Note: Descriptions are shown in the official language in which they were submitted.
88793254
PHARMACEUTICAL COMPOSITIONS COMPRISING MELOXICAM
Inventor: Herriot Tabuteau
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Pat. App. Nos.
62/802,198, filed
February 6, 2019; 62/803,756, filed February 11, 2019; 62/835,613, filed April
18, 2019;
62/846,311, filed May 10, 2019; 62/860,705, filed June 12, 2019; 62/895,933,
filed September 4,
2019; 62/895,956, filed September 4, 2019; 62/955,905, and filed December 31,
2019.
BACKGROUND
[0002] Meloxicam, which has the structure:
CH3
OH
H
=3,-' Nz:o CH3
is a nonsteroidal anti-inflammatory (NSAID) drug that exhibits anti-
inflammatory, analgesic,
and antipyretic activities. The nneloxicam mechanism of action may be related
to
prostaglandin synthetase (cyclo-oxygenase, COX) inhibition which is involved
in the initial
steps of the arachidonic acid cascade, resulting in the reduced formation of
prostaglandins,
thromboxanes and prostacylin.
SUMMARY
[0003] Meloxicam and some other NSAIDs have poor aqueous solubility which
may
reduce bioavailability and slow the onset of pain relief resulting from their
use. One means
of increasing the solubility and bioavailability of meloxicam is through the
use of
cyclodextrins. Cyclodextrin (also known as cycloamyloses) are generally cyclic
polysaccharides which form a bucket-like shape. Cyclodextrins help to increase
bioavailability
1
Date Recue/Date Received 2023-01-10
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
of other molecules because cyclodextrins are hydrophobic on the inside and
hydrophilic on
the inside which helps to facilitate the transport of molecules. The naturally
occurring
cyclodextrins include six, seven, and eight glucose units (a, 13, and y-
cyclodextrin,
respectively). However, synthetic cyclodextrins containing more or less
glucose units are
possible. In aqueous solutions, cyclodextrins can form complexes (i.e., an
inclusion complex)
with drugs by incorporating the drug into the center/hydrophobic portion of
the cyclodextrin
ring; although cyclodextrin compounds are also known to aggregate around a
drug in a
micelle-type structure. This ability of cyclodextrins may allow them to act as
carriers to
increase the bioavailability of less soluble drugs.
[0004] Some embodiments include a method of treating migraine comprising:
selecting a
human migraine patient with a history of inadequate response to prior migraine
treatments,
and orally administering a dosage form to the migraine patient, wherein the
dosage form
comprises a combination of: 1) a complex of meloxicam with a sulfobutyl ether
13-cyclodextrin
(SBE13CD), 2) a bicarbonate, and 3) a rizatriptan.
[0005] Some embodiments include an inclusion complex of meloxicam in a
cyclodextrin.
[0006] Some embodiments include a dosage form comprising: 1) an inclusion
complex of
meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or a
bicarbonate.
[0007] Some embodiments include a method of administering meloxicam orally,
comprising orally administering a dosage form described herein to a patient in
need of
treatment.
[0008] Some embodiments include a method of administering meloxicam
intravenously,
comprising intravenously administering a dosage form described herein to a
patient in need
of treatment.
[0009] Disclosed herein are formulations for an inclusion complex of
cyclodextrin and
meloxicam with bicarbonate and methods of use thereof.
[0010] Disclosed herein are formulations and methods for delivering
meloxicam with
cyclodextrin to a subject by oral, enteral, intravenous, intramuscular,
subcutaneous,
intranasal, or other parenteral means.
2
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0011]
Disclosed also are methods for treating pain and pain associated with
conditions
by delivering a dosage form with meloxicam, cyclodextrin, and bicarbonate by
oral, enteral,
intravenous, intramuscular, subcutaneous, intranasal, or other parenteral
means to a subject.
[0012] A
combination of rizatriptan and meloxicam (referred to herein for convenience
as a "subject combination") may be used to treat a variety of pain conditions.
Rizatriptan has the structure as shown below.
7N
Rizatriptan
[0013] Some
embodiments include a subject combination comprising: 1) an inclusion
complex of meloxicam and a cyclodextrin, 2) rizatriptan, and 3) a bicarbonate
for treating
migraine in a human being. The migraine may be treatment-resistant migraine.
The human
being may have a history of inadequate response to prior treatments.
[0014] Some
embodiments include a subject combination comprising rizatriptan and
meloxicam that has rapid, sustained, substantial and statistically significant
efficacy as
compared to placebo, rizatriptan, or meloxicam in the acute treatment of
migraine in patients
with a history of inadequate response to prior acute treatments.
[0015] Some
embodiments include a subject combination comprising rizatriptan and
meloxicam that requires significantly less use of rescue medication as
compared to
rizatriptan, meloxicam, or placebo.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure
1 is a depiction of the results described in Example 2 and contained in Table
6.
3
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0017] Figure
2 is another depiction of the results described in Example 2 and contained
in Table 6.
[0018] Figure
3 is another depiction of the results described in Example 2 and contained
in Table 6.
[0019] Figure
4 is another depiction of the results described in Example 2 and contained
in Table 6.
[0020] Figure
5 is another depiction of the results described in Example 2 and contained
in Table 6.
[0021] Figure
6 is another depiction of the results described in Example 2 and contained
in Table 6.
[0022] Figure
7 is another depiction of the results described in Example 2 and contained
in Table 6.
[0023] Figure
8 is another depiction of the results described in Example 2 and contained
in Table 6.
[0024] Figure
9 is another depiction of the results described in Example 2 and contained
in Table 6.
[0025] Figure
10 is another depiction of the results described in Example 2 and contained
in Table 6.
[0026] FIG.
11 is a plot of meloxicam plasma concentration at various time points over
the first 24 hours for an embodiment of a dosage form described herein and a
commercially
available meloxicam dosage form.
[0027] FIG.
12 is a plot of meloxicam plasma concentration at various time points over
the first 24 hours for a dosage form of Meloxicam/Rizatriptan described in
Example 6 and a
commercially available meloxicam dosage form.
[0028] FIG.
13 is a plot of rizatriptan plasma concentration at various time points over
the
first 12 hours for a dosage form of MeloxicamMizatriptan described in Example
6 and a
commercially available meloxicam dosage form.
4
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0029] Fig.
14 shows plots of the percentages of subjects reporting pain relief at various
time points over the first 4 hours post dose of the dosage forms of
Meloxicam/Rizatriptan,
rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
[0030] Fig.
15 shows the percentages of subjects achieving pain freedom at 2 hours, 4
hours, 12 hours, and 16 hours post dose of the dosage forms of
Meloxicam/Rizatriptan,
rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.
[0031] Fig.
16A shows the percentages of subjects achieving sustained pain freedom from
2 hours to 24 hours post dose of the dosage forms of Meloxicam/Rizatriptan,
rizatriptan,
MoSEIC meloxicam, and placebo described in Example 11.
[0032] Fig.
16B shows the percentages of subjects achieving sustained pain relief from 2
hours to 24 hours post dose of the dosage forms of Meloxicam/Rizatriptan,
rizatriptan,
MoSEIC meloxicam, and placebo described in Example 11.
[0033] Fig.
17A shows the percentages of subjects achieving sustained pain freedom from
2 hours to 48 hours post dose of the dosage forms of Meloxicam/Rizatriptan,
rizatriptan,
MoSEIC meloxicam, and placebo described in Example 11.
[0034] Fig.
17B shows the percentages of subjects achieving sustained pain relief from 2
hours to 48 hours post dose of the dosage forms of Meloxicam/Rizatriptan,
rizatriptan,
MoSEIC meloxicam, and placebo described in Example 11.
[0035] Fig.
18 shows the percentages of subjects who took rescue medication through
hour 24 post dose of the dosage forms of Meloxicam/Rizatriptan, rizatriptan,
MoSEIC
meloxicam, and placebo described in Example 11.
DETAILED DESCRIPTION
[0036]
Provided herein are dosage forms with NSAIDs (such as meloxicam) and
cyclodextrin (optionally in an inclusion complex), and/or bicarbonate, and
methods of
treatment using the dosage form.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0037] A
dosage form may be given enterally including, but not limited to, oral,
sublingual,
or rectal delivery, or parenterally including, but not limited to,
intravenous, intramuscular,
intra nasal, or subcutaneous delivery.
[0038] Some
methods include administration of a product that combines an NSAID that
is formulated with: a) a cyclodextrin and/or b) a buffering agent. In some
embodiments, the
method involves treating a patient with a pharmaceutical formulation
comprising meloxicam
and a cyclodextrin and/or a carbonate/bicarbonate. Method embodiments may also
include
treating a patient to increase the bioavailability of meloxicam in the patient
or increase the
rate at which the meloxicam becomes bioavailable.
[0039] The
combination of meloxicam, a cyclodextrin (such as SBE6CD), and a bicarbonate
(such as sodium bicarbonate) may substantially increase the solubility and
rate of absorption
of meloxicam after oral administration, while maintaining its extended plasma
concentration
half-life in mammals, such as humans after oral administration.
[0040] The
combination of meloxicam, a cyclodextrin (such as SBE6CD), and a
bicarbonate (such as sodium bicarbonate) may substantially increase the oral
bioavailability
of meloxicam in mammals, such as humans, after oral administration.
[0041] Unless
otherwise indicated, any reference to a compound herein, such as
meloxicam or rizatriptan, by structure, name, or any other means, includes
pharmaceutically
acceptable salts, alternate solid forms, such as polymorphs, solvates,
hydrates, enantiomers,
tautomers, deuterium-modified forms, or any other chemical species, such as
precursors,
prod rugs, or any other chemical species that may rapidly convert to a
compound described
herein under conditions in which the compounds are used as described herein.
[0042] A
subject combination may be given enterally including, but not limited to,
oral,
sublingual, or rectal delivery, or parenterally including, but not limited to,
intravenous,
intramuscular, intranasal, or subcutaneous delivery. In some embodiments, both
meloxicam
and rizatriptan are administered orally. In some embodiments, meloxicam is
administered
intravenously and rizatriptan is administered orally. In some embodiments,
meloxicam is
administered intramuscularly and rizatriptan is administered orally.
[0043]
Normally, the combination of meloxicam and rizatriptan is administered so that
the human being receives the meloxicam and rizatriptan within a short period
of time with
6
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
respect to one another. For example, the meloxicam and rizatriptan may be
administered
within about 2 hours, within about 1 hour, within about 30 minutes, within
about 20 minutes,
within about 15 minutes, within about 10 minutes, within about 5 minutes, or
within about 1
minute of one another. In
some embodiments, the meloxicam and rizatriptan are
administered simultaneously, which for the purpose of this disclosure includes
administration
within about 5 minutes. In some embodiments, the meloxicam and rizatriptan are
administered in a single dosage form.
[0044] The
term "treating" or "treatment" broadly includes any kind of treatment
activity,
including the diagnosis, cure, mitigation, or prevention of disease in man or
other animals, or
any activity that otherwise affects the structure or any function of the body
of man or other
animals.
[0045] The
dosage form or the subject combination may be used to treat, or provide relief
of, any type of pain including, but not limited to, migraine and other types
of headache,
inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute
pain, localized
pain, systemic pain, cancer-related pain, acute pain, pain due to injury, pain
due to illness
(e.g., fever), post-operative pain, etc. In some instances, pain relief may be
palliative, or pain
relief may be provided independent of improvement of the disease or condition
or the
underlying cause of the disease or condition. For example, although the
underlying disease
may not improve, or may continue to progress, an individual suffering from the
disease may
experience pain relief. In some embodiments, the pain affects a muscle, nerve,
cartilage,
bone, ligament, tendon, tendon sheaths, bursae, or joint.
[0046]
Migraine is a disabling neurological disorder characterized by recurrent
attacks of
pulsating head pain accompanied by nausea and sensitivity to light and sound.
This pain may
be moderate to severe, but is often severe and incapacitating, requiring bed
rest. The
headaches may affect one half of the head, may be pulsating in nature, and may
last from 2
to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity
to light
(photophobia), sound (phonophobia), or smell. The pain can be made worse by
physical
activity. Migraines may be associated with an aura, which may be a short
period of visual
disturbance which signals that the headache will soon occur. Some migraine
patients may
not have aura.
7
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0047] In
some embodiments, the human being who is being treated for migraine pain
suffers from allodynia with their migraine attacks. Allodynia, which is pain
from normally non-
painful stimuli (such as brushing hair, wearing glasses, taking a shower,
etc.). Patients having
a llodynia are believed to be less likely to respond well to triptan
medications.
[0048]
Current treatments are suboptimal, with more than 70% of sufferers reporting
dissatisfaction with existing acute treatments. The most commonly reported
reasons for
patient dissatisfaction are slow onset of pain relief, inconsistent pain
relief, and recurrence of
pain during the same day. Suboptimal acute treatment is associated with a
significantly
increased risk of new-onset chronic migraine, which may be prevented by
improving acute
treatment outcomes.
[0049]
Administering a subject combination to a human being suffering from migraine,
such as an acute attack of migraine pain or aura, may quickly result in a
reduction in a migraine
symptom, such as pain, nausea, vomiting, photophobia, or phonophobia, such as
at or within
about 5 minutes (intended as a shorthand for "at about 5 minutes, or within
about 5
minutes"), at or within about 10 minutes, at or within about 30 minutes, at or
within about 1
hour, at or within about 90 minutes, at or within about 2 hours, at or within
about 2.5 hours,
or at or within about 3 hours. In some embodiments, a human being experiences
a reduction
of, or complete relief from, pain, such as headache pain or migraine pain,
nausea, vomiting,
photophobia, and/or phonophobia, at or within about 1 hour, at or within about
90 minutes,
at or within about 2 hours, at or within about 2.5 hours, or at or within
about 3 hours. In
some embodiments, the relief experienced, is greater than would be experienced
by receiving
the same amount of rizatriptan without meloxicam. In some embodiments, the
relief
experienced, is greater than would be experienced by receiving the same amount
of
meloxicam without rizatriptan.
[0050] The
combination of meloxicam and rizatriptan may have distinct dual mechanisms
of action for the acute treatment of migraine. Meloxicam is a potent, COX-2
preferential
NSAID which is limited by slow absorption. Rizatriptan is a potent 5-
HT1B/Dagonist believed
to have efficacy in migraine.
[0051]
Observation of relief or reduction in a symptom at a specific period of time,
such
as "at 2 hours," is useful because it allows the effectiveness of the
treatment to be evaluated
at a specific or consistent time point, which facilitates comparison between
patients.
8
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Observation of relief or reduction in a symptom within a specific period of
time, such as
"within about 2 hours," is useful because it is desirable for relief or
reduction of a symptom
to occur as early as possible, and specifying that relief occur within a
specified time sets a
guideline in which it is desirable that relief occur.
[0052] For
some methods, administration of the subject combination may achieve a
reduction in migraine pain, nausea, vomiting, photophobia, or phonophobia that
lasts at least
about one hour, at least about two hours, at least about three hours, at least
about four hours,
at least about six hours, at least about eight hours, about 8-24 hours, about
24 hours, or more
than 24 hours.
