Note: Descriptions are shown in the official language in which they were submitted.
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
PULSATILE RELEASE COMPOSITIONS OF MILNACIPRAN
Field of the Invention
The present invention generally relates to novel milnacipran pulsatile
release compositions.
This application claims priority to U.S.S.N. 60/421,640 filed October
25, 2002; U.S.S.N. 60/431,626 filed December O5, 2002; U.S.S.N.
60/431,627 filed December O5, 2002; U.S.S.N. 60/431,906 filed December
09, 2002; U.S.S.N. 60/431,861 filed December 09, 2002; U.S.S.N.
60/443,618 filed January 29, 2003; U.S.S.N. 60/459,061 filed March 28,
2003; U.S.S.N. 60/458,994 filed March 28, 2003; U.S.S.N. 60/458,995 filed
March 28, 2003.
Background of the Invention
Efficacy and tolerability are important factors determining the choice
of a medication for treatment of mental depression and other mental
disorders including Functional Somatic Disorders. The move from tricyclic
antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs)
involved not only the loss of the direct receptor interactions responsible for
the adverse side effects of TCAs, but also the ability to inhibit the
reuptalce
of norepinephrine. Selectivity for the single neurotransmitter, serotonin, may
explain why SSRIs tend to be less efficacious than the TCAs, especially in
more serious forms of depression (Lopez-Ibor J. et al., 1996, Int. Clin.
Psychopharm., 11:41-46). Older TCAs are associated with significant
behavioral toxicity, notably psychomotor and cognitive impairment and
sedation. SSRIs are largely devoid of these effects, but gastrointestinal
disturbances such as nausea and dyspepsia are common with these agents
(Hindmarch L, 1997, Human Psychopharmacology, 12:115-119). For
example, for widely prescribed SSRI sertraline (Zoloft~, Pfizer) the top three
adverse events associated with discontinuation of treatment were nausea,
insomnia, and diarrhea (Physician's Desk Reference, 57th Edition, 2003,
Thomson Medical).
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Efforts toward improving antidepressant medications are guided by
cumulative evidence from neurochemical and clinical studies supporting the
therapeutic potential of enhancing monoamine function in depression. A
number of antidepressant drugs, serotonin and norepinephrine reuptake
inhibitors (SNRIs), including duloxetine, venlafaxine, and milnacipran, have
been developed based on their interaction with both serotonin (5-HT) and
norepinephrine (NE) receptors. Milnacipran is more appropriately referred
to as norepinephrine and serotonin reuptake inhibitor (NSRI) since its
norepinephrine ("NE") to serotonin ("5-HT") ratio is 2:1 (Moret et al., 1985,
Neuropharmacology, 24:1211-1219; Palmier et al., 1989, Eur. J. Clin.
Pharmacol., 37:235-238). Current clinical evidence suggests that these new
agents may offer improved efficacy and/or faster onset of action compared
with SSRIs (Tran P.V. et al., 2003, J. Clin. Psychopharmacol., 23:78-86).
Recent trials with NSRI milnacipran suggest that this compound is effective
in relieving pain both associated with, and independent of, depression (Briley
M., 2003, Curr. Opin. Investig. Drugs, 4:42-45; Cypress Bioscience Inc.,
Cypress Bioscience Inc. Announces Final Results of Milnacipran Phase II
Clinical Trial in Fibromyalgia, Media Release, March 21, 2003, Available
from: URL: http://www.cypressbio com).
Unfortunately these SNRI and NSRI compounds have demonstrated
numerous side effects in human clinical trials.
For example, the safety and tolerability of duloxetine (Cymbalta°,
Eli
Lilly and Company) was assessed in a pooled analysis of 7 double-blind
trials involving 1032 patients treated with duloxetine (40-120 mg/day) and
732 patients treated with placebo. Adverse events which occurred at a rate
of more than 5% for duloxetine were nausea, dry mouth, fatigue, dizziness,
constipation, somnolence, decreased appetite, and sweating. Adverse events
which led to discontinuation of treatment were nausea, dizziness,
somnolence, dermatitis, insomnia, headache, and fatigue. Nausea and
dizziness led to significantly more duloxetine-treated patients discontinuing
treatment, compared with placebo (Mallinckrodt C. et al., American
Psychiatric Association 2002 Annual Meeting, New Research Abstracts,
2
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
119, May 18, 2002; Detke M.J. et al., American Psychiatric Association
2002 Annual Meeting, New Research Abstracts, 33-34, May 18, 2002).
Nausea was the only adverse event reported as a reason for discontinuation
(Eli Lilly and Company, New Research Shows Cymbalta Reduces Anxiety
Symptoms Associated With Depression, Media Release: September 18,
2003, Available from: URL: .
For venlafaxine (Effexor~, Wyeth-Ayerst), a member of the SNRI
family, major reported side effects are the ones that affected the
gastrointestinal system. In 4- to 8-week placebo-controlled clinical trials
treatment-emergent major gastrointestinal adverse experience incidence for
Effexor~ versus placebo (n=1,033 vs. 609) were: nausea (37% vs. 11%),
constipation (15% vs. 7%), anorexia (11% vs. 2%), and vomiting (6% vs.
2%). In the same clinical trials treatment-emergent major central nervous
system adverse experience incidence were: somnolence (23% vs. 9%), dry
mouth (22% vs. 11%), dizziness (19% vs 7%), insomnia (18% vs. 10%),
nervousness (13% vs. 6%), anxiety (6% vs. 3%), tremor (5% vs. 1%).
Importantly, nausea, in addition to being the most common reported side
effect (see above), was the top reason venlafaxine patients in Phase 2 and
Phase 3 depression studies discontinued treatment: almost 32% of patients
who discontinued treatment did so due to nausea (Physician's Desk
Reference, 57th Edition, 2003, Thomson Medical).
Milnacipran (Ixel~, Pierre Fabre), has demonstrated numerous
adverse reactions in human clinical trials with tolerability decreasing with
increasing dose (Puech A. et al., 1997, Int. Clin. Psychopharm., 12:99-108).
In the double-blind, randomized, multicenter clinical study the most frequent
spontaneously reported adverse events for 100 mg/day milnacipran twice
daily were as follows: abdominal pain (13%), constipation (10%), and
headache (9%). Interestingly, when in the same study milnacipran was given
200 mg/day twice daily, pain related adverse reactions decreased (headache
to 8% and abdominal pain to 7%) but nausea and vomiting were more
pronounced side effects and were reported by 7% of the patients (Guelfi J.D.,
1998, Int. Clin. Psychopharm., 13:121-128). In a double-blind comparative
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
study involving 219 elderly patients with depression the only adverse event
reported more frequently for milnacipran recipients than for TCA
imipramine recipients was nausea. Patients received either milnacipran or
imipramine 75-100 mg/day twice daily for 8 weeks (Tignol J. et al., 1998,
Acta Psychiatrica Scandinavica, 97:157-165). It was also observed that
when milnacipran was administered intravenously to 10 patients, five of
them reported transient nausea. Nausea was primarily reported at the
moment of peak of milnacipran plasma level (Caron J. et al., 1993, Eur.
Neuropsychopharmacol., 3:493-500). This study clearly demonstrates that
nausea is directly correlated with the milnacipran blood plasma
concentration. In addition, it strongly suggests that the nausea can be a
centrally mediated side effect since the drug was given intravenously in this
study. Data from other studies suggest that milnacipran may also induce a
locally mediated nausea via gastric irritation (the rapid onset of the nausea
was observed even prior to achieving peak plasma levels).
The incidence of spontaneously reported milnacipran adverse
experiences in placebo-controlled clinical trials is given in Table 1 (adverse
effect is listed if frequency was more than 2% in milnacipran 100 mg/day
group). As it can be clearly seen from data presented in Table 1, the
incidence of certain adverse events increases with dosage, including nausea,
vomiting, sweating, hot flashes, palpitations, tremor, anxiety, dysuria, and
insomnia.
