FORMES POSOLOGIQUES STABLES DE LEVOMILNACIPRAN

STABLE DOSAGE FORMS OF LEVOMILNACIPRAN

Abrégé français

La présente invention concerne des formes posologiques stables de levomilnacipran et de sels pharmaceutiquement acceptables de celles-ci. L'invention porte également sur des procédés de préparation de ces formes posologiques et sur des méthodes d'utilisation de ces formes posologiques.

Abrégé anglais

The present invention relates to stable dosage forms of levomilnacipran and pharmaceutically acceptable salts thereof. Processes for the preparation of these dosage forms and methods of using these dosage forms are also described.

Revendications

WHAT IS CLAIMED IS:
1. A stable dosage form comprising levomilnacipran or a pharmaceutically
acceptable salt thereof.
2. A stable dosage form comprising an active ingredient that comprises at
least 98%
by weight of levomilnacipran or pharmaceutically acceptable salt thereof.
3. The stable dosage form of claim 2, wherein the dosage form comprises an X-
ray
powder diffraction (XRD) pattern that comprises characteristic peaks at 12.0,
20.1 and
22.5 ~ 0.2 degrees 2.SLZERO..
4. The stable dosage form of claim 3, wherein the XRD pattern further
comprises a
characteristic peak at 32.7 ~ 0.2 degrees 2.SLZERO..
5. The stable dosage form of claim 3, wherein the XRD pattern further
comprises a
characteristic peak at 6.0 ~ 0.2 degrees 2.SLZERO..
6. The stable dosage form of claim 2, wherein the dosage form comprises a XRD
pattern that comprises characteristic peaks at 6.0, 12.0 and 20.1 ~ 0.2
degrees 2.SLZERO..
7. The stable dosage form of claim 2, wherein the dosage form comprises about
0.001% to about 0.5% by weight of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-
2-one.
8. The stable dosage form of claim 2, wherein the dosage form comprises about
0.001% to about 0.2% by weight of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-
2-one.
9. The stable dosage form of claim 2, wherein the dosage form comprises about
45
wt.% to about 60 wt.% of the active ingredient, and about 30 wt.% to about 45
wt.% of
an inert substrate or filler.
10. The stable dosage form of claim 2, wherein the dosage form comprises about
45
wt.% to about 60 wt.% the active ingredient; about 30 wt.% to about 45 wt.% of
an inert
substrate or filler; about 4 wt.% to about 10 wt.% of a binder; and about 1
wt.% to about
wt.% of an anti-adherent or lubricant.
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11. The stable dosage form of claim 2, wherein the dosage form comprises about
50
wt.% to about 60 wt.% of the active ingredient; about 30 wt.% to about 40 wt.%
of an
inert substrate or filler; about 4 wt.% to about 8 wt.% of a binder; and about
1 wt.% to
about 5 wt.% of an anti-adherent or lubricant.
12. The stable dosage form of claim 9, wherein the dosage form is an immediate-
release oral dosage form.
13. The stable dosage form of claim 2, wherein the dosage form comprises about
40%
to about 55% by weight of levomilnacipran or pharmaceutically acceptable salt
thereof,
about 5% to about 15% by weight of a release controlling agent, about 25% to
about 40%
by weight of an inert substrate, about 3% to about 10% by weight of a binder,
about 3%
to about 10% by weight of an anti-adherent, and about 0.1% to about 5% by
weight of a
plasticizer.
14. The stable dosage form of claim 13, wherein the dosage form is a modified-
release oral dosage form.
15. The dosage form of claim 2, wherein the dosage form provides a dissolution
rate
of at least about 80% after about 6 hours to about 16 hours following entry
into a use
environment.
16. A stable dosage form comprising an active ingredient that comprises
substantially
pure levomilnacipran or pharmaceutically acceptable salt thereof, and about
0.01% to
about 0.2% by weight of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-2-one,
wherein
the dosage form comprises an X-ray powder diffraction (XRD) pattern that
comprises
characteristic peaks at 12.0, 20.1 and 22.5 ~ 0.2 degrees 2.SLZERO..
17. The stable dosage form of claim 16, wherein the dosage form comprises
about 45
wt.% to about 60 wt.% of the active ingredient; and about 4 wt.% to about 10
wt.% of a
binder.
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18. A method for treating major depressive disorder comprising administering
the
stable dosage form of claim 1 to a patient in need thereof.
19. A method for treating major depressive disorder comprising administering
the
stable dosage form of claim 2 to a patient in need thereof.
20. A method for treating major depressive disorder comprising administering
the
stable dosage form of claim 16 to a patient in need thereof.
21. A method for preparing the stable dosage form of claim 1, wherein the
method
comprises contacting an inert substrate with levomilnacipran or a
pharmaceutically
acceptable salt thereof and a dehydrated alcohol.
22. A method for preparing the stable dosage form of claim 2, wherein the
method
comprises contacting an inert substrate with levomilnacipran or a
pharmaceutically
acceptable salt thereof and a dehydrated alcohol.
23. A method for preparing the stable dosage form of claim 16, wherein the
method
comprises contacting an inert substrate with levomilnacipran or a
pharmaceutically
acceptable salt thereof and a dehydrated alcohol.
53