[0053] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater pain relief than the human being would have experienced two hours
after receiving
the same amount of meloxicam without the rizatriptan.
[0054] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater pain relief than the human being would have experienced
twenty-four
hours after receiving the same amount of meloxicam without the rizatriptan.
[0055] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater pain relief than the human being would have experienced two hours
after receiving
the same amount of rizatriptan without the meloxicam.
[0056] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater pain relief than the human being would have experienced
twenty-four
hours after receiving the same amount of rizatriptan without the meloxicam.
9
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0057] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from nausea than the human being would have experienced two
hours after
receiving the same amount of meloxicam without the rizatriptan.
[0058] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from nausea than the human being would have
experienced
twenty-four hours after receiving the same amount of meloxicam without the
rizatriptan.
[0059] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from nausea than the human being would have experienced two
hours after
receiving the same amount of rizatriptan without the meloxicam.
[0060] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from nausea than the human being would have
experienced
twenty-four hours after receiving the same amount of rizatriptan without the
meloxicam.
[0061] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from vomiting than the human being would have experienced two
hours after
receiving the same amount of meloxicam without the rizatriptan.
[0062] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from vomiting than the human being would have
experienced
twenty-four hours after receiving the same amount of meloxicam without the
rizatriptan.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0063] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from vomiting than the human being would have experienced two
hours after
receiving the same amount of rizatriptan without the meloxicam.
[0064] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from vomiting than the human being would have
experienced
twenty-four hours after receiving the same amount of rizatriptan without the
meloxicam. In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g.
in a single dosage form, such as a single oral dosage form), and two hours
after the meloxicam
and the rizatriptan are administered, the human being experiences greater
relief from
photophobia than the human being would have experienced two hours after
receiving the
same amount of meloxicam without the rizatriptan.
[0065] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from photophobia than the human being would have
experienced
twenty-four hours after receiving the same amount of meloxicam without the
rizatriptan.
[0066] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from photophobia than the human being would have experienced
two hours
after receiving the same amount of rizatriptan without the meloxicam.
[0067] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from photophobia than the human being would have
experienced
twenty-four hours after receiving the same amount of rizatriptan without the
meloxicam.
11
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0068] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from phonophobia than the human being would have experienced
two hours
after receiving the same amount of meloxicam without the rizatriptan.
[0069] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from phonophobia than the human being would have
experienced
twenty-four hours after receiving the same amount of meloxicam without the
rizatriptan.
[0070] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from phonophobia than the human being would have experienced
two hours
after receiving the same amount of rizatriptan without the meloxicam.
[0071] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from phonophobia than the human being would have
experienced
twenty-four hours after receiving the same amount of rizatriptan without the
meloxicam.
[0072] In
some embodiments, the human being receiving the subject combination has a
history of inadequate response to prior migraine treatments. For example, if
the human
being is asked whether he or she was pain-free within two hours of treatment
for most
attacks, and given the option of answering "never," "rarely," "less than half
the time," or "half
the time or more;" and the human being answers "never," "rarely," or "less
than half the
time," then the human being has had an inadequate response to the treatment.
Similarly, if
the human being is asked whether one dose of medication usually relieved the
human being's
headache and kept it away for at least 24 hours, and given the option of
answering "never,"
"rarely," "less than half the time," or "half the time or more;" and the human
being answers
"never," "rarely," or "less than half the time," then the human being has had
an inadequate
response to the treatment.
12
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0073] In
some embodiments, the human being receiving the subject combination has
indicated that he or she was "never" pain-free within two hours of treatment
for most attacks.
In some embodiments, the human being receiving the subject combination has
indicated that
he or she was "rarely" pain-free within two hours of treatment for most
attacks. In some
embodiments, the human being receiving the subject combination has indicated
that he or
she was pain-free within two hours of treatment for most attacks "less than
half the time."
[0074] In
some embodiments, the human being receiving the subject combination has
indicated that one dose of medication "never" relieved the respondent's
headache and kept
it away for at least 24 hours. In some embodiments, the human being receiving
the subject
combination has indicated that one dose of medication "rarely" relieved the
respondent's
headache and kept it away for at least 24 hours. In some embodiments, the
human being
receiving the subject combination has indicated that one dose of medication
relieved the
respondent's headache and kept it away for at least 24 hours "less than half
the time."
[0075] In
some embodiments, the human being receiving the subject combination has a
history of inadequate response to prior migraine treatments as assessed by a
total mean score
of less than 7, less than 6, less than 5, less than 4, less than 3, less than
2, 1-2, 2-3, 3-4, 4-5, 5-
6, or 6-7 on the Migraine Treatment Optimization Questionnaire (mT0Q-4). In
some
embodiments, the human being has had prior triptan use before receives the
subject
combination, such as a combination comprising meloxicam and rizatriptan.
[0076] In
some embodiments, the human being receiving the subject combination, such
as a combination comprising meloxicam and rizatriptan, has migraine, and may
have a history
of inadequate response to prior migraine treatments. In some embodiments, the
human
being having migraine does not have cluster headaches or other types of
migraines. In some
embodiments, the human being having migraine does not have chronic daily
headache. In
some embodiments, the human being having migraine does not have more than 15,
15-20,
20-25, 25-28, 28-30, or 30-31 non-migraine headache days per month. In
some
embodiments, the human being having migraine does not have a history of
significant
cardiovascular disease. In some embodiments, the human being having migraine
does not
have uncontrolled hypertension.
[0077] In
some embodiments, the dosage form may also be administered to relieve
arthritis pain. In some embodiments the dosage form may be administered to
relieve other
13
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
signs and/or symptoms of arthritis. Examples of arthritis include, but are not
limited to,
rheumatoid arthritis, juvenile rheumatoid arthritis (pauciarticular and
polyarticular course),
osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid),
arthropathies, non-
articular rheumatism, peri-articular disorders, axial spondyloarthritis,
transient osteoarthritis
of the hip, vertebral crush fractures, osteoporosis, and neuropathic
arthropathies including
Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and
SAPHO syndrome.
In other embodiments, the arthritis pain may be chronic or acute. In some
embodiments the
dosage form may be administered to relief the signs and/or symptoms of an
arthritis including
but not limited osteoarthritis
[0078] For
some methods, administration of the dosage form may achieve a reduction in
pain that lasts at least about one hour, two hours, three hours, four hours,
six hours, at least
about eight hours, about eight to about 24 hours, or about 24 hours. In other
embodiments,
administration of the dosage form may achieve a reduction in pain that is
observed at about
minutes, at about 30 minutes, at about one hour, at about two hours, at about
three hours,
at about four hours, at about five hours, at about six hours, at less than 15
minutes, at less
than 20 minutes, 30 minutes, at less than one hour, at less than two hours, at
less than three
hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or other
time period bound
by these ranges, after administration of the dosage form.
[0079] In
some embodiments, the dosage form may also be administered to relieve
neuropathic pain, including diabetic peripheral neuropathy, post-herpetic
neuralgia,
trigeminal neuralgia, monoradiculopathies, phantom limb pain, sciatica,
pudendal neuralgia,
and central pain. Other causes of neuropathic pain may include, but are not
limited to,
cancer-related pain, lumbar nerve root compression, spinal cord injury, post-
stroke pain,
central multiple sclerosis pain, HIV-associated neuropathy, and radio-therapy
or chemo-
therapy associated neuropathy. The neuropathic pain treated may be chronic or
acute.
[0080] In
some methods, the dosage form may be administered to relieve inflammatory
pain including inflammatory musculoskeletal pain, pain due to injury,
arthritis pain, and
complex regional pain syndrome. In other embodiments, the inflammatory pain
may be
chronic or acute.
[0081]
Arthritis refers to inflammatory joint diseases that can be associated with
pain.
Examples of arthritis pain include but are not limited to pain associated with
osteoarthritis,
14
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis,
sero-negative (non-
rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders,
neuropathic
arthropathies including Charcot's foot, axial spondyloarthritis including
ankylosing
spondylitis, and SAPHO syndrome. The inflammatory joint disease treated may be
chronic or
acute.
[0082] For
some methods, the meloxicam may be administered to relieve
musculoskeletal pain. Examples of musculoskeletal pain may include, but are
not limited to,
back pain, low back pain (e.g., lumbosacral pain), neck pain, infection,
cramps, tendonitis,
epidondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to
injury, Tunnel
syndromes, pain associated with bone fractures, sprains, fibrous dysplasia,
osteogenesis
imperfecta, Paget's disease of bone, transient osteoporosis, and transient
osteoporosis of the
hip. In other embodiments, the musculoskeletal pain may be chronic or acute.
[0083] For
some methods, administration of the dosage form or the subject combination
may achieve a reduction in pain that lasts at least about one hour, at least
about two hours,
at least about three hours, at least about four hours, at least about six
hours, at least about
eight hours, about 8 to about 24 hours, or about 24 hours. In other
embodiments,
administration of the subject combination may achieve a reduction in pain that
is observed
at about 10 minutes, at about 30 minutes, at about one hour, at about two
hours, at about
three hours, at about four hours, at about five hours, at about six hours, at
or within about 5
minutes, at or within about 10 minutes, at or within about 15 minutes, at or
within about
20 minutes, at or within about 25 minutes, at or within about 30 minutes, at
or within about
35 minutes, at or within about 40 minutes, at or within about 45 minutes, at
or within about
50 minutes, or at or within about 60 minutes, at two hours or less, at three
hours or less, or
other time period bound by these ranges, after administration of the subject
combination.
[0084] A
human being that is treated for a disease or condition with the dosage forms
described herein may be of any age. For example the person may have an age of
about 10
years to about 90 years, about 20 years to about 80 years, about 30 years to
about 75 years,
about 40 years to about 70 years, about 1 year to about 16 years, about 80
years to about 95
years, about 18 years or more, about 20 years or more, about 25 years or more,
about 30
years or more, about 40 years or more, about 45 years or more, about 50 years
or more,
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
about 55 years or more, about 60 years or more, about 65 years or more, or any
other age in
a range bounded by, or between, these values.
[0085] In
some embodiments, a human being who is treated for migraine with the dosage
forms described herein, for example comprising meloxicam, rizatriptan, SBERCD,
and a
bicarbonate such as sodium bicarbonate, may be of 18 years to 65 years of age,
about 18-20
years of age, about 20-25 years of age, about 25-30 years of age, about 30-40
years of age,
about 40-45 years of age, about 40-50 years of age, about 50-60 years of age,
about 60-65
years of age, or any other age in a range bounded by, or between, these
values.
[0086] In
some embodiments, a human being who is treated for migraine with a dosage
forms described herein, such as a dosage form comprising meloxicam,
rizatriptan, SBE6CD,
and a bicarbonate such as sodium bicarbonate, may be white, black or African
American, or
Asian.
[0087] In
some embodiments, a human being that is treated for a disease or condition
with a dosage form comprising meloxicam or another NSAID has suffered from the
pain or
condition associated with the pain for at least 1 day, at least one week, at
least 2 weeks, at
least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at
least 6 months, or at
least 1 year, or any duration in a range bounded by, or between, these values.
[0088] In
some embodiments, a human being that is treated for migraine with a dosage
form comprising meloxicam and rizatriptan has been diagnosed of migraine with
or without
aura as defined by the ICHD-3 criteria for at least 3 months, at least 6
months, at least 1 year,
at least 2 years, about 1-2 years, 2-3 years, or longer, or at least 1 year,
or any duration in a
range bounded by, or between, these values.
[0089] In
some embodiments, a human being has an average 2 to 8, 2-3, 3-4, 4-5, 5-6, 6-
7, or 7-8 moderate to severe migraines per month.
[0090] A
cyclodextrin used in a dosage form with meloxicam could include a
cyclodextrin,
a cyclodextrin derivative, and/or a salt thereof. An inclusion complex of
meloxicam and
cyclodextrin may be more water-soluble relative to the non-complexed
meloxicam. The
cyclodextrin may be a naturally-occurring cyclodextrin (e.g., a, 13, or y-
cyclodextrins) or a
synthetic cyclodextrin. In some embodiments, a-cyclodextrins, derivatives, or
salts thereof
may be used. a-Cyclodextrins may include, but are not limited to, (2,3,6-tri-O-
acetyp-a-
16
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
cyclodextrin, (2,3,6-tri-0-methyl)-a-cyclodextrin, (2,3,6-tri-0-octy1)-a-
cyclodextrin, 6-bromo-
6-deoxy-a-cyclodextrin, 6-iodo-
6-deoxy-a-cyclodextrin, (6-0-tertbutyl-dimethylsi lyI)-a-
cyclodextrin, butyl-a-cyclodextrin, succinyl-a-cyclodextrin, (2-hydroxypropy1)-
a-cyclodextrin,
or combinations thereof.
[0091] In
some embodiments, 13-cyclodextrins, derivatives, or salts thereof may be used.
3-cyclodextrins may include, but are not limited to, hydroxypropyl-P-
cyclodextrin, 6-
monodeoxy-6-monoamino-8-cyclodextrin, glucosy1-8-cyclodextrin, nnaltosyl-P-
cyclodextrin,
6-0-a-D-glucosy1-8-cyclodextrin, 6-0-a-
maltosy1-8-cyclodextrin, 6-azido-6-deoxy-13-
cyclodextrin, (2,3-di-O-acety1-6-0-sulfo)-3-cyclodextrin, methy1-13-
cyclodextrin, di methyl-13-
cyclodextrin (DMI3CD), trinnethy1-8-cyclodextrin (TIVII3CD), (2,3-di-0-methy1-
6-0-sulfo)-13-
cyclodextrin, (2,6-di-0-methyl)-13-cyclodextrin, (2,6-di-0-ethyl)- 8-
cyclodextri n, (2,3,6-tri-0-
methyl)-8-cyclodextrin, (2,3,6-
tri-0-acetyl)-13-cyclodextrin, -(2,3,6-tri-0-benzoy1)-13-
cyclodextrin, ( 2,3,64 ri-0-ethyl)-13-cyclodextrin, 6-iodo-6-deoxy-I3-
cyclodextri n, 6-(d imethyl-
tert-butylsi lyI)-6-deoxy-3-cyclodextrin, 6-
bromo-6-deoxy-3-cyclodextrin, monoacety113-
cyclodextrin, diacety1-8-cyclodextrin, triacety1-13-cyclodextrin, (3-0-acety1-
2,6-di-0-methyl)-13-
cyclodextrin, (6-0-ma Itosyl)-13-cyclodextrin, (6-0-
sulfo)-3-cyclodextrin, (6-0-t-
butyldimethylsily1-2,3-di-0-acety1)13-cyclodextrin, succinyl-(2-hydroxypropy1)-
3-cyclodextrin,
(2,6-d i-0-)ethy1-8-cyc lodextrin, ( 2-ca rboxyethyl)-8-cyclodextrin (CM
Ei3CD), hyd roxyethy1-13-
cyclodextrin (HE13CD), (2-hydroxypropy0-13-cyclodextrin, (2-hydroxypropyI)-3-
cyclodextrin
(HP13CD), (3-hydroxypropyI)-8-cyclodextrin (3HP13CD), (2,3-hydroxypropyI)-8-
cyclodextrin
(DHPI3CD), butyl-3-cyclodextrin, methyl-3-cyclodextrin, sily1((6-0-tert-
butyldimethyl)-2,3,-di-
0-acetyl)-8-cyclodextrin, succiny1-8-cyclodextrin, (2-hydroxyisobuty1)- 3-
cyclodextrin,
randomly methylated-8-cyclodextrin, branched-P-cyclodextrin, or combinations
thereof.