4
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Table 1. Incidence of spontaneously reported milnacipran adverse
experiences in placebo-controlled clinical trials
Frequency
of Adverse
Experiences
(%)
Placebo 50 mg/day 100 mg/day 200 mg/day
Adverse twice dailytwice dailytwice daily
Event N = 394 N = 426 N =1871 N = 865
Nausea 10.9 12.7 11.2 19.4*
Headache 17.0 14.6 8.4 13.5
Increased 1.3 14.0 4.3* 11.6*
Sweating
Constipation4.3 8.0 6.5 11.4*
Insomnia 10.7 9.2 6.1 11.3
Dry mouth 5.6 9.4 7.9 9.0
Vomiting 3.6 3.8 3.9 7.9*
Abdominal S.1 6.1 6.5 7.6
Pain
Tremor 1.5 0.9 2.5 6.7*
Anxiety 1.3 2.8 4.1 5.1
Palpitations1.8 2.3 2.7 4.6
Vertigo 1.8 1.6 5.0 4.5
Fatigue 3.0 2.8 2.5 4.4
Dysuria 0.3 1.4 2.1 * 3.7*
Hot flushes0 1.6 3.0 3.6
Somnolence3.8 5.4 2.3 3.5
Agitation 3.0 1.6 3.3 2.9
Nervousness2.0 4.2 2.0 2.8
Dyspepsia 4.1 3.5 2.1 2.2
5igniticantly greater than placebo
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
It is important to note that in one of the early depression trials, even
after one week of milnacipran dose escalation employed to reduce side
effects, the most commonly reported reason for discontinuation of treatment
because of adverse effects was nausea and vomiting (Leinonen E., 1997,
Acta Psychiatr. Scand., 96:497-504). In the recent fibromyalgia clinical trial
with the long dose escalation period (four weeks) which was implemented in
order to reduce milnacipran side effects and increase patient's tolerance, the
most common dose-related side effect reported by patients was nausea
(Cypress Bioscience Inc., Cypress Bioscience Inc. Announces Final Results
of Milnacipran Phase II Clinical Trial in Fibromyalgia, Media Release,
March 21, 2003).
The data presented in Table I demonstrates that the currently
available immediate release formulation of milnacipran is not ideal for the
treatment of health conditions that require milnacipran doses equal or above
100 mg/day given either as once a day or twice a day due to high incidence
of treatment-emergent side effects that leads to poor patient tolerance.
Higher doses are required in the treatment of severe depression and other
associated disorders. As shown in one of the early antidepressant clinical
trials, milnacipran dosage of 200 mg/day was superior to the lower doses
(Von Frenclcell R et al., 1990, Int. Clin. Psychopharmacology., 5:49-56).
Milnacipran dosing regime of 100-250 mg daily was recently reported for the
treatment of fibromyalgia (US Patent No. 6,602,911). It would be very
difficult to reach the upper limits of the dose range using the currently
available formulation due to the dose related treatment emergent side effects
and the need to titrate over a long period to reach the required dose.
Moreover, an immediate release formulation of milnacipran may not
be suitable for a once-daily dosing regimen for a treatment of depression due
to milnacipran's relatively short, approximately 8 hours, half life (Ansseau
M. et al., 1994, Psychopharmacology, 114:131-137). Milnacipran's half life
could also be responsible for the fact that twice-a-day administration (versus
once-a-day) of immediate release formulation in fibromyalgia trial resulted
in pain improvement statistically superior to that of placebo treatment
6
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
(Cypress Bioscience Inc., Cypress Bioscience Inc. Announces Final Results
of Milnacipran Phase II Clinical Trial in Fibromyalgia, Media Release,
March 21, 2003.
It is therefore an object of the present invention to provide
milnacipran formulations which will lower incidence and intensity of side
effects, especially for higher dosages, and lower or reduce the frequency of
dosing and the need to slowly titrate the drug in order to get to the
therapeutic dose levels required for treatment of these disorders.
It is therefore an object of the present invention to provide
milnacipran formulations that produce a therapeutic effect over
approximately 24 hours when administered to a patient in need, wherein the
release rate and dosage are effective to provide relief from at least one
disorder selected from the group consisting of depression, fibromyalgia
syndrome, chronic fatigue syndrome, pain, attention deficit/hyperactivity
disorder, and visceral pain syndromes (VPS), such as irritable bowel
syndrome (IBS), noncardiac chest pain (NCCP), functional dyspepsia,
interstitial cystitis, essential vulvodynia, urethral syndrome, orchialgia,
and
affective disorders, including depressive disorders (major depressive
disorder, dysthymia, atypical depression) and anxiety disorders (generalized
anxiety disorder, phobias, obsessive compulsive disorder, panic disorder,
post-traumatic stress disorder), premenstrual dysphoric disorder,
temperomandibular disorder, atypical face pain, migraine headache, and
tension headache, with diminished incidence and reduced intensity of
common milnacipran side effects reported for immediate release formulation.
It is a further object of the present invention to provide formulations
that provide alternative pharmacokinetic release profiles that eliminate or
diminish unwanted side effects and the current need to slowly increase
(titrate) doses in order to achieve the desired therapeutic dose.
It is still another object of the present invention to provide a
formulation that provides a unit dose between 25 and 500 mg which provides
for flexibility in morning or evening administration.
7
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Summary of the Invention
A once-a-day oral milnacipran pulsatile release composition has been
developed. This pulsatile composition, when administered orally, releases
drug in spaced apart "pulses". This delivery profile minimizes the exposure
of the internal mucosal surfaces to the drug substance and thus reduces
milnacipran gastrointestinal side effects such as nausea and vomiting while
maintaining therapeutic milnacipran blood plasma levels. Furthermore, this
pulsatile composition is ideally suited for the delivery of milnacipran since
it
has been shown that twice-a-day milnacipran administration results in an
enhanced therapeutic response as compared to once-a-day administration.
This dosage form provides ih vivo drug plasma levels characterized by C",
below 3000 ng/ml, preferably below 2000 ng/ml, and most preferably below
1000 ng/ml. These levels help to avoid stimulation of the cholinergic effects
on the CNS. The composition delivers milnacipran over approximately 24
hours, resulting in diminished incidence and decreased intensity of common
milnacipran side effects such as nausea, vomiting, sleep disturbance,
headache, tremulousness, anxiety, panic attacks, palpitations, urinary
retention, orthostatic hypotension, diaphoresis, chest pain, rash, weight
gain,
back pain, constipation, vertigo, increased sweating, agitation, hot flushes,
tremors, fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth,
abdominal pain, irritability, and insomnia.
Detailed description of the Invention
Pulsatile Release Milnacipran Formulations
The composition provides an initial rapid release of a therapeutically
effective dose of milnacipran followed by so-called "delayed release" pulses
such that a second and optional third delayed dose of the active agent is
released from the dosage form. By incorporating both an immediate release
dosage unit and one or more delayed release dosage units of the active agent,
the dosage form mimics a multiple dosing profile without repeated dosing,
i.e., with only a single administration in a day. For example, the dosage form
provides a twice daily dosing profile when the dosage form contains both an
immediate release dosage unit and a single delayed release dosage unit.
8
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Alternatively, the dosage form provides a three times daily dosing profile
when the dosage form contains an immediate release dosage unit and two
delayed release dosage units.
The formulation provides a pulsatile release dosage form for treating
conditions responsive to the administration of milnacipran, wherein the
dosage form comprises an immediate release dosage unit, a delayed release
dosage unit and an optional second delayed release dosage unit. The
immediate release dosage unit comprises a first dose of an active agent that
is
released substantially immediately following oral administration of the
dosage form to a patient. The delayed release dosage unit comprises a second
dose of the active agent and a means for delaying release of the second dose
until approximately 3 hours to less than 14 hours following oral
administration of the dosage form. The second delayed release dosage unit,
when present, comprises a third dose of the active agent and a means for
delaying release of the third dose until at least 5 hours to approximately 18
hours following oral administration of the dosage form.
Each dosage form contains a therapeutically effective amount of
active agent. For dosage forms that mimic the twice daily dosing profile,
approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the
total amount of active agent in the dosage form is released in the initial
pulse,
and, correspondingly approximately 70 wt. % to 30 wt. %, preferably 60 wt.
to 40 wt. %, of the total amount of active agent in the dosage form is
released in the second pulse. For dosage forms mimicking the twice daily
dosing profile, the second pulse is preferably released approximately 3 hours
to less than 14 hours, and most preferably approximately 5 hours to 12 hours,
following administration.
For dosage forms mimicking the three times daily dosing profile,
approximately 25 wt. % to 40 wt. % of the total amount of active agent in the
dosage form is released in the initial pulse, and approximately 25 wt. % to 40
wt. % of the total amount of active agent in the dosage form is released in
each of the second and third pulses. For dosage forms that mimic the three
times daily dosing profile, release of the second pulse preferably takes place
9
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
approximately 3 hours to 10 hours, and most preferably approximately 4 to 9
hours, following oral administration. Release of the third pulse occurs about
2 hours to about 8 hours following the second pulse, and is typically about 5
hours to approximately 18 hours following oral administration.
In one aspect, a dosage form comprising a closed capsule housing at
least two drug-containing dosage units is used. Each dosage unit comprises
two or more compressed tablets, or may be comprised of a plurality of beads,
granules or particles, providing that each dosage unit has a different drug
release profile. The immediate release dosage unit releases drug substantially
immediately following oral administration to provide an initial dose. The
delayed release dosage unit releases drug approximately 3 hours to 14 hours
following oral administration to provide a second dose. Finally, an optional
second delayed release dosage unit releases drug about 2 hours to 8 hours
following the release of the second dose, and is typically 5 hours to 18 hours
following oral administration.
