
that is a
dispersible tablet, dispersible powder, dispersible granules, dispersible
minitablets, or
dispersible pellets comprises about 0.5 wt/wt% to about 2 wt/wt% magnesium
stearate.
In some aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible
powder, dispersible granules, dispersible minitablets, or dispersible pellets
comprises 0
wt/wt %, about 0.1 wt/wt A), about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4
wt/wt %,
about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %,
about 0.9
wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3
wt/wt %,
about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %,
about 1.8
wt/wt %, about 1.9 wt/wt %, about 2 wt/wt %, about 2.1 wt/wt%, about 2.2
wt/wt%,
about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about
2.7
wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1
wt/wt%,
about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt %, about
3.6
wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0
wt/wt %,
about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%,
about 4.5
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wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9
wt/wt %, or
about 5 wt/wt % magnesium stearate. In some aspects, the pharmaceutical
composition
that is a dispersible tablet, dispersible powder, dispersible granules,
dispersible
minitablets, or dispersible pellets comprises 0 wt/wt % magnesium stearate. In
some
aspects, the pharmaceutical composition that is a dispersible tablet,
dispersible powder,
dispersible granules, dispersible minitablets, or dispersible pellets
comprises about 1
wt/wt % magnesium stearate.
Methods of Treatment and Uses
[0135] In some aspects, the present disclosure provides a method of
treating a tumor, a
cancer, or a Rasopathy disorder comprising administering to a subject in need
of such
treatment a pharmaceutical composition described herein.
[0136] In some aspects, the tumor is a neurofibroma. In some aspects,
the tumor is a
neurofibroma associated with Neurofibromatosis Type 1. In some aspects, the
tumor is
selected from the group consisting of cutaneous neurofibroma, plexiform
neurofibroma,
optic pathway glioma, low grade glioma, high grade glioma, or malignant
peripheral
nerve sheath tumor. In some aspects, the tumor is plexiform neurofibroma.
[0137] In some aspects, the subject has been diagnosed with a Rasopathy
disorder
selected from the group consisting of neurofibromatosis type 1,
neurofibromatosis type 2,
cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan
syndrome, and Noonan syndrome with multiple lentigines.
[0138] In some aspects, the cancer is selected from the group
consisting of skin cancer,
malignant peripheral nerve sheath cancer, leukemia, lymphoma, hi stiocytic
neoplasm,
lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer,
thyroid cancer,
cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer,
sarcoma, bladder
cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid
cystic
carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer,
pancreatic
cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous
carcinoma of the
peritoneum. In some aspects, the leukemia is selected from the group
consisting of acute
lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic
leukemia, and
chronic myelogenous leukemia. In some aspects, the lymphoma is selected from
the
group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma,
follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
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lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the
lung
cancer is selected from the group consisting of lung adenocarcinoma, squamous
non-
small cell lung cancer, non-squamous non-small cell lung cancer, and small
cell lung
cancer.
[0139] In some aspects, the subject bears a mutation or other
aberration in one or more
genes for which the mutation or other aberration causes a gain or loss of
function
characteristic of certain cancers, wherein the mutation or other aberration in
one or more
genes is a mutation or other aberration in one or more of KRAS, NRAS, BRAS,
BRAF,
MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0140] In some aspects, an individual dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more
than one
tablet, more than one dose of dispersible powder, more than one dose of
dispersible
granules, more than one dose of minitablets, more than one dose of pellets, or
a
combination thereof. For example, a dose of 3 mg of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as
two
dispersible tablets ¨ one containing 2 mg and the other containing 1 mg or as
three
dispersible tablets each containing 1 mg.
[0141] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg to about
20 mg
per dose of the pharmaceutical compositions described herein. In some aspects,
the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
provided in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4
mg, about
0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg,
about 2 mg,
about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about
9 mg,
about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,
about
16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose. In some
aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 0.5 mg per dose. In
some
aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 1 mg per dose. In
some
aspects, the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 2 mg per dose. In
some
aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
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phenylamino)-benzamide is provided in an amount of about 3 mg per dose. In
some
aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 4 mg per dose. In
some
aspects, the N-((R)-2,3-dihy droxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 5 mg per dose. In
some
aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 10 mg per dose. In
some
aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is provided in an amount of about 20 mg per dose.
[0142] In some aspects, the pharmaceutical composition comprising N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered one time, two times, three times, or four times per day. In some
aspects, the
total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-
4-iodo-
phenylamino)-benzamide is administered two times per day.
[0143] In some aspects, the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered in a total daily dose that does
not exceed 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some aspects,
the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 8 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose does not exceed 2 mg. In some aspects, the
N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 1 mg.
[0144] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising: (a)
21 days in which the total daily dose is administered; and (b) 7 days in which
no
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-
fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising (a) 21 consecutive days in which the total daily dose is
administered;
followed by (b) 7 consecutive days in which no N4R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. In some
aspects,
the N -((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-
phenylamino)-
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benzamide is administered on a 28-day dosing cycle comprising (a) three 7-day
periods
each comprising (i) 5 days in which the total daily dose is administered and
(ii) 2 days in
which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered. In some aspects, the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) three 7-day periods each
comprising (i) 5 consecutive days in which the total daily dose is
administered and (ii) 2
consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0145] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle
comprising 28
days in which the total daily dose is administered.
[0146] In some aspects, the 28-day dosing cycle is repeated up to a
total of 24
consecutive 28-day dosing cycles.
[0147] In some aspects, the subject experiences dysphagia. In some
aspects, the subject
experiences dysphagia caused by one or more of: disease of the nervous system,
muscle
weakening, developmental disability, stroke, injury, anatomical defect,
cancer, treatment
for cancer, allergic reaction, dementia, memory loss, or cognitive decline. In
some
aspects, the subject has been diagnosed with an autism spectrum disorder. In
some
aspects, the subject has been diagnosed with a craniofacial disorder. In some
aspects, the
subject has been diagnosed with myasthenia gravis In some aspects, the subject
has been
diagnosed with tardive dyskinesia.