[0092] In
other embodiments, a 8-cyclodextrin may be a sulfoalkyl ether cyclodextrin,
derivative, or salt thereof. Examples of sulfoalkyl ether cyclodextrin
derivatives may include,
but are not limited to, sulfobutyl ether-8-cyclodextrin (e.g., SBEI3CD,
betadex, CAPTISOL ). In
some embodiments, a SBE 8CD may have about 4-8, about 5-8, about 4-7, about 6-
7, or about
6.5 sulfobutyl ether groups per cyclodextrin molecule.
[0093] In
some embodiments, y-cyclodextrins, derivatives, or salts thereof may be used.
y-cyclodextrins may include carboxymethyl-y-cyclodextrin, (2,3,6-tri-0-acetyl)-
y-cyclodextrin,
(2,3,6-tri-0-methyl)-y-cyclodextrin, (2, 6-
di-O-penty1)-y-cyclodextrin, 6-(di methyl-tert-
17
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
butylsily1)-6-deoxy-y-cyclodextrin, 6-
bronno-6-deoxy-y-cyclodextrin, 6-iodo-6-deoxy-y-
cyclodextrin, (6-0-t-butyldimethylsilyI)-y-cyclodextrin,
succinyl-y-cyclodextrin,
hydroxypropyl-y-cyclodextrin (2-hydroxypropyI)-y-cyclodextrin, acetyl-y-
cyclodextrin, butyl-
y-cyclodextrin, or combinations thereof.
[0094] In
some embodiments, the dosage form may include a bicarbonate, such as
sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium
bicarbonate,
ammonium bicarbonate, or a combination thereof. A bicarbonate may help to
increase
bioavailability of the meloxicam.
[0095] In
other embodiments, the dosage form may include a carbonate, derivatives, or
salts thereof. Examples of carbonates may include aluminum carbonate, ammonium
carbonate, barium carbonate, calcium carbonate, cobalt(II) carbonate,
lanthanum carbonate,
lithium carbonate, magnesium carbonate, manganese(II) carbonate, potassium
carbonate,
sodium carbonate, or combinations thereof.
[0096] In
some embodiments, enhanced bioavailability of the dosage form may be
achieved in treating one of these conditions by administering a dosage form
comprising a salt
form of the meloxicam, by creating an inclusion complex with meloxicam and
cyclodextrin,
and/or by including a bicarbonate. This may allow a reduced molar amount of
the meloxicam
to be used as compared to other meloxicam dosage forms.
[0097] Unless
otherwise indicated, any reference to a compound herein, such as
meloxicam or a cyclodextrin, by structure, name, or any other means, includes
pharmaceutically acceptable salts, alternate solid forms, such as polymorphs,
solvates,
hydrates, enantiomers, tautomers, deuterium-modified forms, or any other
chemical species
that may rapidly convert to a compound described herein under conditions in
which the
compounds are used as described herein.
[0098] In
some embodiments, use of a cyclodextrin, a carbonate, or a bicarbonate may
improve the oral bioavailability of meloxicam by at least about 10%, at least
about 20%, at
least about 30%, at least about 40%, at least about 50%, at least about 60%,
at least about
70%, at least about 80%, at least about 90%, up to about 100%, up to about
200%, or any
amount in a range bounded by, or between, these values as compared to
administration of
meloxicam alone.
18
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0099] Due to
the improved bioavailability, the dosage form may contain, or a subject
may receive, on a molar basis, less of the meloxicam than would otherwise be
administered.
For example, a dosage form may contain, or a mammal may receive, at least
about 10 mole%
less, at least about 20 mole% less, at least about 30 mole% less, at least
about 40 mole% less,
at least about 50 mole% less, at least about 60 mole% less, at least about 70
mole% less, at
least about 80 mole% less, at least about 85 mole% less, and/or up to about 90
mole% less,
95 mole% less, or any amount in a range bounded by, or between, these values
as would
otherwise be administered of meloxicam.
[0100] In
other embodiments, use of other NSAIDs, opioids, or other pain medications
may be reduced by at least about 5%, at least about 10%, at least about 15%,
at least about
20%, at least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least
about 45%, at least about 50%, at least about 60%, at least about 70%, at
least about 80%, or
at least about 90%, up to about 100%, as compared to the use of other NSAIDs,
opioids or
other pain medications without administration of meloxicam with cyclodextrin,
carbonate,
and/or bicarbonate.
[0101] In
some embodiments, a dosage form may contain meloxicam in an amount from
about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about 1-35 mg;
about 1-25
mg; about 1-15 mg; about 5-20 mg; about 5-10 mg; about 5-15 mg; about 10-20
mg; about
20-30 mg; about 30-40 mg; about 40-50 mg; about 5 mg; about 7,5 mg; about 10
mg; about
15 mg; about 30 mg; or any amount in a range bounded by, or between, any of
these values.
These doses may be a safe dose for repeated administration, such as once
hourly dosing to
once daily dosing, twice daily dosing, dosing one to 12 times daily, doing 3,
4, 5, or 6 times
daily, etc. In some embodiments, the meloxicam may be safely administered 2,
3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times a day,
once a day, or less
frequently, such as once a week, once every two weeks, once a month, etc.
[0102] For
some dosage forms, meloxicam forms a complex with the substituted-13-
cyclodextrin or other another cyclodextrin which may be formulated into a
solid dosage form.
Such a dosage form may be suitable for oral administration. A meloxicam-
cyclodextrin
inclusion complex may also be dissolved in water or another solvent to form a
parenteral
formulation. However, physical mixtures of meloxicam and the substituted-13-
cyclodextrin or
other cyclodextrins may also be used in oral or parenteral dosage forms.
19
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0103]
Formation of an inclusion complex of meloxicam and a cyclodextrin may help to
improve the properties of a dosage form. For some inclusion complexes, the
meloxicam and
the cyclodextrin (e.g., SBE13CD) may have a molar ratio of about 0.5-2 (a
molar ratio of 0.5 is
0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-
0.8, about 0.7-
0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4,
about 1.3-1.5, about
1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-
1.2, about 1, or
any ratio in a range bounded by any of these values.
[0104] For
some dosage forms, a cyclodextrin (e.g., SBE13CD) may be employed in a weight
ratio to the meloxicam within the range from about 1-1000 (e.g. 1 g of
cyclodextrin per 1 g of
meloxicam is a weight ratio of 1); about 1-20; about 1-10; about 1-15; about 2-
4, about 3-5,
about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in
a range bounded
by, or between, any of these values. For some dosage forms, a cyclodextrin
(e.g., SBEr3CD)
may be employed in a weight ratio to the meloxicam within the range from about
0.001-1
(e.g. 0.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 0.1);
about 0.01-1; about
0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about
0.6-1, about
0.7-1, about 0.8-1, or any weight ratio in a range bounded by, or between, any
of these values.
Each type of cyclodextrin employed may have a different ratio.
[0105] For
some dosage forms, the cyclodextrin may be present in an amount from about
1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about
100-175
mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about 80-100 mg; about 80-
120 mg;
about 100-120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about
30-90
mg; about 40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any
amount in a
range bounded by, or between, any of these values.
[0106] For
some methods, the inclusion complex of meloxicam and cyclodextrin such as
a substituted-13-cyclodextrin is delivered orally (for example by tablet,
capsule, elixir, or the
like). Other potential routes of administration include intravenous,
intramuscular, intranasal,
lyophilized parenteral, subcutaneous, transdermal, transmucosal, or through
other
parenteral means. The meloxicam may also be delivered alone or non-complexed
with
cyclodextrin.
[0107] Some
dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in amount
from about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about 200-800 mg;
about 1-
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg;
about 100-
500 mg; about 100-300 mg; about 500-1000 mg; about 300-700 mg; about 400-600
mg; about
50-250 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400
mg;
about 400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about
440-540
mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about 480-580 mg;
about 490-
590 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about 800-900
mg; about
150-650 mg; about 350-850 mg; or any amount in a range bounded by, or between,
any of
these values.
[0108] Some
dosage forms contain a carbonate in amount from about 1-1000 mg; about
1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg;
about
100-500 mg; about 100-300 mg; about 200-800 mg; about 500-1000 mg; about 300-
700 mg;
about 400-600 mg; about 50-250 mg; about 250-750 mg; about 100-200 mg; about
200-300
mg; about 300-400 mg; about 400-500 mg; about 500-600 mg; about 600-700 mg;
about 700-
800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or any amount in
a range
bounded by, or between, any of these values.
[0109] In
some embodiments, the daily dose of meloxicam (e.g., an oral dose, a
parenteral
dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-
9 mg, about
2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-
15 mg, about
2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-
21 mg, about
2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-
27 mg, about
2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-
10 mg, about
10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or
any amount
in a range bounded by any of these values.
[0110] In
some embodiments, the weekly dose of meloxicam (e.g., an oral dose) is about
1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg;
about
10-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about 30-70 mg;
about 40-
60 mg; about 50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55
mg; about
100-150 mg; about 30-100 mg; or any amount in a range bounded by, or between,
any of
these values. The weekly dose may be given as a single dose, given once during
the week, or
may be given in 2, 3, 4, 5, 6, or 7 individual doses during the week.
21
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0111] In
some embodiments, the monthly dose of meloxicam (e.g., an oral dose), or a
dose administered over a period of a month, is about 5000 mg or less; about
4000 mg or less;
about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700
mg or less;
about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg;
about 50-1000
mg; about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg; about
50-200
mg; about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg;
about 360-
400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350
mg; about
100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800
mg;
about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; or any monthly dose in
a range
bounded by, or between, any of these values. A monthly dose may be given as a
single dose,
or as two or more individual doses administered during the month. In some
embodiments,
the monthly dose is administered in 2 or 3 bi-weekly doses. In some
embodiments, the
monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the
monthly
dose is administered in 28 to 31 daily doses, or in 56 to 62 daily doses or
more. In some
embodiments, the monthly dose is administered in 5 to 15 individual doses
during the month.
The monthly dose may be administered for only 1 month, or may be repeatedly
administered
for 2 or more months.
[0112] In
other embodiments, the dosage form may be administered weekly for about
one, two, three, four, or more consecutive weeks, every other week or bi-
weekly, or once
every three weeks. This regimen may be repeated once weekly, twice in a month,
three times
in a month, once monthly, once every two months, once every three months, or
as directed
by a medical professional.
[0113] In
certain embodiments, the pharmaceutical composition results in increased
bioavailability (e.g., reduced Tmax, increased Crnax, increased AUC, etc.) of
the meloxicam from
the dosage form as compared to a dosage form containing meloxicam but not
containing a
cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).
In some
embodiments, the bioavailability of meloxicam will increase with multiple
dosing. For
example, the bioavailability of meloxicam in the dosage form may increase
after about 1-10
days of dosing; about 2-6 days of dosing; about 3-5 days of dosing; about 4-6
days of dosing;
about 5-8 days of dosing; about 5 days of dosing; about 6 days of dosing;
about 7 days of
dosing; about 8 days of dosing; about 10 days of dosing; about 15 days of
dosing; or time in
22
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
any range bounded by, or between, any of these values; as compared to the
bioavailability of
meloxicam in a dosage form not containing a cyclodextrin, an acid inhibitor,
or a buffering
agent (such as a bicarbonate).
[0114] Some
of the dosage forms may result in a desired range for an area under the
plasma concentration curve (AUC) of meloxicam. For example the dosage with
meloxicam
may result in an AUC of meloxicam of about 1-150 p.g-hr/mL; about 10-30 lig-
hr/mL; about
20-40 pg=hrimL; about 30-50 pg.hr/mL; about 40-60 pg.hr/mL; about 50-70
lig=hrimL; about
60-80 pg-hr/mL; about 70-90 g-hr/mL; about 80-100 p.g.hrimL; about 10-100 g-
hr/mL;
about 50-150 pg-hr/mL; about 25-125 pg-hr/mL; about 75-150 pg-hrinnL; about 20-
50
lig.hrimL; about 40-70 pg.hrirnL; about 60-90 Fig.hrimL; about 80-110
lig.hr/mL; about 100-
130 p.g=hr/mL; about 120-150 1.,tg=hr/mL; or any AUC in a range bounded by, or
between, any
of these values.
[0115] Unless
otherwise indicated, the AUC refers to the AUC calculated to the last
measured concentration (AUCa-t), such as, over a period of 6 hours (AUC0-6),
over a period of
12 hours (AUC0_12), over a period of 24 hours (AUC0_24), or extrapolated to
infinity (AUCo-inf).
[0116] In
Example 3 below, the AUC0_24of meloxicam in human beings for an oral dosage
form containing sodium bicarbonate and sulfobutylether 3-cyclodextrin (SBE3CD)
was about
27 iig-hrimL. This dosage form contained 15 mg of meloxicam.
[0117] The 15
mg IV and intramuscular doses also provide an AUC0_24 of meloxicam in
human beings that is about 27 pg=hr/mL. The AUC of meloxicam is believed to be
approximately dose proportional. So for this oral dosage form, or for an IV or
intramuscular
dosage form, a meloxicam dose of, for example, approximately 17 mg to about 30
mg would
be expected to result in an AUC0_24of meloxicam of about 30-50 pg.hrimL.
[0118] For
some acute pain conditions, such as migraine and other types of headache, the
AUC for a short period after oral administration, such as an AUC measured over
6 hours (or
AUC0_6), may be of particular interest. For example, some dosage forms may
result in an AUCo_
6 of at least about 6 g=hr/mL; at least about 7 pg=hr/mL; at least about 8
lig=hrimL; at least
about 9 pg-hr/mL; about 6-10 p.g.hrinnL; about 7-11 p.g.hr/mL; about 8-12 lig-
hr/mL; about 9-
13 pg.hr/mL; or any AUC in a range bounded by, or between, any of these
values.