Another dosage form comprises a compressed tablet having a drug-
containing immediate release dosage unit, a delayed release dosage unit and
an optional second delayed release dosage unit. In this dosage form, the
immediate release dosage unit comprises a plurality of beads, granules or
particles that release drug substantially immediately following oral
administration to provide an initial dose. The delayed release dosage unit
comprises a plurality of coated beads or granules, which release drug
approximately 3 hours to 14 hours following oral administration to provide a
second dose.
. An optional second delayed release dosage unit comprises coated
beads or granules that release drug about 2 to 8 hours following
administration of the initial delayed release dose, typically 5 to 18 hours
following oral administration. The beads or granules in the delayed release
dosage units) are coated with a bioerodible polymeric material. This coating
prevents the drug from being released until the appropriate time, i.e.,
approximately 3 hours to less than 14 hours following oral administration for
the delayed release dosage unit and at least 5 hours to approximately 18
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
hours following oral administration for the optional second delayed release
dosage unit. In this dosage form the components may be admixed in the
tablet or may be layered to form a laminated tablet.
Another dosage form is a tablet having a drug-containing immediate
release dosage unit, a delayed release dosage unit, and an optional second
delayed release dosage unit, wherein the immediate release dosage unit
comprises an outer layer that releases the drug substantially immediately
following oral administration. The arrangement of the remaining delayed
release dosage(s), however, depends upon whether the dosage form is
designed to mimic twice daily dosing or three times daily dosing.
In the dosage form mimicking twice daily dosing, the delayed release
dosage unit comprises an inner core that is coated with a bioerodible
polymeric material. The coating is applied such that release of the drug
occurs approximately 3 hours to less than 14 hours following oral
administration. In this form, the outer layer completely surrounds the inner
core.
In the dosage form mimicking three times a day dosing, the (first)
delayed release dose comprises an internal layer that releases drug
approximately 3 hours to less than 14 hours following oral administration.
This internal layer is surrounded by the outer layer. The second delayed
release dosage unit generally comprises an inner core that releases the drug
at least 5 hours to approximately 18 hours following oral administration.
Thus, the layers of this tablet (starting from the external surface) comprise
an
outer layer, an internal layer and an inner core. The inner core comprises
delayed release beads or granules. Furthermore, the internal layer comprises
the drug coated with a bioerodible polymeric material. Alternatively, in this
particular dosage form mimiclcing three times a day dosing, both the delayed
release dosage unit and second delayed release dosage units are surrounded
by an inner layer. This inner layer is free of active agent. Thus, the layers
of
this tablet (starting from the external surface) comprise an outer layer,
inner
layer and an admixture of the delayed release dosage units. The first delayed
release pulse occurs once the inner layer is substantially eroded thereby
11
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
releasing the admixture of the delayed release dosage units. The dose
corresponding to the (first) delayed release dosage unit is released
immediately since the inner layer has prevented access to this dose for the
appropriate time, e.g., from approximately 3 hours to 10 hours. The second
delayed release dose, however, is formulated to effectively delay release for
at least 5 hours to approximately 18 hours following oral administration.
For formulations mimicking twice daily dosing, it is preferred that
the delayed release dose is released approximately 3 hours to less than 14
hours, most preferably approximately 5 hours to 12 hours, following oral
administration. For formulations mimicking three times daily dosing, it is
preferred that the (first) delayed release dose is released approximately 3 to
10 hours, preferably 4 hours to 9 hours, following oral administration. For
dosage forms containing a third dose, the third dose (i.e., the second delayed
release dose) is released at least 5 hours to approximately 18 hours following
oral administration.
These drug dosage forms are administered orally and can be used for the
treatment of depression, for fibromyalgia syndrome, chronic fatigue
syndrome, pain, attention deficit/hyperactivity disorder, and visceral pain
syndromes (VPS) such as irritable bowel syndrome (IBS), noncaxdiac chest
pain (NCCP), functional dyspepsia, interstitial cystitis, essential
vulvodynia,
urethral syndrome, orchialgia, and affective disorders, including depressive
disorders (major depressive disorder, dysthymia, atypical depression) and
anxiety disorders (generalized anxiety disorder, phobias, obsessive
compulsive disorder, panic disorder, post-traumatic stress disorder),
premenstrual dysphoric disorder, temperomandibular disorder, atypical face
pain, migraine headache, and tension headache.
Unless otherwise indicated this formulation and method of use
thereof is not limited to specific pharmaceutical carriers or to particular
administration regimens, as such may vary. It is also to be understood that
the terminology used herein is for the purpose of describing particular
embodiments only and is not intended to be limiting.
12
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
It must be noted that, as used in the specification and the appended
claims, the singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example, reference to "an
active agent" includes a single active agent as well as combinations of
different active agents, reference to "a pharmaceutical carrier" includes a
single pharmaceutical carrier as well as combinations of two or more
carriers, reference to "a compressed tablet" includes a single as well as a
plurality of compressed tablets, reference to "an immediate release dosage
form" includes a single immediate release dosage form in addition to a group
of two or more immediate release dosage forms, reference to "a coating" as
in "a delayed release coating" includes a single coating as well as two or
more coatings, and the like.
"Optional" or "optionally" means that the subsequently described
circumstance may or may not occur, so that the description includes
instances where the circumstance occurs and instances where it does not. For
example, when an "optional second delayed release dosage unit" appears in
describing the dosage forms, "optional second delayed release dosage unit,"
means that the second delayed release dosage unit may or may not be
present, and thus, the description includes dosage forms wherein the second
delayed release dosage unit is present and dosage forms wherein the second
delayed release dosage unit is not present. As used herein, "about" means
approximately plus or minus 10%.
The milnacipran composition provides a pulsatile delivery dosage
form for administering milnacipran and mimics twice or three times daily
dosing of milnacipran. That is, the composition provides an immediate dose
followed by one or more pulsatile doses several hours after ingestion of the
dosage form.
Optionally, only less than 10% of the first pulse releases substantially
immediately after ingestion of the dosage form. More than 90% of the first
pulse becomes available after formulation passes through the stomach and
enters the small intestines. The composition further provides second and,
optionally, third drug doses several hours after ingestion of the dosage form.
13
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Since milnacipran is known to cause gastrointestinal disturbances, delay of
the first dose should substantially reduce exposure of stomach mucosa to the
drug and, hence, diminish milnacipran local side effects such as nausea and
vomiting.
The expected therapeutic benefit of these formulations is further
supported by the results of a 12-week randomized, double-blind placebo-
controlled dose escalation monotherapy trial that evaluated milnacipran in
patients with a diagnosis of Fibromyalgia Syndrome (FMS) presented by
Cypress Bioscience, Inc. at the 41St Annual Meeting of American College of
Neuropsychopharmacology, San Juan, Puerto Rico (Gendreau R.M. et al.,
December 9, 2002, Poster presentation, Poster# 85 "Development of
milnacipran, a dual reuptake inhibitor for treatment of chronic pain
associated with fibromyalgia").
In the FMS trial conducted by Cypress Bioscience, all patients were
escalated over a 4-week period in weekly steps from 25 mg daily, to 50, 100,
and finally 200 mg daily, or until dose-limiting toxicity was evident. The
currently available immediate release (IR) milnacipran formulation was used
as the only milnacipran dosage form in this study. Patients who successfully
reached the 200 mg daily dose were then treated for an additional 8 weeks at
that dose. It is important to emphasize that at any given dose level,
milnacipran once daily (QD-IR) patients received the full dose of immediate
release milnacipran in the morning and received a placebo at night.
Milnacipran twice daily (BID-IR) patients received the same total amount in
a split dose, given morning and evening.
The primary endpoint used by Cypress Bioscience was defined as the
change in pain score from baseline to endpoint based on pain scores
collected on the patient electronic diary. Endpoint was defined as week
twelve for assessments with a single value (such as clinical measures) or the
average of scores at weeks 11 and 12 for diary-based outcomes. It was
shown that milnacipran effectively treated pain associated with fibromyalgia
syndrome and, additionally, improved mood in depressed patients with FMS.
The improvement in pain scores reported by study participants, when 200 mg
14
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
daily dose was reached, indicates that this substantially higher dose than the
one typically used for depression treatment is needed to the alleviation of
pain. On a 1-7 scale the global pain scores for all patients who reached
endpoint at the time of the analysis, where 1 is very much improved, 4 is
unchanged, and 7 is very much worse, the mean value for milnacipran
patients was 2.3, while the mean value for placebo patients was 4.3 (the
difference between the milnacipran groups and placebo is statistically
significant at p=0.0001). Importantly, within the milnacipran groups, twice
daily dosing was significantly more effective than once daily dosing in pain
reduction. Twice daily dosing regimen in addition to being more
therapeutically effective, also demonstrated fewer dose-related adverse
events and resulted in a lower rate of dose intolerance than once daily
regimen (19% of participants in QD-IR group failed the dose escalation vs.
only 6% in BID-IR group). Note that no dose escalation failures were _
recorded in the placebo group.