[0148] In some aspects, the subject is a pediatric subject. In some
aspects, the subject is
less than 18 years old, less than 17 years old, less than 16 years old, less
than 15 years
old, less than 14 years old, less than 13 years old, less than 12 years old,
less than 11
years old, less than 10 years old, less than 9 years old, less than 8 years
old, less than 7
years old, less than 6 years old, less than 5 years old, less than 4 years
old, less than 3
years old, less than 2 years old, or less than 1 year old. In some aspects,
the subject is 1
year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7
years old, 8 years
old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14
years old, 15
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years old, 16 years old, or 17 years old. In some aspects, the subject is less
than 13 years
old. In some aspects, the subject is less than 12 years old. In some aspects,
the subject is
less than 11 years old. In some aspects, the subject is less than 10 years
old. In some
aspects, the subject is less than 9 years old. In some aspects, the subject is
less than 8
years old. In some aspects, the subject is less than 7 years old. In some
aspects, the
subject is less than 6 years old. In some aspects, the subject is less than 5
years old. In
some aspects, the subject is less than 4 years old. In some aspects, the
subject is less than
3 years old. In some aspects, the subject is less than 2 years old. In some
aspects, the
subject is less than 1 year old. In some aspects, the subject is about 2 to
about 18 years
old. In some aspects, the subject is about 3 to about 17 years old. In some
aspects, the
subject is about 4 to about 16 years old. In some aspects, the subject is
about 5 to about
15 years old. In some aspects, the subject is about 6 to about 14 years old.
In some
aspects, the subject is about 7 to about 13 years old. In some aspects, the
subject is about
8 to about 12 years old.
[0149] In some aspects, the subject is a geriatric subject. In some
aspects, the subject is
more than 30 years old, more than 35 years old, more than 40 years old, more
than 45
years old, more than 50 years old, more than 55 years old, more than 60 years
old, more
than 65 years old, more than 70 years old, more than 75 years old, more than
80 years old,
more than 85 years old, more than 90 years old, more than 95 years old, or
more than 100
year old. In some aspects, the subject is more than 50 years old. In some
aspects, the
subject is more than 60 years old. In some aspects, the subject is more than
70 years old.
In some aspects, the subject is more than 80 years old. In some aspects, the
subject is
more than 90 years old. In some aspects, the subject is more than 100 years
old.
[0150] In some aspects, if the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-fluoro-4-
iodo-phenylamino)-benzamide is to be administered more than one time a day,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide can be divided so the patient receives different doses
at each
administration. For example, if the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is to be 2 mg
administered two
times per day, the patient can receive 0.5 mg (e.g., as one 0.5 mg dispersible
tablet) in the
morning and 1.5 mg (e.g., as one 0.5 mg dispersible tablet and one 1 mg
dispersible
tablet) in the evening.
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[0151] In some aspects, the total daily dose of N-((R)-2,3-
dihydroxypropoxy)-3,4-
di fluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is administered two
times daily. In
some aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
0.1 mg to about 10 mg each. In some aspects, the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.1 mg, about 0.2 mg, about
0.3 mg,
about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about
0.9 mg,
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about
7 mg,
about 8 mg, about 9 mg, or about 10 mg. In some aspects, the total daily dose
of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered two times daily at a dose of about 0.25 mg each. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 0.5
mg each.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-
(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a
dose of
about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each. In some aspects,
the total daily
dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered two times daily at a dose of about 4 mg
each. In
some aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose
of about
mg each In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two
times daily
at a dose of about 10 mg each.
[0152] In some aspects, the total daily dose of the N4R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily.
In some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 0.1
mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg,
about 0.4
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mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg,
about 1 mg,
about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about
8 mg,
about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg,
about 15
mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 0.5
mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily
at a dose
of about 1 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once
daily at a
dose of about 2 mg. In some aspects, the total daily dose of the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 4 mg. In some aspects, the total
daily dose of
the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is administered once daily at a dose of about 8 mg. In some aspects,
the total
daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide is administered once daily at a dose of about 10 mg. In
some
aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-
2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of
about 20
mg.
[0153] In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-
(2-fluoro-4-
iodo-phenylamino)-benzamide is administered via a pharmaceutical composition
described herein, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide is provided at a total daily dose that does not
exceed 1 mg,
2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14
mg,
15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some aspects, the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 20 mg. In some
aspects, the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 10 mg. In some
aspects, the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered in a total daily dose that does not exceed 8 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
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administered in a total daily dose that does not exceed 6 mg. In some aspects,
the N-((R)-
2,3 -di hydroxypropoxy)-3 ,4-di fluoro-2-(2-fluoro-4-iodo-phenyl amino)-
benzami de is
administered in a total daily dose that does not exceed 4 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 2 mg. In some aspects,
the N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered in a total daily dose that does not exceed 1 mg.
[0154] In some aspects, the present disclosure provides use of a
pharmaceutical
composition described herein for the manufacture of a medicament for treating
a tumor, a
cancer, or a Rasopathy disorder.
EXAMPLES
Example 1: Production of Seed Crystals of Form IV
Step 1: Preparation of "Side Chain", PD-0337792
[0155] 14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6%
enantiomeric
excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA) solution in
toluene
(overall yield ¨60%). The triflate activation was performed in the 200 L
reactor by
maintaining temperatures under ¨20 C during triflic anhydride addition. The
resulting
activated alcohol was then transferred to a 400 L reactor containing solid N-
hydroxypthalimide (NHP) and the reaction was allowed to occur at ambient
temperature
to completion. The final base de-protection was performed by adding aqueous
ammonia
(-28% soln, 5 equiv., 34 kg). After reaction completion, water was removed by
distillation from toluene, and the resulting solid side product was filtered
out to yield the
product solution.
Step 2: Preparation of PD-0315209
[0156] The process yielded 21.4 kg (99.4% w/w assay), which is 80% of
theoretical from
starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 eq.) and 2-fluoro-4-
iodoaniline
(16.4 kg, 1.02 eq.) with lithium amide base (5 kg, 3.2 eq.). The reaction was
initiated by
adding 5% of total solution of TFBA and FIA into lithium amide slurry at 50
C. This
reaction demonstrated a minimal initiation period of ¨10 minutes, which was
observed by
color change and slight exotherm. The remaining TFBA/FIA solution in THF was
slowly
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added through a pressure can in an hour while maintaining the reaction
temperatures
within 45-55 C. There was no appreciable pressure rise (due to ammonia gas
release)
observed during the entire operation.
Step 3: Preparation of PD-0325901
[0157] A modification was made to the CDI charging to mitigate
potential gas
generation. Two equal portions of CDI were added into solid FIPFA before and
after
solvent addition (through a shot loader). The timing between the two solid CDI
additions
(4.6 kg each) should not exceed 30 minutes. Then two intermediate filter cakes
were
dissolved with ethanol. The excess ethanol was distilled and replaced with
toluene to
approximately 5% y/y ethanol prior to PD-0325901 recrystallization. Lab
studies
suggested that the crystallization from toluene and acetonitrile and
recrystallization from
ethanol in toluene would not be able to reduce impurities which is essential
for the
polymorph transformation. The presence of a dimeric impurity (PF-00191189) at
a level
greater than 0.2% has been known to result in the formation of undesired
polymorph.