Description

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STABLE DOSAGE FORMS
OF LEVOMILNACIPRAN
This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional
Application No. 61/294,898, filed on January 14, 2010, and under 35 U.S.C. 120
to U.S.
Patent Application No. 12/941,293, filed on November 8, 2010, which claims
priority
under 35 U.S.C. 119(e) to U.S. Provisional Application No. 61/258,652, filed
on
November 6, 2009. The entire contents of these applications are incorporated
herein by
reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to stable dosage formulations of levomilnacipran
or
a pharmaceutically acceptable salt thereof. Processes for the preparation of
these dosage
forms and methods of using these dosage forms are also described.
BACKGROUND OF THE INVENTION
Levomilnacipran is the international nonproprietary name for (IS, 2R)-2-(amino
methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide. It is a highly potent
selective
norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor with greater
selectivity for
NE reuptake inhibition than for 5-HT reuptake inhibition. In particular,
levomilnacipran
has an inhibitory selectivity ratio for NE:5-HT of approximately 1.5:1.
Accordingly,
levomilnacipran is considered a norepinephrine-serotonin reuptake inhibitor
(NSRI) that
is pharmacologically distinct from serotonin-norepinephrine reuptake
inhibitors (SNRI)
having equal or higher inhibitory selectivity for 5-HT than for NE.
While formulations of levomilnacipran are generally discussed in the prior
art,
difficulties have been encountered in preparing stable dosage forms of
levomilnacipran.
These difficulties have arisen, at least in part, due to the sensitivity of
levomilnacipran to
certain reaction conditions and its reactivity with certain commonly-used
excipients.
Accordingly, there is an existing and continual need for improved formulations
of
levomilnacipran having improved purity and stability. In addition, the
improved-stability
formulations must achieve a desirable pharmacokinetic profile that is
associated with a
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low incidence of undesirable adverse events (for example, nausea, vomiting and
gastric
bleeding) in patients.
Improved formulations of levomilnacipran have now been discovered which
achieve a desirable release of levomilnacipran upon entering a use environment
and
which have surprisingly high stability. These improved formulations of
levomilnacipran
are described herein.
SUMMARY OF THE INVENTION
The present invention relates to novel dosage forms of levomilnacipran, as
well as
processes for preparing these dosage forms and methods for using the dosage
forms.
In some embodiments, the present invention relates to a stable dosage form
that
comprises levomilnacipran or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention relates to a stable dosage form
that
comprises, or consists essentially of, an active ingredient that comprises
substantially
pure levomilnacipran or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention relates to a stable dosage form
that
comprises, or consists essentially of, an active ingredient that comprises at
least about
98% by weight (e.g., at least 98% by weight) of levomilnacipran or a
pharmaceutically
acceptable salt thereof.
In some embodiments, the present invention relates to a stable dosage form
comprising levomilnacipran or a pharmaceutically acceptable salt thereof,
wherein the
dosage form comprises a X-ray powder diffraction (XRD) pattern that comprises
characteristic peaks at 12.0, 20.1 and 22.5 0.2 degrees 20. In some
embodiments, the
XRD pattern also comprises a characteristic peak at 32.7 0.2 degrees 20. In
some
embodiments, the XRD pattern also comprises a characteristic peak at 32.7
0.2 degrees
20. In some embodiments, the XRD pattern also comprises a characteristic peak
at 6.0
0.2 degrees 20.
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In some embodiments, the present invention relates to a stable dosage form
comprising levomilnacipran or a pharmaceutically acceptable salt thereof
wherein the
dosage form comprises a X-ray powder diffraction (XRD) pattern that comprises
characteristic peaks at 6.0, 12.0 and 20.1 0.2 degrees 20. In some
embodiments, the
XRD pattern also comprises a characteristic peak at 22.5 0.2 degrees 20.
In some embodiments, the present invention relates to a stable dosage form
comprising levomilnacipran or a pharmaceutically acceptable salt thereof and
about
0.001% to about 0.5% by weight of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-
2-one.
In some embodiments, the present invention relates to a stable dosage form
comprising levomilnacipran or a pharmaceutically acceptable salt thereof and
about
0.001% to about 0.2% by weight of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-
2-one.
In some embodiments, the stable dosage form comprises about 45 wt.% to about
60 wt.% an active ingredient comprising substantially pure levomilnacipran or
a
pharmaceutically acceptable salt thereof.
In some embodiments, the stable dosage form comprises about 45 wt.% to about
60 wt.% an active ingredient comprising substantially pure levomilnacipran or
a
pharmaceutically acceptable salt thereof, and about 4 wt.% to about 10 wt.% of
a binder.
In some embodiments, the stable dosage form comprises about 45 wt.% to about
60 wt.% an active ingredient comprising substantially pure levomilnacipran or
a
pharmaceutically acceptable salt thereof; about 30 wt.% to about 45 wt.% of an
inert
substrate or filler; and about 4 wt.% to about 10 wt.% of a binder.
In some embodiments, the stable dosage form comprises about 45 wt.% to about
60 wt.% an active ingredient comprising substantially pure levomilnacipran or
a
pharmaceutically acceptable salt thereof; about 30 wt.% to about 45 wt.% of an
inert
substrate or filler; about 4 wt.% to about 10 wt.% of a binder; and about 1
wt.% to about
5 wt.% of an anti-adherent or lubricant.
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In some embodiments, the stable dosage form comprises about 50 wt.% to about
60 wt.% of levomilnacipran or a pharmaceutically acceptable salt thereof;
about 30 wt.%
to about 40 wt.% of an inert substrate or filler; about 4 wt.% to about 8 wt.%
of a binder;
and about 1 wt.% to about 5 wt.% of an anti-adherent or lubricant.
In some embodiments, the stable dosage form comprises about 40% to about 55%
by weight of levomilnacipran or pharmaceutically acceptable salt thereof,
about 5% to
about 15% by weight of a release controlling agent, about 25% to about 40% by
weight
of an inert substrate, about 3% to about 10% by weight of a binder, about 3%
to about
10% by weight of an anti-adherent, and about 0.1% to about 5% by weight of a
plasticizer.
In some embodiments, the stable dosage form provides a dissolution rate of at
least about 80% after about 6 hours to about 16 hours following entry into a
use
environment.
In some embodiments, the present invention relates to a stable oral dosage
form
comprising an active ingredient that comprises between about 10 mg and about
200 mg
of levomilnacipran, wherein the dosage form comprises a X-ray powder
diffraction
(XRD) pattern that comprises characteristic peaks at 12.0, 20.1 and 22.5 0.2
degrees
20.
In some embodiments, the present invention relates to an oral dosage form
comprising between about 10 mg and about 200 mg of levomilnacipran and about
0.0001% to about 0.5% by weight (e.g., about 0.0001% to about 0.2% by weight
or even
about 0.0001% to about 0.1% by weight) of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-
0]
hexane-2-one.
In some embodiments, the present invention relates to an oral dosage form
comprising between about 10 mg and about 200 mg of levomilnacipran and about
0.0001% to about 0.5% by weight (e.g., about 0.0001% to about 0.2% by weight
or even
about 0.0001% to about 0.1% by weight) of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-
0]
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hexane-2-one, wherein the dosage form comprises a X-ray powder diffraction
(XRD)
pattern that comprises characteristic peaks at 12.0, 20.1 and 22.5 0.2
degrees 20.
In some embodiments, the dosage form provides a dissolution rate of at least
about 80% after about 6 hours to about 16 hours following entry into a use
environment.
In some embodiments, the present invention relates to a stable dosage form
comprising levomilnacipran or a pharmaceutically acceptable salt thereof and a
release
controlling agent, the dosage form sustaining release of the levomilnacipran
or
pharmaceutically acceptable salt thereof following entry of the dosage form
into a use
environment.
In some embodiments, the present invention relates to a stable oral dosage
form
comprising about 20 mg, about 40 mg, about 80mg or about 120 mg of
levomilnacipran
or a pharmaceutically acceptable salt thereof.
In some embodiments, the present invention relates to a method for treating
major
depressive disorder comprising administering the stable dosage form of
levomilnacipran
or a pharmaceutically acceptable salt thereof to a patient in need thereof.
In some embodiments, the present invention relates to a method for treating
major
depressive disorder with concomitant fatigue comprising administering the
stable dosage
form of levomilnacipran or a pharmaceutically acceptable salt thereof to a
patient in need
thereof.
In some embodiments, the present invention relates to a method for preparing
the
stable dosage form, wherein the method comprises contacting an inert substrate
with
levomilnacipran or a pharmaceutically acceptable salt thereof and a dehydrated
alcohol.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the dissolution rates for a stable dosage form of
levomilnacipran
in accordance with an embodiment of the present invention.
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Figure 2 show the dissolution rates for a stable dosage form of
levomilnacipran in
accordance with an embodiment of the present invention following one month of
storage
at 40 C and 75% relative humidity (RH).
Figure 3 show the dissolution rates for a stable dosage form of
levomilnacipran in
accordance with an embodiment of the present invention following two months of
storage
at 40 C and 75% RH.
Figure 4 show the dissolution rates for a stable dosage form of
levomilnacipran in
accordance with an embodiment of the present invention following three months
of
storage at 40 C and 75% RH.
Figure 5 show the dissolution rates for a stable dosage form of
levomilnacipran in
accordance with an embodiment of the present invention following three months
of
storage at 40 C and 75% RH wherein the dosage form contained 1 gram of
desiccant.
Figure 6 shows an X-ray powder diffraction pattern (XRD) for an active
pharmaceutical ingredient comprising substantially pure levomilnacipran.
Figure 7 shows an XRD of a stable immediate-release dosage form of
levomilnacipran in accordance with an embodiment of the invention.
Figure 8 shows an XRD of a stable sustained-release dosage form of
levomilnacipran in accordance with an embodiment of the invention.
Figure 9 shows the mean plasma concentration of levomilnacipran versus time
that may be achieved via single administration of Stable dosage forms of
levomilnacipran
to human patients.
DETAILED DESCRIPTION OF THE INVENTION
Novel stable dosage forms of levomilnacipran, methods of treatment using these
dosage forms, and methods for preparing these dosage forms are provided
herein. The
dosage forms of levomilnacipran have been found to achieve a desirable
dissolution
profile upon entering a use environment and to have surprisingly high
stability.
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Definitions
As used herein, the term "levomilnacipran" refers to (1 S,2R)-2-(amino methyl)-
N,N-diethyl-l-phenyl cyclopropane carboxamide and pharmaceutically acceptable
salts
thereof. The term is not inclusive of other isomers of 2-(amino methyl)-N,N-
diethyl-l-
phenyl cyclopropane carboxamide (e.g., 1R,2S 2-(amino methyl)-N,N-diethyl-l-
phenyl
cyclopropane carboxamide) or degradants of (1S,2R)-2-(amino methyl)-N,N-
diethyl-l-
phenyl cyclopropane carboxamide (e.g., (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0]
hexane-
2-one). The term "pharmaceutically acceptable salt" refers to any salt of
levomilnacipran
that is physiologically tolerated by a patient (for example, levomilnacipran
hydrochloride). The structural formula of levomilnacipran is shown below:
NH~
(1)
The term "substantially pure levomilnacipran" is used herein to mean at least
98%
by weight of levomilnacipran. For example, an active pharmaceutical ingredient
(i.e.,
active ingredient) that comprises substantially pure levomilnacipran comprises
at least
98% by weight (e.g., about 98.5% by weight) of levomilnacipran and at most 2%
by
weight of total combined other components (such as other isomers of 2-(amino
methyl)-
N,N-diethyl-l-phenyl cyclopropane carboxamide and/or degradants of (1S,2R)-2-
(amino
methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide).
The term "stable", when used herein to refer to the dosage form means that the
dosage form comprises an active ingredient that comprises substantially pure
levomilnacipran.
The terms "dehydrated alcohol" and "dehydrated solvent" are defined herein as
they are defined in the U.S. Pharmacopeia to mean an alcohol or solvent that
contains
less than or equal to 0.8% by weight of water, which corresponds to less or
equal to
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99.5% by volume of water. The term "dehydrated solvent" is used herein
synonymously
with the terms "substantially pure solvent," "anhydrous solvent," and
"absolute solvent".
Likewise, the term "dehydrated alcohol" is used herein synonymously with the
terms
"substantially pure alcohol," "anhydrous alcohol," and "absolute alcohol".
The term "treating" is used herein, unless otherwise indicated, to mean to
relieve,
alleviate, delay, reduce, reverse, improve or prevent at least one symptom of
a disease,
disorder or condition in a patient which may be treated by inhibition of
norepinephrine
(NE) and serotonin (5-HT) reuptake. The term "treating" may also mean to
arrest, delay
the onset (i.e., the period prior to clinical manifestation of a disease,
disorder or
condition) and/or reduce the risk of developing or worsening a disease,
disease or
condition which may be treated by inhibition of norepinephrine (NE) and
serotonin (5-
HT) reuptake.
The terms "dosage form" is used herein, unless otherwise indicated, to refer
to
any formulation of levomilnacipran that is suitable for oral administration to
a human
patient. For example, the term "dosage form" encompasses any oral dosage form
or any
solid oral dosage form, for example, compositions that are suitable for
loading into
capsules (e.g., beads, granules, microgranules, or the like), tablets,
gelcaps, caplets,
lozenges or powders). In some embodiments, the dosage form is a dosage form
(e.g.,
bead, granule, microgranule or the like) that is suited for loading into
capsules. In some
embodiments, the dosage form is an immediate-release dosage form (e.g., an
immediate-
release solid dosage form, an immediate-release oral dosage form or an
immediate-
release solid oral dosage form).
In some embodiments, the dosage form is an immediate-release composition that
is coated with a modified-release (e.g., sustained-release, delayed-release
and/or extended
release) composition. In some embodiments, the dosage form is a sustained-
release
dosage form (e.g., a sustained-release solid dosage form, a sustained-release
oral dosage
form, or a sustained-release solid oral dosage form). In some embodiments, the
dosage
form is a capsule (e.g., a bead-, granule- or microgranule-filled capsule). In
some
embodiments, the dosage form is a tablet. In some embodiments, the dosage form
is a
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once-daily solid oral dosage form. In some embodiments, the dosage form is a
once-
daily capsule.
The term "sustained release" is used herein, unless otherwise indicated, to
refer to
dosage forms that release levomilnacipran (and optionally additional active
agents
contained therein) at a time other than promptly after administration, e.g.,
over an
extended period of time that exceeds the duration of drug release from
conventional
instant- and immediate-release dosage forms of levomilnacipran.
The term "entry into a use environment" is used herein, unless otherwise
indicated, to refer to contact of the stable dosage form of levomilnacipran
with gastric or
intestinal fluid of a patient to whom it is administered, with a fluid
intended to simulate
gastric or intestinal fluid, or with deionized water at a temperature of about
37 C and
subjected to USP apparatus II at 75 rpm (for example, with 1000 mL of
deionized water
at a temperature of about 37 C and subjected to USP apparatus II at 75 rpm).
As used herein, unless otherwise indicated, dissolution rates define the
percentage
of levomilnacipran originally contained in an stable dosage form that is
released from the
dosage form within a specified period of time following entry of the dosage
form into a
use environment.
As used herein, unless otherwise indicated, the terms "effective amount" and
"therapeutically effective amount" refer to an amount or quantity of
levomilnacipran
which is sufficient to elicit an appreciable biological response when
administered to a
patient. For example, the terms "effective amount" and "therapeutically
effective
amount" refer to an amount of levomilnacipran (or additional active agent
contained in
the dosage form) that, when administered to a patient (e.g., human or other
mammal) for
treating a disease, condition or disorder which may be treated by inhibition
of
norepinephrine (NE) and serotonin (5-HT) reuptake (e.g., major depressive
disorder or
anxiety), is sufficient to effect such treatment of one or more symptoms of
the disease,
disorder or condition, or an amount of levomilnacipran (or additional active
agent
contained in the dosage form) that is sufficient for inhibition of NE and 5-HT
reuptake in
a patient. It will be appreciated that the precise therapeutic dose will
depend on the age,
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condition, weight, etc. of the patient and the nature of the condition being
treated and will
be ultimately be at the discretion of the attending physician.
For example, in some embodiments, the therapeutically effective dosage of
levomilnacipran within the stable dosage form for treating depression (e.g.,
major
depressive disorder) was found to be between about 10mg and about 150mg of an
active
ingredient comprising substantially pure levomilnacipran (e.g., between about
20mg and
about 120mg of the active ingredient). In some embodiments, the dosage form
comprises
between about 15mg and about 25mg of an active ingredient comprising
substantially
pure levomilnacipran (e.g., about 20mg). In some embodiments, the dosage form
comprises between about 35mg and about 45mg of an active ingredient comprising
substantially pure levomilnacipran (e.g., about 40mg). In some embodiments,
the dosage
form comprises between about 70 mg and about 90 mg of an active ingredient
comprising
substantially pure levomilnacipran (e.g., about 80mg). In some embodiments,
the dosage
form comprises between about 100mg and about 140mg of an active ingredient
comprising substantially pure levomilnacipran (e.g., about 120mg).
As used herein, unless otherwise indicated, the term "purity" when used in
referring to the stable dosage forms means the degree to which the dosage form
is free
from (or lacks) specific undesirable components or impurities (for example,
degradants or
the like).
The term "consisting essentially of', when used in reference to the dosage
form,
means that the dosage form contains no additional active pharmaceutical
ingredients but
may contain additional inactive components or excipients.
As used herein, unless otherwise indicated, the terms "about" and
"approximately" should be understood to mean within an acceptable error range
for the
particular value as determined by one of ordinary skill in the art, which will
depend in
part on how the value is measured or determined, i.e., the limitations of the
measurement
system. For example, "about" can mean within 1 or more than 1 standard
deviations, per
the practice in the art. Alternatively, "about" can mean a range of up to 20%,
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up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a
given
value.
X-Ray Powder Diffraction Pattern of Oral Dosage Form
In some preferred embodiments, the stable dosage form, or the active
ingredient
contained within the dosage form, is crystalline in structure. In some
preferred
embodiments, the stable dosage form and the active ingredient contained within
the
dosage form are crystalline in structure. In some embodiments, the stable
dosage form
has an X-ray powder diffraction pattern (XRD) comprising one or more
characteristic
peaks as provided in Table 1. In some embodiments, the stable dosage form
comprises
an active ingredient comprising levomilnacipran wherein the active ingredient
has an X-
ray powder diffraction pattern (XRD) comprising one or more characteristic
peaks as
provided in Table 1.
As used herein, unless otherwise indicated, the phrase "one or more peaks"
should
be understood to be inclusive of (i) stable dosage forms that have XRD peaks
at every
peak value recited after this phrase, (ii) stable dosage forms that have an
XRD peak at
only one of the peak values recited after this phrase, as well (iii) stable
dosage forms that
have XRD peaks at two or more (e.g., three or more, four or more, five or
more, six or
more, or even seven or more) of the peak values recited after this phrase.
Table 1
2-Theta d(,A) 2-Theta d(A)
6.0 14.8 22.4 4.0
12.0 7.4 24.1 3.7
12.4 7.1 24.6 3.6
14.2 6.2 24.8 3.6
17.4 5.1 28.8 3.1
18.2 4.9 30.7 2.9
20.1 4.4 32.7 2.7
21.1 4.2 35.2 2.5
21.6 4.1
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In some embodiments, the stable dosage form of levomilnacipran has an X-ray
powder diffraction pattern (XRD) comprising one or more characteristic peaks
as
provided in Table 2.
Table 2
2-Theta d(,k) 2-Theta d(A)
2.3 39.2 20.0 4.4
5.9 14.9 21.7 4.1
9.5 9.3 22.4 4.0
11.9 7.4 24.5 3.6
12.3 7.2 28.6 3.1
14.1 6.3 30.6 2.9
16.5 5.4 32.7 2.7
17.3 5.1 34.5 2.6
18.1 4.9
In some embodiments, the stable dosage form of levomilnacipran is a modified-
release dosage form (e.g., a sustain-release dosage form) and has an X-ray
powder
diffraction pattern (XRD) comprising one or more characteristic peaks as
provided in
Table 3.
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Table 3
2-Theta d(A) 2-Theta (1(,A)
6.0 14.7 22.1 4.0
8.3 10.6 22.5 4.0
9.6 9.2 23.6 3.8
12.0 7.4 24.7 3.6
12.8 6.9 25.2 3.5
13.1 6.7 26.4 3.4
14.2 6.2 27.5 3.2
15.6 5.7 28.7 3.1
16.4 5.4 30.6 2.9
16.8 5.3 31.0 2.9
17.4 5.1 32.0 2.8
18.3 4.8 32.7 2.7
18.9 4.7 33.5 2.7
19.6 4.5 34.6 2.6
20.0 4.4 36.2 2.5
20.4 4.4 37.3 2.4
20.9 4.2 38.3 2.3
21.6 4.1
In some embodiments, the present invention relates to a stable dosage form
comprising levomilnacipran or a pharmaceutically acceptable salt thereof
wherein the
dosage form comprises a X-ray powder diffraction (XRD) pattern that comprises
characteristic peaks at 12.0, 20.1 and 22.5 0.2 degrees 20. In some
embodiments, the
XRD pattern also comprises a characteristic peak at 32.7 0.2 degrees 20. In
some
embodiments, the XRD pattern also comprises a characteristic peak at 32.7
0.2 degrees
20. In some embodiments, the XRD pattern also comprises a characteristic peak
at 6.0
0.2 degrees 20.
In some embodiments, the stable dosage form of levomilnacipran has an XRD
comprising characteristic peaks at about 6.0, about 12.0 and about 20.1 0.2
degrees 20.
In some embodiments, the stable dosage form has an XRD comprising
characteristic
peaks at about 6.0, about 12.0 and about 22.4 0.2 degrees 20. In some
embodiments,
the stable dosage form has an XRD comprising characteristic peaks at about
6.0, about
12.0, about 20.1 and about 22.4 0.2 degrees 20. In some embodiments, the
stable
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dosage form has an XRD comprising characteristic peaks at about 6.0, about
20.1 and
about 22.4 0.2 degrees 20. In some embodiments, the stable dosage form has
an XRD
comprising characteristic peaks at about 12.0, about 20.1 and about 22.4 0.2
degrees
20. In some embodiments, the stable dosage form has an XRD comprising
characteristic
peaks at about 6.0 and about 12.0 0.2 degrees 20. In some embodiments, the
stable
dosage form has an XRD comprising characteristic peaks at about 6.0 and about
20.1
0.2 degrees 20. In some embodiments, the stable dosage form has an XRD
comprising
characteristic peaks at about 6.0 and about 22.4 0.2 degrees 20.
In some embodiments, the stable dosage form has an XRD comprising
characteristic peaks at about 12.0 and about 20.1 0.2 degrees 20. In some
embodiments, the stable dosage form has an XRD comprising characteristic peaks
at
about 12.0 and about 22.4 0.2 degrees 20. In some embodiments, the stable
dosage
form has an XRD comprising characteristic peaks at about 20.1 0.2 degrees 20
and at
about 22.4 0.2 degrees 20. In some embodiments, the stable dosage form
comprises a
crystalline form of levomilnacipran having an XRD that comprises
characteristic peaks at
one or more of about 6.0 0.2 degrees 20, about 12.0 0.2 degrees 20, about
20.1 0.2
degrees 20 and about 22.4 0.2 degrees 20.
In some embodiments, the stable dosage form comprises an active ingredient
that
comprises substantially pure levomilnacipran wherein the active ingredient
comprises
one or more of the characteristic peaks shown in Table 1. In some embodiments,
the
stable dosage form comprises an active ingredient that comprises substantially
pure
levomilnacipran wherein the stable dosage form comprises one or more of the
characteristic peaks shown in Table 1 or Table 2.
Purity of the Stable Dosage Forms
The stable dosage form and the active ingredient in the dosage form have been
found to comprise a surprisingly low concentration of (1S, 5R) 1-phenyl-3-
azabicyclo[3-
1-0] hexane-2-one, which is represented by Formula (II):
14