23
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0119] In
some embodiments, the dosage form may result in a C. of meloxicam of about
10-2500 ng/mL; about 100-2250 ng/mL; about 500-2000 ng/mL; about 1000-2500
ng/mL;
about 1000-2000 ng/mL; about 100-900 ng/mL; about 750-1500 ng/mL; about 1250-
2000
ng/mL; about 1500-2300 ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL;
about 50-
500 ng/mL; about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200 ng/mL;
about
1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100 ng/mL; about 1500-1900
ng/mL; about 1600-2100 ng/mL; about 1700-2000 ng/mL; about 1800-2000 ng/mL;
about
1900-2500 ng/mL; about 150-1700 ng/mL; about 1600-1800 ng/mL; about 1700-1900
ng/mL;
about 1800-2000 ng/mL; about 1900-2100 ng/mL; about 2000-2200 ng/mL; about
2100-2300
ng/mL; about 2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or
any
C. in a range bounded by, or between, any of these values.
[0120] For
example, a method described herein may reduce the Tmax of meloxicam. In
some embodiments, the method may include treating a patient to achieve the
Tmax of
meloxicam in the patient within about 10 minutes; about 20 minutes; about 30
minutes;
about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about
80 minutes;
about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes;
about 180
minutes; about 1-10 hr; about 2-9 hr; about 3-7 hr; about 4-6 hr; about 1-5
hr; about 2-7 hr;
about 3-8 hr; about 4-9 hr; about 1-4 hr; about 2-5 hr; about 3-6 hr; about 4-
7 hr; about 5-8
hr; about 6-9 hr; about 7-10 hr; after administration or any Tmax in a range
bounded by, or
between, any of these values.
[0121] In
some embodiments, an oral dosage form may have a T. of meloxicam that is
shorter than would be achieved by administering meloxicam by intramuscular
injection. In
some embodiments, an oral dosage form may have a Tmax of meloxicam that is
shorter, or
may increase meloxicam plasma levels at a faster rate, by a factor of at least
about 1.5, about
2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,
about 12, about
15, about 20, or by a factor of about 1.5-1000, about 2-100, about 3-100,
about 4-100, about
5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about
12-100,
about 15-100, about 20-100, or by a factor in a range bounded by any of these
values.
[0122] In
some embodiments, a dosage form comprising meloxicam may result in a
plasma concentration of meloxicam at 12 hours that is about 0.01-0.5 lig/nnL;
about 0.5-0.7
p.g/ml.; about 0.6-0.8 p.g/mL; about 0.7-0.9 p.g / m L ; about 0.8-1 pg/mL;
about 0.9-1.1 I.J.g/nriL;
24
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
about 1-1.2 p.g/mL; about 1.1-1.3 p.g/mL; about 1.2-1.4 p.g/mL; about 1.3-1.5
pg/mL; about
1.4-1.6 pg/mL; about 1.5-1.7 pg/mL; about 1.6-1.8 g/mL; about 1.7-1.9 pg/mL;
about 1.8-2
g/mL; about 1.9-2.1 pginnL; about 2-2.2 pg/nnL; about 2.1-2.3 pg/mL; about 2.2-
2.4 p.g/mL;
about 2.3-2.5 pg/mL; about 2.4-2.6 g/mL; about 2.5-2.7 pg/mL; about 2.6-2.8
pg/mL; about
2.7-2.9 p.g/mL; about 2.8-3 p.g/mL; about 2.9-3.1 p.g/mL; about 3-3.2 p.g/mL;
about 3.1-3.3
pg/mL; about 3.2-3.4 Wm L; about 3.3-3.5 g/mL; about 3.4-3.6 p.g/mL; about
3.5-3.7 pg/mL;
about 3.6-3.8 p.g/mL; about 3.7-3.9 pg/mL; about 3.8-4 p.g/mL; or any plasma
concentration
in a range bounded by, or between, any of these values.
[0123] In
some embodiments, meloxicam is administered at a dose that results in a
meloxicam plasma level (such as a Cavg, or average plasma level) of about 0.01-
0.5 pg/mL;
about 0.5-0.7 g/mL; about 0.6-0.8 p.g/mL; about 0.7-0.9 pg/mL; about 0.8-1
p.g/mL; about
0.9-1.1 p.g/mL; about 1-1.2 pg/mL; about 1.1-1.3 g/mL; about 1.2-1.4 pg/nnL;
about 1.3-1.5
Ont.; about 1.4-1.6 p,g/mL; about 1.5-1.7 dm L; about 1.6-1.8 pg/mL; about
1.7-1.9 pg/mL;
about 1.8-2 p.g/mL; about 1.9-2.1 pg/mL; about 2-2.2 pginnL; about 2.1-2.3
p.g/mL; about 2.2-
2.4 pg/mL; about 2.3-2.5 pg/mL; about 2.4-2.6 pg/mL; about 2.5-2.7 pg/mL;
about 2.6-2.8
pg/mL; about 2.7-2.9 p.g/mL; about 2.8-3 p.g/mL; about 2.9-3.1 pg/mL; about 3-
3.2 p.g/mL;
about 3.1-3.3 pg/mL; about 3.2-3.4 g/mL; about 3.3-3.5 pg/mL; about 3.4-3.6
pg/mL; about
3.5-3.7 ilg/mL; about 3.6-3.8 p.g/mL; about 3.7-3.9 p.g/mL; about 3.8-4
p.g/mL; about 0.1-20
pg/mL; about 0.5-15 pginnL; about 0.5-10 pg/nnL; about 5-15 pg/mL; about 10-20
pg/mL;
about 7.5-15 g/mL; about 2-10 p.g/mL; about 1-8 g/mL; about 1-6 p.g/nnL;
about 1-2 pg/mL;
about 0.5-3.5 p.g/mL; about 0.5-7 p.g/mL; about 12-20 pginnL; about 8-12
p.g/mL; about 1-4
pg/mL; about 4-7 g/mL; about 7-11 pg/mL; about 11-15 pg/mL; about 15-19
pg/mL; about
16-20 pg/nnL; or any amount of meloxicam plasma level in a range bounded by,
or between,
any of these values.
[0124]
Administration of a dosage form described herein may result in a decreased
time
to therapeutic plasma concentration of meloxicam. The therapeutic plasma
concentration is
the Cavg for a 15 mg dose of Mobic meloxicam. In some embodiments, the time
to
therapeutic plasma concentration of meloxicam (T ) i
about 10-30 minutes, about 10-15
thera, .S
minutes, about 15-20 minutes, about 20-25 minutes, about 25-30 minutes, about
10-20
minutes, about 20-30 minutes, about 16-18 minutes, or about 17 minutes.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0125] A
method described herein may reduce the Tmax of rizatriptan. For example, the
method may achieve a Tmax of rizatriptan in the patient within about 50
minutes; within about
60 minutes; within about 70 minutes; within about 80 minutes; or within about
90 minutes;
at about 40-60 minutes, at about 40-45 minutes, at about 45-50 minutes, at
about 50-55
minutes, or about 55-60 minutes after administration, or any Tmax in a range
bounded by any
of these values.
[0126] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from allodynia than the human being would have experienced two
hours after
receiving the same amount of meloxicam without the rizatriptan.
[0127] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from allodynia than the human being would have
experienced
twenty-four hours after receiving the same amount of meloxicam without the
rizatriptan.
[0128] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and two hours
after the meloxicam and the rizatriptan are administered, the human being
experiences
greater relief from allodynia than the human being would have experienced two
hours after
receiving the same amount of rizatriptan without the meloxicam.
[0129] In
some embodiments, the meloxicam and the rizatriptan are administered
simultaneously (e.g. in a single dosage form, such as a single oral dosage
form), and twenty-
four hours after the meloxicam and the rizatriptan are administered, the human
being
experiences greater relief from allodynia than the human being would have
experienced
twenty-four hours after receiving the same amount of rizatriptan without the
meloxicam.
[0130] One
embodiment is a method for reducing the risk of gastrointestinal side effects
in people taking NSAIDs for pain relief and for other conditions, particularly
during chronic
treatment, and improving the bioavailability of the NSAID. In one embodiment,
the method
involves the administration of a product that combines: a) an agent that
actively raises
26
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
intragastric pH; and b) an NSAID that is formulated with a cyclodextrin. In
another
embodiment, the method involves the administration of a product that combines:
a) an agent
that actively raises intragastric pH; b) an NSAID that is formulated with a
cyclodextrin; and c)
a buffering agent. Either short or long acting acid inhibitors can be
effectively used in the
dosage forms. This method has the added benefit of being able to protect
patients from other
gastrointestinal ulcerogens whose effect may otherwise be enhanced by the
disruption of
gastroprotective prostaglandins due to NSAID therapy.
[0131] The
meloxicam formulation in an aqueous parenteral form may include a buffer to
adjust the pH of an aqueous formulation, within a range of about 2 to about 5;
about 3.5 to
about 5; about 5 to about 11; about 6 to about 9; about 6 to about 8; about 6
to about 7; or
any other pH in a range bounded by, or between, any of these values. The
meloxicam
formulation in an oral form may include a buffer to adjust the pH of stomach
fluid within a
range of about 2 to about 5; about 3.5 to about 5; about 5 to about 11; about
6 to about 9;
about 6 to about 8; about 6 to about 7; or any other pH in a range bounded by,
or between,
any of these values. Examples of buffers suitable for use herein include
sulfate buffers,
phosphate buffers, borate buffers, carbonate buffers, citrate buffers, etc.
[0132] In
some embodiments, the dosage form may be formulated for oral
administration, for example, with an inert diluent or with an edible carrier,
or it may be
enclosed in hard or soft shell gelatin capsules, compressed into tablets, or
incorporated
directly with the food of the diet. For oral therapeutic administration, the
active compound
may be incorporated with an excipient and used in the form of ingestible
tablets, buccal
tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions,
solutions, syrups,
wafers, patches, and the like.
[0133]
Tablets, troches, pills, capsules and the like may also contain one or more of
the
following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an
excipient, such
as dicalcium phosphate; a disintegrating agent such as corn starch, potato
starch, a lginic acid
and the like; a lubricant such as magnesium stearate; a sweetening agent such
as sucrose,
lactose or saccharin; or a flavoring agent such as peppermint, oil of
wintergreen or cherry
flavoring. When the unit dosage form is a capsule, it may contain, in addition
to materials of
the above type, a liquid carrier. Various other materials may be present as
coating, for
instance, tablets, pills, or capsules may be coated with shellac, sugar or
both. A syrup or elixir
27
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
may contain the active compound, sucrose as a sweetening agent, methyl and
propylpa ra bens as preservatives, a dye and flavoring, such as cherry or
orange flavor. It may
be desirable for material in a dosage form or pharmaceutical composition to be
pharmaceutically pure and substantially non-toxic in the amounts employed.
[0134] Some
compositions or dosage forms may be a liquid, or may comprise a solid
phase dispersed in a liquid.
[0135] The
dosage form may further comprise a second therapeutically active agent, such
as an acid inhibitor or an analgesic.
[0136] In
some embodiments, the dosage form may further comprise an acid inhibitor
present in an amount effective to raise the gastric pH of a patient to at
least 2, to at least 2.5,
to at least 3, to at least 3.5, to at least 4, and more to at least 5, when
one or more unit dosage
forms are administered. The term "acid inhibitor" refers to agents that
inhibit gastric acid
secretion and increase gastric pH. Specific H2 blockers, also referred to as
H2 antagonists or
histamine H2 blockers or antagonists, that may be used include but are not
limited to
cimetidine, ranitidine, ebrotidine, pa butidine, lafutidine, loxtidine,
famotidine, or
combinations thereof.
[0137] Other
agents that may be effectively used as acid inhibitors are the proton pump
inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole,
dexlansoprazole,
rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments
the daily
dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg,
about 40-80 mg,
about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg,
about 15-
50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg or
any other
amount in a range bounded by, or between, any of these values.
[0138]
Examples of particular proton pump inhibitors include esomeprazole, present in
unit dosage forms in an amount of between 5 mg and 50 mg; omeprazole, present
in unit
dosage forms in an amount of between 5 mg and 50 mg; lansoprazole, present in
unit dosage
forms in an amount of between 5 mg and 150 mg (and preferably at between 5 mg
and 30
mg); and pantoprazole, present in unit dosage forms in an amount of between 10
mg and 200
mg. In some embodiments, the proton pump inhibitor is present in the dosage
form in an
amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg,
about 50-70
28
88793254
mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newer
class of acid
inhibitor has been developed which competes with potassium at the acid pump.
The
compounds in this class have been referred to as "reversible proton pump
inhibitors" or "acid
pump antagonists" and may also be used. Examples include AZD-0865, AR-H047108,
CS-526,
punnaprazole, revaprazan and soraprazan (see W09605177 and W09605199). Other
compounds in this group are H-335/25 (AstraZeneca, Dialog file 128, accession
number
020806); Sch-28080 (Schering Plough, Dialog file 128, accession number
009663); Sch-32651
(Schering Plough, Dialog file 128, accession number 006883) and SK&F-96067
(CAS Registry
no. 115607-61-9).
[0139] The second
therapeutically active agent may include an analgesic such as a second
non-steroidal anti-inflammatory drug, an opioid, a steroid, a triptan, etc.
In some
embodiments, the dosage form or treatment also further comprises administering
a second
non-steroidal anti-inflammatory drug in an amount effective to reduce or
eliminate pain or
inflammation. The NSAID may include, but is not limited to, celecoxib,
rofecoxib, lumiracoxib,
valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398,
aspirinTM, acetaminophen
(considered to be an NSAID for the purposes of the present disclosure),
ibuprofen,
flu rbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indonnethacin,
ketorolac,
lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac,
meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen,
suprofen,
benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone,
phenylbutazone, or combinations thereof. It will be understood that, for the
purposes of the
present disclosure, reference to an acid inhibitor, NSAID, or analgesic agent
will include all of
the common forms of these compounds and, in particular, their pharmaceutically
acceptable
salts. The amounts of NSAIDs which are therapeutically effective may be lower
in the current
embodiments than otherwise found in practice due to potential positive kinetic
interaction
and NSAID absorption in the presence of an acid inhibitor, and or in the
presence of a
buffering agent.
[0140] In other
embodiments, the dosage form or treatment may further comprise
administering an opioid in an amount effective to reduce or eliminate pain or
inflammation.
The opioid may include, but is not limited to, (dextro)propoxyphene, A-
methylfentanyl,
a lfentanil, a I lylprodine, bezitramide,
buprenorphine, butorphanol, carfentanyl,
29
Date Recue/Date Received 2023-01-10
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
desmethylprodine, dextromoramide, dezocine, diacetylmorphine,
dihydrocodeinone,
dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl,
ketobemidone, lefetamine, levacetylmethadol, levomethorphan, levorphanol,
loperamide,
meperidine, meptazinol, methadone, nnethylmorphine, morphine, nalbuphine,
nalmefene,
naloxone, naltrexone, nicomorphine, ohmefentanyl, oripavine, oxycodone,
oxymorphone,
PEPAP, paramorphine, pentazocine, phenazocine, piritramide, prodine,
remifentanil,
sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.
[0141] Useful
triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan,
donitriptan, alnnotriptan, frovatriptan, alvitriptan, zolmatriptan, etc. In
some embodiments,
the triptan comprises rizatriptan. In some embodiments, the dosage form may
contain about
1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11
mg, about 7-
12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 15-20 mg, or about
20-30 mg,
of the triptan, such as rizatriptan, or any amount in a range bounded by any
of these values.