F F
HN
H 0
-N 0
HO - 0
oH N
aCOI
PF-00191189
Exact Mass: 856.93
[0158] The crude crystallization from the final reaction mixture
reduced dimeric impurity
PF-00191189 to approximately 1.9% and the subsequent recrystallization further
reduced
it to approximately 0.4%. As a consequence, undesired polymorphs were
produced. The
DSC patterns indicated two different melting points ¨80 C (low melt Form II)
and
¨117 C (Form I). Also during the processing, the solids crystallized at a much
lower
temperature than expected (actual -10 C, expected - 40 C). It is suspected
that the
unsuccessful recrystallization is due to a change in the solvent composition
as a result of
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incomplete drying of the crude. Drying of the crude wet cake prior to ethanol
dissolution
was stopped after about 36 hours when the crude product was ¨28 kg (26 kg
theoretical).
Polymorph Transformation
[0159] Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the
final
Et0H/Water crystallization and precipitated materials from the earlier
Et0H/Toluene
filtrate were taken forward to the polymorph transformation. Both crops were
separately
dried in the filter until constant weights and each was dissolved in Et0H. The
combined
Et0H solution was analyzed by HPLC and resulted in an estimated amount of 16.4
kg
PD-0325901. The recrystallization was started after removing Et0H via vacuum
distillation and adjusting the solvent composition to about 5% Et0H in Toluene
at 65 C
(i.e., Et0H is added dropwise at 65 C until complete solids dissolution).
[0160] A slow 4-hour cooling ramp to 5 C followed by 12 h stirring was
performed to
ensure satisfactory results. The resulting slurry was filtered and again it
was completely
dried in the filter until constant weight (approximately 3 days). The purified
solid showed
99.8% pure PD-0325901 with not detected level of dimeric impurity PF-00191189.
[0161] The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes
of Et0H (62 L)
off of the filter, transferred to the reactor and precipitated by a slow (-3
h) water addition
(308 L) at 30-35 C, cooled to 20 C and stirred for 12 h. The DSC analysis of
a slurry
sample taken at 2 h shows the solids to be completely Form IV (desired
polymorph).
[0162] 21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of
9.7% PD-
0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg of PD-
0325901
(assay 99.4%, 100% Form IV, Yield ¨ 48%).
Example 2: Assay/Impurities and Identification of PD-0325901
101631 PD-0325901 is separated from process impurities and degradants
by reversed-
phase liquid chromatography with UV detection at 275 nm. Identification of PD-
0325901 is performed by obtaining either an infrared or proton NM_R spectrum,
in
addition to the HPLC retention time. For purity evaluation, process impurities
and
degradants are identified by their characteristic relative retention times and
quantitated by
area normalization.
[0164] Chromatographic Conditions: Agilent Zorbax SB C18, 5 hm, 4.6 x
250 mm (or
equivalent); flow rate is 1.0 mL/min; column temperature is 30 C; detector
wavelength is
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275 nm; diluent is 50/50 acetonitrile/water; mobile phase A is 0.1%
trifluoroacetic acid
(TF A) in water; mobile phase B is methanol; and the gradient conditions
below. The
assay is determined against a reference standard and reported on an anhydrous,
solvent
free basis. Quantification of specified and unspecified impurities is reported
by area
percent. Total impurities is the sum of all impurities present above the
reporting
threshold of 0.05%.
Time (minutes) 0 15 40 45 46
% mobile phase B 70 70 100 100 70
Example 3: Improved Process for Preparation of Form IV
[0165] As described in Example 1, synthetic methods of producing
mirdametinib as Form
IV produced Form IV with dimeric impurity PF-00191189, and further steps were
required to transform the product into essentially pure Form IV without
undesired
polymorphs Form I and Form IT. Therefore, it was necessary to develop a method
of
producing essentially pure Form IV without additional processing steps.
Mirdametinib Manufacturing Process
[0166] The route is a convergent four step synthesis with six chemical
steps overall, using
the proposed starting materials (S)-(+)-2,2-dimethy1-1,3-dioxolane-4-methanol
(SGA),
2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-idodoaniline (FIA), and N-
hydroxyphthalimide (NHP). The final step (Step 4) provides essentially pure
Form IV of
mirdametinib.
CA 03207271 2023- 8-2
n
>
o
u ,
r . ,
o
, 1
Scheme for Preparation of Mirdametinib:
Step 1
o
t..)
t..)
0
,--,
-1
-4
_ HO-N NHP - 1 .).
u,
0
Tf __ o 0 i MW 163.13
--0,)) O'N ul
0 /-.C" 0
2 N710,$)
______________________________________________________________ .
NH40H
(S)-(+)-2,2-dimethy1-1,3- TEA - CF
0 3 toluene, TEA 0
toluene toluene P0-0337792
dioxolane-4-methanol (S)-glycerol
(SGA) _ acetonide triflate_ PD-
0333760 (IPGA)
MW 132.16 MIN 264.22
(IPGAP) MW 147.17
- MW 277
28 -
Step 2 T3P
HO 0
NH2 HO 0 (50% in Et0Ac) .
F 1, F H F
v,
2 i-Pr2NEt 1..)
N AI _______
Ir
F + I
THF, LiNHMTBE
MO
F F I THF, toluene
2,3,4-trifluoro-benzoic acid 2-fluoro-4-iodoaniline
toluene, ac. HCI
MTBE, aq. NaOH
(TFBA) (FIA) P0-0315209
MW 176.09 MW 237.02
(FIPFA)
MW 393.10
Step 3
Step 4
H H
H t
HOO'N H F
H00,N H F aq. HCI 0/ 0,N H F r)
OH N Et0H OH N
40
toluene, ACN _.-\\--0 N
c7)
t..)
Et0H F lei I t=J
F Si I water F I
,-,
F F
F O-
,--,
Mirdametinib Crude
P0-0325901 901 Acetonide oo
w
(P0-0325901) MW 482.20
MW 522.26
w
MW 482.20
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[0167] Step 1 (Preparation of PD-0337792 (IPGA)): A clean, dry 100-
gallon reactor was
charged with toluene (139.3 kg, 8 volumes) and (S)-(+)-2,2-Dimethy1-1,3-
dioxolane-4-
methanol (SGA; 20.0 kg, 1.0 equivalents). Triethylamine (18.8 kg, 1.22
equivalents) was
charged to the reactor. The reactor contents were agitated and cooled to -10
10 C.
Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was added to a
clean 50-
L round bottom flask under nitrogen then cooled to a temperature of < -10 'C.