These clinical differences between QD-IR and BID-IR are most
likely due to the distinct differences in the drug plasma levels (especially
C",~) that these two dosing regiments support. The BID-IR dosing regimen
supports drug plasma levels characterized by lower C",~ and lower drug
plasma fluctuations over 24 hour time period than that of QD-IR. When a
daily dose is administered QD-IR, the C",~ is approximately twice higher
than that of BID-IR dosing regimen. Higher C",~ causes an increase in the
severity of the adverse side effects (that also might interfere with the
objective pain level self assessment by the patient) and leads to a lower drug
tolerance and patient compliance. Therefore, the observed superior
milnacipran performance when drug was administered BID-IR is thought to
be due to more "sustained" drug plasma levels over a 24 hour period.
Based on the clinical trial data obtained and presented by Cypress
Bioscience, sleep quality improves, albeit marginally, when milnacipran was
administered BID-IR. This could be interpreted as another indication that
the formulation that provides more "sustained" drug plasma levels over a 24
hour period should demonstrate superior performance when compared to
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
standard immediate release formulation and, importantly, cause less
insomnia.
Definitions
Delayed release dosage form: A delayed release dosage form is one
that releases a drug (or drugs) at a time other than promptly after
administration.
Pulsatile release dosage form: A pulsatile release dosage form is one
that mimics a multiple dosing profile without repeated dosing and allows at
least a twofold reduction in dosing frequency as compared to that drug
presented as a conventional dosage form (e.g. as a solution or prompt drug-
releasing, conventional solid dosage form). A pulsatile release profile is
characterized by a time period of no release (lag time) followed by rapid
drug release.
Milnacipran
Milnacipran and methods for its synthesis are described in U.S.
Patent No. 4,478,836. Milnacipran (midalcipran, midacipran, F 2207)
inhibits the uptake of both, norepinephrine (NE) and serotonin (5-HT), with
an NE to 5-HT ratio of 2:1 (Moret et al., 1985, Neuropharmacology,
24:1211-1219; Palmier et al., 1989, Eur. J. Clin. Pharmacol., 37:235-238) but
does not affect the uptake of dopamine. Milnacipran has no affinity for
alpha or beta adrenergic, muscarinic, histaminergic, and dopaminergic
receptors. This suggests that milnacipran has a low potential to produce
anticholinergic, sedative, and stimulant effects. Milnacipran does not affect
the number of beta adrenoceptors in rat cortex after chronic administration
(Briley M. et al., Int. Clin. Psychopharmac., 1996, 11:10-14). Additional
information regarding milnacipran may be found in the Merclc Index, 12t''
Edition, at entry 6281.
As used herein "milnacipran" also encompasses pharmaceutically
acceptable, pharmacologically active derivatives of milnacipran including
both individual enantiomers of milnacipran (dextrogyral and levrogyral
enantiomers) and their pharmaceutically acceptable salts, mixtures of
milnacipran enantiomers and their pharmaceutically acceptable salts, and
16
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
active metabolites of milnacipran and their pharmaceutically acceptable salts,
unless otherwise noted. It is understood that in some cases dosages of
enantiomers, derivatives, and metabolites may need to be adjusted based on
relative activity of the racemic mixture of milnacipran.
As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound is
modified by malting acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or organic salts
of
acidic residues such as carboxylic acids. The pharmaceutically acceptable
salts include the conventional non-toxic salts or the quaternary ammonium
salts of the parent compound formed, for example, from non-toxic inorganic
or organic acids. For example, such conventional non-toxic salts include
those derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared
from
organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic,
phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fiunaric,
tolunesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
0 The pharmaceutically acceptable salts of the compounds can be
synthesized from the parent compound, which contains a basic or acidic
moiety, by conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or in an
organic solvent, or in a mixture of the two; generally, non-aqueous media
like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are
preferred.
Lists of suitable salts are found in Remington's Pharmaceutical Sciences,
20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704.
The phrase "pharmaceutically acceptable" is employed herein to refer
to those compounds, materials, compositions, and/or dosage forms which
are, within the scope of sound medical judgment, suitable for use in contact
with the tissues of human beings and animals without excessive toxicity,
17
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
irritation, allergic response, or other problems or complications
commensurate with a reasonable benefit/risk ratio.
As used herein, the term "stereoisomers" refers to compounds made
up of the same atoms bonded by the same bonds but having different spatial
structures which are not interchangeable. The three-dimensional structures
are called configurations. As used herein, the term "enantiomers" refers to
two stereoisomers whose molecules are nonsuperimposable mirror images of
one another. As used herein, the term "optical isomer" is equivalent to the
term "enantiomer". The terms "racemate", "racemic mixture" or "racemic
modification" refer to a mixture of equal parts of enantiomers. The term
"chiral center" refers to a carbon atom to which four different groups are
attached. The term "enantiomeric enrichment" as used herein refers to the
increase in the amount of one enantiomer as compared to the other.
Enantiomeric enrichment is readily determined by one of ordinary skill in the
art using standard techniques and procedures, such as gas or high
performance liquid chromatography with a chiral column. Choice of the
appropriate chiral column, eluent and conditions necessary to effect
separation of the enantiomeric pair is well within the knowledge of one of
ordinary skill in the art using standard techniques well known in the. art,
such
as those described by J. Jacques, et al., "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, Inc., 1981. Examples of resolutions
include recrystallization of diastereomeric salts/derivatives or preparative
chiral chromatography.
Combinations with Other Active Compounds
The milnacipran can be administered adjunctively with other active
compounds such as analgesics, anti-inflammatory drugs, antipyretics,
antidepressants, antiepileptics, antihistamines, antimigraine drugs,
antimuscaxinics, anxioltyics, sedatives, hypnotics, antipsychotics,
bronchodilators, anti asthma drugs, cardiovascular drugs, corticosteroids,
dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants,
nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics,
and anti-narcoleptics.
18
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Specific examples of compounds that can be adjunctively
administered with milnacipran include, but are not limited to, aceclofenac,
acetaminophen, adomexetine, almotriptan, alprazolam, amantadine,
amcinonide, aminocyclopropane, amitriptyline, amolodipine, amoxapine,
amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine,
beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone,
bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone,
butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol,
celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram,
clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam,
cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine,
cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone,
dexanabinol, dextroamphetamine sulfate, dextromoramide,
dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium,
diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine,
dimetacrine, divalproxex, dizatriptan, dolasetron, donepezil, dothiepin,
doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide,
etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam,
fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine,
frovatriptan, gabapentin, galantamine, gepirone, ginko bilboa, granisetron,
haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone,
hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen,
iprindole, ipsapirone, ketaserin, ketoprofen, ketorolac, lesopitron, levodopa,
lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic
acid, melatonin, melitracen, memantine, meperidine, meprobamate,
mesalamine, metapramine, metaxalone, methadone, methadone,
methamphetamine, methocarbamol, methyldopa, methylphenidate,
methylsalicylate, methysergid(e), metoclopramide, mianserin, mifepristone,
milnacipran, minaprine, mirtazapine, moclobemide, modafinil, molindone,
morphine, morphine hydrochloride, nabumetone, nadolol, naproxen,
naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine,
olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprazin,
19
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib,
paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin,
phendimetrazine, phenmetrazine, phenylbutazone, phenytoin,
phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline,
pramipexole, prednisolone, prednisone, pregabalin, propanolol, propizepine,
propoxyphene, protriptyline, quazepam, quinupramine, reboxitine, reserpine,
risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole,
rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine,
sulindac, sumatriptan, tacrine, temazepam, tetrabenozine, thiazides,
thioridazine, thiothixene, tiapride, tiasipirone, tizanidine, tofenacin,
tolmetin,
toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine,
trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid,
venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan,
zolpidem, zopiclone and isomers, salts, and combinations thereof.
By adjunctive administration is meant simultaneous administration of
the compounds, in the same dosage form, simultaneous administration in
separate dosage forms, and separate administration of the compounds.
Formulations
Formulations are prepared using a pharmaceutically acceptable
"carrier" composed of materials that are considered safe and effective and
may be administered to an individual without causing undesirable biological
side effects or unwanted interactions. The "carrier" is all components
present in the pharmaceutical formulation other than the active ingredient or
ingredients. The term "carrier" includes but is not limited to diluents,
binders, lubricants, desintegrators, fillers, and coating compositions.
"Carrier" also includes all components of the coating composition
which may include plasticizers, pigments, colorants, stabilizing agents, and
glidants. The delayed release dosage formulations may be prepared as
described in references such as "Pharmaceutical dosage form tablets", eds.
Liberman et. al. (New York, Marcel Dekker, Inc., 1989), "Remington - The
science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins,
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery
systems", 6th Edition, Ansel et.al., (Media, PA: Williams and Wilkins, 1995)
which provides information on carriers, materials, equipment and process for
preparing tablets and capsules and delayed and/or pulsatile release dosage
forms of tablets, capsules, and granules.