[0142] In
some embodiments; a dosage form comprising the subject combination may
contain rizatriptan in an amount of about 1-50 mg; about 1-10 mg; about 10-20
mg; about
20-30 mg; about 30-40 mg; or about 40-50 mg; about 10-40 mg; about 1-35 mg;
about 1-25
mg; about 1-15 mg; about 1-10 mg; about 5-20 mg; about 1-5 mg; about 2-6 mg;
about 3-7
mg; about 4-8 mg; about 5-10 mg; about 6-11 mg; about 7-12 mg; about 8-13 mg;
about 9-11
mg; about 9-14 mg; about 10-15 mg; about 11-16 mg; about 12-17 mg; about 13-18
mg; about
14-19 mg; about 15-20 mg; about 5-15 mg; about 0.5 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 6
mg; about 7 mg; about 7.5 mg; about 8 mg, about 9 mg, about 10 mg; about 15
mg; about 20
mg, about 25 mg, about 30 mg; or any amount in a range bounded by, or between,
any of
these values.
[0143] For
acute migraines, the amount of meloxicam and/or rizatriptan in a single dose,
or the AUC of the meloxicam and/or rizatriptan associated with a single dose,
is of particular
interest. For example, after a single dose, the symptoms may be relieved for
an extended
period of time, such that, in the short term, repeated doses may not be
needed. For more
continuous conditions, including more chronic, continuous, or frequent
migraine symptoms,
daily, weekly, or monthly doses may be of particular interest.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0144] For
any amounts of rizatriptan described herein, salt forms of rizatriptan may be
present in the amounts recited above, or amounts that are molar equivalents to
these
amounts for the rizatriptan free base. For example, assuming that the
molecular weight of
rizatriptan free base is 269.3 g/mol, 10 mg of rizatriptan is 37.1 mmol of
rizatriptan. Thus, a
molar equivalent of 10 mg of rizatriptan free base would be the mass of 37.1
mmol of that
salt form. For example, for the benzoate salt (mw = 391.2 g/mol), the molar
equivalent of 10
mg of the free base (or 37.1 mmol), would be 14.5 mg. These doses may be safe
for repeated
administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval
of 2 days, 3 days, 4
days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13
days, 14 days, 15
days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days,
24 days, 25 days,
26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks,
about 1-2 months,
about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6
months,
about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about
10-11
months, about 11-12 months, etc.
[0145] A
pharmaceutical composition may be in the form of a tablet or capsule that has:
(a) the acid inhibitor; and/or (b) a buffering agent; and (c) the non-
steroidal anti-inflammatory
drug (NSAID) present in an amount effective to reduce or eliminate pain or
inflammation in a
patient upon administration of one or more of said unit dosage forms. The
components of
the pharmaceutical composition may be in an immediate or extended release form
individually or in total.
[0146] The
term "unit dosage form" as used herein refers to a single entity for drug
administration. For example, a single tablet or capsule combining both an acid
inhibitor and
an NSAID would be a unit dosage form. A "unit dosage form" (or "unit dose
form") may also
be referred to as a "fixed dosage form" (or "fixed dose form") or "fixed
dosage combination"
(or "fixed dose combination") and are otherwise interchangeable. In one
embodiment, the
unit dosage form is a multilayer tablet.
[0147] In
another embodiment, the unit dosage form is suitable for oral administration
to a patient. In yet another embodiment, the unit dosage form is a tablet. In
still another
embodiment, the unit dosage form is a multilayer tablet comprising a single
core and one or
more layers outside of the core.
31
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0148] Some
dosage forms may comprise a first layer comprising meloxicam, an SBE3CD,
and a bicarbonate; and a second layer comprising a second therapeutically
active agent and
a bicarbonate.
[0149] The
first layer may contain, for example, any amount of meloxicam in one of the
ranges recited above. For example, all of the meloxicam in the dosage form may
be present
in the first layer. The second layer may contain all of the second
therapeutically active agent,
such that any amount in the ranges recited above with respect to the second
therapeutically
active agent may apply to the second layer.
[0150] In
some embodiments, the first layer contains about 10-200 mg, about 50-150 mg,
about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of the
bicarbonate,
such as sodium bicarbonate, or any amount of the bicarbonate in a range
bounded by any of
these values.
[0151] In
some embodiments, the second layer contains about 100-500 mg, about 200-
500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg
of the
bicarbonate, such as sodium bicarbonate, or any amount of the bicarbonate in a
range
bounded by any of these values.
[0152] In
some embodiments, the pharmaceutical composition may have an effective
amount of meloxicam, a cyclodextrin, and a carbonate or bicarbonate to
increase
bioavailability of meloxicam. In other embodiments, the pharmaceutical
composition may
have an effective amount of meloxicam, sulfobutylether-3-cyclodextrin
(SBE3CD), and
sodium bicarbonate to increase bioavailability of meloxicam or reduce the T.
of meloxicam.
[0153] Some
oral dosage forms may have enteric coatings or film coatings. In some
embodiments, a dosage form may comprise a tablet or a capsule having an
enteric coating.
In some embodiments, a dosage form may comprise a tablet or a capsule having a
film
coating.
[0154] An
embodiment of the present disclosure is directed to a pharmaceutical
composition in unit dosage form suitable for administration to a patient,
comprising:
(a) esomeprazole, which may or may not be surrounded by an enteric coating;
(b) sodium or potassium bicarbonate and/or sodium or potassium carbonate;
and
32
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
(c)
meloxicam, which may or may not be formulated with a cyclodextrin, and
which may or may not be surrounded by an enteric coating
[0155] An
embodiment of the present disclosure is directed to a pharmaceutical
composition in unit dosage form suitable for administration to a patient for
treat a disease, a
condition, or disorder, such as migraine, comprising:
(1) an inclusion complex of a meloxicam and a sulfobutyl ether P-
cyclodextrin
(SBERCD);
(2) a bicarbonate, such as sodium bicarbonate or potassium bicarbonate; and
(3) a triptan, such as rizatriptan.
[0156] In
certain embodiments, the pharmaceutical composition results in faster release
or dissolution of the meloxicam from the dosage form as compared to a dosage
form
containing meloxicam but not containing the acid inhibitor, or not containing
the buffering
agent.
[0157] A
dosage form comprising a combination of rizatriptan and meloxicam (a "subject
combination") may be used to treat migraine. The subject combination may be
used for the
acute treatment of migraine. The subject combination may provide substantially
greater and
more sustained migraine pain relief compared to rizatriptan, meloxicam, or
placebo. The
subject combination may provide rapid relief of migraine pain. The subject
combination may
significantly reduce the use of rescue medication compared to rizatriptan,
meloxicam and
placebo. The migraine patients being treated with a combination of rizatriptan
and
meloxicam described herein may have a history of inadequate response to prior
acute
treatments. The migraine patients being treated with a combination of
rizatriptan and
meloxicam described herein may have allodynia. The migraine patients being
treated with a
combination of rizatriptan and meloxicam described herein may have severe pain
intensity.
The migraine patients being treated with a combination of rizatriptan and
meloxicam
described herein may have obesity. The migraine patients being treated with a
combination
of rizatriptan and meloxicam described herein may have morning migraine. The
migraine
patients being treated with a combination of rizatriptan and meloxicam
described herein may
have a total mean score of the Migraine Treatment Optimization Questionnaire
(mT0Q-4) of
less than 7, such as 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. The migraine patients
being treated with a
combination of rizatriptan and meloxicam described herein may have allodynia,
severe pain
33
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
intensity, obesity, morning migraine, a total mean score of the rinT0Q-4 of
less than 7, and a
history of inadequate response to prior acute treatments. A dosage form
comprising a
combination of rizatriptan and meloxicam described herein is safe and well
tolerated in the
migraine patients being treated.
[0158] A
dosage form comprising a combination of rizatriptan and meloxicam described
herein may provide rapid relief of migraine pain in less than 15 minutes,
about 15 minutes,
less than 30 minutes, 15-30 minutes, less than 1 hour, 03-0.75 hour, or 0.75-1
hour post dose.
The combination of rizatriptan and meloxicam described herein may provide
relief of
migraine pain that is numerically greater than rizatriptan at less than 15
minutes, about 5
minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-
30 minutes,
about 30-45 minutes, about 45-60 minutes, about 1-1.5 hours, about 1.5-2
hours, about 2-
2.5 hours, about 2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5
hours, about 5-
6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-24
hours, about 24-
48 hours, or longer, post dose. The percentage of migraine patients reporting
pain relief with
the treatment of a combination of rizatriptan and meloxicam described herein
may be 1-
100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-
60%, 60-
70%, 70-80%, 80-90%, 90-95%, or 95-100%.
[0159] The
migraine patients receiving a dosage form comprising a combination of
rizatriptan and meloxicam described herein ("subject combination") may achieve
pain
freedom at less than 2 hours, about 2 hours, about 2-3 hours, about 3-4 hours,
about 4-6
hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16
hours, about 16-
20 hours, about 20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40
hours, about
40-44 hours, about 44-48 hours, or longer post dose.
[0160] The
percentage of migraine patients achieving pain freedom increases over time
after receiving a dose of a combination of rizatriptan and meloxicam described
herein. For
example, at 2 h post dose, the percentage of migraine patients achieving pain
freedom may
be about 15-25%, about 15-20%, about 20%, about 20-25%. At 4 h post dose, the
percentage
of migraine patients achieving pain freedom may be about 30-50%, about 30-40%,
about 40%,
about 40-45%, about 45-47%, about 47-50%. At 12 h post dose, the percentage of
migraine
patients achieving pain freedom may be about 45-70%, about 45-50%, about 50-
55%, about
55-60%, about 56-57%, about 60-65%, about 65-70%. At 16 h post dose, the
percentage of
34
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
migraine patients achieving pain freedom may be about 45-70%, about 45-50%,
about 50-
55%, about 55-60%, about 58-59%, about 60-65%, about 65-70%. The combination
of
rizatriptan and meloxicam described herein may provide significant improvement
over
rizatriptan in pain freedom in the migraine patients. There may be about 2-
10%, 2-3%, 3-5%,
5-7%, 6-7%, 7-8%, 8-9%, or 9-10% more migraine patients receiving the
combination of
rizatriptan and meloxicam described herein achieving pain freedom than the
migraine
patients receiving rizatriptan at 2-16 hours post dose with an improvement of
about 10-25%,
10-15%, 14-15%, 15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25%. For
example, at 4 hours post dose, if about 40% migraine patients receiving the
subject
combination achieve pain freedom, while 33% migraine patients receiving
rizatriptan achieve
pain freedom, then the improvement of the subject combination is about 21%
[((40-
33)/33)x100%]. The improvement with the subject combination over meloxicam may
be
bigger than over rizatriptan in migraine patients achieving pain freedom. For
example, The
improvement with the subject combination over meloxicam in migraine patients
achieving
pain freedom may be about 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-
60%, 55-
50%, 60-70%, 65-75%, or 70-75% at 2-16 hours post dose.
[0161] There
may be at least 50%, at least 60%, at least 70%, at least 80%, about 70-80%,
about 80-90%, about 90-95%, about 80% of migraine patients receiving the
combination of
rizatriptan and meloxicam described herein ("subject combination") achieving
pain freedom
at 2 hours may maintain it through 24 hours post dose. The increase of the
number of
migraine patients (or improvement) achieving sustained pain freedom from 2-24
hours post
dose of the subject combination may be about 35-55%, about 35-40%, about 40-
45%, about
45-50%, or about 50-55% as compared to administering rizatriptan. The increase
of the
number of migraine patients (or improvement) achieving sustained pain freedom
from 2-24
hours post dose of the subject combination may be about 100-165%, about 100-
110%, about
110-120%, about 120-130%, about 130-140%, about 140-150%, about 150-160%, or
about
160-165% as compared to administering meloxicam.
[0162] The
increase of the number of migraine patients (or improvement) achieving
sustained pain relief from 2-24 hours post dose of the subject combination may
be about 15-
30%, about 15-20%, about 20-25%, about 25-30%, about 20-22%, or about 21% as
compared
to administering rizatriptan. The increase of the number of migraine patients
(or
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
improvement) achieving sustained pain relief from 2-24 hours post dose of the
subject
combination may be about 20-35%, about 20-25%, about 25-30%, about 30-35%,
about 25-
26%, about 26-27%, about 27-28%, about 28-30%, or about 27% as compared to
administering meloxicam.
[0163] There
may be at least 50%, at least 60%, at least 70%, at least 80%, about 70-80%,
about 80-90%, about 90-95%, or about 77% of migraine patients receiving the
combination
of rizatriptan and meloxicam described herein ("subject combination")
achieving pain
freedom at 2 hours may maintain it through 48 hours post dose. The increase of
the number
of migraine patients (or improvement) achieving sustained pain freedom from 2-
48 hours
post dose of the subject combination may be about 60-90%, about 60-70%, about
70-75%,
about 75-80%, about 80-90%, or about 75% as compared to administering
rizatriptan. The
increase of the number of migraine patients (or improvement) achieving
sustained pain
freedom from 2-48 hours post dose of the subject combination may be about 70-
110%, about
70-80%, about 80-90%, about 90-100%, about 100-110%, or about 90% as compared
to
administering meloxicam.
[0164] The
increase of the number of migraine patients (or improvement) achieving
sustained pain relief from 2-48 hours post dose of the subject combination may
be about 20-
35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%,
about 27-
28%, about 28-20%, or about 27% as compared to administering rizatriptan. The
increase of
the number of migraine patients (or improvement) achieving sustained pain
relief from 2-48
hours post dose of the subject combination may be about 15-30%, about 15-20%,
about 20-
25%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%,
about 24-
25%, or about 23% as compared to administering meloxicam.
[0165] There
may be at least 50%, at least 60%, at least 70%, about 60-65%, about 65-
70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or
about
77% of migraine patients receiving the combination of rizatriptan and
meloxicam described
herein ("subject combination") may not require rescue medication. The decrease
of the
number of migraine patients who took rescue medication through 24 hours post
dose of the
subject combination may be about 35-60%, about 35-40%, about 40-45%, about 45-
50%,
about 50-55%, about 55-60%, about 47-48%, or about 47% as compared to
administering
placebo. The decrease of the number of migraine patients who took rescue
medication
36
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
through 24 hours post dose of the subject combination may be about 25-45%,
about 25-30%,
about 30-35%, about 35-40%, about 40-45%, about 34-36%, or about 35% as
compared to
administering meloxicam. The decrease of the number of migraine patients who
took rescue
medication through 24 hours post dose of the subject combination may be about
25-40%,
about 25-30%, about 30-35%, about 35-40%, about 33-35%, or about 34% as
compared to
administering rizatriptan.
[0166] The following embodiments are contemplated:
Embodiment 1. An inclusion complex of meloxicam in a cyclodextrin.
Embodiment 2. A dosage form comprising: 1) the inclusion complex of
embodiment 1,
or 2) meloxicam and a carbonate or a bicarbonate.
Embodiment 3. The dosage form of embodiment 2 comprising the inclusion
complex,
wherein the cyclodextrin comprises substituted .3-cyclodextrin.
Embodiment 4. The dosage form of embodiment 3, wherein the substituted 13-
cyclodextrin is a sulfobutyl ether 13-cyclodextrin (SBEBCD) or hydroxypropyl
13-cyclodextrin
(HPBCD).
Embodiment 5. The dosage form of embodiment 4, wherein the cyclodextrin is
the
SBE13CD.