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llllnnõ
O N
N (II).
In some embodiments, the stable dosage form comprises about 0.0001 to about
0.2% by weight of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-2-one, as
defined by
the International Conference on Harmonization (ICH) guidelines, for example
after
storage for one, two or three months of storage at 40 C and 75% relative
humidity. In
some embodiments, the stable dosage form comprises less than about 0.2% by
weight of
(1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-2-one, for example after storage
for one,
two or three months of storage at 40 C and 75% relative humidity. In some
embodiments, the stable dosage form comprises about 0.0001 to about 0.1% by
weight of
(1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-2-one, for example, after storage
for one,
two or three months of storage at 40 C and 75% relative humidity.
In some preferred embodiments, the stable dosage form comprises about 0.001 to
about 0.2 wt.%, about 0.01 to about 0.2 wt.%, about 0.0001 to about 0.15 wt.%,
about
0.001 to about 0.15 wt.%, about 0.01 to about 0.15 wt.%, about 0.001 to about
0.1 wt.%,
about 0.01 to about 0.1 wt.%, about 0.01 to about 0.08 wt.%, or even about
0.001 to
about 0.08 wt.% of (1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-2-one, for
example,
after storage for one, two, three, four, five or six months of storage at 40 C
and 75%
relative humidity. In some embodiments, the stable dosage form comprises about
0.01 to
about 0.08 wt.% (e.g., about 0.001 to about 0.08 wt.%) of (1S, 5R) 1-phenyl-3-
azabicyclo [3 - 1 -0] hexane-2-one, for example, after storage for one, two,
three, four, five
or six months of storage at 40 C and 75% relative humidity.
Preparation of the Stable Dosage Form
The stable dosage forms of levomilnacipran can be prepared by any suitable
process. In some preferred embodiments, the stable dosage forms are prepared
by a