The cooled
trifluoromethanesulfonic anhydride was slowly transferred to the 100-gallon
reactor while
maintaining the internal temperature at -10 10 C. The reaction mixture was
agitated at
-10 10 C for 30 minutes. Reaction monitoring by TLC indicated the
conversion to be
complete. While maintaining the internal temperature at -10 10 C, anhydrous
toluene
(99.8 kg, 5.75 volumes) was charged to the reactor followed by N-
hydroxyphthalimide
(26.4 kg, 1.07 equivalents). The contents were warmed to 20 5 C then
agitated at this
temperature for at least 5 hours, until the triflate intermediate was not
detectable by TLC.
The reaction mixture was split into two equal portions. Each toluene solution
was
quenched with USP purified water (66 kg, 6.7 volumes). The toluene solution
was then
washed twice with USP purified water (66 kg, 6.7 volumes).
[0168] The toluene solutions were recombined in a 100-gallon reactor.
The organic
solution was treated with 28% ammonium hydroxide solution (41.5 kg, 7.8
equivalents).
The contents were heated to 35 5 C then agitated for not less than (-NLT")
12 hours.
Upon reaction completion, the lower, aqueous phase was removed. The toluene
solution
was dried via azeotropic distillation of toluene. The toluene solution was
then
concentrated to minimum stir volume. The concentrated solution was filtered to
remove
by-product solids. The cake was washed with toluene and the filtrates were
combined.
Assay of the toluene solution indicated 8.6 kg (36.7% yield) of PD-0337792
(IPGA) was
present.
[0169] Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon
reactor was purged
with nitrogen then charged with lithium amide (LiNH2, 8.8 kg, 3.4 equivalents)
followed
by tetrahydrofuran (THF, 56.8 kg, 3.2 volumes). The mixture was cooled to 10
10 C
then additional THF (15.1 kg, 0.85 volumes) was charged to the reactor,
followed by a
solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equivalent) in THF
(26.4 kg,
1.15 volumes). The reaction mixture was heated to NMT ("not more than") 50 C.
A
solution of 2-flouro-4-iodoaniline (FIA, 27.5 kg, 1.02 equivalents) in THF
(17.8 kg, 1
volumes) was added portion wise to the reactor, maintaining the batch
temperature at
NMT 50 C and stifling for 1 hour between additions. After completing the
additions, the
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reaction mixture stirred for an additional 3 hours at 50 10 C. Upon
reaction
completion, the mixture was cooled to NMT 10 C then quenched with USP
purified
water (120.3 kg, 6 volumes). The reaction mixture was distilled to
approximately 30
gallons after which methyl t-butyl ether (MTBE, 118.6 kg, 8 volumes) was
added. The
MTBE solution was then quenched with 2M hydrochloric acid solution (89.5 kg)
to a pH
= 7. The aqueous phase was then removed. The MTBE solution was filtered
through
celite then washed twice with 5% brine solution (104.1 kg, 5.2 volumes)
followed by 1M
hydrochloric acid solution (77.4 kg). The MTBE solution was solvent swapped
with
toluene followed by volume adjustment to approximately 50 gallons. This
mixture was
heated to 75 5 C for 1 hour then cooled to 20 5 C and stirred for 1
hour. The
product was filtered, washed with toluene (68.1 kg, -4 volumes), then dried
under
vacuum at 40 C to obtain 25.2 kg of PD-0315209 (56.4% yield).
[0170] Step 3 (Preparation of crude PD-0325901): A clean, dry 100-
gallon reactor was
purged with nitrogen then charged with PD-0315209 (18.0 kg, 1 equivalent) and
THF
(113.0 kg, 7 volumes). The mixture was cooled to 5 5 C. N,N-
diisopropylethylamine
(15.1 kg, 2.55 equivalents) was charged maintaining the temperature NMT 25 C.
The
mixture was cooled to 5 5 C then stirred for 10 minutes. PD-0337792
solution in
toluene (121.7 kg total, 1.3 equivalents) was charged to the reactor at 5 5
C, followed
by 50% T3P in ethyl acetate (42.0 kg, 1.45 equivalents). The reaction mixture
stirred at
5 C for NLT 3 hours. An additional charge of N,N-diisopropylethylamine (1.9
kg,
0.3 equivalents) and 50% T3P in ethyl acetate (4.1 kg, 0.15 equivalents) were
made to
advance the coupling to completion. The reaction was reverse quenched into a
5% sodium
hydroxide solution (50 kg), followed by washing with 5% brine (55.4 kg). The
organic
solution was concentrated then solvent swapped with toluene. Acetonitrile
(43.0 kg, 2.4
volumes) was added to the reactor followed by 2M hydrochloric acid (117.6 kg,
5.1
equivalents). The mixture stirred at 25 5 C until reaction completion after
16 hours.
The bottom aqueous was removed then the reaction mixture was washed with 5%
brine
(75.2 kg). The organic phase was concentrated then solvent swapped with
toluene to an
appropriate volume. The mixture was then heated to 75 5 C for 30 minutes
then slowly
cooled to 20 C. The solids were filtered then washed with toluene (31.1 kg,
1.7 volumes)
[0171] The crude solids were charged back to the 100-gallon reactor,
followed by 5%
ethanol in toluene (170.0 kg). The mixture was heated to 75 5 "V for 60
minutes to
achieve a solution then slowly cooled to 20 C. The solids were filtered then
washed
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twice with toluene (31 kg, 1.7 volumes). The wet cake was dried under vacuum
at 45 C
to obtain 8.2 kg of crude PD-0325901 (37.1% yield).
[0172] Step 4 (Preparation of Essentially Pure Form IV Mirdametinib): A
clean, dry
100-gallon reactor was purged with nitrogen then charged with USP Purified
Water
(164.1 kg, 20 volumes) followed by ethanol (200 proof, 20.8 kg, 3.25 volumes).
The
solution was heated to 35 5 C. In a separate vessel, crude PD-0325901 (8.1
kg, 1
equivalent) was dissolved in ethanol (200 proof, 40.5 kg, 6.3 volumes). A
portion of this
solution (14.4 kg) was added to the 100-gallon reactor over 60 minutes. PD-
0325901
Form IV seeds as prepared in Example 1 (82.6 g, 1%wt) was added to the reactor
to
facilitate precipitation. The remainder of the crude PD-0325901/ethanol
solution (34.3
kg) was added to the reactor over 90 minutes as the mixture stirred at 35 5
C. The
reactor contents continued to stir at 35 5 C for 5.5 hours then were slowly
cooled to 20
C. The solids were then filtered, washed with USP purified water (16.5 kg, 2
volumes),
then dried under vacuum at 45 C for 16 hours. The dried solids were screened
through a
10-mesh sieve to obtain 5.7 kg PD-0325901 Form IV (70.4% yield).