Embodiment 6. The dosage form of embodiment 5, wherein the SBE13CD has
about 6 to
about 7 sulfobutyl ether groups for each molecule of 3-cyclodextrin.
Embodiment 7. The dosage form of embodiment 6, wherein the meloxicam and
the
SBEBCD have a molar ratio of about 0.8 to about 1.2.
Embodiment 8. The dosage form of embodiment 6, wherein the meloxicam and
the
SBE13CD have a molar ratio of about 1.
Embodiment 9. The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8,
comprising a
bicarbonate.
Embodiment 10. The dosage form of embodiment 9, wherein the bicarbonate
comprises
sodium bicarbonate.
37
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 11. The
dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is an
oral dosage form.
Embodiment 12. The
dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein
about 50 mg to about 200 mg of SBEPCD is present in the dosage form.
Embodiment 13. The
dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,
wherein the carbonate or bicarbonate is present in an amount in a range of
about 400 mg to
about 600 mg.
Embodiment 14. The
dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13,
wherein the T. of meloxicam is decreased as compared to a dosage form not
having a
carbonate, a bicarbonate, or a cyclodextrin.
Embodiment 15. The
method of embodiment 14, wherein the Tmax of meloxicam is
achieved in the patient at a time in a range of about 10 minutes to about 180
minutes after
administration.
Embodiment 16. The
dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
or 15, having an oral bioavailability of meloxicam that is higher than a
dosage form not having
a carbonate, a bicarbonate, or a cyclodextrin.
Embodiment 17. The
dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, or 20, further comprising an acid inhibitor.
Embodiment 18. The
dosage form of embodiment 17, wherein the acid inhibitor is a
proton pump inhibitor.
Embodiment 19. The
dosage form of embodiment 18, wherein the proton pump
inhibitor is esomeprazole.
Embodiment 20. The
dosage form of embodiment 19, wherein about 30 mg to about 50
mg of esonneprazole is present in the dosage form.
Embodiment 21. A
method of administering meloxicam orally, comprising orally
administering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17,
18, 19, or 20 to a patient in need of treatment.
Embodiment 22. The
method of embodiment 21, wherein the dosage form is
administered to treat pain.
38
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 23. The
method of embodiment 21, wherein the dosage form is
administered to treat inflammatory pain.
Embodiment 24. The
method of embodiment 21, wherein the dosage form is
administered to treat osteoarthritis, rheumatoid arthritis, or juvenile
rheumatoid arthritis.
Embodiment 25. A
method of administering meloxicam intravenously, comprising
intravenously administering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8,
9, 10, 12, 13, 14,
or 15, to a patient in need of treatment.
Embodiment 26. The
method of embodiment 21, wherein the dosage form is
administered to treat migraine.
Embodiment 27. A
dosage form comprising: 1) the inclusion complex of meloxicam in a
cyclodextrin, 2) a bicarbonate, and 3) a triptan.
Embodiment 28. The
dosage form of embodiment 27, wherein the triptan is rizatriptan.
Embodiment 29. The
dosage form of embodiment 27, wherein the bicarbonate
comprises sodium bicarbonate.
Embodiment 30. The
dosage form of embodiment 27, wherein the cyclodextrin is a
sulfobutyl ether 3-cyclodextrin (SBE3CD).
Embodiment 31. The
dosage form of embodiment 30, wherein the SBE3CD has about 6
to about 7 sulfobutyl ether groups for each molecule of 3-cyclodextrin.
Embodiment 32. The
dosage form of embodiment 30, wherein the meloxicam and the
SBE3CD have a molar ratio of about 0.8 to about 1.2.
Embodiment 33. The
dosage form of embodiment 32, wherein the meloxicam and the
SBE3CD have a molar ratio of about 1.
Embodiment 34. The
dosage form of embodiment 27, 28, 29, 30, 31, 32, or 33, which is
an oral dosage form.
Embodiment 35. The
dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34,
wherein about 50 mg to about 200 mg of SBE3CD is present in the dosage form.
39
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 36. The
dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35,
wherein the bicarbonate is present in an amount of about 400 mg to about 1000
mg.
Embodiment 37. A
method of treating migraine, comprising administering a dosage form
comprising meloxicam, at least 400 mg of a bicarbonate, and a rizatriptan to a
human being
suffering from migraine; wherein the Tmax of rizatriptan in the dosage form is
shorter than
that in a reference dosage form comprising a) same amount of rizatriptan; 2)
no meloxicam;
and c) no bicarbonate.
Embodiment 38. A
method of treating migraine, comprising administering meloxicam
and about 8 mg to about 13 mg of rizatriptan, based upon the weight of the
rizatriptan in the
free base form, to a human being who is suffering from an acute attack of
migraine pain or
migraine aura, wherein the meloxicam and the rizatriptan are administered
within about 30
minutes of one another, wherein administering the meloxicam to the human being
results in
a Tmax of meloxicam of 110 minutes or less, and an AUC0_24of meloxicam of
about 30 pg.hr/mL
to about 50 p.g.hrimL.
Embodiment 39. A
pharmaceutical dosage form comprising: 1) about 0.028 nnnnol to
about 0.085 mmol of meloxicam in a free acid or a salt form, 2) about 0,019
mmol to about
0.056 mmol of rizatriptan in a free base or a salt form, 3) about 100 mg to
about 175 mg of a
sulfobutylether-P-cyclodextrin (SBEI3CD), and 4) about 400 mg to about 600 mg
of sodium
bicarbonate.
Embodiment 40. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
P-cyclodextrin
(SBE13CD)), 2) a bicarbonate, and 3) a rizatriptan.
Embodiment 41. The
method of embodiment 40, wherein the human migraine patient
experiences relief of the migraine pain as a result of orally administering
the dosage form to
the migraine patient.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 42. The
method of embodiment 40 or 41, wherein the human migraine
patient is free of migraine pain two hours after the dosage form is orally
administered to the
human migraine patient.
Embodiment 43. The
method of embodiment 40, 41, or 42, wherein the migraine
patient experiences a reduction in nausea as a result of orally administering
the dosage form
to the migraine patient.
Embodiment 44. The
method of embodiment 40, 41, 42, or 43, wherein the human
migraine patient is free of nausea two hours after the dosage form is orally
administered to
the human migraine patient.
Embodiment 45. The
method of embodiment 40, 41, 42, 43, or 44, wherein the migraine
patient experiences a reduction in photophobia as a result of orally
administering the dosage
form to the migraine patient.
Embodiment 46. The
method of embodiment 40, 41, 42, 43, 44, or 45, wherein the
human migraine patient is free of photophobia two hours after the dosage form
is orally
administered to the human migraine patient.
Embodiment 47. The
method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein the
migraine patient experiences a reduction in phonophobia as a result of orally
administering
the dosage form to the migraine patient.
Embodiment 48. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, or 47, wherein
the human migraine patient is free of phonophobia two hours after the dosage
form is orally
administered to the human migraine patient.
Embodiment 49. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, or 48,
wherein the dosage form contains 400 mg to 600 mg of the bicarbonate.
Embodiment 50. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49,
wherein the dosage form contains about 5 mg to about 50 mg of meloxicam.
Embodiment 51. The
method of embodiment 40, 41, 42,43, 44, 45, 46, 47,48, 49, or 50,
wherein the dosage form contains about 50 mg to about 200 mg of the SBE13CD.
41
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 52. The
method of embodiment 40, 41, 42,43, 44, 45, 46, 47,48, 49, 50, or
51, wherein the dosage form is a solid oral dosage form having a shorter Tmax
of meloxicam
in the human being than a reference dosage form that: 1) contains the same
amount of
meloxicam, 2) does not contain an SBE13CD, and 3) does not contain a
bicarbonate.
Embodiment 53. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, or 52, wherein about 1 mg to about 50 mg of the rizatriptan is present in
the oral dosage
form based upon the weight of the rizatriptan in the free base form.
Embodiment 54. The
method of embodiment 53, wherein the rizatriptan is present in a
salt form in an amount that is a molar equivalent of about 10 mg of the
rizatriptan in the free
base form.
Embodiment 55. The
method of embodiment 53 or 54, wherein the rizatriptan is present
as rizatriptan benzoate.
Embodiment 56. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, or 55, wherein the oral dosage form contains about 10 mg to
about 30 mg of
meloxicam.
Embodiment 57. The
method of embodiment 56, wherein the oral dosage form contains
about 20 mg of meloxicam.
Embodiment 58. The
method of embodiment 56, wherein the oral dosage form contains
about 15 mg of meloxicam.
Embodiment 59. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, or 58, wherein the SBE13CD has about 6 to about 7
sulfobutyl ether
groups for each molecule of 13-cyclodextrin.
Embodiment 60. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the oral dosage form contains
about 50 mg to
about 150 mg of the SBEPCD.
Embodiment 61. The
method of embodiment 60, wherein the oral dosage form contains
about 100 mg of the SEIE13CD.
42
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 62. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61, wherein the molar ratio of the
SBE3CD to
meloxicam is about 0.5 to about 2.
Embodiment 63. The
method of embodiment 62, wherein the molar ratio of the SBE3CD
to meloxicam is about 0.8 to about 1.2.
Embodiment 64. The
method of embodiment 62, wherein the molar ratio of the SBE3CD
to meloxicam is about 1.
Embodiment 65. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64, wherein the oral
dosage form contains
about 10 mg to about 40 mg of meloxicam, and about 5 mg to about 50 mg of
rizatriptan.
Embodiment 66. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, wherein the
oral dosage form
contains SBE3CD that is in a weight ratio to rizatriptan that is within a
range of about 1 to
about 100.
Embodiment 67. The
method of embodiment 66, wherein the oral dosage form contains
SBE3CD that is in a weight ratio to rizatriptan that is about 10.
Embodiment 68. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67, wherein
the bicarbonate
comprises sodium bicarbonate.
Embodiment 69. The
method of embodiment 68, wherein the oral dosage form contains
500 mg of sodium bicarbonate.
Embodiment 70. The
method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69,
wherein the oral
dosage form has been shown to have a median Tmax of meloxicam that is less
than about 90
minutes in fasted human subjects.
43
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 71. The
method of embodiment 70, wherein the oral dosage form has been
shown to have a median Tmax of meloxicam that is less than about 2 hours in
fasted human
subjects.
Embodiment 72. The
method of embodiment 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,
63, 64, 65, 66, 67, 68, 69, 70, or 71, wherein the oral dosage form has been
shown to have
faster time to therapeutic plasma concentration in the human being as compared
to the
reference dosage form.
Embodiment 73. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBEPCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine
patient
experiences relief of the migraine pain as a result of orally administering
the dosage form to
the migraine patient.
Embodiment 74. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBERCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine
patient is free
of migraine pain two hours after the dosage form is orally administered to the
human
migraine patient.
Embodiment 75. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBERCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine
patient experiences a
reduction in nausea as a result of orally administering the dosage form to the
migraine
patient.
44
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 76. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBEI3CD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine
patient is free
of nausea two hours after the dosage form is orally administered to the human
migraine
patient.
Embodiment 77. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
P-cyclodextrin
(SBE13CD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine
patient experiences a
reduction in photophobia as a result of orally administering the dosage form
to the migraine
patient.
Embodiment 78. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBE13CD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine
patient is free
of photophobia two hours after the dosage form is orally administered to the
human migraine
patient.
Embodiment 79. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBEPCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine
patient experiences a
reduction in phonophobia as a result of orally administering the dosage form
to the migraine
patient.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Embodiment 80. A
method of treating migraine comprising: selecting a human migraine
patient with a history of inadequate response to prior migraine treatments,
and orally
administering a dosage form to the migraine patient, wherein the dosage form
comprises a
combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether
13-cyclodextrin
(SBEI3CD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine
patient is free
of phonophobia two hours after the dosage form is orally administered to the
human
migraine patient.
Example 1
[0167] The
effect of varying amounts of potassium carbonate (K2CO3) and sodium
bicarbonate (NaHCO3) on the pH of acidic media was tested. The acidic media
was chosen to
simulate gastric conditions. K2CO3 or NaHCO3 was added to 50 mL of a 0.01 N
HCI solution
(pH 2). The pH of the solution was measured after addition of the K2CO3 or
NaHCO3. Deionized
water (240 nnL) was then added to the mixture and pH was measured again. The
results are
shown in Tables 1-4.
Table 1. Results with K2CO3 (0.01 N HCI)
K2CO3 (mg) pH
25 2.84
35 6.29
45 8.05
50 8.29
100 9.43
200 10.14
300 10.39
400 10.55
450 10.58
Table 2. Results with K2CO3 (0.01 N HCI + Water)
K2CO3 (mg) pH
200 10.27
300 10.46
400 10.57
450 10.63
46
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Table 3. Results with NaHCO3 (0.01 N HCI)
NaHCO3 (mg) pH
200 5.28
300 5.90
400 6.44
450 6.86
500 8.23
750 8.30
1000 8.36
Table 4. Results with NaHCO3 (0.01 N HCl + Water)
NaHCO3 (mg) pH
200 5.41
300 5.89
400 6.11
450 6.46
500 8.33
750 8.54
1000 8.60
Example 2
[0168]
Tablets containing meloxicam and combinations of a sulfobutylether-13-
cyclodextrin (SBEfICD) (a cyclodextrin, containing about 6 to about 7
sulfobutyl ether groups
for each molecule of 13-cyclodextrin), K2CO3, or NaHCO3 were manufactured and
tested for
dissolution. Tablets containing meloxicam alone (MOBIC) were purchased and
also tested
for dissolution. The tested tablets are listed in Table 5. Meloxicam in the
form of meloxicam/
SBEPCD inclusion complexes was used in the tablets containing meloxicam and
SBE13CD. The
inclusion complexes were formed by mixing meloxicam and SBEr3CD in an aqueous
pH-
adjusted solution. The pH of the solution was adjusted using buffering agents.
The resulting
soluble meloxicam/ SBE13CD inclusion complexes were then spray dried. This
spray-dried
dispersion was used in the manufacture of the tablets containing SBEPCD.
47
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Table 5. Tablets
Tablet A 15 mg meloxicam + 25 mg K2CO3
Tablet B 15 mg meloxicam + 50 mg K2CO3
Tablet C 15 mg meloxicam + 100 mg K2CO3
Tablet D 15 mg meloxicam + 150 mg K2CO3
Tablet E 15 mg meloxicam + 500 mg NaHCO3
Tablet F 15 mg meloxicam + 100 mg SBEBCD
Tablet G 15 mg meloxicam + 100 mg SBEBCD + 25 mg K2CO3
Tablet H 15 mg meloxicam + 100 mg SBEBCD + 50 mg K2CO3
Tablet I 15 mg meloxicam + 100 mg SBEBCD + 100 mg K2CO3
Tablet J 15 mg meloxicam + 100 mg SBEBCD + 150 mg K2CO3
Tablet K 15 mg meloxicam + 100 mg SBEPCD + 500 mg NaHCO3
Tablet L 15 mg meloxicam (MOBIC )
[0169]
Dissolution testing in acidic medium (chosen to simulate gastric conditions)
was
performed by placing the tablets in a 0.01 N HCI solution, at an agitation
rate of 75 RPM, and
vessel temperature of approximately 37 'C. The results are presented in Tables
6 and in
Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120
minutes) are
presented as percent (%) of meloxicam dissolved.