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method comprising contacting an inert substrate or filler with a solution that
comprises
(or consists essentially of or consists of) levomilnacipran, a solvent (e.g.,
a solvent
comprising less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2
wt.%, less
than 1 wt.%, less than 0.8 wt.%, less than 0.5 wt.%, or even less than 0.1
wt.% of water)
(e.g., a dehydrated alcohol such as 200-proof ethanol) and optionally a binder
and an
anti-adherent or lubricant, to form a levomilnacipran composition. In some
embodiments, the dosage forms of levomilnacipran are then coated to render
them
sustained-release dosage forms by contacting the levomilnacipran composition
with a
solution that comprises a release controlling agent, a solvent (e.g., a
solvent comprising
less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less
than 1 wt.%,
less than 0.8 wt.%, less than 0.5 wt.%, or even less than 0.1 wt.% of water)
(e.g., a
dehydrated alcohol such as 200-proof ethanol) and optionally a plasticizer, an
anti-
adherent or glidant.
In some preferred embodiments, the stable dosage forms are prepared by a
method comprising contacting an inert substrate or filler with a solution that
comprises
levomilnacipran, a solvent (e.g., a solvent comprising less than 5 wt.%, less
than 4 wt.%,
less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.8 wt.%, less
than 0.5
wt.%, or even less than 0.1 wt.% of water), a binder, and an anti-adherent or
lubricant, to
form a levomilnacipran composition. In some embodiments, the dosage forms of
levomilnacipran are then coated to render them sustained-release dosage forms
by
contacting the levomilnacipran composition with a solution that comprises a
release
controlling agent, a plasticizer, an anti-adherent or glidant, and a solvent
(e.g., a solvent
comprising less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2
wt.%, less
than 1 wt.%, less than 0.8 wt.%, less than 0.5 wt.%, or even less than 0.1
wt.% of water).
In some embodiments, the stable dosage forms are prepared by a method
comprising contacting an inert substrate or filler with levomilnacipran and
optionally a
binder, an anti-adherent or lubricant, and/or a solvent (e.g., a solvent
comprising less than
5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1
wt.%, less than
0.8 wt.%, less than 0.5 wt.%, or even less than 0.1 wt.% of water) to form a
levomilnacipran composition (e.g., a levomilnacipran core or levomilnacipran
beads or
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granules). In some embodiments, the dosage forms of levomilnacipran are then
coated to
render them sustained-release dosage forms by contacting the levomilnacipran
composition with a release controlling agent and optionally a plasticizer, an
anti-adherent
or lubricant; and/or a solvent (e.g., a solvent comprising less than 5 wt.%,
less than 4
wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.8
wt.%, less than
0.5 wt.%, or even less than 0.1 wt.% of water).
In some embodiments, the stable dosage forms are prepared by a method
comprising contacting an inert substrate or filler with a solution that
comprises
levomilnacipran, a solvent (e.g., a solvent comprising less than 5 wt.%, less
than 4 wt.%,
less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than 0.8 wt.%, less
than 0.5
wt.%, or even less than 0.1 wt.% of water) and optionally a binder and an anti-
adherent
(or lubricant) to form a levomilnacipran composition (e.g., a core, bead or
granule
comprising levomilnacipran). In some embodiments, the method further comprises
coating the levomilnacipran composition with a solution that comprises (or
consists
essentially of or consists of) a release controlling agent and optionally a
plasticizer, an
anti-adherent or lubricant; and/or a solvent (e.g., a solvent comprising less
than 5 wt.%,
less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less
than 0.8 wt.%,
less than 0.5 wt.%, or even less than 0.1 wt.% of water).
In some embodiments, the stable dosage forms are prepared by a method
comprising contacting an inert substrate or filler with a solution comprising
levomilnacipran, a binder, an anti-adherent or lubricant, and a solvent (e.g.,
a solvent
comprising less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2
wt.%, less
than 1 wt.%, less than 0.8 wt.%, less than 0.5 wt.%, or even less than 0.1
wt.% of water).
In some embodiments, the contacting step comprises layering the inert
substrate with a
drug layering solution that consists essentially of levomilnacipran, a binder,
an anti-
adherent (or lubricant) and a solvent (e.g., a solvent comprising less than 5
wt.%, less
than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, less than
0.8 wt.%, less
than 0.5 wt.%, or even less than 0.1 wt.% of water).
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In some preferred embodiments, the contacting step (e.g., drug layering step)
is
performed by a Wurster process (e.g., within a Wurster apparatus) or the like.
In some
preferred embodiments, the coating step is performed by a Wurster process
(e.g., within a
Wurster apparatus) or the like. In some preferred embodiments, the combining
step and
the contacting steps are both performed by a Wurster process or the like.
The process for determining the relative percentages of levomilnacipran and
other
isomers of 2-(amino methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide
(e.g.,
1R,2S 2-(amino methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide) in the
active
pharmaceutical ingredient can be performed using any suitable method,
preferably by
reverse phase high performance liquid chromatograph (RP HPLC) (for example,
with a
UV detection at 220 nm).
Components of the stable dosage forms
The stable dosage form can comprise any therapeutically effective amount of
levomilnacipran. In some embodiments, the stable dosage form comprises about 5
to
about 200 mg of levomilnacipran. In some embodiments, the stable dosage form
comprises about 10 to about 180 mg of levomilnacipran. In some embodiments,
the
stable dosage form comprises about 20 to about 150 mg of levomilnacipran. In
some
embodiments, the stable dosage form comprises about 20 to about 120 mg of
levomilnacipran. For example, the stable dosage form can comprise about 20 mg,
about
40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, 120 mg, or about
240 mg
of levomilnacipran. In this regard, the stable dosage form can comprise any
suitable
weight percentage of levomilnacipran relative to other components of the
dosage form.
For example, the stable dosage form can comprise about 35 to about 65% by
weight (e.g.,
about 35 to about 60 wt.%, about 35 to about 55 wt.%, about 40 to about 55
wt.%, or
about 40 to about 50 wt.%) of levomilnacipran.
The stable dosage form of levomilnacipran also comprises an inert substrate or
filler. In some preferred embodiments, the stable dosage form comprises an
inert
substrate that comprises sugar for example sucrose (e.g., sugar spheres).
Other suitable
inert substrates or fillers include, for example, isomalt, dicalcium phosphate
dihydrate,
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calcium sulfate, lactose, mannitol, sorbitol, cellulose, microcrystalline
cellulose, kaolin,
sodium chloride, dry starch, hydrolyzed starches, pre-gelatinized starch,
silicone dioxide,
titanium oxide, magnesium aluminum silicate, or a mixture thereof.
The stable dosage form can comprise any suitable amount of the inert substrate
or
filler (e.g., sugar spheres). In some embodiments, the stable dosage form
comprises
about 15 to about 45% by weight of the inert substrate or filler. In some
embodiments,
the stable dosage form comprises about 20 to about 40 wt.% of the inert
substrate or
filler. In some embodiments, the stable dosage form comprises about 25 to
about 40
wt.% of the inert substrate or filler. In some embodiments, the stable dosage
form
comprises about 30 to about 40 wt.% of the inert substrate or filler In some
embodiments,
the stable dosage form comprises about 35 to about 40 wt.% of the inert
substrate or
filler.
The stable dosage form can comprise sugar spheres in any suitable size. In
some
embodiments, the stable dosage form comprises sugar spheres having a size of
about 20
to about 50 mesh. In some embodiments, the stable dosage form comprises sugar
spheres
having a size of approximately about 25 to about 45 mesh. In some embodiments,
the
stable dosage form comprises sugar spheres having a size of about 25 to about
40 mesh.
In some preferred embodiments, the stable dosage form comprises sugar spheres
having a
size of approximately about 30 to about 40 mesh (for example, about 30 to
about 35
mesh). For example, the stable dosage form may comprise about 30 to about 40
wt.%
(e.g., about 35 to about 40 wt.%) of sugar spheres having a size of about 30
to about 40
mesh.
The stable dosage form also comprises a binder in some preferred embodiments,
for example polyvinyl pyrrolidone (e.g., Povidone K30). Other suitable binders
include,
for example, starch, polyvinyl alcohol, pre-gelatinized starch, gelatin,
sucrose, glucose,
dextrose, lactose, sorbitol, polyethylene glycol, waxes, natural and synthetic
gums such
as acacia, tragacanth, sodium alginate, hydroxypropylmethylcellulose,
hydroxypropylcellulose, ethylcellulose, veegum, and synthetic polymers such as
acrylic
acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl
methacrylate
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copolymers, aminoalkyl methacrylate copolymers, polyacrylic
acid/polymethacrylic acid,
or a mixture thereof.
The stable dosage form can comprise any suitable amount of the binder (e.g.,
PVP). In some embodiments, the stable dosage form comprises about 0.1 to about
15%
by weight of a binder. In some embodiments, the stable dosage form comprises
about 1
to about 12% by weight of a binder. In some embodiments, the stable dosage
form
comprises about 1 to about 10% by weight of a binder. In some embodiments, the
stable
dosage form comprises about 2 to about 10% by weight of a binder.
In some preferred embodiments, the stable dosage form comprises about 3 to
about 10% by weight of a binder (e.g., PVP). In some embodiments, the stable
dosage
form comprises about 4 to about 10% by weight of the binder. In some
embodiments, the
stable dosage form comprises about 2 to about 8% by weight of the binder. In
some
embodiments, the stable dosage form comprises about 4 to about 8% by weight of
the
binder. In some embodiments, the stable dosage form comprises about 5 to about
7% by
weight of the binder.
The stable dosage form also comprises an anti-adherent or lubricant in some
preferred embodiments, for example, talc. Other suitable anti-adherents or
lubricants
include, for example, magnesium stearate, calcium stearate, stearic acid,
glycerol
behenate, polyethylene glycol, talc, mineral oil, sodium stearyl fumarate or
mixtures
thereof.
The stable dosage form can comprise any suitable amount of the lubricant or
anti-
adherent (for example, talc). In some embodiments, the stable dosage form
comprises
about 0.1 to about 15% by weight of the lubricant or anti-adherent. In some
embodiments, the stable dosage form comprises about 1 to about 12% by weight
of the
lubricant or anti-adherent. In some embodiments, the stable dosage form
comprises
about 2 to about 10% by weight of the lubricant or anti-adherent. In some
embodiments,
the stable dosage form comprises about 3 to about 10% by weight of the
lubricant or anti-
adherent. In some embodiments, the stable dosage form comprises about 4 to
about 10%
by weight of the lubricant or anti-adherent. In some embodiments, the stable
dosage

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form comprises about 4 to about 8% by weight of the lubricant or anti-
adherent. In some
embodiments, the stable dosage form comprises about 5 to about 8% by weight of
the
lubricant or anti-adherent.
In some preferred embodiments, the stable dosage form comprises about 4 to
about 7.5% by weight of the lubricant or anti-adherent. In some preferred
embodiments,
the stable dosage form comprises about 5 to about 7% by weight of the
lubricant or anti-
adherent.
In some embodiments, the stable dosage form is a sustained-release (SR) dosage
form and comprises a release controlling agent, polymeric agent or coating
polymer (e.g.,
ethyl cellulose) which substantially contributes to sustaining the release of
levomilnacipran from the dosage form. Other suitable release controlling
agents include,
for example, a cellulose and cellulose derivative, wax, carbomer, polyalkylene
polyol,
polycarbophil, methacrylic acid derivative, gelatin, gum, polyethylene oxide,
and
polyvinyl pyrrolidone, or mixtures thereof. In some embodiments, the release
controlling
agent, polymeric additive or coating polymer is selected from ethyl cellulose,
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,
hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate
succinate,
hydroxypropylmethyl cellulose phthalate, methylcellulose, cellulose acetate,
cellulose
acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose
sodium;
acrylic acid polymers and copolymers (preferably formed from acrylic acid,
methacrylic
acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl
methacrylate), and
other methacrylic resins that are commercially available under the trade name
EudragitTM
(Rohm Pharma; Westerstadt, Germany), including EudragitTM L30D-55 and L100-55,
EudragitTM, EudragitTM and EudragitTM NE, RL and RS; vinyl polymers and
copolymers
such as polyvinyl pyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl
acetate
crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically
degradable polymers such as azo polymers, pectin, chitosan, amylose and guar
gum; zein
and shellac, or mixtures thereof.
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The stable dosage form can comprise any suitable amount of the release
controlling agent, polymeric agent or coating polymer (e.g., ethyl cellulose).
The stable
dosage form preferably comprises about 5 to about 15% by weight of the release
controlling agent, polymeric agent or coating polymer. However, n some
embodiments,
the stable dosage form comprises about 2 to about 20% by weight of a release
controlling
agent, polymeric agent or coating polymer. In some embodiments, the stable
dosage
form comprises about 5 to about 12% by weight of a release controlling agent,
polymeric
agent or coating polymer. In some embodiments, the stable dosage form
comprises about
8 to about 12% by weight of a release controlling agent, polymeric agent or
coating
polymer. In some embodiments, the stable dosage form comprises about 8 to
about 11%
by weight of a release controlling agent, polymeric agent or coating polymer.
In some
embodiments, the stable dosage form comprises about 8 to about 10% by weight
of a
release controlling agent, polymeric agent or coating polymer.
The stable dosage form also comprises a plasticizer in some preferred
embodiments, for example triethyl citrate. Other suitable plasticizers
include, for
example, polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate,
diethyl
phthalate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, triethyl
acetyl citrate,
glycerol monostearate, castor oil, acetylated monoglycerides, or a mixture
thereof.
The stable dosage form can comprise any suitable amount of the plasticizer
(for
example, triethyl citrate). In some embodiments, the stable dosage form
comprises about
0.1 to about 10% by weight of the plasticizer. In some embodiments, the stable
dosage
form comprises about 0.5 to about 8% by weight of the plasticizer. In some
embodiments, the stable dosage form comprises about 0.5 to about 5% by weight
of the
plasticizer. In some embodiments, the stable dosage form comprises about 1 to
about 5%
by weight of the plasticizer. In some embodiments, the stable dosage form
comprises
about 1 to about 3% by weight of the plasticizer.
In addition, the stable dosage form of levomilnacipran can comprise any
additional excipients or additives in some embodiments, such as plasticizers,
pigments,
colorants, stabilizing agents, glidants, or the like.
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In some preferred embodiments, the dosage form comprises about 30 wt.% to
about 65 wt.% (e.g., about 40 wt.% to about 60 wt.%, about 45 wt.% to about 60
wt.% or
even about 50 wt.% to about 60 wt.%) of levomilnacipran (or an active
ingredient
comprising at least 98% by weight or even substantially pure levomilnacipran);
about 25
wt.% to about 55 wt.% (e.g., about 30 wt.% to about 45 wt.% or even about 30
wt.% to
about 40 wt.%) of an inert substrate or filler; about 2 wt.% to about 12 wt.%
(e.g., about 4
wt.% to about 10 wt.% or even about 4 wt.% to about 8 wt.%) of a binder; and
about 0.5
wt.% to about 10 wt.% (e.g., about 1 wt.% to about 8 wt.%, about 1 wt.% to
about 5 wt.%
or even about 2 wt.% to about 5 wt.%) of an anti-adherent or lubricant.
In some preferred embodiments, the dosage form comprises about 45 wt.% to
about 60 wt.% of levomilnacipran (or an active ingredient comprising at least
98% by
weight or even substantially pure levomilnacipran); about 30 wt.% to about 45
wt.% of
an inert substrate or filler; about 4 wt.% to about 10 wt.% of a binder; and
about 1 wt.%
to about 5 wt.% of an anti-adherent or lubricant.
In some preferred embodiments, the dosage form comprises about 50 wt.% to
about 60 wt.% of levomilnacipran (or an active ingredient comprising at least
98% by
weight or even substantially pure levomilnacipran); about 30 wt.% to about 40
wt.% of
an inert substrate or filler; about 4 wt.% to about 8 wt.% of a binder; and
about 1 wt.% to
about 5 wt.% of an anti-adherent or lubricant.
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 10
wt.%
(e.g., about 4 to about 8 wt.%) of a binder (e.g., PVP); and about 0.1 to
about 4 wt.%
(e.g., about 1 to about 3 wt.%) of a plasticizer (e.g., triethyl citrate).
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 7
wt.% (e.g.,
about 4 to about 7 wt.%) of an anti-adherent or lubricant (for example, talc);
and about
0.1 to about 4 wt.% (e.g., about 1 to about 3 wt.%) of a plasticizer (e.g.,
triethyl citrate).
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In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 10
wt.%
(e.g., about 4 to about 8 wt.%) of a binder (e.g., PVP); about 3 to about 7
wt.% (e.g.,
about 4 to about 7 wt.%) of an anti-adherent or lubricant (for example, talc);
and about
0.1 to about 4 wt.% (e.g., about 1 to about 3 wt.%) of a plasticizer (e.g.,
triethyl citrate).
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 10
wt.%
(e.g., about 4 to about 8 wt.%) of a binder (e.g., PVP); and about 5-10.5% by
weight
(e.g., about 6 to about 10 wt.%) of a release controlling agent (for example,
ethyl
cellulose).
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 7
wt.% (e.g.,
about 4 to about 7 wt.%) of an anti-adherent or lubricant (for example, talc);
and about 5-
10.5% by weight (e.g., about 6 to about 10 wt.%) of a release controlling
agent (for
example, ethyl cellulose).
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 10
wt.%
(e.g., about 4 to about 8 wt.%) of a binder (e.g., PVP); about 5-10.5% by
weight (e.g.,
about 6 to about 10 wt.%) of a release controlling agent (for example, ethyl
cellulose);
and about 5-10.5% by weight (e.g., about 6 to about 10 wt.%) of a release
controlling
agent (for example, ethyl cellulose).
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 3 to about 7
wt.% (e.g.,
about 4 to about 7 wt.%) of an anti-adherent or lubricant (for example, talc);
about 5-
10.5% by weight (e.g., about 6 to about 10 wt.%) of a release controlling
agent (for
example, ethyl cellulose); and about 5-10.5% by weight (e.g., about 6 to about
10 wt.%)
of a release controlling agent (for example, ethyl cellulose).
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In some preferred embodiments, the stable dosage form comprises about 35 to
about 60% by weight (e.g., about 35 to about 55 wt.% or about 40 to about 55
wt.%) of
levomilnacipran; about 20 to about 45% by weight (e.g., about 20 to about 40
wt.%,
about 25 to about 40 wt.% or about 25 to 35 wt.%) of an inert substrate or
filler (e.g.,
sugar spheres); about 1 to about 15% by weight (e.g., about 2 to about 12
wt.%, about 3
to about 10 wt.%, about 3 to about 9 wt.% or about 4 to about 8 wt.%) of a
binder (for
example, PVP); about 1 to about 15% by weight (e.g., about 2 to about 12 wt.%,
about 3
to about 10 wt.%, about 3 to about 9 wt.%, about 4 to about 8 wt.% or about 4
to about 7
wt.%) of an anti-adherent or lubricant (for example, talc); about 1-20% by
weight (e.g.,
about 5 to about 15 wt.% or about 8 to about 12 wt.%) of a release controlling
agent (for
example, ethyl cellulose); and about 0.1 to about 10% by weight (e.g., about
0.1 to about
5 wt.% or about 1 to about 5 wt.% or about 1 to about 3 wt.%) of a plasticizer
(for
example, triethyl citrate).
In some preferred embodiments, the stable dosage form comprises about 35 to
about 60% by weight (e.g., about 35 to about 55 wt.% or about 40 to about 55
wt.%) of
levomilnacipran; about 20 to about 45% by weight (e.g., about 20 to about 40
wt.%,
about 25 to about 40 wt.% or about 25 to 35 wt.%) of an inert substrate (e.g.,
sugar
substrate) (e.g., about 30-35 mesh sugar spheres); about 1 to about 15% by
weight (e.g.,
about 2 to about 12 wt.%, about 3 to about 10 wt.%, about 3 to about 9 wt.% or
about 4 to
about 8 wt.%) of PVP (e.g., Povidone K30); about 1 to about 15% by weight
(e.g., about
2 to about 12 wt.%, about 3 to about 10 wt.%, about 3 to about 9 wt.%, about 3
to about 8
wt.%, about 4 to about 8 wt.% or about 4 to about 7 wt.%) of talc; about 1-20%
by
weight (e.g., about 5 to about 15 wt.% or about 8 to about 12 wt.%) of ethyl
cellulose;
and about 0.1 to about 10% by weight (e.g., about 0.1 to about 5 wt.% or about
1 to about
5 wt.% or about 1 to about 3 wt.%) of triethyl citrate.
In some preferred embodiments, the stable dosage form comprises 40 to about 55
wt.% (e.g., about 40 to about 50 wt.%) of levomilnacipran; about 25 to about
40 wt.% of
sugar spheres (e.g., about 30-35 mesh sugar spheres); about 2 to about 10 wt.%
(e.g.,
about 4 to about 8 wt.%) of PVP (e.g., Povidone K30); about 2 to about 10 wt.%
(e.g.,