10173] An XRPD pattern for essentially pure Form IV used herein is
shown in FIG. 1A.
TGA and DSC analysis of essentially pure Form IV used herein are shown in FIG.
1B.
Example 4: 0.5 mg and 1.0 mg Dispersible Tablet Formulations
[0174]
Examples of dispersible tablet formulations are shown in Table 1.
Table 1.
Formulation Composition
Ingredient Function 0.5 mg 1.0 mg
mg/tab
mg/tab
(w/w) (w/w)
Mirdametinib a Active 0.75 0.50 0.75 1.00
Ingredient
Microcrystalline
Diluent 90.52 60.60 90.52
121.20
Cellulose b
Croscarmellose Disintegrant 4.85 3.25 4.85 6.50
sodium
Grape flavor Flavor 1.94 1.30 1.94 2.60
Sucralose Sweetener 0.97 0.65 0.97 1.30
Magnesium
Lubricant 0.97 0.65 0.97 1.30
Stearate
Total
100.00 66.95 100.00 133.90
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a = Based on theoretical potency of 1.000. Quantity may be adjusted based on
the actual potency.
b = Quantity of microcrystalline cellulose can be adjusted for slight potency
changes of
mirdametinib
Example 5: A Manufacturing Process for Mirdametinib Dispersible Tablets
[0175] A non-limiting example of an exemplary process for producing
mirdametinib
dispersible tablets is described herein.
[0176] Microcrystalline cellulose (approximately 30% w/w of
microcrystalline cellulose
in final composition) is blended in a vessel. Mirdametinib, croscarmellose,
and
microcrystalline cellulose (approximately 50% w/w of microcrystalline
cellulose in final
composition) are added to the vessel and blended. The remaining
microcrystalline
cellulose is added to the vessel and blended. Intragranular magnesium stearate
is added
for lubrication, and the blend is roller compacted into dry granules. Grape
flavor and
sucralose are blended into the granules, and extragranular magnesium stearate
is added
for lubrication. The blend is compressed, and checked for in-process control
based on
appearance, weight, thickness, hardness, friability, and disintegration. The
tablets are
dedusted and checked for metal impurities, then bulk packaged.
[0177] All publications, patents, and patent applications mentioned in
this specification
are incorporated herein by reference in their entirety to the same extent as
if each
individual publication, patent, or patent application was specifically and
individually
indicated to be incorporated by reference in its entirety. Where a term in the
present
application is found to be defined differently in a document incorporated
herein by
reference, the definition provided herein is to serve as the definition for
the term.
[0178] While the invention has been described in connection with
specific aspects
thereof, it will be understood that invention is capable of further
modifications and this
application is intended to cover any variations, uses, or adaptations
following, in general,
the principles and including such departures from the present disclosure that
come within
known or customary practice within the art to which the invention pertains and
can be
applied to the essential features hereinbefore set forth, and follows in the
scope of the
claimed.
[0179] In addition to the various embodiments described herein, the
present disclosure
includes the following embodiments numbered El through E141. This list of
embodiments is presented as an exemplary list and the application is not
limited to these
embodiments.
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[0180] El. A pharmaceutical composition comprising an amount of N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of
Formula
H N
OH õ 1
yl
F
wherein the pharmaceutical composition is dispersible in a potable liquid or
orodispersible in a subject's saliva.
[0181] E2. The pharmaceutical composition of El, wherein the N-((R)-
2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
crystalline.
[0182] E3. The pharmaceutical composition of E2, wherein the
crystalline form of N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
selected from the group consisting of:
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
4.6
0.2, 7.3 0.2, and 14.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
one or
more of 10.6 0.2, 13.7 0.2, 19.0 0.2, and 23.7 0.2 degrees two theta;
and
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at
one or
more of 5.5 0.2 and 19.6 0.2 degrees two theta.
[0183] E4. The pharmaceutical composition of E2 or E3, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an MOD pattern having peaks at 4.6 0.2, 7.3
0.2, and
14.6 + 0.2 degrees two theta.
[0184] E5. The pharmaceutical composition of any one of E2-E4,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6
0.2,
7.3 0.2, 14.6 0.2, and 25.0 0.2 degrees two theta.
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[0185] E6. The pharmaceutical composition of any one of E2-E5,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by an XRPD pattern substantially as
shown in
FIG. 1A.
[0186] E7. The pharmaceutical composition of any one of E2-E6,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by one or both of:
a) a TGA profile substantially as shown in FIG. 1B; and/or
b) a DSC profile substantially as shown in FIG. 1B.
[0187] E8. The pharmaceutical composition of any one of E2-E7,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by a DSC profile which does not
include an
endotherm with an onset at about 117 C.
[0188] E9. The pharmaceutical composition of any one of E2-E8,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide does not contain any amount of Form I or Form II
detectable by
XRPD and/or DSC.
[0189] E10. The pharmaceutical composition of any one of E2-E9, wherein
the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for 3 months at standard warehouse
conditions
(15 C-25 C and <65% relative humidity).
[0190] Eli. The pharmaceutical composition of any one of E2-E10,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for 6 months at standard warehouse
conditions
(15 C-25 C and <65% relative humidity).
[0191] E12. The pharmaceutical composition of any one of E2-Ell,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i
odo-
phenylamino)-benzami de exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for 1 year at standard warehouse
conditions (15 C-
25 C and <65% relative humidity).
[0192] E13. The pharmaceutical composition of any one of E2-E12,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
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phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for 68 months at standard warehouse
conditions
(15 C-25 C and <65% relative humidity).
[0193] E14. The pharmaceutical composition of any one of E2-E13,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide exhibits an XRPD pattern and/or DSC profile which is
substantially unchanged after storage for >140 months at standard warehouse
conditions
(15 C-25 C and <65% relative humidity).
[0194] E15. The pharmaceutical composition of any one of E2-E14,
wherein the DSC
pattern is generated using a TA Instruments Q100 or Q2000 differential
scanning
calorimeter at a rate of temperature increase of about 15 C/min.
[0195] E16. The pharmaceutical composition of any one of E2-E15,
wherein the
crystalline form is anhydrous.
[0196] E17. The pharmaceutical composition of any one of E2-E16,
wherein the
crystalline form is Form IV.
[0197] E18. The pharmaceutical composition of E2 or E3, wherein the
crystalline form
of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is characterized by an XRPD pattern having peaks at one or more of
10.6
0.2, 13.7 0.2, 19.0 0.2, and 23.7 0.2 degrees two theta.