Table 6. Dissolution Results
15 30 45 60 90 120
0 mins mins mins mins mins mins mins
Tablet A 0% 23% 17% 15% 13% 12% 11%
Tablet B 0% 27% 20% 17% 16% 17% 15%
Tablet C 0% 31% 26% 25% 24% 23% 21%
Tablet D 0% 30% 26% 25% 24% 23% 22%
Tablet E 0% 50% 66% 77% 84% 92% 95%
Tablet F 0% 26% 17% 14% 12% 11% 10%
Tablet G 0% 48% 39% 26% 20% 16% 14%
Tablet H 0% 44% 30% 22% 17% 16% 13%
Tablet I 0% 32% 33% 27% 21% 16% .3/0
4-)
Tablet J 0% 26% 27% 19% 15% 12% 11%
Tablet K 0% 85% 86% 86% 86% 86% 86%
Tablet L 0% 2% 2% 2% 2% 2% 2%
[0170]
Dissolution of meloxicam was greater with the tablets containing various
combinations of meloxicam and SBEBCD, K2CO3, or NaHCO3, as compared to tablets
containing meloxicam alone. For example, after 120 minutes, dissolution of
meloxicam
48
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
tablets containing NaHCO3 was 95% as compared to 2% for tablets containing
meloxicam
alone.
[0171]
Dissolution of meloxicam increases with increasing amounts of K2CO3 in the
absence of SBE13CD. However, in the presence of SBE13CD, increasing amounts of
K2CO3 did
not appear to increase meloxicam dissolution. At the highest dose of potassium
carbonate
tested, meloxicam dissolution in the presence of SBEf3CD was reduced by
approximately 50%
as compared to meloxicam dissolution in the absence of SBERCD at 120 minutes.
[0172]
Dissolution of meloxicam with NaHCO3 was significantly greater than that
observed with the highest dose of K2CO3 at 15 minutes (50% versus 30%), and at
120 minutes
(92% versus 23%). Meloxicam dissolution in the presence of SBE13CD was also
significantly
greater with NaHCO3 as compared to the highest dose of K2CO3 at 15 minutes
(85% versus
26%), and at 120 minutes (86% versus 12%). NaHCO3 in the presence of SBEPCD
increased
meloxicam dissolution more at 15 minutes as compared to potassium carbonate,
which
resulted in a reduction in dissolution.
Example 3
[0173] A
bilayer tablet containing 1) an inclusion complex of SBEPCD with meloxicam,
prepared as described below, and 2) sodium bicarbonate was prepared (SBEI3CD-
Meloxicam/Bicarbonate). The first layer contained an inclusion complex of 15
mg meloxicam
and 100 mg SBEr3CD, and 100 mg of sodium bicarbonate. The second layer
contained 40 mg
of esomeprazole and 400 mg of sodium bicarbonate.
[0174] A
total of 20 human subjects were randomly assigned in a 1:1 ratio to treatment
with the SBEPCD-Meloxicarn/Bicarbonate tablets described above or Mobic6
tablets (15 mg
meloxicam), once daily for 6 days under fasting conditions.
[0175] On the
first day of dosing, plasma samples were collected for concentration
analysis of meloxicam at several time points. Concentrations of meloxicam were
determined
using LC-MS/MS. Pharmacokinetic parameters were calculated. The results are
depicted in
FIG. 11.
49
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0176] The
median Tn,ax for meloxicam, the trial's primary endpoint, was 9 times faster
for
the SBERCD-Meloxicam/Bicarbonate tablets as compared to Mobic (0.5 hour
versus 4.5
hours respectively, p<0.0001).
[0177] The
SBE13CD-Meloxicam/Bicarbonate tablets also demonstrated higher mean
maximum plasma concentration (C.) (p=0.0018), faster time to therapeutic
plasma
concentration (p<0.0001), and faster time to half-maximal plasma concentration
(p<0.0001)
as compared to Mobic .
[0178]
Meloxicam in the form of meloxicam/ SBE8CD inclusion complexes was used in the
tablets containing meloxicam and SBE13CD. The inclusion complexes were formed
by mixing
meloxicam and SBE13CD in an aqueous pH-adjusted solution. The pH of the
solution was
adjusted using buffering agents. The resulting soluble meloxicam/S8E8CD
inclusion
complexes were then spray dried. This spray-dried dispersion was used in the
manufacture of
the tablets containing SBERCD.
Example 4
A monolayer tablet containing 1) the inclusion complex of SBEfICD with
meloxicam; 2)
rizatriptan; and 3) sodium bicarbonate was
prepared (SBE8CD-
Meloxicamirizatriptan/Bicarbonate). The monolayer tablet contained 20 mg of
meloxicam,
mg of rizatriptan, and 500 mg of sodium bicarbonate. The inclusion complex was
the same
as the inclusion complex of Example 3.
Dissolution testing of the tablets in acidic medium (chosen to simulate
gastric
conditions) was performed by placing the tablets in a 0.01 N HCI solution, at
an agitation rate
of 75 RPM, and vessel temperature of approximately 37 'C. The results are
presented in Table
7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are
presented as
percent (%) of meloxicam, and percent (%) of rizatriptan dissolved.
Table 7. Dissolution Results
Time-point (minutes) 0 min 15 min 30 min 45 min 60 min 90 min 120 min
Rizatriptan 0% 89% 102% 103% 103% 103% 103%
Meloxicam 0% 79% 92% 93% 93% 93% 94%
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
As shown in Table 7, the dissolution results of the tablets in Example 4 are
very similar
to the dissolution result of Example 3. Therefore, we expected the
pharmacokinetic
properties, including bioavailability, Tmax of meloxicam, etc., of the tablets
in Example 4 to be
similar to those described in Example 3 and FIG. 11. This expectation turned
out to be correct,
as shown in the examples below.
Example 5
[0179] The
monolayer tablet of Example 4 was administered to six human subjects. On
the first day of dosing, plasma samples were collected for concentration
analysis of rizatriptan
at several time points. Concentrations of rizatriptan and meloxicam were
determined using
LC-MS/MS. Pharmacokinetic parameters were calculated. The results for
meloxicam were
comparable to those reported for the bilayer dosage form of Example 3. The
median Tmax of
rizatriptan was 0.75 hours and the mean Cmax of rizatriptan was 20,710 ng/mL.
By
comparison, the reported Tmax of the commercial rizatriptan dosage form,
Maxalt6, is 1.0-1.5
hours.
Example 6
[0180] A
Phase 1, randomized, single-dose, parallel-group clinical study was conducted
to
evaluate the PK, safety and tolerability of 1) a combination of meloxicam (20
mg), rizatriptan
(10 mg), SBE13CD, and sodium bicarbonate (meloxicam/rizatriptan), as compared
to 2) and
Maxalt (10 mg rizatriptan), in healthy human volunteers after oral
administration under
fasted conditions. A total of 20 healthy, adult male or female volunteers were
randomized in
a 1:1 ratio to receive a single dose of meloxicam/rizatriptan, or Maxa it (10
mg rizatriptan).
[0181] Blood
samples for PK analysis were collected pre dose and at multiple time points
post dose. The pre-specified primary endpoint was Tthera, the time to reach a
therapeutic
plasma concentration of meloxicam, defined as the Cavg of meloxicam after
administration of
the highest approved dose (15 mg) of standard meloxicam, which is
approximately 1000
ng/mL. PK results for the rizatriptan component of meloxicam/rizatriptan were
compared to
those for Maxalt (rizatriptan).
[0182] PK
results for the meloxicam (20 mg) component of meloxicam/rizatriptan from
this trial were compared to PK results for Mobic (15 mg meloxicam) from
Example 3.
Phase 1 Results
51
CA 03128940 2021-08-03
WO 2020/163620 PCT/US2020/017046
[0183] Meloxicam was rapidly absorbed after oral administration of
meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan), with a median time
to
therapeutic plasma concentration (Tthera) of 17 minutes, the primary endpoint
(Figure 12 and
Table 8). Median Tmax was 1 hour compared to 4.5 hours for 15 mg standard
meloxicam
(Mobie). The very short Tmax suggests the potential for meloxicam/rizatriptan
to have rapid
onset of action in treating migraine. Mean plasma elimination half-life (Tip)
for meloxicam
was 18.2 hours after administration of meloxicam/rizatriptan, which compares
to 21.5 hours
for standard meloxicam. The long elimination half-life suggests the potential
for
meloxicam/rizatriptan to enhanced and sustained efficacy, and to reduce
migraine pain
recurrence.
Table 8. Meloxicam Pharmacokinetic Parameters for Meloxicam/Rizatriptan
Statistic AU CO-inf Tin el (hr) Cmax(ngimL) Tmax (h r)a
Tthera (hr)a
(ng=hrimL)
10 10 10 10
Geometric 46,865 17.5 2,532 1.0 0.29
Mean
SD 11,965 5.25 607 0.5-2.5 0.20-0.61
aTma. and Tthera present the value as a median or a range.
[0184] Rizatriptan was rapidly absorbed after oral administration of
meloxicam/rizatriptan, with a Tmax of 0.64 hour (38 min), which compares to
0.88 hour for the
same dose of standard rizatriptan (Maxale) (Figure 13 and Table 9). Systemic
exposure
measured using Cmax and AUC were also numerically greater for rizatriptan
after
administration of meloxicam/rizatriptan versus standard rizatriptan.
Table 9. Rizatriptan Pharmacokinetic Parameters for Meloxicam/Rizatriptan and
Standard
Rizatriptan
Statistic AU CO-inf T1/2 el Cmax Tmax (hr)a
(pg-hr/mL)
(hr) (nernL)
10 10 10 10
Geometric 83,800 1.98 29,991 0.64
Mean
52
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Statistic AUC0-1nf Tv2 el Cmax Tmax
(hr)a
(pg-hrimL)
(hr) (ndinL)
Meloxica m/Rizatriptan SD 22,787 0.28 11,041 0.5-2.5
(20 mg meloxicam/10
mg rizatriptan)
Standard Rizatripta n N 10 10 10 10
(Maxale) (10 mg Geometric 71,811 1.81 23,236 0.88
Mean
rizatriptan)
SD 24,287 0.11 9,476 0.5-2
aTmax presents the value as a median or a range.
[0185]
Meloxicamirizatriptan was well tolerated with no relevant differences in
safety
profile between the two treatment arms. There were no serious adverse events
in the study.
Example 7
[0186] A
Phase 3, randomized, double-blind, multicenter, active- and placebo-controlled
trial is carried out to assess the efficacy and safety of
meloxicam/rizatriptan in the acute
treatment of moderate and severe migraine, in patients with a history of
inadequate response
to prior acute migraine treatments. Eligible patients are randomized in a
2:2:2:1 ratio to
treatment with meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, with
SBE3CD and
sodium bicarbonate as described in Example 4 above), rizatriptan (10 mg)
(rizatriptan arm),
meloxicam (20 mg) with SBE3CD and sodium bicarbonate (meloxicam arm), or
placebo. Co-
primary endpoints are freedom from headache pain, and freedom from the most
bothersome
migraine-associated symptom (nausea, photophobia, or phonophobia), two hours
after
dosing, for meloxicam/rizatriptan as compared to placebo.
[0187]
Superiority of meloxicam/rizatriptan to the rizatriptan and the meloxicam arms
(component contribution) will be established based on sustained freedom from
headache
pain from 2 hours to 24 hours after dosing (key secondary endpoint).
[0188]
Eligible patients must have a history of inadequate response to prior acute
migraine treatments, assessed using the Migraine Treatment Optimization
Questionnaire
(mT0Q-4). The mT0Q-4 is a validated questionnaire that assesses efficacy
response to prior
53
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
acute treatments based on four aspects (two-hour pain freedom, efficacy for at
least 24 hours
with one dose, ability to plan daily activities, and disruption of daily
activities).
[0189] It is
expected that meloxicam/rizatriptan will show significant improvement over
placebo and superiority over the rizatriptan and the meloxicam arms because of
the rapid
absorption and distinct dual mechanisms of action of meloxicam/rizatriptan
described herein.
Example 8
[0190] A
female migraine sufferer visits her physician in the hope of having relief
from
her migraine pain. Her doctor gives her 10 mg rizatriptan (Maxalt ), which she
takes during
her next acute migraine. It provides some relief of pain, nausea, allodynia,
photophobia, and
phonophobia, but not complete relief from these symptoms. On her next visit,
her doctor
gives her 20 mg of meloxicam in a tablet also containing SBEPCD and 500 mg of
sodium
bicarbonate, which she takes during her next acute migraine. It provides some
relief of pain,
nausea, allodynia, photophobia, and phonophobia, but not complete relief from
these
symptoms. On her next visit, her doctor gives her a tablet described in
Example 4 above. She
reports that at 2 hours and 24 hours after taking the tablet, she has about 10-
30%
improvement in pain, nausea, allodynia, photophobia, and/or phonophobia over
what she
experienced after taking meloxicam or rizatriptan alone.
Example 9
[0191] A male
migraine sufferer visits his physician in the hope of having relief from his
migraine pain. His doctor gives him 10 mg rizatriptan (Maxalt6), which he
takes during his
next acute migraine. It provides some relief of pain, nausea, allodynia,
photophobia, and
phonophobia, but not complete relief from these symptoms. On his next visit,
his doctor gives
his 20 mg of meloxicam in a tablet also containing SBE13CD and 500 mg of
sodium bicarbonate,
which he takes during his next acute migraine. It provides some relief of
pain, nausea,
allodynia, photophobia, and phonophobia, but not complete relief from these
symptoms. On
his next visit, his doctor gives him a tablet described in Example 4 above. He
reports that at
2 hours and 24 hours after taking the tablet, he has about 30-60% improvement
in pain,
nausea, allodynia, photophobia, and/or phonophobia over what he experienced
after taking
meloxicam or rizatriptan alone.
54
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Example 10
[0192] A
female migraine sufferer visits her physician in the hope of having relief
from
her migraine pain. Her doctor gives her 10 mg rizatriptan (Maxalt ), which she
takes during
her next acute migraine. It provides some relief of pain, nausea, allodynia,
photophobia, and
phonophobia, but not complete relief from these symptoms. On her next visit,
her doctor
gives her 20 mg of nneloxicam in a tablet also containing SBERCD and 500 mg of
sodium
bicarbonate, which she takes during her next acute migraine. It provides some
relief of pain,
nausea, allodynia, photophobia, and phonophobia, but not complete relief from
these
symptoms. On her next visit, her doctor gives her a tablet described in
Example 4 above. She
reports that at 2 hours and 24 hours after taking the tablet, she has about 60-
100%
improvement in pain, nausea, allodynia, photophobia, and/or phonophobia over
what she
experienced after taking meloxicam or rizatriptan alone.