Examples of suitable coating materials include, but are not limited to,
cellulose polymers such as cellulose acetate phthalate, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl
acetate phthalate, acrylic acid polymers and copolymers, and methacrylic
resins that are commercially available under the trade name Eudragit~ (Roth
Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides. Other
polymers that can be used include biodegradable polymers such as
polyhydroxyacids like poly(lactic acid-glycolic acid), and other approved
hydrolytically or enzymatically degradable polymers.
Additionally, the coating material may contain conventional carriers
such as plasticizers, pigments, colorants, glidants, stabilization agents,
pore
formers and surfactants.
Optional pharmaceutically acceptable excipients present in the drug-
containing tablets, beads, granules or particles include, but are not limited
to,
diluents, binders, lubricants, disintegrants, colorants, stabilizers, and
surfactants. Diluents, also termed "fillers," are typically necessary to
increase the bulk of a solid dosage form so that a practical size is provided
for compression of tablets or formation of beads and granules. Suitable
diluents include, but are not limited to, for example, dicalcium phosphate
dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose,
microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed
starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium
aluminum silicate and powder sugar.
Binders are used to impart cohesive qualities to a solid dosage
formulation, and thus ensure that a tablet or bead or granule remains intact
after the formation of the dosage forms. Suitable binder materials include,
21
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
but are not limited to, starch, pregelatinized starch, gelatin, sugars
(including
sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes,
natural and synthetic gums such as acacia, tragacanth, sodium alginate,
cellulose,including hydorxypropylmethylcellulose, hydroxypropylcellulose,
ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and
methacrylic acid copolymers, methacrylic acid copolymers, methyl
methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic
acid/polymethacrylic acid and polyvinylpyrrolidone.
Lubricants are used to facilitate tablet manufacture. Examples of
suitable lubricants include, but are not limited to, magnesium stearate,
calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc,
and mineral oil.
Disintegrants are used to facilitate dosage form disintegration or
"breakup" after administration, and generally include, but are not limited to,
starch, sodium starch glycolate, sodium carboxymethyl starch, sodium
carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch,
clays, cellulose, alginine, gums or cross linked polymers, such as cross-
linked PVP (Polyplasdone XL from GAF Chemical Corp).
Stabilizers are used to inhibit or retard drug decomposition reactions
which include, by way of example, oxidative reactions.
Surfactants may be anionic, cationic, amphoteric or nonionic surface
active agents. Suitable anionic surfactants include, but are not limited to,
those containing carboxylate, sulfonate and sulfate ions. Examples of anionic
surfactants include sodium, potassium, ammonium of long chain alkyl
sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene
sulfonate; diallcyl sodium sulfosuccinates, such as sodium dodecylbenzene
sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-
ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl
sulfate.
Cationic surfactants include, but are not limited to, quaternary ammonium
compounds such as benzalkonium chloride, benzethonium chloride,
cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride,
polyoxyethylene and coconut amine. Examples of nonionic surfactants
22
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
include ethylene glycol monostearate, propylene glycol myristate, glyceryl
monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate,
sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene
monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000
cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether,
Poloxamer~ 401, stearoyl monoisopropanolamide, and polyoxyethylene
hydrogenated tallow amide. Examples of amphoteric surfactants include
sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,
myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
If desired, the tablets, beads granules or particles may also contain
minor amount of nontoxic auxiliary substances such as wetting or
emulsifying agents, dyes, pH buffering agents, and preservatives.
The amount of active agent released in each dose will be a
therapeutically effective amount. In the case of milnacipran, the total
amount in the dosage form is in the range of approximately 25 to 500 mg.
The pharmaceutical dosage forms provide pulsatile delivery of
milnacipran. By "pulsatile" is meant that a plurality of drug doses are
released at spaced apart intervals of time. Generally, upon ingestion of the
dosage form, release of the initial dose is substantially immediate, i.e., the
first drug release "pulse" occurs within about one hour of ingestion. This
initial pulse is followed by a first time interval (lag time) during which
very
little or no drug is released from the dosage form, after which a second dose
is then released. Similarly, a second nearly drug release-free interval
between
the second and third drug release pulses may be designed. The duration of
the nearly drug release-free time interval will vary depending upon the
dosage form design e.g., a twice daily dosing profile, a three times daily
dosing profile, etc. For dosage forms providing a twice daily dosage profile,
the nearly drug release-free interval has a duration of approximately 3 hours
to 14 hours between the first and second dose. For dosage forms providing a
three times daily profile, the nearly drug release-free interval has a
duration
of approximately 2 hours to 8 hours between each of the three doses.
23
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
In one embodiment, the pulsatile release profile is achieved with
dosage forms that are closed and preferably sealed capsules housing at least
two drug-containing "dosage units" wherein each dosage unit within the
capsule provides a different drug release profile. Control of the delayed
release dosage units) is accomplished by a controlled release polymer
coating on the dosage unit, or by incorporation of the active agent in a
controlled release polymer matrix. Each dosage unit may comprise a
compressed or molded tablet, wherein each tablet within the capsule provides
a different drug release profile. For dosage forms mimicking a twice a day
dosing profile, a first tablet releases drug substantially immediately
following ingestion of the dosage form, while a second tablet releases drug
approximately 3 hours to less than 14 hours following ingestion of the
dosage form. For dosage forms mimicking a three times daily dosing profile,
a first tablet releases drug substantially immediately following ingestion of
the dosage form, a second tablet releases drug approximately 3 hours to less
than 10 hours following ingestion of the dosage form, and the third tablet
releases drug at least 5 hours to approximately 18 hours following ingestion
of the dosage form. It is possible that the dosage form includes more than
three tablets. While the dosage form will not generally include more than a
third tablet, dosage forms housing more than three tablets can be utilized.
Alternatively, each dosage unit in the capsule may comprise a
plurality of drug-containing beads, granules or particles. As is known in the
art, drug-containing ''beads" refer to beads made with drug and one or more
excipients or polymers. Drug-containing beads can be produced by applying
drug to an inert support, e.g., inert sugar beads coated with drug or by
creating a "core" comprising both drug and one or more excipients. As is
also known, drug-containing "granules" and "particles" comprise drug
particles that may or may not include one or more additional excipients or
polymers: In contrast to drug-containing beads, granules and particles do not
contain an inert support. Granules generally comprise drug particles and
require further processing. Generally, particles are smaller than granules,
and
are not further processed. Although beads, granules and particles may be
24
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
formulated to provide immediate release, beads and granules are generally
employed to provide delayed release.
For dosage forms mimicking a twice a day dosing profile, a first
group beads, granules or particles releases drug substantially immediately
following ingestion of the dosage form, while a second group of beads or
granules preferably releases drug approximately 3 hours to less than 14 hours
following ingestion of the dosage form. For dosage forms mimicking a three
times daily dosing profile, a first group of beads, granules or particles
releases drug substantially immediately following ingestion of the dosage
form, a second group of beads or granules preferably releases drug
approximately 3 hours to 10 hours following ingestion of the dosage form,
and a third group of beads, granules or particles releases drug at least 5
hours
to approximately 18 hours following ingestion of the dosage form. The
above-mentioned tablets, beads, granules or particles of different drug
release profiles (e.g., immediate and delayed release profiles) may be mixed
and included in a capsule, tablet or matrix to provide a pulsatile dosage form
having the desired release profile.
In another embodiment, the individual dosage units are compacted in
a single tablet, and may represent integral but discrete segments thereof
(e.g.,
layers), or may be present as a simple admixture. For example, drug-
containing beads, granules or particles with different drug release profiles
(e.g., immediate and delayed release profiles) can be compressed together
into a single tablet. using conventional tableting means.
In a further alternative embodiment, a dosage form is provided that
~25 comprises an inner drug-containing core and at least one drug-containing
layer surrounding the inner core. An outer layer of this dosage form contains
an initial, immediate release dose of the drug. For dosage forms mimicking
twice daily dosing, the dosage form has an outer layer that releases drug
substantially immediately following oral administration and an inner core
having a polymeric-coating that preferably releases the active agent
approximately 3 hours to less than 14 hours following ingestion of the
dosage unit. For dosage forms mimicking three times daily dosing, the
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
dosage form has an outer layer that releases drug substantially immediately
following oral administration, an inner core that preferably releases drug at
least 5 hours to 18 hours following oral administration and a layer interposed
between the inner core and outer layer that preferably releases drug
approximately 3 hours to 10 hours following ingestion of the dosage form.
The inner core of the dosage form mimicking three times daily a dosing may
be formulated as compressed delayed release beads or granules.
Alternatively, for dosage forms mimicking three times daily dosing,
the dosage form has an outer layer and an inner layer free of drug. The outer
layer releases drug substantially immediately following oral administration,
and completely surrounds the inner layer. The inner layer surrounds both the
second and third doses and preferably prevents release of these doses for
approximately 3 hours to 10 hours following oral administration. Once
released, the second dose is immediately available while the third dose is
formulated as delayed release beads or granules such that release of the third
dose is effected approximately 2 hours to 8 thereafter effectively resulting
in
release of the third dose at least 5 hours to approximately 18 hours following
ingestion of the dosage form. The second and third doses may be formulated
by admixing immediate release and delayed release beads, granules or
particles and compressing the admixture to form a second and third dose-
containing core followed by polymeric coating to achieve the desired three
times daily dosing profile.