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about 4 to about 8 wt.%) of talc; about 5 to about 15 wt.% of ethyl cellulose;
about 0.1 to
about 5 wt.% (e.g., about 1 to about 5 wt.%) of triethyl citrate.
The stable dosage forms can comprise beads or granules (e.g., microgranules or
other like core) of levomilnacipran that are coated with release controlling
agent in any
suitable thickness to achieve a desired pK profile. In some embodiments, for
example,
the stable dosage form is a capsule that contains beads or granules (or
similar core),
wherein the beads or granules (or similar core) are coated with a coating
composition
comprising a release controlling agent (and optionally a plasticizer, anti-
adherent or
lubricant, and/or a solvent) having any desired average thickness. For
example, the
coating composition can be applied to the beads or granules (or similar core)
with an
average thickness of about 1 to about 100 microns (e.g., about 5 to about 75
microns,
about 5 to about 60 microns, about 5 to about 50 microns, about 5 to about 40
microns,
about 5 to about 30 microns, about 10 to about 30 microns, about 15 to about
30 microns,
about 20 to about 30 microns, about 25 to about 35 microns, or even about 25
to about 35
microns).
In some preferred embodiments, for example, the stable dosage form comprises
coated beads or granules (or similar core) of levomilnacipran wherein the
coating
comprises one or more release controlling agents (e.g., ethyl cellulose) and
wherein the
average thickness of the coating on the beads or granules (or similar core) is
about 20 to
about 35 microns (e.g., about 20 to about 30 microns). For example, the dosage
form
can be a bead-, granule- or microgranule-filled capsule wherein the beads,
granules or
microgranules (or similar core) are coated with a coating composition (e.g.,
comprising
ethyl cellulose) at an average thickness of about 20 to about 30 microns
(e.g.,
approximately 25 microns).
In some embodiments, the stable dosage form is in the form of beads or
granules
(e.g., coated beads or granules) which have an average diameter of about 400
to about
900 microns. In some embodiments, the stable dosage form is in the form of
beads or
granules (e.g., coated beads or granules) which have an average diameter of
about 500 to
about 800 microns. In some embodiments, the stable dosage form is in the form
of beads
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or granules (e.g., coated beads or granules) which have an average diameter of
about 600
to about 800 microns. In some embodiments, the stable dosage form is in the
form of
beads or granules (e.g., coated beads or granules) which have an average
diameter of
about 600 to about 750 microns. In some embodiments, the stable dosage form is
in the
form of beads or granules (e.g., coated beads or granules) which have an
average
diameter of about 650 to about 850 microns. In some embodiments, the stable
dosage
form is in the form of beads or granules (e.g., coated beads or granules)
which have an
average diameter of less than about 1000 microns. In some embodiments, the
stable
dosage form is in the form of beads or granules (e.g., coated beads or
granules) which
have an average diameter of less than about 900 microns.
The invention also provides a method for using the stable dosage form of
levomilnacipran in the manufacture of a medicament for the treatment of a
disorder that
can be managed by inhibition of 5-HT and NE reuptake, for example, anxiety
disorders
or depression (e.g., major depressive disorder).
In some embodiments, the stable dosage form is loaded into a capsule (e.g., an
HPMC or gelatin capsule). For example, in some preferred embodiments, the
stable
dosage form is loaded into an HPMC capsule. Such an HPMC capsule can then be
packaged in bottles or canisters with or without a desiccant (e.g., about 0.01
to about 2
grams, about 0.01 to about 1 gram or even about 0.01 to about 0.8 grams of
desiccant).
In some preferred embodiments, the stable dosage form is contained within HPMC
capsules and packaged without a desiccant. In some preferred embodiments, the
stable
dosage form is contained within HPMC capsules and packaged with a desiccant.
In some
embodiments, the stable dosage form is contained within gelatin capsules and
packaged
without a desiccant. In some embodiments, the stable dosage form is contained
within
gelatin capsules and packaged with a desiccant..
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Dissolution Rate of the stable dosage forms
The stable dosage forms of levomilnacipran have been found to provide
desirable
dissolution rates following entry into a use environment. In some embodiments,
the
stable dosage form provides a dissolution rate (e.g., a single phase
dissolution rate) of at
least about 80% (e.g., at least 80%) after about 6 hours to about 16 hours
following entry
into a use environment. In some embodiments, the stable dosage form provides a
dissolution rate of at least about 80% after about 6 hours to about 12 hours
following
entry into a use environment.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 60% after about 2 hours
following entry
into a use environment. In some embodiments, the stable dosage form provides a
dissolution rate (e.g., a single phase dissolution rate) of less than about
55% after about 2
hours following entry into a use environment. In some embodiments, the stable
dosage
form provides a dissolution rate of less than about 50% after about 2 hours
following
entry into a use environment. In some embodiments, the stable dosage form
provides a
dissolution rate of less than about 45% after about 2 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
of less than about 40% after about 2 hours following entry into a use
environment. In
some embodiments, the stable dosage form provides a dissolution rate of about
20% to
about 60% after about 2 hours following entry into a use environment. In some
embodiments, the stable dosage form provides a dissolution rate of about 25%
to about
55% after about 2 hours following entry into a use environment. In some
embodiments,
the stable dosage form provides a dissolution rate of about 30% to about 50%
after about
2 hours following entry into a use environment.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 90% after about 4 hours
following entry
into a use environment. In some embodiments, the stable dosage form provides a
dissolution rate of less than about 80% after about 4 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
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of less than about 70% after about 4 hours following entry into a use
environment. In
some embodiments, the stable dosage form provides a dissolution rate of less
than about
65% after about 4 hours following entry into a use environment. In some
embodiments,
the stable dosage form provides a dissolution rate of less than about 60%
after about 4
hours following entry into a use environment. In some embodiments, the stable
dosage
form provides a dissolution rate of about 40% to about 80% after about 4 hours
following
entry into a use environment. In some embodiments, the stable dosage form
provides a
dissolution rate of about 45% to about 75% after about 4 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
of about 40% to about 70% after about 4 hours following entry into a use
environment.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 90% after about 6 hours
following entry
into a use environment. In some embodiments, the stable dosage form provides a
dissolution rate of less than about 85% after about 6 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
of less than about 80% after about 6 hours following entry into a use
environment. In
some embodiments, the stable dosage form provides a dissolution rate of less
than about
75% after about 6 hours following entry into a use environment. In some
embodiments,
the stable dosage form provides a dissolution rate of less than about 70%
after about 6
hours following entry into a use environment. In some embodiments, the stable
dosage
form provides a dissolution rate of about 40% to about 95% after about 6 hours
following
entry into a use environment. In some embodiments, the stable dosage form
provides a
dissolution rate of about 50% to about 90% after about 6 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
of about 60% to about 85% after about 6 hours following entry into a use
environment.
In some embodiments, the stable dosage form provides a dissolution rate of
about 60% to
about 80% after about 6 hours following entry into a use environment.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 95% after about 8 hours
following entry
into a use environment. In some embodiments, the stable dosage form provides a
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dissolution rate of less than about 90% after about 8 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
of less than about 85% after about 8 hours following entry into a use
environment. In
some embodiments, the stable dosage form provides a dissolution rate of about
65% to
about 95% after about 8 hours following entry into a use environment. In some
embodiments, the stable dosage form provides a dissolution rate of about 65%
to about
90% after about 8 hours following entry into a use environment. In some
embodiments,
the stable dosage form provides a dissolution rate of about 65% to about 85%
after about
8 hours following entry into a use environment. In some embodiments, the
stable dosage
form provides a dissolution rate of about 70% to about 85% after about 8 hours
following
entry into a use environment. In some embodiments, the stable dosage form
provides a
dissolution rate of about 70% to about 80% after about 8 hours following entry
into a use
environment.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 95% after about 12 hours
following entry
into a use environment. In some embodiments, the stable dosage form provides a
dissolution rate of less than about 90% after about 12 hours following entry
into a use
environment. In some embodiments, the stable dosage form provides a
dissolution rate
of about 75% to about 95% after about 12 hours following entry into a use
environment.
In some embodiments, the stable dosage form provides a dissolution rate of
about 80% to
about 95% after about 12 hours following entry into a use environment. In some
embodiments, the stable dosage form provides a dissolution rate of about 80%
to about
90% after about 12 hours following entry into a use environment.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of at least about 80% (e.g., at least 80%)
after about 6 hours
to about 16 hours following entry into deionized water at a temperature of
about 37 C and
subjected to USP apparatus II at 75 rpm (for example, after entry into 1000 mL
of
deionized water at a temperature of 37 C and subjected to USP apparatus II at
75 rpm,
wherein levomilnacipran is quantified using HPLC with a UV detector at a
wavelength of
220 nm). In some embodiments, the stable dosage form provides a dissolution
rate of at