[0198] E19. The pharmaceutical composition of E2, E3, or E18, wherein
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern having peaks at one or more of
10.6
0.2, 13.7 0.2, 14.6 0.2, 17.3 0.2, 18.0 0.2, 18.2 0.2, 19.0 0.2,
19.3 0.2, 20.1
0.2, 21.0 0.2, 21.9 0.2, 22.4 0.2, 23.7 0.2, 24.0 0.2, 24.9 0.2,
26.3 0.2,
27.6 0.2, 28.0 0.2, 30.1 0.2, 32.1 0.2, 32.3 0.2, 32.9 0.2, 35.8
0.2, and 37.7
0.2 degrees two theta.
[0199] E20. The pharmaceutical composition of E2, E3, E18, or E19,
wherein the
crystalline form is characterized by a DSC profile with an endotherm with
onset at about
117 C.
[0200] E21. The pharmaceutical composition of any one of E2, E3, and El
8-E20,
wherein the crystalline form is Form I.
[0201] E22. The pharmaceutical composition of E2 or E3, wherein the
crystalline form
of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl amino)-
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benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2 and/or
19.6
0.2 degrees two theta.
[0202] E23. The pharmaceutical composition of E2, E3, or E22, wherein
the crystalline
form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide is characterized by an XRPD pattern having peaks at one or more of
5.5 0.2,
10.7 0.2, 16.5 0.2, 19.6 0.2, 22.0 0.2, 22.5 0.2, 23.6 0.2, 24.1
0.2, 25.0
0.2, 26.2 + 0.2, 27.6 + 0.2, 29.1 10.2, 30.5 0.2, 31.7 0.2, 33.31 0.2, and
39.0+0.2
degrees two theta.
[0203] E24. The pharmaceutical composition of E2, E3, E22, or E23,
wherein the
crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
iodo-
phenylamino)-benzamide is characterized by a DSC profile with an endotherm
with onset
at about 87 C.
[0204] E25. The pharmaceutical composition of any one of E2, E3, and
E22-E24,
wherein the crystalline form is Form II.
[0205] E26. The pharmaceutical composition of any one of E1-E25,
wherein the
pharmaceutical composition further comprises one or more pharmaceutically
acceptable
carriers.
[0206] E27. The pharmaceutical composition of any one of E1-E26,
wherein the
pharmaceutical composition is for oral administration.
[0207] E28. The pharmaceutical composition of any one of E1-E27,
wherein the
pharmaceutical composition is orodispersible.
[0208] E29. The pharmaceutical composition of any one of El -E28,
wherein the
pharmaceutical composition is a tablet, a powder, granules, minitablets, or
pellets.
[0209] E30. The pharmaceutical composition of E29, wherein the
pharmaceutical
composition is a powder.
[0210] E31. The pharmaceutical composition of E30, wherein the powder
is a
dispersible powder.
[0211] E32. The pharmaceutical composition of E30 or E31, wherein a
capsule or
sachet comprises the powder or dispersible powder.
[0212] E33. The pharmaceutical composition of E29, wherein the
pharmaceutical
composition is in the form of granules.
[0213] E34. The pharmaceutical composition of E33, wherein the granules
are
dispersible granules.
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[0214] E35. The pharmaceutical composition of E33 or E34, wherein a
capsule or
sachet comprises the granules or dispersible granules.
[0215] E36. The pharmaceutical composition of E29, wherein the
pharmaceutical
composition is in the form of minitablets.
[0216] E37. The pharmaceutical composition of E36, wherein the
minitablets are
dispersible minitablets.
[0217] E38. The pharmaceutical composition of E36 or E37, wherein a
capsule or
sachet comprises the minitablets or dispersible minitablets.
[0218] E39. The pharmaceutical composition of E29, wherein the
pharmaceutical
composition is in the form of pellets.
[0219] E40. The pharmaceutical composition of E39, wherein the pellets
are
dispersible pellets.
[0220] E41. The pharmaceutical composition of E39 or E40, wherein a
capsule or
sachet comprises the minitablets or dispersible minitablets.
[0221] E42. The pharmaceutical composition of E29, wherein the
pharmaceutical
composition is a tablet.
[0222] E43. The pharmaceutical composition of E42, wherein the
pharmaceutical
composition is a dispersible tablet.
[0223] E44. The pharmaceutical composition of any one of El -
E43, comprising:
about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide;
and wherein each component of the pharmaceutical composition is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/vvt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and
f. about 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0224] E45. The pharmaceutical composition of any one of El -E43,
comprising:
about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-
4-iodo-phenylamino)-benzamide;
and wherein each component of the pharmaceutical composition is as follows:
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a. about 0.5 wt/wt% to about 1.2 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 85 wt/wt% to about 95 wt/wt% of one or more diluents;
c. about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and
f. about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
[0225] E46. The pharmaceutical composition of E44 or E45, wherein the
pharmaceutical composition comprises about 0.5 mg of N-((R)-2,3-
dihydroxypropoxy)-
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
[0226] E47. The pharmaceutical composition of E44 or E45, wherein the
pharmaceutical composition comprises about 1 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-
di fluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzami de.
[0227] E48. The pharmaceutical composition of E44 or E45, wherein the
pharmaceutical composition comprises about 2 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
[0228] E49. The pharmaceutical composition of E44 or E45, wherein the
pharmaceutical composition comprises about 3 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-
di fluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzami de.
[0229] E50. The pharmaceutical composition of E44 or E45, wherein the
pharmaceutical composition comprises about 4 mg of N-((R)-2,3-
dihydroxypropoxy)-3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
[0230] E51. The pharmaceutical composition of any one of E44-E50,
wherein at least
one of the diluents is selected from the group consisting of microcrystalline
cellulose,
lactose, mannitol, starch, sorbitol, xylitol, sucrose, pregelatinized starch,
calcium sulfate,
calcium carbonate, and dibasic calcium phosphate.
[0231] E52. The pharmaceutical composition of E51, wherein at least one
of the
diluents is microcrystalline cellulose.
[0232] E53. The pharmaceutical composition of any one of E44-E52,
wherein at least
one of the di sintegrants is selected from the group consisting of
croscarmellose sodium,
sodium starch glycolate, crospovidone, microcrystalline cellulose, starch,
pregelatinized
starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0233] E54. The pharmaceutical composition of E53, wherein at least one
of the
di sintegrants is croscarmellose sodium.
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[0234] E55. The pharmaceutical composition of any one of E44-E54,
wherein at least
one of the flavoring agents is selected from the group consisting of natural
or synthetic
flavors including but not limited to, grape flavoring, bubble gum flavoring,
caramel
flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry
flavoring,
mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple
flavoring, pear
flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry
flavoring.