In still another embodiment, a dosage form comprises a coated core-
type delivery system wherein the outer layer is comprised of an immediate
release dosage unit, such that active agent therein is immediately release
following oral administration, an intermediate layer thereunder surrounds a
core, and the core is comprised of immediate release beads or granules and
delayed release beads or granules, such that the second dose is provided by
the immediate release beads or granules and the third dose is provided by the
delayed release beads or granules.
As will be appreciated by those skilled in the art and as described in
the pertinent texts and literature, a number of methods are available for
26
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
preparing drug-containing tablets, beads, granules or particles that provide a
variety of drug release profiles. Such methods include, but are not limited
to,
the following: coating a drug or drug-containing composition with an
appropriate coating material, typically although not necessarily a
incorporating a polymeric material; increasing drug particle size; placing the
drug within a matrix; and forming complexes of the drug with a suitable
complexing agent.
The delayed release dosage units in any of the above embodiments
can be prepared, for example, by coating a drug or a drug-containing
composition with a selected coating material. The drug-containing
composition may be, e.g., a tablet for incorporation into a capsule, a tablet
for use as an inner core in a "coated core" dosage form, or a plurality of
drug-containing beads, particles or granules, for incorporation into either a
tablet or capsule. Preferred coating materials are comprised of bioerodible,
gradually hydrolyzable, gradually water-soluble, and/or enzymatically
degradable polymers, and may be conventional "enteric" polymers. Enteric
polymers, as will be appreciated by those skilled in the art, become soluble
in
the higher pH environment of the lower gastrointestinal tract or slowly erode
as the dosage form passes through the gastrointestinal tract, while
enzymatically degradable polymers are degraded by bacterial enzymes
present in the lower gastrointestinal tract, particularly in the colon.
Suitable
coating materials for effecting delayed release include, but are not limited
to,
cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl -
methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate,
methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate
phthalate,
i
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 cormnercially
available under the tradename Eudragit® (Rohm Pharma; Westerstadt,
Germany), including Eudragit® L30D-55 and L100-55 (soluble at pH
27
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
5.5 and above), Eudragit® L-100 (soluble at pH 6.0 and above),
Eudragit® S (soluble at pH 7.0 and above, as a result of a higher degree
of esterification), and Eudragits® NE, RL and RS (water-insoluble
polymers having different degrees of permeability and expandability); vinyl
polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate,
vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-
vinyl acetate copolymer; enzymatically degradable polymers such as azo
polymers, pectin, chitosan, amylose and guar gum; and shellac.
Combinations of different coating materials may also be used. Multi-layer
coatings using different polymers may also be applied.
The preferred coating weights for particular coating materials may be
readily determined by those skilled in the art by evaluating individual
release
profiles for tablets, beads and granules prepared with different quantities of
various coating materials. It is the combination of materials, method and
form of application that produce the desired release characteristics, which
one can determine only from the clinical studies.
The coating composition may include conventional additives, such as
plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A
plasticizer is normally present to reduce the fragility of the coating, and
will
generally represent about 10 wt. % to 50 wt. % relative to the dry weight of
the polymer. Examples of typical plasticizers are, but not limited to,
polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl
citrate,
triethyl acetyl citrate, castor oil and acetylated monoglycerides. A
stabilizing
agent is preferably used to stabilize particles in the dispersion. Typical
stabilizing agents are nonionic emulsifiers such as sorbitan esters,
polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce
sticlcing effects during film formation and drying, and will generally
represent approximately 25 wt. % to 100 wt. % of the polymer weight in the
coating solution. One effective glidant is talc. Other glidants such as
magnesium stearate and glycerol monostearates may also be used. Pigments
such as titanium dioxide may also be used. Small quantities of an anti-
28
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
foaming agent, such as a silicone (e.g., simethicone), may also be added to
the coating composition.
The delayed release dosage units may be coated with the delayed
release polymer coating using conventional techniques, e.g., using a
conventional coating pan, an airless spray technique, fluidized bed coating
equipment (with or without a Wurster insert), or the like. For detailed
information concerning materials, equipment and processes for preparing
tablets and delayed release dosage, reference may be made to Pharmaceutical
Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker,
Inc., 1989), and to Ansel et al., Pharmaceutical Dosage Forms and Drug
Delivery Systems, 6th Ed. (Media, PA: Williams & Wilkins, 1995).
Alternatively, a delayed release tablet may be formulated by
dispersing the drug within a matrix of a suitable material such as a
hydrophilic polymer or a fatty compound. The hydrophilic polymers may be
comprised of polymers or copolymers of cellulose, cellulose ester, acrylic
acid, methacrylic acid, methyl acrylate, ethyl acrylate, and vinyl or
enzymatically degradable polymers or copolymers as described above. These
hydrophilic polymers are particularly useful for providing a delayed release
matrix. Fatty compounds for use as a matrix material include, but are not
limited to, waxes (e.g. carnauba wax) and glycerol tristearate. Once the
active ingredient is mixed with the matrix material, the mixture can be
compressed into tablets.
The immediate release dosage unit of the dosage form--i.e., a tablet, a
plurality of drug-containing beads, granules or particles, or an outer layer
of
a coated core dosage form--contains a therapeutically effective quantity of
the active agent with conventional pharmaceutical excipients. The immediate
release dosage unit may or may not be coated, and may or may not be
admixed with the delayed release dosage unit or units (as in an encapsulated
mixture of immediate release drug-containing granules, particles or beads
and delayed release drug-containing granules or beads). A preferred method
for preparing immediate release tablets (e.g., as incorporated into a capsule)
is by compressing a drug-containing blend, e.g., blend of granules, prepared
29
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
using a direct blend, wet-granulation or dry-granulation process. Immediate
release tablets may also be molded rather than compressed, starting with a
moist material containing a suitable water-soluble lubricant. However,
preferred tablets herein axe manufactured using compression rather than
molding. A preferred method for forming immediate release drug-containing
blend is to mix drug particles directly with one or more excipients such as
diluents (or fillers), binders, disintegrants, lubricants, glidants, colorants
or
the like. As an alternative to direct blending, a drug-containing blend may be
prepared by using a wet-granulation or dry-granulation processes. Beads
containing the active agent may also be prepared by any one of a number of
conventional techniques, typically starting from a fluid dispersion. For
example, a typical method for preparing drug-containing beads involves
blending the active agent with conventional pharmaceutical excipients such
as microcrystalline cellulose, starch, polyvinylpyrrolidone, methylcellulose,
talc, metallic stearates, silicone dioxide, or the like. The admixture is used
to
coat a bead core such as a sugar sphere (or so-called "non-pareil") having a
size of approximately 20 to 60 mesh.
An alternative procedure for preparing drug beads is by blending
drug with one or more pharmaceutically acceptable excipients, such as
microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc,
magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing
the extrudate, drying and optionally coating to form the immediate release
beads.
Optional pharmaceutically acceptable excipients present in the drug-
containing tablets, beads, granules or particles include, but are not limited
to,
diluents, binders, lubricants, disintegrants, colorants, stabilizers,
surfactants
and the like. Diluents, also termed "fillers," are typically necessary to
increase the bulk of a solid dosage form so that a practical size is provided
for compression of tablets or formation of beads and granules. Suitable
diluents include, for example, dicalcium phosphate dihydrate, calcium
sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline
cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches,
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum
silicate and powder sugar. Binders are used to impart cohesive qualities to a
solid dosage formulation, and thus ensure that a tablet or bead or granule
remains intact after the formation of the dosage forms. Suitable binder
materials include, but are not limited to, starch, pregelatinized starch,
gelatin,
sugars (including sucrose, glucose, dextrose, lactose and sorbitol),
polyethylene glycol, waxes, natural and synthetic gums such as acacia,
tragacanth, sodium alginate, cellulose and veegum, and synthetic polymers
such as acrylic acid and methacrylic acid copolymers, methacrylic acid
copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate
copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
Lubricants are used to facilitate tablet manufacture; examples of suitable
lubricants include, for example, magnesium stearate, calcium stearate, stearic
acid, glycerol behenate, and polyethylene glycol, talc, and mineral oil.
Disintegrants are used to facilitate dosage form disintegration or "breakup"
after administration, and are generally starch, sodium starch glycolate,
sodium carboxymethyl starch, sodium carboxymethylcellulose,
hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine,
gums or cross linleed polymers, such as cross-linked PVP (Polyplasdone XL
from GAF Chemical Corp). Stabilizers are used to inhibit or retard drug
decomposition reactions which include, by way or example, oxidative
reactions. Surfactants may be anionic, cationic, amphoteric or nonionic
surface active agents. Suitable anionic surfactants include, but not limited
to
those containing carboxylate, sulfonate and sulfate ions. Examples for
anionic surfactants are sodium, potassium, ammonium of long chain alkyl
sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene
sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene
sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-
ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl
sulfate.