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least about 80% after about 6 hours to about 12 hours following entry into
deionized
water at a temperature of about 37 C and subjected to USP apparatus II at 75
rpm.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 60% after about 2 hours
following entry
into deionized water at a temperature of about 37 C and subjected to USP
apparatus II at
75 rpm. In some embodiments, the stable dosage form provides a dissolution
rate (e.g., a
single phase dissolution rate) of less than about 55% after about 2 hours
following entry
into deionized water at a temperature of about 37 C and subjected to USP
apparatus II at
75 rpm. In some embodiments, the stable dosage form provides a dissolution
rate of less
than about 50% after about 2 hours following entry into deionized water at a
temperature
of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the
stable dosage form provides a dissolution rate of less than about 45% after
about 2 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of less than about 40% after about 2 hours following entry
into deionized
water at a temperature of about 37 C and subjected to USP apparatus II at 75
rpm. In
some embodiments, the stable dosage form provides a dissolution rate of about
20% to
about 60% after about 2 hours following entry into deionized water at a
temperature of
about 37 C and subjected to USP apparatus II at 75 rpm. In some embodiments,
the
stable dosage form provides a dissolution rate of about 25% to about 55% after
about 2
hours following entry into deionized water at a temperature of about 37 C and
subjected
to USP apparatus II at 75 rpm. In some embodiments, the stable dosage form
provides a
dissolution rate of about 30% to about 50% after about 2 hours following entry
into
deionized water at a temperature of about 37 C and subjected to USP apparatus
II at 75
rpm.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 90% after about 4 hours
following entry
into deionized water at a temperature of about 37 C and subjected to USP
apparatus II at
75 rpm. In some embodiments, the stable dosage form provides a dissolution
rate of less
than about 80% after about 4 hours following entry into deionized water at a
temperature
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of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the
stable dosage form provides a dissolution rate of less than about 70% after
about 4 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of less than about 65% after about 4 hours following entry
into deionized
water at a temperature of about 37 C and subjected to USP apparatus II at 75
rpm. In
some embodiments, the stable dosage form provides a dissolution rate of less
than about
60% after about 4 hours following entry into deionized water at a temperature
of about
37 C and subjected to USP apparatus II at 75 rpm. In some embodiments, the
stable
dosage form provides a dissolution rate of about 40% to about 80% after about
4 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of about 45% to about 75% after about 4 hours following entry
into
deionized water at a temperature of about 37 C and subjected to USP apparatus
II at 75
rpm. In some embodiments, the stable dosage form provides a dissolution rate
of about
40% to about 70% after about 4 hours following entry into deionized water at a
temperature of about 37 C and subjected to USP apparatus II at 75 rpm.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 90% after about 6 hours
following entry
into deionized water at a temperature of about 37 C and subjected to USP
apparatus II at
75 rpm. In some embodiments, the stable dosage form provides a dissolution
rate of less
than about 85% after about 6 hours following entry into deionized water at a
temperature
of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the
stable dosage form provides a dissolution rate of less than about 80% after
about 6 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of less than about 75% after about 6 hours following entry
into deionized
water at a temperature of about 37 C and subjected to USP apparatus II at 75
rpm. In
some embodiments, the stable dosage form provides a dissolution rate of less
than about
70% after about 6 hours following entry into deionized water at a temperature
of about
37 C and subjected to USP apparatus II at 75 rpm. In some embodiments, the
stable
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dosage form provides a dissolution rate of about 40% to about 95% after about
6 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of about 50% to about 90% after about 6 hours following entry
into
deionized water at a temperature of about 37 C and subjected to USP apparatus
II at 75
rpm. In some embodiments, the stable dosage form provides a dissolution rate
of about
60% to about 85% after about 6 hours following entry into deionized water at a
temperature of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the stable dosage form provides a dissolution rate of about 60%
to about
80% after about 6 hours following entry into deionized water at a temperature
of about
37 C and subjected to USP apparatus II at 75 rpm.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 95% after about 8 hours
following entry
into deionized water at a temperature of about 37 C and subjected to USP
apparatus II at
75 rpm. In some embodiments, the stable dosage form provides a dissolution
rate of less
than about 90% after about 8 hours following entry into deionized water at a
temperature
of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the
stable dosage form provides a dissolution rate of less than about 85% after
about 8 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of about 65% to about 95% after about 8 hours following entry
into
deionized water at a temperature of about 37 C and subjected to USP apparatus
II at 75
rpm. In some embodiments, the stable dosage form provides a dissolution rate
of about
65% to about 90% after about 8 hours following entry into deionized water at a
temperature of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the stable dosage form provides a dissolution rate of about 65%
to about
85% after about 8 hours following entry into deionized water at a temperature
of about
37 C and subjected to USP apparatus II at 75 rpm. In some embodiments, the
stable
dosage form provides a dissolution rate of about 70% to about 85% after about
8 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
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dissolution rate of about 70% to about 80% after about 8 hours following entry
into
deionized water at a temperature of about 37 C and subjected to USP apparatus
II at 75
rpm.
In some embodiments, the stable dosage form provides a dissolution rate (e.g.,
a
single phase dissolution rate) of less than about 95% after about 12 hours
following entry
into deionized water at a temperature of about 37 C and subjected to USP
apparatus II at
75 rpm. In some embodiments, the stable dosage form provides a dissolution
rate of less
than about 90% after about 12 hours following entry into deionized water at a
temperature of about 37 C and subjected to USP apparatus II at 75 rpm. In some
embodiments, the stable dosage form provides a dissolution rate of about 75%
to about
95% after about 12 hours following entry into deionized water at a temperature
of about
37 C and subjected to USP apparatus II at 75 rpm. In some embodiments, the
stable
dosage form provides a dissolution rate of about 80% to about 95% after about
12 hours
following entry into deionized water at a temperature of about 37 C and
subjected to USP
apparatus II at 75 rpm. In some embodiments, the stable dosage form provides a
dissolution rate of about 80% to about 90% after about 12 hours following
entry into
deionized water at a temperature of about 37 C and subjected to USP apparatus
II at 75
rpm.
In some embodiments, the stable dosage form of levomilnacipran achieves the
discussed dissolution rates after storage of the dosage form for one, two, or
even three
months at 40 C and 75% relative humidity (RH).
Pharmacokinetic (pK) Performance of the stable dosage forms
The stable dosage forms provide sustained release of levomilnacipran over an
extended period of time upon entering a use environment and are expected to
achieve a
desirable pK profile upon administration to human patients. In some
embodiments, the
stable dosage forms may provide (i.e., are expected to achieve) a therapeutic
blood
plasma level of levomilnacipran over approximately a twenty-four hour period,
for
example after single administration. For example, in some embodiments, the
stable
dosage forms may release levomilnacipran for about 4 hours to about 24 hours
(e.g., for
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about 5 to about 24 hours, or even for about 6 hours to about 24 hours)
following entry of
the dosage form into a use environment.
In some embodiments, the stable dosage form may provide a mean Tmax
(average time to maximum plasma concentration) of at least 1 hour following
administration (e.g., single administration) to a patient. In some
embodiments, the stable
dosage form may provide a mean Tmax (average time to maximum plasma
concentration) of at least 2 hours following administration (e.g., single
administration) to
a patient. In some embodiments, the stable dosage form may provide a mean Tmax
(average time to maximum plasma concentration) of at least 3 hours following
administration (e.g., single administration) to a patient. In some
embodiments, the stable
dosage form may provide a mean Tmax of at least 3.5 hours. Preferably, the
stable
dosage form of the present invention may provide a mean Tmax of at least 4
hours. For
example, the stable dosage form may provide a mean Tmax of at least 4.5 hours.
In some embodiments, the dosage form may provide a mean Tmax of at least 5
hours. In some embodiments, the dosage form may provide a mean Tmax of at
least 5.5
hours. In some embodiments, the dosage form may provide a mean Tmax of at
least 6
hours. The stable dosage form can also provide a mean Tmax of about 4 hours to
about
12 hours. For example, the stable dosage form can provide a mean Tmax of about
4
hours to about 10 hours. In some embodiments, the stable dosage form may
provide a
mean Tmax of about 4.5 hours to about 12 hours. In some embodiments, the
dosage
form may provide a mean Tmax of about 4.5 hours to about 10 hours. In some
embodiments, the dosage form may provide a mean Tmax of about 5 hours to about
12
hours. In some embodiments, the dosage form may provide a mean Tmax of about 5
hours to about 10 hours. In some embodiments, the dosage form may provide a
mean
Tmax of about 4 hours to about 8 hours. In some embodiments, the dosage form
may
provide a mean Tmax of about 4.5 hours to about 8.5 hours. In some
embodiments, the
dosage form may provide a mean Tmax of about 5 hours to about 8 hours. In some
embodiments, the dosage form may provide a mean Tmax of about 4 hours to about
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In some embodiments, the stable dosage form may provide a mean AUCO-oc
(plasma concentration of levomilnacipran over time) of about 500 to about
20,000 ng
hr/mL. In some embodiments, the stable dosage form may provide a mean AUCO-oc
(plasma concentration of levomilnacipran over time) of about 500 to about
15,000 ng
hr/mL. In some embodiments, the stable dosage form may provide a mean AUCO-oc
(plasma concentration of levomilnacipran over time) of about 500 to about
10,000 ng
hr/mL. In some embodiments, the stable dosage form may provide a mean AUCO-oc
(plasma concentration of levomilnacipran over time) of about 1000 to about
9000 ng. In
some embodiments, the stable dosage form may provide a mean AUCO-oc (plasma
concentration of levomilnacipran over time) of about 500 to about 5,000 ng
hr/mL. In
some embodiments, the stable dosage form may provide a mean AUCO-oc (plasma
concentration of levomilnacipran over time) of about 500 to about 2500 ng
hr/mL. In
some embodiments, the dosage form may provide a mean AUCO-oc of about 500 to
about
2200 ng hr/mL. In some embodiments, the dosage form may provide a mean AUCO-oc
of
about 700 to about 2500 ng hr/mL.
In some embodiments, the dosage form may provide a mean AUCO-oc of about
700 to about 2200 ng hr/mL. In some embodiments, the dosage form may provide a
mean
AUCO-oc of about 800 to about 2200 ng hr/mL. In some embodiments, the dosage
form
may provide a mean AUCO-oc of about 700 to about 2300 ng hr/mL. In some
embodiments, the dosage form may provide a mean AUCO-oc of about 1000 to about
2000 ng hr/mL. In some embodiments, the dosage form may provide a mean AUCO-oc
of
about 1000 to about 1800 ng hr/mL. In some embodiments, the dosage form may
provide a mean AUCO-oc of about 1100 to about 1800 ng hr/mL. In some
embodiments,
the dosage form may provide a mean AUCO-oc of about 1200 to about 1700 ng
hr/mL. In
some embodiments, the dosage form may provide a mean AUCO-oc of about 1300 to
about 1700 ng hr/mL. In some embodiments, the dosage form may provide a mean
AUCO-oc of about 1300 to about 1650 ng hr/mL.
The average maximum plasma concentration (Cmax) provided by the stable
dosage forms can be modified (e.g., without substantially affecting the Tmax
of the
dosage form) by changing the strength of the dosage form. In some embodiments,
the
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dosage form may provide a mean Cmax of less than about 200 ng/ml following
administration (e.g., single administration) to a patient. In some
embodiments, the
dosage form may provide a mean Cmax of less than about 180 ng/ml. In some
embodiments, the dosage form may provide a mean Cmax of less than about 170
ng/ml.
In some embodiments, the dosage form may provide a mean Cmax of less than
about 160
ng/ml. In some embodiments, the dosage form may provide a mean Cmax of less
than
about 150 ng/ml. In some embodiments, the dosage form may provide a mean Cmax
of
less than about 140 ng/ml. In some embodiments, the dosage form may provide a
mean
Cmax of less than about 130 ng/ml.
In some embodiments, the dosage form may provide a mean Cmax of less than
about 120 ng/ml. In some embodiments, the dosage form may provide a mean Cmax
of
less than about 110 ng/ml. In some embodiments, the dosage form may provide a
mean
Cmax of less than about 100 ng/ml. In some embodiments, the dosage form may
provide a mean Cmax between about 20 and about 250 ng/mL. In some embodiments,
the dosage form may provide a mean Cmax between about 20 and about 200 ng/mL.
In
some embodiments, the dosage form may provide a mean Cmax between about 20 and
about 180 ng/mL. In some embodiments, the dosage form may provide a mean Cmax
between about 30 and about 140 ng/mL. In some embodiments, the dosage form may
provide a mean Cmax between about 40 and about 140 ng/mL. In some embodiments,
the dosage form may provide a mean Cmax between about 20 and about 150 ng/mL.
The stable dosage forms have also been found, in some embodiments, to provide
a mean half life (TI/2) of at least about 6 hours. In some embodiments, the
dosage form
may provide a mean T1/2 of at least about 7 hours. In some embodiments, the
dosage
form may provide a mean T1/2 of at least about 8 hours. In some embodiments,
the
dosage form may provide a mean T1/2 of at least about 9 hours. In some
embodiments,
the dosage form may provide a mean T1/2 of at least about 10 hours. In some
embodiments, the dosage form may provide a mean T1/2 of at least about 11
hours.
In some embodiments, the dosage form may provide a mean T1/2 of at least about
12 hours. In some embodiments, the dosage may provide a mean T1/2 of about 6
hours to
37