[0235] E56. The pharmaceutical composition of E55, wherein at least one
of the
flavoring agents is grape flavoring.
[0236] E57. The pharmaceutical composition of any one of E44-E56,
wherein at least
one of the sweeteners is selected from the group consisting of sucralose,
acesulfame,
saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and
aspartame.
[0237] E58. The pharmaceutical composition of E57, wherein at least one
of the
sweeteners is sucralose.
[0238] E59. The pharmaceutical composition of any one of E44-E58,
wherein at least
one of the lubricants is selected from the group consisting of magnesium
stearate, sodium
stearyl fumarate, glycerol dibehenate, stearic acid, calcium stearate, zinc
stearate,
beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, and talc.
[0239] E60. The pharmaceutical composition of E59, wherein at least one
of the
lubricants is magnesium stearate.
[0240] E61. The pharmaceutical composition of any one of E1-E60,
wherein the
potable liquid is water milk or a juice.
[0241] E62. The pharmaceutical composition of any one of El -E60,
wherein the
pharmaceutical composition is dispersible in a subject's saliva.
[0242] E63. A method of treating a tumor, a cancer, or a Rasopathy
disorder
comprising administering to a subject in need of such treatment the
pharmaceutical
composition of any one of E1-E62.
[0243] E64. The method of E63, wherein the tumor is a
neurofibroma.
[0244] E65. The method of E64, wherein the tumor is a neurofibroma
associated with
Neurofibromatosis Type 1.
[0245] E66. The method of any one of E63-E65, wherein the tumor is
selected from the
group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic
pathway
glioma, low grade glioma, high grade glioma, or malignant peripheral nerve
sheath tumor.
[0246] E67. The method of E66, wherein the tumor is plexiform
neurofibroma.
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[0247] E68. The method of E67, wherein the subject has been diagnosed
with a
Rasopathy disorder selected from the group consisting of neurofibromatosis
type 1,
neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome,
Legius
syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
[0248] E69. The method of E63, wherein the cancer is selected from the
group
consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia,
lymphoma,
hi stiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal
cancer, colorectal
cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine
neoplasm, gastric
cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer,
esophageal
cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral
cancer,
cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary
tract cancer,
and serous carcinoma of the peritoneum.
[0249] E70. The method of E69, wherein the leukemia is selected from
the group
consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, and chronic myelogenous leukemia.
[0250] E711. The method of E69, wherein the lymphoma is selected from
the group
consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macroglobulinemi a.
[0251] E72. The method of E69, wherein the lung cancer is selected from
the group
consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-
squamous
non-small cell lung cancer, and small cell lung cancer.
[0252] E73. The method of any one of E63-E72, wherein the subject bears
a mutation
or other aberration in one or more genes for which the mutation or other
aberration causes
a gain or loss of function characteristic of certain cancers, wherein the
mutation or other
aberration in one or more genes is a mutation or other aberration in one or
more of
KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0253] E74. The method of any one of E63-E73, wherein an individual
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered as more than one tablet, more than one dose of dispersible
powder, more
than one dose of dispersible granules, more than one dose of minitablets, more
than one
dose of pellets, or a combination thereof.
[0254] E75. The method of any one of E63-E74, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
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administered on a 28-day dosing cycle comprising: (a) 21 days in which the
total daily
dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0255] E76. The method of any one of E63-E74, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) 21 consecutive days in
which the
total daily dose is administered; followed by (b) 7 consecutive days in which
no N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0256] E77. The method of any one of E63-E74, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) three 7-day periods each
comprising (i) 5 days in which the total daily dose is administered and (ii) 2
days in
which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered.
[0257] E78. The method of any one of E63-E74, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) three 7-day periods each
comprising (i) 5 consecutive days in which the total daily dose is
administered and (ii) 2
consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-
((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0258] E79. The method of any one of E63-E74, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising 28 days in which the total
daily dose is
administered.
[0259] E80. The method of any one of E78-E79, wherein the 28-day dosing
cycle is
repeated up to a total of 24 consecutive 28-day dosing cycles.
[0260] E81. The method of any one of E63-E80, wherein the subject
experiences
dysphagia.
[0261] E82. The method of E81, wherein the subject experiences
dysphagia caused by
one or more of: disease of the nervous system, muscle weakening, developmental
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disability, stroke, injury, anatomical defect, cancer, treatment for cancer,
allergic reaction,
dementia, memory loss, or cognitive decline.
[0262] E83. The method of any one of E63-E80, wherein the subject is a
pediatric
subject.
[0263] E84. The method of any one of claims E63-E83, wherein the total
daily dose of
N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide
is administered two times daily.
[0264] E85. The method of E84, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.1 mg to about 10 mg each.
[0265] E86. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.25 mg each.
[0266] E87. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.5 mg each.
[0267] E88. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 1 mg each.
[0268] E89. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each.
[0269] E90. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 4 mg each.
[0270] E91. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 5 mg each.
[0271] E92. The method of E85, wherein the total daily dose of the N-
((R)-2,3-
di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzamide is
administered two times daily at a dose of about 10 mg each.
[0272] E93. The method of any one of E63-E83, wherein the total daily
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered once daily.
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[0273] E94. The method of E93, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.1 mg to about 20 mg.
[0274] E95. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.5 mg.
[0275] E96. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 1 mg.
[0276] E97. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 2 mg.
[0277] E98. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 4 mg.
[0278] E99. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 8 mg.
[0279] E100. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 10 mg.
[0280] E101. The method of E94, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 20 mg.
[0281] E102. The method of any one of E63-E101, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 20 mg.
[0282] E103. The method of any one of claims E63-E101, wherein the N-
((R)-2,3-
di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 10 mg.
[0283] E104. The method of any one of claims E63-E101, wherein the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 8 mg.
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[0284] E105. The method of any one of E63-E101, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 6 mg.
[0285] E106. The method of any one of E63-E101, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 4 mg.
[0286] E107. The method of any one of E63-E101, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 2 mg.
[0287] E108. The method of any one of E63-E101, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 1 mg.
[0288] E109. Use of the pharmaceutical composition of any one of El -
E62 for the
manufacture of a medicament for treating a tumor, a cancer, or a Rasopathy
disorder.
[0289] E110. The use of E109, wherein the tumor is a
neurofibroma.
[0290] E111. The use of E110, wherein the tumor is a neurofibroma
associated with
Neurofibromatosis Type 1.