Cationic surfactants include, but not limited quaternary ammonium
compounds such as benzallconium chloride, benzethonium chloride,
cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride,
31
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
polyoxyethylene (15) and coconut amine. Examples for nonionic surfactants
are, but not limited to, ethylene glycol monostearate, propylene glycol
myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate,
sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate,
polyoxyethylene (8) monolaurate, polysorbates, ii polyoxyethylene (9)
octylphenylether, PEG-1000 cetyl ether, polyoxyethylene (3) tridecyl ether,
polypropylene glycol (18) butyl ether, Poloxamer 401, stearoyl
monoisopropanolamide, and polyoxyethylene (5) hydrogenated tallow
amide. Examples for amphoteric surfactants are, but not limited to, sodium
N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,
myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. If desired, the
tablets, beads granules or particles may also contain minor amount of
nontoxic auxiliary substances such as wetting or emulsifying agents, pH
buffering agents, preservatives, and the like.
The amount of active agent released in each dose will be a
therapeutically effective amount. In the case of milnacipran, the total
amount in the dosage form is in the range of approximately 25 to 500 mg.
Typically, the total amount of active agent in a dosage form is divided evenly
between each pulse contained in the dosage form. For dosage forms that
mimic a twice a day profile, the active agent in immediate release form
generally represents about 30 wt. % to 70 wt. %, preferably 40 wt. % to 60
wt. %, of the total active agent in one dosage form, while, correspondingly,
the active agent in the delayed release form generally represents about 70 wt.
to 30 wt. %, preferably 60 wt. % to 40 wt. %, of the total active agent in
one dosage form. Similarly, for dosage forms that mimic three times daily
dosing profile, the active agent in the immediate release units) and in each
of the two delayed release units represents about 20 wt. % to 50 wt. %,
preferably 25 wt. % to 40 wt. %, of the total active agent in one dosage form.
All publications mentioned herein are incorporated by reference in
their entireties.
32
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Kit containing pulsatile release formulations
A kit is provided wherein the once a day pulsatile release dosage
form is packaged to provide a method to conveniently begin dose titration at
lower doses, for example, beginning at 25mg, gradually increasing to 50 mg,
75 mg, 100 mg, 200 mg, 400 mg, 500 mg, over a period ranging from three
days up to 16 weeks. The kit wherein the packaging material may be a box,
bottle, blister package, tray, or card. The kit will include a package insert
instructing the patient to take a specific dose at a specific time, for
example,
a first dose on day one, a second higher dose on day two, a third higher dose
on day three, and so on, until a maintenance dose is reached.
Methods of manufacturing
As will be appreciated by those skilled in the art and as described in
the pertinent texts and literature, a number of methods are available for
preparing drug-containing tablets, beads, granules or particles that provide a
variety of drug release profiles. Such methods include, but are not limited
to,
the following: coating a drug or drug-containing composition with an
appropriate coating material, typically although not necessarily incorporating
a polymeric material, increasing drug particle size, placing the drug within a
matrix, and forming complexes of the drug with a suitable complexing agent.
The pulsatile release dosage units may be coated with the delayed
release polymer coating using conventional techniques, e.g., using a
conventional coating pan, an airless spray technique, fluidized bed coating
equipment (with or without a Wurster insert), or the like. For detailed
information concerning materials, equipment and processes for preparing
tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms:
Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and
Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,
6th Ed. (Media, PA: Williams & Wilkins, 1995).
Administration of Milnacipran Formulations
The formulation can be administered to any patient in need thereof.
Although preferred patients are human, typically any mammal including
domestic animals such as dogs, cats and horses, may also be treated.
33
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
The amount of the active ingredients to be administered is chosen
based on the amount which provides the desired dose to the patient in need
of such treatment to alleviate symptoms or treat a condition.
Milnacipran has been used as an antidepressant in approximately
400,000 patients, and is known to be non-toxic in humans. Pharmacokinetic
studies have shown that oral doses of milnacipran are rapidly absorbed and
extensively distributed in the body within 1-2 hours. Maximum plasma
levels are quickly reached, with a half life in humans of approximately 8
hours. Metabolism in the liver leads to the formation of ten chemically
identified metabolites, although these metabolites represent only about 10%
of the concentration of the parent drug. In humans, 90% of the parent drug is
eliminated unchanged via the kidneys. This pharmacokinetic profile gives
milnacipran certain pharmacokinetic advantages, such as low inter-individual
variation in plasma levels, low potential for drug interactions, and limited
impact on hepatic cytochrome P-450 systems. These pharmacokinetic
properties differentiate milnacipran from most other antidepressant drugs and
contribute to the good safety profile of milnacipran (Puozzo C. et al., 1996,
Int. Clin. Psychopharmacol., 11:15-27; Caccia S., 1998, Clin.
Pharmacokinet., 34:281-302; Puozzo C. et al., 1998, Eur. J. Drug Metab.
Pharmacokinet., 23:280-286).
Milnacipran can be administered for the treatment of depression, for
fibromyalgia syndrome, chronic fatigue syndrome, pain, attention
deficit/hyperactivity disorder, and visceral pain syndromes (VPS) such as
irritable bowel syndrome (IBS), noncardiac chest pain (NCCP), functional
dyspepsia, interstitial cystitis, essential vulvodynia, urethral syndrome,
orchialgia, and affective disorders, including depressive disorders (major
depressive disorder, dysthymia, atypical depression) and anxiety disorders
(generalized anxiety disorder, phobias, obsessive compulsive disorder, panic
disorder, post-traumatic stress disorder), premenstrual dysphoric disorder,
temperomandibular disorder, atypical face pain, migraine headache, and
tension headache.
34
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Adverse reactions to the oral administration of milnacipran typically
include at least one of the following: nausea, vomiting, headache, dyspepsia,
abdominal pain, insomnia, tremulousness, anxiety, panic attack, palpitations,
urinary retention, orthostatic hypotension, diaphoresis, chest pain, rash,
weight gain, back pain, constipation, vertigo, increased sweating, agitation,
hot flushes, tremors, fatigue, somnolence, ,dysoria, nervousness, dry mouth,
and irritability.
The vomiting reflex is triggered by stimulation of chemoreceptors in
the upper GI tract and mechanoreceptors in the wall of the GI tract which
are activated by both contraction and distension of the gut wall as well as by
physical damage. A coordinating center in the central nervous system
controls the emetic response. The center is located in the parvicellular
reticular formation in the lateral medullary region of the brain. Afferent
nerves to the vomiting center arise from the abdominal splanchic and vagal
nerves, vestibule-labyrinthine receptors, the cerebral cortex and the
cehmoreceptors trigger zone (CTZ). The CTZ lies adjacent in the area
postrema and contains chemoreceptors that sample both blood and cerebro
spinal fluid. Direct links exist between the emetic center and the CTZ. The
CTZ is exposed to emetic stimuli of endogenous origin and to stimuli of
exogenous origin such as drugs. The efferent branches of the cranial nerves
V, VII, and IX, as well as the vagus nerve and sympathetic trunk produce the
complex coordinated set of muscular contractions, cardiovascular responses
and reverse peristalsis that characterizes vomiting. The area postrema is rich
in dopamine receptors as well as 5-hydroxytryptamine (SHT) receptors.
When administered orally, the formulation provides an immediate
dose followed by one or more pulsatile doses several hours after ingestion of
the dosage form. The pharmaceutical composition of milnacipran provides
the ih vivo drug plasma levels characterized by the first initial peak plasma
concentration ( C",~ ) below 3000 ng/ml, preferably below 2000 ng/ml, and
most preferably below 1000 ng/ml that occurs in about 0.05 to about 3 hours
after oral administration (first Tm~). The second ih vivo plasma
concentration peak occurs in about 3 to about 14 hours after oral
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
administration (second T",~) and is characterized by C",~ below 3000 ng/ml,
preferably below 2000 ng/ml, and most preferably below 1000 ng/ml. The
third, optional, in vivo plasma concentration peak occurs in about 5 to about
18 hours after oral administration (third T",~) and is characterized by C",
below 3000 ng/ml, preferably below 2000 ng/ml, and most preferably below
1000 ng/ml.
When enteric coating is added to the formulation described above, the
formulation after oral administration first passes through the stomach
releasing less than approximately 10% of the first "pulse" milnacipran dose
and then enters the intestines where the remaining portion of the first
"pulse"
is released. The release profile is characterized by a 0.05-4 hours lag time
period during which less than approximately 10% of the first "pulse"
milnacipran dose is released followed by a complete release of the first
"pulse". The use of enteric coating minimizes direct milnacipran interaction
with the stomach mucosa and, thus, further diminishes incidence and reduces
intensity of common milnacipran side effects. An enteric coated formulation
demonstrates similar i~ vivo plasma Cmax levels to the uncoated one, but
T~"~ for the first pulse increases by 0.05-4 hours. T",~ for the second and
the
third (optional) pulses may be kept the same as for an uncoated formulation
by adjusting the formulation ingredients to meet the desired release profile.