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about 24 hours. In some embodiments, the dosage may provide a mean T1/2 of
about 6
hours to about 18 hours. In some embodiments, the dosage may provide a mean
T1/2 of
about 7 hours to about 18 hours. In some embodiments, the dosage may provide a
mean
T1/2 of about 8 hours to about 24 hours. In some embodiments, the dosage may
provide a
mean T1/2 of about 8 hours to about 18 hours.
In some preferred embodiments, the stable dosage form is a modified-release
dosage form and provides a mean AUC0_,c, between about 1000 and about 9000 ng
hr/mL.
In some preferred embodiments, the stable dosage form is a modified-release
dosage form and provides a mean Cmax between about 50 and about 350 ng/ml.
In some preferred embodiments, the stable dosage form is a modified-release
dosage form and provides a mean Tmax between about 5 and 12 hours.
In some preferred embodiments, the stable dosage form is a modified-release
dosage form and provides a mean T1/2 between about 9 hours and about 20 hours.
In some preferred embodiments, the stable dosage form is a modified-release
dosage form and provides a mean AUC0_,c, between about 1000 and about 9000 ng
hr/mL,
a mean Cmax between about 50 and about 350 ng/ml, a mean Tmax between about 5
and
12 hours, and a mean T1/2 between about 9 hours and about 20 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 200 ng/ml, a mean AUC0_,,, of less than about 2500 ng hr/mL and a
mean
Tmax of at least about 4 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 180 ng/ml, a mean AUC0_,c, of less than about 2500 ng hr/mL and a
mean
Tmax of at least about 4 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 160 ng/ml, a mean AUC0_,c, of less than about 2500 ng hr/mL and a
mean
Tmax of at least about 4 hours.
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In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 150 ng/ml, a mean AUC0_,,, of less than about 2500 ng hr/mL and a
mean
Tmax of at least about 4 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 140 ng/ml, a mean AUC0_,c, of less than about 2500 ng hr/mL and a
mean
Tmax of at least about 4 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 140 ng/ml, a mean AUC0_,c, of less than about 2200 ng hr/mL and a
mean
Tmax of at least about 4 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 180 ng/ml, a mean AUC0_,c, of less than about 2200 ng hr/mL and a
mean
Tmax of at least about 5 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of less
than about 180 ng/ml, a mean AUC0_,,, of less than about 2200 ng hr/mL and a
mean
Tmax of at least about 6 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of about
10 to about 200 ng/ml, a mean AUC0_,c, of about 500 to about 2500 ng hr/mL and
a mean
Tmax between about 4 to about 10 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of about
25 to about 175 ng/ml, a mean AUC0_,c, of about 500 to about 2500 ng hr/mL and
a mean
Tmax between about 4 to about 10 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of about
to about 150 ng/ml, a mean AUC0_,,, of about 500 to about 2500 ng hr/mL and a
mean
Tmax between about 4 to about 10 hours.
25 In some embodiments, the stable dosage form may provide a mean Cmax of
about
30 to about 120 ng/ml, a mean AUC0_,c, of about 500 to about 2500 hr/mL and a
mean
Tmax between about 4 to about 10 hours.
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In some embodiments, the stable dosage form may provide a mean Cmax of about
to about 200 ng/ml, a mean AUC0_,,, of about 600 to about 2200 ng hr/mL and a
mean
Tmax between about 4 to about 10 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of about
5 10 to about 200 ng/ml, a mean AUC0_,c, of about 800 to about 2100 ng hr/mL
and a mean
Tmax between about 4 to about 10 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of about
10 to about 200 ng/ml, a mean AUC0_,c, of about 900 to about 2100 ng hr/mL and
a mean
Tmax between about 4 to about 10 hours.
10 In some embodiments, the stable dosage form may provide a mean Cmax of
about
30 to about 150 ng/ml, a mean AUC0_,c, of about 600 to about 2200 ng hr/mL and
a mean
Tmax between about 4 to about 10 hours.
In some embodiments, the stable dosage form may provide a mean Cmax of about
30 to about 120 ng/ml, a mean AUC0_,,, of about 600 to about 2200 ng hr/mL and
a mean
Tmax between about 4 to about 10 hours.
In some embodiments, the stable dosage form may provide an in vivo plasma
profile with a mean Cmax of about 10 to about 200 ng/ml, a mean AUC0_'c' of
about 500
to about 2500 ng hr/mL and a mean Tmax between about 4 to about 8 hours.
In some embodiments, the stable dosage form may provide an in vivo plasma
profile with a mean Cmax of about 10 to about 200 ng/ml, a mean AUC0_'c' of
about 500
to about 2500 ng hr/mL and a mean Tmax between about 5 to about 8 hours.
In some embodiments, the stable dosage form may provide an in vivo plasma
profile with a mean Cmax of about 25 to about 175 ng/ml, a mean AUC0_,,, of
about 600
to about 2200 ng hr/mL ng hr/mL and a mean Tmax between about 4 to about 9
hours.
In some embodiments, the stable dosage form may provide an in vivo plasma
profile with a mean Cmax of about 30 to about 150 ng/ml, a mean AUC0_'c' of
about 800
to about 2100 ng hr/mL ng hr/mL and a mean Tmax between about 4 to about 9
hours.