[0291] E112. The use of any one of E109-E111, wherein the tumor is
selected from the
group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic
pathway
glioma, low grade glioma, high grade glioma, or malignant peripheral nerve
sheath tumor.
[0292] E113. The use of E112, wherein the tumor is plexiform
neurofibroma.
[0293] E114. The use of E109, wherein the subject has been diagnosed
with a Rasopathy
disorder selected from the group consisting of neurofibromatosis type 1,
neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome,
Legius
syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
[0294] E115. The use of E109, wherein the cancer is selected from the
group consisting
of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma,
histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal
cancer, colorectal
cancer, thyroid cancer, cholangiocarcinoma, urotheli al cancer, uterine
neoplasm, gastric
cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer,
esophageal
cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral
cancer,
cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary
tract cancer,
and serous carcinoma of the peritoneum.
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[0295] E116. The use of E115, wherein the leukemia is selected from the
group
consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic
lymphocytic leukemia, and chronic myelogenous leukemia.
[0296] E117. The use of E115, wherein the lymphoma is selected from the
group
consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular
lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small
lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
[0297] E118. The use of E115, wherein the lung cancer is selected from
the group
consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-
squamous
non-small cell lung cancer, and small cell lung cancer.
[0298] El 19. The use of any one of El 09-E118, wherein the subject
bears a mutation or
other aberration in one or more genes for which the mutation or other
aberration causes a
gain or loss of function characteristic of certain cancers, wherein the
mutation or other
aberration in one or more genes is a mutation or other aberration in one or
more of
KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0299] E120. The use of any one of E109-E119, wherein an individual
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered as more than one tablet, more than one dose of dispersible
powder, more
than one dose of dispersible granules, more than one dose of minitablets, more
than one
dose of pellets, or a combination thereof.
[0300] E121. The use of any one of E109-E119, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising: (a) 21 days in which the
total daily
dose is administered; and (b) 7 days in which no N#R)-2,3-dihydroxypropoxy)-
3,4-
difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0301] E122. The use of any one of E109-E119, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) 21 consecutive days in
which the
total daily dose is administered; followed by (b) 7 consecutive days in which
no N-((R)-
2,3 -di hydroxypropoxy)-3 ,4-di fl uoro-2-(2-fluoro-4-i odo-phenyl amino)-
benzami de is
administered.
[0302] E123. The use of any one of E109-E119, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) three 7-day periods each
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comprising (i) 5 days in which the total daily dose is administered and (ii) 2
days in
which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
phenylamino)-
benzamide, and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-
difluoro-2-(2-
fluoro-4-iodo-phenylamino)-benzamide is administered.
[0303] E124. The use of any one of E109-E119, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising (a) three 7-day periods each
comprising (i) 5 consecutive days in which the total daily dose is
administered and (ii) 2
consecutive days in which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-
fluoro-4-
iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered.
[0304] El 25. The use of any one of E109-E119, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered on a 28-day dosing cycle comprising 28 days in which the total
daily dose is
administered.
[0305] E126. The use of any one of E124-E125, wherein the 28-day dosing
cycle is
repeated up to a total of 24 consecutive 28-day dosing cycles.
[0306] E127. The use of any one of E109-E126, wherein the subject
experiences
dysphagia.
[0307] E128. The use of E127, wherein the subject experiences dysphagia
caused by one
or more of: disease of the nervous system, muscle weakening, developmental
disability,
stroke, injury, anatomical defect, cancer, treatment for cancer, allergic
reaction, dementia,
memory loss, or cognitive decline.
[0308] E129. The use of any one of E109-E128, wherein the subject is a
pediatric
subject.
[0309] E130. The use of any one of E109-E129, wherein the total daily
dose of N-((R)-
2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
is
administered two times daily.
[0310] El 31. The use of El 30, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.1 mg to about 10 mg each.
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103111 E132. The use of E131, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 0.25 mg each.
[0312] E133. The use of E131, wherein the total daily dose of the N-
((R)-2,3-
di hy droxyprop oxy)-3 ,4-di fluoro-2-(2-fluoro-44 o do-phenyl ami no)-b enz
ami de is
administered two times daily at a dose of about 0.5 mg each.
10313] E134. The use of E131, wherein the total daily dose of the N-
((R)-2,3-
di hy droxyprop oxy)-3 ,4-di fluoro-2-(2-fluoro-44 o do-phenyl ami no)-b enz
ami de is
administered two times daily at a dose of about 1 mg each.
[0314] E135. The use of E131, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered two times daily at a dose of about 2 mg each.
[0315] El 36. The use of El 31, wherein the total daily dose of the N-
((R)-2,3-
di hy droxyprop oxy)-3 ,4-di fluoro-2-(2-fluoro-44 o do-phenyl ami no)-b enz
ami de is
administered two times daily at a dose of about 4 mg each.
[0316] E137. The use of E131, wherein the total daily dose of the N-
((R)-2,3-
di hy droxyprop oxy)-3 ,4-di fluoro-2-(2-fluoro-44 o do-phenyl ami no)-b enz
ami de is
administered two times daily at a dose of about 5 mg each.
[0317] E138. The use of E131, wherein the total daily dose of the N-
((R)-2,3-
di hy droxyprop oxy)-3 ,4-di fluoro-2-(2-fluoro-4 o do-phenyl ami no)-b enz
ami de is
administered two times daily at a dose of about 10 mg each.
[0318] E139. The use of any one of E109-E129, wherein the total daily
dose of the N-
((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-
benzamide is
administered once daily.
[0319] E140. The use of E139, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 0.1 mg to about 20 mg.
[0320] E141. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami no)-b enzami
de is
administered once daily at a dose of about 0.5 mg.
[0321] E142. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 1 mg.
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[0322] E143. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 2 mg.
[0323] E144. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 4 mg.
[0324] E145. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 8 mg.
[0325] E146. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 10 mg.
[0326] E147. The use of E140, wherein the total daily dose of the N-
((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered once daily at a dose of about 20 mg.
[0327] E148. The use of any one of E109-E147, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 20 mg.
[0328] E149. The use of any one of E109-E148, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 10 mg.
[0329] E150. The use of any one of E109-E148, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 8 mg.
[0330] E151. The use of any one of E109-E148, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 6 mg.
[0331] E152. The use of any one of E109-E148, wherein the N-((R)-
2,3-
di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de
is
administered in a total daily dose that does not exceed 4 mg.
[0332] The use of any one of claims 109-148, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 2 mg.
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103331 The use of any one of claims 109-148, wherein the N-((R)-2,3-
dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
administered in a total daily dose that does not exceed 1 mg.
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