This dosage form offers many advantages, when compared to
immediate release delivery systems, such as: minimization of peak-trough-
fluctuations, avoidance of undesirable side effects and/or lowering their
intensity/severity, reduced frequency of administration and improved patient
compliance.
This formulation is designed to be administered once-a-day to a
patient in need thereof, so that milnacipran is delivered over approximately
24 hours, with diminished incidence and decreased intensity of one or more
common milnacipran side effects such as nausea, vomiting, headache,
tremulousness, anxiety, panic attacks, palpitations, urinary retention,
orthostatic hypotension, diaphoresis, chest pain, rash, weight gain, back
pain,
constipation, vertigo, increased sweating, agitation, hot flushes, tremors,
36
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth, abdominal
pain, irritability, and insomnia.
Exemplification
The present invention will be further understood by reference to the
following non-limiting examples.
Example 1: Preparation of an Immediate Release Portion of Pulsatile
Release Milnacipran Formulation
Ingredients, manufacturing process, and tablet parameters for the
immediate release portion of the pulsatile release milnacipran pharmaceutical
composition (Lot# 1).
Ingredient Quantity per tablet,
mg
Milnacipran HCl 50.00
Microcrystalline Cellulose (Avicel10.00
PH 101)
Pre-gelatinized Starch (Starch 10.00
1500)
Purified Water QS
Magnesium Stearate 0.35
The formulations were prepared using aqueous media for wet
granulation step. To prepare an immediate release tablet, weighed quantities
of milnacipran hydrochloride, microcrystalline cellulose, and pre-gelatinized
starch were mixed. Purified water was added slowly, while mixing. The wet
mass was forced through a #12 mesh screen. Obtained wet granules were
dried on a tray dryer at 50°C and then passed through a #30 mesh
screen.
Finally, dried granules were lubricated by mixing with magnesium stearate
and the blend was then compressed on a 16 station single rotary compression
machine.
37
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Tablet parameterLot# 1
Weight (mg) 69-72
Thickness (Inches)0.123-0.127
Diameter (Inches)0.2187
Hardness (kP) 4.5-5.5
Friability (%) 0.15
Disintegration 5 minutes
time
in water
Example 2: Preparation of an Alternative Immediate Release Portion of
Pulsatile Release Milnacipran Formulation
Ingredients, manufacturing process, and tablet parameters for an
alternative immediate release portion of the pulsatile release milnacipran
pharmaceutical composition (Lot# 2).
Ingredient Quantity per tablet,
mg
Milnacipran HCl 50.00
Microcrystalline Cellulose 10.00
(Avicel PH 101)
Pre-gelatinized Starch (Starch10.00
1500)
Purified Water QS
Magnesium Stearate 0.35
The formulations were prepared as described above.
Tablet parameterLot# 2
Weight (mg) 72-74
Thickness (Inches)0.168-170
Diameter (Inches)0.1875
Hardness (kP) 5-6
Friability (%) 0.08%
Disintegration 5.5 minutes
time
in water
38
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Example 3: Preparation of an Enteric Coated Portion of Pulsatile
Release Milnacipran Formulation
Ingredients, manufacturing process, and ih vitro dissolution data for
the enteric coated portion of the pulsatile release milnacipran pharmaceutical
composition.
Lot# 1 immediate release tablets were used for preparation of enteric
coated dosage form. The manufacturing procedure consisted of spraying an
aqueous enteric coating suspension onto the immediate release tablets
fluidized in the GPCG-1 (Glatt Air Techniques, Inc.). 20% coat weight gain
was achieved for Lot# 3. The process parameters were adjusted to
accomplish good quality coating. The ingredients of aqueous enteric coating
suspension are given below.
Ingredient Manufacturer
Quantity per
batch, g
Acryl-Eze White Colorcon 98.00
Dow Corning ~ 7-9245 30% Dow Corning 0.490
Simethicone Emulsion USP
FD&C Blue # 1 Lake ConcentrateWarner 0.10
Jenkinson
D & C Red # 33 Aluminum Warner 0.10
Lake
Jenkinson
Purified Water USP 392.00
I~ vitro dissolution data for Lot# 3 enteric coated tablets is given
below. Ih vitro drug release studies were conducted using USP dissolution
apparatus II (paddles) at 50 rpm. Experiments were conducted in dissolution
media (37.00.5°C), first for 2 hours in 0.1 N hydrochloric acid,
followed by
1.5 hours in pH 6.8 phosphate buffer (see USP 26 <724> Method B for
Delayed Release Articles). Sample aliquots were withdrawn after 2 hours in
0.1 N hydrochloric acid, and after 15, 30, 45 and 90 minutes in pH 6.8 buffer
and analyzed using the HPLC method.
39
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Cumulative Lot# 3
incubation time,Milnacipran released,
min % of the total
dose
Mean values (n=6) Standard deviation
O.INHCI
120 NS NA
pH 6.8 buffer
135 6.0 5.6
150 80.0 5.5
165 97.8 0.8
210 98.5 0.8
1~~ - less tnan 1% was detected
NA - Not applicable
Example 4: Preparation of a Delayed Release Portion of Pulsatile
Release Milnacipran Formulation
Ingredients, manufacturing process, and ih vitro dissolution data for
the delayed release portion of the pulsatile release milnacipran
pharmaceutical composition.
Lot# 2 immediate release tablets were used for preparation of delayed
release dosage form. The manufacturing procedure consisted of spraying an
aqueous coating suspension onto the immediate release tablets fluidized in
the GPCG-1 (Glatt Air Techniques, Inc.). 30% coat weight gain was
achieved for Lot# 4. The process parameters were adjusted to accomplish
good quality coating. After coating process was completed, tablets were
fuxther dried in the GPCG-1 for 30 minutes at 40°C followed by 60 hours
of
"curing" at 30°C in the oven drier. The "curing" time could be
shortened by
increasing the drying temperature, for example, only 6 hours of drying is
needed at 50 °C. The ingredients of aqueous enteric coating suspension
are
given below.
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Ingredient Manufacturer Quantity
per
batch,
g
Eudragit S 100 Powder Rohm Pharma 268.8
Polymers
1 N Ammonia solution in waterSpectrum 136.8
(1.7%)
Triethyl Citrate FCC Spectrum 188.2
Talc USP Spectrum 26.8
Purified Water USP 1584.0
The samples were subjected to the i~ vitro dissolution tests that
mimic the ih vivo conditions to which final dosage form is exposed when
administered orally, i.e. approximately 2 hours in the stomach at acidic pH
followed by several hours in the intestines at neutral pH (Multiparticulate
Oral Drug Delivery, 1994, Ghebre-Sellassie L, Ed., Marcel Dekker, Inc.;
Willing LR., 2001, Adv. Drug Deliv. Rev., 46:103-124). 1~ vitro drug
i
release studies were conducted using USP dissolution apparatus II (paddles)
at 50 rpm. Experiments were conducted in dissolution media (37.00.5°C)
first for 2 hours in 0.1 N hydrochloric acid followed by 0.5 hours in pH 6.0
phosphate buffer, 4 hours in pH 6.5 phosphate buffer and ,finally, 4 hours in
pH 7.2 phosphate buffer. Samples were withdrawn and analyzed using
validated UV method (in a separate experiment it was shown that the UV
method gives substantially the same results as the HPLC method).
41
CA 02503121 2005-04-21
WO 2004/039361 PCT/US2003/033685
Cumulative Lot# 4
incubation time,Milnacipran released,
hours % of the total
dose
Mean values (n=3) Standaxd deviation
O.INHCI
2 NS NA
pH 6.0 buffer
2.5 NS NA
pH 6.5 buffer
6.5 NS NA
pH 7.2 buffer
7 NS NA
7.5 NS NA
8 5.1 1.3
8.5 26.7 3.2
9 91.4 4.7
9.5 104.9 1.1
10.5 104.2 0.5
NS - less than
1 % was detected
NA - Not applicable
Example 5: Preparation of a Pulsatile Release Milnacipran Formulation
The final dosage form for pulsatile delivery of milnacipran is prepared by
combining in the desired proportion an immediate release portion of the
Examples 1 or 2 with a delayed release portion of the Example 4. Different
size capsules could be prepared depending on the required daily dose.
Example 6: Preparation of an Alternative Pulsatile Release Milnacipran
Formulation
The final dosage form for pulsatile delivery of milnacipran is prepared by
combining in the desired proportion an enteric coated portion of the Example
3 with a delayed release portion of the Example 4. Different size capsules
could be prepared depending on the required daily dose.
42