Example 11
[0193] Over
37 million Americans suffer from migraine according to the Centers for
Disease Control, and it is the leading cause of disability among neurological
disorders in the
United States according to the American Migraine Foundation. Migraine is
characterized by
recurrent attacks of pulsating, often severe and disabling head pain
associated with nausea,
and sensitivity to light and or sound. It is estimated that migraine accounts
for $78 billion in
direct (e.g. doctor visits, medications) and indirect (e.g. missed work, lost
productivity) costs
each year in the United States [Gooch CL, Pracht E, Borenstein AR, The burden
of neurological
disease in the United States: A summary report and call to action. Ann Neurol.
2017 Apr;
81(4):479-484]. Published surveys of migraine sufferers indicate that more
than 70% are not
fully satisfied with their current treatment, that nearly 80% would try a new
therapy, and that
they desire treatments that work faster, more consistently, and result in less
symptom
recurrence [(1) Smelt AF, Louter MA, Kies DA, Blom JW, Terwindt GM, van der
Heijden GJ, De
Gucht V, Ferrari MD, Assendelft WJ, What do patients consider to be the most
important
outcomes for effectiveness studies on migraine treatment? Results of a Delphi
study. PLoS
One. 2014 Jun 16;9(6):e98933, 6; and (2) Lipton RB, Stewart WF, Acute migraine
therapy: do
doctors understand what patients with migraine want from therapy? Headache.
1999;39(suppl 2):520-526].
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0194] The
World Health Organization classifies severe migraine attacks as among the
most disabling illnesses, comparable to dementia, quadriplegia and active
psychosis [(1)
Menken et al. Arch Neural. 2000;57:418-420; and (2) Shapiro and Goadsby.
Cephalalgia.
2007;27:991-4]. Debilitating pain, and the often-constant fear of the next
migraine attack,
damage family life, social life, and employment [Global Burden of Disease
Study. Lancet.
2017;390:1211-1259]. Depression and anxiety are twice as common in people with
migraine
than in healthy individuals [Antonaci et al. J Headache Pain. 2011;12:115-
125]. Widespread
misperception of the seriousness of migraine contributes to its under-
recognition and under-
treatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The
majority of
patients are not fully satisfied with their current treatment. Thus, there is
an urgent need for
new treatments that provide improved efficacy for this serious neurological
disease.
[0195] A
Phase 3, randomized, double-blind, multicenter, placebo- and active-controlled
trial was conducted to assess the efficacy and safety of the combination of
meloxicam and
rizatriptan (meloxicam/rizatriptan) in the acute treatment of moderate and
severe migraine.
Eligible patients must have an age of 18 to 65 years, an established diagnosis
(at least 1 year)
of migraine with or without aura as defined by ICHD-3 criteria, an average of
2 to 8 moderate
to severe migraines per month, had a history of inadequate response to prior
acute migraine
treatments, assessed by a score of 7 using the Migraine Treatment Optimization
Questionnaire (mT0Q-4) (the average score was 3.6), corresponding to poor
response to prior
acute treatments. Exclusion criteria included cluster headaches or other types
of migraines,
chronic daily headache 15 non-
migraine headache days per month), history of significant
cardiovascular disease, and uncontrolled hypertension. In addition to a
history of inadequate
response, enrolled patients exhibited a high rate of characteristics that are
strongly
associated with poor treatment outcomes including cutaneous allodynia (75.4%),
severe
migraine pain intensity (41.2%), obesity (43.7%), and morning migraine
(36.6%). A total of
1,594 patients were randomized in a 2:2:2:1 ratio to the monolayer tablet of
Example 4 (20
mg meloxicam/l0 mg rizatriptan, with SBERCD and sodium bicarbonate),
rizatriptan (10 mg),
meloxicam (20 mg) with SBEBCD (MoSEIC Meloxicam), or placebo, to treat a
single migraine
attack of moderate or severe intensity. The two co-primary endpoints of the
trial were the
proportion of patients who are free from headache pain two hours after dosing,
and the
proportion of patients who no longer suffered from their most bothersome
migraine-
56
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
associated symptom (nausea, photophobia, or phonophobia) two hours after
dosing, for
meloxicam/rizatriptan as compared to placebo. Superiority of
meloxicam/rizatriptan to the
rizatriptan and meloxicam arms (component contribution) was to be established
based on
sustained freedom from headache pain from two to 24 hours after dosing (key
secondary
endpoint). The study was conducted pursuant to an FDA Special Protocol
Assessment (SPA).
Rizatriptan, an active comparator in the trial, is considered to be the
fastest acting oral triptan
and one of the most effective medications currently available for the acute
treatment of
migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby Pi. Oral triptans
(serotonin 5-HT(1B/1D)
agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet.
2001 Nov
17;358(9294):1668-75.)
[0196]
Meloxicamirizatriptan provided rapid relief of migraine pain with the
percentage
of patients achieving pain relief with meloxicam/rizatriptan being numerically
greater than
with rizatriptan at every time point measured starting at 15 minutes, and
statistically
significant by 60 minutes (p=0.04) (Fig. 14). The proportions of patients
experiencing pain
relief 1.5 hours after dosing were 60.5% for meloxicam/rizatriptan compared to
52.5% for
rizatriptan and 48.3% for placebo (p=0.019, p=0.04, respectively versus
meloxicam/rizatriptan) (Fig. 14).
[0197]
Meloxicam/rizatriptan met the two regulatory co-primary endpoints by
demonstrating, with high statistical significance, a greater percentage of
patients as
compared to placebo achieving pain freedom (19.9% versus 6.7%, p<0.001, Fig.
15), and
absence of most bothersome symptom (36.9% versus 24.4%, p=0.002), 2 hours
after dosing.
[0198]
Superiority of meloxicam/rizatriptan to rizatriptan (active comparator and
MoSElCTM meloxicam (component contribution) was established as specified in
the SPA, by
the demonstration of a greater percentage of patients receiving
meloxicam/rizatriptan
achieving sustained pain freedom from 2 hours to 24 hours after dosing,
compared to
rizatriptan, MoSElCTM meloxicam, and placebo (16.1%, 11.2%, 6.8% and 5.3%,
respectively;
p=0.038, p=0.001, and p<0.001, respectively versus meloxicam/rizatriptan, Fig.
16A), the pre-
specified key secondary endpoint to demonstrate component contribution. About
80% of the
patients treated with meloxicam/rizatriptan who achieved pain freedom at 2
hours
maintained pain freedom through 24 hours. These results demonstrated the
significant
57
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
improvement in pain freedom and superiority of meloxicam/rizatriptan to
rizatriptan in
treating migraine.
[0199]
Meloxicam/rizatriptan provided substantially greater and more sustained
migraine pain relief compared to placebo and rizatriptan, which translated to
a significant
reduction in rescue medication use for meloxicam/rizatriptan compared to
placebo and
rizatriptan. The percentage of patients experiencing sustained pain relief
from 2 hours to 24
hours after dosing was 53.3% for meloxicam/rizatriptan, compared to 33.5% for
placebo and
43.9% for rizatriptan (p<0.001, p=0.006, respectively versus
meloxicam/rizatriptan) (Fig. 168).
[0200]
Sustained pain relief from 2 hours to 48 hours was also experienced by a
statistically significantly greater proportion of meloxicam/rizatriptan
patients (46.5%),
compared to placebo (31.1%) and rizatriptan (36.5%) patients (p<0.001,
p=0.003, respectively
versus meloxicam/rizatriptan) (Fig. 17B). The sustained pain freedom from 2
hours to 48
hours was also experienced by a statistically significantly greater proportion
of
meloxicam/rizatriptan patients (15.4%), compared to placebo (5.3%), and
rizatriptan (8.8%),
and MoSElCTM meloxicam (8.1%) patients (p<0.001, p=0.003, p=<0.001,
respectively versus
meloxicam/rizatriptan) (Fig. 17A). About 77% of patients treated with
meloxicam/rizatriptan
who achieved pain freedom at 2 hours maintained the pain freedom through 48
hours.
[0201] Rescue
medication was used by 23.0% patients received meloxicam/rizatriptan,
compared to 43.5% patients received placebo and 34.7% patients received
rizatriptan
(p<0.001 for each group versus meloxicam/rizatriptan) (Fig. 18). About 77% of
patients
receiving meloxicam/rizatriptan did not require rescue medication. These
results
demonstrated the superiority of meloxicam/rizatriptan to rizatriptan, an
active comparator,
in treating migraine.
[0202]
Meloxicarn/rizatriptan was statistically significantly superior to rizatriptan
on
several other secondary endpoints, including Patient Global Impression of
Change (PGI-C)
(p=0.022), and return to normal functioning at 24 hours (p=0.027).
[0203] Some
of the p-values for meloxicam/rizatriptan versus rizatriptan for various
endpoints are listed in Table 10 below, demonstrating the statistically
significant superiority
of meloxicam/rizatriptan over rizatriptan in treating migraine.
58
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
Table 10. P-Values for Meloxicam/Rizatriptan vs Rizatriptan for Various
Endpoints
Endpoint P-value
Meloxicam/Rizatriptan vs Rizatriptan
1 hour Pain Relief 0.04
2-24 hour Sustained Pain Relief 0.006
2-48 hour Sustained Pain Relief 0.003
2-24 hour Sustained Pain Freedom 0.038
2-48 hour Sustained Pain Freedom 0.003
PG I-C 0.022
Functional Improvement at 24 hours 0.027
Use of Rescue Medication <0.001
[0204] Given
that Rizatriptan, an active comparator in the trial, is considered to be the
fastest acting oral triptan and one of the most effective medications
currently available for
the acute treatment of migraine, and that this trial enrolled patients with
difficult-to-treat
migraine, the observed treatment effects with meloxicam/rizatriptan that
provided greater
and more lasting migraine pain relief than rizatriptan, is highly significant.
Many patients
experience a suboptimal response to their current acute migraine treatments,
placing them
at increased risk of headache related disability and progression to chronic
migraine, factors
associated with increased healthcare costs. The results of this study suggest
that
meloxicam/rizatriptan may provide an important treatment option for people
with difficult-
to-treat migraine.
[0205]
Meloxicam/rizatriptan was safe and well tolerated in the patients studied in
the
trial. The most commonly reported adverse events with meloxicam/rizatriptan
were nausea,
dizziness and somnolence, none of which occurred at a rate greater than
placebo or greater
than 3%. There was one serious adverse event in the meloxicam/rizatriptan arm
which was
deemed by the investigator not to be related to the study drug.
59
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0206] The
results of this trial demonstrate the ability of meloxicam/rizatriptan to
provide
unique benefits to migraine patients, with fast, strong, and durable relief of
migraine pain as
compared to a potent active comparator, rizatriptan, in a stringently designed
trial enriched
with patients with difficult-to-treat migraine. These results have potentially
important
implications for patient care based on the high rate of inadequate response to
and patient
dissatisfaction with current treatments.
[0207]
Meloxicam/rizatriptan incorporates multiple mechanisms of action to address
various migraine processes with the goal of providing enhanced effectiveness.
Meloxicam/rizatriptan is thought to act by inhibiting CGRP release, reversing
CGRP-mediated
vasodilation, and inhibiting neuro-inflammation, pain signal transmission, and
central
sensitization. The results of this trial validate this approach, demonstrating
that
meloxicam/rizatriptan can provide significant benefit that is greater than
that of currently
available treatments, even in patients with difficult-to-treat migraine.
Meloxicam/rizatriptan
may be used for the acute treatment of migraine in adults with or without aura
effectively.
Example 12
[0208]
Meloxicam/rizatriptan is also being evaluated in another Phase 3 trial which
is a
randomized, double-blind, placebo-controlled study evaluating the early
treatment of
migraine with meloxicam/rizatriptan. In contrast to this ongoing trial in
which patients with
a history of inadequate response treated migraine attacks once they have
developed
moderate or severe intensity of migraine, in the other trial, patients are to
administer
meloxicam/rizatriptan at the earliest sign of migraine pain.
[0209] Eligible patients are randomized in a 1:1 ratio to treatment with
meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, with SBE13CD and
sodium
bicarbonate as described in Example 4 above), or placebo. Adult subjects with
an established
diagnosis of migraine with or without aura. The treatment with
meloxicam/rizatriptan is
initiated at the first sign of migraine pain onset.
[0210] Co-
primary endpoints are freedom from headache pain, and freedom from the
most bothersome migraine-associated symptom (nausea, photophobia, or
phonophobia),
two hours after dosing, for meloxicam/rizatriptan as compared to placebo.
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
[0211] Unless
otherwise indicated, all numbers expressing quantities of ingredients,
properties such as amounts, percentage, and so forth used in the specification
and claims are
to be understood in all instances as indicating both the exact values as shown
and as being
modified by the term "about." Accordingly, unless indicated to the contrary,
the numerical
parameters set forth in the specification and attached claims are
approximations that may
vary depending upon the desired properties sought to be obtained. At the very
least, and not
as an attempt to limit the application of the doctrine of equivalents to the
scope of the claims,
each numerical parameter should at least be construed in light of the number
of reported
significant digits and by applying ordinary rounding techniques.
[0212] The
terms "a," "an," "the" and similar referents used in the context of describing
the embodiments (especially in the context of the following claims) are to be
construed to
cover both the singular and the plural, unless otherwise indicated herein or
clearly
contradicted by context. All methods described herein can be performed in any
suitable order
unless otherwise indicated herein or otherwise clearly contradicted by
context. The use of
any and all examples, or exemplary language (e.g., "such as") provided herein
is intended
merely to better illuminate the embodiments and does not pose a limitation on
the scope of
any claim. No language in the specification should be construed as indicating
any non-claimed
element essential to the practice of the claims.
[0213]
Groupings of alternative elements or embodiments disclosed herein are not to
be
construed as limitations. Each group member may be referred to and claimed
individually or
in any combination with other members of the group or other elements found
herein. It is
anticipated that one or more members of a group may be included in, or deleted
from, a
group for reasons of convenience and/or to expedite prosecution. When any such
inclusion
or deletion occurs, the specification is deemed to contain the group as
modified thus fulfilling
the written description of all Markush groups if used in the appended claims.
[0214]
Certain embodiments are described herein, including the best mode known to the
inventors for carrying out the claimed embodiments. Of course, variations on
these described
embodiments will become apparent to those of ordinary skill in the art upon
reading the
foregoing description. The inventor expects skilled artisans to employ such
variations as
appropriate, and the inventors intend for the claimed embodiments to be
practiced otherwise
than specifically described herein. Accordingly, the claims include all
modifications and
61
CA 03128940 2021-08-03
WO 2020/163620
PCT/US2020/017046
equivalents of the subject matter recited in the claims as permitted by
applicable law.
Moreover, any combination of the above-described elements in all possible
variations thereof
is contemplated unless otherwise indicated herein or otherwise clearly
contradicted by
context.
[0215] In
closing, it is to be understood that the embodiments disclosed herein are
illustrative of the principles of the claims. Other modifications that may be
employed are
within the scope of the claims. Thus, by way of example, but not of
limitation, alternative
embodiments may be utilized in accordance with the teachings herein.
Accordingly, the
claims are not limited to embodiments precisely as shown and described.
62