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In some embodiments, a dosage form is provided, wherein the dosage form may
provide an in vivo plasma profile with a mean Cmax of less than about 125
ng/ml, a mean
AUC0_. of less than about 1000 to about 2200 ng hr/mL and a mean Tmax of at
least
about 4 hours.
Methods of Treatment Using the stable dosage forms
The present invention also provides methods for treating a disease, disorder
or
condition that can be managed by inhibition (e.g., double inhibition and/or
selective
inhibition) of 5-HT and NE reuptake, for example, anxiety disorders or
depression (e.g.,
major depressive disorder (MDD)) in a mammal (e.g., human) by administering
the
stable dosage form to a patient in need thereof.
In some embodiments, a method is provided for treating or preventing
depression
(e.g., atypical depression or MDD), anxiety (e.g., generalized anxiety
disorder) or fatigue
associated with depression or anxiety in a patient in need thereof by
administering the
stable dosage form of levomilnacipran to said patient. In some embodiments, a
method is
provided for treating or preventing major depressive disorder (MDD) (e.g.,
acute MDD
or atypical MDD) in a patient in need thereof by administering the stable
dosage form of
levomilnacipran to said patient. In some embodiments, a method is provided for
treating
or preventing MDD with unresolved, concomitant or accompanying fatigue in a
patient in
need thereof by administering the stable dosage form of levomilnacipran to
said patient.
In some embodiments, the stable dosage form of levomilnacipran is used to
treat
or prevent relapse of MDD in a patient in need thereof by administering the
dosage form
to said patient. In some embodiments, the stable dosage form is used to treat
or prevent
fatigue (e.g., fatigue associated with MDD or other form of depression) in a
patient in
need thereof by administering the dosage form to said patient. In some
embodiments, the
stable dosage form is used to treat or prevent sexual dysfunction (e.g.,
erectile
dysfunction) in a patient in need thereof by administering the dosage form to
said patient.
In some embodiments, the stable dosage form is used to treat or prevent pain
associated
with depression (e.g., MDD) in a patient in need thereof by administering the
dosage
form to said patient.
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In some embodiments, the stable dosage form of the present invention is used
to
treat or prevent melancholia, dysthymia, somnolence, cognitive impairment,
sleep
disorders and/or hyperlipidemia associated (or concomitant) with depression
(e.g., MDD)
in a patient in need thereof by administering the stable dosage form to said
patient.
In some embodiments, a method is provided for treating or preventing
neuropathic pain (e.g., diabetic polyneuropathic pain (DPNP)) in a patient in
need
thereof, wherein the method comprises administering an effective amount of the
stable
dosage form of levomilnacipran to the patient.
Through administration of the stable dosage form of levomilnacipran, there is
provided a method for obtaining a flattened drug plasma concentration to time
profile,
thereby affording a tighter plasma therapeutic range control than can be
obtained with
multiple daily dosing. In other words, a method is provided for eliminating
the sharp
peaks and troughs in blood plasma drug levels induced by multiple daily dosing
with
conventional immediate release formulations of levomilnacipran. In essence,
the plasma
levels of levomilnacipran rise after administration of the stable dosage forms
of this
invention for several hours and then begin to fall through a protracted,
substantially linear
decrease from the peak plasma level for the remainder of an approximately
twenty-four
hour period, maintaining at least a threshold therapeutic level of
levomilnacipran during
the entire period.
The following examples are merely illustrative of the present invention and
should not be construed as limiting the scope of the invention in any way as
many
variations and equivalents that are encompassed by the present invention will
become
apparent to those skilled in the art upon reading the present disclosure.
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EXAMPLES
Example 1: Preparation of a Dosage Form of Levomilnacipran
Beads of levomilnacipran were prepared by preheating sugar spheres
(approximately 30-35 mesh) and layering the preheated sugar spheres with a
drug layer
solution for about 3.5 hours via a Wurster process to form drug-loaded beads.
The drug
layer solution included levomilnacipran, Povidone K30, talc and a dehydrated
alcohol.
The drug-loaded beads were dried in the fluid bed for about 30 minutes and
sieved to
yield immediate-release levomilnacipran beads (approx. 540 mg/g) which
comprised
approximately the concentrations of components shown in Table 4:
Table 4
Formulation
Components
w/w kg/Batch
Levomilnacipran 54 30
Sugar Spheres 20
37
Povidone K30 6 3
Talc 3 2
Dehydrated alcohol' - -
Total 100 55
Eliminated during the manufacturing process
The levomilnacipran beads were then preheated and coated with a dispersion
solution via a Wurster process. The dispersion solution comprised ethyl
cellulose N22,
triethyl citrate, talc and a dehydrated alcohol. The coated beads were
carefully cured in
the fluid bed and screened to yield sustained release beads of levomilnacipran
(approx.
460 mg/g) prior to filling into capsules. The sustained release
levomilnacipran beads
comprised approximately the concentrations of components shown in Table 5:
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Table 5
Formulation
Components
w/w kg/Batch
Levomilnacipran Beads 85 51
Ethyl cellulose N22 10 6
Triethyl citrate 2 1.2
Talc 3 1.8
Dehydrated alcohol' g.s. g.s.
Total 100 60
i Eliminated during the manufacturing process
Example 2: Stability of the Dosage Form Prepared in Example 1
The stability of the dosage form of levomilnacipran prepared in Example 1 was
assessed following storage of the dosage form in two different types of
capsules (namely,
hard gelatin capsules and HPMC capsules) for three months at 40 C and 75%
relative
humidity (RH).
Table 6 shows the approximate concentrations of impurities that were found
within the hard gelatin capsules of the stable dosage form of levomilnacipran
following
three months of storage.
Table 6
Impurities Concentration
(1S, 5R) 1-phenyl-3-azabicyclo [3-1-0] hexane-2-one Approx. 0.06%
Total unknown related substances Less than appox. 0.05%
Total all related substances Approx. 0.06%
Table 7 shows the approximate concentrations of impurities that were found
within HPMC capsules of the stable dosage form of levomilnacipran.
Table 7
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Impurities Concentration
(1S, 5R) 1-phenyl-3-azabicyclo[3-1-0] hexane-2-one Less than approx. 0.05%
Total unknown related substances Less than approx. 0.05%
Total all related substances Less than 0.05%
Example 3: Dissolution Rates of Dosage Form Prepared in Example 1
The dissolution rates of the stable dosage form of levomilnacipran prepared in
Example 1 was evaluated in 1000 rnL of deionized water at 37 C using USP
apparatus II
at 75 rpm. Quantification of levomilnacipran was determined using I-IPLC with
a L7V
detector at a wavelength of 220 nm.
The dissolution profile of the stable dosage form prepared in Example 1 (and
loaded into an HPMC capsule containing no desiccant) is shown in Figure 1 and
in Table
8.
The dissolution profile of the stable dosage form prepared in Example 1 was
also
determined after storing the dosage form for one, two and three months at 40 C
and 75%
relative humidity (RH), wherein the dosage form was loaded into HPMC capsules
(containing 1 gram or no desiccant), as is shown in Table 8 and in Figures 1-
5.
In particular, Figure 1 shows the dissolution rate for the stable dosage form
of
levomilnacipran after no storage, wherein the dosage form is loaded into an
HPMC
capsule that contains no desiccant. Figure 2 shows the dissolution rate for
the stable
dosage form of levomilnacipran after 1 month of storage at 40 C and 75% RH,
wherein
the dosage form is loaded into an HPMC capsule that contains no desiccant.
Figure 3
shows the dissolution rate for the stable dosage form of levomilnacipran after
2 months of
storage at 40 C and 75% RH, wherein the dosage form is loaded into an HPMC
capsule
that contains no desiccant. Figure 4 shows the dissolution rate for the stable
dosage form
of levomilnacipran after 3 months of storage at 40 C and 75% RH, wherein the
dosage
form is loaded into an HPMC capsule that contains no desiccant. Figure 5 shows
the
dissolution rate for the stable dosage form of levomilnacipran after 3 months
of storage at

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40 C and 75% RH, wherein the dosage form is loaded into an HPMC capsule that
contains 1 gram of desiccant.
Table 8
1 month 2 months 3 months 3 months
Initial storage storage storage storage
(no (no (no (no (1 g
desiccant) desiccant) desiccant) desiccant) desiccant)
Time Average Average Average Average Average
(hrs) % Release % Release % Release % Release % Release
0.5 0 1 0 1 0
1.0 5 9 12 14 8
2.0 31 33 37 39 35
4.0 56 56 59 60 57
6.0 68 67 70 71 69
8.0 76 75 77 77 77
10.0 82 81 83 82 82
12.0 86 84 86 86 86
16.0 92 90 92 91 92
24.0 98 97 98 97 99
Example 4 - X-Ray Powder Diffractometry (XRD) Analysis of an Active Ingredient
Comprising Substantially Pure Levomilnacipran
A sample of an active ingredient comprising at least 98% by weight of
levomilnacipran hydrochloride was loaded onto a deep aluminum holder and
exposed to
CuKa radiation (40kV x 40 mA) in a wide-angle bench-top X-ray diffractometer
(Model
D8, Bruker AXS Inc., Madison WI). The instrument was operated in the step-scan
mode
in increments of 0.05 20. The angular range was 5 to 40 20, and the scan rate
was
0.15 20/min. The data collection and analyses were performed with commercially
available software.
Peak positions for the XRD pattern in Figure 6 are provided in Table 1.
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Table 1
2-Theta d(,A) 2-Theta d(,A)
6.0 14.8 22.4 4.0
12.0 7.4 24.1 3.7
12.4 7.1 24.6 3.6
14.2 6.2 24.8 3.6
17.4 5.1 28.8 3.1
18.2 4.9 30.7 2.9
20.1 4.4 32.7 2.7
21.1 4.2 35.2 2.5
21.6 4.1
Example 5 - X-Ray Powder Diffractometry (XRD) Analysis of the Immediate-
Release Levomilnacipran Beads Prepared in Example 1
IR Levomilnacipran beads prepared in Example 1 were loaded onto a deep
aluminum holder and exposed to CuKa radiation (40kV x 40 mA) in a wide-angle
bench-
top X-ray diffractometer (Model D8, Bruker AXS Inc., Madison WI). The
instrument
was operated in the step-scan mode in increments of 0.05 20. The angular range
was 5 to
40 20, and the scan rate was 0.15 20/min. The data collection and analyses
were
performed with commercially available software.
Peak positions for the XRD pattern in Figure 7 are provided in Table 2.
Table 2
2-Theta d(,A) 2-Theta d(,A)
2.3 39.2 20.0 4.4
5.9 14.9 21.7 4.1
9.5 9.3 22.4 4.0
11.9 7.4 24.5 3.6
12.3 7.2 28.6 3.1
14.1 6.3 30.6 2.9
16.5 5.4 32.7 2.7
17.3 5.1 34.5 2.6
18.1 4.9
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Example 6 - X-Ray Powder Diffractometry (XRD) Analysis of the Sustained-
Release
Dosage Form Prepared in Example 1
A small amount of the sustained-release dosage form prepared in Example 1 was
loaded on a deep aluminum holder and exposed to CuKa radiation (40kV x 40 mA)
in a
wide-angle bench-top X-ray diffractometer (Model D8, Bruker AXS Inc., Madison
WI).
The instrument was operated in a step-scan mode in increments of 0.05 20. The
angular
range was 5 to 40 20, and the scan rate was 0.15 20/min. Data collection and
analyses
were performed with commercially available software (specifically, DIFFRACp1us
XRD
Commander, Bruker-AXS GmbH; and JADE, Materials Data, Inc.).
The XRD pattern for the stable dosage form of levomilnacipran is shown in
Figure 7. Peak positions for the XRD pattern in Figure 8 are provided in Table
3.
Table 3
2-Theta d(A) 2-Theta d(A)
6.0 14.7 22.1 4.0
8.3 10.6 22.5 4.0
9.6 9.2 23.6 3.8
12.0 7.4 24.7 3.6
12.8 6.9 25.2 3.5
13.1 6.7 26.4 3.4
14.2 6.2 27.5 3.2
15.6 5.7 28.7 3.1
16.4 5.4 30.6 2.9
16.8 5.3 31.0 2.9
17.4 5.1 32.0 2.8
18.3 4.8 32.7 2.7
18.9 4.7 33.5 2.7
19.6 4.5 34.6 2.6
20.0 4.4 36.2 2.5
20.4 4.4 37.3 2.4
20.9 4.2 38.3 2.3
21.6 4.1
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Example 7 - Administration of Stable Dosage Forms of Levomilnacipran to Human
Patients (Prophetic)
The stable dosage forms of levomilnacipran of the present invention can be
administered to human patients in the form of capsules that contain 50 mg of
levomilnacipran. The capsules may contain microgranules that are coated with
about 7.5
wt.% of ethyl cellulose (EC) ("dosage form 1"), about 10 wt.% EC ("dosage form
2") and
about 12.5 wt.% EC ("dosage form 3").
Dosage forms 1-3 can be administered to patients after a fasting period of at
least
about 10 hours. Blood samples can be collected from each patient before
administration
and at several time points after administration (e.g., at 30 minutes, 1 hour,
2 hours, 3
hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 24
hours, 48 hours
and 72 hours). Plasma samples from each patient can be assayed for
levomilnacipran
quantification using a validated on-line extraction method (Turbulent Flow
Chromatography) coupled with LC/MS-MS detection.
Oral administration of the stable dosage form is expected to yield
pharmacokinetic (pK) parameters substantially as shown for any of dosage forms
1-3 in
Table 9. In some preferred embodiments, the stable dosage form will yield pK
parameters substantially as shown for dosage form 2. These PK parameters are
expressed
as geometric mean (geometric CV%) and [range].
Table 9
Dosage Cmax Tmax* AUCo_,c, T1/2 Tlag* F
Form (ng.mL-1) (h) (h.ng.mL-1) (h) (h) (%)
1 83 (23%) 5 1585 (19%) 12(11%) 0.3 107(5%)
[53-120] [5-7] [1035-2018] [10-15] [0-0.5] [96-113]
2 70 (25%) 6 1477 (17%) 13 (13%) 0.5 100 (11%)
[43-97] [5-7] [1032-1825] [10-15] [0-1] [82-114]
3 58(16%) 7 1331 (15%) 13(14%) 1 89(9%)
[42.5-75] [5-8] [967-1592] [10-16.5] [0-1] [73-100]
* - Median value for Tmax and Tlag.
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The mean levomilnacipran plasma concentration versus time profiles that may be
obtained after single oral administrations (up to 24 hours post dosing) are
shown in
Figure 9 (log-linear scale expressed as geometric mean).
While the invention has been depicted and described by reference to exemplary
embodiments of the invention, such a reference does not imply a limitation on
the
invention, and no such limitation is to be inferred. The invention is capable
of
considerable modification, alteration, and equivalents in form and function,
as will occur
to those ordinarily skilled in the pertinent arts having the benefit of this
disclosure.
The depicted and described embodiments of the invention are exemplary only,
and are not exhaustive of the scope of the invention. Consequently, the
invention is
intended to be limited only by the spirit and scope of the appended claims,
giving full
cognizance to equivalence in all respects.